Pharmacology

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with a 5-fold increase in the risk of ischemic stroke and the risk increases with age.^1-3 Oral anticoagulation (OAC) therapy effectively reduces the risk of ischemic stroke in patients with nonvalvular AF. However, OAC therapy carries a bleeding risk.⁴

Several bleeding risk scores have been developed and validated for patients with AF who are taking warfarin: HEMORR₂HAGES (Hepatic or renal disease, Ethanol abuse, Malignancy, Older age, Reduced platelet count or function, Re-bleeding, Hypertension, Anemia, Genetic factors, Excessive fall risk, Stroke), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and HAS-BLED (Hypertension, Abnormal renal and/or liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio [INR], Elderly, and Drugs and/or alcohol excess concomitantly).^4,5 All 3 bleeding risk scores demonstrate only modest ability to predict clinically relevant bleeding in patients taking warfarin. The HAS-BLED score was superior to HEMORR₂HAGES and ATRIA for predicting any clinically relevant bleeding and was the only bleeding risk score that demonstrated significant predictive performance for intracranial hemorrhage.⁵ Compared with HEMORR₂HAGES, the HAS-BLED score is simpler to use and to assess risk factors that can be gathered from medical history or routinely tested in patients with AF.⁴ Unlike HAS-BLED, HEMORR₂HAGES and ATRIA do not consider medications that could increase the risk of bleeding.

Despite the availability of validated bleeding risk scores, clinical application of these measures should not be used to exclude a patient from OAC therapy for patients who reach a threshold score. Rather, current guideline and expert consensus agree with the recommendation to use bleeding risk scores to identify risk factors and address those factors that are modifiable to reduce the risk of anticoagulant-associated major bleeding.^6-8

The authors identified modifiable bleeding risk factors using the HAS-BLED score and evaluated pharmacist interventions to correct these factors in patients with nonvalvular AF who are taking warfarin. To the authors’ knowledge, there have been no published studies evaluating interventions to reduce modifiable bleeding risk factors identified by the HAS-BLED score.

Methods

Clinical pharmacy specialists (CPSs) in the primary care (PC) clinics at the Clement J. Zablocki VAMC (CJZVAMC) in Milwaukee, Wisconsin, have prescriptive authority within their scope of practice to manage smoking cessation and diseases, including anticoagulation, diabetes mellitus, heart failure, hypertension, and dyslipidemia. Patients who are on OAC therapy, including warfarin, receive comprehensive anticoagulation management from PC CPSs, including prescribing OAC therapy, education, dosage adjustments, and laboratory monitoring.

Patients were included in the HAS-BLED risk scoring and intervention if their warfarin therapy was managed by a PC CPS, had an active warfarin prescription with a diagnosis of nonvalvular AF in their problem list, and had ≥ 1 modifiable risk factor(s) from the HAS-BLED risk score. Modifiable risk factors evaluated were systolic blood pressure (SBP) > 160 mm Hg, an active prescription for VA or non-VA (which generally indicates over-the-counter [OTC] medication use) aspirin, clopidogrel, or a nonsteroidal anti-inflammatory drug (NSAID). Excess alcohol consumption was not listed as a modifiable risk factor in this assessment because nearly all the anticoagulation patients already receive regular recommendations to minimize alcohol use from the PC CPSs.

Patients were excluded from analysis if they had an indication for warfarin use other than nonvalvular AF, such as atrial flutter, acute/chronic deep vein thrombosis or pulmonary embolism, history of venous thromboembolism, peripheral vascular disease, or aortic or mitral mechanical valve. Patients also were excluded if they were on antiplatelet therapy for unstable coronary artery disease (CAD), experienced acute coronary syndrome within the past 1 year, history of stent placement, carotid endarterectomy, carotid stenosis, or noncardioembolic stroke and no other modifiable risk factors. Last, patients were excluded if clinic SBP readings were > 160 mm Hg but there was documented white coat hypertension or home SBP readings < 160 mm Hg.

The following definitions or measurements were used for assessing the HAS-BLED bleeding risk score⁴:

• Uncontrolled hypertension: most recently charted SBP > 160 mm Hg;
• Abnormal renal function: dialysis, renal transplant, serum creatinine > 2.26 mg/dL;
• Abnormal liver function: chronic hepatic disease, biochemical evidence of significant hepatic derangement (bilirubin > 2 × upper limit of normal and/or AST/ALT/alkaline phosphatase > 3 × upper limit of normal);
• Stroke: including history of transient ischemic attack;
• Bleeding history or predisposition: history of major bleeding (intracranial and/or any bleeding requiring hospitalization and/or causing a decrease in hemoglobin (Hgb) level of > 2 g/dL and/or requiring blood transfusion), anemia (males: Hgb < 13 g/dL; females: Hgb < 12 g/dL);
• Labile INR: percentage of INRs in therapeutic range < 60% (using the CJZVAMC anticoagulation management tool, which calculates percentage of INRs in goal reported since the first visit);
• Geriatric: age > 65 years at initial assessment;
• Concomitant drug use (VA prescription or non-VA medication list): aspirin, clopidogrel, or NSAID; and
• Alcohol in excess: > 8 alcohol servings per week from chart documentation of the patient’s self-report.

In the HAS-BLED bleeding risk score, patients receive 1 point for each component for a maximum score of 9 points. The score is stratified into low (0 points), intermediate (1 to 2 points), and high (≥ 3 points) bleeding risk.⁴

The HAS-BLED risk factors were obtained from patient chart review, including problem list, laboratory results, and PC CPS anticoagulation notes. Interventions included primary care provider (PCP) notification of elevated BP and offer of BP management by a PC CPS, patient education and/or PCP contact to discontinue concurrent NSAID or addition of a proton pump inhibitor (PPI) based on bleeding risk factor if the NSAID was deemed necessary, and discontinuation of concomitant antiplatelet drug(s) or reduction in aspirin dosage in consultation with patient’s PCP and cardiologist.⁹ In order to complete the initial HAS-BLED assessment and implement interventions, a note template was developed and entered into the electronic health record (EHR) that identified the patient’s modifiable risk factors.

Once the PCP and cardiologist (if applicable) responded to the note, by either accepting or declining the PC CPS recommendation(s), the HAS-BLED score was recalculated and recorded. If the provider did not respond to the initial note, an attempt was made to follow up at 3 months and at 6 months if necessary. If the provider did not respond at 6 months, the nonresponse was documented. For patients whose PCP requested PC CPS management of BP, the HAS-BLED score was recalculated 6 months after response from the PCP.

The primary outcome was the proportion of patients whose HAS-BLED score was reduced by at least 1 point. Secondary outcomes included the proportion of patients whose HAS-BLED score was reduced from one category of bleeding risk to a lesser one, total number of pharmacist interventions completed, number of pharmacist interventions made of each type (BP management, NSAID use, or antiplatelet drug use), and PCP acceptance rate.

Results

A total of 897 patients taking warfarin received anticoagulation management by a PC CPS at CJZVAMC in 2015. Of these, 819 patients were excluded based on the exclusion criteria (eFigure).

Seventy-eight patients were included in the assessment. Baseline HAS-BLED scores were calculated, and recommendations were made via an EHR progress note to the PCP and cardiologist (if applicable). Recommended interventions in the 78 patients resulted in 44 patients (56%) who experienced reduction in their HAS-BLED score by at least 1 point (Table 1). Twenty patients (25%) saw their HAS-BLED category reduced from a higher level of bleeding risk to a lower risk. The average HAS-BLED score in the 44 patients was 2.38 before intervention and 1.55 after the intervention.

A total of 82 interventions were recommended; 57 interventions were accepted, resulting in a provider acceptance rate of 69.5% (Tables 2 and 3). Thirty-five of the accepted interventions (61%) involved discontinuing an antiplatelet (aspirin or clopidogrel) in consultation with the patient’s PCP and cardiologist. Twenty-seven of these patients had no documented CAD, and 8 of the patients had stable CAD. Seventeen (30%) of the accepted recommendations were for discontinuing NSAID therapy, 2 (4%) were for BP management by a PC CPS, 2 (4%) for addition of PPI with continued NSAID use (meloxicam), and 1 (1%) for decreasing aspirin dosage from 325 to 81 mg/d. The NSAIDs that were discontinued included ibuprofen, indomethacin, meloxicam, and naproxen.

Discussion

This project is the first, to the authors’ knowledge, to evaluate pharmacist interventions to reduce modifiable bleeding risk factors identified by the HAS-BLED bleeding risk score. Most of the patients with nonvalvular AF in the PC clinics did not have modifiable bleeding risk factors. However, of the patients who received a recommendation to reduce a specific modifiable risk factor, most of the interventions were accepted by PCPs and cardiologists, and the HAS-BLED score was reduced. Furthermore, many interventions also resulted in reduction of the bleeding risk level.

Most of the interventions recommended evaluating the use of antiplatelet agents, particularly aspirin. The benefits of antiplatelet therapy for secondary prevention of cardiovascular disease are well established. However, for AF patients on OAC therapy, the concomitant use of antiplatelet therapy significantly increases the risk of bleeding and should be reserved for high-risk patients.¹⁰ The 2012 American College of Chest Physicians guidelines support the use of OAC monotherapy in patients with AF with stable CAD, including patients with a myocardial infarction or percutaneous coronary intervention more than 1 year previously, which has been corroborated with guideline and expert consensus recommendations released in 2016.^7,8,10,11

For patients taking warfarin for AF without CAD, the possible benefit of concomitant aspirin therapy for primary prevention is outweighed by the increased risk of major bleeding.¹² Furthermore, warfarin monotherapy has been shown to be effective in primary prevention of CAD and seems to have cardiovascular benefit for secondary prevention but with increased bleeding.^13,14 As a result, through the exclusion criteria this project aimed to evaluate warfarin patients with AF at low risk of cardiovascular events who might be taking unnecessary concurrent antiplatelet therapy.

More than one-half of the interventions involved discontinuing antiplatelet therapy. Chart reviews revealed a lack of documentation for the indication and intended duration of antiplatelet therapy. In many patients, it is likely that aspirin use predated AF diagnosis and warfarin initiation. In some of these cases, it would have been appropriate to discontinue aspirin when starting warfarin use. Although there is guidance to support the use of OAC monotherapy in patients with AF with stable CAD, the patient’s provider and cardiologist made the decision to discontinue an antiplatelet agent after weighing benefits and risks. Regardless of the outcome, this analysis revealed the importance and need for routine review of antiplatelet therapy and documenting the rationale for antiplatelet use in addition to anticoagulation.

The second largest category of interventions accepted was for evaluation of NSAID use. A 2014 study by Lamberts and colleagues found that concomitant use of oral anticoagulants and NSAIDs conferred an independent risk for major bleeding and thromboembolism in patients with AF.¹⁵ The increase in serious bleeding (absolute risk difference of 2.5 events per 1,000 patients) was observed even with short-term NSAID exposure of 14 days across all NSAID types (selective COX-2 inhibitors or nonselective NSAIDs). In addition, there was an incremental increase in bleeding risk with high NSAID dosages. The risk of serious bleeding was even greater when an NSAID is added to OAC therapy and aspirin. Seven out of 17 warfarin patients (41%) who were taking an NSAID also were on an antiplatelet agent. As a result of the pharmacist interventions, NSAIDs were discontinued in all of these patients, but the antiplatelet remained because of stent placement or carotid stenosis.

This analysis captured only those patients with a documented active prescription or self-reported OTC use of an NSAID. It is unknown how many patients might take OTC NSAIDs occasionally but not report this use to a provider or pharmacist. Primary care CPSs educate patients to not use NSAIDs while taking warfarin during their initial visit and periodically thereafter; however, with the number of different NSAIDs available without a prescription and the various brand and generic names offered, it can be difficult for patients to understand what they should or should not take for minor pain or fever. Therefore, it is imperative that NSAID use is reviewed regularly at anticoagulant follow-up visits and patients are educated about alternative OTC agents for pain relief (eg, acetaminophen, topical agents, heating pad) when necessary. It also is equally important for PCPs to weigh the benefit vs risk for each patient before prescribing an NSAID if alternatives have been exhausted especially if the patient also is taking an OAC and antiplatelet agent.

The smallest number of interventions completed was for BP management. According to the HAS-BLED bleeding risk score, BP management was recommended only if the most recent clinic SBP was > 160 mm Hg, excluding patients with documented white-coat syndrome or home SBP readings < 160 mm Hg. One potential explanation for the small number of patients with SBP > 160 mm Hg is that for many of the patients taking warfarin, the PC CPSs at CJZVAMC have been involved in their BP management through earlier consultation by providers.

Limitations

A limitation of the BP component of the HAS-BLED score was that the assessment of BP for this project was only one point in time. In 3 cases, the SBP was > 160 mm Hg only during the most recent measurement, and these patients had normal BP readings on return to the clinic for follow-up. This category of recommendation also took more time for follow-up because a PC CPS would need to evaluate the patient in clinic, implement changes to BP medications, and follow-up at subsequent visits. Although some PCPs felt that the patient did not need pharmacist intervention, the elevated SBPs were brought to the provider’s attention, and some patients received further monitoring by the PCP or through a specialty clinic (eg, nephrology).

