Applied Evidence

CASE › A 68-year-old woman with hypertension and hyperlipidemia comes into your office for evaluation of a 30-minute episode of sudden-onset right-hand weakness and difficulty speaking that occurred 4 days earlier. The patient, who is also a smoker, has come in at the insistence of her daughter. On examination, her blood pressure (BP) is 145/88 mm Hg and her heart rate is 76 beats/minute and regular. She appears well and her language function is normal. The rest of her examination is normal. How would you proceed?

Stroke—the death of nerve cells due to a lack of blood supply from either infarction or hemorrhage—strikes nearly 800,000 people in the United States every year.^1,2 Of these events, 130,000 are fatal, making stroke the fifth leading cause of death.³ Effective, early evaluation and cause-specific treatment are crucial parts of stroke care.

Data indicate that evaluation of symptoms suggestive of stroke within 24 hours of an event confers substantial benefit.

Research has helped to clarify the critical role primary care physicians play in recognizing, triaging, and managing stroke and transient ischemic attacks (TIA). This article reviews what we know about the different ways that a stroke and a TIA can present, the appropriate diagnostic work-up for patients presenting with symptoms of either event, and management strategies for subacute care (24 hours to up to 14 days after a stroke has occurred).^4,5 Unless otherwise specified, this review will focus on ischemic stroke because 87% of strokes are attributable to ischemia.¹

A follow-up to this article on secondary stroke prevention will appear in the journal next month.

IMAGE: © 2017 ALEX NUBAUM C/O THE ISPOT

Look to onset more than type of symptoms for clues

Stroke presents as a sudden onset of neurologic deficits (language, motor, sensory, cerebellar, or brainstem functions) (TABLE 1⁴). Because presenting symptoms can vary widely, sudden onset, rather than particular symptoms, should raise a red flag for potential stroke.

The differential diagnosis includes: seizure, complex migraine, medication effect (eg, slurred speech or confusion after taking a central nervous system [CNS] depressant), toxin exposure, electrolyte abnormalities (especially hypoglycemia), concussion/trauma, infection of the CNS, peripheral vertigo, demyelination, intracranial mass, Bell’s palsy, and psychogenic disorders. The history and physical, along with laboratory findings and brain imaging (detailed later in this article), will guide the FP toward (or away from) these various etiologies.

Optimal triage is a subject of ongoing interest and research

If stroke or TIA remains a possibility after an initial assessment, it’s time to stratify patients by risk.

One of the most widely accepted tools is the ABCD² score (see TABLE 2⁶). Clinicians can employ the ABCD² risk stratification tool when trying to determine whether it is reasonable to pursue an expedited work-up (ie, <1 day) in the outpatient setting or recommend that the patient be evaluated in an emergency department (ED). The 90-day stroke rate following a TIA ranges from 3% with an ABCD² score of 0 to 3 to 18% with a score of 6 or 7. A score of 0 to 3 is considered relatively low risk; in the absence of other compelling factors, rapid outpatient evaluation is appropriate. For patients with an ABCD² score ≥4, referral to the ED or direct admission to the hospital is advised.

The validity of the ABCD² score for risk stratification has been studied extensively with conflicting results.^7-10 As with any assessment tool, it should be used as a guide, and should not supplant a full assessment of the patient or the judgment of the examining physician. In making the decision regarding inpatient or outpatient evaluation, it’s also important to consider available resources, access to specialists, and patient preference.

In a 2016 population-based study, the 30-day recurrent stroke/TIA rate for patients hospitalized for TIA was 3% compared with 10.7% for those discharged from the ED with referral to a stroke clinic and 10.6% for those discharged from the ED without a referral to a stroke clinic.¹¹ These data suggest that only patients for whom you have a low clinical suspicion of stroke/TIA should be worked up as outpatients, and that hospital admission is advised in moderate- and high-risk cases. The findings also highlight the critical role that primary care physicians can play in triaging and managing these patients for secondary prevention.

CASE › This patient’s recent history of sudden-onset right-sided weakness and expressive language dysfunction is suspicious for left hemispheric ischemia. She has several risk factors for stroke, and her ABCD² score is 5 (hypertension, age ≥60 years, unilateral weakness, and duration 10-59 min), which places her at moderate risk. Thus, the recommendation would be to have her go directly to an ED for rapid evaluation.

The diagnostic work-up

Even when a patient is sent to the ED, the FP plays a critical role in his or her continuing care. FPs will often coordinate with inpatient care and manage transition of care to the outpatient setting. (And in many communities, the ED or hospital physicians may themselves be family practitioners.)

In terms of care, not even an aspirin should be administered in a case like this because the patient has not yet had any neuroimaging, and differentiation of ischemic from hemorrhagic stroke cannot be made on clinical grounds alone. Once an ischemic stroke is confirmed, determining the etiology is critical given the significant management differences between the different types of stroke (atherosclerotic, cardioembolic, lacunar, or other).

Which imaging method, and when?

While a computerized tomography (CT) scan is the preferred initial imaging strategy for acute stroke to discern the ischemic type from the hemorrhagic, MRI is preferred for the evaluation of acute ischemic stroke because the method has a higher sensitivity for infarction and a greater ability to identify findings (such as demyelination) that would suggest an alternative diagnosis.

Because presenting symptoms can vary widely, sudden onset, rather than particular symptoms, should raise the red flag for potential stroke.

In addition to evaluating the brain parenchyma, physicians must also assess the cerebral vasculature. CT angiography (CTA) or MR angiography (MRA) of the head and neck are preferred over carotid ultrasound because they are capable of evaluating the entire cerebrovascular system^12,13 and can be instrumental in identifying potential causes of stroke, as well as guiding therapeutic decisions. Carotid ultrasound is a reasonable alternative for patients presenting with symptoms indicative of anterior circulation involvement when CTA and MRA are unavailable or contraindicated, but it will not identify intracranial vascular disease, proximal common carotid disease, or vertebrobasilar disease.

Getting to the cause of suspected stroke: Labs and other diagnostic tests

A routine work-up includes BP checks, routine labs (complete blood count, complete metabolic panel, coagulation profile, and troponin), an electrocardiogram (EKG), a transthoracic echocardiogram (TTE) with bubble study if possible, and a minimum of 24 to 48 hours of cardiac rhythm monitoring. Cardiac rhythm monitoring should be extended in the setting of clinical concern for unidentified paroxysmal atrial fibrillation, such as an embolism without a proximal vascular source, multiple embolic infarcts in different vascular territories, a dilated left atrium, or other risk factors for atrial fibrillation that include smoking, systolic hypertension, diabetes, and heart failure (see TABLE 3^12,13,17,18).^14-16 This standard diagnostic work-up will identify the cause of stroke in 70% to 80% of patients.¹⁹

Additional investigations to consider if the etiology is not yet elucidated include a transesophageal echocardiogram (TEE), cerebral angiography, a coagulopathy evaluation, a lumbar puncture, and a vasculitis work-up. If available, consultation with a neurologist is appropriate for any patient who has had a stroke or TIA. Patients with unclear etiologies or for whom there are questions concerning strategies for preventing secondary stroke should be referred to Neurology and preferably a stroke specialist.

Timing matters, even when symptoms have resolved (ie, TIA).^11,20 The EXPRESS trial¹⁷ (the Early use of eXisting PREventive Strategies for Stroke) looked at the effect of urgent assessment and treatment (≤1 day) of patients presenting with a TIA or minor stroke on the risk of recurrent stroke within 90 days. The diagnostic work-up included brain and vascular imaging together with an EKG. This intensive approach led to an absolute risk reduction of 8.2% (from 10.3% to 2.1%) in the risk of recurrent stroke at 90 days (number needed to treat [NNT]=12).¹⁷

Expedited work-up and treatment was also recently evaluated in a non-trial, real-world setting and was associated with reducing recurrent stroke by more than half the rate reported in older studies.²⁰ Overall, the data suggest that evaluation within 24 hours confers substantial benefit, and that this evaluation can happen in an outpatient setting.^21-23

Acute management: Use of tPA

Once imaging rules out intracranial hemorrhage, patients should be treated with tissue plasminogen activator (tPA) or an endovascular intervention as per guidelines.²⁴ For patients with ischemic stroke ineligible for tPA or endovascular treatments, the initial focus is to determine the etiology of the symptoms so that the best strategies for prevention of secondary stroke may be employed.

Aspirin should be provided within 24 to 48 hours to all patients after intracranial hemorrhage is ruled out. Aspirin should be delayed for 24 hours in those given thrombolytics. The initial recommended dose of aspirin is 325 mg with continued low-dose (81 mg) aspirin daily.¹³ The addition of clopidogrel to aspirin within 24 hours of an event and continued for 21 days, followed by aspirin alone, was shown to be beneficial in a Chinese population with high-risk TIA (ABCD² score ≥4) or minor stroke (National Institutes of Health Stroke Scale [NIHSS] ≤3).²⁵ Anticoagulation with heparin, warfarin, or a novel oral anticoagulant is generally not indicated in the acute setting due to the risk of hemorrhagic transformation.

Acute BP management depends upon the type of stroke (ischemic or hemorrhagic), eligibility for thrombolytics, timing of presentation, and possible comorbidities such as myocardial infarction or aortic dissection (see TABLE 4^13,26). In the absence of contraindications, high-intensity statins should be initiated in all patients able to take oral medications.

CASE › You appropriately referred your patient to the local ED. A head CT with head and neck CTA was performed. While the head CT did not show any abnormalities, the CTA demonstrated high-grade left internal carotid artery stenosis. The patient was given an initial dose of aspirin 325 mg and a high-intensity statin and admitted for further management. An MRI revealed a small shower of emboli in the left hemisphere, confirming the diagnosis of stroke over TIA. Labs were marginally remarkable with a low-density lipoprotein level of 115 mg/dL and an HbA1c of 6.2. Telemetry monitoring did not reveal any arrhythmias, and TTE was normal. BP remained in the high-normal to low-hypertensive range.

Timing matters, even when symptoms have resolved, such as with a TIA.

A Vascular Surgery consultation was obtained and the patient underwent a left carotid endarterectomy the following day. She did well without surgical complications. Her BP medications were adjusted; a combination of an angiotensin-converting enzyme inhibitor and a thiazide diuretic achieved a goal BP <140/90 mm Hg.

Permissive hypertension was not indicated due to her presentation >48 hours beyond the acute event. Low-dose aspirin and a high-intensity statin were continued, for secondary stroke prevention in the setting of atherosclerotic disease. She received smoking cessation counseling, which will continue.

CORRESPONDENCE
Stephen A. Martin, MD, EdM, Barre Family Health Center, 151 Worcester Road, Barre, MA 01005; [email protected].

CASE › A 68-year-old woman with hypertension and hyperlipidemia comes into your office for evaluation of a 30-minute episode of sudden-onset right-hand weakness and difficulty speaking that occurred 4 days earlier. The patient, who is also a smoker, has come in at the insistence of her daughter. On examination, her blood pressure (BP) is 145/88 mm Hg and her heart rate is 76 beats/minute and regular. She appears well and her language function is normal. The rest of her examination is normal. How would you proceed?

Stroke—the death of nerve cells due to a lack of blood supply from either infarction or hemorrhage—strikes nearly 800,000 people in the United States every year.^1,2 Of these events, 130,000 are fatal, making stroke the fifth leading cause of death.³ Effective, early evaluation and cause-specific treatment are crucial parts of stroke care.

Data indicate that evaluation of symptoms suggestive of stroke within 24 hours of an event confers substantial benefit.

Research has helped to clarify the critical role primary care physicians play in recognizing, triaging, and managing stroke and transient ischemic attacks (TIA). This article reviews what we know about the different ways that a stroke and a TIA can present, the appropriate diagnostic work-up for patients presenting with symptoms of either event, and management strategies for subacute care (24 hours to up to 14 days after a stroke has occurred).^4,5 Unless otherwise specified, this review will focus on ischemic stroke because 87% of strokes are attributable to ischemia.¹

A follow-up to this article on secondary stroke prevention will appear in the journal next month.

IMAGE: © 2017 ALEX NUBAUM C/O THE ISPOT

Look to onset more than type of symptoms for clues

Stroke presents as a sudden onset of neurologic deficits (language, motor, sensory, cerebellar, or brainstem functions) (TABLE 1⁴). Because presenting symptoms can vary widely, sudden onset, rather than particular symptoms, should raise a red flag for potential stroke.

The differential diagnosis includes: seizure, complex migraine, medication effect (eg, slurred speech or confusion after taking a central nervous system [CNS] depressant), toxin exposure, electrolyte abnormalities (especially hypoglycemia), concussion/trauma, infection of the CNS, peripheral vertigo, demyelination, intracranial mass, Bell’s palsy, and psychogenic disorders. The history and physical, along with laboratory findings and brain imaging (detailed later in this article), will guide the FP toward (or away from) these various etiologies.

Optimal triage is a subject of ongoing interest and research

If stroke or TIA remains a possibility after an initial assessment, it’s time to stratify patients by risk.

One of the most widely accepted tools is the ABCD² score (see TABLE 2⁶). Clinicians can employ the ABCD² risk stratification tool when trying to determine whether it is reasonable to pursue an expedited work-up (ie, <1 day) in the outpatient setting or recommend that the patient be evaluated in an emergency department (ED). The 90-day stroke rate following a TIA ranges from 3% with an ABCD² score of 0 to 3 to 18% with a score of 6 or 7. A score of 0 to 3 is considered relatively low risk; in the absence of other compelling factors, rapid outpatient evaluation is appropriate. For patients with an ABCD² score ≥4, referral to the ED or direct admission to the hospital is advised.

The validity of the ABCD² score for risk stratification has been studied extensively with conflicting results.^7-10 As with any assessment tool, it should be used as a guide, and should not supplant a full assessment of the patient or the judgment of the examining physician. In making the decision regarding inpatient or outpatient evaluation, it’s also important to consider available resources, access to specialists, and patient preference.

In a 2016 population-based study, the 30-day recurrent stroke/TIA rate for patients hospitalized for TIA was 3% compared with 10.7% for those discharged from the ED with referral to a stroke clinic and 10.6% for those discharged from the ED without a referral to a stroke clinic.¹¹ These data suggest that only patients for whom you have a low clinical suspicion of stroke/TIA should be worked up as outpatients, and that hospital admission is advised in moderate- and high-risk cases. The findings also highlight the critical role that primary care physicians can play in triaging and managing these patients for secondary prevention.

CASE › This patient’s recent history of sudden-onset right-sided weakness and expressive language dysfunction is suspicious for left hemispheric ischemia. She has several risk factors for stroke, and her ABCD² score is 5 (hypertension, age ≥60 years, unilateral weakness, and duration 10-59 min), which places her at moderate risk. Thus, the recommendation would be to have her go directly to an ED for rapid evaluation.

The diagnostic work-up

Even when a patient is sent to the ED, the FP plays a critical role in his or her continuing care. FPs will often coordinate with inpatient care and manage transition of care to the outpatient setting. (And in many communities, the ED or hospital physicians may themselves be family practitioners.)

In terms of care, not even an aspirin should be administered in a case like this because the patient has not yet had any neuroimaging, and differentiation of ischemic from hemorrhagic stroke cannot be made on clinical grounds alone. Once an ischemic stroke is confirmed, determining the etiology is critical given the significant management differences between the different types of stroke (atherosclerotic, cardioembolic, lacunar, or other).

Which imaging method, and when?

While a computerized tomography (CT) scan is the preferred initial imaging strategy for acute stroke to discern the ischemic type from the hemorrhagic, MRI is preferred for the evaluation of acute ischemic stroke because the method has a higher sensitivity for infarction and a greater ability to identify findings (such as demyelination) that would suggest an alternative diagnosis.

Because presenting symptoms can vary widely, sudden onset, rather than particular symptoms, should raise the red flag for potential stroke.

In addition to evaluating the brain parenchyma, physicians must also assess the cerebral vasculature. CT angiography (CTA) or MR angiography (MRA) of the head and neck are preferred over carotid ultrasound because they are capable of evaluating the entire cerebrovascular system^12,13 and can be instrumental in identifying potential causes of stroke, as well as guiding therapeutic decisions. Carotid ultrasound is a reasonable alternative for patients presenting with symptoms indicative of anterior circulation involvement when CTA and MRA are unavailable or contraindicated, but it will not identify intracranial vascular disease, proximal common carotid disease, or vertebrobasilar disease.

Getting to the cause of suspected stroke: Labs and other diagnostic tests

A routine work-up includes BP checks, routine labs (complete blood count, complete metabolic panel, coagulation profile, and troponin), an electrocardiogram (EKG), a transthoracic echocardiogram (TTE) with bubble study if possible, and a minimum of 24 to 48 hours of cardiac rhythm monitoring. Cardiac rhythm monitoring should be extended in the setting of clinical concern for unidentified paroxysmal atrial fibrillation, such as an embolism without a proximal vascular source, multiple embolic infarcts in different vascular territories, a dilated left atrium, or other risk factors for atrial fibrillation that include smoking, systolic hypertension, diabetes, and heart failure (see TABLE 3^12,13,17,18).^14-16 This standard diagnostic work-up will identify the cause of stroke in 70% to 80% of patients.¹⁹

Additional investigations to consider if the etiology is not yet elucidated include a transesophageal echocardiogram (TEE), cerebral angiography, a coagulopathy evaluation, a lumbar puncture, and a vasculitis work-up. If available, consultation with a neurologist is appropriate for any patient who has had a stroke or TIA. Patients with unclear etiologies or for whom there are questions concerning strategies for preventing secondary stroke should be referred to Neurology and preferably a stroke specialist.

Timing matters, even when symptoms have resolved (ie, TIA).^11,20 The EXPRESS trial¹⁷ (the Early use of eXisting PREventive Strategies for Stroke) looked at the effect of urgent assessment and treatment (≤1 day) of patients presenting with a TIA or minor stroke on the risk of recurrent stroke within 90 days. The diagnostic work-up included brain and vascular imaging together with an EKG. This intensive approach led to an absolute risk reduction of 8.2% (from 10.3% to 2.1%) in the risk of recurrent stroke at 90 days (number needed to treat [NNT]=12).¹⁷

Expedited work-up and treatment was also recently evaluated in a non-trial, real-world setting and was associated with reducing recurrent stroke by more than half the rate reported in older studies.²⁰ Overall, the data suggest that evaluation within 24 hours confers substantial benefit, and that this evaluation can happen in an outpatient setting.^21-23

Acute management: Use of tPA

Once imaging rules out intracranial hemorrhage, patients should be treated with tissue plasminogen activator (tPA) or an endovascular intervention as per guidelines.²⁴ For patients with ischemic stroke ineligible for tPA or endovascular treatments, the initial focus is to determine the etiology of the symptoms so that the best strategies for prevention of secondary stroke may be employed.

Aspirin should be provided within 24 to 48 hours to all patients after intracranial hemorrhage is ruled out. Aspirin should be delayed for 24 hours in those given thrombolytics. The initial recommended dose of aspirin is 325 mg with continued low-dose (81 mg) aspirin daily.¹³ The addition of clopidogrel to aspirin within 24 hours of an event and continued for 21 days, followed by aspirin alone, was shown to be beneficial in a Chinese population with high-risk TIA (ABCD² score ≥4) or minor stroke (National Institutes of Health Stroke Scale [NIHSS] ≤3).²⁵ Anticoagulation with heparin, warfarin, or a novel oral anticoagulant is generally not indicated in the acute setting due to the risk of hemorrhagic transformation.

Acute BP management depends upon the type of stroke (ischemic or hemorrhagic), eligibility for thrombolytics, timing of presentation, and possible comorbidities such as myocardial infarction or aortic dissection (see TABLE 4^13,26). In the absence of contraindications, high-intensity statins should be initiated in all patients able to take oral medications.

CASE › You appropriately referred your patient to the local ED. A head CT with head and neck CTA was performed. While the head CT did not show any abnormalities, the CTA demonstrated high-grade left internal carotid artery stenosis. The patient was given an initial dose of aspirin 325 mg and a high-intensity statin and admitted for further management. An MRI revealed a small shower of emboli in the left hemisphere, confirming the diagnosis of stroke over TIA. Labs were marginally remarkable with a low-density lipoprotein level of 115 mg/dL and an HbA1c of 6.2. Telemetry monitoring did not reveal any arrhythmias, and TTE was normal. BP remained in the high-normal to low-hypertensive range.

Timing matters, even when symptoms have resolved, such as with a TIA.

A Vascular Surgery consultation was obtained and the patient underwent a left carotid endarterectomy the following day. She did well without surgical complications. Her BP medications were adjusted; a combination of an angiotensin-converting enzyme inhibitor and a thiazide diuretic achieved a goal BP <140/90 mm Hg.

Permissive hypertension was not indicated due to her presentation >48 hours beyond the acute event. Low-dose aspirin and a high-intensity statin were continued, for secondary stroke prevention in the setting of atherosclerotic disease. She received smoking cessation counseling, which will continue.

CORRESPONDENCE
Stephen A. Martin, MD, EdM, Barre Family Health Center, 151 Worcester Road, Barre, MA 01005; [email protected].

CASE › A 68-year-old woman with hypertension and hyperlipidemia comes into your office for evaluation of a 30-minute episode of sudden-onset right-hand weakness and difficulty speaking that occurred 4 days earlier. The patient, who is also a smoker, has come in at the insistence of her daughter. On examination, her blood pressure (BP) is 145/88 mm Hg and her heart rate is 76 beats/minute and regular. She appears well and her language function is normal. The rest of her examination is normal. How would you proceed?

Stroke—the death of nerve cells due to a lack of blood supply from either infarction or hemorrhage—strikes nearly 800,000 people in the United States every year.^1,2 Of these events, 130,000 are fatal, making stroke the fifth leading cause of death.³ Effective, early evaluation and cause-specific treatment are crucial parts of stroke care.

Data indicate that evaluation of symptoms suggestive of stroke within 24 hours of an event confers substantial benefit.

Research has helped to clarify the critical role primary care physicians play in recognizing, triaging, and managing stroke and transient ischemic attacks (TIA). This article reviews what we know about the different ways that a stroke and a TIA can present, the appropriate diagnostic work-up for patients presenting with symptoms of either event, and management strategies for subacute care (24 hours to up to 14 days after a stroke has occurred).^4,5 Unless otherwise specified, this review will focus on ischemic stroke because 87% of strokes are attributable to ischemia.¹

A follow-up to this article on secondary stroke prevention will appear in the journal next month.

IMAGE: © 2017 ALEX NUBAUM C/O THE ISPOT

Look to onset more than type of symptoms for clues

Stroke presents as a sudden onset of neurologic deficits (language, motor, sensory, cerebellar, or brainstem functions) (TABLE 1⁴). Because presenting symptoms can vary widely, sudden onset, rather than particular symptoms, should raise a red flag for potential stroke.

The differential diagnosis includes: seizure, complex migraine, medication effect (eg, slurred speech or confusion after taking a central nervous system [CNS] depressant), toxin exposure, electrolyte abnormalities (especially hypoglycemia), concussion/trauma, infection of the CNS, peripheral vertigo, demyelination, intracranial mass, Bell’s palsy, and psychogenic disorders. The history and physical, along with laboratory findings and brain imaging (detailed later in this article), will guide the FP toward (or away from) these various etiologies.

Optimal triage is a subject of ongoing interest and research

If stroke or TIA remains a possibility after an initial assessment, it’s time to stratify patients by risk.

One of the most widely accepted tools is the ABCD² score (see TABLE 2⁶). Clinicians can employ the ABCD² risk stratification tool when trying to determine whether it is reasonable to pursue an expedited work-up (ie, <1 day) in the outpatient setting or recommend that the patient be evaluated in an emergency department (ED). The 90-day stroke rate following a TIA ranges from 3% with an ABCD² score of 0 to 3 to 18% with a score of 6 or 7. A score of 0 to 3 is considered relatively low risk; in the absence of other compelling factors, rapid outpatient evaluation is appropriate. For patients with an ABCD² score ≥4, referral to the ED or direct admission to the hospital is advised.

The validity of the ABCD² score for risk stratification has been studied extensively with conflicting results.^7-10 As with any assessment tool, it should be used as a guide, and should not supplant a full assessment of the patient or the judgment of the examining physician. In making the decision regarding inpatient or outpatient evaluation, it’s also important to consider available resources, access to specialists, and patient preference.

In a 2016 population-based study, the 30-day recurrent stroke/TIA rate for patients hospitalized for TIA was 3% compared with 10.7% for those discharged from the ED with referral to a stroke clinic and 10.6% for those discharged from the ED without a referral to a stroke clinic.¹¹ These data suggest that only patients for whom you have a low clinical suspicion of stroke/TIA should be worked up as outpatients, and that hospital admission is advised in moderate- and high-risk cases. The findings also highlight the critical role that primary care physicians can play in triaging and managing these patients for secondary prevention.

CASE › This patient’s recent history of sudden-onset right-sided weakness and expressive language dysfunction is suspicious for left hemispheric ischemia. She has several risk factors for stroke, and her ABCD² score is 5 (hypertension, age ≥60 years, unilateral weakness, and duration 10-59 min), which places her at moderate risk. Thus, the recommendation would be to have her go directly to an ED for rapid evaluation.

The diagnostic work-up

Even when a patient is sent to the ED, the FP plays a critical role in his or her continuing care. FPs will often coordinate with inpatient care and manage transition of care to the outpatient setting. (And in many communities, the ED or hospital physicians may themselves be family practitioners.)

In terms of care, not even an aspirin should be administered in a case like this because the patient has not yet had any neuroimaging, and differentiation of ischemic from hemorrhagic stroke cannot be made on clinical grounds alone. Once an ischemic stroke is confirmed, determining the etiology is critical given the significant management differences between the different types of stroke (atherosclerotic, cardioembolic, lacunar, or other).

Which imaging method, and when?

While a computerized tomography (CT) scan is the preferred initial imaging strategy for acute stroke to discern the ischemic type from the hemorrhagic, MRI is preferred for the evaluation of acute ischemic stroke because the method has a higher sensitivity for infarction and a greater ability to identify findings (such as demyelination) that would suggest an alternative diagnosis.

Because presenting symptoms can vary widely, sudden onset, rather than particular symptoms, should raise the red flag for potential stroke.

In addition to evaluating the brain parenchyma, physicians must also assess the cerebral vasculature. CT angiography (CTA) or MR angiography (MRA) of the head and neck are preferred over carotid ultrasound because they are capable of evaluating the entire cerebrovascular system^12,13 and can be instrumental in identifying potential causes of stroke, as well as guiding therapeutic decisions. Carotid ultrasound is a reasonable alternative for patients presenting with symptoms indicative of anterior circulation involvement when CTA and MRA are unavailable or contraindicated, but it will not identify intracranial vascular disease, proximal common carotid disease, or vertebrobasilar disease.

Getting to the cause of suspected stroke: Labs and other diagnostic tests

A routine work-up includes BP checks, routine labs (complete blood count, complete metabolic panel, coagulation profile, and troponin), an electrocardiogram (EKG), a transthoracic echocardiogram (TTE) with bubble study if possible, and a minimum of 24 to 48 hours of cardiac rhythm monitoring. Cardiac rhythm monitoring should be extended in the setting of clinical concern for unidentified paroxysmal atrial fibrillation, such as an embolism without a proximal vascular source, multiple embolic infarcts in different vascular territories, a dilated left atrium, or other risk factors for atrial fibrillation that include smoking, systolic hypertension, diabetes, and heart failure (see TABLE 3^12,13,17,18).^14-16 This standard diagnostic work-up will identify the cause of stroke in 70% to 80% of patients.¹⁹

Additional investigations to consider if the etiology is not yet elucidated include a transesophageal echocardiogram (TEE), cerebral angiography, a coagulopathy evaluation, a lumbar puncture, and a vasculitis work-up. If available, consultation with a neurologist is appropriate for any patient who has had a stroke or TIA. Patients with unclear etiologies or for whom there are questions concerning strategies for preventing secondary stroke should be referred to Neurology and preferably a stroke specialist.

Timing matters, even when symptoms have resolved (ie, TIA).^11,20 The EXPRESS trial¹⁷ (the Early use of eXisting PREventive Strategies for Stroke) looked at the effect of urgent assessment and treatment (≤1 day) of patients presenting with a TIA or minor stroke on the risk of recurrent stroke within 90 days. The diagnostic work-up included brain and vascular imaging together with an EKG. This intensive approach led to an absolute risk reduction of 8.2% (from 10.3% to 2.1%) in the risk of recurrent stroke at 90 days (number needed to treat [NNT]=12).¹⁷

Expedited work-up and treatment was also recently evaluated in a non-trial, real-world setting and was associated with reducing recurrent stroke by more than half the rate reported in older studies.²⁰ Overall, the data suggest that evaluation within 24 hours confers substantial benefit, and that this evaluation can happen in an outpatient setting.^21-23

Acute management: Use of tPA

Once imaging rules out intracranial hemorrhage, patients should be treated with tissue plasminogen activator (tPA) or an endovascular intervention as per guidelines.²⁴ For patients with ischemic stroke ineligible for tPA or endovascular treatments, the initial focus is to determine the etiology of the symptoms so that the best strategies for prevention of secondary stroke may be employed.

Aspirin should be provided within 24 to 48 hours to all patients after intracranial hemorrhage is ruled out. Aspirin should be delayed for 24 hours in those given thrombolytics. The initial recommended dose of aspirin is 325 mg with continued low-dose (81 mg) aspirin daily.¹³ The addition of clopidogrel to aspirin within 24 hours of an event and continued for 21 days, followed by aspirin alone, was shown to be beneficial in a Chinese population with high-risk TIA (ABCD² score ≥4) or minor stroke (National Institutes of Health Stroke Scale [NIHSS] ≤3).²⁵ Anticoagulation with heparin, warfarin, or a novel oral anticoagulant is generally not indicated in the acute setting due to the risk of hemorrhagic transformation.

Acute BP management depends upon the type of stroke (ischemic or hemorrhagic), eligibility for thrombolytics, timing of presentation, and possible comorbidities such as myocardial infarction or aortic dissection (see TABLE 4^13,26). In the absence of contraindications, high-intensity statins should be initiated in all patients able to take oral medications.

CASE › You appropriately referred your patient to the local ED. A head CT with head and neck CTA was performed. While the head CT did not show any abnormalities, the CTA demonstrated high-grade left internal carotid artery stenosis. The patient was given an initial dose of aspirin 325 mg and a high-intensity statin and admitted for further management. An MRI revealed a small shower of emboli in the left hemisphere, confirming the diagnosis of stroke over TIA. Labs were marginally remarkable with a low-density lipoprotein level of 115 mg/dL and an HbA1c of 6.2. Telemetry monitoring did not reveal any arrhythmias, and TTE was normal. BP remained in the high-normal to low-hypertensive range.

Timing matters, even when symptoms have resolved, such as with a TIA.

A Vascular Surgery consultation was obtained and the patient underwent a left carotid endarterectomy the following day. She did well without surgical complications. Her BP medications were adjusted; a combination of an angiotensin-converting enzyme inhibitor and a thiazide diuretic achieved a goal BP <140/90 mm Hg.

Permissive hypertension was not indicated due to her presentation >48 hours beyond the acute event. Low-dose aspirin and a high-intensity statin were continued, for secondary stroke prevention in the setting of atherosclerotic disease. She received smoking cessation counseling, which will continue.

CORRESPONDENCE
Stephen A. Martin, MD, EdM, Barre Family Health Center, 151 Worcester Road, Barre, MA 01005; [email protected].

More than one-third of American adults and approximately 17% of children and adolescents between the ages of 2 and 19 years are obese.^1,2 Poor diet coupled with a sedentary lifestyle is the highest ranked cause of non-communicable disease and a leading cause of preventable death, according to the National Research Council.³

Bariatric surgery (BS) is a viable therapeutic option for obese patients who do not respond to conventional lifestyle interventions for losing weight. There are multiple gastrointestinal (GI) procedures available that are classified as either malabsorptive (Roux-en-Y gastric bypass [RYGB] and biliopancreatic diversion [BPD] with or without duodenal switch) or restrictive (laparoscopic adjustable gastric banding [LAGB] and vertical sleeve gastrectomy [VSG]).

Approximately half of the 196,000 bariatric procedures performed in the United States in 2015 were of the sleeve variety, another 23% were RYGB, and the remaining percentage was divided among the other types.⁴ Postoperative risks include nutritional deficiencies, decreased bone mineral density (BMD), dumping syndrome (when food rapidly dumps from the stomach to the intestine), and gastroesophageal reflux disease (GERD) with possible ulceration.

Despite these potential complications, a systematic review and meta-analysis found that obese people who underwent BS (gastric banding or gastric bypass) had significantly reduced risks of global, non-cardiovascular (CV), and CV mortality compared with obese controls.⁵ Helping patients to realize these benefits requires that the entire health care team—especially the family physician—is aware of the special considerations for this population.

Patients undergoing bariatric surgery require routine lifetime screening for nutritional deficiencies.

To that end, this article reviews the details of diagnosing and managing post-surgical complications. It also addresses issues unique to managing certain subpopulations, such as post-BS patients who require revision surgery or who want to pursue body contouring surgery; adolescents who undergo BS surgery; and women who want to get pregnant postoperatively.

Monitor patients for these post-surgery complications

Postoperative BS follow-up varies depending on location, surgeon preference, and availability of multidisciplinary resources. At our institution, patients have a minimum of 3 follow-up visits with their surgeon (during hospitalization and 2 weeks and 2 months postoperatively). This is followed by visits with Endocrinology 6 months after surgery and annually thereafter. Given the variability of follow-up, family physicians should coordinate with specialists where appropriate and be aware of postoperative complications and monitoring since it is likely they will have the most frequent contact with these patients.

Nutritional deficiencies are common and require lifelong screening

Nutritional deficiencies are the most common complications of malabsorptive BS. Guidelines from the Endocrine Society, as well as guidelines from the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), and the American Society for Metabolic and Bariatric Surgery (ASMBS), recommend routine lifetime screening for deficiencies after surgery.^6,7 Complete blood cell count, electrolytes, glucose, creatinine, and liver function tests should be obtained at one, 3, 6, 12, 18, and 24 months following surgery and annually thereafter.⁶

Multiple factors contribute to nutritional and micronutrient deficiencies, including reduced oral intake of food, decreased GI absorption, food intolerance, nausea/vomiting, and nonadherence with dietary supplements.⁸ Oral supplementation should be in chewable, powder, or liquid form because pill and capsule absorption may be altered.^8,9 Over-the-counter multivitamins may not contain the requisite daily doses recommended after BS.⁹ Patients and physicians should evaluate supplements together to ensure appropriate nutritional and micronutrient supplementation (TABLE 1^6,8-11).

Bone mineral density can start to decrease soon after surgery

Studies evaluating BMD after BS have produced variable findings. In obese patients, dual-energy x-ray absorptiometry (DEXA) measurements may not be accurate due to adipose tissue artifact and table weight limits. In addition, limited data exist on the incidence of fractures after BS. Of 2 notable studies, only one, a population-based study involving 258 Minnesota residents who underwent a first bariatric surgery between 1985 and 2004, demonstrated a significantly increased incidence of fractures.^12,13

In addition, studies show bone turnover markers, including C-terminal telopeptide, increase as early as 3 months after BS.¹⁴ Several guidelines recommend routine BMD screening after BS (TABLE 2).^6,7 The mechanism of bone demineralization is likely multifactorial—a function of the magnitude of the weight loss and skeletal unloading, calcium and vitamin D deficiencies, and associated secondary hyperparathyroidism.¹⁵ Treatment for secondary hyperparathyroidism is adequate supplementation with vitamin D and calcium.

Optimal dosing for vitamin D has not been determined. One recent systematic review suggests routine prophylaxis with at least 2000 international units (IU)/d and found the greatest improvement for known deficiency with doses of 1500-9100 IU/d following malabsorptive surgeries.¹¹ After laparoscopic sleeve gastrectomy, at least 1000 IU/d vitamin D is recommended.¹¹

Overall, high variability exists among patients, and an individualized approach for dosing is recommended.¹¹ Vitamin D levels should be monitored 2 and 4 weeks after initiation of treatment and every 3 months thereafter.¹¹ Normal levels of serum calcium, 25-OH vitamin D, bone-specific alkaline phosphatase, and 24-hour urinary calcium excretion indicate adequate calcium and vitamin D supplementation.⁶

Dumping syndrome can lead to hypoglycemia

Dumping syndrome is a common complication following BS, with prevalence ranging from 25% to 75%, depending upon the type of procedure performed.^16,17 There are 2 types: early and late. Early dumping syndrome occurs within 30 minutes of eating. Symptoms are related to the robust release of gastrointestinal hormones caused by rapid gastric emptying. Symptoms include nausea, abdominal pain, diarrhea, flushing, hypotension, and tachycardia.