Another limitation of this project was that the bleeding risk evaluation occurred at only 1 visit. Patients’ medications and medical issues often change with time. Therefore, it is important to implement a process to regularly review (eg, annually) patients’ bleeding risk factors and to identify and act on modifiable risk factors. Another limitation was a lack of a comparator group and the time frame of the evaluation. As a result, the authors were unable to evaluate bleeding outcomes because of the small sample size and limited time frame. Future studies could consider evaluating bleeding events as an outcome, including additional modifiable risk factors, such as excess alcohol and labile INR, expanding the review to patients taking warfarin for indications other than AF, and review of patients on direct-acting oral anticoagulants (DOACs) with AF; keeping in mind that currently available bleeding risk calculators were developed for patients taking warfarin, not DOACs with AF. Patients could be counselled on reducing alcohol intake or switching to a DOAC if INR is labile despite adherence.

Conclusion

This quality improvement project successfully implemented use of the HAS-BLED bleeding risk score to identify and reduce modifiable bleeding risk factors in patients with AF taking warfarin. Pharmacist intervention resulted in a reduction of HAS-BLED scores and bleeding risk categories.

Click here to read the digital edition.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with a 5-fold increase in the risk of ischemic stroke and the risk increases with age.^1-3 Oral anticoagulation (OAC) therapy effectively reduces the risk of ischemic stroke in patients with nonvalvular AF. However, OAC therapy carries a bleeding risk.⁴

Several bleeding risk scores have been developed and validated for patients with AF who are taking warfarin: HEMORR₂HAGES (Hepatic or renal disease, Ethanol abuse, Malignancy, Older age, Reduced platelet count or function, Re-bleeding, Hypertension, Anemia, Genetic factors, Excessive fall risk, Stroke), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and HAS-BLED (Hypertension, Abnormal renal and/or liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio [INR], Elderly, and Drugs and/or alcohol excess concomitantly).^4,5 All 3 bleeding risk scores demonstrate only modest ability to predict clinically relevant bleeding in patients taking warfarin. The HAS-BLED score was superior to HEMORR₂HAGES and ATRIA for predicting any clinically relevant bleeding and was the only bleeding risk score that demonstrated significant predictive performance for intracranial hemorrhage.⁵ Compared with HEMORR₂HAGES, the HAS-BLED score is simpler to use and to assess risk factors that can be gathered from medical history or routinely tested in patients with AF.⁴ Unlike HAS-BLED, HEMORR₂HAGES and ATRIA do not consider medications that could increase the risk of bleeding.

Despite the availability of validated bleeding risk scores, clinical application of these measures should not be used to exclude a patient from OAC therapy for patients who reach a threshold score. Rather, current guideline and expert consensus agree with the recommendation to use bleeding risk scores to identify risk factors and address those factors that are modifiable to reduce the risk of anticoagulant-associated major bleeding.^6-8

The authors identified modifiable bleeding risk factors using the HAS-BLED score and evaluated pharmacist interventions to correct these factors in patients with nonvalvular AF who are taking warfarin. To the authors’ knowledge, there have been no published studies evaluating interventions to reduce modifiable bleeding risk factors identified by the HAS-BLED score.

Methods

Clinical pharmacy specialists (CPSs) in the primary care (PC) clinics at the Clement J. Zablocki VAMC (CJZVAMC) in Milwaukee, Wisconsin, have prescriptive authority within their scope of practice to manage smoking cessation and diseases, including anticoagulation, diabetes mellitus, heart failure, hypertension, and dyslipidemia. Patients who are on OAC therapy, including warfarin, receive comprehensive anticoagulation management from PC CPSs, including prescribing OAC therapy, education, dosage adjustments, and laboratory monitoring.

Patients were included in the HAS-BLED risk scoring and intervention if their warfarin therapy was managed by a PC CPS, had an active warfarin prescription with a diagnosis of nonvalvular AF in their problem list, and had ≥ 1 modifiable risk factor(s) from the HAS-BLED risk score. Modifiable risk factors evaluated were systolic blood pressure (SBP) > 160 mm Hg, an active prescription for VA or non-VA (which generally indicates over-the-counter [OTC] medication use) aspirin, clopidogrel, or a nonsteroidal anti-inflammatory drug (NSAID). Excess alcohol consumption was not listed as a modifiable risk factor in this assessment because nearly all the anticoagulation patients already receive regular recommendations to minimize alcohol use from the PC CPSs.

Patients were excluded from analysis if they had an indication for warfarin use other than nonvalvular AF, such as atrial flutter, acute/chronic deep vein thrombosis or pulmonary embolism, history of venous thromboembolism, peripheral vascular disease, or aortic or mitral mechanical valve. Patients also were excluded if they were on antiplatelet therapy for unstable coronary artery disease (CAD), experienced acute coronary syndrome within the past 1 year, history of stent placement, carotid endarterectomy, carotid stenosis, or noncardioembolic stroke and no other modifiable risk factors. Last, patients were excluded if clinic SBP readings were > 160 mm Hg but there was documented white coat hypertension or home SBP readings < 160 mm Hg.

The following definitions or measurements were used for assessing the HAS-BLED bleeding risk score⁴:

• Uncontrolled hypertension: most recently charted SBP > 160 mm Hg;
• Abnormal renal function: dialysis, renal transplant, serum creatinine > 2.26 mg/dL;
• Abnormal liver function: chronic hepatic disease, biochemical evidence of significant hepatic derangement (bilirubin > 2 × upper limit of normal and/or AST/ALT/alkaline phosphatase > 3 × upper limit of normal);
• Stroke: including history of transient ischemic attack;
• Bleeding history or predisposition: history of major bleeding (intracranial and/or any bleeding requiring hospitalization and/or causing a decrease in hemoglobin (Hgb) level of > 2 g/dL and/or requiring blood transfusion), anemia (males: Hgb < 13 g/dL; females: Hgb < 12 g/dL);
• Labile INR: percentage of INRs in therapeutic range < 60% (using the CJZVAMC anticoagulation management tool, which calculates percentage of INRs in goal reported since the first visit);
• Geriatric: age > 65 years at initial assessment;
• Concomitant drug use (VA prescription or non-VA medication list): aspirin, clopidogrel, or NSAID; and
• Alcohol in excess: > 8 alcohol servings per week from chart documentation of the patient’s self-report.

In the HAS-BLED bleeding risk score, patients receive 1 point for each component for a maximum score of 9 points. The score is stratified into low (0 points), intermediate (1 to 2 points), and high (≥ 3 points) bleeding risk.⁴

The HAS-BLED risk factors were obtained from patient chart review, including problem list, laboratory results, and PC CPS anticoagulation notes. Interventions included primary care provider (PCP) notification of elevated BP and offer of BP management by a PC CPS, patient education and/or PCP contact to discontinue concurrent NSAID or addition of a proton pump inhibitor (PPI) based on bleeding risk factor if the NSAID was deemed necessary, and discontinuation of concomitant antiplatelet drug(s) or reduction in aspirin dosage in consultation with patient’s PCP and cardiologist.⁹ In order to complete the initial HAS-BLED assessment and implement interventions, a note template was developed and entered into the electronic health record (EHR) that identified the patient’s modifiable risk factors.

Once the PCP and cardiologist (if applicable) responded to the note, by either accepting or declining the PC CPS recommendation(s), the HAS-BLED score was recalculated and recorded. If the provider did not respond to the initial note, an attempt was made to follow up at 3 months and at 6 months if necessary. If the provider did not respond at 6 months, the nonresponse was documented. For patients whose PCP requested PC CPS management of BP, the HAS-BLED score was recalculated 6 months after response from the PCP.

The primary outcome was the proportion of patients whose HAS-BLED score was reduced by at least 1 point. Secondary outcomes included the proportion of patients whose HAS-BLED score was reduced from one category of bleeding risk to a lesser one, total number of pharmacist interventions completed, number of pharmacist interventions made of each type (BP management, NSAID use, or antiplatelet drug use), and PCP acceptance rate.

Results

A total of 897 patients taking warfarin received anticoagulation management by a PC CPS at CJZVAMC in 2015. Of these, 819 patients were excluded based on the exclusion criteria (eFigure).

Seventy-eight patients were included in the assessment. Baseline HAS-BLED scores were calculated, and recommendations were made via an EHR progress note to the PCP and cardiologist (if applicable). Recommended interventions in the 78 patients resulted in 44 patients (56%) who experienced reduction in their HAS-BLED score by at least 1 point (Table 1). Twenty patients (25%) saw their HAS-BLED category reduced from a higher level of bleeding risk to a lower risk. The average HAS-BLED score in the 44 patients was 2.38 before intervention and 1.55 after the intervention.

A total of 82 interventions were recommended; 57 interventions were accepted, resulting in a provider acceptance rate of 69.5% (Tables 2 and 3). Thirty-five of the accepted interventions (61%) involved discontinuing an antiplatelet (aspirin or clopidogrel) in consultation with the patient’s PCP and cardiologist. Twenty-seven of these patients had no documented CAD, and 8 of the patients had stable CAD. Seventeen (30%) of the accepted recommendations were for discontinuing NSAID therapy, 2 (4%) were for BP management by a PC CPS, 2 (4%) for addition of PPI with continued NSAID use (meloxicam), and 1 (1%) for decreasing aspirin dosage from 325 to 81 mg/d. The NSAIDs that were discontinued included ibuprofen, indomethacin, meloxicam, and naproxen.

Discussion

This project is the first, to the authors’ knowledge, to evaluate pharmacist interventions to reduce modifiable bleeding risk factors identified by the HAS-BLED bleeding risk score. Most of the patients with nonvalvular AF in the PC clinics did not have modifiable bleeding risk factors. However, of the patients who received a recommendation to reduce a specific modifiable risk factor, most of the interventions were accepted by PCPs and cardiologists, and the HAS-BLED score was reduced. Furthermore, many interventions also resulted in reduction of the bleeding risk level.

Most of the interventions recommended evaluating the use of antiplatelet agents, particularly aspirin. The benefits of antiplatelet therapy for secondary prevention of cardiovascular disease are well established. However, for AF patients on OAC therapy, the concomitant use of antiplatelet therapy significantly increases the risk of bleeding and should be reserved for high-risk patients.¹⁰ The 2012 American College of Chest Physicians guidelines support the use of OAC monotherapy in patients with AF with stable CAD, including patients with a myocardial infarction or percutaneous coronary intervention more than 1 year previously, which has been corroborated with guideline and expert consensus recommendations released in 2016.^7,8,10,11

For patients taking warfarin for AF without CAD, the possible benefit of concomitant aspirin therapy for primary prevention is outweighed by the increased risk of major bleeding.¹² Furthermore, warfarin monotherapy has been shown to be effective in primary prevention of CAD and seems to have cardiovascular benefit for secondary prevention but with increased bleeding.^13,14 As a result, through the exclusion criteria this project aimed to evaluate warfarin patients with AF at low risk of cardiovascular events who might be taking unnecessary concurrent antiplatelet therapy.

More than one-half of the interventions involved discontinuing antiplatelet therapy. Chart reviews revealed a lack of documentation for the indication and intended duration of antiplatelet therapy. In many patients, it is likely that aspirin use predated AF diagnosis and warfarin initiation. In some of these cases, it would have been appropriate to discontinue aspirin when starting warfarin use. Although there is guidance to support the use of OAC monotherapy in patients with AF with stable CAD, the patient’s provider and cardiologist made the decision to discontinue an antiplatelet agent after weighing benefits and risks. Regardless of the outcome, this analysis revealed the importance and need for routine review of antiplatelet therapy and documenting the rationale for antiplatelet use in addition to anticoagulation.

The second largest category of interventions accepted was for evaluation of NSAID use. A 2014 study by Lamberts and colleagues found that concomitant use of oral anticoagulants and NSAIDs conferred an independent risk for major bleeding and thromboembolism in patients with AF.¹⁵ The increase in serious bleeding (absolute risk difference of 2.5 events per 1,000 patients) was observed even with short-term NSAID exposure of 14 days across all NSAID types (selective COX-2 inhibitors or nonselective NSAIDs). In addition, there was an incremental increase in bleeding risk with high NSAID dosages. The risk of serious bleeding was even greater when an NSAID is added to OAC therapy and aspirin. Seven out of 17 warfarin patients (41%) who were taking an NSAID also were on an antiplatelet agent. As a result of the pharmacist interventions, NSAIDs were discontinued in all of these patients, but the antiplatelet remained because of stent placement or carotid stenosis.

This analysis captured only those patients with a documented active prescription or self-reported OTC use of an NSAID. It is unknown how many patients might take OTC NSAIDs occasionally but not report this use to a provider or pharmacist. Primary care CPSs educate patients to not use NSAIDs while taking warfarin during their initial visit and periodically thereafter; however, with the number of different NSAIDs available without a prescription and the various brand and generic names offered, it can be difficult for patients to understand what they should or should not take for minor pain or fever. Therefore, it is imperative that NSAID use is reviewed regularly at anticoagulant follow-up visits and patients are educated about alternative OTC agents for pain relief (eg, acetaminophen, topical agents, heating pad) when necessary. It also is equally important for PCPs to weigh the benefit vs risk for each patient before prescribing an NSAID if alternatives have been exhausted especially if the patient also is taking an OAC and antiplatelet agent.