Late dumping is characterized as postprandial hypoglycemia occurring one to 3 hours after eating. Late dumping is likely caused by a combination of changes within the pancreatic beta cells and abnormal insulin response to glucose.^16-18 Rapid gastric emptying leads to rapid release of glucose in the gut, which, in turn, leads to brisk insulin secretion. Since glucose is absorbed faster than insulin’s half-life, the resulting (relatively) high levels of insulin may cause hypoglycemia.^16-18

Sigstad’s scoring system can be used to confirm suspected cases of dumping syndrome (TABLE 3^16,17,19). A diagnosis can also be made with an oral glucose challenge in which pulse, blood pressure, glucose, and hematocrit are measured after ingestion of 50 g glucose. The test is positive if heart rate increases by 10 beats per minute, hematocrit increases by 3% 30 minutes after ingestion, or glucose falls below 60 mg/dL 2 to 3 hours after ingestion.¹⁷

First-line treatment of dumping syndrome consists of dietary modifications. The goal is to slow the rate of gastric emptying by eating smaller, more frequent meals; separating beverages from food; decreasing carbohydrates; and increasing fiber and protein content.

If results are suboptimal after dietary changes, medications can be prescribed including acarbose to prevent postprandial hypoglycemia; anticholinergics such as dicyclomine to slow gastric emptying; and somatostatin to decrease gastric emptying and inhibit GI hormone release.¹⁷ Lastly, for resistant and severe postprandial hypoglycemia, a few patients have undergone pancreatectomy, but only about 65% experienced improvement in symptoms and 12% developed diabetes post-surgically.²⁰

Gout attacks may initially increase, but then decrease

BS affects the incidence of gout attacks in patients with a history of gout. One comparative study of approximately 150 patients demonstrated that those with a history of gout had significantly more gout attacks in the first month after BS compared with obese patients with a history of gout undergoing other upper GI surgeries.²¹ There was no difference between malabsorptive and restrictive procedures. But after the first month, BS patients had significantly fewer gout attacks and lower uric acid levels than their obese counterparts.²¹

Protein rich diets, catabolism potentiated by aggressive caloric restriction following BS, and dehydration contribute to the initial increase. Therefore, patients who have had at least one gout attack in the year prior to surgery or who are on hypouricemic medication may benefit from at least one month of prophylactic therapy (eg, allopurinol and colchicine) after surgery.

GERD and ulceration: How to respond

Obesity is a known risk factor for GERD, but the effect of BS on GERD is uncertain and seems to vary with the procedure performed. RYGB decreases GERD and is, therefore, used as both a secondary treatment in those not responding to medications and a revision treatment for fundoplication and other types of BSs. Sleeve gastrectomy and adjustable gastric banding have mixed effects on GERD. A systematic review by de Jong et al revealed a decreased prevalence of reflux symptoms and GERD medication use after LAGB; however, during longer follow-up, 15% of previously unaffected patients reported experiencing GERD.²² The 2011 International Sleeve Gastrectomy Expert Panel Consensus Statement retrospectively noted a postoperative incidence of GERD as high as 31%.²³

BS patients with GERD should be treated with a proton pump inhibitor. If this fails, refer patients to a gastroenterologist for further evaluation.²⁴

Ulcers after BS may be an indication for revision surgery. Data are mixed regarding increased risk of marginal ulceration from nonsteroidal anti-inflammatory drug (NSAID) use, but NSAIDs have been linked to an increased risk of anastomotic leakage.^25-28 Thus, it seems prudent to avoid NSAIDs in people who have undergone BS.

Keeping watch over psychiatric comorbidities

A recent meta-analysis by Dawes et al²⁹ showed that about 23% of patients pursuing BS have a comorbid mood disorder. Specifically, the preoperative prevalence of depression (19%) and binge-eating disorder (17%) were found to be higher than rates in the general population.²⁹ The meta-analysis found improvement in the prevalence of depression with fewer symptoms and less antidepressant medication use in the first 3 years after surgery and a decrease in the rate of binge-eating disorder, although there were fewer supporting data for the latter. These findings were observed with both restrictive and malabsorptive procedures.

The data are mixed regarding rates of alcohol abuse and suicide. Further research is necessary in this field. Patients who have had BS should receive ongoing psychiatric and psychological care from a multidisciplinary team as a matter of course.

Will a second surgery be needed?

Revision surgery. In 2015, about 14% of the almost 200,000 BSs performed were revisions.⁴ Revision surgery is indicated in BS patients with weight regain, recurrent comorbid diseases (eg, diabetes, hypertension), or complications of primary BS. Restrictive procedures have a higher revision rate than malabsorptive procedures, primarily due to a higher rate of weight regain.^6,30

Because revision surgery is associated with more complications and possibly longer hospital stays than primary BS, it should be performed by a bariatric surgeon with extensive experience.^30,31 Restrictive revisions are typically converted to malabsorptive procedures. Cost is a limiting factor as many patients’ insurance coverage is limited to one BS per lifetime.

Body contouring. Body contouring surgery (BCS) can improve physical and mental well-being and may be a protective factor for weight regain after bariatric surgery.³² Despite its desirability—particularly to women, adolescents, and those with large decreases in body mass index (BMI)—few patients can afford BCS since it is rarely covered by insurance.

Complications of BCS vary, but are most commonly infection and wound dehiscence. This is, in part, due to poorer wound healing in BS patients compared to those with nonsurgical massive weight loss. The cause of poor wound healing is thought to be secondary to nutritional deficiencies and the catabolic state induced by post-surgical weight loss. Recommendations for BCS include weight stability for more than one year after BS, age >16 years, excess skin causing significant functional impairment, non-smoking status, and presence of good social support.³³

Bariatric surgery in adolescents is on the rise

Children in the highest body mass index quartile have more than twice the death rate of those in the lowest BMI quartile.³⁴ Thus, it is not surprising that the rate of BS in adolescents is increasing.⁷ BS in this age group is successful for weight loss and improvement of comorbid conditions, with relatively low complication rates.³⁵ Options include malabsorptive and restrictive procedures, although gastric banding has not been approved by the US Food and Drug Administration for patients under the age of 18 years.

Monitor vitamin D levels 2 and 4 weeks after initiation of treatment and every 3 months thereafter.After BS, adolescent girls should be counseled regarding the possibility of pregnancy (restoration of fertility) and appropriate contraception. Adolescent patients require nutritional supplementation after BS as indicated in TABLE 1.^6,8-11

When determining which adolescents to refer for BS, we recommend the following criteria: ^35-38

• failure of a minimum 6-month trial of a staged treatment approach, as recommended by Barlow et al,³⁶ including diet, exercise, and pharmacologic treatment
• BMI ≥35 with type 2 diabetes or severe sleep apnea (apnea hypopnea index [AHI] >15)³⁷
• BMI ≥40 with mild sleep apnea (AHI >5), hypertension, or pre-diabetes³⁷
• Tanner stage IV or V
• at least 95% skeletal growth (for malabsorptive surgery).³⁷ This can be determined using an estimated adult height from mid-parental height formula and assessing growth plate closure with hand radiographs for bone age
• appropriate maturity level permitting adherence
• good psychological support
• a multidisciplinary team for postoperative and long-term follow-up care.

Planning for the future: Exploring the possibility of pregnancy

Obesity is the primary cause of maternal and fetal morbidity during pregnancy. It is associated with increased rates of early miscarriage, congenital defects, macrosomia, and fetal death. Maternal risks of obesity include: gestational hypertension, gestational diabetes mellitus (GDM), and pre-eclampsia. Obese mothers also have a higher incidence of failed induction, caesarean section, and breastfeeding failure.^10,39 Given that half of all BSs are performed in women of reproductive age, this population deserves special consideration.¹⁰

A recent meta-analysis by Galazis et al⁴⁰ concluded that BS performed prior to pregnancy led to decreased rates of preeclampsia, GDM, large neonates, preterm birth, and neonatal intensive care unit admission. Perinatal mortality did not increase after BS. However, BS led to higher rates of maternal anemia. There was no significant difference between groups in incidence of cesarean section.

The post BS female patient should be advised to use a reliable form of contraception for a minimum of 12 to 18 months after surgery.^6,10,39 Involve high-risk obstetric specialists during pregnancies. Diet should be supplemented as indicated in TABLE 1.^6,8-11

CORRESPONDENCE
Amy Rothberg, MD, PhD, Domino’s Farms, Lobby G, Suite 1500, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106; [email protected].

More than one-third of American adults and approximately 17% of children and adolescents between the ages of 2 and 19 years are obese.^1,2 Poor diet coupled with a sedentary lifestyle is the highest ranked cause of non-communicable disease and a leading cause of preventable death, according to the National Research Council.³

Bariatric surgery (BS) is a viable therapeutic option for obese patients who do not respond to conventional lifestyle interventions for losing weight. There are multiple gastrointestinal (GI) procedures available that are classified as either malabsorptive (Roux-en-Y gastric bypass [RYGB] and biliopancreatic diversion [BPD] with or without duodenal switch) or restrictive (laparoscopic adjustable gastric banding [LAGB] and vertical sleeve gastrectomy [VSG]).

Approximately half of the 196,000 bariatric procedures performed in the United States in 2015 were of the sleeve variety, another 23% were RYGB, and the remaining percentage was divided among the other types.⁴ Postoperative risks include nutritional deficiencies, decreased bone mineral density (BMD), dumping syndrome (when food rapidly dumps from the stomach to the intestine), and gastroesophageal reflux disease (GERD) with possible ulceration.

Despite these potential complications, a systematic review and meta-analysis found that obese people who underwent BS (gastric banding or gastric bypass) had significantly reduced risks of global, non-cardiovascular (CV), and CV mortality compared with obese controls.⁵ Helping patients to realize these benefits requires that the entire health care team—especially the family physician—is aware of the special considerations for this population.

Patients undergoing bariatric surgery require routine lifetime screening for nutritional deficiencies.

To that end, this article reviews the details of diagnosing and managing post-surgical complications. It also addresses issues unique to managing certain subpopulations, such as post-BS patients who require revision surgery or who want to pursue body contouring surgery; adolescents who undergo BS surgery; and women who want to get pregnant postoperatively.

Monitor patients for these post-surgery complications

Postoperative BS follow-up varies depending on location, surgeon preference, and availability of multidisciplinary resources. At our institution, patients have a minimum of 3 follow-up visits with their surgeon (during hospitalization and 2 weeks and 2 months postoperatively). This is followed by visits with Endocrinology 6 months after surgery and annually thereafter. Given the variability of follow-up, family physicians should coordinate with specialists where appropriate and be aware of postoperative complications and monitoring since it is likely they will have the most frequent contact with these patients.

Nutritional deficiencies are common and require lifelong screening

Nutritional deficiencies are the most common complications of malabsorptive BS. Guidelines from the Endocrine Society, as well as guidelines from the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), and the American Society for Metabolic and Bariatric Surgery (ASMBS), recommend routine lifetime screening for deficiencies after surgery.^6,7 Complete blood cell count, electrolytes, glucose, creatinine, and liver function tests should be obtained at one, 3, 6, 12, 18, and 24 months following surgery and annually thereafter.⁶

Multiple factors contribute to nutritional and micronutrient deficiencies, including reduced oral intake of food, decreased GI absorption, food intolerance, nausea/vomiting, and nonadherence with dietary supplements.⁸ Oral supplementation should be in chewable, powder, or liquid form because pill and capsule absorption may be altered.^8,9 Over-the-counter multivitamins may not contain the requisite daily doses recommended after BS.⁹ Patients and physicians should evaluate supplements together to ensure appropriate nutritional and micronutrient supplementation (TABLE 1^6,8-11).

Bone mineral density can start to decrease soon after surgery

Studies evaluating BMD after BS have produced variable findings. In obese patients, dual-energy x-ray absorptiometry (DEXA) measurements may not be accurate due to adipose tissue artifact and table weight limits. In addition, limited data exist on the incidence of fractures after BS. Of 2 notable studies, only one, a population-based study involving 258 Minnesota residents who underwent a first bariatric surgery between 1985 and 2004, demonstrated a significantly increased incidence of fractures.^12,13

In addition, studies show bone turnover markers, including C-terminal telopeptide, increase as early as 3 months after BS.¹⁴ Several guidelines recommend routine BMD screening after BS (TABLE 2).^6,7 The mechanism of bone demineralization is likely multifactorial—a function of the magnitude of the weight loss and skeletal unloading, calcium and vitamin D deficiencies, and associated secondary hyperparathyroidism.¹⁵ Treatment for secondary hyperparathyroidism is adequate supplementation with vitamin D and calcium.

Optimal dosing for vitamin D has not been determined. One recent systematic review suggests routine prophylaxis with at least 2000 international units (IU)/d and found the greatest improvement for known deficiency with doses of 1500-9100 IU/d following malabsorptive surgeries.¹¹ After laparoscopic sleeve gastrectomy, at least 1000 IU/d vitamin D is recommended.¹¹

Overall, high variability exists among patients, and an individualized approach for dosing is recommended.¹¹ Vitamin D levels should be monitored 2 and 4 weeks after initiation of treatment and every 3 months thereafter.¹¹ Normal levels of serum calcium, 25-OH vitamin D, bone-specific alkaline phosphatase, and 24-hour urinary calcium excretion indicate adequate calcium and vitamin D supplementation.⁶

Dumping syndrome can lead to hypoglycemia

Dumping syndrome is a common complication following BS, with prevalence ranging from 25% to 75%, depending upon the type of procedure performed.^16,17 There are 2 types: early and late. Early dumping syndrome occurs within 30 minutes of eating. Symptoms are related to the robust release of gastrointestinal hormones caused by rapid gastric emptying. Symptoms include nausea, abdominal pain, diarrhea, flushing, hypotension, and tachycardia.

Late dumping is characterized as postprandial hypoglycemia occurring one to 3 hours after eating. Late dumping is likely caused by a combination of changes within the pancreatic beta cells and abnormal insulin response to glucose.^16-18 Rapid gastric emptying leads to rapid release of glucose in the gut, which, in turn, leads to brisk insulin secretion. Since glucose is absorbed faster than insulin’s half-life, the resulting (relatively) high levels of insulin may cause hypoglycemia.^16-18

Sigstad’s scoring system can be used to confirm suspected cases of dumping syndrome (TABLE 3^16,17,19). A diagnosis can also be made with an oral glucose challenge in which pulse, blood pressure, glucose, and hematocrit are measured after ingestion of 50 g glucose. The test is positive if heart rate increases by 10 beats per minute, hematocrit increases by 3% 30 minutes after ingestion, or glucose falls below 60 mg/dL 2 to 3 hours after ingestion.¹⁷

First-line treatment of dumping syndrome consists of dietary modifications. The goal is to slow the rate of gastric emptying by eating smaller, more frequent meals; separating beverages from food; decreasing carbohydrates; and increasing fiber and protein content.

If results are suboptimal after dietary changes, medications can be prescribed including acarbose to prevent postprandial hypoglycemia; anticholinergics such as dicyclomine to slow gastric emptying; and somatostatin to decrease gastric emptying and inhibit GI hormone release.¹⁷ Lastly, for resistant and severe postprandial hypoglycemia, a few patients have undergone pancreatectomy, but only about 65% experienced improvement in symptoms and 12% developed diabetes post-surgically.²⁰

Gout attacks may initially increase, but then decrease

BS affects the incidence of gout attacks in patients with a history of gout. One comparative study of approximately 150 patients demonstrated that those with a history of gout had significantly more gout attacks in the first month after BS compared with obese patients with a history of gout undergoing other upper GI surgeries.²¹ There was no difference between malabsorptive and restrictive procedures. But after the first month, BS patients had significantly fewer gout attacks and lower uric acid levels than their obese counterparts.²¹

Protein rich diets, catabolism potentiated by aggressive caloric restriction following BS, and dehydration contribute to the initial increase. Therefore, patients who have had at least one gout attack in the year prior to surgery or who are on hypouricemic medication may benefit from at least one month of prophylactic therapy (eg, allopurinol and colchicine) after surgery.

GERD and ulceration: How to respond

Obesity is a known risk factor for GERD, but the effect of BS on GERD is uncertain and seems to vary with the procedure performed. RYGB decreases GERD and is, therefore, used as both a secondary treatment in those not responding to medications and a revision treatment for fundoplication and other types of BSs. Sleeve gastrectomy and adjustable gastric banding have mixed effects on GERD. A systematic review by de Jong et al revealed a decreased prevalence of reflux symptoms and GERD medication use after LAGB; however, during longer follow-up, 15% of previously unaffected patients reported experiencing GERD.²² The 2011 International Sleeve Gastrectomy Expert Panel Consensus Statement retrospectively noted a postoperative incidence of GERD as high as 31%.²³

BS patients with GERD should be treated with a proton pump inhibitor. If this fails, refer patients to a gastroenterologist for further evaluation.²⁴

Ulcers after BS may be an indication for revision surgery. Data are mixed regarding increased risk of marginal ulceration from nonsteroidal anti-inflammatory drug (NSAID) use, but NSAIDs have been linked to an increased risk of anastomotic leakage.^25-28 Thus, it seems prudent to avoid NSAIDs in people who have undergone BS.

Keeping watch over psychiatric comorbidities

A recent meta-analysis by Dawes et al²⁹ showed that about 23% of patients pursuing BS have a comorbid mood disorder. Specifically, the preoperative prevalence of depression (19%) and binge-eating disorder (17%) were found to be higher than rates in the general population.²⁹ The meta-analysis found improvement in the prevalence of depression with fewer symptoms and less antidepressant medication use in the first 3 years after surgery and a decrease in the rate of binge-eating disorder, although there were fewer supporting data for the latter. These findings were observed with both restrictive and malabsorptive procedures.

The data are mixed regarding rates of alcohol abuse and suicide. Further research is necessary in this field. Patients who have had BS should receive ongoing psychiatric and psychological care from a multidisciplinary team as a matter of course.

Will a second surgery be needed?

Revision surgery. In 2015, about 14% of the almost 200,000 BSs performed were revisions.⁴ Revision surgery is indicated in BS patients with weight regain, recurrent comorbid diseases (eg, diabetes, hypertension), or complications of primary BS. Restrictive procedures have a higher revision rate than malabsorptive procedures, primarily due to a higher rate of weight regain.^6,30

Because revision surgery is associated with more complications and possibly longer hospital stays than primary BS, it should be performed by a bariatric surgeon with extensive experience.^30,31 Restrictive revisions are typically converted to malabsorptive procedures. Cost is a limiting factor as many patients’ insurance coverage is limited to one BS per lifetime.

Body contouring. Body contouring surgery (BCS) can improve physical and mental well-being and may be a protective factor for weight regain after bariatric surgery.³² Despite its desirability—particularly to women, adolescents, and those with large decreases in body mass index (BMI)—few patients can afford BCS since it is rarely covered by insurance.

Complications of BCS vary, but are most commonly infection and wound dehiscence. This is, in part, due to poorer wound healing in BS patients compared to those with nonsurgical massive weight loss. The cause of poor wound healing is thought to be secondary to nutritional deficiencies and the catabolic state induced by post-surgical weight loss. Recommendations for BCS include weight stability for more than one year after BS, age >16 years, excess skin causing significant functional impairment, non-smoking status, and presence of good social support.³³

Bariatric surgery in adolescents is on the rise

Children in the highest body mass index quartile have more than twice the death rate of those in the lowest BMI quartile.³⁴ Thus, it is not surprising that the rate of BS in adolescents is increasing.⁷ BS in this age group is successful for weight loss and improvement of comorbid conditions, with relatively low complication rates.³⁵ Options include malabsorptive and restrictive procedures, although gastric banding has not been approved by the US Food and Drug Administration for patients under the age of 18 years.

Monitor vitamin D levels 2 and 4 weeks after initiation of treatment and every 3 months thereafter.After BS, adolescent girls should be counseled regarding the possibility of pregnancy (restoration of fertility) and appropriate contraception. Adolescent patients require nutritional supplementation after BS as indicated in TABLE 1.^6,8-11

When determining which adolescents to refer for BS, we recommend the following criteria: ^35-38

• failure of a minimum 6-month trial of a staged treatment approach, as recommended by Barlow et al,³⁶ including diet, exercise, and pharmacologic treatment
• BMI ≥35 with type 2 diabetes or severe sleep apnea (apnea hypopnea index [AHI] >15)³⁷
• BMI ≥40 with mild sleep apnea (AHI >5), hypertension, or pre-diabetes³⁷
• Tanner stage IV or V
• at least 95% skeletal growth (for malabsorptive surgery).³⁷ This can be determined using an estimated adult height from mid-parental height formula and assessing growth plate closure with hand radiographs for bone age
• appropriate maturity level permitting adherence
• good psychological support
• a multidisciplinary team for postoperative and long-term follow-up care.

Planning for the future: Exploring the possibility of pregnancy

Obesity is the primary cause of maternal and fetal morbidity during pregnancy. It is associated with increased rates of early miscarriage, congenital defects, macrosomia, and fetal death. Maternal risks of obesity include: gestational hypertension, gestational diabetes mellitus (GDM), and pre-eclampsia. Obese mothers also have a higher incidence of failed induction, caesarean section, and breastfeeding failure.^10,39 Given that half of all BSs are performed in women of reproductive age, this population deserves special consideration.¹⁰

A recent meta-analysis by Galazis et al⁴⁰ concluded that BS performed prior to pregnancy led to decreased rates of preeclampsia, GDM, large neonates, preterm birth, and neonatal intensive care unit admission. Perinatal mortality did not increase after BS. However, BS led to higher rates of maternal anemia. There was no significant difference between groups in incidence of cesarean section.

The post BS female patient should be advised to use a reliable form of contraception for a minimum of 12 to 18 months after surgery.^6,10,39 Involve high-risk obstetric specialists during pregnancies. Diet should be supplemented as indicated in TABLE 1.^6,8-11

CORRESPONDENCE
Amy Rothberg, MD, PhD, Domino’s Farms, Lobby G, Suite 1500, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106; [email protected].

More than one-third of American adults and approximately 17% of children and adolescents between the ages of 2 and 19 years are obese.^1,2 Poor diet coupled with a sedentary lifestyle is the highest ranked cause of non-communicable disease and a leading cause of preventable death, according to the National Research Council.³

Bariatric surgery (BS) is a viable therapeutic option for obese patients who do not respond to conventional lifestyle interventions for losing weight. There are multiple gastrointestinal (GI) procedures available that are classified as either malabsorptive (Roux-en-Y gastric bypass [RYGB] and biliopancreatic diversion [BPD] with or without duodenal switch) or restrictive (laparoscopic adjustable gastric banding [LAGB] and vertical sleeve gastrectomy [VSG]).

Approximately half of the 196,000 bariatric procedures performed in the United States in 2015 were of the sleeve variety, another 23% were RYGB, and the remaining percentage was divided among the other types.⁴ Postoperative risks include nutritional deficiencies, decreased bone mineral density (BMD), dumping syndrome (when food rapidly dumps from the stomach to the intestine), and gastroesophageal reflux disease (GERD) with possible ulceration.

Despite these potential complications, a systematic review and meta-analysis found that obese people who underwent BS (gastric banding or gastric bypass) had significantly reduced risks of global, non-cardiovascular (CV), and CV mortality compared with obese controls.⁵ Helping patients to realize these benefits requires that the entire health care team—especially the family physician—is aware of the special considerations for this population.

Patients undergoing bariatric surgery require routine lifetime screening for nutritional deficiencies.

To that end, this article reviews the details of diagnosing and managing post-surgical complications. It also addresses issues unique to managing certain subpopulations, such as post-BS patients who require revision surgery or who want to pursue body contouring surgery; adolescents who undergo BS surgery; and women who want to get pregnant postoperatively.

Monitor patients for these post-surgery complications

Postoperative BS follow-up varies depending on location, surgeon preference, and availability of multidisciplinary resources. At our institution, patients have a minimum of 3 follow-up visits with their surgeon (during hospitalization and 2 weeks and 2 months postoperatively). This is followed by visits with Endocrinology 6 months after surgery and annually thereafter. Given the variability of follow-up, family physicians should coordinate with specialists where appropriate and be aware of postoperative complications and monitoring since it is likely they will have the most frequent contact with these patients.

Nutritional deficiencies are common and require lifelong screening

Nutritional deficiencies are the most common complications of malabsorptive BS. Guidelines from the Endocrine Society, as well as guidelines from the American Association of Clinical Endocrinologists (AACE), The Obesity Society (TOS), and the American Society for Metabolic and Bariatric Surgery (ASMBS), recommend routine lifetime screening for deficiencies after surgery.^6,7 Complete blood cell count, electrolytes, glucose, creatinine, and liver function tests should be obtained at one, 3, 6, 12, 18, and 24 months following surgery and annually thereafter.⁶

Multiple factors contribute to nutritional and micronutrient deficiencies, including reduced oral intake of food, decreased GI absorption, food intolerance, nausea/vomiting, and nonadherence with dietary supplements.⁸ Oral supplementation should be in chewable, powder, or liquid form because pill and capsule absorption may be altered.^8,9 Over-the-counter multivitamins may not contain the requisite daily doses recommended after BS.⁹ Patients and physicians should evaluate supplements together to ensure appropriate nutritional and micronutrient supplementation (TABLE 1^6,8-11).

Bone mineral density can start to decrease soon after surgery

Studies evaluating BMD after BS have produced variable findings. In obese patients, dual-energy x-ray absorptiometry (DEXA) measurements may not be accurate due to adipose tissue artifact and table weight limits. In addition, limited data exist on the incidence of fractures after BS. Of 2 notable studies, only one, a population-based study involving 258 Minnesota residents who underwent a first bariatric surgery between 1985 and 2004, demonstrated a significantly increased incidence of fractures.^12,13

In addition, studies show bone turnover markers, including C-terminal telopeptide, increase as early as 3 months after BS.¹⁴ Several guidelines recommend routine BMD screening after BS (TABLE 2).^6,7 The mechanism of bone demineralization is likely multifactorial—a function of the magnitude of the weight loss and skeletal unloading, calcium and vitamin D deficiencies, and associated secondary hyperparathyroidism.¹⁵ Treatment for secondary hyperparathyroidism is adequate supplementation with vitamin D and calcium.

Optimal dosing for vitamin D has not been determined. One recent systematic review suggests routine prophylaxis with at least 2000 international units (IU)/d and found the greatest improvement for known deficiency with doses of 1500-9100 IU/d following malabsorptive surgeries.¹¹ After laparoscopic sleeve gastrectomy, at least 1000 IU/d vitamin D is recommended.¹¹

Overall, high variability exists among patients, and an individualized approach for dosing is recommended.¹¹ Vitamin D levels should be monitored 2 and 4 weeks after initiation of treatment and every 3 months thereafter.¹¹ Normal levels of serum calcium, 25-OH vitamin D, bone-specific alkaline phosphatase, and 24-hour urinary calcium excretion indicate adequate calcium and vitamin D supplementation.⁶

Dumping syndrome can lead to hypoglycemia

Dumping syndrome is a common complication following BS, with prevalence ranging from 25% to 75%, depending upon the type of procedure performed.^16,17 There are 2 types: early and late. Early dumping syndrome occurs within 30 minutes of eating. Symptoms are related to the robust release of gastrointestinal hormones caused by rapid gastric emptying. Symptoms include nausea, abdominal pain, diarrhea, flushing, hypotension, and tachycardia.

Late dumping is characterized as postprandial hypoglycemia occurring one to 3 hours after eating. Late dumping is likely caused by a combination of changes within the pancreatic beta cells and abnormal insulin response to glucose.^16-18 Rapid gastric emptying leads to rapid release of glucose in the gut, which, in turn, leads to brisk insulin secretion. Since glucose is absorbed faster than insulin’s half-life, the resulting (relatively) high levels of insulin may cause hypoglycemia.^16-18

Sigstad’s scoring system can be used to confirm suspected cases of dumping syndrome (TABLE 3^16,17,19). A diagnosis can also be made with an oral glucose challenge in which pulse, blood pressure, glucose, and hematocrit are measured after ingestion of 50 g glucose. The test is positive if heart rate increases by 10 beats per minute, hematocrit increases by 3% 30 minutes after ingestion, or glucose falls below 60 mg/dL 2 to 3 hours after ingestion.¹⁷

First-line treatment of dumping syndrome consists of dietary modifications. The goal is to slow the rate of gastric emptying by eating smaller, more frequent meals; separating beverages from food; decreasing carbohydrates; and increasing fiber and protein content.

If results are suboptimal after dietary changes, medications can be prescribed including acarbose to prevent postprandial hypoglycemia; anticholinergics such as dicyclomine to slow gastric emptying; and somatostatin to decrease gastric emptying and inhibit GI hormone release.¹⁷ Lastly, for resistant and severe postprandial hypoglycemia, a few patients have undergone pancreatectomy, but only about 65% experienced improvement in symptoms and 12% developed diabetes post-surgically.²⁰

Gout attacks may initially increase, but then decrease

BS affects the incidence of gout attacks in patients with a history of gout. One comparative study of approximately 150 patients demonstrated that those with a history of gout had significantly more gout attacks in the first month after BS compared with obese patients with a history of gout undergoing other upper GI surgeries.²¹ There was no difference between malabsorptive and restrictive procedures. But after the first month, BS patients had significantly fewer gout attacks and lower uric acid levels than their obese counterparts.²¹

Protein rich diets, catabolism potentiated by aggressive caloric restriction following BS, and dehydration contribute to the initial increase. Therefore, patients who have had at least one gout attack in the year prior to surgery or who are on hypouricemic medication may benefit from at least one month of prophylactic therapy (eg, allopurinol and colchicine) after surgery.

GERD and ulceration: How to respond

Obesity is a known risk factor for GERD, but the effect of BS on GERD is uncertain and seems to vary with the procedure performed. RYGB decreases GERD and is, therefore, used as both a secondary treatment in those not responding to medications and a revision treatment for fundoplication and other types of BSs. Sleeve gastrectomy and adjustable gastric banding have mixed effects on GERD. A systematic review by de Jong et al revealed a decreased prevalence of reflux symptoms and GERD medication use after LAGB; however, during longer follow-up, 15% of previously unaffected patients reported experiencing GERD.²² The 2011 International Sleeve Gastrectomy Expert Panel Consensus Statement retrospectively noted a postoperative incidence of GERD as high as 31%.²³

BS patients with GERD should be treated with a proton pump inhibitor. If this fails, refer patients to a gastroenterologist for further evaluation.²⁴

Ulcers after BS may be an indication for revision surgery. Data are mixed regarding increased risk of marginal ulceration from nonsteroidal anti-inflammatory drug (NSAID) use, but NSAIDs have been linked to an increased risk of anastomotic leakage.^25-28 Thus, it seems prudent to avoid NSAIDs in people who have undergone BS.

Keeping watch over psychiatric comorbidities

A recent meta-analysis by Dawes et al²⁹ showed that about 23% of patients pursuing BS have a comorbid mood disorder. Specifically, the preoperative prevalence of depression (19%) and binge-eating disorder (17%) were found to be higher than rates in the general population.²⁹ The meta-analysis found improvement in the prevalence of depression with fewer symptoms and less antidepressant medication use in the first 3 years after surgery and a decrease in the rate of binge-eating disorder, although there were fewer supporting data for the latter. These findings were observed with both restrictive and malabsorptive procedures.

The data are mixed regarding rates of alcohol abuse and suicide. Further research is necessary in this field. Patients who have had BS should receive ongoing psychiatric and psychological care from a multidisciplinary team as a matter of course.

Will a second surgery be needed?

Revision surgery. In 2015, about 14% of the almost 200,000 BSs performed were revisions.⁴ Revision surgery is indicated in BS patients with weight regain, recurrent comorbid diseases (eg, diabetes, hypertension), or complications of primary BS. Restrictive procedures have a higher revision rate than malabsorptive procedures, primarily due to a higher rate of weight regain.^6,30

Because revision surgery is associated with more complications and possibly longer hospital stays than primary BS, it should be performed by a bariatric surgeon with extensive experience.^30,31 Restrictive revisions are typically converted to malabsorptive procedures. Cost is a limiting factor as many patients’ insurance coverage is limited to one BS per lifetime.

Body contouring. Body contouring surgery (BCS) can improve physical and mental well-being and may be a protective factor for weight regain after bariatric surgery.³² Despite its desirability—particularly to women, adolescents, and those with large decreases in body mass index (BMI)—few patients can afford BCS since it is rarely covered by insurance.

Complications of BCS vary, but are most commonly infection and wound dehiscence. This is, in part, due to poorer wound healing in BS patients compared to those with nonsurgical massive weight loss. The cause of poor wound healing is thought to be secondary to nutritional deficiencies and the catabolic state induced by post-surgical weight loss. Recommendations for BCS include weight stability for more than one year after BS, age >16 years, excess skin causing significant functional impairment, non-smoking status, and presence of good social support.³³

Bariatric surgery in adolescents is on the rise

Children in the highest body mass index quartile have more than twice the death rate of those in the lowest BMI quartile.³⁴ Thus, it is not surprising that the rate of BS in adolescents is increasing.⁷ BS in this age group is successful for weight loss and improvement of comorbid conditions, with relatively low complication rates.³⁵ Options include malabsorptive and restrictive procedures, although gastric banding has not been approved by the US Food and Drug Administration for patients under the age of 18 years.

Monitor vitamin D levels 2 and 4 weeks after initiation of treatment and every 3 months thereafter.After BS, adolescent girls should be counseled regarding the possibility of pregnancy (restoration of fertility) and appropriate contraception. Adolescent patients require nutritional supplementation after BS as indicated in TABLE 1.^6,8-11

When determining which adolescents to refer for BS, we recommend the following criteria: ^35-38

• failure of a minimum 6-month trial of a staged treatment approach, as recommended by Barlow et al,³⁶ including diet, exercise, and pharmacologic treatment
• BMI ≥35 with type 2 diabetes or severe sleep apnea (apnea hypopnea index [AHI] >15)³⁷
• BMI ≥40 with mild sleep apnea (AHI >5), hypertension, or pre-diabetes³⁷
• Tanner stage IV or V
• at least 95% skeletal growth (for malabsorptive surgery).³⁷ This can be determined using an estimated adult height from mid-parental height formula and assessing growth plate closure with hand radiographs for bone age
• appropriate maturity level permitting adherence
• good psychological support
• a multidisciplinary team for postoperative and long-term follow-up care.

Planning for the future: Exploring the possibility of pregnancy

Obesity is the primary cause of maternal and fetal morbidity during pregnancy. It is associated with increased rates of early miscarriage, congenital defects, macrosomia, and fetal death. Maternal risks of obesity include: gestational hypertension, gestational diabetes mellitus (GDM), and pre-eclampsia. Obese mothers also have a higher incidence of failed induction, caesarean section, and breastfeeding failure.^10,39 Given that half of all BSs are performed in women of reproductive age, this population deserves special consideration.¹⁰

A recent meta-analysis by Galazis et al⁴⁰ concluded that BS performed prior to pregnancy led to decreased rates of preeclampsia, GDM, large neonates, preterm birth, and neonatal intensive care unit admission. Perinatal mortality did not increase after BS. However, BS led to higher rates of maternal anemia. There was no significant difference between groups in incidence of cesarean section.

The post BS female patient should be advised to use a reliable form of contraception for a minimum of 12 to 18 months after surgery.^6,10,39 Involve high-risk obstetric specialists during pregnancies. Diet should be supplemented as indicated in TABLE 1.^6,8-11

CORRESPONDENCE
Amy Rothberg, MD, PhD, Domino’s Farms, Lobby G, Suite 1500, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106; [email protected].

CASE › Amber S,* a 33-year-old woman who works on the production line at a bread factory, sought care at my health center with a several month history of non-bloody diarrhea that was increasing in frequency and urgency and was accompanied by painful abdominal bloating and cramping. She said that these symptoms were negatively impacting her interpersonal relationships, as well as her productivity at work. She reported that “almost everything” she ate upset her stomach and “goes right through her,” including fruits, vegetables, and meat, as well as greasy fast food. She had researched her symptoms on the Internet and was worried that she might have something serious like inflammatory bowel disease or cancer.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder (FGID) that negatively impacts the quality of life (QOL) of millions of people worldwide.¹ In fact, one study of 179 people with IBS found that 76% of survey respondents reported some degree of IBS-related impairment in at least 5 domains of daily life: daily activities, comorbid psychiatric diagnoses, symptom severity, QOL, and symptom-specific cognitive affective factors related to IBS.²

Estimating prevalence and incidence is a formidable challenge given various diagnostic criteria, the influence of population selection, inclusion or exclusion of non-GI comorbidities, and various cultural influences.³ That said, it’s estimated that IBS impacts approximately 11% of the world’s population, and approximately 30% of these individuals seek treatment.^1,4 While there are no significant differences in GI symptoms between those who consult physicians and those who do not, those who do seek treatment report higher pain scores, greater levels of anxiety, and a greater reduction in QOL.⁵

All ages affected. IBS has been reported in patients of all ages, including children and the elderly, with no definable difference reported in the frequency of subtypes (diarrhea- or constipation-predominant).

This article reviews the latest explanations, diagnostic criteria, and treatment guidelines for this challenging condition so that you can offer your patients confident care without needless testing or referral.

[polldaddy:9755564]

A lack of consensus among practicing physicians

Historically, IBS has been regarded by many primary care physicians (PCPs) as a diagnosis of exclusion. Lab tests would be ordered, nothing significant would be found, and the patient would be referred to the gastroenterologist for a definitive diagnosis.

Perceptions and misconceptions about IBS continue to abound to this day. Many are neither completely right nor wrong partly because so many triggers for IBS exist and partly because of the heretofore lack of simple, standardized criteria to diagnose the condition. Other factors contributing to the confusion are that the diagnosis of IBS is purely symptom-based and that proposals of its pathophysiology have traditionally been complex.

It is presumed that IBS shares common pathophysiologic mechanisms—including visceral hypersensitivity—with syndromes like functional dyspepsia.For example, a 2006 survey-based study of PCPs and gastroenterologists found that PCPs were less likely than gastroenterologists to believe that IBS was related to prior physical or sexual abuse, previous infection, or learned behavior, but were more likely to associate dietary factors or a linkable genetic etiology with IBS.⁶ Both sets of beliefs, however, may be considered correct.

Similarly, a 2009 qualitative study conducted in the Netherlands found that general practitioners (GPs) considered smoking, caffeine, diet, “hasty lifestyle,” and lack of exercise as potential triggers for IBS symptoms, while PCPs in the United Kingdom considered diet, infection, and travel to be possible triggers.⁷ Again, all play a role.

While GPs reported that patients should take responsibility for managing their IBS and for minimizing its impact on their daily lives, they admitted limited awareness of the extent to which IBS affected their patients’ daily living.⁷

A 2013 survey-based study in England determined that GPs understand the relationship between IBS and psychological symptoms including anxiety and stress, and posited that the majority of patients could be managed within primary care without referral for psychological interventions.⁸ Moreover, they reported that a dedicated risk assessment tool for patients with IBS would be helpful to stratify severity of disease. The study concluded that the reluctance of GPs to refer patients for evidence-based psychological treatments may prevent them from obtaining appropriate services and care.

Newer explanatory model shines light on IBS

A newer explanation that is based on 3 main hypotheses is elucidating the true nature of IBS and providing a pragmatic model for the clinical setting (FIGURE 1).⁹ According to the model, IBS entails the following 3 elements, which combined lead to the symptoms of IBS:

• Altered or abnormal peripheral regulation of gut function (including sensory and secretory mechanisms)
• Altered brain-gut signaling (including visceral hypersensitivity)
• Psychological distress.

It is reasonable to consider that epigenetic changes may underlie the etiology and pathophysiology of IBS and could increase one’s susceptibility to developing the disorder. Additionally, it is presumed that IBS shares common pathophysiologic mechanisms, including visceral hypersensitivity, with other associated functional syndromes, such as functional dyspepsia.

New criteria make diagnosis on symptoms alone easier

In addition to a new explanatory model, clear criteria for diagnosing the disorder now exist, which should make it easier for PCPs to make the diagnosis without additional testing or referral. The 2016 Rome IV criteria³ provide guidelines for diagnosing the various subtypes of IBS including IBS-D (diarrhea predominant), IBS-C (constipation predominant), and IBS-M (mixed subtypes). A laboratory evaluation is really only needed for patients who fall outside the criteria or who have alarm symptoms, which include:

• age >50 years at onset of symptoms,

• new onset of constipation in the elderly,

• rectal bleeding,
• unexplained weight loss or anemia,
• family history of organic GI disease, and
• a palpable abdominal or rectal mass.

These symptoms should prompt referral to a gastroenterologist. Once alarm symptoms have been excluded, the diagnosis of IBS is based upon the presence of characteristic symptoms and changes in stool habits (FIGURE 2^3,10).

Patterns of migration. Over time, patients may migrate between subtypes, most commonly from IBS-C or IBS-D to IBS-M; switching between IBS-C and IBS-D occurs less commonly.¹¹ Patients who meet criteria for IBS but whose bowel habits and symptoms cannot be grouped into any of these 3 categories are considered to have IBS unclassified. The Bristol Stool Form Scale (available at: https://www.niddk.nih.gov/health-information/health-communication-programs/bowel-control-awareness-campaign/Documents/Bristol_Stool_Form_Scale_508.pdf) should be used to gauge and track stool consistency.

A novel diagnostic test for IBS has been validated for differentiating patients with IBS-D from those with inflammatory bowel disease (IBD).¹² The test focused on the beliefs that cytolethal distending toxin B (CdtB) is produced by bacteria that cause acute viral gastroenteritis (eg, norovirus, rotavirus), and that host antibodies to CdtB cross-react with the protein vinculin in the host gut, producing an “IBS-like phenotype.”

Additional treatment options for diarrhea-predominant IBS include antidepressants (tricyclics or SSRIs) and antispasmodics, such as dicyclomine and hyoscyamine.In a 2015 large-scale multicenter trial, both anti-CdtB and anti-vinculin antibodies were found to be significantly elevated in subjects with IBS-D compared to non-IBS subjects,¹² providing evidence to support the long-held belief that viral gastroenteritis is often at the root of IBS.

Treatment aims to decrease symptoms and improve QOL

Treatment of IBS is directed at decreasing symptoms of abdominal pain and discomfort, bloating, diarrhea, and constipation while improving QOL. Therapeutic options for treatment of each symptom are listed in FIGURE 3,^13,14 including several that are commonly used and have moderate efficacy, but are not currently approved by the US Food and Drug Administration for this purpose.

Current evidence-based pharmacologic guidelines from the American Gastroenterological Association (AGA) can be found at: https://www.guideline.gov/summaries/summary/49122?osrc=12. Figure 3^13,14 provides a few additional options not included in the AGA guidelines and presents the information in a simple schematic.

Pharmacologic therapies for IBS-D

Eluxadoline is a novel mixed mu opioid receptor agonist and delta opioid receptor antagonist developed for the treatment of IBS-D. It normalizes GI transit and defecation under conditions of environmental stress or post-inflammatory altered GI function.¹⁵ A 2016 study involving almost 2500 patients found that eluxadoline was significantly better than placebo at decreasing abdominal pain and improving stool consistency on the same day for at least half of a 26-week period.¹³ The most common adverse effects were nausea, constipation, and abdominal pain. Pancreatitis occurred rarely.

Rifaximin. Because GI flora play a central role in the pathophysiology of IBS, researchers have found that rifaximin, a minimally absorbed antibiotic, is a potentially important player in treatment. Two double-blind, placebo-controlled trials (TARGET 1 and TARGET 2) found that after 4 weeks of treatment, patients experienced significant improvement in global IBS symptoms including bloating, abdominal pain, and stool consistency on rifaximin vs placebo (40.7% vs 31.7%; P<.001 in the 2 studies combined).¹⁶ The incidence of adverse effects (headache, upper respiratory infection, nausea, abdominal pain, diarrhea, and urinary tract infection) was comparable to that with placebo.

Alosetron. Research has shown this selective 5-HT3 receptor antagonist to improve all IBS QOL measures, restriction of daily activities, and patient satisfaction significantly more than placebo in women.¹⁷ While initial use of alosetron in 2000 was widespread, the rare serious adverse event of ischemic colitis led to its withdrawal from the US market within a few months.¹⁸ Alosetron returned to the market in 2002 with restricted marketing (to treat only women with severe diarrhea-predominant IBS). (See Lotronex [alosetron hydrochloride] full prescribing information available at: https://lotronex.com/hcp/index.html.) Data from a 9-year risk management program subsequently found a cumulative incidence rate for ischemic colitis of 1.03 cases per 1000 patient/years.¹⁹

Current evidence suggests that targeted carbohydrate and gluten exclusion plays a role in the treatment and symptomatic improvement of patients with IBS.Other possible options include various antidepressants (tricyclics such as amitriptyline, imipramine, and nortriptyline; or selective serotonin reuptake inhibitors [SSRIs] such as citalopram, fluoxetine, and paroxetine) and antispasmodics such as dicyclomine and hyoscyamine.

Pharmacologic therapies for IBS-C

Linaclotide is a guanylate cyclase-C agonist with an indication for treatment of IBS-C. A double-blind, parallel-group, placebo-controlled trial found that the percentage of patients who experienced a decrease in abdominal pain was nearly 25%, with statistically significant improvements in bloating, straining, and stool consistency over a 26-week period.²⁰ In a report on 2 phase 3 trials, researchers found that linaclotide improved global symptom scores and significantly decreased abdominal bloating and fullness, pain, cramping, and discomfort vs placebo. Diarrhea was the most commonly reported adverse event in patients with severe abdominal symptoms (18.8%-21%).²¹

Lubiprostone is a prostaglandin E1 analogue that activates type-2-chloride channels on the apical membrane of epithelial cells in the intestine. In a combined analysis of 2 phase 3 randomized trials, lubiprostone was administered twice daily for 12 weeks vs placebo and patients were asked to describe how they felt after the trial period. Survey responders reported significant improvements in global IBS-C symptoms (17.9% vs 10.1%; P=.001).²² A meta-analysis of studies on lubiprostone found that diarrhea, nausea, and abdominal pain were the most common adverse effects, but their occurrence was not that much greater than with placebo.²³

Diet and probiotics can play a significant role

The role of dietary components in the treatment of IBS is gaining increasing attention. Such components can have a direct effect on gastric and intestinal motility, visceral sensation, immune activation, brain-gut interactions, and the microbiome. Current evidence suggests that targeted carbohydrate and gluten exclusion plays a favorable role in the treatment and symptomatic improvement of patients with IBS.²⁴

A 2014 study conducted in Australia showed that a diet low in FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols), which is characterized by avoiding foods containing gluten and those that are high in fructose, reduced overall GI symptom scores (including scores involving abdominal bloating, pain, and flatus) in patients with IBS compared to those consuming a normal Australian diet.²⁵ The International Foundation for Functional Gastrointestinal Disorders’ Web site provides a detailed guide to low FODMAP foods and can be found at: http://www.aboutibs.org/low-fodmap-diet.html.

Probiotics are now commonly used in the symptomatic treatment of many upper and lower GI disorders. While much anecdotal evidence exists to support their benefit, there is a paucity of large-scale and rigorous research to provide substantial outcomes-based evidence. The theory for their use is that they support regulation of the gut microbiome, which in turn improves the imbalance between the intestinal microbiome and a dysfunctional intestinal barrier.

Probiotics are now used in the symptomatic treatment of many upper and lower GI disorders.A 2014 randomized, double-blind, placebo-controlled trial involving multispecies probiotics (a mixture of Bifidobacterium longum, B. bifidum, B. lactis, Lactobacillus acidophilus, L. rhamnosus, and Streptococcus thermophilus) found that patients who received probiotics had significantly reduced symptoms of IBS after 4 weeks compared with placebo, and modest improvement in abdominal pain and discomfort as well as bloating.²⁶ One study involving 122 patients from 2011 found that B. bifidum MIMBb75 reduced the global assessment of IBS symptoms by -88 points (95% CI, -1.07 to -0.69) when compared with only -0.16 (95% CI, -.32 to 0.00) points in the placebo group (P<.0001).²⁷ MIMBb75 also significantly improved the IBS symptoms of pain/discomfort, distension/bloating, urgency, and digestive disorder. And one randomized, double-blind, placebo-controlled study involving 67 patients found that QOL scores improved two-fold when patients took Saccharomyces boulardii (15.4% vs 7.0%; P<.05).²⁸

Dried plums or prunes have been used successfully for decades for the symptomatic treatment of constipation. A single-blinded, randomized, cross-over study compared prunes 50 g/d to psyllium fiber 11 g/d and found that prunes were more efficacious (P<.05) with spontaneous bowel movements and stool consistency scores.²⁹

Peppermint oil has been studied as an alternative therapy for symptoms of IBS, but efficacy and tolerability are concerns. A meta-analysis of randomized controlled trials with a minimum duration of 2 weeks found that compared with placebo, peppermint oil provided improvement in abdominal pain, bloating, and global symptoms, but some patients reported transient heartburn.³⁰ A 4-week, randomized, double-blind, placebo-controlled clinical trial sponsored by IM HealthScience found a novel oral formulation of triple-enteric-coated sustained-release peppermint oil microspheres caused less heartburn than was reported in the previous study, but still significantly improved abdominal symptoms and lessened pain on defecation and fecal urgency.³¹

CASE › Suspecting IBS-D, the FP ordered a complete blood count, tissue transglutaminase antibodies, and a stool culture, all of which were unremarkable. Ms. S has been trying to follow a low FODMAP diet and has been taking some over-the-counter probiotics with only minimal relief of abdominal bloating and cramping and no improvement in stool consistency. Her FP started her on eluxadoline 100 mg twice daily with food. After 12 weeks of therapy, she reports significant improvement in global IBS symptoms and nearly complete resolution of her diarrhea.

*Amber S is a real patient in my practice. Her name has been changed to protect her identity.

CORRESPONDENCE
Joel J. Heidelbaugh, MD, FAAFP, FACG, Ypsilanti Health Center, 200 Arnet Suite 200, Ypsilanti, MI 48198; [email protected].

CASE › Amber S,* a 33-year-old woman who works on the production line at a bread factory, sought care at my health center with a several month history of non-bloody diarrhea that was increasing in frequency and urgency and was accompanied by painful abdominal bloating and cramping. She said that these symptoms were negatively impacting her interpersonal relationships, as well as her productivity at work. She reported that “almost everything” she ate upset her stomach and “goes right through her,” including fruits, vegetables, and meat, as well as greasy fast food. She had researched her symptoms on the Internet and was worried that she might have something serious like inflammatory bowel disease or cancer.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder (FGID) that negatively impacts the quality of life (QOL) of millions of people worldwide.¹ In fact, one study of 179 people with IBS found that 76% of survey respondents reported some degree of IBS-related impairment in at least 5 domains of daily life: daily activities, comorbid psychiatric diagnoses, symptom severity, QOL, and symptom-specific cognitive affective factors related to IBS.²

Estimating prevalence and incidence is a formidable challenge given various diagnostic criteria, the influence of population selection, inclusion or exclusion of non-GI comorbidities, and various cultural influences.³ That said, it’s estimated that IBS impacts approximately 11% of the world’s population, and approximately 30% of these individuals seek treatment.^1,4 While there are no significant differences in GI symptoms between those who consult physicians and those who do not, those who do seek treatment report higher pain scores, greater levels of anxiety, and a greater reduction in QOL.⁵

All ages affected. IBS has been reported in patients of all ages, including children and the elderly, with no definable difference reported in the frequency of subtypes (diarrhea- or constipation-predominant).

This article reviews the latest explanations, diagnostic criteria, and treatment guidelines for this challenging condition so that you can offer your patients confident care without needless testing or referral.

[polldaddy:9755564]

A lack of consensus among practicing physicians

Historically, IBS has been regarded by many primary care physicians (PCPs) as a diagnosis of exclusion. Lab tests would be ordered, nothing significant would be found, and the patient would be referred to the gastroenterologist for a definitive diagnosis.

Perceptions and misconceptions about IBS continue to abound to this day. Many are neither completely right nor wrong partly because so many triggers for IBS exist and partly because of the heretofore lack of simple, standardized criteria to diagnose the condition. Other factors contributing to the confusion are that the diagnosis of IBS is purely symptom-based and that proposals of its pathophysiology have traditionally been complex.

It is presumed that IBS shares common pathophysiologic mechanisms—including visceral hypersensitivity—with syndromes like functional dyspepsia.For example, a 2006 survey-based study of PCPs and gastroenterologists found that PCPs were less likely than gastroenterologists to believe that IBS was related to prior physical or sexual abuse, previous infection, or learned behavior, but were more likely to associate dietary factors or a linkable genetic etiology with IBS.⁶ Both sets of beliefs, however, may be considered correct.

Similarly, a 2009 qualitative study conducted in the Netherlands found that general practitioners (GPs) considered smoking, caffeine, diet, “hasty lifestyle,” and lack of exercise as potential triggers for IBS symptoms, while PCPs in the United Kingdom considered diet, infection, and travel to be possible triggers.⁷ Again, all play a role.

While GPs reported that patients should take responsibility for managing their IBS and for minimizing its impact on their daily lives, they admitted limited awareness of the extent to which IBS affected their patients’ daily living.⁷

A 2013 survey-based study in England determined that GPs understand the relationship between IBS and psychological symptoms including anxiety and stress, and posited that the majority of patients could be managed within primary care without referral for psychological interventions.⁸ Moreover, they reported that a dedicated risk assessment tool for patients with IBS would be helpful to stratify severity of disease. The study concluded that the reluctance of GPs to refer patients for evidence-based psychological treatments may prevent them from obtaining appropriate services and care.

Newer explanatory model shines light on IBS

A newer explanation that is based on 3 main hypotheses is elucidating the true nature of IBS and providing a pragmatic model for the clinical setting (FIGURE 1).⁹ According to the model, IBS entails the following 3 elements, which combined lead to the symptoms of IBS:

• Altered or abnormal peripheral regulation of gut function (including sensory and secretory mechanisms)
• Altered brain-gut signaling (including visceral hypersensitivity)
• Psychological distress.

It is reasonable to consider that epigenetic changes may underlie the etiology and pathophysiology of IBS and could increase one’s susceptibility to developing the disorder. Additionally, it is presumed that IBS shares common pathophysiologic mechanisms, including visceral hypersensitivity, with other associated functional syndromes, such as functional dyspepsia.

New criteria make diagnosis on symptoms alone easier

In addition to a new explanatory model, clear criteria for diagnosing the disorder now exist, which should make it easier for PCPs to make the diagnosis without additional testing or referral. The 2016 Rome IV criteria³ provide guidelines for diagnosing the various subtypes of IBS including IBS-D (diarrhea predominant), IBS-C (constipation predominant), and IBS-M (mixed subtypes). A laboratory evaluation is really only needed for patients who fall outside the criteria or who have alarm symptoms, which include:

• age >50 years at onset of symptoms,

• new onset of constipation in the elderly,

• rectal bleeding,
• unexplained weight loss or anemia,
• family history of organic GI disease, and
• a palpable abdominal or rectal mass.

These symptoms should prompt referral to a gastroenterologist. Once alarm symptoms have been excluded, the diagnosis of IBS is based upon the presence of characteristic symptoms and changes in stool habits (FIGURE 2^3,10).

Patterns of migration. Over time, patients may migrate between subtypes, most commonly from IBS-C or IBS-D to IBS-M; switching between IBS-C and IBS-D occurs less commonly.¹¹ Patients who meet criteria for IBS but whose bowel habits and symptoms cannot be grouped into any of these 3 categories are considered to have IBS unclassified. The Bristol Stool Form Scale (available at: https://www.niddk.nih.gov/health-information/health-communication-programs/bowel-control-awareness-campaign/Documents/Bristol_Stool_Form_Scale_508.pdf) should be used to gauge and track stool consistency.

A novel diagnostic test for IBS has been validated for differentiating patients with IBS-D from those with inflammatory bowel disease (IBD).¹² The test focused on the beliefs that cytolethal distending toxin B (CdtB) is produced by bacteria that cause acute viral gastroenteritis (eg, norovirus, rotavirus), and that host antibodies to CdtB cross-react with the protein vinculin in the host gut, producing an “IBS-like phenotype.”

Additional treatment options for diarrhea-predominant IBS include antidepressants (tricyclics or SSRIs) and antispasmodics, such as dicyclomine and hyoscyamine.In a 2015 large-scale multicenter trial, both anti-CdtB and anti-vinculin antibodies were found to be significantly elevated in subjects with IBS-D compared to non-IBS subjects,¹² providing evidence to support the long-held belief that viral gastroenteritis is often at the root of IBS.

Treatment aims to decrease symptoms and improve QOL

Treatment of IBS is directed at decreasing symptoms of abdominal pain and discomfort, bloating, diarrhea, and constipation while improving QOL. Therapeutic options for treatment of each symptom are listed in FIGURE 3,^13,14 including several that are commonly used and have moderate efficacy, but are not currently approved by the US Food and Drug Administration for this purpose.

Current evidence-based pharmacologic guidelines from the American Gastroenterological Association (AGA) can be found at: https://www.guideline.gov/summaries/summary/49122?osrc=12. Figure 3^13,14 provides a few additional options not included in the AGA guidelines and presents the information in a simple schematic.

Pharmacologic therapies for IBS-D

Eluxadoline is a novel mixed mu opioid receptor agonist and delta opioid receptor antagonist developed for the treatment of IBS-D. It normalizes GI transit and defecation under conditions of environmental stress or post-inflammatory altered GI function.¹⁵ A 2016 study involving almost 2500 patients found that eluxadoline was significantly better than placebo at decreasing abdominal pain and improving stool consistency on the same day for at least half of a 26-week period.¹³ The most common adverse effects were nausea, constipation, and abdominal pain. Pancreatitis occurred rarely.

Rifaximin. Because GI flora play a central role in the pathophysiology of IBS, researchers have found that rifaximin, a minimally absorbed antibiotic, is a potentially important player in treatment. Two double-blind, placebo-controlled trials (TARGET 1 and TARGET 2) found that after 4 weeks of treatment, patients experienced significant improvement in global IBS symptoms including bloating, abdominal pain, and stool consistency on rifaximin vs placebo (40.7% vs 31.7%; P<.001 in the 2 studies combined).¹⁶ The incidence of adverse effects (headache, upper respiratory infection, nausea, abdominal pain, diarrhea, and urinary tract infection) was comparable to that with placebo.

Alosetron. Research has shown this selective 5-HT3 receptor antagonist to improve all IBS QOL measures, restriction of daily activities, and patient satisfaction significantly more than placebo in women.¹⁷ While initial use of alosetron in 2000 was widespread, the rare serious adverse event of ischemic colitis led to its withdrawal from the US market within a few months.¹⁸ Alosetron returned to the market in 2002 with restricted marketing (to treat only women with severe diarrhea-predominant IBS). (See Lotronex [alosetron hydrochloride] full prescribing information available at: https://lotronex.com/hcp/index.html.) Data from a 9-year risk management program subsequently found a cumulative incidence rate for ischemic colitis of 1.03 cases per 1000 patient/years.¹⁹

Current evidence suggests that targeted carbohydrate and gluten exclusion plays a role in the treatment and symptomatic improvement of patients with IBS.Other possible options include various antidepressants (tricyclics such as amitriptyline, imipramine, and nortriptyline; or selective serotonin reuptake inhibitors [SSRIs] such as citalopram, fluoxetine, and paroxetine) and antispasmodics such as dicyclomine and hyoscyamine.

Pharmacologic therapies for IBS-C

Linaclotide is a guanylate cyclase-C agonist with an indication for treatment of IBS-C. A double-blind, parallel-group, placebo-controlled trial found that the percentage of patients who experienced a decrease in abdominal pain was nearly 25%, with statistically significant improvements in bloating, straining, and stool consistency over a 26-week period.²⁰ In a report on 2 phase 3 trials, researchers found that linaclotide improved global symptom scores and significantly decreased abdominal bloating and fullness, pain, cramping, and discomfort vs placebo. Diarrhea was the most commonly reported adverse event in patients with severe abdominal symptoms (18.8%-21%).²¹

Lubiprostone is a prostaglandin E1 analogue that activates type-2-chloride channels on the apical membrane of epithelial cells in the intestine. In a combined analysis of 2 phase 3 randomized trials, lubiprostone was administered twice daily for 12 weeks vs placebo and patients were asked to describe how they felt after the trial period. Survey responders reported significant improvements in global IBS-C symptoms (17.9% vs 10.1%; P=.001).²² A meta-analysis of studies on lubiprostone found that diarrhea, nausea, and abdominal pain were the most common adverse effects, but their occurrence was not that much greater than with placebo.²³

Diet and probiotics can play a significant role

The role of dietary components in the treatment of IBS is gaining increasing attention. Such components can have a direct effect on gastric and intestinal motility, visceral sensation, immune activation, brain-gut interactions, and the microbiome. Current evidence suggests that targeted carbohydrate and gluten exclusion plays a favorable role in the treatment and symptomatic improvement of patients with IBS.²⁴

A 2014 study conducted in Australia showed that a diet low in FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols), which is characterized by avoiding foods containing gluten and those that are high in fructose, reduced overall GI symptom scores (including scores involving abdominal bloating, pain, and flatus) in patients with IBS compared to those consuming a normal Australian diet.²⁵ The International Foundation for Functional Gastrointestinal Disorders’ Web site provides a detailed guide to low FODMAP foods and can be found at: http://www.aboutibs.org/low-fodmap-diet.html.

Probiotics are now commonly used in the symptomatic treatment of many upper and lower GI disorders. While much anecdotal evidence exists to support their benefit, there is a paucity of large-scale and rigorous research to provide substantial outcomes-based evidence. The theory for their use is that they support regulation of the gut microbiome, which in turn improves the imbalance between the intestinal microbiome and a dysfunctional intestinal barrier.

Probiotics are now used in the symptomatic treatment of many upper and lower GI disorders.A 2014 randomized, double-blind, placebo-controlled trial involving multispecies probiotics (a mixture of Bifidobacterium longum, B. bifidum, B. lactis, Lactobacillus acidophilus, L. rhamnosus, and Streptococcus thermophilus) found that patients who received probiotics had significantly reduced symptoms of IBS after 4 weeks compared with placebo, and modest improvement in abdominal pain and discomfort as well as bloating.²⁶ One study involving 122 patients from 2011 found that B. bifidum MIMBb75 reduced the global assessment of IBS symptoms by -88 points (95% CI, -1.07 to -0.69) when compared with only -0.16 (95% CI, -.32 to 0.00) points in the placebo group (P<.0001).²⁷ MIMBb75 also significantly improved the IBS symptoms of pain/discomfort, distension/bloating, urgency, and digestive disorder. And one randomized, double-blind, placebo-controlled study involving 67 patients found that QOL scores improved two-fold when patients took Saccharomyces boulardii (15.4% vs 7.0%; P<.05).²⁸

Dried plums or prunes have been used successfully for decades for the symptomatic treatment of constipation. A single-blinded, randomized, cross-over study compared prunes 50 g/d to psyllium fiber 11 g/d and found that prunes were more efficacious (P<.05) with spontaneous bowel movements and stool consistency scores.²⁹

Peppermint oil has been studied as an alternative therapy for symptoms of IBS, but efficacy and tolerability are concerns. A meta-analysis of randomized controlled trials with a minimum duration of 2 weeks found that compared with placebo, peppermint oil provided improvement in abdominal pain, bloating, and global symptoms, but some patients reported transient heartburn.³⁰ A 4-week, randomized, double-blind, placebo-controlled clinical trial sponsored by IM HealthScience found a novel oral formulation of triple-enteric-coated sustained-release peppermint oil microspheres caused less heartburn than was reported in the previous study, but still significantly improved abdominal symptoms and lessened pain on defecation and fecal urgency.³¹

CASE › Suspecting IBS-D, the FP ordered a complete blood count, tissue transglutaminase antibodies, and a stool culture, all of which were unremarkable. Ms. S has been trying to follow a low FODMAP diet and has been taking some over-the-counter probiotics with only minimal relief of abdominal bloating and cramping and no improvement in stool consistency. Her FP started her on eluxadoline 100 mg twice daily with food. After 12 weeks of therapy, she reports significant improvement in global IBS symptoms and nearly complete resolution of her diarrhea.

*Amber S is a real patient in my practice. Her name has been changed to protect her identity.

CORRESPONDENCE
Joel J. Heidelbaugh, MD, FAAFP, FACG, Ypsilanti Health Center, 200 Arnet Suite 200, Ypsilanti, MI 48198; [email protected].

CASE › Amber S,* a 33-year-old woman who works on the production line at a bread factory, sought care at my health center with a several month history of non-bloody diarrhea that was increasing in frequency and urgency and was accompanied by painful abdominal bloating and cramping. She said that these symptoms were negatively impacting her interpersonal relationships, as well as her productivity at work. She reported that “almost everything” she ate upset her stomach and “goes right through her,” including fruits, vegetables, and meat, as well as greasy fast food. She had researched her symptoms on the Internet and was worried that she might have something serious like inflammatory bowel disease or cancer.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder (FGID) that negatively impacts the quality of life (QOL) of millions of people worldwide.¹ In fact, one study of 179 people with IBS found that 76% of survey respondents reported some degree of IBS-related impairment in at least 5 domains of daily life: daily activities, comorbid psychiatric diagnoses, symptom severity, QOL, and symptom-specific cognitive affective factors related to IBS.²

Estimating prevalence and incidence is a formidable challenge given various diagnostic criteria, the influence of population selection, inclusion or exclusion of non-GI comorbidities, and various cultural influences.³ That said, it’s estimated that IBS impacts approximately 11% of the world’s population, and approximately 30% of these individuals seek treatment.^1,4 While there are no significant differences in GI symptoms between those who consult physicians and those who do not, those who do seek treatment report higher pain scores, greater levels of anxiety, and a greater reduction in QOL.⁵

All ages affected. IBS has been reported in patients of all ages, including children and the elderly, with no definable difference reported in the frequency of subtypes (diarrhea- or constipation-predominant).

This article reviews the latest explanations, diagnostic criteria, and treatment guidelines for this challenging condition so that you can offer your patients confident care without needless testing or referral.

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A lack of consensus among practicing physicians

Historically, IBS has been regarded by many primary care physicians (PCPs) as a diagnosis of exclusion. Lab tests would be ordered, nothing significant would be found, and the patient would be referred to the gastroenterologist for a definitive diagnosis.

Perceptions and misconceptions about IBS continue to abound to this day. Many are neither completely right nor wrong partly because so many triggers for IBS exist and partly because of the heretofore lack of simple, standardized criteria to diagnose the condition. Other factors contributing to the confusion are that the diagnosis of IBS is purely symptom-based and that proposals of its pathophysiology have traditionally been complex.

It is presumed that IBS shares common pathophysiologic mechanisms—including visceral hypersensitivity—with syndromes like functional dyspepsia.For example, a 2006 survey-based study of PCPs and gastroenterologists found that PCPs were less likely than gastroenterologists to believe that IBS was related to prior physical or sexual abuse, previous infection, or learned behavior, but were more likely to associate dietary factors or a linkable genetic etiology with IBS.⁶ Both sets of beliefs, however, may be considered correct.

Similarly, a 2009 qualitative study conducted in the Netherlands found that general practitioners (GPs) considered smoking, caffeine, diet, “hasty lifestyle,” and lack of exercise as potential triggers for IBS symptoms, while PCPs in the United Kingdom considered diet, infection, and travel to be possible triggers.⁷ Again, all play a role.

While GPs reported that patients should take responsibility for managing their IBS and for minimizing its impact on their daily lives, they admitted limited awareness of the extent to which IBS affected their patients’ daily living.⁷

A 2013 survey-based study in England determined that GPs understand the relationship between IBS and psychological symptoms including anxiety and stress, and posited that the majority of patients could be managed within primary care without referral for psychological interventions.⁸ Moreover, they reported that a dedicated risk assessment tool for patients with IBS would be helpful to stratify severity of disease. The study concluded that the reluctance of GPs to refer patients for evidence-based psychological treatments may prevent them from obtaining appropriate services and care.

Newer explanatory model shines light on IBS

A newer explanation that is based on 3 main hypotheses is elucidating the true nature of IBS and providing a pragmatic model for the clinical setting (FIGURE 1).⁹ According to the model, IBS entails the following 3 elements, which combined lead to the symptoms of IBS:

• Altered or abnormal peripheral regulation of gut function (including sensory and secretory mechanisms)
• Altered brain-gut signaling (including visceral hypersensitivity)
• Psychological distress.

It is reasonable to consider that epigenetic changes may underlie the etiology and pathophysiology of IBS and could increase one’s susceptibility to developing the disorder. Additionally, it is presumed that IBS shares common pathophysiologic mechanisms, including visceral hypersensitivity, with other associated functional syndromes, such as functional dyspepsia.

New criteria make diagnosis on symptoms alone easier

In addition to a new explanatory model, clear criteria for diagnosing the disorder now exist, which should make it easier for PCPs to make the diagnosis without additional testing or referral. The 2016 Rome IV criteria³ provide guidelines for diagnosing the various subtypes of IBS including IBS-D (diarrhea predominant), IBS-C (constipation predominant), and IBS-M (mixed subtypes). A laboratory evaluation is really only needed for patients who fall outside the criteria or who have alarm symptoms, which include:

• age >50 years at onset of symptoms,

• new onset of constipation in the elderly,

• rectal bleeding,
• unexplained weight loss or anemia,
• family history of organic GI disease, and
• a palpable abdominal or rectal mass.

These symptoms should prompt referral to a gastroenterologist. Once alarm symptoms have been excluded, the diagnosis of IBS is based upon the presence of characteristic symptoms and changes in stool habits (FIGURE 2^3,10).

Patterns of migration. Over time, patients may migrate between subtypes, most commonly from IBS-C or IBS-D to IBS-M; switching between IBS-C and IBS-D occurs less commonly.¹¹ Patients who meet criteria for IBS but whose bowel habits and symptoms cannot be grouped into any of these 3 categories are considered to have IBS unclassified. The Bristol Stool Form Scale (available at: https://www.niddk.nih.gov/health-information/health-communication-programs/bowel-control-awareness-campaign/Documents/Bristol_Stool_Form_Scale_508.pdf) should be used to gauge and track stool consistency.

A novel diagnostic test for IBS has been validated for differentiating patients with IBS-D from those with inflammatory bowel disease (IBD).¹² The test focused on the beliefs that cytolethal distending toxin B (CdtB) is produced by bacteria that cause acute viral gastroenteritis (eg, norovirus, rotavirus), and that host antibodies to CdtB cross-react with the protein vinculin in the host gut, producing an “IBS-like phenotype.”

Additional treatment options for diarrhea-predominant IBS include antidepressants (tricyclics or SSRIs) and antispasmodics, such as dicyclomine and hyoscyamine.In a 2015 large-scale multicenter trial, both anti-CdtB and anti-vinculin antibodies were found to be significantly elevated in subjects with IBS-D compared to non-IBS subjects,¹² providing evidence to support the long-held belief that viral gastroenteritis is often at the root of IBS.

Treatment aims to decrease symptoms and improve QOL

Treatment of IBS is directed at decreasing symptoms of abdominal pain and discomfort, bloating, diarrhea, and constipation while improving QOL. Therapeutic options for treatment of each symptom are listed in FIGURE 3,^13,14 including several that are commonly used and have moderate efficacy, but are not currently approved by the US Food and Drug Administration for this purpose.

Current evidence-based pharmacologic guidelines from the American Gastroenterological Association (AGA) can be found at: https://www.guideline.gov/summaries/summary/49122?osrc=12. Figure 3^13,14 provides a few additional options not included in the AGA guidelines and presents the information in a simple schematic.

Pharmacologic therapies for IBS-D

Eluxadoline is a novel mixed mu opioid receptor agonist and delta opioid receptor antagonist developed for the treatment of IBS-D. It normalizes GI transit and defecation under conditions of environmental stress or post-inflammatory altered GI function.¹⁵ A 2016 study involving almost 2500 patients found that eluxadoline was significantly better than placebo at decreasing abdominal pain and improving stool consistency on the same day for at least half of a 26-week period.¹³ The most common adverse effects were nausea, constipation, and abdominal pain. Pancreatitis occurred rarely.

Rifaximin. Because GI flora play a central role in the pathophysiology of IBS, researchers have found that rifaximin, a minimally absorbed antibiotic, is a potentially important player in treatment. Two double-blind, placebo-controlled trials (TARGET 1 and TARGET 2) found that after 4 weeks of treatment, patients experienced significant improvement in global IBS symptoms including bloating, abdominal pain, and stool consistency on rifaximin vs placebo (40.7% vs 31.7%; P<.001 in the 2 studies combined).¹⁶ The incidence of adverse effects (headache, upper respiratory infection, nausea, abdominal pain, diarrhea, and urinary tract infection) was comparable to that with placebo.