The smallest number of interventions completed was for BP management. According to the HAS-BLED bleeding risk score, BP management was recommended only if the most recent clinic SBP was > 160 mm Hg, excluding patients with documented white-coat syndrome or home SBP readings < 160 mm Hg. One potential explanation for the small number of patients with SBP > 160 mm Hg is that for many of the patients taking warfarin, the PC CPSs at CJZVAMC have been involved in their BP management through earlier consultation by providers.

Limitations

A limitation of the BP component of the HAS-BLED score was that the assessment of BP for this project was only one point in time. In 3 cases, the SBP was > 160 mm Hg only during the most recent measurement, and these patients had normal BP readings on return to the clinic for follow-up. This category of recommendation also took more time for follow-up because a PC CPS would need to evaluate the patient in clinic, implement changes to BP medications, and follow-up at subsequent visits. Although some PCPs felt that the patient did not need pharmacist intervention, the elevated SBPs were brought to the provider’s attention, and some patients received further monitoring by the PCP or through a specialty clinic (eg, nephrology).

Another limitation of this project was that the bleeding risk evaluation occurred at only 1 visit. Patients’ medications and medical issues often change with time. Therefore, it is important to implement a process to regularly review (eg, annually) patients’ bleeding risk factors and to identify and act on modifiable risk factors. Another limitation was a lack of a comparator group and the time frame of the evaluation. As a result, the authors were unable to evaluate bleeding outcomes because of the small sample size and limited time frame. Future studies could consider evaluating bleeding events as an outcome, including additional modifiable risk factors, such as excess alcohol and labile INR, expanding the review to patients taking warfarin for indications other than AF, and review of patients on direct-acting oral anticoagulants (DOACs) with AF; keeping in mind that currently available bleeding risk calculators were developed for patients taking warfarin, not DOACs with AF. Patients could be counselled on reducing alcohol intake or switching to a DOAC if INR is labile despite adherence.

Conclusion

This quality improvement project successfully implemented use of the HAS-BLED bleeding risk score to identify and reduce modifiable bleeding risk factors in patients with AF taking warfarin. Pharmacist intervention resulted in a reduction of HAS-BLED scores and bleeding risk categories.

Click here to read the digital edition.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with a 5-fold increase in the risk of ischemic stroke and the risk increases with age.^1-3 Oral anticoagulation (OAC) therapy effectively reduces the risk of ischemic stroke in patients with nonvalvular AF. However, OAC therapy carries a bleeding risk.⁴

Several bleeding risk scores have been developed and validated for patients with AF who are taking warfarin: HEMORR₂HAGES (Hepatic or renal disease, Ethanol abuse, Malignancy, Older age, Reduced platelet count or function, Re-bleeding, Hypertension, Anemia, Genetic factors, Excessive fall risk, Stroke), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and HAS-BLED (Hypertension, Abnormal renal and/or liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio [INR], Elderly, and Drugs and/or alcohol excess concomitantly).^4,5 All 3 bleeding risk scores demonstrate only modest ability to predict clinically relevant bleeding in patients taking warfarin. The HAS-BLED score was superior to HEMORR₂HAGES and ATRIA for predicting any clinically relevant bleeding and was the only bleeding risk score that demonstrated significant predictive performance for intracranial hemorrhage.⁵ Compared with HEMORR₂HAGES, the HAS-BLED score is simpler to use and to assess risk factors that can be gathered from medical history or routinely tested in patients with AF.⁴ Unlike HAS-BLED, HEMORR₂HAGES and ATRIA do not consider medications that could increase the risk of bleeding.

Despite the availability of validated bleeding risk scores, clinical application of these measures should not be used to exclude a patient from OAC therapy for patients who reach a threshold score. Rather, current guideline and expert consensus agree with the recommendation to use bleeding risk scores to identify risk factors and address those factors that are modifiable to reduce the risk of anticoagulant-associated major bleeding.^6-8

The authors identified modifiable bleeding risk factors using the HAS-BLED score and evaluated pharmacist interventions to correct these factors in patients with nonvalvular AF who are taking warfarin. To the authors’ knowledge, there have been no published studies evaluating interventions to reduce modifiable bleeding risk factors identified by the HAS-BLED score.

Methods

Clinical pharmacy specialists (CPSs) in the primary care (PC) clinics at the Clement J. Zablocki VAMC (CJZVAMC) in Milwaukee, Wisconsin, have prescriptive authority within their scope of practice to manage smoking cessation and diseases, including anticoagulation, diabetes mellitus, heart failure, hypertension, and dyslipidemia. Patients who are on OAC therapy, including warfarin, receive comprehensive anticoagulation management from PC CPSs, including prescribing OAC therapy, education, dosage adjustments, and laboratory monitoring.

Patients were included in the HAS-BLED risk scoring and intervention if their warfarin therapy was managed by a PC CPS, had an active warfarin prescription with a diagnosis of nonvalvular AF in their problem list, and had ≥ 1 modifiable risk factor(s) from the HAS-BLED risk score. Modifiable risk factors evaluated were systolic blood pressure (SBP) > 160 mm Hg, an active prescription for VA or non-VA (which generally indicates over-the-counter [OTC] medication use) aspirin, clopidogrel, or a nonsteroidal anti-inflammatory drug (NSAID). Excess alcohol consumption was not listed as a modifiable risk factor in this assessment because nearly all the anticoagulation patients already receive regular recommendations to minimize alcohol use from the PC CPSs.

Patients were excluded from analysis if they had an indication for warfarin use other than nonvalvular AF, such as atrial flutter, acute/chronic deep vein thrombosis or pulmonary embolism, history of venous thromboembolism, peripheral vascular disease, or aortic or mitral mechanical valve. Patients also were excluded if they were on antiplatelet therapy for unstable coronary artery disease (CAD), experienced acute coronary syndrome within the past 1 year, history of stent placement, carotid endarterectomy, carotid stenosis, or noncardioembolic stroke and no other modifiable risk factors. Last, patients were excluded if clinic SBP readings were > 160 mm Hg but there was documented white coat hypertension or home SBP readings < 160 mm Hg.

The following definitions or measurements were used for assessing the HAS-BLED bleeding risk score⁴:

• Uncontrolled hypertension: most recently charted SBP > 160 mm Hg;
• Abnormal renal function: dialysis, renal transplant, serum creatinine > 2.26 mg/dL;
• Abnormal liver function: chronic hepatic disease, biochemical evidence of significant hepatic derangement (bilirubin > 2 × upper limit of normal and/or AST/ALT/alkaline phosphatase > 3 × upper limit of normal);
• Stroke: including history of transient ischemic attack;
• Bleeding history or predisposition: history of major bleeding (intracranial and/or any bleeding requiring hospitalization and/or causing a decrease in hemoglobin (Hgb) level of > 2 g/dL and/or requiring blood transfusion), anemia (males: Hgb < 13 g/dL; females: Hgb < 12 g/dL);
• Labile INR: percentage of INRs in therapeutic range < 60% (using the CJZVAMC anticoagulation management tool, which calculates percentage of INRs in goal reported since the first visit);
• Geriatric: age > 65 years at initial assessment;
• Concomitant drug use (VA prescription or non-VA medication list): aspirin, clopidogrel, or NSAID; and
• Alcohol in excess: > 8 alcohol servings per week from chart documentation of the patient’s self-report.

In the HAS-BLED bleeding risk score, patients receive 1 point for each component for a maximum score of 9 points. The score is stratified into low (0 points), intermediate (1 to 2 points), and high (≥ 3 points) bleeding risk.⁴

The HAS-BLED risk factors were obtained from patient chart review, including problem list, laboratory results, and PC CPS anticoagulation notes. Interventions included primary care provider (PCP) notification of elevated BP and offer of BP management by a PC CPS, patient education and/or PCP contact to discontinue concurrent NSAID or addition of a proton pump inhibitor (PPI) based on bleeding risk factor if the NSAID was deemed necessary, and discontinuation of concomitant antiplatelet drug(s) or reduction in aspirin dosage in consultation with patient’s PCP and cardiologist.⁹ In order to complete the initial HAS-BLED assessment and implement interventions, a note template was developed and entered into the electronic health record (EHR) that identified the patient’s modifiable risk factors.

Once the PCP and cardiologist (if applicable) responded to the note, by either accepting or declining the PC CPS recommendation(s), the HAS-BLED score was recalculated and recorded. If the provider did not respond to the initial note, an attempt was made to follow up at 3 months and at 6 months if necessary. If the provider did not respond at 6 months, the nonresponse was documented. For patients whose PCP requested PC CPS management of BP, the HAS-BLED score was recalculated 6 months after response from the PCP.

The primary outcome was the proportion of patients whose HAS-BLED score was reduced by at least 1 point. Secondary outcomes included the proportion of patients whose HAS-BLED score was reduced from one category of bleeding risk to a lesser one, total number of pharmacist interventions completed, number of pharmacist interventions made of each type (BP management, NSAID use, or antiplatelet drug use), and PCP acceptance rate.

Results

A total of 897 patients taking warfarin received anticoagulation management by a PC CPS at CJZVAMC in 2015. Of these, 819 patients were excluded based on the exclusion criteria (eFigure).

Seventy-eight patients were included in the assessment. Baseline HAS-BLED scores were calculated, and recommendations were made via an EHR progress note to the PCP and cardiologist (if applicable). Recommended interventions in the 78 patients resulted in 44 patients (56%) who experienced reduction in their HAS-BLED score by at least 1 point (Table 1). Twenty patients (25%) saw their HAS-BLED category reduced from a higher level of bleeding risk to a lower risk. The average HAS-BLED score in the 44 patients was 2.38 before intervention and 1.55 after the intervention.

A total of 82 interventions were recommended; 57 interventions were accepted, resulting in a provider acceptance rate of 69.5% (Tables 2 and 3). Thirty-five of the accepted interventions (61%) involved discontinuing an antiplatelet (aspirin or clopidogrel) in consultation with the patient’s PCP and cardiologist. Twenty-seven of these patients had no documented CAD, and 8 of the patients had stable CAD. Seventeen (30%) of the accepted recommendations were for discontinuing NSAID therapy, 2 (4%) were for BP management by a PC CPS, 2 (4%) for addition of PPI with continued NSAID use (meloxicam), and 1 (1%) for decreasing aspirin dosage from 325 to 81 mg/d. The NSAIDs that were discontinued included ibuprofen, indomethacin, meloxicam, and naproxen.

Discussion

This project is the first, to the authors’ knowledge, to evaluate pharmacist interventions to reduce modifiable bleeding risk factors identified by the HAS-BLED bleeding risk score. Most of the patients with nonvalvular AF in the PC clinics did not have modifiable bleeding risk factors. However, of the patients who received a recommendation to reduce a specific modifiable risk factor, most of the interventions were accepted by PCPs and cardiologists, and the HAS-BLED score was reduced. Furthermore, many interventions also resulted in reduction of the bleeding risk level.

Most of the interventions recommended evaluating the use of antiplatelet agents, particularly aspirin. The benefits of antiplatelet therapy for secondary prevention of cardiovascular disease are well established. However, for AF patients on OAC therapy, the concomitant use of antiplatelet therapy significantly increases the risk of bleeding and should be reserved for high-risk patients.¹⁰ The 2012 American College of Chest Physicians guidelines support the use of OAC monotherapy in patients with AF with stable CAD, including patients with a myocardial infarction or percutaneous coronary intervention more than 1 year previously, which has been corroborated with guideline and expert consensus recommendations released in 2016.^7,8,10,11

For patients taking warfarin for AF without CAD, the possible benefit of concomitant aspirin therapy for primary prevention is outweighed by the increased risk of major bleeding.¹² Furthermore, warfarin monotherapy has been shown to be effective in primary prevention of CAD and seems to have cardiovascular benefit for secondary prevention but with increased bleeding.^13,14 As a result, through the exclusion criteria this project aimed to evaluate warfarin patients with AF at low risk of cardiovascular events who might be taking unnecessary concurrent antiplatelet therapy.

More than one-half of the interventions involved discontinuing antiplatelet therapy. Chart reviews revealed a lack of documentation for the indication and intended duration of antiplatelet therapy. In many patients, it is likely that aspirin use predated AF diagnosis and warfarin initiation. In some of these cases, it would have been appropriate to discontinue aspirin when starting warfarin use. Although there is guidance to support the use of OAC monotherapy in patients with AF with stable CAD, the patient’s provider and cardiologist made the decision to discontinue an antiplatelet agent after weighing benefits and risks. Regardless of the outcome, this analysis revealed the importance and need for routine review of antiplatelet therapy and documenting the rationale for antiplatelet use in addition to anticoagulation.