Alosetron. Research has shown this selective 5-HT3 receptor antagonist to improve all IBS QOL measures, restriction of daily activities, and patient satisfaction significantly more than placebo in women.¹⁷ While initial use of alosetron in 2000 was widespread, the rare serious adverse event of ischemic colitis led to its withdrawal from the US market within a few months.¹⁸ Alosetron returned to the market in 2002 with restricted marketing (to treat only women with severe diarrhea-predominant IBS). (See Lotronex [alosetron hydrochloride] full prescribing information available at: https://lotronex.com/hcp/index.html.) Data from a 9-year risk management program subsequently found a cumulative incidence rate for ischemic colitis of 1.03 cases per 1000 patient/years.¹⁹

Current evidence suggests that targeted carbohydrate and gluten exclusion plays a role in the treatment and symptomatic improvement of patients with IBS.Other possible options include various antidepressants (tricyclics such as amitriptyline, imipramine, and nortriptyline; or selective serotonin reuptake inhibitors [SSRIs] such as citalopram, fluoxetine, and paroxetine) and antispasmodics such as dicyclomine and hyoscyamine.

Pharmacologic therapies for IBS-C

Linaclotide is a guanylate cyclase-C agonist with an indication for treatment of IBS-C. A double-blind, parallel-group, placebo-controlled trial found that the percentage of patients who experienced a decrease in abdominal pain was nearly 25%, with statistically significant improvements in bloating, straining, and stool consistency over a 26-week period.²⁰ In a report on 2 phase 3 trials, researchers found that linaclotide improved global symptom scores and significantly decreased abdominal bloating and fullness, pain, cramping, and discomfort vs placebo. Diarrhea was the most commonly reported adverse event in patients with severe abdominal symptoms (18.8%-21%).²¹

Lubiprostone is a prostaglandin E1 analogue that activates type-2-chloride channels on the apical membrane of epithelial cells in the intestine. In a combined analysis of 2 phase 3 randomized trials, lubiprostone was administered twice daily for 12 weeks vs placebo and patients were asked to describe how they felt after the trial period. Survey responders reported significant improvements in global IBS-C symptoms (17.9% vs 10.1%; P=.001).²² A meta-analysis of studies on lubiprostone found that diarrhea, nausea, and abdominal pain were the most common adverse effects, but their occurrence was not that much greater than with placebo.²³

Diet and probiotics can play a significant role

The role of dietary components in the treatment of IBS is gaining increasing attention. Such components can have a direct effect on gastric and intestinal motility, visceral sensation, immune activation, brain-gut interactions, and the microbiome. Current evidence suggests that targeted carbohydrate and gluten exclusion plays a favorable role in the treatment and symptomatic improvement of patients with IBS.²⁴

A 2014 study conducted in Australia showed that a diet low in FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols), which is characterized by avoiding foods containing gluten and those that are high in fructose, reduced overall GI symptom scores (including scores involving abdominal bloating, pain, and flatus) in patients with IBS compared to those consuming a normal Australian diet.²⁵ The International Foundation for Functional Gastrointestinal Disorders’ Web site provides a detailed guide to low FODMAP foods and can be found at: http://www.aboutibs.org/low-fodmap-diet.html.

Probiotics are now commonly used in the symptomatic treatment of many upper and lower GI disorders. While much anecdotal evidence exists to support their benefit, there is a paucity of large-scale and rigorous research to provide substantial outcomes-based evidence. The theory for their use is that they support regulation of the gut microbiome, which in turn improves the imbalance between the intestinal microbiome and a dysfunctional intestinal barrier.

Probiotics are now used in the symptomatic treatment of many upper and lower GI disorders.A 2014 randomized, double-blind, placebo-controlled trial involving multispecies probiotics (a mixture of Bifidobacterium longum, B. bifidum, B. lactis, Lactobacillus acidophilus, L. rhamnosus, and Streptococcus thermophilus) found that patients who received probiotics had significantly reduced symptoms of IBS after 4 weeks compared with placebo, and modest improvement in abdominal pain and discomfort as well as bloating.²⁶ One study involving 122 patients from 2011 found that B. bifidum MIMBb75 reduced the global assessment of IBS symptoms by -88 points (95% CI, -1.07 to -0.69) when compared with only -0.16 (95% CI, -.32 to 0.00) points in the placebo group (P<.0001).²⁷ MIMBb75 also significantly improved the IBS symptoms of pain/discomfort, distension/bloating, urgency, and digestive disorder. And one randomized, double-blind, placebo-controlled study involving 67 patients found that QOL scores improved two-fold when patients took Saccharomyces boulardii (15.4% vs 7.0%; P<.05).²⁸

Dried plums or prunes have been used successfully for decades for the symptomatic treatment of constipation. A single-blinded, randomized, cross-over study compared prunes 50 g/d to psyllium fiber 11 g/d and found that prunes were more efficacious (P<.05) with spontaneous bowel movements and stool consistency scores.²⁹

Peppermint oil has been studied as an alternative therapy for symptoms of IBS, but efficacy and tolerability are concerns. A meta-analysis of randomized controlled trials with a minimum duration of 2 weeks found that compared with placebo, peppermint oil provided improvement in abdominal pain, bloating, and global symptoms, but some patients reported transient heartburn.³⁰ A 4-week, randomized, double-blind, placebo-controlled clinical trial sponsored by IM HealthScience found a novel oral formulation of triple-enteric-coated sustained-release peppermint oil microspheres caused less heartburn than was reported in the previous study, but still significantly improved abdominal symptoms and lessened pain on defecation and fecal urgency.³¹

CASE › Suspecting IBS-D, the FP ordered a complete blood count, tissue transglutaminase antibodies, and a stool culture, all of which were unremarkable. Ms. S has been trying to follow a low FODMAP diet and has been taking some over-the-counter probiotics with only minimal relief of abdominal bloating and cramping and no improvement in stool consistency. Her FP started her on eluxadoline 100 mg twice daily with food. After 12 weeks of therapy, she reports significant improvement in global IBS symptoms and nearly complete resolution of her diarrhea.

*Amber S is a real patient in my practice. Her name has been changed to protect her identity.

CORRESPONDENCE
Joel J. Heidelbaugh, MD, FAAFP, FACG, Ypsilanti Health Center, 200 Arnet Suite 200, Ypsilanti, MI 48198; [email protected].

More than 29 million Americans have diabetes, and each year another 1.7 million are given the diagnosis.¹ Prediabetes is even more common; over one-third of US adults ages 20 years and older, and more than half of those who are ages 65 and older, have attained this precursor status, representing another 86 million Americans.¹

Because the evidence base for the management of diabetes is rapidly expanding, the American Diabetes Association’s (ADA) Professional Practice Committee updates its Standards of Medical Care in Diabetes annually to incorporate new evidence into its recommendations. The 2017 Standards of Care are available at: professional.diabetes.org/jfp.²

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality for people with diabetes, and is the largest contributor to the direct and indirect costs of the disease.² As a result, all patients with diabetes should have cardiovascular (CV) risk factors, including dyslipidemia, hypertension, smoking, a family history of premature coronary disease, and the presence of albuminuria, assessed at least annually.² Numerous studies have demonstrated the efficacy of controlling individual CV risk factors in preventing or slowing ASCVD in people with diabetes. Even larger benefits, including reduced ASCVD morbidity and mortality, can be achieved when multiple risk factors are addressed simultaneously.³

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality for the 29 million Americans with diabetes, and is the largest contributor to the direct and indirect costs of diabetes.

To hone your management of CV risks in patients with diabetes, we’ve put together this Q&A pointing out the elements of the ADA’s 2017 Standards of Care that are most relevant to the management of patients at risk for, or with established, ASCVD.

Screening

Since ASCVD so commonly co-occurs with diabetes, should I routinely screen asymptomatic patients with diabetes for heart disease?

No. The current evidence suggests that outcomes are NOT improved by screening people before they develop symptoms of ASCVD,⁴ and widespread ASCVD screening has not been shown to be cost-effective. Cardiac testing should be reserved for those with typical or atypical symptoms or those with an abnormal resting electrocardiogram (EKG).

Lifestyle modification

What are the benefits of lifestyle interventions?

The benefits include not only lost pounds, but improved mobility, physical and sexual functioning, and health-related quality of life. Recommend that all overweight patients with diabetes take advantage of intensive lifestyle interventions focusing on weight loss through decreased caloric intake and increased physical activity as per the Look AHEAD (Action for Health in Diabetes) trial.⁵ Although the intensive lifestyle intervention in the Look AHEAD trial did not decrease CV outcomes over 10 years of follow-up, it did improve control of CV risk factors and led to people in the intervention group taking fewer glucose-, blood pressure (BP)-, and lipid-lowering medications than those in the standard care group.

There is no one diet that is recommended for all people with diabetes. Weight reduction often requires intensive intervention. In order for weight loss diets to be sustainable, they must include patient preferences.

People with diabetes should be encouraged to receive individualized medical nutrition therapy (MNT), preferably from a registered dietitian who is well versed in nutritional management for diabetes. Such MNT is associated with a 0.5% to 2% decrease in A1c levels for people with type 2 diabetes.^6-9 Specific healthy diets include the Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and plant-based diets.

A new lifestyle recommendation in this year’s ADA Standards is that periods of prolonged sitting should be interrupted every 30 minutes with a period of physical activity. This appears to have glycemic benefits.²

Hypertension/BP management

When should I initiate hypertension treatment in patients with diabetes?

Nonpharmacologic therapy is reasonable in people with diabetes and mildly elevated BP (>120/80 mm Hg). If systolic blood pressure (SBP) is confirmed to be >140 mm Hg and/or diastolic blood pressure (DBP) is confirmed to be >90 mm Hg, the ADA recommends initiating pharmacologic therapy along with nonpharmacologic strategies. For patients with confirmed office-based BP >160/100 mm Hg, the ADA advises initiating lifestyle modifications as well as 2 pharmacologic medications (or a single pill combination of agents).²

What is the recommended BP target for patients with diabetes and hypertension?

These patients should be treated with a combination of measures, including lifestyle modification and pharmacologic therapy, to a target BP of <140/90 mm Hg. Randomized controlled trials (RCTs) have shown benefits with this target in terms of a reduction in the incidence of coronary heart disease (CHD) events, stroke, and diabetic kidney disease.^10,11

A 2012 meta-analysis of randomized trials involving adults with type 2 diabetes mellitus (T2DM) and comparing intensive BP targets (≤130 mm Hg SBP and ≤80 mm Hg DBP) with standard targets (≤140-160 mm Hg SBP and ≤85-100 mm Hg DBP) found no significant reduction in mortality or nonfatal MIs associated with more intense BP control. There was a statistically significant 35% relative risk (RR) reduction in stroke with intensive targets, but lower BP was also associated with an increased risk of hypotension and syncope.¹²

A new lifestyle recommendation in this year’s ADA Standards states that periods of prolonged sitting should be interrupted every 30 minutes with a period of physical activity.

The 2010 Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,¹³ which randomized 5518 patients with T2DM at high risk for ASCVD to either a target SBP of <120 mm Hg or 130 to 140 mm Hg, found that the patients with the lower SBP target did not benefit in the primary end point (a composite of nonfatal MI, nonfatal stroke, and CV death), but did benefit from nominally significant lower rates of total stroke and nonfatal stroke.

Based on these data, the ADA Standards of Care suggest that, “more intensive BP control may be reasonable in certain motivated, ACCORD-like patients (40-79 years of age with prior evidence of CVD or multiple CV risk factors) who have been educated about the added treatment burden, side effects, and costs of more intensive BP control and for patients who prefer to lower their risk of stroke beyond what can be achieved with usual care.”

Another major study, the 2015 Systolic Blood Pressure Intervention Trial (SPRINT) trial,¹⁴ demonstrated that treating patients with hypertension to a target SBP <120 mm Hg compared to the usual target of <140 mm Hg resulted in a 25% lower RR of the primary outcome (a composite of MI, other acute coronary syndromes, stroke, heart failure, or death from CV causes) and about a 25% reduction in all-cause mortality; however, people with diabetes were not included in the trial, so the applicability of the results to decisions about BP management in patients with diabetes is not known.

In people with diabetes at high risk for ASCVD and/or with albuminuria, ACE inhibitors and ARBs do reduce ASCVD outcomes and the progression of kidney disease.

A 2015 systematic review and meta-analysis of over 100,000 participants looked at SBP lowering in adults with T2DM and found that each 10-mm Hg reduction in SBP was associated with a significantly lower risk of morbidity, CV events, CHD, stroke, albuminuria, and retinopathy.¹⁰ When trials were stratified by mean baseline SBP (<140 mm Hg or ≥140 mm Hg), RRs for outcomes other than stroke, retinopathy, and renal failure were lower in studies with greater baseline SBP.

The latest ADA Standards of Care recommend that a lower BP target of 130/80 mm Hg may be appropriate for patients at high risk of CVD if this target can be achieved without undue treatment burden. A DBP of <80 mm Hg may also be appropriate in certain patients including those with a long life expectancy, CKD, elevated urinary albumin excretion, and those with evidence of CVD or associated risk factors.¹⁵ Of note, treating older adults with diabetes to an SBP target of <130 mm Hg has not been shown to improve cardiovascular outcomes,¹⁶ and treating to a diastolic target of <70 mm Hg has been associated with a greater risk of mortality.¹⁷

What are the current recommended treatment options?

Treatment for hypertension in adults with diabetes without albuminuria should include any of the classes of medications demonstrated to reduce CV events in patients with diabetes, such as:

• angiotensin-converting enzyme (ACE) inhibitors,
• angiotensin receptor blockers (ARBs),
• thiazide-like diuretics, and
• dihydropyridine calcium channel blockers.

These recommendations are based on evidence suggesting the lack of superiority of ACE inhibitors and ARBs over other classes of antihypertensive agents for the prevention of CV outcomes in all patients with diabetes.¹⁸ However, in people with diabetes at high risk for ASCVD and/or with albuminuria, ACE inhibitors and ARBs do reduce ASCVD outcomes and the progression of kidney disease.^19-24 Thus, ACE inhibitors and ARBs continue to be recommended as first-line medications for the treatment of hypertension in patients with diabetes and urine albumin/creatinine ratios ≥30 mg/g, as these medications are associated with a reduction in the rate of kidney disease progression.

The use of both an ACE inhibitor and an ARB in combination is not recommended.^25,26 For patients treated with ACE inhibitors, ARBs, or diuretics, serum creatinine/estimated glomerular filtration rate (eGFR) and serum potassium levels should be monitored.

What are the recommended lifestyle modifications for patients with diabetes and hypertension?

Regular exercise and healthy eating are recommended for all people with diabetes to optimize glycemic control and lose weight (if they are overweight or obese). For patients with hypertension, the DASH diet (available at: https://www.nhlbi.nih.gov/health/health-topics/topics/dash/) is effective at lowering BP. The DASH diet emphasizes reducing sodium intake, increasing potassium intake, limiting alcohol intake, and increasing physical activity. Specifically, sodium intake should be restricted to <2300 mg/d and patients should consume approximately 8 to 10 servings of fruits and vegetables per day and 2 to 3 servings of low-fat dairy per day. Alcohol should be limited to 2 drinks per day for men and one drink per day for women.

People with diabetes who have hypertension should be treated with lifestyle modification and pharmacologic therapy to a target blood pressure of <140/90 mm Hg.

Most adults with diabetes should perform 150 minutes per week of moderate to vigorous exercise, spread over at least 3 days/week. In addition, it is recommended that resistance exercises be performed at least 2 to 3 days/week. Prolonged inactivity is detrimental to health and should be interrupted with activity every 30 minutes.²⁷

Finally, as a part of lifestyle management for all patients with diabetes, smoking cessation is important, as is attention to stress, depression, and anxiety.

Is there an advantage to nighttime dosing of antihypertensive medications?

Yes. Growing evidence suggests that there is an ASCVD benefit to avoiding nocturnal BP dipping. A 2011 RCT of 448 participants with T2DM and hypertension showed a decrease in CV events and mortality during 5.4 years of follow-up if at least one antihypertensive medication was taken at bedtime.²⁸ As a result of this and other evidence,²⁹ consider administering one or more antihypertensive medications at bedtime, although this is not a formal recommendation in the ADA Standards of Care.

Are there any additional issues to be aware of when treating patients with diabetes and hypertension?

Yes. Sometimes patients who have had diabetes for many years have significant orthostatic hypotension secondary to autonomic neuropathy. Postural changes in BP and pulse may require adjustment of BP targets. Home BP self-monitoring and 24-hour ambulatory BP monitoring may indicate white-coat or masked hypertension.

Lipid management

What is the current evidence for lipid treatment in diabetes?

Lipid abnormalities are common in people with diabetes and contribute to the overall high risk of ASCVD in these patients. Subgroup analyses of patients in large trials with diabetes³⁰ and trials involving patients with diabetes³¹ have shown significant improvements in primary and secondary prevention of ASCVD with statin use. A 2008 meta-analysis of 18,686 people with diabetes showed a 9% reduction in all-cause mortality and a 13% reduction in vascular mortality for each 39-mg/dL reduction in low-density lipoprotein (LDL) cholesterol.³² Absolute reductions in mortality are greatest in those with highest risk, but the benefits of statin therapy are clear for low- and moderate-risk individuals with diabetes, too.^33,34 As a result, statins are the medications of choice for lipid lowering and CV risk reduction and should be used in addition to lifestyle management.

Who should get a statin, and how do I choose the optimum dosage?

Patients ages 40 to 75 years with diabetes but without additional ASCVD risk factors should receive a moderate-intensity statin, according to the ADA (see TABLES 1² and 2²). For those with additional CV risk factors, a high-intensity statin should be considered. The American College of Cardiology/American Heart Association ASCVD risk calculator (available at: http://www.cvriskcalculator.com/) may be useful for some patients, but generally, risk is already known to be high for most patients with diabetes. For patients of all ages with diabetes and established ASCVD, high-intensity statin therapy should be added to lifestyle modifications.^35-37

For patients with diabetes who are <40 years with additional ASCVD risk factors, few clinical trial data exist; nevertheless, consider a moderate- or high-intensity statin and lifestyle therapy. Similarly, for patients >75 years who have diabetes and no additional ASCVD risk factors, consider a moderate-intensity statin and lifestyle modifications. For older adults with additional ASCVD risk factors, consider high-intensity statin therapy.^35-37

Statins and cognition. It should be noted that published data have not demonstrated an adverse effect of statins on cognition.³⁸ Statins, however, have been linked to an increased risk of developing diabetes,^39,40 although the absolute increase in risk is small, and much smaller than the benefit derived from preventing the development of coronary disease.

Should total cholesterol and LDL levels be used as targets with statin treatment?

No. Statin doses have primarily been tested against placebo in clinical trials, rather than testing to specific target LDL levels, suggesting that the initiation and intensification of statin therapy be based on a patient’s risk profile.³⁵ When maximally tolerated doses of statins do not lower LDL cholesterol by more than 30% from the patient’s baseline, there is currently no good evidence that combination therapy would be helpful, so regular monitoring of lipid levels has limited value. A lipid profile that includes levels of total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides should be obtained at initial medical evaluation, at diagnosis of diabetes, and every 5 years thereafter or before the initiation of statin therapy. Ongoing testing may be appropriate in individual circumstances and to monitor for adherence to, or efficacy of, therapy.

What should I do for my patients who can’t tolerate statins?

Try a lower dose or a different statin before eliminating the class. Research has shown that even small doses (eg, rosuvastatin 5 mg) have some benefit.⁴¹

How do combination treatments figure into the current treatment of lipids in patients with diabetes?

It depends on the agent and the patient’s profile.

Fenofibrate. The ADA does not recommend automatically adding fenofibrate to statin therapy because the combination is associated with increased risks for abnormal transaminase levels, myositis, and rhabdomyolysis. In the ACCORD trial, the combination of fenofibrate and simvastatin did not reduce the rate of fatal CV events, nonfatal MIs, or nonfatal strokes compared with simvastatin alone.⁴²

Recommend statin therapy to all patients with diabetes over age 40; use a moderate- or high-intensity agent depending upon the degree of cardiac risk.

That said, a subgroup analysis suggested a benefit for men with both a triglyceride level ≥204 mg/dL (2.3 mmol/L) and an HDL cholesterol level ≤34 mg/dL (0.9 mmol/L).⁴² For this reason, the combination of a statin and fenofibrate may be considered for men who meet these laboratory parameters. In addition, consider medical therapy for triglyceride levels ≥500 mg/dL to reduce the risk of pancreatitis.

Ezetimibe. Recommendations regarding ezetimibe are based on the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), a 2015 RCT including over 18,000 patients that compared treatment with ezetimibe and simvastatin to simvastatin alone.⁴³ Individuals in the trial were ≥50 years of age and had experienced an ACS within the preceding 10 days. In those with diabetes, the combination of moderate-intensity simvastatin (40 mg) and ezetimibe (10 mg) significantly reduced major adverse CV events with an absolute risk reduction of 5% (40% vs 45%) and an RR reduction of 14% over moderate-intensity simvastatin (40 mg) alone.

Based on these results, patients with diabetes and a recent ACS should be considered for combination therapy with ezetimibe and a moderate-intensity statin. The combination should also be considered in patients with diabetes and a history of ASCVD who cannot tolerate high-intensity statins.⁴³

Recommend daily aspirin therapy to patients ages ≥50 years who have diabetes and at least one additional cardiovascular risk factor, but no bleeding risk.

Niacin. The ADA currently does not recommend niacin in combination with a statin because of lack of efficacy on major ASCVD outcomes, possible increased risk of ischemic stroke, and adverse effects.⁴⁴

What are the recommendations for the use of PCSK-9 inhibitors?

Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors (ie, evolucumab and alirocumab) may be considered as adjunctive therapy to statins for patients with diabetes at high risk for ASCVD events who require additional lowering of LDL cholesterol. They may also be considered for those in whom high-intensity statin therapy is indicated, but not tolerated.

Antiplatelet agents

Who should take aspirin for primary prevention of CVD?

Both women and men ages ≥50 years who have diabetes and at least one additional CV risk factor (family history of premature ASCVD, hypertension, tobacco use, dyslipidemia, or albuminuria) should consider taking daily aspirin therapy (75-162 mg/d) if they do not have an excessive bleeding risk.^45,46 The most common dose in the United States is 81 mg. This recommendation is supported by a 2010 consensus statement of the American Diabetes Association, American Heart Association, and the American College of Cardiology.⁴⁷

Should patients with diabetes and heart disease receive antiplatelet therapy?

Yes. The evidence is clear that people with known diabetes and ASCVD benefit from aspirin therapy, according to the 2017 Standards of Care. Clopidogrel 75 mg/d is an appropriate alternative for patients who are allergic to aspirin. Dual antiplatelet therapy (a P2Y12 receptor antagonist and aspirin) should be used for as long as one year after an ACS and may have benefits beyond this period.⁴⁸

Established heart disease

Are there specific recommendations for patients with diabetes and CHD?

According to the ADA Standards, there is good evidence that both aspirin and statin therapy are beneficial for patients with known ASCVD, and that high-intensity statin therapy should be used. In addition, consider ACE inhibitors to reduce the future risk of CV events. In patients with a prior MI, continue beta-blocker therapy for at least 2 years post event.⁴⁹

Which medications should I avoid, or approach with caution, in patients with congestive heart failure (CHF)?

Thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, and metformin all require careful attention. This is especially important to know when you consider that almost half of all patients with T2DM will develop heart failure.⁵⁰

Thiazolidinediones. The 2017 Standards of Care state that patients with diabetes and symptomatic congestive heart failure should not receive thiazolidinediones, as they can worsen heart failure status via fluid retention. As such, they are contraindicated in patients with class III and IV heart failure.⁵¹

DPP-4 inhibitors. The studies on DPP-4 inhibitors and heart failure have had mixed results. The 2013 SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction) 53 trial⁵² showed that patients treated with saxagliptin were more likely to be hospitalized for heart failure than those taking placebo (3.5% vs 2.8%, respectively). However, the 2015 EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin vs Standard of Care)⁵³ trial and the 2015 TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin)⁵⁴ trial evaluated heart failure and mortality outcomes in patients with alogliptin and sitagliptin, respectively, compared to placebo, and did not show a relationship to heart failure.

Metformin may be used in people who have T2DM and stable CHF if their eGFR remains >30 mL/min; it should be withheld from patients with unstable heart failure and those who are hospitalized with CHF.

Are there antihyperglycemic medications that reduce CV morbidity and mortality in those with established ASCVD?

Yes. This year’s ADA Standards indicate that certain glucose-lowering medications—specifically empagliflozin (a sodium–glucose cotransporter [SGLT]-2 inhibitor) and liraglutide (a glucagon-like peptide [GLP]-1 receptor agonist)—have been shown to be beneficial for those with established CVD. According to the 2017 Standards of Care, “In patients with longstanding suboptimally controlled T2DM and established ASCVD, empagliflozin or liraglutide should be considered, as they have been shown to reduce CV and all-cause mortality when added to standard care.”² The studies that provide support for their use are summarized below. Ongoing studies are investigating the CV effects of other agents in these drug classes.

There is good evidence that both aspirin and statin therapy are beneficial for patients with known ASCVD, and that high-intensity statin therapy should be used.

Empagliflozin. The 2015 EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study⁵⁵ was a randomized double-blind study of empagliflozin vs placebo and usual care in patients with diabetes and established CVD. Over a median follow-up of 3.1 years, treatment with empagliflozin reduced the aggregate outcome of MI, stroke, and CV death by 14%, reduced CV deaths by 38%, and decreased deaths from any cause by 32%. In December 2016, the FDA announced a new indication for empagliflozin: to reduce the risk of CV death in adult patients with T2DM and CVD.⁵⁶

Liraglutide. The LEADER (Liraglutide Effect and Action in Diabetes Evaluation of Cardiovascular Outcome Results: A Long Term Evaluation) trial⁵⁷ was a double-blind randomized trial of liraglutide vs placebo added to usual care in patients with T2DM at high risk for CVD or with existing CVD. More than 80% of the participants had existing CVD including a history of prior MI, cerebrovascular disease, or peripheral vascular disease. After a median follow-up of 3.8 years, the group taking liraglutide demonstrated a 13% reduction in the composite outcome of MI, stroke, or CV death, a 22% reduction in CV death, and a 15% reduction in death from any cause, compared with placebo.⁵⁷

CORRESPONDENCE
Neil Skolnik, MD, Abington-Jefferson Health, 500 Old York Rd, Ste 108, Jenkintown, PA 19046; [email protected].

The authors thank Sarah Bradley, director, professional engagement & collaboration at the American Diabetes Association, for her editorial and organizational assistance in the preparation of this manuscript.

More than 29 million Americans have diabetes, and each year another 1.7 million are given the diagnosis.¹ Prediabetes is even more common; over one-third of US adults ages 20 years and older, and more than half of those who are ages 65 and older, have attained this precursor status, representing another 86 million Americans.¹

Because the evidence base for the management of diabetes is rapidly expanding, the American Diabetes Association’s (ADA) Professional Practice Committee updates its Standards of Medical Care in Diabetes annually to incorporate new evidence into its recommendations. The 2017 Standards of Care are available at: professional.diabetes.org/jfp.²

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality for people with diabetes, and is the largest contributor to the direct and indirect costs of the disease.² As a result, all patients with diabetes should have cardiovascular (CV) risk factors, including dyslipidemia, hypertension, smoking, a family history of premature coronary disease, and the presence of albuminuria, assessed at least annually.² Numerous studies have demonstrated the efficacy of controlling individual CV risk factors in preventing or slowing ASCVD in people with diabetes. Even larger benefits, including reduced ASCVD morbidity and mortality, can be achieved when multiple risk factors are addressed simultaneously.³

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality for the 29 million Americans with diabetes, and is the largest contributor to the direct and indirect costs of diabetes.

To hone your management of CV risks in patients with diabetes, we’ve put together this Q&A pointing out the elements of the ADA’s 2017 Standards of Care that are most relevant to the management of patients at risk for, or with established, ASCVD.

Screening

Since ASCVD so commonly co-occurs with diabetes, should I routinely screen asymptomatic patients with diabetes for heart disease?

No. The current evidence suggests that outcomes are NOT improved by screening people before they develop symptoms of ASCVD,⁴ and widespread ASCVD screening has not been shown to be cost-effective. Cardiac testing should be reserved for those with typical or atypical symptoms or those with an abnormal resting electrocardiogram (EKG).

Lifestyle modification

What are the benefits of lifestyle interventions?

The benefits include not only lost pounds, but improved mobility, physical and sexual functioning, and health-related quality of life. Recommend that all overweight patients with diabetes take advantage of intensive lifestyle interventions focusing on weight loss through decreased caloric intake and increased physical activity as per the Look AHEAD (Action for Health in Diabetes) trial.⁵ Although the intensive lifestyle intervention in the Look AHEAD trial did not decrease CV outcomes over 10 years of follow-up, it did improve control of CV risk factors and led to people in the intervention group taking fewer glucose-, blood pressure (BP)-, and lipid-lowering medications than those in the standard care group.

There is no one diet that is recommended for all people with diabetes. Weight reduction often requires intensive intervention. In order for weight loss diets to be sustainable, they must include patient preferences.

People with diabetes should be encouraged to receive individualized medical nutrition therapy (MNT), preferably from a registered dietitian who is well versed in nutritional management for diabetes. Such MNT is associated with a 0.5% to 2% decrease in A1c levels for people with type 2 diabetes.^6-9 Specific healthy diets include the Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and plant-based diets.

A new lifestyle recommendation in this year’s ADA Standards is that periods of prolonged sitting should be interrupted every 30 minutes with a period of physical activity. This appears to have glycemic benefits.²

Hypertension/BP management

When should I initiate hypertension treatment in patients with diabetes?

Nonpharmacologic therapy is reasonable in people with diabetes and mildly elevated BP (>120/80 mm Hg). If systolic blood pressure (SBP) is confirmed to be >140 mm Hg and/or diastolic blood pressure (DBP) is confirmed to be >90 mm Hg, the ADA recommends initiating pharmacologic therapy along with nonpharmacologic strategies. For patients with confirmed office-based BP >160/100 mm Hg, the ADA advises initiating lifestyle modifications as well as 2 pharmacologic medications (or a single pill combination of agents).²

What is the recommended BP target for patients with diabetes and hypertension?

These patients should be treated with a combination of measures, including lifestyle modification and pharmacologic therapy, to a target BP of <140/90 mm Hg. Randomized controlled trials (RCTs) have shown benefits with this target in terms of a reduction in the incidence of coronary heart disease (CHD) events, stroke, and diabetic kidney disease.^10,11

A 2012 meta-analysis of randomized trials involving adults with type 2 diabetes mellitus (T2DM) and comparing intensive BP targets (≤130 mm Hg SBP and ≤80 mm Hg DBP) with standard targets (≤140-160 mm Hg SBP and ≤85-100 mm Hg DBP) found no significant reduction in mortality or nonfatal MIs associated with more intense BP control. There was a statistically significant 35% relative risk (RR) reduction in stroke with intensive targets, but lower BP was also associated with an increased risk of hypotension and syncope.¹²

A new lifestyle recommendation in this year’s ADA Standards states that periods of prolonged sitting should be interrupted every 30 minutes with a period of physical activity.

The 2010 Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,¹³ which randomized 5518 patients with T2DM at high risk for ASCVD to either a target SBP of <120 mm Hg or 130 to 140 mm Hg, found that the patients with the lower SBP target did not benefit in the primary end point (a composite of nonfatal MI, nonfatal stroke, and CV death), but did benefit from nominally significant lower rates of total stroke and nonfatal stroke.

Based on these data, the ADA Standards of Care suggest that, “more intensive BP control may be reasonable in certain motivated, ACCORD-like patients (40-79 years of age with prior evidence of CVD or multiple CV risk factors) who have been educated about the added treatment burden, side effects, and costs of more intensive BP control and for patients who prefer to lower their risk of stroke beyond what can be achieved with usual care.”

Another major study, the 2015 Systolic Blood Pressure Intervention Trial (SPRINT) trial,¹⁴ demonstrated that treating patients with hypertension to a target SBP <120 mm Hg compared to the usual target of <140 mm Hg resulted in a 25% lower RR of the primary outcome (a composite of MI, other acute coronary syndromes, stroke, heart failure, or death from CV causes) and about a 25% reduction in all-cause mortality; however, people with diabetes were not included in the trial, so the applicability of the results to decisions about BP management in patients with diabetes is not known.

In people with diabetes at high risk for ASCVD and/or with albuminuria, ACE inhibitors and ARBs do reduce ASCVD outcomes and the progression of kidney disease.

A 2015 systematic review and meta-analysis of over 100,000 participants looked at SBP lowering in adults with T2DM and found that each 10-mm Hg reduction in SBP was associated with a significantly lower risk of morbidity, CV events, CHD, stroke, albuminuria, and retinopathy.¹⁰ When trials were stratified by mean baseline SBP (<140 mm Hg or ≥140 mm Hg), RRs for outcomes other than stroke, retinopathy, and renal failure were lower in studies with greater baseline SBP.

The latest ADA Standards of Care recommend that a lower BP target of 130/80 mm Hg may be appropriate for patients at high risk of CVD if this target can be achieved without undue treatment burden. A DBP of <80 mm Hg may also be appropriate in certain patients including those with a long life expectancy, CKD, elevated urinary albumin excretion, and those with evidence of CVD or associated risk factors.¹⁵ Of note, treating older adults with diabetes to an SBP target of <130 mm Hg has not been shown to improve cardiovascular outcomes,¹⁶ and treating to a diastolic target of <70 mm Hg has been associated with a greater risk of mortality.¹⁷

What are the current recommended treatment options?

Treatment for hypertension in adults with diabetes without albuminuria should include any of the classes of medications demonstrated to reduce CV events in patients with diabetes, such as:

• angiotensin-converting enzyme (ACE) inhibitors,
• angiotensin receptor blockers (ARBs),
• thiazide-like diuretics, and
• dihydropyridine calcium channel blockers.

These recommendations are based on evidence suggesting the lack of superiority of ACE inhibitors and ARBs over other classes of antihypertensive agents for the prevention of CV outcomes in all patients with diabetes.¹⁸ However, in people with diabetes at high risk for ASCVD and/or with albuminuria, ACE inhibitors and ARBs do reduce ASCVD outcomes and the progression of kidney disease.^19-24 Thus, ACE inhibitors and ARBs continue to be recommended as first-line medications for the treatment of hypertension in patients with diabetes and urine albumin/creatinine ratios ≥30 mg/g, as these medications are associated with a reduction in the rate of kidney disease progression.

The use of both an ACE inhibitor and an ARB in combination is not recommended.^25,26 For patients treated with ACE inhibitors, ARBs, or diuretics, serum creatinine/estimated glomerular filtration rate (eGFR) and serum potassium levels should be monitored.

What are the recommended lifestyle modifications for patients with diabetes and hypertension?

Regular exercise and healthy eating are recommended for all people with diabetes to optimize glycemic control and lose weight (if they are overweight or obese). For patients with hypertension, the DASH diet (available at: https://www.nhlbi.nih.gov/health/health-topics/topics/dash/) is effective at lowering BP. The DASH diet emphasizes reducing sodium intake, increasing potassium intake, limiting alcohol intake, and increasing physical activity. Specifically, sodium intake should be restricted to <2300 mg/d and patients should consume approximately 8 to 10 servings of fruits and vegetables per day and 2 to 3 servings of low-fat dairy per day. Alcohol should be limited to 2 drinks per day for men and one drink per day for women.

People with diabetes who have hypertension should be treated with lifestyle modification and pharmacologic therapy to a target blood pressure of <140/90 mm Hg.

Most adults with diabetes should perform 150 minutes per week of moderate to vigorous exercise, spread over at least 3 days/week. In addition, it is recommended that resistance exercises be performed at least 2 to 3 days/week. Prolonged inactivity is detrimental to health and should be interrupted with activity every 30 minutes.²⁷

Finally, as a part of lifestyle management for all patients with diabetes, smoking cessation is important, as is attention to stress, depression, and anxiety.

Is there an advantage to nighttime dosing of antihypertensive medications?

Yes. Growing evidence suggests that there is an ASCVD benefit to avoiding nocturnal BP dipping. A 2011 RCT of 448 participants with T2DM and hypertension showed a decrease in CV events and mortality during 5.4 years of follow-up if at least one antihypertensive medication was taken at bedtime.²⁸ As a result of this and other evidence,²⁹ consider administering one or more antihypertensive medications at bedtime, although this is not a formal recommendation in the ADA Standards of Care.