The second largest category of interventions accepted was for evaluation of NSAID use. A 2014 study by Lamberts and colleagues found that concomitant use of oral anticoagulants and NSAIDs conferred an independent risk for major bleeding and thromboembolism in patients with AF.¹⁵ The increase in serious bleeding (absolute risk difference of 2.5 events per 1,000 patients) was observed even with short-term NSAID exposure of 14 days across all NSAID types (selective COX-2 inhibitors or nonselective NSAIDs). In addition, there was an incremental increase in bleeding risk with high NSAID dosages. The risk of serious bleeding was even greater when an NSAID is added to OAC therapy and aspirin. Seven out of 17 warfarin patients (41%) who were taking an NSAID also were on an antiplatelet agent. As a result of the pharmacist interventions, NSAIDs were discontinued in all of these patients, but the antiplatelet remained because of stent placement or carotid stenosis.

This analysis captured only those patients with a documented active prescription or self-reported OTC use of an NSAID. It is unknown how many patients might take OTC NSAIDs occasionally but not report this use to a provider or pharmacist. Primary care CPSs educate patients to not use NSAIDs while taking warfarin during their initial visit and periodically thereafter; however, with the number of different NSAIDs available without a prescription and the various brand and generic names offered, it can be difficult for patients to understand what they should or should not take for minor pain or fever. Therefore, it is imperative that NSAID use is reviewed regularly at anticoagulant follow-up visits and patients are educated about alternative OTC agents for pain relief (eg, acetaminophen, topical agents, heating pad) when necessary. It also is equally important for PCPs to weigh the benefit vs risk for each patient before prescribing an NSAID if alternatives have been exhausted especially if the patient also is taking an OAC and antiplatelet agent.

The smallest number of interventions completed was for BP management. According to the HAS-BLED bleeding risk score, BP management was recommended only if the most recent clinic SBP was > 160 mm Hg, excluding patients with documented white-coat syndrome or home SBP readings < 160 mm Hg. One potential explanation for the small number of patients with SBP > 160 mm Hg is that for many of the patients taking warfarin, the PC CPSs at CJZVAMC have been involved in their BP management through earlier consultation by providers.

Limitations

A limitation of the BP component of the HAS-BLED score was that the assessment of BP for this project was only one point in time. In 3 cases, the SBP was > 160 mm Hg only during the most recent measurement, and these patients had normal BP readings on return to the clinic for follow-up. This category of recommendation also took more time for follow-up because a PC CPS would need to evaluate the patient in clinic, implement changes to BP medications, and follow-up at subsequent visits. Although some PCPs felt that the patient did not need pharmacist intervention, the elevated SBPs were brought to the provider’s attention, and some patients received further monitoring by the PCP or through a specialty clinic (eg, nephrology).

Another limitation of this project was that the bleeding risk evaluation occurred at only 1 visit. Patients’ medications and medical issues often change with time. Therefore, it is important to implement a process to regularly review (eg, annually) patients’ bleeding risk factors and to identify and act on modifiable risk factors. Another limitation was a lack of a comparator group and the time frame of the evaluation. As a result, the authors were unable to evaluate bleeding outcomes because of the small sample size and limited time frame. Future studies could consider evaluating bleeding events as an outcome, including additional modifiable risk factors, such as excess alcohol and labile INR, expanding the review to patients taking warfarin for indications other than AF, and review of patients on direct-acting oral anticoagulants (DOACs) with AF; keeping in mind that currently available bleeding risk calculators were developed for patients taking warfarin, not DOACs with AF. Patients could be counselled on reducing alcohol intake or switching to a DOAC if INR is labile despite adherence.

Conclusion

This quality improvement project successfully implemented use of the HAS-BLED bleeding risk score to identify and reduce modifiable bleeding risk factors in patients with AF taking warfarin. Pharmacist intervention resulted in a reduction of HAS-BLED scores and bleeding risk categories.

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In the U.S., about 5.1 million people have clinically manifested heart failure (HF).¹ The absolute mortality rate for HF is about 50% within 5 years of diagnosis, and 1 in 9 death certificates in the U.S. list HF as a cause of death.² Heart failure is the primary diagnosis in more than 1 million hospitalizations annually.¹ Patients with HF who are at risk for all-cause rehospitalization have a 1-month readmission rate of 25%, and their median survival time decreases with each hospitalization.^3,4 Heart failure is the top reason for discharge of veterans treated within the VA health care system.⁵

Some medications decrease morbidity and mortality in patients with systolic dysfunction.⁶ These medications include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and β-blockers (BBs). Studies have demonstrated effectiveness of these medications in patients with reduced ejection fraction (EF) of less or equal to 40%. Other medications with proven success include aldosterone antagonists, hydralazine in combination with a nitrate, and digoxin. The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines provide medication recommendations based on the ACCF/AHA stages of HF and the New York Heart Association (NYHA) functional classifications, designated as guideline-directed medical therapy (GDMT).^6,7 Therapeutic interventions are aimed at reducing morbidity and mortality for ACCF/AHA stage C HF. The ACCF/AHA guidelines also recommend establishing multidisciplinary HF disease management programs for patients at high risk for hospital readmission to facilitate implementation of GDMT, address different barriers to behavior change, and reduce the risk of subsequent rehospitalization for HF.⁶

In October 2010, the Jesse Brown VAMC (JBVAMC) in Chicago, Illinois, opened its Heart Failure Disease Management Program (HFDMP) to prevent readmissions by targeting patients discharged after HF exacerbations and arranging follow-up in the HFDMP clinic. Enrollment in the clinic is initiated when an inpatient physician places a consultation. A cardiology nurse practitioner (NP) receives the consultation and schedules an in-clinic appointment for the patient within 1 week of discharge. The patient goes to the clinic on average every 2 weeks until he or she is on a stable, optimal medication regimen and is competent in self-management. After 3 months, the patient transitions to the general cardiology clinic. This process allows the HFDMP to see new patients in need of intense care and education for HF. The multidisciplinary HFDMP began with a NP and a cardiologist and 6 months later in April 2011 added a pharmacist.

After enrolling in HFDMP, the patient can be referred to the pharmacist for independent optimization of medication therapy in the Pharmacy Medication Titration Clinic (PMTC). The PMTC at JBVAMC is different from other HF clinics in that the pharmacist has prescribing authority and can interact face-to-face with patients to titrate medications. Once a patient is on an optimal medication regimen, he or she is referred to the NP and cardiologist. The PMTC is open 4 hours twice per month and offers 30-minute time slots. The authors conducted a study of the effectiveness of face-to-face PMTC appointments within the HFDMP.

Methods

This study, approved by the institutional review board at the University of Illinois at Chicago and the research and development service at JBVAMC, was a retrospective electronic chart review of patients enrolled in the HFDMP. Study patients were aged ≥ 18 years and were enrolled in the HFDMP between April 15, 2011 and April 15, 2013. Exclusion criteria included EF higher than 40%, 1 or no appointment attended, and enrollment before April 15, 2011. There were 2 study groups: HFDMP patients enrolled in PMTC (PMTC group) and HFDMP patients not enrolled in PMTC (no-PMTC group). For 1:1 comparison, the number of patients who met the criteria for the PMTC group was used to determine the number of patients to include in the no-PMTC group. Baseline date was the date of enrollment into either HFDMP or PMTC.

Data collected at baseline included demographics, NYHA class of HF, blood pressure (BP), heart rate, ejection fraction (EF), date of HF diagnosis, number of hospitalizations for HF within previous 6 months, serum creatinine level, height, weight, comorbidities, and HF medications. Data collected at the end date included NYHA class of HF; BP; heart rate; EF; HF medications; reason for not achieving target dose of medication or GDMT; ACEI, ARB, or BB adherence, defined as 80% of medication refills 6 months after date of discharge from group; readmission for HF within 30 days and 90 days; length of stay (LOS), including bed type if readmitted; emergency department (ED) visits for HF within 6 months of date of discharge from group; and death within 6 months of date of discharge from group. Clinical GDMT was defined as reaching the maximum tolerable or target dose of each HF medication for each patient depending on clinical presentation, as recommended by the ACCF/AHA guidelines for HF.⁶ It incorporated NYHA class of HF, contraindications, hypotension, bradycardia, dizziness, and hyperkalemia as well as the prescribing of aldosterone antagonists, hydralazine and isosorbide dinitrate, and digoxin.

Study Outcomes

There were 2 primary endpoints: difference in percentage of patients who achieved target ACEI or ARB doses and difference in percentage of patients who achieved target BB doses. Secondary endpoints were difference between PMTC and no-PMTC groups in percentage of patient achievement in clinical GDMT; percentage medication adherence; percentage of patients with change in NYHA class of HF; percentage of patients with change in EF, including mean change; percentage of patients with 30-day and 90-day readmissions for HF; mean LOS if readmitted within 30 days and 90 days; percentage of patients with ED visits for HF within 6 months after baseline; and percentage mortality within 6 months after baseline.

Statistical Analysis

A 2-tailed Fisher exact test was used for nominal data, and a Student t test for continuous data. Statistical significance was set at P < .05.

Results

Of the 228 HFDMP enrollees, 29 were seen in the PMTC during the study period, and 199 were not seen in the PMTC. Of the 29 patients seen in the PMTC, 24 met the criteria for the PMTC study group. Charts of 106 of the 199 patients not seen in the PMTC were randomly reviewed until 24 patients who met the study criteria were selected for the no-PMTC study group. Thus, the PMTC group and the no-PMTC group each had 24 patients for 1:1 comparison. Eighty-seven patients were excluded from the study: 22 with EF > 40%, 50 with 1 or no appointment attended, and 15 who were enrolled in HFDMP before April 15, 2011.

Mean age was 66 years. All patients were male, and most were African American. The baseline characteristics of the PMTC and no-PMTC groups were similar, except a higher percentage of patients in the PMTC group had NYHA class II or III of HF (Table 1).

The ACEI or ARB target dose was achieved by a higher percentage of patients in the PMTC group, 79.2% (n = 19) vs 50% (n = 12), but the difference was not significant (P = .07) (Figure 1). However, BB target dose was achieved by a significantly higher (P = .01) percentage of patients in the PMTC group, 87.5% (n = 21) vs 20.8% (n = 5)(Figure 2). Furthermore, a significantly higher (P = .02) percentage of patients in the PMTC group, 62.5% (n = 15) vs 25% (n = 6), achieved composite clinical GDMT (Table 2). Last, there was not a statistically significant difference in 80% adherence with ACEI or ARB dosing or with BB dosing between the PMTC group (70.8%; n = 17) and the no-PMTC group (75%; n = 18).

For a higher percentage of patients in the PMTC group, 50% (n = 12) vs 29.2% (n = 7), NYHA class of HF improved, but the difference was not significant (P = .24). In addition, EF improved in a higher percentage of patients in the PMTC group, 71.4% (n = 10) vs 41.7% (n = 5), and mean (SD) improvement in EF was higher in the PMTC group, 12.5% (12%) vs 5.4% (13%), but neither difference was significant (P = .23 and P = .16, respectively).

A higher percentage of patients in the no-PMTC group were readmitted for HF within 30 days, 8.3% (n = 2) vs 0%, but the difference was not significant. Likewise, a higher percentage of patients in the no-PMTC group were readmitted for HF within 90 days, 20.8% (n = 5) vs 4.2% (n = 1; P = .19). Mean LOS for these readmissions was longer in the PMTC group, 8 days (n = 1) vs 6.5 days (n = 8). There was a higher percentage of ED visits for HF in the no-PMTC group, 37.5% (n = 9) vs 20.8% (n = 5), but did not reach statistical significance (P = .34). Last, the no-PMTC group had a higher percentage of deaths within 6 months after baseline, 37.5% (n = 9) vs 20.8% (n = 9), which also was not significant.

Discussion

This study demonstrated that, within HFDMPs, there is a role for a pharmacist who has prescribing authority and interacts face-to-face with patients in the clinic. Significantly more patients in the PMTC group achieved target BB doses by the end of the study. Target doses of BBs have been found to decrease morbidity and mortality.^8-10

The present study also found a positive trend toward achieving target ACEI or ARB doses. Reasons for not achieving target doses included contraindication to the medication, medication discontinuation during hospital admission, hypotension, hyperkalemia, and titration not complete by end of study period. Two of the many reasons for titration not being complete were clinic enrollment timing and nonadherence. Although achievement of target ACEI or ARB doses did not reach statistical significance, statistically significantly more patients achieved composite clinical GDMT.

As defined in the study, clinical GDMT captured the prescribing of hydralazine and isosorbide dinitrate in patients intolerant to ACEIs and ARBs. This study, the first known to evaluate achievement in GDMT, demonstrated a pharmacist’s ability to titrate more than just ACEI, ARB, and BB doses. This finding is clinically important in that appropriate pharmacologic therapy can reduce the number of hospitalizations for HF and improve survival, even though the study found that its PMTC group showed only trends toward fewer 30-day and 90-day readmissions for HF, fewer ED visits for HF, and less mortality.⁶ This finding may be attributable to the small number of readmissions for HF and deaths among the study groups.

One endpoint that did not show an expected difference with pharmacist intervention was medication adherence. However, medication nonadherence likely was a reason for patient referral to the PMTC. Baseline medication adherence was not determined, so improvement in adherence could not be assessed. Findings might have been different, too, if medication adherence had been evaluated with patient interviews and refill history, not just refill history.