Are there any additional issues to be aware of when treating patients with diabetes and hypertension?

Yes. Sometimes patients who have had diabetes for many years have significant orthostatic hypotension secondary to autonomic neuropathy. Postural changes in BP and pulse may require adjustment of BP targets. Home BP self-monitoring and 24-hour ambulatory BP monitoring may indicate white-coat or masked hypertension.

Lipid management

What is the current evidence for lipid treatment in diabetes?

Lipid abnormalities are common in people with diabetes and contribute to the overall high risk of ASCVD in these patients. Subgroup analyses of patients in large trials with diabetes³⁰ and trials involving patients with diabetes³¹ have shown significant improvements in primary and secondary prevention of ASCVD with statin use. A 2008 meta-analysis of 18,686 people with diabetes showed a 9% reduction in all-cause mortality and a 13% reduction in vascular mortality for each 39-mg/dL reduction in low-density lipoprotein (LDL) cholesterol.³² Absolute reductions in mortality are greatest in those with highest risk, but the benefits of statin therapy are clear for low- and moderate-risk individuals with diabetes, too.^33,34 As a result, statins are the medications of choice for lipid lowering and CV risk reduction and should be used in addition to lifestyle management.

Who should get a statin, and how do I choose the optimum dosage?

Patients ages 40 to 75 years with diabetes but without additional ASCVD risk factors should receive a moderate-intensity statin, according to the ADA (see TABLES 1² and 2²). For those with additional CV risk factors, a high-intensity statin should be considered. The American College of Cardiology/American Heart Association ASCVD risk calculator (available at: http://www.cvriskcalculator.com/) may be useful for some patients, but generally, risk is already known to be high for most patients with diabetes. For patients of all ages with diabetes and established ASCVD, high-intensity statin therapy should be added to lifestyle modifications.^35-37

For patients with diabetes who are <40 years with additional ASCVD risk factors, few clinical trial data exist; nevertheless, consider a moderate- or high-intensity statin and lifestyle therapy. Similarly, for patients >75 years who have diabetes and no additional ASCVD risk factors, consider a moderate-intensity statin and lifestyle modifications. For older adults with additional ASCVD risk factors, consider high-intensity statin therapy.^35-37

Statins and cognition. It should be noted that published data have not demonstrated an adverse effect of statins on cognition.³⁸ Statins, however, have been linked to an increased risk of developing diabetes,^39,40 although the absolute increase in risk is small, and much smaller than the benefit derived from preventing the development of coronary disease.

Should total cholesterol and LDL levels be used as targets with statin treatment?

No. Statin doses have primarily been tested against placebo in clinical trials, rather than testing to specific target LDL levels, suggesting that the initiation and intensification of statin therapy be based on a patient’s risk profile.³⁵ When maximally tolerated doses of statins do not lower LDL cholesterol by more than 30% from the patient’s baseline, there is currently no good evidence that combination therapy would be helpful, so regular monitoring of lipid levels has limited value. A lipid profile that includes levels of total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides should be obtained at initial medical evaluation, at diagnosis of diabetes, and every 5 years thereafter or before the initiation of statin therapy. Ongoing testing may be appropriate in individual circumstances and to monitor for adherence to, or efficacy of, therapy.

What should I do for my patients who can’t tolerate statins?

Try a lower dose or a different statin before eliminating the class. Research has shown that even small doses (eg, rosuvastatin 5 mg) have some benefit.⁴¹

How do combination treatments figure into the current treatment of lipids in patients with diabetes?

It depends on the agent and the patient’s profile.

Fenofibrate. The ADA does not recommend automatically adding fenofibrate to statin therapy because the combination is associated with increased risks for abnormal transaminase levels, myositis, and rhabdomyolysis. In the ACCORD trial, the combination of fenofibrate and simvastatin did not reduce the rate of fatal CV events, nonfatal MIs, or nonfatal strokes compared with simvastatin alone.⁴²

Recommend statin therapy to all patients with diabetes over age 40; use a moderate- or high-intensity agent depending upon the degree of cardiac risk.

That said, a subgroup analysis suggested a benefit for men with both a triglyceride level ≥204 mg/dL (2.3 mmol/L) and an HDL cholesterol level ≤34 mg/dL (0.9 mmol/L).⁴² For this reason, the combination of a statin and fenofibrate may be considered for men who meet these laboratory parameters. In addition, consider medical therapy for triglyceride levels ≥500 mg/dL to reduce the risk of pancreatitis.

Ezetimibe. Recommendations regarding ezetimibe are based on the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), a 2015 RCT including over 18,000 patients that compared treatment with ezetimibe and simvastatin to simvastatin alone.⁴³ Individuals in the trial were ≥50 years of age and had experienced an ACS within the preceding 10 days. In those with diabetes, the combination of moderate-intensity simvastatin (40 mg) and ezetimibe (10 mg) significantly reduced major adverse CV events with an absolute risk reduction of 5% (40% vs 45%) and an RR reduction of 14% over moderate-intensity simvastatin (40 mg) alone.

Based on these results, patients with diabetes and a recent ACS should be considered for combination therapy with ezetimibe and a moderate-intensity statin. The combination should also be considered in patients with diabetes and a history of ASCVD who cannot tolerate high-intensity statins.⁴³

Recommend daily aspirin therapy to patients ages ≥50 years who have diabetes and at least one additional cardiovascular risk factor, but no bleeding risk.

Niacin. The ADA currently does not recommend niacin in combination with a statin because of lack of efficacy on major ASCVD outcomes, possible increased risk of ischemic stroke, and adverse effects.⁴⁴

What are the recommendations for the use of PCSK-9 inhibitors?

Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors (ie, evolucumab and alirocumab) may be considered as adjunctive therapy to statins for patients with diabetes at high risk for ASCVD events who require additional lowering of LDL cholesterol. They may also be considered for those in whom high-intensity statin therapy is indicated, but not tolerated.

Antiplatelet agents

Who should take aspirin for primary prevention of CVD?

Both women and men ages ≥50 years who have diabetes and at least one additional CV risk factor (family history of premature ASCVD, hypertension, tobacco use, dyslipidemia, or albuminuria) should consider taking daily aspirin therapy (75-162 mg/d) if they do not have an excessive bleeding risk.^45,46 The most common dose in the United States is 81 mg. This recommendation is supported by a 2010 consensus statement of the American Diabetes Association, American Heart Association, and the American College of Cardiology.⁴⁷

Should patients with diabetes and heart disease receive antiplatelet therapy?

Yes. The evidence is clear that people with known diabetes and ASCVD benefit from aspirin therapy, according to the 2017 Standards of Care. Clopidogrel 75 mg/d is an appropriate alternative for patients who are allergic to aspirin. Dual antiplatelet therapy (a P2Y12 receptor antagonist and aspirin) should be used for as long as one year after an ACS and may have benefits beyond this period.⁴⁸

Established heart disease

Are there specific recommendations for patients with diabetes and CHD?

According to the ADA Standards, there is good evidence that both aspirin and statin therapy are beneficial for patients with known ASCVD, and that high-intensity statin therapy should be used. In addition, consider ACE inhibitors to reduce the future risk of CV events. In patients with a prior MI, continue beta-blocker therapy for at least 2 years post event.⁴⁹

Which medications should I avoid, or approach with caution, in patients with congestive heart failure (CHF)?

Thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, and metformin all require careful attention. This is especially important to know when you consider that almost half of all patients with T2DM will develop heart failure.⁵⁰

Thiazolidinediones. The 2017 Standards of Care state that patients with diabetes and symptomatic congestive heart failure should not receive thiazolidinediones, as they can worsen heart failure status via fluid retention. As such, they are contraindicated in patients with class III and IV heart failure.⁵¹

DPP-4 inhibitors. The studies on DPP-4 inhibitors and heart failure have had mixed results. The 2013 SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction) 53 trial⁵² showed that patients treated with saxagliptin were more likely to be hospitalized for heart failure than those taking placebo (3.5% vs 2.8%, respectively). However, the 2015 EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin vs Standard of Care)⁵³ trial and the 2015 TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin)⁵⁴ trial evaluated heart failure and mortality outcomes in patients with alogliptin and sitagliptin, respectively, compared to placebo, and did not show a relationship to heart failure.

Metformin may be used in people who have T2DM and stable CHF if their eGFR remains >30 mL/min; it should be withheld from patients with unstable heart failure and those who are hospitalized with CHF.

Are there antihyperglycemic medications that reduce CV morbidity and mortality in those with established ASCVD?

Yes. This year’s ADA Standards indicate that certain glucose-lowering medications—specifically empagliflozin (a sodium–glucose cotransporter [SGLT]-2 inhibitor) and liraglutide (a glucagon-like peptide [GLP]-1 receptor agonist)—have been shown to be beneficial for those with established CVD. According to the 2017 Standards of Care, “In patients with longstanding suboptimally controlled T2DM and established ASCVD, empagliflozin or liraglutide should be considered, as they have been shown to reduce CV and all-cause mortality when added to standard care.”² The studies that provide support for their use are summarized below. Ongoing studies are investigating the CV effects of other agents in these drug classes.

There is good evidence that both aspirin and statin therapy are beneficial for patients with known ASCVD, and that high-intensity statin therapy should be used.

Empagliflozin. The 2015 EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study⁵⁵ was a randomized double-blind study of empagliflozin vs placebo and usual care in patients with diabetes and established CVD. Over a median follow-up of 3.1 years, treatment with empagliflozin reduced the aggregate outcome of MI, stroke, and CV death by 14%, reduced CV deaths by 38%, and decreased deaths from any cause by 32%. In December 2016, the FDA announced a new indication for empagliflozin: to reduce the risk of CV death in adult patients with T2DM and CVD.⁵⁶

Liraglutide. The LEADER (Liraglutide Effect and Action in Diabetes Evaluation of Cardiovascular Outcome Results: A Long Term Evaluation) trial⁵⁷ was a double-blind randomized trial of liraglutide vs placebo added to usual care in patients with T2DM at high risk for CVD or with existing CVD. More than 80% of the participants had existing CVD including a history of prior MI, cerebrovascular disease, or peripheral vascular disease. After a median follow-up of 3.8 years, the group taking liraglutide demonstrated a 13% reduction in the composite outcome of MI, stroke, or CV death, a 22% reduction in CV death, and a 15% reduction in death from any cause, compared with placebo.⁵⁷

CORRESPONDENCE
Neil Skolnik, MD, Abington-Jefferson Health, 500 Old York Rd, Ste 108, Jenkintown, PA 19046; [email protected].

The authors thank Sarah Bradley, director, professional engagement & collaboration at the American Diabetes Association, for her editorial and organizational assistance in the preparation of this manuscript.

More than 29 million Americans have diabetes, and each year another 1.7 million are given the diagnosis.¹ Prediabetes is even more common; over one-third of US adults ages 20 years and older, and more than half of those who are ages 65 and older, have attained this precursor status, representing another 86 million Americans.¹

Because the evidence base for the management of diabetes is rapidly expanding, the American Diabetes Association’s (ADA) Professional Practice Committee updates its Standards of Medical Care in Diabetes annually to incorporate new evidence into its recommendations. The 2017 Standards of Care are available at: professional.diabetes.org/jfp.²

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality for people with diabetes, and is the largest contributor to the direct and indirect costs of the disease.² As a result, all patients with diabetes should have cardiovascular (CV) risk factors, including dyslipidemia, hypertension, smoking, a family history of premature coronary disease, and the presence of albuminuria, assessed at least annually.² Numerous studies have demonstrated the efficacy of controlling individual CV risk factors in preventing or slowing ASCVD in people with diabetes. Even larger benefits, including reduced ASCVD morbidity and mortality, can be achieved when multiple risk factors are addressed simultaneously.³

Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality for the 29 million Americans with diabetes, and is the largest contributor to the direct and indirect costs of diabetes.

To hone your management of CV risks in patients with diabetes, we’ve put together this Q&A pointing out the elements of the ADA’s 2017 Standards of Care that are most relevant to the management of patients at risk for, or with established, ASCVD.

Screening

Since ASCVD so commonly co-occurs with diabetes, should I routinely screen asymptomatic patients with diabetes for heart disease?

No. The current evidence suggests that outcomes are NOT improved by screening people before they develop symptoms of ASCVD,⁴ and widespread ASCVD screening has not been shown to be cost-effective. Cardiac testing should be reserved for those with typical or atypical symptoms or those with an abnormal resting electrocardiogram (EKG).

Lifestyle modification

What are the benefits of lifestyle interventions?

The benefits include not only lost pounds, but improved mobility, physical and sexual functioning, and health-related quality of life. Recommend that all overweight patients with diabetes take advantage of intensive lifestyle interventions focusing on weight loss through decreased caloric intake and increased physical activity as per the Look AHEAD (Action for Health in Diabetes) trial.⁵ Although the intensive lifestyle intervention in the Look AHEAD trial did not decrease CV outcomes over 10 years of follow-up, it did improve control of CV risk factors and led to people in the intervention group taking fewer glucose-, blood pressure (BP)-, and lipid-lowering medications than those in the standard care group.

There is no one diet that is recommended for all people with diabetes. Weight reduction often requires intensive intervention. In order for weight loss diets to be sustainable, they must include patient preferences.

People with diabetes should be encouraged to receive individualized medical nutrition therapy (MNT), preferably from a registered dietitian who is well versed in nutritional management for diabetes. Such MNT is associated with a 0.5% to 2% decrease in A1c levels for people with type 2 diabetes.^6-9 Specific healthy diets include the Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and plant-based diets.

A new lifestyle recommendation in this year’s ADA Standards is that periods of prolonged sitting should be interrupted every 30 minutes with a period of physical activity. This appears to have glycemic benefits.²

Hypertension/BP management

When should I initiate hypertension treatment in patients with diabetes?

Nonpharmacologic therapy is reasonable in people with diabetes and mildly elevated BP (>120/80 mm Hg). If systolic blood pressure (SBP) is confirmed to be >140 mm Hg and/or diastolic blood pressure (DBP) is confirmed to be >90 mm Hg, the ADA recommends initiating pharmacologic therapy along with nonpharmacologic strategies. For patients with confirmed office-based BP >160/100 mm Hg, the ADA advises initiating lifestyle modifications as well as 2 pharmacologic medications (or a single pill combination of agents).²

What is the recommended BP target for patients with diabetes and hypertension?

These patients should be treated with a combination of measures, including lifestyle modification and pharmacologic therapy, to a target BP of <140/90 mm Hg. Randomized controlled trials (RCTs) have shown benefits with this target in terms of a reduction in the incidence of coronary heart disease (CHD) events, stroke, and diabetic kidney disease.^10,11

A 2012 meta-analysis of randomized trials involving adults with type 2 diabetes mellitus (T2DM) and comparing intensive BP targets (≤130 mm Hg SBP and ≤80 mm Hg DBP) with standard targets (≤140-160 mm Hg SBP and ≤85-100 mm Hg DBP) found no significant reduction in mortality or nonfatal MIs associated with more intense BP control. There was a statistically significant 35% relative risk (RR) reduction in stroke with intensive targets, but lower BP was also associated with an increased risk of hypotension and syncope.¹²

A new lifestyle recommendation in this year’s ADA Standards states that periods of prolonged sitting should be interrupted every 30 minutes with a period of physical activity.

The 2010 Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,¹³ which randomized 5518 patients with T2DM at high risk for ASCVD to either a target SBP of <120 mm Hg or 130 to 140 mm Hg, found that the patients with the lower SBP target did not benefit in the primary end point (a composite of nonfatal MI, nonfatal stroke, and CV death), but did benefit from nominally significant lower rates of total stroke and nonfatal stroke.

Based on these data, the ADA Standards of Care suggest that, “more intensive BP control may be reasonable in certain motivated, ACCORD-like patients (40-79 years of age with prior evidence of CVD or multiple CV risk factors) who have been educated about the added treatment burden, side effects, and costs of more intensive BP control and for patients who prefer to lower their risk of stroke beyond what can be achieved with usual care.”

Another major study, the 2015 Systolic Blood Pressure Intervention Trial (SPRINT) trial,¹⁴ demonstrated that treating patients with hypertension to a target SBP <120 mm Hg compared to the usual target of <140 mm Hg resulted in a 25% lower RR of the primary outcome (a composite of MI, other acute coronary syndromes, stroke, heart failure, or death from CV causes) and about a 25% reduction in all-cause mortality; however, people with diabetes were not included in the trial, so the applicability of the results to decisions about BP management in patients with diabetes is not known.

In people with diabetes at high risk for ASCVD and/or with albuminuria, ACE inhibitors and ARBs do reduce ASCVD outcomes and the progression of kidney disease.

A 2015 systematic review and meta-analysis of over 100,000 participants looked at SBP lowering in adults with T2DM and found that each 10-mm Hg reduction in SBP was associated with a significantly lower risk of morbidity, CV events, CHD, stroke, albuminuria, and retinopathy.¹⁰ When trials were stratified by mean baseline SBP (<140 mm Hg or ≥140 mm Hg), RRs for outcomes other than stroke, retinopathy, and renal failure were lower in studies with greater baseline SBP.

The latest ADA Standards of Care recommend that a lower BP target of 130/80 mm Hg may be appropriate for patients at high risk of CVD if this target can be achieved without undue treatment burden. A DBP of <80 mm Hg may also be appropriate in certain patients including those with a long life expectancy, CKD, elevated urinary albumin excretion, and those with evidence of CVD or associated risk factors.¹⁵ Of note, treating older adults with diabetes to an SBP target of <130 mm Hg has not been shown to improve cardiovascular outcomes,¹⁶ and treating to a diastolic target of <70 mm Hg has been associated with a greater risk of mortality.¹⁷

What are the current recommended treatment options?

Treatment for hypertension in adults with diabetes without albuminuria should include any of the classes of medications demonstrated to reduce CV events in patients with diabetes, such as:

• angiotensin-converting enzyme (ACE) inhibitors,
• angiotensin receptor blockers (ARBs),
• thiazide-like diuretics, and
• dihydropyridine calcium channel blockers.

These recommendations are based on evidence suggesting the lack of superiority of ACE inhibitors and ARBs over other classes of antihypertensive agents for the prevention of CV outcomes in all patients with diabetes.¹⁸ However, in people with diabetes at high risk for ASCVD and/or with albuminuria, ACE inhibitors and ARBs do reduce ASCVD outcomes and the progression of kidney disease.^19-24 Thus, ACE inhibitors and ARBs continue to be recommended as first-line medications for the treatment of hypertension in patients with diabetes and urine albumin/creatinine ratios ≥30 mg/g, as these medications are associated with a reduction in the rate of kidney disease progression.

The use of both an ACE inhibitor and an ARB in combination is not recommended.^25,26 For patients treated with ACE inhibitors, ARBs, or diuretics, serum creatinine/estimated glomerular filtration rate (eGFR) and serum potassium levels should be monitored.

What are the recommended lifestyle modifications for patients with diabetes and hypertension?

Regular exercise and healthy eating are recommended for all people with diabetes to optimize glycemic control and lose weight (if they are overweight or obese). For patients with hypertension, the DASH diet (available at: https://www.nhlbi.nih.gov/health/health-topics/topics/dash/) is effective at lowering BP. The DASH diet emphasizes reducing sodium intake, increasing potassium intake, limiting alcohol intake, and increasing physical activity. Specifically, sodium intake should be restricted to <2300 mg/d and patients should consume approximately 8 to 10 servings of fruits and vegetables per day and 2 to 3 servings of low-fat dairy per day. Alcohol should be limited to 2 drinks per day for men and one drink per day for women.

People with diabetes who have hypertension should be treated with lifestyle modification and pharmacologic therapy to a target blood pressure of <140/90 mm Hg.

Most adults with diabetes should perform 150 minutes per week of moderate to vigorous exercise, spread over at least 3 days/week. In addition, it is recommended that resistance exercises be performed at least 2 to 3 days/week. Prolonged inactivity is detrimental to health and should be interrupted with activity every 30 minutes.²⁷

Finally, as a part of lifestyle management for all patients with diabetes, smoking cessation is important, as is attention to stress, depression, and anxiety.

Is there an advantage to nighttime dosing of antihypertensive medications?

Yes. Growing evidence suggests that there is an ASCVD benefit to avoiding nocturnal BP dipping. A 2011 RCT of 448 participants with T2DM and hypertension showed a decrease in CV events and mortality during 5.4 years of follow-up if at least one antihypertensive medication was taken at bedtime.²⁸ As a result of this and other evidence,²⁹ consider administering one or more antihypertensive medications at bedtime, although this is not a formal recommendation in the ADA Standards of Care.

Are there any additional issues to be aware of when treating patients with diabetes and hypertension?

Yes. Sometimes patients who have had diabetes for many years have significant orthostatic hypotension secondary to autonomic neuropathy. Postural changes in BP and pulse may require adjustment of BP targets. Home BP self-monitoring and 24-hour ambulatory BP monitoring may indicate white-coat or masked hypertension.

Lipid management

What is the current evidence for lipid treatment in diabetes?

Lipid abnormalities are common in people with diabetes and contribute to the overall high risk of ASCVD in these patients. Subgroup analyses of patients in large trials with diabetes³⁰ and trials involving patients with diabetes³¹ have shown significant improvements in primary and secondary prevention of ASCVD with statin use. A 2008 meta-analysis of 18,686 people with diabetes showed a 9% reduction in all-cause mortality and a 13% reduction in vascular mortality for each 39-mg/dL reduction in low-density lipoprotein (LDL) cholesterol.³² Absolute reductions in mortality are greatest in those with highest risk, but the benefits of statin therapy are clear for low- and moderate-risk individuals with diabetes, too.^33,34 As a result, statins are the medications of choice for lipid lowering and CV risk reduction and should be used in addition to lifestyle management.

Who should get a statin, and how do I choose the optimum dosage?

Patients ages 40 to 75 years with diabetes but without additional ASCVD risk factors should receive a moderate-intensity statin, according to the ADA (see TABLES 1² and 2²). For those with additional CV risk factors, a high-intensity statin should be considered. The American College of Cardiology/American Heart Association ASCVD risk calculator (available at: http://www.cvriskcalculator.com/) may be useful for some patients, but generally, risk is already known to be high for most patients with diabetes. For patients of all ages with diabetes and established ASCVD, high-intensity statin therapy should be added to lifestyle modifications.^35-37

For patients with diabetes who are <40 years with additional ASCVD risk factors, few clinical trial data exist; nevertheless, consider a moderate- or high-intensity statin and lifestyle therapy. Similarly, for patients >75 years who have diabetes and no additional ASCVD risk factors, consider a moderate-intensity statin and lifestyle modifications. For older adults with additional ASCVD risk factors, consider high-intensity statin therapy.^35-37

Statins and cognition. It should be noted that published data have not demonstrated an adverse effect of statins on cognition.³⁸ Statins, however, have been linked to an increased risk of developing diabetes,^39,40 although the absolute increase in risk is small, and much smaller than the benefit derived from preventing the development of coronary disease.

Should total cholesterol and LDL levels be used as targets with statin treatment?

No. Statin doses have primarily been tested against placebo in clinical trials, rather than testing to specific target LDL levels, suggesting that the initiation and intensification of statin therapy be based on a patient’s risk profile.³⁵ When maximally tolerated doses of statins do not lower LDL cholesterol by more than 30% from the patient’s baseline, there is currently no good evidence that combination therapy would be helpful, so regular monitoring of lipid levels has limited value. A lipid profile that includes levels of total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides should be obtained at initial medical evaluation, at diagnosis of diabetes, and every 5 years thereafter or before the initiation of statin therapy. Ongoing testing may be appropriate in individual circumstances and to monitor for adherence to, or efficacy of, therapy.

What should I do for my patients who can’t tolerate statins?

Try a lower dose or a different statin before eliminating the class. Research has shown that even small doses (eg, rosuvastatin 5 mg) have some benefit.⁴¹

How do combination treatments figure into the current treatment of lipids in patients with diabetes?

It depends on the agent and the patient’s profile.

Fenofibrate. The ADA does not recommend automatically adding fenofibrate to statin therapy because the combination is associated with increased risks for abnormal transaminase levels, myositis, and rhabdomyolysis. In the ACCORD trial, the combination of fenofibrate and simvastatin did not reduce the rate of fatal CV events, nonfatal MIs, or nonfatal strokes compared with simvastatin alone.⁴²

Recommend statin therapy to all patients with diabetes over age 40; use a moderate- or high-intensity agent depending upon the degree of cardiac risk.

That said, a subgroup analysis suggested a benefit for men with both a triglyceride level ≥204 mg/dL (2.3 mmol/L) and an HDL cholesterol level ≤34 mg/dL (0.9 mmol/L).⁴² For this reason, the combination of a statin and fenofibrate may be considered for men who meet these laboratory parameters. In addition, consider medical therapy for triglyceride levels ≥500 mg/dL to reduce the risk of pancreatitis.

Ezetimibe. Recommendations regarding ezetimibe are based on the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), a 2015 RCT including over 18,000 patients that compared treatment with ezetimibe and simvastatin to simvastatin alone.⁴³ Individuals in the trial were ≥50 years of age and had experienced an ACS within the preceding 10 days. In those with diabetes, the combination of moderate-intensity simvastatin (40 mg) and ezetimibe (10 mg) significantly reduced major adverse CV events with an absolute risk reduction of 5% (40% vs 45%) and an RR reduction of 14% over moderate-intensity simvastatin (40 mg) alone.

Based on these results, patients with diabetes and a recent ACS should be considered for combination therapy with ezetimibe and a moderate-intensity statin. The combination should also be considered in patients with diabetes and a history of ASCVD who cannot tolerate high-intensity statins.⁴³

Recommend daily aspirin therapy to patients ages ≥50 years who have diabetes and at least one additional cardiovascular risk factor, but no bleeding risk.

Niacin. The ADA currently does not recommend niacin in combination with a statin because of lack of efficacy on major ASCVD outcomes, possible increased risk of ischemic stroke, and adverse effects.⁴⁴

What are the recommendations for the use of PCSK-9 inhibitors?

Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors (ie, evolucumab and alirocumab) may be considered as adjunctive therapy to statins for patients with diabetes at high risk for ASCVD events who require additional lowering of LDL cholesterol. They may also be considered for those in whom high-intensity statin therapy is indicated, but not tolerated.

Antiplatelet agents

Who should take aspirin for primary prevention of CVD?

Both women and men ages ≥50 years who have diabetes and at least one additional CV risk factor (family history of premature ASCVD, hypertension, tobacco use, dyslipidemia, or albuminuria) should consider taking daily aspirin therapy (75-162 mg/d) if they do not have an excessive bleeding risk.^45,46 The most common dose in the United States is 81 mg. This recommendation is supported by a 2010 consensus statement of the American Diabetes Association, American Heart Association, and the American College of Cardiology.⁴⁷

Should patients with diabetes and heart disease receive antiplatelet therapy?

Yes. The evidence is clear that people with known diabetes and ASCVD benefit from aspirin therapy, according to the 2017 Standards of Care. Clopidogrel 75 mg/d is an appropriate alternative for patients who are allergic to aspirin. Dual antiplatelet therapy (a P2Y12 receptor antagonist and aspirin) should be used for as long as one year after an ACS and may have benefits beyond this period.⁴⁸

Established heart disease

Are there specific recommendations for patients with diabetes and CHD?

According to the ADA Standards, there is good evidence that both aspirin and statin therapy are beneficial for patients with known ASCVD, and that high-intensity statin therapy should be used. In addition, consider ACE inhibitors to reduce the future risk of CV events. In patients with a prior MI, continue beta-blocker therapy for at least 2 years post event.⁴⁹

Which medications should I avoid, or approach with caution, in patients with congestive heart failure (CHF)?

Thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, and metformin all require careful attention. This is especially important to know when you consider that almost half of all patients with T2DM will develop heart failure.⁵⁰

Thiazolidinediones. The 2017 Standards of Care state that patients with diabetes and symptomatic congestive heart failure should not receive thiazolidinediones, as they can worsen heart failure status via fluid retention. As such, they are contraindicated in patients with class III and IV heart failure.⁵¹

DPP-4 inhibitors. The studies on DPP-4 inhibitors and heart failure have had mixed results. The 2013 SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction) 53 trial⁵² showed that patients treated with saxagliptin were more likely to be hospitalized for heart failure than those taking placebo (3.5% vs 2.8%, respectively). However, the 2015 EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin vs Standard of Care)⁵³ trial and the 2015 TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin)⁵⁴ trial evaluated heart failure and mortality outcomes in patients with alogliptin and sitagliptin, respectively, compared to placebo, and did not show a relationship to heart failure.

Metformin may be used in people who have T2DM and stable CHF if their eGFR remains >30 mL/min; it should be withheld from patients with unstable heart failure and those who are hospitalized with CHF.

Are there antihyperglycemic medications that reduce CV morbidity and mortality in those with established ASCVD?

Yes. This year’s ADA Standards indicate that certain glucose-lowering medications—specifically empagliflozin (a sodium–glucose cotransporter [SGLT]-2 inhibitor) and liraglutide (a glucagon-like peptide [GLP]-1 receptor agonist)—have been shown to be beneficial for those with established CVD. According to the 2017 Standards of Care, “In patients with longstanding suboptimally controlled T2DM and established ASCVD, empagliflozin or liraglutide should be considered, as they have been shown to reduce CV and all-cause mortality when added to standard care.”² The studies that provide support for their use are summarized below. Ongoing studies are investigating the CV effects of other agents in these drug classes.

There is good evidence that both aspirin and statin therapy are beneficial for patients with known ASCVD, and that high-intensity statin therapy should be used.

Empagliflozin. The 2015 EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study⁵⁵ was a randomized double-blind study of empagliflozin vs placebo and usual care in patients with diabetes and established CVD. Over a median follow-up of 3.1 years, treatment with empagliflozin reduced the aggregate outcome of MI, stroke, and CV death by 14%, reduced CV deaths by 38%, and decreased deaths from any cause by 32%. In December 2016, the FDA announced a new indication for empagliflozin: to reduce the risk of CV death in adult patients with T2DM and CVD.⁵⁶

Liraglutide. The LEADER (Liraglutide Effect and Action in Diabetes Evaluation of Cardiovascular Outcome Results: A Long Term Evaluation) trial⁵⁷ was a double-blind randomized trial of liraglutide vs placebo added to usual care in patients with T2DM at high risk for CVD or with existing CVD. More than 80% of the participants had existing CVD including a history of prior MI, cerebrovascular disease, or peripheral vascular disease. After a median follow-up of 3.8 years, the group taking liraglutide demonstrated a 13% reduction in the composite outcome of MI, stroke, or CV death, a 22% reduction in CV death, and a 15% reduction in death from any cause, compared with placebo.⁵⁷

CORRESPONDENCE
Neil Skolnik, MD, Abington-Jefferson Health, 500 Old York Rd, Ste 108, Jenkintown, PA 19046; [email protected].

The authors thank Sarah Bradley, director, professional engagement & collaboration at the American Diabetes Association, for her editorial and organizational assistance in the preparation of this manuscript.

CASE › A 57-year-old man had been experiencing intermittent pain in his left ankle for the past 2.5 years. About 6 weeks before coming to our clinic, his symptoms became significantly worse after playing a pickup game of basketball. At the clinic visit, he reported no other recent injury or trauma to the leg. However, 15 years earlier he had fractured his left ankle and was treated conservatively with a short period in a cast followed by a course of physical therapy. After completing the physical therapy, he noted significant improvement, although he continued to have minor episodes of pain. He felt no instability or mechanical locking but did note a decreased ability to move the ankle. And it felt much stiffer than his right ankle.

Examination of his left ankle revealed tenderness over the anterior aspect at the tibiotalar joint. He also exhibited decreased dorsiflexion and was unable to perform a toe raise. There was no tenderness over the major ligaments, and results of anterior drawer and talar tilt tests were normal. X-rays revealed tibiotalar joint arthritis (FIGURE).

How would you proceed if this were your patient?

Arthritis of the tibiotalar joint, which has an estimated prevalence of approximately 1%, occurs much less frequently than arthritis of the knee or hip joints.¹ This low prevalence is primarily due to the ankle joint’s unique biomechanics and the features of the cartilage within the joint, including its thickness.²

Specifically, the hip and knee joints have greater degrees of freedom than the tibiotalar articulation, which is significantly constrained. The bony congruity between the talus, tibia, and fibula provides inherent stability to the ankle joint, thus protecting against primary osteoarthritis (OA).

Additionally, the large number of ligamentous structures and overall strength of the ligaments provide significant supplemental stability to the ankle joint articulation. Articular cartilage within the ankle joint is thicker than that of the knee and hip (1-1.7 mm). This cartilage also tends to retain its tensile strength with age, unlike cartilage in the hip; the ankle is therefore more resistant to age-related degeneration.³

Pain experienced walking down stairs likely indicates posterior ankle injury; pain going up stairs is likely anterior injury.Metabolic factors also protect against arthritis. Chondrocytes in the ankle are less responsive to inflammatory mediators, including interleukin-1 (IL-1), and therefore produce fewer matrix metalloproteinases.^1,2,4 There are also fewer IL-1 receptors on ankle chondrocytes.

The role of trauma in ankle OA. Given the ankle joint’s inherent stability, the most common cause of ankle OA is trauma,⁴ mainly ankle fracture and, less commonly, ligamentous injury.^5,6 Other rarer causes of ankle arthritis include primary OA, crystalline arthropathy, inflammatory disease, septic arthritis, neuroarthropathy, hemochromatosis, and ochronosis.

The ankle’s characteristics that protect it against primary OA may facilitate the pathogenesis of post-traumatic OA through 2 main mechanisms. First, direct trauma to the chondral surfaces can hasten the onset of progressive degeneration. Second, articular incongruity from a fracture can lead to insidious deterioration. The stiffer cartilage layer may be less adaptable to malalignment, and incongruity may cause secondary instability and chronic overloading. Ultimately, the joint breaks down with associated cartilage wear.^6,7

The importance of the normal ankle’s congruity and stability became clear in the landmark study by Ramsey and colleagues,⁸ showing that the contact area between the talus and the tibia decreases as talar displacement increases laterally. This innate stability explains why the contact area of the ankle joint can bear loads similar to those of the hip and knee, yet does not experience primary OA nearly as often.

A stepwise diagnostic appraisal

Ask these questions. Since most ankle pain results from trauma, ask about any recent or remote injury to the affected ankle. Knowing the type of injury that occurred and the exact treatment, if received, may shed light on the relationship between the injury and current symptoms. Acute traumatic events can cause fractures or injury to various soft-tissue structures traversing the ankle joint. Ankle ligament sprains or tendon strains may result after abnormal rotation of the foot. Alternatively, chronic overuse injuries may lead to tendinopathy in any of the tendons that control motion throughout the foot and ankle or degenerative changes within the tibiotalar joint. Knowing the exact location of pain may also help identify the pathology (TABLE 1).

The patient in our case had not suffered a recent injury, so it was important to learn as much as possible about his prior fracture. Was the injury treated conservatively or surgically? If management was conservative, the type and duration of treatment could offer clues to the mechanism underlying symptoms. If a patient has undergone surgery, knowledge of the exact procedure could suggest specific problems. For example, surgical fixation would likely indicate there was ankle instability, thus altering the normal biomechanics in the injured tibiotalar joint.

Other key questions to ask. Most patients with ankle pain also complain of limitations in their usual activities. Ask about the duration and type of pain and other symptoms. Also ask about the position of the foot and ankle when the pain is at its greatest, which will provide insight into likely areas of pathology. For example, if pain arises when the patient navigates uneven ground, subtalar pathology is highly likely. If the patient complains of pain while walking down stairs, suspect injury to the posterior (plantar flexed) ankle; pain while walking up stairs more likely indicates anterior (dorsiflexed) pathology.

Finally, ask about nonorthopedic medical problems and all medications being taken. Systemic conditions, too, can lead to ankle pain—eg, inflammatory arthropathies, infections, and crystalline arthropathy.

Physical examination. Observe the patient’s gait to assess any functional or range-of-motion limitations or abnormal loading throughout the foot and ankle.⁹ With the patient standing, evaluate any malalignment from the foot through the knees and to the hips. Evaluate the skin for any lesions, wounds, or evidence of trauma or surgery. Next, with the patient seated, examine carefully for neuropathy or vascular abnormalities. Evaluate the ankle’s range of motion and assess for any mechanical locking, clicking, or crepitus. Palpate all bony and ligamentous landmarks to reveal areas of tenderness or swelling. Perform anterior drawer and varus tilt tests to determine overall ligamentous stability of the ankle, and compare your findings with test results of the opposite, uninjured ankle.

Diagnostic imaging. Order weight-bearing radiographs of the foot and ankle. Including the foot allows you to identify additional potential concerns such as malalignment, deformity, or adjacent joint arthritis. Look particularly for joint space narrowing, malalignment, post-traumatic changes, or implanted hardware. Advanced imaging studies—computerized tomography, magnetic resonance imaging, bone scan—are reserved for cases that necessitate ruling out alternative diagnoses, or for preoperative evaluation by an orthopedic surgeon.

Management: Make use of multiple modalities

Conservative management options for ankle OA are limited, and high-quality evidence of efficacy is lacking. Surgical alternatives, however, are invasive and yield modest outcomes. Therefore, unless specific indications for surgery are present, exhaust conservative options (TABLE 2) before considering referral.

Weight loss is important for those who are overweight—as with knee OA management—to decrease the reactive forces within the ankle joint and to decrease pain. Weight loss will also enhance the outcomes of other treatment modalities and improve overall health.^10,11

Activity modification is usually required, even though this may make weight loss more difficult. Avoiding vigorous activities, restricting work-related movements that place high-impact stress on the ankle, and decreasing overall walking time often reduce the severity of symptoms and improve functioning in other activities. Use of assistive-devices, such as a cane, can decrease the weight-bearing load on the affected joint.^10,11

Physical therapy has not been shown to alleviate pain in ankle arthritis, although stretching, joint mobilization, and gait training may help prevent further progression of arthritis and improve function.¹¹ The strength of dorsiflexion and plantar-flexion muscles is often decreased in individuals with ankle arthritis. Strengthening exercises may be indicated in individuals exhibiting deficits.

Prescriptive conservative management. Begin with a combination, as needed, of anti-inflammatory medications, orthotic devices, and footwear modifications.

Nonsteroidal anti-inflammatory agents are generally safe, but long-term use requires monitoring. Intra-articular steroid injections have some supporting evidence of effectiveness, but any benefit is short-lived.¹² Glucosamine and chondroitin, although unlikely to cause harm, are not supported by the evidence for use in ankle arthritis. Intra-articular viscosupplementation is controversial, and evidence is limited regarding its efficacy.^13-15 And currently, insurance will not cover viscosupplementaton for any joint other than the knee.

The evidence does not support the use of glucosamine or chondroitin for use in ankle arthritis.Adding a rocker-bottom sole and a solid ankle cushion heel to a shoe helps decrease heel strike impact in individuals with decreased ankle motion, and they aid in the transition from the heel strike to the push-off during level walking.¹¹ If the arthritic joint is unstable, a lace-up ankle support may help with proprioception and stability. A polypropylene ankle-foot orthosis, custom leather ankle corset, or a double-upright brace with a patellar-tendon-bearing support are options to restrict ankle motion and decrease weight-bearing forces.^10,11

Immobilization is not recommended except for short-term use during an arthritic flare. Limiting ankle motion reduces pain, but the downside tradeoff is acquired stiffness and weakness that accompanies prolonged periods of immobilization. A controlled ankle motion walking boot or walking plaster cast are both reasonable options for the short term.

Consider surgical referral for specific indications such as osteophytes, loose bodies, and chondral defects, which may be treated with arthroscopy. Patients with large areas of exposed chondral bone or rapid onset of degeneration have poorer outcomes with conservative management and should also be referred to a surgeon earlier. Otherwise, consider surgical referral only after a full trial of conservative management.¹¹

Surgical options vary in scope and effectiveness and include osteotomy, arthrodesis, and arthroplasty. Osteotomies can be performed in early OA to correct bony alignment deformities. Arthrodesis in neutral dorsiflexion with roughly 5 degrees of external rotation is reserved for end-stage ankle OA to allow for near normal gait and pain relief. Total ankle arthroplasty is an emerging option for severe ankle OA, resulting in improved pain relief, gait, and patient satisfaction, but potentially has a higher reoperation rate when compared with arthrodesis.^1,2

CASE › We prescribed short-term immobilization with a controlled ankle motion boot and administered an intra-articular corticosteroid injection. At the patient’s follow-up visit 6 weeks later, he reported only moderate improvement in pain. We then advised physical therapy at a specialty ankle rehabilitation program to focus on mobilization, strengthening, and gait training. Nearly one year after his initial visit to our clinic, he is doing well. He understands, however, that the nature of his ankle arthrosis may necessitate surgical intervention in the future.

CORRESPONDENCE
Adam Bitterman, DO, Department of Orthopedic Surgery, Hofstra Northwell School of Medicine at Huntington Hospital, 155 East Main Street, Huntington, NY 11743; [email protected].

CASE › A 57-year-old man had been experiencing intermittent pain in his left ankle for the past 2.5 years. About 6 weeks before coming to our clinic, his symptoms became significantly worse after playing a pickup game of basketball. At the clinic visit, he reported no other recent injury or trauma to the leg. However, 15 years earlier he had fractured his left ankle and was treated conservatively with a short period in a cast followed by a course of physical therapy. After completing the physical therapy, he noted significant improvement, although he continued to have minor episodes of pain. He felt no instability or mechanical locking but did note a decreased ability to move the ankle. And it felt much stiffer than his right ankle.

Examination of his left ankle revealed tenderness over the anterior aspect at the tibiotalar joint. He also exhibited decreased dorsiflexion and was unable to perform a toe raise. There was no tenderness over the major ligaments, and results of anterior drawer and talar tilt tests were normal. X-rays revealed tibiotalar joint arthritis (FIGURE).

How would you proceed if this were your patient?

Arthritis of the tibiotalar joint, which has an estimated prevalence of approximately 1%, occurs much less frequently than arthritis of the knee or hip joints.¹ This low prevalence is primarily due to the ankle joint’s unique biomechanics and the features of the cartilage within the joint, including its thickness.²

Specifically, the hip and knee joints have greater degrees of freedom than the tibiotalar articulation, which is significantly constrained. The bony congruity between the talus, tibia, and fibula provides inherent stability to the ankle joint, thus protecting against primary osteoarthritis (OA).

Additionally, the large number of ligamentous structures and overall strength of the ligaments provide significant supplemental stability to the ankle joint articulation. Articular cartilage within the ankle joint is thicker than that of the knee and hip (1-1.7 mm). This cartilage also tends to retain its tensile strength with age, unlike cartilage in the hip; the ankle is therefore more resistant to age-related degeneration.³

Pain experienced walking down stairs likely indicates posterior ankle injury; pain going up stairs is likely anterior injury.Metabolic factors also protect against arthritis. Chondrocytes in the ankle are less responsive to inflammatory mediators, including interleukin-1 (IL-1), and therefore produce fewer matrix metalloproteinases.^1,2,4 There are also fewer IL-1 receptors on ankle chondrocytes.

The role of trauma in ankle OA. Given the ankle joint’s inherent stability, the most common cause of ankle OA is trauma,⁴ mainly ankle fracture and, less commonly, ligamentous injury.^5,6 Other rarer causes of ankle arthritis include primary OA, crystalline arthropathy, inflammatory disease, septic arthritis, neuroarthropathy, hemochromatosis, and ochronosis.

The ankle’s characteristics that protect it against primary OA may facilitate the pathogenesis of post-traumatic OA through 2 main mechanisms. First, direct trauma to the chondral surfaces can hasten the onset of progressive degeneration. Second, articular incongruity from a fracture can lead to insidious deterioration. The stiffer cartilage layer may be less adaptable to malalignment, and incongruity may cause secondary instability and chronic overloading. Ultimately, the joint breaks down with associated cartilage wear.^6,7

The importance of the normal ankle’s congruity and stability became clear in the landmark study by Ramsey and colleagues,⁸ showing that the contact area between the talus and the tibia decreases as talar displacement increases laterally. This innate stability explains why the contact area of the ankle joint can bear loads similar to those of the hip and knee, yet does not experience primary OA nearly as often.

A stepwise diagnostic appraisal

Ask these questions. Since most ankle pain results from trauma, ask about any recent or remote injury to the affected ankle. Knowing the type of injury that occurred and the exact treatment, if received, may shed light on the relationship between the injury and current symptoms. Acute traumatic events can cause fractures or injury to various soft-tissue structures traversing the ankle joint. Ankle ligament sprains or tendon strains may result after abnormal rotation of the foot. Alternatively, chronic overuse injuries may lead to tendinopathy in any of the tendons that control motion throughout the foot and ankle or degenerative changes within the tibiotalar joint. Knowing the exact location of pain may also help identify the pathology (TABLE 1).

The patient in our case had not suffered a recent injury, so it was important to learn as much as possible about his prior fracture. Was the injury treated conservatively or surgically? If management was conservative, the type and duration of treatment could offer clues to the mechanism underlying symptoms. If a patient has undergone surgery, knowledge of the exact procedure could suggest specific problems. For example, surgical fixation would likely indicate there was ankle instability, thus altering the normal biomechanics in the injured tibiotalar joint.

Other key questions to ask. Most patients with ankle pain also complain of limitations in their usual activities. Ask about the duration and type of pain and other symptoms. Also ask about the position of the foot and ankle when the pain is at its greatest, which will provide insight into likely areas of pathology. For example, if pain arises when the patient navigates uneven ground, subtalar pathology is highly likely. If the patient complains of pain while walking down stairs, suspect injury to the posterior (plantar flexed) ankle; pain while walking up stairs more likely indicates anterior (dorsiflexed) pathology.

Finally, ask about nonorthopedic medical problems and all medications being taken. Systemic conditions, too, can lead to ankle pain—eg, inflammatory arthropathies, infections, and crystalline arthropathy.

Physical examination. Observe the patient’s gait to assess any functional or range-of-motion limitations or abnormal loading throughout the foot and ankle.⁹ With the patient standing, evaluate any malalignment from the foot through the knees and to the hips. Evaluate the skin for any lesions, wounds, or evidence of trauma or surgery. Next, with the patient seated, examine carefully for neuropathy or vascular abnormalities. Evaluate the ankle’s range of motion and assess for any mechanical locking, clicking, or crepitus. Palpate all bony and ligamentous landmarks to reveal areas of tenderness or swelling. Perform anterior drawer and varus tilt tests to determine overall ligamentous stability of the ankle, and compare your findings with test results of the opposite, uninjured ankle.

Diagnostic imaging. Order weight-bearing radiographs of the foot and ankle. Including the foot allows you to identify additional potential concerns such as malalignment, deformity, or adjacent joint arthritis. Look particularly for joint space narrowing, malalignment, post-traumatic changes, or implanted hardware. Advanced imaging studies—computerized tomography, magnetic resonance imaging, bone scan—are reserved for cases that necessitate ruling out alternative diagnoses, or for preoperative evaluation by an orthopedic surgeon.

Management: Make use of multiple modalities

Conservative management options for ankle OA are limited, and high-quality evidence of efficacy is lacking. Surgical alternatives, however, are invasive and yield modest outcomes. Therefore, unless specific indications for surgery are present, exhaust conservative options (TABLE 2) before considering referral.

Weight loss is important for those who are overweight—as with knee OA management—to decrease the reactive forces within the ankle joint and to decrease pain. Weight loss will also enhance the outcomes of other treatment modalities and improve overall health.^10,11

Activity modification is usually required, even though this may make weight loss more difficult. Avoiding vigorous activities, restricting work-related movements that place high-impact stress on the ankle, and decreasing overall walking time often reduce the severity of symptoms and improve functioning in other activities. Use of assistive-devices, such as a cane, can decrease the weight-bearing load on the affected joint.^10,11

Physical therapy has not been shown to alleviate pain in ankle arthritis, although stretching, joint mobilization, and gait training may help prevent further progression of arthritis and improve function.¹¹ The strength of dorsiflexion and plantar-flexion muscles is often decreased in individuals with ankle arthritis. Strengthening exercises may be indicated in individuals exhibiting deficits.

Prescriptive conservative management. Begin with a combination, as needed, of anti-inflammatory medications, orthotic devices, and footwear modifications.

Nonsteroidal anti-inflammatory agents are generally safe, but long-term use requires monitoring. Intra-articular steroid injections have some supporting evidence of effectiveness, but any benefit is short-lived.¹² Glucosamine and chondroitin, although unlikely to cause harm, are not supported by the evidence for use in ankle arthritis. Intra-articular viscosupplementation is controversial, and evidence is limited regarding its efficacy.^13-15 And currently, insurance will not cover viscosupplementaton for any joint other than the knee.

The evidence does not support the use of glucosamine or chondroitin for use in ankle arthritis.Adding a rocker-bottom sole and a solid ankle cushion heel to a shoe helps decrease heel strike impact in individuals with decreased ankle motion, and they aid in the transition from the heel strike to the push-off during level walking.¹¹ If the arthritic joint is unstable, a lace-up ankle support may help with proprioception and stability. A polypropylene ankle-foot orthosis, custom leather ankle corset, or a double-upright brace with a patellar-tendon-bearing support are options to restrict ankle motion and decrease weight-bearing forces.^10,11

Immobilization is not recommended except for short-term use during an arthritic flare. Limiting ankle motion reduces pain, but the downside tradeoff is acquired stiffness and weakness that accompanies prolonged periods of immobilization. A controlled ankle motion walking boot or walking plaster cast are both reasonable options for the short term.

Consider surgical referral for specific indications such as osteophytes, loose bodies, and chondral defects, which may be treated with arthroscopy. Patients with large areas of exposed chondral bone or rapid onset of degeneration have poorer outcomes with conservative management and should also be referred to a surgeon earlier. Otherwise, consider surgical referral only after a full trial of conservative management.¹¹

Surgical options vary in scope and effectiveness and include osteotomy, arthrodesis, and arthroplasty. Osteotomies can be performed in early OA to correct bony alignment deformities. Arthrodesis in neutral dorsiflexion with roughly 5 degrees of external rotation is reserved for end-stage ankle OA to allow for near normal gait and pain relief. Total ankle arthroplasty is an emerging option for severe ankle OA, resulting in improved pain relief, gait, and patient satisfaction, but potentially has a higher reoperation rate when compared with arthrodesis.^1,2

CASE › We prescribed short-term immobilization with a controlled ankle motion boot and administered an intra-articular corticosteroid injection. At the patient’s follow-up visit 6 weeks later, he reported only moderate improvement in pain. We then advised physical therapy at a specialty ankle rehabilitation program to focus on mobilization, strengthening, and gait training. Nearly one year after his initial visit to our clinic, he is doing well. He understands, however, that the nature of his ankle arthrosis may necessitate surgical intervention in the future.

CORRESPONDENCE
Adam Bitterman, DO, Department of Orthopedic Surgery, Hofstra Northwell School of Medicine at Huntington Hospital, 155 East Main Street, Huntington, NY 11743; [email protected].

CASE › A 57-year-old man had been experiencing intermittent pain in his left ankle for the past 2.5 years. About 6 weeks before coming to our clinic, his symptoms became significantly worse after playing a pickup game of basketball. At the clinic visit, he reported no other recent injury or trauma to the leg. However, 15 years earlier he had fractured his left ankle and was treated conservatively with a short period in a cast followed by a course of physical therapy. After completing the physical therapy, he noted significant improvement, although he continued to have minor episodes of pain. He felt no instability or mechanical locking but did note a decreased ability to move the ankle. And it felt much stiffer than his right ankle.

Examination of his left ankle revealed tenderness over the anterior aspect at the tibiotalar joint. He also exhibited decreased dorsiflexion and was unable to perform a toe raise. There was no tenderness over the major ligaments, and results of anterior drawer and talar tilt tests were normal. X-rays revealed tibiotalar joint arthritis (FIGURE).

How would you proceed if this were your patient?

Arthritis of the tibiotalar joint, which has an estimated prevalence of approximately 1%, occurs much less frequently than arthritis of the knee or hip joints.¹ This low prevalence is primarily due to the ankle joint’s unique biomechanics and the features of the cartilage within the joint, including its thickness.²

Specifically, the hip and knee joints have greater degrees of freedom than the tibiotalar articulation, which is significantly constrained. The bony congruity between the talus, tibia, and fibula provides inherent stability to the ankle joint, thus protecting against primary osteoarthritis (OA).

Additionally, the large number of ligamentous structures and overall strength of the ligaments provide significant supplemental stability to the ankle joint articulation. Articular cartilage within the ankle joint is thicker than that of the knee and hip (1-1.7 mm). This cartilage also tends to retain its tensile strength with age, unlike cartilage in the hip; the ankle is therefore more resistant to age-related degeneration.³

Pain experienced walking down stairs likely indicates posterior ankle injury; pain going up stairs is likely anterior injury.Metabolic factors also protect against arthritis. Chondrocytes in the ankle are less responsive to inflammatory mediators, including interleukin-1 (IL-1), and therefore produce fewer matrix metalloproteinases.^1,2,4 There are also fewer IL-1 receptors on ankle chondrocytes.

The role of trauma in ankle OA. Given the ankle joint’s inherent stability, the most common cause of ankle OA is trauma,⁴ mainly ankle fracture and, less commonly, ligamentous injury.^5,6 Other rarer causes of ankle arthritis include primary OA, crystalline arthropathy, inflammatory disease, septic arthritis, neuroarthropathy, hemochromatosis, and ochronosis.

The ankle’s characteristics that protect it against primary OA may facilitate the pathogenesis of post-traumatic OA through 2 main mechanisms. First, direct trauma to the chondral surfaces can hasten the onset of progressive degeneration. Second, articular incongruity from a fracture can lead to insidious deterioration. The stiffer cartilage layer may be less adaptable to malalignment, and incongruity may cause secondary instability and chronic overloading. Ultimately, the joint breaks down with associated cartilage wear.^6,7

The importance of the normal ankle’s congruity and stability became clear in the landmark study by Ramsey and colleagues,⁸ showing that the contact area between the talus and the tibia decreases as talar displacement increases laterally. This innate stability explains why the contact area of the ankle joint can bear loads similar to those of the hip and knee, yet does not experience primary OA nearly as often.

A stepwise diagnostic appraisal

Ask these questions. Since most ankle pain results from trauma, ask about any recent or remote injury to the affected ankle. Knowing the type of injury that occurred and the exact treatment, if received, may shed light on the relationship between the injury and current symptoms. Acute traumatic events can cause fractures or injury to various soft-tissue structures traversing the ankle joint. Ankle ligament sprains or tendon strains may result after abnormal rotation of the foot. Alternatively, chronic overuse injuries may lead to tendinopathy in any of the tendons that control motion throughout the foot and ankle or degenerative changes within the tibiotalar joint. Knowing the exact location of pain may also help identify the pathology (TABLE 1).

The patient in our case had not suffered a recent injury, so it was important to learn as much as possible about his prior fracture. Was the injury treated conservatively or surgically? If management was conservative, the type and duration of treatment could offer clues to the mechanism underlying symptoms. If a patient has undergone surgery, knowledge of the exact procedure could suggest specific problems. For example, surgical fixation would likely indicate there was ankle instability, thus altering the normal biomechanics in the injured tibiotalar joint.

Other key questions to ask. Most patients with ankle pain also complain of limitations in their usual activities. Ask about the duration and type of pain and other symptoms. Also ask about the position of the foot and ankle when the pain is at its greatest, which will provide insight into likely areas of pathology. For example, if pain arises when the patient navigates uneven ground, subtalar pathology is highly likely. If the patient complains of pain while walking down stairs, suspect injury to the posterior (plantar flexed) ankle; pain while walking up stairs more likely indicates anterior (dorsiflexed) pathology.

Finally, ask about nonorthopedic medical problems and all medications being taken. Systemic conditions, too, can lead to ankle pain—eg, inflammatory arthropathies, infections, and crystalline arthropathy.

Physical examination. Observe the patient’s gait to assess any functional or range-of-motion limitations or abnormal loading throughout the foot and ankle.⁹ With the patient standing, evaluate any malalignment from the foot through the knees and to the hips. Evaluate the skin for any lesions, wounds, or evidence of trauma or surgery. Next, with the patient seated, examine carefully for neuropathy or vascular abnormalities. Evaluate the ankle’s range of motion and assess for any mechanical locking, clicking, or crepitus. Palpate all bony and ligamentous landmarks to reveal areas of tenderness or swelling. Perform anterior drawer and varus tilt tests to determine overall ligamentous stability of the ankle, and compare your findings with test results of the opposite, uninjured ankle.

Diagnostic imaging. Order weight-bearing radiographs of the foot and ankle. Including the foot allows you to identify additional potential concerns such as malalignment, deformity, or adjacent joint arthritis. Look particularly for joint space narrowing, malalignment, post-traumatic changes, or implanted hardware. Advanced imaging studies—computerized tomography, magnetic resonance imaging, bone scan—are reserved for cases that necessitate ruling out alternative diagnoses, or for preoperative evaluation by an orthopedic surgeon.

Management: Make use of multiple modalities

Conservative management options for ankle OA are limited, and high-quality evidence of efficacy is lacking. Surgical alternatives, however, are invasive and yield modest outcomes. Therefore, unless specific indications for surgery are present, exhaust conservative options (TABLE 2) before considering referral.

Weight loss is important for those who are overweight—as with knee OA management—to decrease the reactive forces within the ankle joint and to decrease pain. Weight loss will also enhance the outcomes of other treatment modalities and improve overall health.^10,11

Activity modification is usually required, even though this may make weight loss more difficult. Avoiding vigorous activities, restricting work-related movements that place high-impact stress on the ankle, and decreasing overall walking time often reduce the severity of symptoms and improve functioning in other activities. Use of assistive-devices, such as a cane, can decrease the weight-bearing load on the affected joint.^10,11

Physical therapy has not been shown to alleviate pain in ankle arthritis, although stretching, joint mobilization, and gait training may help prevent further progression of arthritis and improve function.¹¹ The strength of dorsiflexion and plantar-flexion muscles is often decreased in individuals with ankle arthritis. Strengthening exercises may be indicated in individuals exhibiting deficits.

Prescriptive conservative management. Begin with a combination, as needed, of anti-inflammatory medications, orthotic devices, and footwear modifications.

Nonsteroidal anti-inflammatory agents are generally safe, but long-term use requires monitoring. Intra-articular steroid injections have some supporting evidence of effectiveness, but any benefit is short-lived.¹² Glucosamine and chondroitin, although unlikely to cause harm, are not supported by the evidence for use in ankle arthritis. Intra-articular viscosupplementation is controversial, and evidence is limited regarding its efficacy.^13-15 And currently, insurance will not cover viscosupplementaton for any joint other than the knee.

The evidence does not support the use of glucosamine or chondroitin for use in ankle arthritis.Adding a rocker-bottom sole and a solid ankle cushion heel to a shoe helps decrease heel strike impact in individuals with decreased ankle motion, and they aid in the transition from the heel strike to the push-off during level walking.¹¹ If the arthritic joint is unstable, a lace-up ankle support may help with proprioception and stability. A polypropylene ankle-foot orthosis, custom leather ankle corset, or a double-upright brace with a patellar-tendon-bearing support are options to restrict ankle motion and decrease weight-bearing forces.^10,11

Immobilization is not recommended except for short-term use during an arthritic flare. Limiting ankle motion reduces pain, but the downside tradeoff is acquired stiffness and weakness that accompanies prolonged periods of immobilization. A controlled ankle motion walking boot or walking plaster cast are both reasonable options for the short term.

Consider surgical referral for specific indications such as osteophytes, loose bodies, and chondral defects, which may be treated with arthroscopy. Patients with large areas of exposed chondral bone or rapid onset of degeneration have poorer outcomes with conservative management and should also be referred to a surgeon earlier. Otherwise, consider surgical referral only after a full trial of conservative management.¹¹

Surgical options vary in scope and effectiveness and include osteotomy, arthrodesis, and arthroplasty. Osteotomies can be performed in early OA to correct bony alignment deformities. Arthrodesis in neutral dorsiflexion with roughly 5 degrees of external rotation is reserved for end-stage ankle OA to allow for near normal gait and pain relief. Total ankle arthroplasty is an emerging option for severe ankle OA, resulting in improved pain relief, gait, and patient satisfaction, but potentially has a higher reoperation rate when compared with arthrodesis.^1,2

CASE › We prescribed short-term immobilization with a controlled ankle motion boot and administered an intra-articular corticosteroid injection. At the patient’s follow-up visit 6 weeks later, he reported only moderate improvement in pain. We then advised physical therapy at a specialty ankle rehabilitation program to focus on mobilization, strengthening, and gait training. Nearly one year after his initial visit to our clinic, he is doing well. He understands, however, that the nature of his ankle arthrosis may necessitate surgical intervention in the future.

CORRESPONDENCE
Adam Bitterman, DO, Department of Orthopedic Surgery, Hofstra Northwell School of Medicine at Huntington Hospital, 155 East Main Street, Huntington, NY 11743; [email protected].

Pediatric asthma is the most commonly encountered childhood chronic disease, occurring in approximately 13.5% of children.¹ Due to the interplay between patient, family physician (FP), and the environment, asthma often proves challenging to control. Although national guidelines for the treatment of asthma have not changed since 2007, significant research continues to examine the optimal means of preventing, controlling, and treating asthma in children. This review summarizes the evidence to date so that you can maximize your care for these young patients.

A stepwise approach to asthma control

The 2007 National Heart, Lung, and Blood Institute (NHLBI) guidelines provide a common pathway for the management of asthma (FIGURE).² These guidelines emphasize stepwise treatment, based on symptom severity, which maximizes quality of life while minimizing morbidity. Treatment is escalated after careful assessment of frequency of daytime symptoms, frequency of nighttime symptoms, forced expiratory volume in one second (FEV1), and the number of exacerbations requiring systemic steroids over the past year. It’s also appropriate to de-escalate care when symptoms are controlled to minimize adverse effects.

The 2017 Global Initiative for Asthma (GINA) guidelines recommend a similar stepwise approach, with generally the same progression of control medications as the NHLBI guidelines. One variation is that GINA guidelines recommend considering inhaled corticosteroids (ICS) for all asthma patients—even those with intermittent symptoms.³

The Asthma Control Test and Asthma Control Questionnaire are also available for assessment of efficacy of asthma control and can help guide FPs with the decision of when to escalate control medications. (They are available at: http://bit.ly/2o3CzGX and http://bit.ly/2p1LvAc, respectively.)

A systematic review found that both tools were effective in determining if a patient was well controlled vs not well controlled.⁴ Similarly, a 2012 study found that using the Asthma Control Test score was useful for assessing control and directing changes to treatment.⁵ In addition, using these tools consistently in a primary care setting increased the frequency of assessment without negatively impacting patient flow through a clinic.⁶

Short-acting beta-agonists: A mainstay for intermittent asthma

Inhaled short-acting beta-agonists (SABAs) are the mainstay of treatment for intermittent asthma as well as asthma exacerbations. Short-acting beta-agonists are effective for symptomatic relief and preventing exacerbations prior to known exposures because they dilate smooth muscle in bronchioles and relieve bronchospasm.

Albuterol, the most commonly used SABA, is a mixture of the active R-enantiomer and inactive L-enantiomer. Levalbuterol, which consists of only the active R-enantiomer, is also available and is theoretically more effective with fewer adverse effects. Studies examining the difference in efficacy between albuterol and levalbuterol, however, have been mixed, and current guidelines do not recommend one over the other.⁷

Metered-dose inhalers vs nebulizers

SABAs are typically prescribed in metered-dose inhalers (MDIs), dry powder inhalers, or nebulizers. A meta-analysis comparing the efficacy of nebulizers to MDIs with spacers in both the outpatient and emergency department (ED) settings indicated that MDIs work at least as well as nebulizers and may also reduce length of ED stay.⁸ This trend appears consistent even with children younger than 24 months.⁹

Guidelines emphasize stepwise treatment, based on symptom severity, to maximize quality of life while minimizing morbidity.

If you are prescribing an MDI, be sure to routinely prescribe spacers to help ensure the medication is properly administered. Various types of spacers are available; some consist of an extension of the mouthpiece, while others serve as a chamber with a one-way valve to help improve the ability of the child to inhale the medication. Spacers that do not have antistatic coating should be gently washed with water and detergent.

Masks are also available for younger children and should be properly sized. The same spacer can be used for multiple medications, although they should be administered one at a time. Generally, albuterol should be administered prior to other medications to maximize distribution of subsequent inhaled medications.

Start low with inhaled corticosteroids

Treatment of persistent asthma consists of regular use of inhaled corticosteroids (ICSs; first line) with SABAs, as needed, for exacerbations. Guidelines recommend starting at a low dose and increasing the dose based on symptom control. Patients must consistently use ICSs for one to 2 weeks prior to obtaining full effect of the medication, and parents should be counseled to set appropriate expectations.^2,3 ICSs are dispensed as MDIs, dry powder inhalers, and nebulizers; spacers should be considered.

Studies have shown a slight decrease in height for children on ICSs, with long-term studies indicating a persistent 1- to 2-cm decrease in adult height.^10,11

Patient isn’t well controlled? Time for a long-acting beta-agonist

For patients not well controlled on low-dose ICSs, the dose can be increased or a long-acting beta-agonist (LABA) or leukotriene receptor antagonist (LTRA) can be added. A recent meta-analysis examining children not well controlled with ICSs, found that the addition of LABAs resulted in improved FEV1 and nighttime symptoms, and reduced the requirement for rescue inhalers when compared to increasing the ICS dose alone.¹² In addition, there was no difference in adverse events between the 2 agents, although patients taking ICSs and LABAs had greater growth in height than those with an increased dose of ICS.¹² Adding a LABA, however, did not decrease the need for systemic steroids and also did not reduce the number of exacerbations requiring hospitalizations.¹²

Another recent study demonstrated that the combination of ICSs and LABAs was noninferior to ICSs alone in preventing hospitalizations, intubations, and deaths.¹³ There are limited data on whether patients already on LABAs and ICSs should be continued on dual medications. Additionally, there is no clear method describing how to de-escalate therapy for those patients who are well controlled on ICSs and LABAs. A reasonable approach is to reduce doses of both medications and discontinue the LABA if tolerated.^14,15 The US Food and Drug Administration has issued a black box warning that LABAs should not be used as a single controller medication because patients may be at increased risk of asthma-related deaths.^16,17

What role for leukotriene receptor antagonists?

According to NHLBI guidelines, LTRAs can be considered as an alternative to ICSs when starting a control medication for mild persistent asthma.² A recent meta-analysis, however, showed that there were increased rates of hospitalizations with LTRAs alone when compared to ICSs.¹⁸ The NHLBI guidelines also suggest that LTRAs can be used as adjunctive medication for those patients not well controlled on ICSs rather than increasing the ICS dose or adding a LABA.²

Consider de-escalating care when symptoms are controlled to minimize adverse effects.

A 2011 clinical trial found no difference in quality of life measures between LTRAs and LABAs as adjunctive therapy at 2 months, but LABAs were more effective when patients were reassessed in 2 years.¹⁹ Similarly, the same study also found that adding LTRAs to low-dose ICSs rather than increasing the ICS dose was equivalent in the short term but not at 2 years.¹⁹

2 other adjunctive therapy options: Xanthines, cromolyn

Similar to LTRAs, xanthines can be considered as adjunctive therapy for children older than 5 years who are not well controlled on a low-dose ICS. Although xanthines decrease asthma symptoms when compared to placebo alone, they are not more effective than ICSs alone and should be considered only as adjunctive therapy.^2,20 There have been few studies comparing xanthines to other adjunctive medications.²¹

Cromolyn is another adjunctive medication cited in the NHLBI guidelines for escalation of therapy.² Although the medication has few adverse effects, its use is generally limited in the United States because data supporting its efficacy are lacking.

Omalizumab for allergy-related asthma exacerbations

Omalizumab, an anti-IgE antibody injected every 2 to 4 weeks, is available for children older than 6 years with moderate to severe asthma that is not responsive to ICSs and LABAs.²² The medication is effective in reducing allergy-related asthma exacerbations and hospitalizations, but data comparing it to other adjunctive medications are limited.²² Due to their significant systemic effects, the role of oral steroids as control medications is reserved for patients with severe asthma who are refractory to other medications. Children should be placed on oral steroids for the least amount of time required to achieve symptom control.

Acute exacerbation treatment: What to consider

Although there is no agreed-upon definition for an acute asthma exacerbation, the American Thoracic Society defines it as "an event characterized by a change from the patient’s previous status."²³ All patients should be given an asthma action plan that clearly delineates the escalation of therapy in the event of an exacerbation, although only half of all patients report experiencing one.²⁴ Symptom-based plans may prevent more acute care visits when compared to plans that use peak-flow measurements, although children on peak-flow plans may have fewer symptomatic days.²⁵

Start with short-acting beta-agonists

The SABAs serve as the initial treatment of choice for management of asthma exacerbations. In young children (0-3 years), SABAs delivered by MDI with a spacer were more effective in reducing admission rates (11.3% vs 21.7%) when compared to SABAs delivered by nebulizers, resulting in a number needed to treat to prevent one admission of 10.²⁶

In older children (3-18 years), SABAs delivered via spacer reduced ED length of stay, but did not significantly affect hospitalization rates. Additionally, SABAs administered with anticholinergics such as ipratropium bromide were more effective than SABAs alone in reducing admissions (16.9% vs 23.2%), particularly in older children with moderate to severe asthma, while also minimizing adverse effects.^8,26

Corticosteroids: A mainstay in the ED

In addition to albuterol administration, corticosteroids remain the mainstay of ED management for asthma exacerbations. Administration of systemic steroids has been shown to reduce hospitalizations in children under 6 years, although, paradoxically, studies examining outpatient administration have demonstrated an increase in hospitalizations when compared to placebo.²⁷

Dexamethasone and prednisone are the 2 most commonly used systemic steroids, and studies haven't indicated superiority of either.^28,29 There is no difference in efficacy between oral and intravenous steroids.³⁰ A recent clinical trial found a 2-day course of dexamethasone (0.6 mg/kg) had similar efficacy with fewer adverse effects when compared to a 5-day course of prednisone (1-2 mg/kg/day).²⁸

Patient isn’t responding? Try IV magnesium

For patients who don't respond to corticosteroids and albuterol treatments, IV magnesium sulfate (usual dose, 25-75 mg/kg/d; maximum dose, 2000 mg/d) has been shown to improve respiratory function, but not necessarily decrease admission rates.³¹ Inhaled magnesium sulfate hasn't been shown to be more effective than IV administration and isn'trecommended.³²

Evidence doesn’t support use of heliox

Heliox, which consists of 80% helium, is theorized to be effective in the treatment of asthma by increasing laminar flow and increasing the delivery of medications to the alveoli.³² Overall, the evidence does not support the use of heliox, which is typically restricted to patients with severe asthma exacerbations.³³

Is it worth considering noninvasive positive pressure ventilation?

If patients don't improve with medical treatment, noninvasive positive pressure ventilation can be considered. A recent meta-analysis suggests that there is no definitive benefit or harm from this treatment, although several studies have indicated a decrease in symptom severity.³⁴

Inhaled short-acting beta-agonists are the mainstay of treatment for intermittent asthma, as well as asthma exacerbations.

Intubation should be considered for hypoxemia unresponsive to medications, or in cases of exhaustion, worsening mental status, or respiratory acidosis unresponsive to medication. Ventilation should allow for a permissive respiratory acidosis (pH, 7.2), while maintaining adequate oxygenation.³⁵

Reducing the burden of asthma

Due to the complex task of reducing triggers and providing effective controller medications, working with parents and children is integral to improving the quality of life for patients with asthma. Although there is an obvious genetic predisposition, family physicians can help reduce the risk of developing asthma by encouraging healthy behaviors at home before the child is born. In the prenatal period, this includes avoiding tobacco-smoke exposure, lessening maternal obesity, decreasing maternal antibiotic and acetaminophen use, and curtailing stress.

Evidence suggests that after birth, breastfeeding and reducing childhood obesity can help lower the risk of asthma.³⁶ Atopic disease, in general, can be reduced by breastfeeding until at least 4 months, as well as encouraging a varied diet that does not restrict potential allergens during pregnancy or lactation, and introducing foods (including potential allergens) after the age of 4 months.

The risk of atopic disease can also be lowered by lessening potential triggers at home. These include restricting exposure to cats (but not dogs), reducing home mold by decreasing humidity and ensuring adequate ventilation, avoiding volatile organic compounds, such as chlorine, and curtailing exposure to vehicle emissions. Although often marketed to be effective in reducing allergies, dust-mite covers and soy-based formulas don't prevent or minimize allergies and are often costly.^37,38 In addition, there is no evidence that vaccinations areassociated with allergies.³⁹

CORRESPONDENCE
Douglas M. Maurer, 9040A Jackson Ave, Joint-Base Lewis-McChord, WA 98431; [email protected].