In the PMTC group, LOS for readmissions for HF did not improve. However, the group had only 1 readmission, which may have skewed the result. No studies have linked outpatient pharmacist intervention to decreased LOS for readmission for HF. The endpoint was evaluated to assess whether medication stability leads to reduced LOS and to complete a limited cost analysis. Analysis of mean cost based on number of readmissions, bed type, and LOS revealed a cost savings of $167,556.82 for the PMTC group (Table 3). Other potential cost savings that are difficult to quantify and that were not accounted for include extended time between ED visits or readmissions for HF and increased quality of life and daily functioning.

This is the first study known to evaluate a pharmacist who had prescribing authority and interacted face-to-face with patients. Other studies have evaluated the role of the pharmacist in the multidisciplinary management of patients with HF. In 1999, the Pharmacist in Heart Failure Assessment Recommendation and Monitoring (PHARM) study reported the effect of direct HF-related patient care by a pharmacist who performed medication evaluations, provided patient education, and made medication recommendations to a physician.¹¹

After a medication dosing change, the pharmacist provided telephone follow-up to assess for problems with the drug therapy and then, if any were identified, referred patients to the physician. Pharmacist intervention demonstrated a decrease in all-cause mortality and HF events and an increase in ACEI doses. Unlike the pharmacist in the present study, the pharmacist had to get recommendations approved and prescribed by a physician. The present PMTC allows for pharmacist intervention, including medication therapy changes and follow-up appointments without consultation with a physician. If needed, the HF cardiologist is available in the HFDMP clinic or by telephone.

Jain and colleagues evaluated a protocol-driven medication titration clinic staffed by nurse and pharmacist specialists.¹² Although their study was limited by its descriptive nature, the authors concluded that the clinic increased the number of patients who achieved target ACEI/ARB or target BB doses. In the present study, the percentage of PMTC patients who achieved target doses increased during the study period, from 50% to 79.2% (ACEI/ARB) and from 20.8% to 87.5% (BB). Unlike other clinic pharmacists, however, the PMTC pharmacist titrates medications independently and does not follow a set clinic protocol.

Similar to the PHARM study, the Heart Failure Optimal Outcomes From Pharmacy Study (HOOPS) evaluated pharmacists who worked collaboratively with physicians to optimize HF therapy.¹³ As in the PMTC, patients and pharmacists had 30-minute appointments together. In HOOPS, however, physician agreement was needed before pharmacist recommendations were implemented. That study found that more patients with pharmacist intervention started an ACEI or ARB, had the medication titrated, and received recommended doses. More patients also either started a BB or increased its dose, but this did not increase the number of patients who received recommended BB doses. In addition, pharmacist intervention did not affect clinical outcomes. The authors acknowledged this finding might be attributable to the pharmacists’ lack of proper HF management training. Patients in the study were also more stable, whereas PMTC patients arrived after HF discharge and were followed until medication therapy was optimized. The HOOPS followed patients for only 3 or 4 visits, regardless of target dose achievement status.

In a study conducted within the VA health care system, Martinez and colleagues evaluated the use of pharmacists who had prescribing authority and were permitted to order laboratory tests under a scope of practice similar to that in the present study.¹⁴ However, their coordination agreement allowed them only to initiate and adjust doses of certain HF medications according to defined protocols. The pharmacist conducted monthly education classes and had medication titration appointments with individual patients by telephone over 2-week intervals. Face-to-face appointments were limited to medication reconciliations, whereas all appointments in the present study were face-to-face. In addition, Martinez and colleagues found that a higher percentage of patients who attended pharmacist appointments achieved target ACEI, ARB, and BB doses, whereas the present study found a higher percentage only of achieved target BB doses, not ACEI or ARB. However, the present study also found increased composite clinical GDMT achievement, which Martinez and colleagues did not evaluate. As mentioned, GDMT achievement may be a broader evaluation of optimal HF medical therapy, as it incorporates ACEI or ARB intolerance.

Martinez and colleagues acknowledged several study limitations different from those of the present study.¹⁴ Most members of their study population were white men, unlike this study’s population. Combining these 2 studies’ results may support use of pharmacist intervention for both white and African American men. In addition, the authors noted that patients often forgot their medications or were confused about doses, and concluded that forgetfulness and confusion may stem from having only telephone interviews and lacking written instructions for the interval between clinic appointments. By contrast, all PMTC patients were seen face-to-face, and handouts detailing any changes helped minimized confusion. Even with face-to-face appointments, however, patient nonadherence persisted, making it difficult to optimize HF therapy. Patients did not always follow instructions to bring HF medications (or medication lists) and daily weight measurements to clinic visits, which complicated medication reconciliations, interventions, and educational efforts regarding dose changes. Furthermore, patients sometimes missed face-to-face appointments, often because of transportation difficulties. In these situations, telephone appointments may be beneficial. The obstacle of transportation is removed, and, during the at-home telephone call, the patient has easy access to medications and measurements.

Limitations

This study had several limitations. It was retrospective, and its sample size was too small for conclusions regarding morbidity and mortality. As the population was predominantly African American males, results may not be applicable to other races and females. Furthermore, not evaluating HF causes at baseline could have confounded results, as disease progression, response to medications, and prognosis can vary, depending on etiology. Moreover, as patients are referred from the HFDMP to the PMTC, there may have been a bias in patient selection for the PMTC group. Patients in the PMTC group may have been more clinically stable yet had a larger knowledge deficit, an adherence issue, or a need for difficult, frequent titrations. Patients also may have been less likely to be seen during the first 30 days after discharge. In addition, it could have been beneficial to match patients on NYHA class of HF at baseline to ensure HF severity was balanced between groups. Last, the adherence analysis may not be accurate, as it relied on refill history, which may not reflect how medications were taken at home.

It would be beneficial to expand this initial study with a larger sample. Presumed HF causes and medication adherence should be captured at baseline. Additional endpoints, including quality of life and patient cognition, could enhance results. Furthermore, comparing the HFDMP with the general cardiology clinic may reveal other benefits of a focused HFDMP and its PMTC. Last, evaluating patients who are recently discharged from HF admission yet not enrolled in the HFDMP may provide more information regarding the utility of both the HFDMP and the PMTC.

Conclusion

For the PMTC group in this study, achievement of target BB doses and achievement in composite clinical GDMT were significant, but achievement of target ACEI/ARB doses were not.

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In the U.S., about 5.1 million people have clinically manifested heart failure (HF).¹ The absolute mortality rate for HF is about 50% within 5 years of diagnosis, and 1 in 9 death certificates in the U.S. list HF as a cause of death.² Heart failure is the primary diagnosis in more than 1 million hospitalizations annually.¹ Patients with HF who are at risk for all-cause rehospitalization have a 1-month readmission rate of 25%, and their median survival time decreases with each hospitalization.^3,4 Heart failure is the top reason for discharge of veterans treated within the VA health care system.⁵

Some medications decrease morbidity and mortality in patients with systolic dysfunction.⁶ These medications include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and β-blockers (BBs). Studies have demonstrated effectiveness of these medications in patients with reduced ejection fraction (EF) of less or equal to 40%. Other medications with proven success include aldosterone antagonists, hydralazine in combination with a nitrate, and digoxin. The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines provide medication recommendations based on the ACCF/AHA stages of HF and the New York Heart Association (NYHA) functional classifications, designated as guideline-directed medical therapy (GDMT).^6,7 Therapeutic interventions are aimed at reducing morbidity and mortality for ACCF/AHA stage C HF. The ACCF/AHA guidelines also recommend establishing multidisciplinary HF disease management programs for patients at high risk for hospital readmission to facilitate implementation of GDMT, address different barriers to behavior change, and reduce the risk of subsequent rehospitalization for HF.⁶

In October 2010, the Jesse Brown VAMC (JBVAMC) in Chicago, Illinois, opened its Heart Failure Disease Management Program (HFDMP) to prevent readmissions by targeting patients discharged after HF exacerbations and arranging follow-up in the HFDMP clinic. Enrollment in the clinic is initiated when an inpatient physician places a consultation. A cardiology nurse practitioner (NP) receives the consultation and schedules an in-clinic appointment for the patient within 1 week of discharge. The patient goes to the clinic on average every 2 weeks until he or she is on a stable, optimal medication regimen and is competent in self-management. After 3 months, the patient transitions to the general cardiology clinic. This process allows the HFDMP to see new patients in need of intense care and education for HF. The multidisciplinary HFDMP began with a NP and a cardiologist and 6 months later in April 2011 added a pharmacist.

After enrolling in HFDMP, the patient can be referred to the pharmacist for independent optimization of medication therapy in the Pharmacy Medication Titration Clinic (PMTC). The PMTC at JBVAMC is different from other HF clinics in that the pharmacist has prescribing authority and can interact face-to-face with patients to titrate medications. Once a patient is on an optimal medication regimen, he or she is referred to the NP and cardiologist. The PMTC is open 4 hours twice per month and offers 30-minute time slots. The authors conducted a study of the effectiveness of face-to-face PMTC appointments within the HFDMP.

Methods

This study, approved by the institutional review board at the University of Illinois at Chicago and the research and development service at JBVAMC, was a retrospective electronic chart review of patients enrolled in the HFDMP. Study patients were aged ≥ 18 years and were enrolled in the HFDMP between April 15, 2011 and April 15, 2013. Exclusion criteria included EF higher than 40%, 1 or no appointment attended, and enrollment before April 15, 2011. There were 2 study groups: HFDMP patients enrolled in PMTC (PMTC group) and HFDMP patients not enrolled in PMTC (no-PMTC group). For 1:1 comparison, the number of patients who met the criteria for the PMTC group was used to determine the number of patients to include in the no-PMTC group. Baseline date was the date of enrollment into either HFDMP or PMTC.

Data collected at baseline included demographics, NYHA class of HF, blood pressure (BP), heart rate, ejection fraction (EF), date of HF diagnosis, number of hospitalizations for HF within previous 6 months, serum creatinine level, height, weight, comorbidities, and HF medications. Data collected at the end date included NYHA class of HF; BP; heart rate; EF; HF medications; reason for not achieving target dose of medication or GDMT; ACEI, ARB, or BB adherence, defined as 80% of medication refills 6 months after date of discharge from group; readmission for HF within 30 days and 90 days; length of stay (LOS), including bed type if readmitted; emergency department (ED) visits for HF within 6 months of date of discharge from group; and death within 6 months of date of discharge from group. Clinical GDMT was defined as reaching the maximum tolerable or target dose of each HF medication for each patient depending on clinical presentation, as recommended by the ACCF/AHA guidelines for HF.⁶ It incorporated NYHA class of HF, contraindications, hypotension, bradycardia, dizziness, and hyperkalemia as well as the prescribing of aldosterone antagonists, hydralazine and isosorbide dinitrate, and digoxin.

Study Outcomes

There were 2 primary endpoints: difference in percentage of patients who achieved target ACEI or ARB doses and difference in percentage of patients who achieved target BB doses. Secondary endpoints were difference between PMTC and no-PMTC groups in percentage of patient achievement in clinical GDMT; percentage medication adherence; percentage of patients with change in NYHA class of HF; percentage of patients with change in EF, including mean change; percentage of patients with 30-day and 90-day readmissions for HF; mean LOS if readmitted within 30 days and 90 days; percentage of patients with ED visits for HF within 6 months after baseline; and percentage mortality within 6 months after baseline.

Statistical Analysis

A 2-tailed Fisher exact test was used for nominal data, and a Student t test for continuous data. Statistical significance was set at P < .05.

Results

Of the 228 HFDMP enrollees, 29 were seen in the PMTC during the study period, and 199 were not seen in the PMTC. Of the 29 patients seen in the PMTC, 24 met the criteria for the PMTC study group. Charts of 106 of the 199 patients not seen in the PMTC were randomly reviewed until 24 patients who met the study criteria were selected for the no-PMTC study group. Thus, the PMTC group and the no-PMTC group each had 24 patients for 1:1 comparison. Eighty-seven patients were excluded from the study: 22 with EF > 40%, 50 with 1 or no appointment attended, and 15 who were enrolled in HFDMP before April 15, 2011.

Mean age was 66 years. All patients were male, and most were African American. The baseline characteristics of the PMTC and no-PMTC groups were similar, except a higher percentage of patients in the PMTC group had NYHA class II or III of HF (Table 1).

The ACEI or ARB target dose was achieved by a higher percentage of patients in the PMTC group, 79.2% (n = 19) vs 50% (n = 12), but the difference was not significant (P = .07) (Figure 1). However, BB target dose was achieved by a significantly higher (P = .01) percentage of patients in the PMTC group, 87.5% (n = 21) vs 20.8% (n = 5)(Figure 2). Furthermore, a significantly higher (P = .02) percentage of patients in the PMTC group, 62.5% (n = 15) vs 25% (n = 6), achieved composite clinical GDMT (Table 2). Last, there was not a statistically significant difference in 80% adherence with ACEI or ARB dosing or with BB dosing between the PMTC group (70.8%; n = 17) and the no-PMTC group (75%; n = 18).

For a higher percentage of patients in the PMTC group, 50% (n = 12) vs 29.2% (n = 7), NYHA class of HF improved, but the difference was not significant (P = .24). In addition, EF improved in a higher percentage of patients in the PMTC group, 71.4% (n = 10) vs 41.7% (n = 5), and mean (SD) improvement in EF was higher in the PMTC group, 12.5% (12%) vs 5.4% (13%), but neither difference was significant (P = .23 and P = .16, respectively).

A higher percentage of patients in the no-PMTC group were readmitted for HF within 30 days, 8.3% (n = 2) vs 0%, but the difference was not significant. Likewise, a higher percentage of patients in the no-PMTC group were readmitted for HF within 90 days, 20.8% (n = 5) vs 4.2% (n = 1; P = .19). Mean LOS for these readmissions was longer in the PMTC group, 8 days (n = 1) vs 6.5 days (n = 8). There was a higher percentage of ED visits for HF in the no-PMTC group, 37.5% (n = 9) vs 20.8% (n = 5), but did not reach statistical significance (P = .34). Last, the no-PMTC group had a higher percentage of deaths within 6 months after baseline, 37.5% (n = 9) vs 20.8% (n = 9), which also was not significant.

Discussion

This study demonstrated that, within HFDMPs, there is a role for a pharmacist who has prescribing authority and interacts face-to-face with patients in the clinic. Significantly more patients in the PMTC group achieved target BB doses by the end of the study. Target doses of BBs have been found to decrease morbidity and mortality.^8-10

The present study also found a positive trend toward achieving target ACEI or ARB doses. Reasons for not achieving target doses included contraindication to the medication, medication discontinuation during hospital admission, hypotension, hyperkalemia, and titration not complete by end of study period. Two of the many reasons for titration not being complete were clinic enrollment timing and nonadherence. Although achievement of target ACEI or ARB doses did not reach statistical significance, statistically significantly more patients achieved composite clinical GDMT.

As defined in the study, clinical GDMT captured the prescribing of hydralazine and isosorbide dinitrate in patients intolerant to ACEIs and ARBs. This study, the first known to evaluate achievement in GDMT, demonstrated a pharmacist’s ability to titrate more than just ACEI, ARB, and BB doses. This finding is clinically important in that appropriate pharmacologic therapy can reduce the number of hospitalizations for HF and improve survival, even though the study found that its PMTC group showed only trends toward fewer 30-day and 90-day readmissions for HF, fewer ED visits for HF, and less mortality.⁶ This finding may be attributable to the small number of readmissions for HF and deaths among the study groups.

One endpoint that did not show an expected difference with pharmacist intervention was medication adherence. However, medication nonadherence likely was a reason for patient referral to the PMTC. Baseline medication adherence was not determined, so improvement in adherence could not be assessed. Findings might have been different, too, if medication adherence had been evaluated with patient interviews and refill history, not just refill history.

In the PMTC group, LOS for readmissions for HF did not improve. However, the group had only 1 readmission, which may have skewed the result. No studies have linked outpatient pharmacist intervention to decreased LOS for readmission for HF. The endpoint was evaluated to assess whether medication stability leads to reduced LOS and to complete a limited cost analysis. Analysis of mean cost based on number of readmissions, bed type, and LOS revealed a cost savings of $167,556.82 for the PMTC group (Table 3). Other potential cost savings that are difficult to quantify and that were not accounted for include extended time between ED visits or readmissions for HF and increased quality of life and daily functioning.

This is the first study known to evaluate a pharmacist who had prescribing authority and interacted face-to-face with patients. Other studies have evaluated the role of the pharmacist in the multidisciplinary management of patients with HF. In 1999, the Pharmacist in Heart Failure Assessment Recommendation and Monitoring (PHARM) study reported the effect of direct HF-related patient care by a pharmacist who performed medication evaluations, provided patient education, and made medication recommendations to a physician.¹¹

After a medication dosing change, the pharmacist provided telephone follow-up to assess for problems with the drug therapy and then, if any were identified, referred patients to the physician. Pharmacist intervention demonstrated a decrease in all-cause mortality and HF events and an increase in ACEI doses. Unlike the pharmacist in the present study, the pharmacist had to get recommendations approved and prescribed by a physician. The present PMTC allows for pharmacist intervention, including medication therapy changes and follow-up appointments without consultation with a physician. If needed, the HF cardiologist is available in the HFDMP clinic or by telephone.

Jain and colleagues evaluated a protocol-driven medication titration clinic staffed by nurse and pharmacist specialists.¹² Although their study was limited by its descriptive nature, the authors concluded that the clinic increased the number of patients who achieved target ACEI/ARB or target BB doses. In the present study, the percentage of PMTC patients who achieved target doses increased during the study period, from 50% to 79.2% (ACEI/ARB) and from 20.8% to 87.5% (BB). Unlike other clinic pharmacists, however, the PMTC pharmacist titrates medications independently and does not follow a set clinic protocol.

Similar to the PHARM study, the Heart Failure Optimal Outcomes From Pharmacy Study (HOOPS) evaluated pharmacists who worked collaboratively with physicians to optimize HF therapy.¹³ As in the PMTC, patients and pharmacists had 30-minute appointments together. In HOOPS, however, physician agreement was needed before pharmacist recommendations were implemented. That study found that more patients with pharmacist intervention started an ACEI or ARB, had the medication titrated, and received recommended doses. More patients also either started a BB or increased its dose, but this did not increase the number of patients who received recommended BB doses. In addition, pharmacist intervention did not affect clinical outcomes. The authors acknowledged this finding might be attributable to the pharmacists’ lack of proper HF management training. Patients in the study were also more stable, whereas PMTC patients arrived after HF discharge and were followed until medication therapy was optimized. The HOOPS followed patients for only 3 or 4 visits, regardless of target dose achievement status.

In a study conducted within the VA health care system, Martinez and colleagues evaluated the use of pharmacists who had prescribing authority and were permitted to order laboratory tests under a scope of practice similar to that in the present study.¹⁴ However, their coordination agreement allowed them only to initiate and adjust doses of certain HF medications according to defined protocols. The pharmacist conducted monthly education classes and had medication titration appointments with individual patients by telephone over 2-week intervals. Face-to-face appointments were limited to medication reconciliations, whereas all appointments in the present study were face-to-face. In addition, Martinez and colleagues found that a higher percentage of patients who attended pharmacist appointments achieved target ACEI, ARB, and BB doses, whereas the present study found a higher percentage only of achieved target BB doses, not ACEI or ARB. However, the present study also found increased composite clinical GDMT achievement, which Martinez and colleagues did not evaluate. As mentioned, GDMT achievement may be a broader evaluation of optimal HF medical therapy, as it incorporates ACEI or ARB intolerance.

Martinez and colleagues acknowledged several study limitations different from those of the present study.¹⁴ Most members of their study population were white men, unlike this study’s population. Combining these 2 studies’ results may support use of pharmacist intervention for both white and African American men. In addition, the authors noted that patients often forgot their medications or were confused about doses, and concluded that forgetfulness and confusion may stem from having only telephone interviews and lacking written instructions for the interval between clinic appointments. By contrast, all PMTC patients were seen face-to-face, and handouts detailing any changes helped minimized confusion. Even with face-to-face appointments, however, patient nonadherence persisted, making it difficult to optimize HF therapy. Patients did not always follow instructions to bring HF medications (or medication lists) and daily weight measurements to clinic visits, which complicated medication reconciliations, interventions, and educational efforts regarding dose changes. Furthermore, patients sometimes missed face-to-face appointments, often because of transportation difficulties. In these situations, telephone appointments may be beneficial. The obstacle of transportation is removed, and, during the at-home telephone call, the patient has easy access to medications and measurements.

Limitations

This study had several limitations. It was retrospective, and its sample size was too small for conclusions regarding morbidity and mortality. As the population was predominantly African American males, results may not be applicable to other races and females. Furthermore, not evaluating HF causes at baseline could have confounded results, as disease progression, response to medications, and prognosis can vary, depending on etiology. Moreover, as patients are referred from the HFDMP to the PMTC, there may have been a bias in patient selection for the PMTC group. Patients in the PMTC group may have been more clinically stable yet had a larger knowledge deficit, an adherence issue, or a need for difficult, frequent titrations. Patients also may have been less likely to be seen during the first 30 days after discharge. In addition, it could have been beneficial to match patients on NYHA class of HF at baseline to ensure HF severity was balanced between groups. Last, the adherence analysis may not be accurate, as it relied on refill history, which may not reflect how medications were taken at home.

It would be beneficial to expand this initial study with a larger sample. Presumed HF causes and medication adherence should be captured at baseline. Additional endpoints, including quality of life and patient cognition, could enhance results. Furthermore, comparing the HFDMP with the general cardiology clinic may reveal other benefits of a focused HFDMP and its PMTC. Last, evaluating patients who are recently discharged from HF admission yet not enrolled in the HFDMP may provide more information regarding the utility of both the HFDMP and the PMTC.

Conclusion

For the PMTC group in this study, achievement of target BB doses and achievement in composite clinical GDMT were significant, but achievement of target ACEI/ARB doses were not.

Click here to read the digital edition.

In the U.S., about 5.1 million people have clinically manifested heart failure (HF).¹ The absolute mortality rate for HF is about 50% within 5 years of diagnosis, and 1 in 9 death certificates in the U.S. list HF as a cause of death.² Heart failure is the primary diagnosis in more than 1 million hospitalizations annually.¹ Patients with HF who are at risk for all-cause rehospitalization have a 1-month readmission rate of 25%, and their median survival time decreases with each hospitalization.^3,4 Heart failure is the top reason for discharge of veterans treated within the VA health care system.⁵

Some medications decrease morbidity and mortality in patients with systolic dysfunction.⁶ These medications include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and β-blockers (BBs). Studies have demonstrated effectiveness of these medications in patients with reduced ejection fraction (EF) of less or equal to 40%. Other medications with proven success include aldosterone antagonists, hydralazine in combination with a nitrate, and digoxin. The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines provide medication recommendations based on the ACCF/AHA stages of HF and the New York Heart Association (NYHA) functional classifications, designated as guideline-directed medical therapy (GDMT).^6,7 Therapeutic interventions are aimed at reducing morbidity and mortality for ACCF/AHA stage C HF. The ACCF/AHA guidelines also recommend establishing multidisciplinary HF disease management programs for patients at high risk for hospital readmission to facilitate implementation of GDMT, address different barriers to behavior change, and reduce the risk of subsequent rehospitalization for HF.⁶

In October 2010, the Jesse Brown VAMC (JBVAMC) in Chicago, Illinois, opened its Heart Failure Disease Management Program (HFDMP) to prevent readmissions by targeting patients discharged after HF exacerbations and arranging follow-up in the HFDMP clinic. Enrollment in the clinic is initiated when an inpatient physician places a consultation. A cardiology nurse practitioner (NP) receives the consultation and schedules an in-clinic appointment for the patient within 1 week of discharge. The patient goes to the clinic on average every 2 weeks until he or she is on a stable, optimal medication regimen and is competent in self-management. After 3 months, the patient transitions to the general cardiology clinic. This process allows the HFDMP to see new patients in need of intense care and education for HF. The multidisciplinary HFDMP began with a NP and a cardiologist and 6 months later in April 2011 added a pharmacist.

After enrolling in HFDMP, the patient can be referred to the pharmacist for independent optimization of medication therapy in the Pharmacy Medication Titration Clinic (PMTC). The PMTC at JBVAMC is different from other HF clinics in that the pharmacist has prescribing authority and can interact face-to-face with patients to titrate medications. Once a patient is on an optimal medication regimen, he or she is referred to the NP and cardiologist. The PMTC is open 4 hours twice per month and offers 30-minute time slots. The authors conducted a study of the effectiveness of face-to-face PMTC appointments within the HFDMP.

Methods

This study, approved by the institutional review board at the University of Illinois at Chicago and the research and development service at JBVAMC, was a retrospective electronic chart review of patients enrolled in the HFDMP. Study patients were aged ≥ 18 years and were enrolled in the HFDMP between April 15, 2011 and April 15, 2013. Exclusion criteria included EF higher than 40%, 1 or no appointment attended, and enrollment before April 15, 2011. There were 2 study groups: HFDMP patients enrolled in PMTC (PMTC group) and HFDMP patients not enrolled in PMTC (no-PMTC group). For 1:1 comparison, the number of patients who met the criteria for the PMTC group was used to determine the number of patients to include in the no-PMTC group. Baseline date was the date of enrollment into either HFDMP or PMTC.

Data collected at baseline included demographics, NYHA class of HF, blood pressure (BP), heart rate, ejection fraction (EF), date of HF diagnosis, number of hospitalizations for HF within previous 6 months, serum creatinine level, height, weight, comorbidities, and HF medications. Data collected at the end date included NYHA class of HF; BP; heart rate; EF; HF medications; reason for not achieving target dose of medication or GDMT; ACEI, ARB, or BB adherence, defined as 80% of medication refills 6 months after date of discharge from group; readmission for HF within 30 days and 90 days; length of stay (LOS), including bed type if readmitted; emergency department (ED) visits for HF within 6 months of date of discharge from group; and death within 6 months of date of discharge from group. Clinical GDMT was defined as reaching the maximum tolerable or target dose of each HF medication for each patient depending on clinical presentation, as recommended by the ACCF/AHA guidelines for HF.⁶ It incorporated NYHA class of HF, contraindications, hypotension, bradycardia, dizziness, and hyperkalemia as well as the prescribing of aldosterone antagonists, hydralazine and isosorbide dinitrate, and digoxin.