Pediatric asthma is the most commonly encountered childhood chronic disease, occurring in approximately 13.5% of children.¹ Due to the interplay between patient, family physician (FP), and the environment, asthma often proves challenging to control. Although national guidelines for the treatment of asthma have not changed since 2007, significant research continues to examine the optimal means of preventing, controlling, and treating asthma in children. This review summarizes the evidence to date so that you can maximize your care for these young patients.

A stepwise approach to asthma control

The 2007 National Heart, Lung, and Blood Institute (NHLBI) guidelines provide a common pathway for the management of asthma (FIGURE).² These guidelines emphasize stepwise treatment, based on symptom severity, which maximizes quality of life while minimizing morbidity. Treatment is escalated after careful assessment of frequency of daytime symptoms, frequency of nighttime symptoms, forced expiratory volume in one second (FEV1), and the number of exacerbations requiring systemic steroids over the past year. It’s also appropriate to de-escalate care when symptoms are controlled to minimize adverse effects.

The 2017 Global Initiative for Asthma (GINA) guidelines recommend a similar stepwise approach, with generally the same progression of control medications as the NHLBI guidelines. One variation is that GINA guidelines recommend considering inhaled corticosteroids (ICS) for all asthma patients—even those with intermittent symptoms.³

The Asthma Control Test and Asthma Control Questionnaire are also available for assessment of efficacy of asthma control and can help guide FPs with the decision of when to escalate control medications. (They are available at: http://bit.ly/2o3CzGX and http://bit.ly/2p1LvAc, respectively.)

A systematic review found that both tools were effective in determining if a patient was well controlled vs not well controlled.⁴ Similarly, a 2012 study found that using the Asthma Control Test score was useful for assessing control and directing changes to treatment.⁵ In addition, using these tools consistently in a primary care setting increased the frequency of assessment without negatively impacting patient flow through a clinic.⁶

Short-acting beta-agonists: A mainstay for intermittent asthma

Inhaled short-acting beta-agonists (SABAs) are the mainstay of treatment for intermittent asthma as well as asthma exacerbations. Short-acting beta-agonists are effective for symptomatic relief and preventing exacerbations prior to known exposures because they dilate smooth muscle in bronchioles and relieve bronchospasm.

Albuterol, the most commonly used SABA, is a mixture of the active R-enantiomer and inactive L-enantiomer. Levalbuterol, which consists of only the active R-enantiomer, is also available and is theoretically more effective with fewer adverse effects. Studies examining the difference in efficacy between albuterol and levalbuterol, however, have been mixed, and current guidelines do not recommend one over the other.⁷

Metered-dose inhalers vs nebulizers

SABAs are typically prescribed in metered-dose inhalers (MDIs), dry powder inhalers, or nebulizers. A meta-analysis comparing the efficacy of nebulizers to MDIs with spacers in both the outpatient and emergency department (ED) settings indicated that MDIs work at least as well as nebulizers and may also reduce length of ED stay.⁸ This trend appears consistent even with children younger than 24 months.⁹

Guidelines emphasize stepwise treatment, based on symptom severity, to maximize quality of life while minimizing morbidity.

If you are prescribing an MDI, be sure to routinely prescribe spacers to help ensure the medication is properly administered. Various types of spacers are available; some consist of an extension of the mouthpiece, while others serve as a chamber with a one-way valve to help improve the ability of the child to inhale the medication. Spacers that do not have antistatic coating should be gently washed with water and detergent.

Masks are also available for younger children and should be properly sized. The same spacer can be used for multiple medications, although they should be administered one at a time. Generally, albuterol should be administered prior to other medications to maximize distribution of subsequent inhaled medications.

Start low with inhaled corticosteroids

Treatment of persistent asthma consists of regular use of inhaled corticosteroids (ICSs; first line) with SABAs, as needed, for exacerbations. Guidelines recommend starting at a low dose and increasing the dose based on symptom control. Patients must consistently use ICSs for one to 2 weeks prior to obtaining full effect of the medication, and parents should be counseled to set appropriate expectations.^2,3 ICSs are dispensed as MDIs, dry powder inhalers, and nebulizers; spacers should be considered.

Studies have shown a slight decrease in height for children on ICSs, with long-term studies indicating a persistent 1- to 2-cm decrease in adult height.^10,11

Patient isn’t well controlled? Time for a long-acting beta-agonist

For patients not well controlled on low-dose ICSs, the dose can be increased or a long-acting beta-agonist (LABA) or leukotriene receptor antagonist (LTRA) can be added. A recent meta-analysis examining children not well controlled with ICSs, found that the addition of LABAs resulted in improved FEV1 and nighttime symptoms, and reduced the requirement for rescue inhalers when compared to increasing the ICS dose alone.¹² In addition, there was no difference in adverse events between the 2 agents, although patients taking ICSs and LABAs had greater growth in height than those with an increased dose of ICS.¹² Adding a LABA, however, did not decrease the need for systemic steroids and also did not reduce the number of exacerbations requiring hospitalizations.¹²

Another recent study demonstrated that the combination of ICSs and LABAs was noninferior to ICSs alone in preventing hospitalizations, intubations, and deaths.¹³ There are limited data on whether patients already on LABAs and ICSs should be continued on dual medications. Additionally, there is no clear method describing how to de-escalate therapy for those patients who are well controlled on ICSs and LABAs. A reasonable approach is to reduce doses of both medications and discontinue the LABA if tolerated.^14,15 The US Food and Drug Administration has issued a black box warning that LABAs should not be used as a single controller medication because patients may be at increased risk of asthma-related deaths.^16,17

What role for leukotriene receptor antagonists?

According to NHLBI guidelines, LTRAs can be considered as an alternative to ICSs when starting a control medication for mild persistent asthma.² A recent meta-analysis, however, showed that there were increased rates of hospitalizations with LTRAs alone when compared to ICSs.¹⁸ The NHLBI guidelines also suggest that LTRAs can be used as adjunctive medication for those patients not well controlled on ICSs rather than increasing the ICS dose or adding a LABA.²

Consider de-escalating care when symptoms are controlled to minimize adverse effects.

A 2011 clinical trial found no difference in quality of life measures between LTRAs and LABAs as adjunctive therapy at 2 months, but LABAs were more effective when patients were reassessed in 2 years.¹⁹ Similarly, the same study also found that adding LTRAs to low-dose ICSs rather than increasing the ICS dose was equivalent in the short term but not at 2 years.¹⁹

2 other adjunctive therapy options: Xanthines, cromolyn

Similar to LTRAs, xanthines can be considered as adjunctive therapy for children older than 5 years who are not well controlled on a low-dose ICS. Although xanthines decrease asthma symptoms when compared to placebo alone, they are not more effective than ICSs alone and should be considered only as adjunctive therapy.^2,20 There have been few studies comparing xanthines to other adjunctive medications.²¹

Cromolyn is another adjunctive medication cited in the NHLBI guidelines for escalation of therapy.² Although the medication has few adverse effects, its use is generally limited in the United States because data supporting its efficacy are lacking.

Omalizumab for allergy-related asthma exacerbations

Omalizumab, an anti-IgE antibody injected every 2 to 4 weeks, is available for children older than 6 years with moderate to severe asthma that is not responsive to ICSs and LABAs.²² The medication is effective in reducing allergy-related asthma exacerbations and hospitalizations, but data comparing it to other adjunctive medications are limited.²² Due to their significant systemic effects, the role of oral steroids as control medications is reserved for patients with severe asthma who are refractory to other medications. Children should be placed on oral steroids for the least amount of time required to achieve symptom control.

Acute exacerbation treatment: What to consider

Although there is no agreed-upon definition for an acute asthma exacerbation, the American Thoracic Society defines it as "an event characterized by a change from the patient’s previous status."²³ All patients should be given an asthma action plan that clearly delineates the escalation of therapy in the event of an exacerbation, although only half of all patients report experiencing one.²⁴ Symptom-based plans may prevent more acute care visits when compared to plans that use peak-flow measurements, although children on peak-flow plans may have fewer symptomatic days.²⁵

Start with short-acting beta-agonists

The SABAs serve as the initial treatment of choice for management of asthma exacerbations. In young children (0-3 years), SABAs delivered by MDI with a spacer were more effective in reducing admission rates (11.3% vs 21.7%) when compared to SABAs delivered by nebulizers, resulting in a number needed to treat to prevent one admission of 10.²⁶

In older children (3-18 years), SABAs delivered via spacer reduced ED length of stay, but did not significantly affect hospitalization rates. Additionally, SABAs administered with anticholinergics such as ipratropium bromide were more effective than SABAs alone in reducing admissions (16.9% vs 23.2%), particularly in older children with moderate to severe asthma, while also minimizing adverse effects.^8,26

Corticosteroids: A mainstay in the ED

In addition to albuterol administration, corticosteroids remain the mainstay of ED management for asthma exacerbations. Administration of systemic steroids has been shown to reduce hospitalizations in children under 6 years, although, paradoxically, studies examining outpatient administration have demonstrated an increase in hospitalizations when compared to placebo.²⁷

Dexamethasone and prednisone are the 2 most commonly used systemic steroids, and studies haven't indicated superiority of either.^28,29 There is no difference in efficacy between oral and intravenous steroids.³⁰ A recent clinical trial found a 2-day course of dexamethasone (0.6 mg/kg) had similar efficacy with fewer adverse effects when compared to a 5-day course of prednisone (1-2 mg/kg/day).²⁸

Patient isn’t responding? Try IV magnesium

For patients who don't respond to corticosteroids and albuterol treatments, IV magnesium sulfate (usual dose, 25-75 mg/kg/d; maximum dose, 2000 mg/d) has been shown to improve respiratory function, but not necessarily decrease admission rates.³¹ Inhaled magnesium sulfate hasn't been shown to be more effective than IV administration and isn'trecommended.³²

Evidence doesn’t support use of heliox

Heliox, which consists of 80% helium, is theorized to be effective in the treatment of asthma by increasing laminar flow and increasing the delivery of medications to the alveoli.³² Overall, the evidence does not support the use of heliox, which is typically restricted to patients with severe asthma exacerbations.³³

Is it worth considering noninvasive positive pressure ventilation?

If patients don't improve with medical treatment, noninvasive positive pressure ventilation can be considered. A recent meta-analysis suggests that there is no definitive benefit or harm from this treatment, although several studies have indicated a decrease in symptom severity.³⁴

Inhaled short-acting beta-agonists are the mainstay of treatment for intermittent asthma, as well as asthma exacerbations.

Intubation should be considered for hypoxemia unresponsive to medications, or in cases of exhaustion, worsening mental status, or respiratory acidosis unresponsive to medication. Ventilation should allow for a permissive respiratory acidosis (pH, 7.2), while maintaining adequate oxygenation.³⁵

Reducing the burden of asthma

Due to the complex task of reducing triggers and providing effective controller medications, working with parents and children is integral to improving the quality of life for patients with asthma. Although there is an obvious genetic predisposition, family physicians can help reduce the risk of developing asthma by encouraging healthy behaviors at home before the child is born. In the prenatal period, this includes avoiding tobacco-smoke exposure, lessening maternal obesity, decreasing maternal antibiotic and acetaminophen use, and curtailing stress.

Evidence suggests that after birth, breastfeeding and reducing childhood obesity can help lower the risk of asthma.³⁶ Atopic disease, in general, can be reduced by breastfeeding until at least 4 months, as well as encouraging a varied diet that does not restrict potential allergens during pregnancy or lactation, and introducing foods (including potential allergens) after the age of 4 months.

The risk of atopic disease can also be lowered by lessening potential triggers at home. These include restricting exposure to cats (but not dogs), reducing home mold by decreasing humidity and ensuring adequate ventilation, avoiding volatile organic compounds, such as chlorine, and curtailing exposure to vehicle emissions. Although often marketed to be effective in reducing allergies, dust-mite covers and soy-based formulas don't prevent or minimize allergies and are often costly.^37,38 In addition, there is no evidence that vaccinations areassociated with allergies.³⁹

CORRESPONDENCE
Douglas M. Maurer, 9040A Jackson Ave, Joint-Base Lewis-McChord, WA 98431; [email protected].

Pediatric asthma is the most commonly encountered childhood chronic disease, occurring in approximately 13.5% of children.¹ Due to the interplay between patient, family physician (FP), and the environment, asthma often proves challenging to control. Although national guidelines for the treatment of asthma have not changed since 2007, significant research continues to examine the optimal means of preventing, controlling, and treating asthma in children. This review summarizes the evidence to date so that you can maximize your care for these young patients.

A stepwise approach to asthma control

The 2007 National Heart, Lung, and Blood Institute (NHLBI) guidelines provide a common pathway for the management of asthma (FIGURE).² These guidelines emphasize stepwise treatment, based on symptom severity, which maximizes quality of life while minimizing morbidity. Treatment is escalated after careful assessment of frequency of daytime symptoms, frequency of nighttime symptoms, forced expiratory volume in one second (FEV1), and the number of exacerbations requiring systemic steroids over the past year. It’s also appropriate to de-escalate care when symptoms are controlled to minimize adverse effects.

The 2017 Global Initiative for Asthma (GINA) guidelines recommend a similar stepwise approach, with generally the same progression of control medications as the NHLBI guidelines. One variation is that GINA guidelines recommend considering inhaled corticosteroids (ICS) for all asthma patients—even those with intermittent symptoms.³

The Asthma Control Test and Asthma Control Questionnaire are also available for assessment of efficacy of asthma control and can help guide FPs with the decision of when to escalate control medications. (They are available at: http://bit.ly/2o3CzGX and http://bit.ly/2p1LvAc, respectively.)

A systematic review found that both tools were effective in determining if a patient was well controlled vs not well controlled.⁴ Similarly, a 2012 study found that using the Asthma Control Test score was useful for assessing control and directing changes to treatment.⁵ In addition, using these tools consistently in a primary care setting increased the frequency of assessment without negatively impacting patient flow through a clinic.⁶

Short-acting beta-agonists: A mainstay for intermittent asthma

Inhaled short-acting beta-agonists (SABAs) are the mainstay of treatment for intermittent asthma as well as asthma exacerbations. Short-acting beta-agonists are effective for symptomatic relief and preventing exacerbations prior to known exposures because they dilate smooth muscle in bronchioles and relieve bronchospasm.

Albuterol, the most commonly used SABA, is a mixture of the active R-enantiomer and inactive L-enantiomer. Levalbuterol, which consists of only the active R-enantiomer, is also available and is theoretically more effective with fewer adverse effects. Studies examining the difference in efficacy between albuterol and levalbuterol, however, have been mixed, and current guidelines do not recommend one over the other.⁷

Metered-dose inhalers vs nebulizers

SABAs are typically prescribed in metered-dose inhalers (MDIs), dry powder inhalers, or nebulizers. A meta-analysis comparing the efficacy of nebulizers to MDIs with spacers in both the outpatient and emergency department (ED) settings indicated that MDIs work at least as well as nebulizers and may also reduce length of ED stay.⁸ This trend appears consistent even with children younger than 24 months.⁹

Guidelines emphasize stepwise treatment, based on symptom severity, to maximize quality of life while minimizing morbidity.

If you are prescribing an MDI, be sure to routinely prescribe spacers to help ensure the medication is properly administered. Various types of spacers are available; some consist of an extension of the mouthpiece, while others serve as a chamber with a one-way valve to help improve the ability of the child to inhale the medication. Spacers that do not have antistatic coating should be gently washed with water and detergent.

Masks are also available for younger children and should be properly sized. The same spacer can be used for multiple medications, although they should be administered one at a time. Generally, albuterol should be administered prior to other medications to maximize distribution of subsequent inhaled medications.

Start low with inhaled corticosteroids

Treatment of persistent asthma consists of regular use of inhaled corticosteroids (ICSs; first line) with SABAs, as needed, for exacerbations. Guidelines recommend starting at a low dose and increasing the dose based on symptom control. Patients must consistently use ICSs for one to 2 weeks prior to obtaining full effect of the medication, and parents should be counseled to set appropriate expectations.^2,3 ICSs are dispensed as MDIs, dry powder inhalers, and nebulizers; spacers should be considered.

Studies have shown a slight decrease in height for children on ICSs, with long-term studies indicating a persistent 1- to 2-cm decrease in adult height.^10,11

Patient isn’t well controlled? Time for a long-acting beta-agonist

For patients not well controlled on low-dose ICSs, the dose can be increased or a long-acting beta-agonist (LABA) or leukotriene receptor antagonist (LTRA) can be added. A recent meta-analysis examining children not well controlled with ICSs, found that the addition of LABAs resulted in improved FEV1 and nighttime symptoms, and reduced the requirement for rescue inhalers when compared to increasing the ICS dose alone.¹² In addition, there was no difference in adverse events between the 2 agents, although patients taking ICSs and LABAs had greater growth in height than those with an increased dose of ICS.¹² Adding a LABA, however, did not decrease the need for systemic steroids and also did not reduce the number of exacerbations requiring hospitalizations.¹²

Another recent study demonstrated that the combination of ICSs and LABAs was noninferior to ICSs alone in preventing hospitalizations, intubations, and deaths.¹³ There are limited data on whether patients already on LABAs and ICSs should be continued on dual medications. Additionally, there is no clear method describing how to de-escalate therapy for those patients who are well controlled on ICSs and LABAs. A reasonable approach is to reduce doses of both medications and discontinue the LABA if tolerated.^14,15 The US Food and Drug Administration has issued a black box warning that LABAs should not be used as a single controller medication because patients may be at increased risk of asthma-related deaths.^16,17

What role for leukotriene receptor antagonists?

According to NHLBI guidelines, LTRAs can be considered as an alternative to ICSs when starting a control medication for mild persistent asthma.² A recent meta-analysis, however, showed that there were increased rates of hospitalizations with LTRAs alone when compared to ICSs.¹⁸ The NHLBI guidelines also suggest that LTRAs can be used as adjunctive medication for those patients not well controlled on ICSs rather than increasing the ICS dose or adding a LABA.²

Consider de-escalating care when symptoms are controlled to minimize adverse effects.

A 2011 clinical trial found no difference in quality of life measures between LTRAs and LABAs as adjunctive therapy at 2 months, but LABAs were more effective when patients were reassessed in 2 years.¹⁹ Similarly, the same study also found that adding LTRAs to low-dose ICSs rather than increasing the ICS dose was equivalent in the short term but not at 2 years.¹⁹

2 other adjunctive therapy options: Xanthines, cromolyn

Similar to LTRAs, xanthines can be considered as adjunctive therapy for children older than 5 years who are not well controlled on a low-dose ICS. Although xanthines decrease asthma symptoms when compared to placebo alone, they are not more effective than ICSs alone and should be considered only as adjunctive therapy.^2,20 There have been few studies comparing xanthines to other adjunctive medications.²¹

Cromolyn is another adjunctive medication cited in the NHLBI guidelines for escalation of therapy.² Although the medication has few adverse effects, its use is generally limited in the United States because data supporting its efficacy are lacking.

Omalizumab for allergy-related asthma exacerbations

Omalizumab, an anti-IgE antibody injected every 2 to 4 weeks, is available for children older than 6 years with moderate to severe asthma that is not responsive to ICSs and LABAs.²² The medication is effective in reducing allergy-related asthma exacerbations and hospitalizations, but data comparing it to other adjunctive medications are limited.²² Due to their significant systemic effects, the role of oral steroids as control medications is reserved for patients with severe asthma who are refractory to other medications. Children should be placed on oral steroids for the least amount of time required to achieve symptom control.

Acute exacerbation treatment: What to consider

Although there is no agreed-upon definition for an acute asthma exacerbation, the American Thoracic Society defines it as "an event characterized by a change from the patient’s previous status."²³ All patients should be given an asthma action plan that clearly delineates the escalation of therapy in the event of an exacerbation, although only half of all patients report experiencing one.²⁴ Symptom-based plans may prevent more acute care visits when compared to plans that use peak-flow measurements, although children on peak-flow plans may have fewer symptomatic days.²⁵

Start with short-acting beta-agonists

The SABAs serve as the initial treatment of choice for management of asthma exacerbations. In young children (0-3 years), SABAs delivered by MDI with a spacer were more effective in reducing admission rates (11.3% vs 21.7%) when compared to SABAs delivered by nebulizers, resulting in a number needed to treat to prevent one admission of 10.²⁶

In older children (3-18 years), SABAs delivered via spacer reduced ED length of stay, but did not significantly affect hospitalization rates. Additionally, SABAs administered with anticholinergics such as ipratropium bromide were more effective than SABAs alone in reducing admissions (16.9% vs 23.2%), particularly in older children with moderate to severe asthma, while also minimizing adverse effects.^8,26

Corticosteroids: A mainstay in the ED

In addition to albuterol administration, corticosteroids remain the mainstay of ED management for asthma exacerbations. Administration of systemic steroids has been shown to reduce hospitalizations in children under 6 years, although, paradoxically, studies examining outpatient administration have demonstrated an increase in hospitalizations when compared to placebo.²⁷

Dexamethasone and prednisone are the 2 most commonly used systemic steroids, and studies haven't indicated superiority of either.^28,29 There is no difference in efficacy between oral and intravenous steroids.³⁰ A recent clinical trial found a 2-day course of dexamethasone (0.6 mg/kg) had similar efficacy with fewer adverse effects when compared to a 5-day course of prednisone (1-2 mg/kg/day).²⁸

Patient isn’t responding? Try IV magnesium

For patients who don't respond to corticosteroids and albuterol treatments, IV magnesium sulfate (usual dose, 25-75 mg/kg/d; maximum dose, 2000 mg/d) has been shown to improve respiratory function, but not necessarily decrease admission rates.³¹ Inhaled magnesium sulfate hasn't been shown to be more effective than IV administration and isn'trecommended.³²

Evidence doesn’t support use of heliox

Heliox, which consists of 80% helium, is theorized to be effective in the treatment of asthma by increasing laminar flow and increasing the delivery of medications to the alveoli.³² Overall, the evidence does not support the use of heliox, which is typically restricted to patients with severe asthma exacerbations.³³

Is it worth considering noninvasive positive pressure ventilation?

If patients don't improve with medical treatment, noninvasive positive pressure ventilation can be considered. A recent meta-analysis suggests that there is no definitive benefit or harm from this treatment, although several studies have indicated a decrease in symptom severity.³⁴

Inhaled short-acting beta-agonists are the mainstay of treatment for intermittent asthma, as well as asthma exacerbations.

Intubation should be considered for hypoxemia unresponsive to medications, or in cases of exhaustion, worsening mental status, or respiratory acidosis unresponsive to medication. Ventilation should allow for a permissive respiratory acidosis (pH, 7.2), while maintaining adequate oxygenation.³⁵

Reducing the burden of asthma

Due to the complex task of reducing triggers and providing effective controller medications, working with parents and children is integral to improving the quality of life for patients with asthma. Although there is an obvious genetic predisposition, family physicians can help reduce the risk of developing asthma by encouraging healthy behaviors at home before the child is born. In the prenatal period, this includes avoiding tobacco-smoke exposure, lessening maternal obesity, decreasing maternal antibiotic and acetaminophen use, and curtailing stress.

Evidence suggests that after birth, breastfeeding and reducing childhood obesity can help lower the risk of asthma.³⁶ Atopic disease, in general, can be reduced by breastfeeding until at least 4 months, as well as encouraging a varied diet that does not restrict potential allergens during pregnancy or lactation, and introducing foods (including potential allergens) after the age of 4 months.

The risk of atopic disease can also be lowered by lessening potential triggers at home. These include restricting exposure to cats (but not dogs), reducing home mold by decreasing humidity and ensuring adequate ventilation, avoiding volatile organic compounds, such as chlorine, and curtailing exposure to vehicle emissions. Although often marketed to be effective in reducing allergies, dust-mite covers and soy-based formulas don't prevent or minimize allergies and are often costly.^37,38 In addition, there is no evidence that vaccinations areassociated with allergies.³⁹

CORRESPONDENCE
Douglas M. Maurer, 9040A Jackson Ave, Joint-Base Lewis-McChord, WA 98431; [email protected].

Although it is often taken for granted, the ability to initiate and maintain sleep throughout the night is elusive for many. About one-third of adults experience a troublesome episode of insomnia.¹ In most, it is transient, but in 10% to 15% (roughly 30 million people), the problem becomes self-perpetuating and chronic.² Chronic insomnia is one of the most prevalent conditions that family physicians (FPs) encounter, a function of it being so closely associated with comorbid conditions that FPs deal with every day, such as depression, chronic pain, and polypharmacy.^3,4

Insomnia can be vexing for a number of reasons. Because it is not acutely dangerous, patients may present it as an “add-on” concern at the end of an already lengthy visit. And because insomnia is often a symptom of multiple underlying physiologic and psychological factors, it requires the FP to engage in a thorough and time-consuming exploration of possible causes and comorbidities. Finally, standard treatment options have drawbacks: reports show that use of pharmacotherapy is troubling to prescribers primarily because of concerns about adverse effects and dependence;^5-7 the other major therapeutic avenue, cognitive behavioral therapy for insomnia (CBT-I), requires training and is time-consuming to deliver in the context of an office visit.^8,9

Despite these obstacles, successful evaluation and treatment of insomnia can be highly rewarding. Chronic insomnia is associated with great individual misery and negative consequences for long-term health. Specifically, it is associated with reduced quality of life and daytime functioning,¹⁰ depression,^11,12 hypertension,^13,14 increased workplace accidents and absenteeism,^15-17 and exacerbations of chronic pain.¹⁸ And while the evaluation and management of insomnia can be laborious, a systematic method can streamline the process.

Insomnia: Symptom or cause?

The International Classification of Sleep Disorders defines chronic insomnia as an inability to sleep sufficiently despite creating adequate opportunity. It occurs at least 3 nights per week for >3 months with perceived negative consequences during the day. Patients typically complain about symptoms including fatigue, diminished cog­nitive performance, and mood disturbance.¹⁹ Acute insomnia triggered by one or more biopsychosocial stresses is, by definition, self-limited and has different underlying mechanisms. As such, it will not be described in this review.

The chief risk factors are female gender, low socioeconomic status, and increasing age.²⁰ However, cohorts of healthy seniors show preserved good sleep; the increase in prevalence of insomnia in the elderly is likely linked more specifically to age-related accumulation of medical/mental health disorders and polypharmacy than aging per se.²¹

Research over the past 20 years has shown that comorbidities have a bidirectional relationship with insomnia, rather than a one-way cause and effect.

In the past, insomnia was viewed as a symptom, occurring secondarily to an underlying cause, usually an acute biopsychosocial stressor or depression. It was assumed that if the primary cause was effectively treated, then healthy sleep would return.

But research over the past 20 years has changed this paradigm in 2 ways. First, when comorbidities such as depression or chronic pain are present, they have a bidirectional relationship with insomnia rather than a one-way cause and effect. For example, instead of depression being a primary disorder from which insomnia can result, it is now recognized that insomnia can be present first and is a risk factor for new-onset depression. When depression and insomnia coexist, they may exacerbate each other in a bidirectional pattern.

Secondly, an estimated 15% of chronic insomnia sufferers have no targetable comorbidity; rather, they are unable to get sufficient sleep in large part because of a trait-like predisposition to fragile sleep, called hyperarousal brain physiology.²² These people used to be described as having “primary insomnia,” although the term has been dropped from the 5th edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM).²³

Assess comorbidities, obtain sleep logs

The evaluation of the chronic form of insomnia should begin with a thorough medical his­tory to assess for comorbid conditions that can exacerbate disturbed sleep. These are generally grouped into medical disorders (TABLE 1²⁰), medications/substances (eg, antidepressants, stimulants, decongestants, narcotic analgesics, cardiovascular drugs, pulmonary agents, alcohol), and mental health disorders (especially depression and anxiety). It’s important to consider whether such comorbidities are contributing to the insomnia and optimize treatment that addresses them.

Take particular care to evaluate signs and symptoms of comorbid primary sleep disorders such as obstructive sleep apnea, restless legs syndrome (RLS), and circadian rhythm disorders since any of these can present with a complaint of insomnia. RLS, usually classified as a sleep disorder because of its circadian pattern (it is experienced more at night than during the day), is present to a troublesome degree in about 3% to 4% of all adults.²⁴ It is important to inquire about symptoms of RLS (urge to move legs in the night more than during the day; relieved with movement; worsened with inactivity) so as not to miss this treatable cause of insomnia.

The physical exam should focus on signs that suggest sleep-disordered breathing—obesity, large neck girth, hypertension, and crowded oropharynx—because people with sleep apnea often present with the complaint of frequent awakenings.

Sleep logs can present a powerful picture

In addition to a history and physical exam, physicians should ask their patients with chronic insomnia to complete sleep logs for 2 to 3 weeks.²⁰ A sleep log with midnight near the middle of the page is preferred by many because it places the typical sleeping hours in the middle of the page, showing relevant information in a way that can be grasped immediately (FIGURE 1). To save time, nurses can provide sleep logs to patients along with instructions about how to complete them.

Patient-completed sleep logs often illuminate obvious detrimental behaviors that reinforce insomnia (eg, spending excessive time in bed, having irregular bed/wake times, daytime napping that diminishes sleep drive in the evening). In addition, they sometimes reveal circadian rhythm abnormalities such as delayed sleep phase syndrome in which the patient attempts to sleep at a normal bedtime, but exhibits a marked delay in falling asleep/waking up compared to societal norms. Seeing such information graphically represented is often a powerful learning experience for both physician and patient.

Sleep studies aren't usually warranted

In its most recent (2008) clinical guideline on the evaluation and management of chronic insomnia, the American Academy of Sleep Medicine (AASM) stated that “routine testing in the sleep lab is not warranted for most cases of insomnia.” Instead, it is reserved for individuals in whom there is a suspicion of a comorbid sleep disorder. FPs should refer patients for formal sleep studies only if, in addition to the insomnia complaint, there is suspicion of:²⁰

• obstructive sleep apnea (based upon some combination of loud snoring, obesity, hypertension, and/or excessive daytime sleepiness),
• narcolepsy (based upon excessive daytime sleepiness without a readily identifiable cause), or
• arousals with the potential for self-injurious behavior (parasomnias).

Treatments: Sleep hygiene, CBT-I, and medication

Sleep hygiene, cognitive/behavioral techniques, and pharmacotherapy serve as the core of therapy for chronic insomnia.

Sleep hygiene: Common-sense strategies

Most FPs are familiar with sleep hygiene instructions; these are simple, common-sense behavioral techniques such as limiting caffeine and screen (television, computer) time at night, avoiding daytime naps, and maintaining regular bed- and out-of-bed times. (See “A sleep hygiene checklist.”) Although it is a logical starting point for behavioral modification, sleep hygiene has not been studied rigorously as a monotherapy for insomnia and, therefore, doesn’t have an evidence rating in terms of effectiveness.²⁰

CBT-I: Treatment of choice

CBT-I seeks to lower cognitive and somatic arousal. Taken together, cognitive and behavioral techniques are effective in 70% to 80% of people, whether they have primary insomnia or comorbidities.^25-27 Furthermore, the benefits are sustained with the passage of time.²⁷ CBT-I is regarded as the treatment of choice for chronic insomnia.²⁰

An experience of successful sleep initiation and maintenance is important psychologically: It renews patients' confidence in the ability to sleep.

When provided by a highly trained mental health professional, CBT-I usually takes the form of a series of 6 to 8 weekly appointments. Descriptions and manuals for CBT-I abound and online programs have also proliferated.^28,29 However, there is a shortage of highly trained providers, and most FPs do not feel proficient to engage fully in CBT-I.^8,9 Nevertheless, some behavioral elements of CBT-I, such as stimulus control and sleep restriction, can be utilized in the family medicine setting and may be effective for a significant subset of patients.

Stimulus control and sleep restriction. Two behavioral techniques for insomnia that can be applied in the family medicine setting are stimulus control and sleep restriction therapy.²⁰

With stimulus control, patients attempt to eliminate stimuli that weaken the psychological association between the bed and successful sleep, namely wakeful activities in bed such as watching television, reading, or even “tossing and turning.” Instead, they are instructed to use their bed only for sleep (and intimacy), to vacate it if awake and not clearly on the verge of sleep, and to avoid looking at a clock during the night. Patients are also advised to sleep only in their own bed and not in other places in their home.

Sleep restriction is predicated on the observation that many people with insomnia habitually spend too much time awake in bed, and this creates a conditioned arousal response to the bed. With sleep restriction, the patient is assigned a narrow window of “allowed time in bed,” usually a 6-hour interval of their choosing, and is instructed to adhere to this schedule for a period of 2 to 4 weeks. Many patients find that they fall asleep more rapidly and stay asleep longer after a few weeks. This experience of “successful” sleep initiation and maintenance is important psychologically; it renews their confidence in their ability to sleep, which is missing in most people with chronic insomnia.

If you use this approach with a patient, be sure to acknowledge that sleep restriction usually engenders some sleep deprivation in the first few weeks. But it is only a short-term intervention designed to change the expectation of nightly insomnia that is so ingrained in these patients. While they engage in sleep restriction, patients should keep sleep logs to track their “sleep efficiency” (ie, estimated time asleep vs time in bed). Once good sleep efficiency (>85%) is achieved, they may gradually lengthen their allowed time in bed by 15 minutes each week until they are obtaining 7 to 9 hours of sleep per night. (See “Breaking the cycle of insomnia by employing sleep restriction.”)

Cognitive therapy. Cognitive therapies for insomnia are usually provided by psychologists with special training. Three specific techniques that have evidence ratings* from the AASM are:²⁰

1. Relaxation training, including progressive muscle relaxation, guided imagery, and abdominal breathing to lower somatic and cognitive arousal states that interfere with sleep (strength of recommendation [SOR]: A).
2. Biofeedback therapy trains patients to control some physiologic variable through visual or auditory feedback. The objective is to reduce somatic arousal (SOR: B).
3. Paradoxical intention in which the patient is trained to confront the fear of staying awake and its potential effects. The objective is to eliminate a patient’s anxiety about sleep performance (SOR: B).

Pharmacotherapy: Overused? Addictive?

For patients who continue to struggle with insomnia despite attempting CBT-I, or for those who prefer a different approach, pharmacotherapy is a reasonable therapeutic option. While hypnotic medications are no guarantee of success, they sometimes provide meaningful benefit when supplied to a patient who has successfully established good cognitive and behavioral techniques, but is still struggling with insomnia.

Use of hypnotic medications has increased dramatically in recent years. Prescriptions for sleep medications approached 60 million in 2008, up 54% from 2004, with sales topping $2 billion.^30,31 A National Health and Nutrition Examination Survey looking at the period between 2005 and 2010 found that about 4% of adults ages 20 and older used prescription sleep aids in the past month.³²

Meta-analyses of pharmacotherapy for chronic insomnia show small to moderate effect sizes for sleep variables such as latency to sleep onset, total sleep time, and wake time after sleep onset.^33,34 Treatment of chronic insomnia with hypnotic medications is of comparable effectiveness to CBT-I in the early phase, but the benefits of CBT-I are more enduring.²⁷

A controversial approach. The appropriateness of hypnotic medications for chronic insomnia is controversial. While their use by health care professionals has been increasing, some authors have raised concerns about sleeping pills, citing a lack of effectiveness and possible adverse effects such as falls, driving impairment, and the potential for addiction, tolerance, and dependence.^33,35 The Beers Criteria of the American Geriatric Society recommends against the use of benzodiazepines in the elderly due to the risks of falls, cognitive impairment, and motor vehicle accidents and advises against the use of benzodiazepine agonists (such as zolpidem) for >90 days.³⁶

Two behavioral techniques for insomnia that can be easily applied in the family medicine setting are stimulus control and sleep restriction therapy.

Despite these concerns, the potential benefits of hypnotic medications for chronic insomnia should not be dismissed. The common strategy of simply addressing comorbidities and advising good sleep hygiene is insufficient for many patients. And some patients prefer the ease of using a hypnotic agent to the commitment required by CBT-I. Several reports suggest that the risk of hypnotic medication misuse in people with no history of substance abuse is overestimated.^37,38 And a panel of insomnia experts convened for the New Clinical Drug Evaluation Unit symposium in 2001 concluded, “Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior.”³⁹

Which hypnotic agent to choose?

US Food and Drug Administration (FDA)-approved hypnotic medications fall into 5 families (TABLE 2⁴⁰): benzodiazepines (BDZs), benzodiazepine agonists (BDZAs, sometimes called “Z drugs”), melatonin agonists (eg, ramelteon), tricyclic antidepressants (eg, low-dose doxepin), and orexin antagonists (eg, suvorexant). BDZs, BDZAs, and melatonin agonists potentiate sleep-promoting systems, while orexin antagonists and antihistaminergics suppress wake-promoting systems.

"Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior."

Studies of physician prescribing patterns show that among prescription medications for insomnia, zolpidem is the most popular, followed by trazodone (off-label use), other benzodiazepines, quetiapine (off-label use), and doxepin.⁴¹ Overall, over-the-counter melatonin may be more widely used than any of the prescription choices.⁴²

One useful basis for selection of an agent is whether the patient complains of difficulty with sleep initiation at the beginning of the night vs sleep maintenance, or both. For sleep initiation complaints, short-acting/sleep-promoting agents are preferred. For sleep maintenance complaints, longer-acting/wake-inhibiting medications that work at the end of the sleep phase may be necessary.

The AASM has recently concluded an exhaustive review of the literature regarding hypnotic medications for chronic insomnia.⁴³ The authors acknowledge important methodologic limitations, most notably a paucity of data on effectiveness and adverse effects, along with industry sponsorship of most studies and publication bias. Nevertheless, their conclusions favor the use of FDA-approved agents to off-label use of trazodone or over-the-counter use of melatonin or diphenhydramine. To summarize the AASM guidelines:³⁸

1. Medications recommended for sleep onset insomnia include: eszopiclone, ramelteon, temazepam, triazolam, zaleplon, and zolpidem.
2. Medications recommended for treating sleep maintenance insomnia include: doxepin, eszopiclone, suvorexant, zolpidem, and temazepam.
3. Medications not recommended for treating either sleep initiation or sleep maintenance insomnia include: diphenhydramine, melatonin, tiagabine, trazodone, tryptophan, and valerian.

These recommendations are similar to a review of hypnotics published by The Medical Letter in 2015.⁴⁰
 

Trazodone, an antidepressant medication with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia. Its popularity may be due to a perception of safety implied by its unscheduled FDA status and the lack of restrictions on prescribing duration. However, several reviews point out that its evidence base is weak.^44,45 There is only one placebo-controlled study involving trazodone use for "primary insomnia" (other studies have been in people with comorbid depression) and it showed insignificant improvements in sleep parameters and less effectiveness compared to zolpidem.⁴⁶

Trazadone, an antidepressant with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia.

Trazodone’s mechanisms of action are thought to be serotonin reuptake inhibition and alpha blockade, which might explain adverse effects such as orthostatic hypotension and psychomotor impairment. The frequency of such adverse effects is difficult to estimate since most studies of trazodone have used higher doses than are commonly used for insomnia in order to address comorbid depression. However, some experts have cautioned against its use—especially in the elderly.

The AASM guidelines recommend against use of trazodone. Others assert that it is probably best reserved for people in whom the complaint of insomnia is linked to comorbid depression.^43,44 

Is long-term use ever appropriate? There are no published guidelines about dosing strategies for hypnotics and whether nightly or intermittent use is preferred. All FDA-approved hypnotic agents are for short-term use, but this designation stems from a lack of long-term studies demonstrating continuing efficacy rather than actual proof of loss of effect. Although tolerance to over-the-counter sleep aids does occur, it has not been demonstrated to occur with FDA-approved agents. Studies of eszopiclone and zolpidem indicate continuing effectiveness as hypnotics with nightly use over a time-frame of several months to one year.^47,48

Regarding the thorny question of long-term use of hypnotics for chronic insomnia, the AASM concluded that long-term use should be reserved for “individuals in whom CBT-I is inaccessible or ineffective, who have been appropriately screened for contraindications to such treatment, who maintain long-term gains with medication, and who are followed regularly.”⁴³

CORRESPONDENCE
Adam J. Sorscher, MD, Dartmouth-Hitchcock Medical Center, 18 Old Etna Road, Lebanon, NH 03766; [email protected].

Although it is often taken for granted, the ability to initiate and maintain sleep throughout the night is elusive for many. About one-third of adults experience a troublesome episode of insomnia.¹ In most, it is transient, but in 10% to 15% (roughly 30 million people), the problem becomes self-perpetuating and chronic.² Chronic insomnia is one of the most prevalent conditions that family physicians (FPs) encounter, a function of it being so closely associated with comorbid conditions that FPs deal with every day, such as depression, chronic pain, and polypharmacy.^3,4

Insomnia can be vexing for a number of reasons. Because it is not acutely dangerous, patients may present it as an “add-on” concern at the end of an already lengthy visit. And because insomnia is often a symptom of multiple underlying physiologic and psychological factors, it requires the FP to engage in a thorough and time-consuming exploration of possible causes and comorbidities. Finally, standard treatment options have drawbacks: reports show that use of pharmacotherapy is troubling to prescribers primarily because of concerns about adverse effects and dependence;^5-7 the other major therapeutic avenue, cognitive behavioral therapy for insomnia (CBT-I), requires training and is time-consuming to deliver in the context of an office visit.^8,9

Despite these obstacles, successful evaluation and treatment of insomnia can be highly rewarding. Chronic insomnia is associated with great individual misery and negative consequences for long-term health. Specifically, it is associated with reduced quality of life and daytime functioning,¹⁰ depression,^11,12 hypertension,^13,14 increased workplace accidents and absenteeism,^15-17 and exacerbations of chronic pain.¹⁸ And while the evaluation and management of insomnia can be laborious, a systematic method can streamline the process.

Insomnia: Symptom or cause?

The International Classification of Sleep Disorders defines chronic insomnia as an inability to sleep sufficiently despite creating adequate opportunity. It occurs at least 3 nights per week for >3 months with perceived negative consequences during the day. Patients typically complain about symptoms including fatigue, diminished cog­nitive performance, and mood disturbance.¹⁹ Acute insomnia triggered by one or more biopsychosocial stresses is, by definition, self-limited and has different underlying mechanisms. As such, it will not be described in this review.

The chief risk factors are female gender, low socioeconomic status, and increasing age.²⁰ However, cohorts of healthy seniors show preserved good sleep; the increase in prevalence of insomnia in the elderly is likely linked more specifically to age-related accumulation of medical/mental health disorders and polypharmacy than aging per se.²¹

Research over the past 20 years has shown that comorbidities have a bidirectional relationship with insomnia, rather than a one-way cause and effect.

In the past, insomnia was viewed as a symptom, occurring secondarily to an underlying cause, usually an acute biopsychosocial stressor or depression. It was assumed that if the primary cause was effectively treated, then healthy sleep would return.

But research over the past 20 years has changed this paradigm in 2 ways. First, when comorbidities such as depression or chronic pain are present, they have a bidirectional relationship with insomnia rather than a one-way cause and effect. For example, instead of depression being a primary disorder from which insomnia can result, it is now recognized that insomnia can be present first and is a risk factor for new-onset depression. When depression and insomnia coexist, they may exacerbate each other in a bidirectional pattern.

Secondly, an estimated 15% of chronic insomnia sufferers have no targetable comorbidity; rather, they are unable to get sufficient sleep in large part because of a trait-like predisposition to fragile sleep, called hyperarousal brain physiology.²² These people used to be described as having “primary insomnia,” although the term has been dropped from the 5th edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM).²³

Assess comorbidities, obtain sleep logs

The evaluation of the chronic form of insomnia should begin with a thorough medical his­tory to assess for comorbid conditions that can exacerbate disturbed sleep. These are generally grouped into medical disorders (TABLE 1²⁰), medications/substances (eg, antidepressants, stimulants, decongestants, narcotic analgesics, cardiovascular drugs, pulmonary agents, alcohol), and mental health disorders (especially depression and anxiety). It’s important to consider whether such comorbidities are contributing to the insomnia and optimize treatment that addresses them.

Take particular care to evaluate signs and symptoms of comorbid primary sleep disorders such as obstructive sleep apnea, restless legs syndrome (RLS), and circadian rhythm disorders since any of these can present with a complaint of insomnia. RLS, usually classified as a sleep disorder because of its circadian pattern (it is experienced more at night than during the day), is present to a troublesome degree in about 3% to 4% of all adults.²⁴ It is important to inquire about symptoms of RLS (urge to move legs in the night more than during the day; relieved with movement; worsened with inactivity) so as not to miss this treatable cause of insomnia.

The physical exam should focus on signs that suggest sleep-disordered breathing—obesity, large neck girth, hypertension, and crowded oropharynx—because people with sleep apnea often present with the complaint of frequent awakenings.

Sleep logs can present a powerful picture

In addition to a history and physical exam, physicians should ask their patients with chronic insomnia to complete sleep logs for 2 to 3 weeks.²⁰ A sleep log with midnight near the middle of the page is preferred by many because it places the typical sleeping hours in the middle of the page, showing relevant information in a way that can be grasped immediately (FIGURE 1). To save time, nurses can provide sleep logs to patients along with instructions about how to complete them.

Patient-completed sleep logs often illuminate obvious detrimental behaviors that reinforce insomnia (eg, spending excessive time in bed, having irregular bed/wake times, daytime napping that diminishes sleep drive in the evening). In addition, they sometimes reveal circadian rhythm abnormalities such as delayed sleep phase syndrome in which the patient attempts to sleep at a normal bedtime, but exhibits a marked delay in falling asleep/waking up compared to societal norms. Seeing such information graphically represented is often a powerful learning experience for both physician and patient.

Sleep studies aren't usually warranted

In its most recent (2008) clinical guideline on the evaluation and management of chronic insomnia, the American Academy of Sleep Medicine (AASM) stated that “routine testing in the sleep lab is not warranted for most cases of insomnia.” Instead, it is reserved for individuals in whom there is a suspicion of a comorbid sleep disorder. FPs should refer patients for formal sleep studies only if, in addition to the insomnia complaint, there is suspicion of:²⁰

• obstructive sleep apnea (based upon some combination of loud snoring, obesity, hypertension, and/or excessive daytime sleepiness),
• narcolepsy (based upon excessive daytime sleepiness without a readily identifiable cause), or
• arousals with the potential for self-injurious behavior (parasomnias).

Treatments: Sleep hygiene, CBT-I, and medication

Sleep hygiene, cognitive/behavioral techniques, and pharmacotherapy serve as the core of therapy for chronic insomnia.

Sleep hygiene: Common-sense strategies

Most FPs are familiar with sleep hygiene instructions; these are simple, common-sense behavioral techniques such as limiting caffeine and screen (television, computer) time at night, avoiding daytime naps, and maintaining regular bed- and out-of-bed times. (See “A sleep hygiene checklist.”) Although it is a logical starting point for behavioral modification, sleep hygiene has not been studied rigorously as a monotherapy for insomnia and, therefore, doesn’t have an evidence rating in terms of effectiveness.²⁰

CBT-I: Treatment of choice

CBT-I seeks to lower cognitive and somatic arousal. Taken together, cognitive and behavioral techniques are effective in 70% to 80% of people, whether they have primary insomnia or comorbidities.^25-27 Furthermore, the benefits are sustained with the passage of time.²⁷ CBT-I is regarded as the treatment of choice for chronic insomnia.²⁰

An experience of successful sleep initiation and maintenance is important psychologically: It renews patients' confidence in the ability to sleep.

When provided by a highly trained mental health professional, CBT-I usually takes the form of a series of 6 to 8 weekly appointments. Descriptions and manuals for CBT-I abound and online programs have also proliferated.^28,29 However, there is a shortage of highly trained providers, and most FPs do not feel proficient to engage fully in CBT-I.^8,9 Nevertheless, some behavioral elements of CBT-I, such as stimulus control and sleep restriction, can be utilized in the family medicine setting and may be effective for a significant subset of patients.

Stimulus control and sleep restriction. Two behavioral techniques for insomnia that can be applied in the family medicine setting are stimulus control and sleep restriction therapy.²⁰

With stimulus control, patients attempt to eliminate stimuli that weaken the psychological association between the bed and successful sleep, namely wakeful activities in bed such as watching television, reading, or even “tossing and turning.” Instead, they are instructed to use their bed only for sleep (and intimacy), to vacate it if awake and not clearly on the verge of sleep, and to avoid looking at a clock during the night. Patients are also advised to sleep only in their own bed and not in other places in their home.

Sleep restriction is predicated on the observation that many people with insomnia habitually spend too much time awake in bed, and this creates a conditioned arousal response to the bed. With sleep restriction, the patient is assigned a narrow window of “allowed time in bed,” usually a 6-hour interval of their choosing, and is instructed to adhere to this schedule for a period of 2 to 4 weeks. Many patients find that they fall asleep more rapidly and stay asleep longer after a few weeks. This experience of “successful” sleep initiation and maintenance is important psychologically; it renews their confidence in their ability to sleep, which is missing in most people with chronic insomnia.

If you use this approach with a patient, be sure to acknowledge that sleep restriction usually engenders some sleep deprivation in the first few weeks. But it is only a short-term intervention designed to change the expectation of nightly insomnia that is so ingrained in these patients. While they engage in sleep restriction, patients should keep sleep logs to track their “sleep efficiency” (ie, estimated time asleep vs time in bed). Once good sleep efficiency (>85%) is achieved, they may gradually lengthen their allowed time in bed by 15 minutes each week until they are obtaining 7 to 9 hours of sleep per night. (See “Breaking the cycle of insomnia by employing sleep restriction.”)

Cognitive therapy. Cognitive therapies for insomnia are usually provided by psychologists with special training. Three specific techniques that have evidence ratings* from the AASM are:²⁰

1. Relaxation training, including progressive muscle relaxation, guided imagery, and abdominal breathing to lower somatic and cognitive arousal states that interfere with sleep (strength of recommendation [SOR]: A).
2. Biofeedback therapy trains patients to control some physiologic variable through visual or auditory feedback. The objective is to reduce somatic arousal (SOR: B).
3. Paradoxical intention in which the patient is trained to confront the fear of staying awake and its potential effects. The objective is to eliminate a patient’s anxiety about sleep performance (SOR: B).

Pharmacotherapy: Overused? Addictive?

For patients who continue to struggle with insomnia despite attempting CBT-I, or for those who prefer a different approach, pharmacotherapy is a reasonable therapeutic option. While hypnotic medications are no guarantee of success, they sometimes provide meaningful benefit when supplied to a patient who has successfully established good cognitive and behavioral techniques, but is still struggling with insomnia.

Use of hypnotic medications has increased dramatically in recent years. Prescriptions for sleep medications approached 60 million in 2008, up 54% from 2004, with sales topping $2 billion.^30,31 A National Health and Nutrition Examination Survey looking at the period between 2005 and 2010 found that about 4% of adults ages 20 and older used prescription sleep aids in the past month.³²

Meta-analyses of pharmacotherapy for chronic insomnia show small to moderate effect sizes for sleep variables such as latency to sleep onset, total sleep time, and wake time after sleep onset.^33,34 Treatment of chronic insomnia with hypnotic medications is of comparable effectiveness to CBT-I in the early phase, but the benefits of CBT-I are more enduring.²⁷

A controversial approach. The appropriateness of hypnotic medications for chronic insomnia is controversial. While their use by health care professionals has been increasing, some authors have raised concerns about sleeping pills, citing a lack of effectiveness and possible adverse effects such as falls, driving impairment, and the potential for addiction, tolerance, and dependence.^33,35 The Beers Criteria of the American Geriatric Society recommends against the use of benzodiazepines in the elderly due to the risks of falls, cognitive impairment, and motor vehicle accidents and advises against the use of benzodiazepine agonists (such as zolpidem) for >90 days.³⁶

Two behavioral techniques for insomnia that can be easily applied in the family medicine setting are stimulus control and sleep restriction therapy.

Despite these concerns, the potential benefits of hypnotic medications for chronic insomnia should not be dismissed. The common strategy of simply addressing comorbidities and advising good sleep hygiene is insufficient for many patients. And some patients prefer the ease of using a hypnotic agent to the commitment required by CBT-I. Several reports suggest that the risk of hypnotic medication misuse in people with no history of substance abuse is overestimated.^37,38 And a panel of insomnia experts convened for the New Clinical Drug Evaluation Unit symposium in 2001 concluded, “Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior.”³⁹

Which hypnotic agent to choose?

US Food and Drug Administration (FDA)-approved hypnotic medications fall into 5 families (TABLE 2⁴⁰): benzodiazepines (BDZs), benzodiazepine agonists (BDZAs, sometimes called “Z drugs”), melatonin agonists (eg, ramelteon), tricyclic antidepressants (eg, low-dose doxepin), and orexin antagonists (eg, suvorexant). BDZs, BDZAs, and melatonin agonists potentiate sleep-promoting systems, while orexin antagonists and antihistaminergics suppress wake-promoting systems.

"Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior."

Studies of physician prescribing patterns show that among prescription medications for insomnia, zolpidem is the most popular, followed by trazodone (off-label use), other benzodiazepines, quetiapine (off-label use), and doxepin.⁴¹ Overall, over-the-counter melatonin may be more widely used than any of the prescription choices.⁴²

One useful basis for selection of an agent is whether the patient complains of difficulty with sleep initiation at the beginning of the night vs sleep maintenance, or both. For sleep initiation complaints, short-acting/sleep-promoting agents are preferred. For sleep maintenance complaints, longer-acting/wake-inhibiting medications that work at the end of the sleep phase may be necessary.

The AASM has recently concluded an exhaustive review of the literature regarding hypnotic medications for chronic insomnia.⁴³ The authors acknowledge important methodologic limitations, most notably a paucity of data on effectiveness and adverse effects, along with industry sponsorship of most studies and publication bias. Nevertheless, their conclusions favor the use of FDA-approved agents to off-label use of trazodone or over-the-counter use of melatonin or diphenhydramine. To summarize the AASM guidelines:³⁸

1. Medications recommended for sleep onset insomnia include: eszopiclone, ramelteon, temazepam, triazolam, zaleplon, and zolpidem.
2. Medications recommended for treating sleep maintenance insomnia include: doxepin, eszopiclone, suvorexant, zolpidem, and temazepam.
3. Medications not recommended for treating either sleep initiation or sleep maintenance insomnia include: diphenhydramine, melatonin, tiagabine, trazodone, tryptophan, and valerian.

These recommendations are similar to a review of hypnotics published by The Medical Letter in 2015.⁴⁰
 

Trazodone, an antidepressant medication with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia. Its popularity may be due to a perception of safety implied by its unscheduled FDA status and the lack of restrictions on prescribing duration. However, several reviews point out that its evidence base is weak.^44,45 There is only one placebo-controlled study involving trazodone use for "primary insomnia" (other studies have been in people with comorbid depression) and it showed insignificant improvements in sleep parameters and less effectiveness compared to zolpidem.⁴⁶

Trazadone, an antidepressant with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia.

Trazodone’s mechanisms of action are thought to be serotonin reuptake inhibition and alpha blockade, which might explain adverse effects such as orthostatic hypotension and psychomotor impairment. The frequency of such adverse effects is difficult to estimate since most studies of trazodone have used higher doses than are commonly used for insomnia in order to address comorbid depression. However, some experts have cautioned against its use—especially in the elderly.

The AASM guidelines recommend against use of trazodone. Others assert that it is probably best reserved for people in whom the complaint of insomnia is linked to comorbid depression.^43,44 

Is long-term use ever appropriate? There are no published guidelines about dosing strategies for hypnotics and whether nightly or intermittent use is preferred. All FDA-approved hypnotic agents are for short-term use, but this designation stems from a lack of long-term studies demonstrating continuing efficacy rather than actual proof of loss of effect. Although tolerance to over-the-counter sleep aids does occur, it has not been demonstrated to occur with FDA-approved agents. Studies of eszopiclone and zolpidem indicate continuing effectiveness as hypnotics with nightly use over a time-frame of several months to one year.^47,48

Regarding the thorny question of long-term use of hypnotics for chronic insomnia, the AASM concluded that long-term use should be reserved for “individuals in whom CBT-I is inaccessible or ineffective, who have been appropriately screened for contraindications to such treatment, who maintain long-term gains with medication, and who are followed regularly.”⁴³

CORRESPONDENCE
Adam J. Sorscher, MD, Dartmouth-Hitchcock Medical Center, 18 Old Etna Road, Lebanon, NH 03766; [email protected].

Although it is often taken for granted, the ability to initiate and maintain sleep throughout the night is elusive for many. About one-third of adults experience a troublesome episode of insomnia.¹ In most, it is transient, but in 10% to 15% (roughly 30 million people), the problem becomes self-perpetuating and chronic.² Chronic insomnia is one of the most prevalent conditions that family physicians (FPs) encounter, a function of it being so closely associated with comorbid conditions that FPs deal with every day, such as depression, chronic pain, and polypharmacy.^3,4

Insomnia can be vexing for a number of reasons. Because it is not acutely dangerous, patients may present it as an “add-on” concern at the end of an already lengthy visit. And because insomnia is often a symptom of multiple underlying physiologic and psychological factors, it requires the FP to engage in a thorough and time-consuming exploration of possible causes and comorbidities. Finally, standard treatment options have drawbacks: reports show that use of pharmacotherapy is troubling to prescribers primarily because of concerns about adverse effects and dependence;^5-7 the other major therapeutic avenue, cognitive behavioral therapy for insomnia (CBT-I), requires training and is time-consuming to deliver in the context of an office visit.^8,9

Despite these obstacles, successful evaluation and treatment of insomnia can be highly rewarding. Chronic insomnia is associated with great individual misery and negative consequences for long-term health. Specifically, it is associated with reduced quality of life and daytime functioning,¹⁰ depression,^11,12 hypertension,^13,14 increased workplace accidents and absenteeism,^15-17 and exacerbations of chronic pain.¹⁸ And while the evaluation and management of insomnia can be laborious, a systematic method can streamline the process.

Insomnia: Symptom or cause?

The International Classification of Sleep Disorders defines chronic insomnia as an inability to sleep sufficiently despite creating adequate opportunity. It occurs at least 3 nights per week for >3 months with perceived negative consequences during the day. Patients typically complain about symptoms including fatigue, diminished cog­nitive performance, and mood disturbance.¹⁹ Acute insomnia triggered by one or more biopsychosocial stresses is, by definition, self-limited and has different underlying mechanisms. As such, it will not be described in this review.

The chief risk factors are female gender, low socioeconomic status, and increasing age.²⁰ However, cohorts of healthy seniors show preserved good sleep; the increase in prevalence of insomnia in the elderly is likely linked more specifically to age-related accumulation of medical/mental health disorders and polypharmacy than aging per se.²¹

Research over the past 20 years has shown that comorbidities have a bidirectional relationship with insomnia, rather than a one-way cause and effect.

In the past, insomnia was viewed as a symptom, occurring secondarily to an underlying cause, usually an acute biopsychosocial stressor or depression. It was assumed that if the primary cause was effectively treated, then healthy sleep would return.

But research over the past 20 years has changed this paradigm in 2 ways. First, when comorbidities such as depression or chronic pain are present, they have a bidirectional relationship with insomnia rather than a one-way cause and effect. For example, instead of depression being a primary disorder from which insomnia can result, it is now recognized that insomnia can be present first and is a risk factor for new-onset depression. When depression and insomnia coexist, they may exacerbate each other in a bidirectional pattern.

Secondly, an estimated 15% of chronic insomnia sufferers have no targetable comorbidity; rather, they are unable to get sufficient sleep in large part because of a trait-like predisposition to fragile sleep, called hyperarousal brain physiology.²² These people used to be described as having “primary insomnia,” although the term has been dropped from the 5th edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM).²³

Assess comorbidities, obtain sleep logs

The evaluation of the chronic form of insomnia should begin with a thorough medical his­tory to assess for comorbid conditions that can exacerbate disturbed sleep. These are generally grouped into medical disorders (TABLE 1²⁰), medications/substances (eg, antidepressants, stimulants, decongestants, narcotic analgesics, cardiovascular drugs, pulmonary agents, alcohol), and mental health disorders (especially depression and anxiety). It’s important to consider whether such comorbidities are contributing to the insomnia and optimize treatment that addresses them.

Take particular care to evaluate signs and symptoms of comorbid primary sleep disorders such as obstructive sleep apnea, restless legs syndrome (RLS), and circadian rhythm disorders since any of these can present with a complaint of insomnia. RLS, usually classified as a sleep disorder because of its circadian pattern (it is experienced more at night than during the day), is present to a troublesome degree in about 3% to 4% of all adults.²⁴ It is important to inquire about symptoms of RLS (urge to move legs in the night more than during the day; relieved with movement; worsened with inactivity) so as not to miss this treatable cause of insomnia.

The physical exam should focus on signs that suggest sleep-disordered breathing—obesity, large neck girth, hypertension, and crowded oropharynx—because people with sleep apnea often present with the complaint of frequent awakenings.

Sleep logs can present a powerful picture

In addition to a history and physical exam, physicians should ask their patients with chronic insomnia to complete sleep logs for 2 to 3 weeks.²⁰ A sleep log with midnight near the middle of the page is preferred by many because it places the typical sleeping hours in the middle of the page, showing relevant information in a way that can be grasped immediately (FIGURE 1). To save time, nurses can provide sleep logs to patients along with instructions about how to complete them.

Patient-completed sleep logs often illuminate obvious detrimental behaviors that reinforce insomnia (eg, spending excessive time in bed, having irregular bed/wake times, daytime napping that diminishes sleep drive in the evening). In addition, they sometimes reveal circadian rhythm abnormalities such as delayed sleep phase syndrome in which the patient attempts to sleep at a normal bedtime, but exhibits a marked delay in falling asleep/waking up compared to societal norms. Seeing such information graphically represented is often a powerful learning experience for both physician and patient.

Sleep studies aren't usually warranted

In its most recent (2008) clinical guideline on the evaluation and management of chronic insomnia, the American Academy of Sleep Medicine (AASM) stated that “routine testing in the sleep lab is not warranted for most cases of insomnia.” Instead, it is reserved for individuals in whom there is a suspicion of a comorbid sleep disorder. FPs should refer patients for formal sleep studies only if, in addition to the insomnia complaint, there is suspicion of:²⁰

• obstructive sleep apnea (based upon some combination of loud snoring, obesity, hypertension, and/or excessive daytime sleepiness),
• narcolepsy (based upon excessive daytime sleepiness without a readily identifiable cause), or
• arousals with the potential for self-injurious behavior (parasomnias).

Treatments: Sleep hygiene, CBT-I, and medication

Sleep hygiene, cognitive/behavioral techniques, and pharmacotherapy serve as the core of therapy for chronic insomnia.

Sleep hygiene: Common-sense strategies

Most FPs are familiar with sleep hygiene instructions; these are simple, common-sense behavioral techniques such as limiting caffeine and screen (television, computer) time at night, avoiding daytime naps, and maintaining regular bed- and out-of-bed times. (See “A sleep hygiene checklist.”) Although it is a logical starting point for behavioral modification, sleep hygiene has not been studied rigorously as a monotherapy for insomnia and, therefore, doesn’t have an evidence rating in terms of effectiveness.²⁰

CBT-I: Treatment of choice

CBT-I seeks to lower cognitive and somatic arousal. Taken together, cognitive and behavioral techniques are effective in 70% to 80% of people, whether they have primary insomnia or comorbidities.^25-27 Furthermore, the benefits are sustained with the passage of time.²⁷ CBT-I is regarded as the treatment of choice for chronic insomnia.²⁰

An experience of successful sleep initiation and maintenance is important psychologically: It renews patients' confidence in the ability to sleep.

When provided by a highly trained mental health professional, CBT-I usually takes the form of a series of 6 to 8 weekly appointments. Descriptions and manuals for CBT-I abound and online programs have also proliferated.^28,29 However, there is a shortage of highly trained providers, and most FPs do not feel proficient to engage fully in CBT-I.^8,9 Nevertheless, some behavioral elements of CBT-I, such as stimulus control and sleep restriction, can be utilized in the family medicine setting and may be effective for a significant subset of patients.

Stimulus control and sleep restriction. Two behavioral techniques for insomnia that can be applied in the family medicine setting are stimulus control and sleep restriction therapy.²⁰

With stimulus control, patients attempt to eliminate stimuli that weaken the psychological association between the bed and successful sleep, namely wakeful activities in bed such as watching television, reading, or even “tossing and turning.” Instead, they are instructed to use their bed only for sleep (and intimacy), to vacate it if awake and not clearly on the verge of sleep, and to avoid looking at a clock during the night. Patients are also advised to sleep only in their own bed and not in other places in their home.

Sleep restriction is predicated on the observation that many people with insomnia habitually spend too much time awake in bed, and this creates a conditioned arousal response to the bed. With sleep restriction, the patient is assigned a narrow window of “allowed time in bed,” usually a 6-hour interval of their choosing, and is instructed to adhere to this schedule for a period of 2 to 4 weeks. Many patients find that they fall asleep more rapidly and stay asleep longer after a few weeks. This experience of “successful” sleep initiation and maintenance is important psychologically; it renews their confidence in their ability to sleep, which is missing in most people with chronic insomnia.

If you use this approach with a patient, be sure to acknowledge that sleep restriction usually engenders some sleep deprivation in the first few weeks. But it is only a short-term intervention designed to change the expectation of nightly insomnia that is so ingrained in these patients. While they engage in sleep restriction, patients should keep sleep logs to track their “sleep efficiency” (ie, estimated time asleep vs time in bed). Once good sleep efficiency (>85%) is achieved, they may gradually lengthen their allowed time in bed by 15 minutes each week until they are obtaining 7 to 9 hours of sleep per night. (See “Breaking the cycle of insomnia by employing sleep restriction.”)

Cognitive therapy. Cognitive therapies for insomnia are usually provided by psychologists with special training. Three specific techniques that have evidence ratings* from the AASM are:²⁰

1. Relaxation training, including progressive muscle relaxation, guided imagery, and abdominal breathing to lower somatic and cognitive arousal states that interfere with sleep (strength of recommendation [SOR]: A).
2. Biofeedback therapy trains patients to control some physiologic variable through visual or auditory feedback. The objective is to reduce somatic arousal (SOR: B).
3. Paradoxical intention in which the patient is trained to confront the fear of staying awake and its potential effects. The objective is to eliminate a patient’s anxiety about sleep performance (SOR: B).

Pharmacotherapy: Overused? Addictive?

For patients who continue to struggle with insomnia despite attempting CBT-I, or for those who prefer a different approach, pharmacotherapy is a reasonable therapeutic option. While hypnotic medications are no guarantee of success, they sometimes provide meaningful benefit when supplied to a patient who has successfully established good cognitive and behavioral techniques, but is still struggling with insomnia.

Use of hypnotic medications has increased dramatically in recent years. Prescriptions for sleep medications approached 60 million in 2008, up 54% from 2004, with sales topping $2 billion.^30,31 A National Health and Nutrition Examination Survey looking at the period between 2005 and 2010 found that about 4% of adults ages 20 and older used prescription sleep aids in the past month.³²

Meta-analyses of pharmacotherapy for chronic insomnia show small to moderate effect sizes for sleep variables such as latency to sleep onset, total sleep time, and wake time after sleep onset.^33,34 Treatment of chronic insomnia with hypnotic medications is of comparable effectiveness to CBT-I in the early phase, but the benefits of CBT-I are more enduring.²⁷

A controversial approach. The appropriateness of hypnotic medications for chronic insomnia is controversial. While their use by health care professionals has been increasing, some authors have raised concerns about sleeping pills, citing a lack of effectiveness and possible adverse effects such as falls, driving impairment, and the potential for addiction, tolerance, and dependence.^33,35 The Beers Criteria of the American Geriatric Society recommends against the use of benzodiazepines in the elderly due to the risks of falls, cognitive impairment, and motor vehicle accidents and advises against the use of benzodiazepine agonists (such as zolpidem) for >90 days.³⁶

Two behavioral techniques for insomnia that can be easily applied in the family medicine setting are stimulus control and sleep restriction therapy.

Despite these concerns, the potential benefits of hypnotic medications for chronic insomnia should not be dismissed. The common strategy of simply addressing comorbidities and advising good sleep hygiene is insufficient for many patients. And some patients prefer the ease of using a hypnotic agent to the commitment required by CBT-I. Several reports suggest that the risk of hypnotic medication misuse in people with no history of substance abuse is overestimated.^37,38 And a panel of insomnia experts convened for the New Clinical Drug Evaluation Unit symposium in 2001 concluded, “Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior.”³⁹

Which hypnotic agent to choose?

US Food and Drug Administration (FDA)-approved hypnotic medications fall into 5 families (TABLE 2⁴⁰): benzodiazepines (BDZs), benzodiazepine agonists (BDZAs, sometimes called “Z drugs”), melatonin agonists (eg, ramelteon), tricyclic antidepressants (eg, low-dose doxepin), and orexin antagonists (eg, suvorexant). BDZs, BDZAs, and melatonin agonists potentiate sleep-promoting systems, while orexin antagonists and antihistaminergics suppress wake-promoting systems.

"Patients with chronic insomnia tend to exhibit therapy-seeking behavior, not drug-seeking behavior."

Studies of physician prescribing patterns show that among prescription medications for insomnia, zolpidem is the most popular, followed by trazodone (off-label use), other benzodiazepines, quetiapine (off-label use), and doxepin.⁴¹ Overall, over-the-counter melatonin may be more widely used than any of the prescription choices.⁴²

One useful basis for selection of an agent is whether the patient complains of difficulty with sleep initiation at the beginning of the night vs sleep maintenance, or both. For sleep initiation complaints, short-acting/sleep-promoting agents are preferred. For sleep maintenance complaints, longer-acting/wake-inhibiting medications that work at the end of the sleep phase may be necessary.

The AASM has recently concluded an exhaustive review of the literature regarding hypnotic medications for chronic insomnia.⁴³ The authors acknowledge important methodologic limitations, most notably a paucity of data on effectiveness and adverse effects, along with industry sponsorship of most studies and publication bias. Nevertheless, their conclusions favor the use of FDA-approved agents to off-label use of trazodone or over-the-counter use of melatonin or diphenhydramine. To summarize the AASM guidelines:³⁸

1. Medications recommended for sleep onset insomnia include: eszopiclone, ramelteon, temazepam, triazolam, zaleplon, and zolpidem.
2. Medications recommended for treating sleep maintenance insomnia include: doxepin, eszopiclone, suvorexant, zolpidem, and temazepam.
3. Medications not recommended for treating either sleep initiation or sleep maintenance insomnia include: diphenhydramine, melatonin, tiagabine, trazodone, tryptophan, and valerian.

These recommendations are similar to a review of hypnotics published by The Medical Letter in 2015.⁴⁰
 

Trazodone, an antidepressant medication with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia. Its popularity may be due to a perception of safety implied by its unscheduled FDA status and the lack of restrictions on prescribing duration. However, several reviews point out that its evidence base is weak.^44,45 There is only one placebo-controlled study involving trazodone use for "primary insomnia" (other studies have been in people with comorbid depression) and it showed insignificant improvements in sleep parameters and less effectiveness compared to zolpidem.⁴⁶

Trazadone, an antidepressant with sedating properties, is not FDA-approved for the treatment of insomnia, yet ranks second to zolpidem in the number of prescriptions written for insomnia.

Trazodone’s mechanisms of action are thought to be serotonin reuptake inhibition and alpha blockade, which might explain adverse effects such as orthostatic hypotension and psychomotor impairment. The frequency of such adverse effects is difficult to estimate since most studies of trazodone have used higher doses than are commonly used for insomnia in order to address comorbid depression. However, some experts have cautioned against its use—especially in the elderly.

The AASM guidelines recommend against use of trazodone. Others assert that it is probably best reserved for people in whom the complaint of insomnia is linked to comorbid depression.^43,44 

Is long-term use ever appropriate? There are no published guidelines about dosing strategies for hypnotics and whether nightly or intermittent use is preferred. All FDA-approved hypnotic agents are for short-term use, but this designation stems from a lack of long-term studies demonstrating continuing efficacy rather than actual proof of loss of effect. Although tolerance to over-the-counter sleep aids does occur, it has not been demonstrated to occur with FDA-approved agents. Studies of eszopiclone and zolpidem indicate continuing effectiveness as hypnotics with nightly use over a time-frame of several months to one year.^47,48

Regarding the thorny question of long-term use of hypnotics for chronic insomnia, the AASM concluded that long-term use should be reserved for “individuals in whom CBT-I is inaccessible or ineffective, who have been appropriately screened for contraindications to such treatment, who maintain long-term gains with medication, and who are followed regularly.”⁴³

CORRESPONDENCE
Adam J. Sorscher, MD, Dartmouth-Hitchcock Medical Center, 18 Old Etna Road, Lebanon, NH 03766; [email protected].