Study Outcomes

There were 2 primary endpoints: difference in percentage of patients who achieved target ACEI or ARB doses and difference in percentage of patients who achieved target BB doses. Secondary endpoints were difference between PMTC and no-PMTC groups in percentage of patient achievement in clinical GDMT; percentage medication adherence; percentage of patients with change in NYHA class of HF; percentage of patients with change in EF, including mean change; percentage of patients with 30-day and 90-day readmissions for HF; mean LOS if readmitted within 30 days and 90 days; percentage of patients with ED visits for HF within 6 months after baseline; and percentage mortality within 6 months after baseline.

Statistical Analysis

A 2-tailed Fisher exact test was used for nominal data, and a Student t test for continuous data. Statistical significance was set at P < .05.

Results

Of the 228 HFDMP enrollees, 29 were seen in the PMTC during the study period, and 199 were not seen in the PMTC. Of the 29 patients seen in the PMTC, 24 met the criteria for the PMTC study group. Charts of 106 of the 199 patients not seen in the PMTC were randomly reviewed until 24 patients who met the study criteria were selected for the no-PMTC study group. Thus, the PMTC group and the no-PMTC group each had 24 patients for 1:1 comparison. Eighty-seven patients were excluded from the study: 22 with EF > 40%, 50 with 1 or no appointment attended, and 15 who were enrolled in HFDMP before April 15, 2011.

Mean age was 66 years. All patients were male, and most were African American. The baseline characteristics of the PMTC and no-PMTC groups were similar, except a higher percentage of patients in the PMTC group had NYHA class II or III of HF (Table 1).

The ACEI or ARB target dose was achieved by a higher percentage of patients in the PMTC group, 79.2% (n = 19) vs 50% (n = 12), but the difference was not significant (P = .07) (Figure 1). However, BB target dose was achieved by a significantly higher (P = .01) percentage of patients in the PMTC group, 87.5% (n = 21) vs 20.8% (n = 5)(Figure 2). Furthermore, a significantly higher (P = .02) percentage of patients in the PMTC group, 62.5% (n = 15) vs 25% (n = 6), achieved composite clinical GDMT (Table 2). Last, there was not a statistically significant difference in 80% adherence with ACEI or ARB dosing or with BB dosing between the PMTC group (70.8%; n = 17) and the no-PMTC group (75%; n = 18).

For a higher percentage of patients in the PMTC group, 50% (n = 12) vs 29.2% (n = 7), NYHA class of HF improved, but the difference was not significant (P = .24). In addition, EF improved in a higher percentage of patients in the PMTC group, 71.4% (n = 10) vs 41.7% (n = 5), and mean (SD) improvement in EF was higher in the PMTC group, 12.5% (12%) vs 5.4% (13%), but neither difference was significant (P = .23 and P = .16, respectively).

A higher percentage of patients in the no-PMTC group were readmitted for HF within 30 days, 8.3% (n = 2) vs 0%, but the difference was not significant. Likewise, a higher percentage of patients in the no-PMTC group were readmitted for HF within 90 days, 20.8% (n = 5) vs 4.2% (n = 1; P = .19). Mean LOS for these readmissions was longer in the PMTC group, 8 days (n = 1) vs 6.5 days (n = 8). There was a higher percentage of ED visits for HF in the no-PMTC group, 37.5% (n = 9) vs 20.8% (n = 5), but did not reach statistical significance (P = .34). Last, the no-PMTC group had a higher percentage of deaths within 6 months after baseline, 37.5% (n = 9) vs 20.8% (n = 9), which also was not significant.

Discussion

This study demonstrated that, within HFDMPs, there is a role for a pharmacist who has prescribing authority and interacts face-to-face with patients in the clinic. Significantly more patients in the PMTC group achieved target BB doses by the end of the study. Target doses of BBs have been found to decrease morbidity and mortality.^8-10

The present study also found a positive trend toward achieving target ACEI or ARB doses. Reasons for not achieving target doses included contraindication to the medication, medication discontinuation during hospital admission, hypotension, hyperkalemia, and titration not complete by end of study period. Two of the many reasons for titration not being complete were clinic enrollment timing and nonadherence. Although achievement of target ACEI or ARB doses did not reach statistical significance, statistically significantly more patients achieved composite clinical GDMT.

As defined in the study, clinical GDMT captured the prescribing of hydralazine and isosorbide dinitrate in patients intolerant to ACEIs and ARBs. This study, the first known to evaluate achievement in GDMT, demonstrated a pharmacist’s ability to titrate more than just ACEI, ARB, and BB doses. This finding is clinically important in that appropriate pharmacologic therapy can reduce the number of hospitalizations for HF and improve survival, even though the study found that its PMTC group showed only trends toward fewer 30-day and 90-day readmissions for HF, fewer ED visits for HF, and less mortality.⁶ This finding may be attributable to the small number of readmissions for HF and deaths among the study groups.

One endpoint that did not show an expected difference with pharmacist intervention was medication adherence. However, medication nonadherence likely was a reason for patient referral to the PMTC. Baseline medication adherence was not determined, so improvement in adherence could not be assessed. Findings might have been different, too, if medication adherence had been evaluated with patient interviews and refill history, not just refill history.

In the PMTC group, LOS for readmissions for HF did not improve. However, the group had only 1 readmission, which may have skewed the result. No studies have linked outpatient pharmacist intervention to decreased LOS for readmission for HF. The endpoint was evaluated to assess whether medication stability leads to reduced LOS and to complete a limited cost analysis. Analysis of mean cost based on number of readmissions, bed type, and LOS revealed a cost savings of $167,556.82 for the PMTC group (Table 3). Other potential cost savings that are difficult to quantify and that were not accounted for include extended time between ED visits or readmissions for HF and increased quality of life and daily functioning.

This is the first study known to evaluate a pharmacist who had prescribing authority and interacted face-to-face with patients. Other studies have evaluated the role of the pharmacist in the multidisciplinary management of patients with HF. In 1999, the Pharmacist in Heart Failure Assessment Recommendation and Monitoring (PHARM) study reported the effect of direct HF-related patient care by a pharmacist who performed medication evaluations, provided patient education, and made medication recommendations to a physician.¹¹

After a medication dosing change, the pharmacist provided telephone follow-up to assess for problems with the drug therapy and then, if any were identified, referred patients to the physician. Pharmacist intervention demonstrated a decrease in all-cause mortality and HF events and an increase in ACEI doses. Unlike the pharmacist in the present study, the pharmacist had to get recommendations approved and prescribed by a physician. The present PMTC allows for pharmacist intervention, including medication therapy changes and follow-up appointments without consultation with a physician. If needed, the HF cardiologist is available in the HFDMP clinic or by telephone.

Jain and colleagues evaluated a protocol-driven medication titration clinic staffed by nurse and pharmacist specialists.¹² Although their study was limited by its descriptive nature, the authors concluded that the clinic increased the number of patients who achieved target ACEI/ARB or target BB doses. In the present study, the percentage of PMTC patients who achieved target doses increased during the study period, from 50% to 79.2% (ACEI/ARB) and from 20.8% to 87.5% (BB). Unlike other clinic pharmacists, however, the PMTC pharmacist titrates medications independently and does not follow a set clinic protocol.

Similar to the PHARM study, the Heart Failure Optimal Outcomes From Pharmacy Study (HOOPS) evaluated pharmacists who worked collaboratively with physicians to optimize HF therapy.¹³ As in the PMTC, patients and pharmacists had 30-minute appointments together. In HOOPS, however, physician agreement was needed before pharmacist recommendations were implemented. That study found that more patients with pharmacist intervention started an ACEI or ARB, had the medication titrated, and received recommended doses. More patients also either started a BB or increased its dose, but this did not increase the number of patients who received recommended BB doses. In addition, pharmacist intervention did not affect clinical outcomes. The authors acknowledged this finding might be attributable to the pharmacists’ lack of proper HF management training. Patients in the study were also more stable, whereas PMTC patients arrived after HF discharge and were followed until medication therapy was optimized. The HOOPS followed patients for only 3 or 4 visits, regardless of target dose achievement status.

In a study conducted within the VA health care system, Martinez and colleagues evaluated the use of pharmacists who had prescribing authority and were permitted to order laboratory tests under a scope of practice similar to that in the present study.¹⁴ However, their coordination agreement allowed them only to initiate and adjust doses of certain HF medications according to defined protocols. The pharmacist conducted monthly education classes and had medication titration appointments with individual patients by telephone over 2-week intervals. Face-to-face appointments were limited to medication reconciliations, whereas all appointments in the present study were face-to-face. In addition, Martinez and colleagues found that a higher percentage of patients who attended pharmacist appointments achieved target ACEI, ARB, and BB doses, whereas the present study found a higher percentage only of achieved target BB doses, not ACEI or ARB. However, the present study also found increased composite clinical GDMT achievement, which Martinez and colleagues did not evaluate. As mentioned, GDMT achievement may be a broader evaluation of optimal HF medical therapy, as it incorporates ACEI or ARB intolerance.

Martinez and colleagues acknowledged several study limitations different from those of the present study.¹⁴ Most members of their study population were white men, unlike this study’s population. Combining these 2 studies’ results may support use of pharmacist intervention for both white and African American men. In addition, the authors noted that patients often forgot their medications or were confused about doses, and concluded that forgetfulness and confusion may stem from having only telephone interviews and lacking written instructions for the interval between clinic appointments. By contrast, all PMTC patients were seen face-to-face, and handouts detailing any changes helped minimized confusion. Even with face-to-face appointments, however, patient nonadherence persisted, making it difficult to optimize HF therapy. Patients did not always follow instructions to bring HF medications (or medication lists) and daily weight measurements to clinic visits, which complicated medication reconciliations, interventions, and educational efforts regarding dose changes. Furthermore, patients sometimes missed face-to-face appointments, often because of transportation difficulties. In these situations, telephone appointments may be beneficial. The obstacle of transportation is removed, and, during the at-home telephone call, the patient has easy access to medications and measurements.

Limitations

This study had several limitations. It was retrospective, and its sample size was too small for conclusions regarding morbidity and mortality. As the population was predominantly African American males, results may not be applicable to other races and females. Furthermore, not evaluating HF causes at baseline could have confounded results, as disease progression, response to medications, and prognosis can vary, depending on etiology. Moreover, as patients are referred from the HFDMP to the PMTC, there may have been a bias in patient selection for the PMTC group. Patients in the PMTC group may have been more clinically stable yet had a larger knowledge deficit, an adherence issue, or a need for difficult, frequent titrations. Patients also may have been less likely to be seen during the first 30 days after discharge. In addition, it could have been beneficial to match patients on NYHA class of HF at baseline to ensure HF severity was balanced between groups. Last, the adherence analysis may not be accurate, as it relied on refill history, which may not reflect how medications were taken at home.

It would be beneficial to expand this initial study with a larger sample. Presumed HF causes and medication adherence should be captured at baseline. Additional endpoints, including quality of life and patient cognition, could enhance results. Furthermore, comparing the HFDMP with the general cardiology clinic may reveal other benefits of a focused HFDMP and its PMTC. Last, evaluating patients who are recently discharged from HF admission yet not enrolled in the HFDMP may provide more information regarding the utility of both the HFDMP and the PMTC.

Conclusion

For the PMTC group in this study, achievement of target BB doses and achievement in composite clinical GDMT were significant, but achievement of target ACEI/ARB doses were not.

Click here to read the digital edition.

CASE:  James G, age 43, recently had blood work performed for a life insurance policy, and his human immunodeficiency virus (HIV) test came back positive. At a follow-up office visit, Mr. G reports having anonymous male sexual partners when traveling to New York on business and rarely using condoms. His last HIV test was “about 4 years ago.” He is otherwise in good health, takes no regular medications, and is not married.

Having recently completed a primary care CME program on HIV disease, you order a CD4/T-cell count, an HIV RNA (viral load) test, and an HIV genotype drug resistance test on Mr. G, along with other baseline lab work, including a complete blood count, chemistry panel, and hepatitis panel. You schedule a follow-up visit with Mr. G in 2 weeks when all of the lab results will be available so that you can discuss his plan of care.

A diagnosis of HIV has moved from being a fatal disease to that of a chronic condition that can be effectively managed with combination antiretroviral therapy (ART) regimens over an almost normal lifespan. As a result, the role of the primary care practitioner in the ongoing care of patients with HIV has grown and will continue to do so, making knowledge of these drug combinations vital.

20 Years Have Changed Everything

Combination ART has existed since 1996 when the first protease inhibitors (PIs) were approved by the U.S. Food and Drug Administration (FDA). Prior to this, treatment was limited to mono or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs). These agents provided some short-term clinical benefit, but didn’t significantly improve patient survival and ultimately failed due to viral resistance.1

Since the approval of zidovudine (AZT) in 1987, the FDA has approved more than 25 drugs in 6 different classes for the treatment of HIV disease.² These include the NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, a fusion inhibitor (FI), a CCR5 antagonist, and, more recently, integrase strand transfer inhibitors (INSTIs). In addition, 2 drugs, cobicistat and ritonavir, are used solely to improve or “boost” the pharmacokinetic profiles of several antiretroviral drugs.²

Most of these newer agents are more potent, have a higher genetic barrier to resistance, and a longer halflife than their predecessors. Moreover, many are less toxic and thus more tolerable than older drugs. With the progressive development and approval of singletablet regimens (STRs) that contain 3 or 4 drugs, the majority of patients with HIV in the United States now take just one pill per day to treat their infection, facilitating far greater medication adherence.

Initiation of Antiretroviral Therapy

The U.S. Department of Health and Human Services (DHHS) guidelines now recommend that all people infected with HIV, regardless of CD4 cell count, begin ART.² The evidence for this recommendation comes largely from the START³ and TEMPRANO⁴ trials, which found that early initiation of ART significantly reduces morbidity and mortality associated with HIV. In addition, the HPTN 052 study concluded that early ART is associated with a 93% lower risk of viral transmission in serodiscordant heterosexual couples.⁵ The DHHS guidelines do note that when initiating ART, it is important to appropriately educate patients on the benefits of treatment and address strategies to optimize adherence.² (For more on factors to consider when selecting an initial HIV regimen, see Table 1.²) On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but it should never be withheld unless the risks clearly outweigh the benefits. Ideally, ART should be initiated as soon as possible after the initial diagnosis of HIV.

The DHHS guidelines divide treatment options into 3 categories²:

• Recommended regimens are backed by randomized controlled trials that show optimal and durable virologic efficacy, they have favorable tolerability and toxicity profiles, and they are easy to use.
• Alternative regimens have less or lower quality supporting data than recommended regimens. Although they are effective and may be optimal for certain individual patients, they have potential disadvantages and/or limitations in certain populations.
• Other regimens have limited supporting data, reduced virologic activity, a higher pill burden, more drug interactions, and greater toxicity.

Currently Recommended First-Line Therapies

An antiretroviral regimen for a treatment-naive patient should consist of 2 NRTIs in combination with a third active antiretroviral drug from one of 3 drug classes. These include: an INSTI, a boosted PI, or, in some situations, an NNRTI. The DHHS guidelines panel currently recommends 6 different ART combinations as first-line treatment in treatment-naive patients (Table 2).²

INSTI-Based Regimens

Dolutegravir/abacavir/lamivudine (Triumeq). Approved by the FDA as a single-tablet regimen in 2014, the combination of dolutegravir/abacavir/lamivudine has proven to be highly effective and well-tolerated in many clinical trials.^6-9 However, before this regimen is started, patients must be screened for the HLA-B*5701 allele, which predicts hypersensitivity to abacavir.¹⁰ Assessing patients’ risk for cardiovascular disease is also advised because some data suggest that abacavir may increase the risk of cardiovascular events, although this remains controversial.²

Dolutegravir is generally well-tolerated with minimal adverse effects (≥ 2% incidence of headache and insomnia) and toxicity.¹¹ Dolutegravir/abacavir/lamivudine should be taken 2 hours before or 6 hours after taking antacids or laxatives, sucralfate, and oral supplements with iron or calcium. However, it may be taken with calcium or iron supplements if it is also taken with food.¹¹ Dolutegravir increases levels of metformin about 2-fold, so patients should not take more than 1000 mg/d of this oral hypoglycemic agent.¹¹

• Dolutegravir plus tenofovir disoproxil fumarate/ emtricitabine (Tivicay plus Truvada). The combination
  of dolutegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine is administered as 2 pills per day. Because tenofovir disoproxil fumarate can cause proximal renal tubular dysfunction, phosphate wasting, and decreased bone mineral density (BMD), avoid prescribing it for patients with underlying renal dysfunction (creatinine clearance [CrCl] <50 mL/min) and prescribe it cautiously for patients with hypertension or diabetes who are at increased risk of renal disease. Emtricitabine is generally safe and well tolerated, but the dose should be reduced in patients with renal insufficiency, which would preclude the use of this fixed-dose combination.¹²
• Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya). The newer 4-drug combination of elvitegravir/ cobicistat/tenofovir alafenamide/emtricitabinethat was approved by the FDA in November 2015,¹³ contains the more recently approved form of tenofovir, which can be used in patients who have a CrCl as low as 30 mL/min. Compared to formulations containing tenofovir disoproxil fumarate, the newer tenofovir alafenamide formulation achieves higher intracellular levels in CD4 lymphocytes (but not in renal tubular cells). This allows for a lower dose of the drug and a smaller tablet size with co-formulation. It does not appear to cause kidney problems or loss of BMD as can be seen with tenofovir disoproxil fumarate.¹⁴ This newer single-tablet regimen may be best suited for older patients with HIV or those with comorbidities such as hypertension or diabetes.
• Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (Stribild). The FDA approved the combination of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine as a single-tablet regimen in 2012. The integrase inhibitor, elvitegravir, requires boosting with the CYP3A inhibitor, cobicistat, and should be taken with food.¹⁵ Two clinical trials demonstrated the superior efficacy of elvitegravir compared to a boosted PI and NNRTI-based regimen.^16,17 Elvitegravir is generally well tolerated, but sometimes causes dyspepsia, nausea, or diarrhea.¹⁵ Similar to dolutegravir, it should not be taken concurrently with certain supplements—in this case, those containing aluminum, calcium, iron, magnesium, or zinc.¹⁵ Because it contains tenofovir disoproxil fumarate as an active agent, it should not be used in patients with a CrCl of <70 mL/min.¹⁵ Cobicistat inhibits tubular secretion of creatinine, so it may produce an elevation in serum creatinine without actually affecting glomerular function. Cobicistat may also cause drug-drug interactions with certain antiarrhythmics, sedative-hypnotics, and erectile dysfunction agents, and is contraindicated with some statins, anticonvulsants, and ergot derivatives.¹⁸
• Raltegravir plus tenofovir disoproxil fumarate/emtricitabine (Isentress plus Truvada). The combination of the integrase inhibitor raltegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine has been recommended by the DHHS as first-line therapy for approximately 5 years. The recommendation is based mainly on data from the STARTMRK trial, a phase III non-inferiority trial that followed more than 500 patients for 5 years and concluded that raltegravir/ tenofovir/emtricitabine has superior efficacy with fewer drug-related adverse effects than efavirenz/tenofovir/emtricitabine.¹⁹ The overall pill burden with this regimen is 3 tablets per day. Although highly effective, the main drawbacks of raltegravir are that it must be dosed twice daily (which may be less preferable if adherence is a concern) and the genetic barrier to resistance is lower than that of the other 2 approved integrase inhibitors. In May 2017, FDA approved a new 1,200 mg once-daily version of raltegravir as an alternative to the twice daily regimen.²⁰ Adverse effects and toxicities (except the renal and bone effects due to tenofovir disoproxil fumarate mentioned earlier) and drug interactions with this regimen are infrequent. Raltegravir can be taken with or without food. Concurrent use of antacids that contain aluminum or magnesium may reduce absorption of raltegravir and so should be avoided.²¹

PI-Based Regimen

Darunavir (Prezista) and ritonavir (Norvir) plus tenofovir disoproxil fumarate/emtricitabine (Truvada). PIs were once the key component of all ART regimens; however, boosted darunavir is now the only PI-based regimen currently recommended as first-line therapy. It is taken as 3 tablets once daily. If the co-formulation with cobicistat is used, just 2 tablets daily are required. One advantage with darunavir with either of the boosting agents is that it does not appear to cause insulin resistance or dyslipidemia as occurs with older PIs, such as indinavir and lopinavir.² The boosting agents do, however, increase the likelihood of drug-drug interactions. As with all PIs, darunavir has a very high genetic barrier to resistance, which is important in patients for whom adherence is a concern.

Adverse effects of the PIs may include nausea, vomiting, and diarrhea, all of which are typically mild and selflimiting.²² Co-formulation of darunavir with cobicistat, tenofovir alafenamide, and emtricitabine is in phase III studies. Projected to be available in 2018, it will provide yet another daily STR option.²³

The Addition of Fixed-Dose Tenofovir Alafenamide/Emtricitabine

In July 2016, the DHHS panel made some additions to their guidelines to reflect the FDA approval of 3 fixed-dose combination products that contain tenofovir alafenamide. Specifically, the combination of tenofovir alafenamide and emtricitabine is recommended for use with the integrase inhibitors—dolutegravir or raltegravir. It is also recommended in combination with ritonavir-boosted darunavir.

DHHS "Alternative" And "Other" Regimens

The DHHS guidelines also include “alternative” (Table 3) and “other” regimens (available at http://aidsinfo.nih.gov/guidelines) that may be used when first-line regimens may not.² These second-line options are very effective, but have some possible clinical disadvantages or limitations. They are also less well supported by data from clinical trials. However, in certain situations, depending on an individual patient’s comorbidities, inability to tolerate one of the preferred regimens, or personal preferences, an alternative regimen may be the optimal choice.

Under the category of alternative regimens, the panel has included tenofovir alafenamide and emtricitabine in combination with the NNRTI efavirenz or with ritonavir or cobicistat-boosted atazanavir or darunavir.

The third group or “other” regimens have reduced virologic activity, increased toxicity, and even more limited data from clinical trials. Generally, medications from the DHHS “alternative” and “other” categories should be prescribed in consultation with an HIV specialist.

The Future of Art

The currently available drugs are highly effective in fully suppressing HIV and allowing for immune recovery and clinical stability for most patients. Life expectancy for patients living with HIV is estimated to be approaching that of uninfected adults—provided they remain on ART.²⁴ As a way to further simplify ART, current clinical trials are looking at 2-drug regimens including an integrase inhibitor with an NRTI, an INSTI, or an NNRTI, or a PI with one NRTI.^25,26 This approach could further reduce pill burden and toxicity and substantially decrease the cost of long-term treatment.²⁷ Also on the horizon are long-acting injectable antiretroviral drugs that will likely be available for clinical use in the next 2 to 3 years.^28,29

CASE:  At the 2-week follow-up visit, you discuss with Mr. G that his CD4+ count is 390 cells/mm3, his HIV RNA level is 32,450 copies/mL, and his HIV genotype test showed no antiviral drug resistance. Explaining that all patients with HIV should be treated with antiviral therapy regardless of CD4+ count, you recommend that Mr. G begin taking fixed-dose tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat (Stribild), noting that it is one of the regimens recommended by the DHHS national treatment guidelines. You provide a patient handout that discusses dosing and adverse effects, including nausea and headache. The patient’s pharmacy was contacted and it was determined that Mr. G’s co-pay for the drug would be $50, which he found acceptable.

In addition, you discuss the importance of good adherence to this medication, and instruct Mr. G to contact the office via phone or patient portal for any concerns or questions that arise after starting the medication. Lastly, you advise him to return in 4 weeks for follow-up blood testing, including viral load monitoring, and additional care, if needed, and strongly recommend that he begin using condoms regularly.

Click here to read the digital edition.

CASE:  James G, age 43, recently had blood work performed for a life insurance policy, and his human immunodeficiency virus (HIV) test came back positive. At a follow-up office visit, Mr. G reports having anonymous male sexual partners when traveling to New York on business and rarely using condoms. His last HIV test was “about 4 years ago.” He is otherwise in good health, takes no regular medications, and is not married.

Having recently completed a primary care CME program on HIV disease, you order a CD4/T-cell count, an HIV RNA (viral load) test, and an HIV genotype drug resistance test on Mr. G, along with other baseline lab work, including a complete blood count, chemistry panel, and hepatitis panel. You schedule a follow-up visit with Mr. G in 2 weeks when all of the lab results will be available so that you can discuss his plan of care.

A diagnosis of HIV has moved from being a fatal disease to that of a chronic condition that can be effectively managed with combination antiretroviral therapy (ART) regimens over an almost normal lifespan. As a result, the role of the primary care practitioner in the ongoing care of patients with HIV has grown and will continue to do so, making knowledge of these drug combinations vital.

20 Years Have Changed Everything

Combination ART has existed since 1996 when the first protease inhibitors (PIs) were approved by the U.S. Food and Drug Administration (FDA). Prior to this, treatment was limited to mono or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs). These agents provided some short-term clinical benefit, but didn’t significantly improve patient survival and ultimately failed due to viral resistance.1

Since the approval of zidovudine (AZT) in 1987, the FDA has approved more than 25 drugs in 6 different classes for the treatment of HIV disease.² These include the NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, a fusion inhibitor (FI), a CCR5 antagonist, and, more recently, integrase strand transfer inhibitors (INSTIs). In addition, 2 drugs, cobicistat and ritonavir, are used solely to improve or “boost” the pharmacokinetic profiles of several antiretroviral drugs.²

Most of these newer agents are more potent, have a higher genetic barrier to resistance, and a longer halflife than their predecessors. Moreover, many are less toxic and thus more tolerable than older drugs. With the progressive development and approval of singletablet regimens (STRs) that contain 3 or 4 drugs, the majority of patients with HIV in the United States now take just one pill per day to treat their infection, facilitating far greater medication adherence.

Initiation of Antiretroviral Therapy

The U.S. Department of Health and Human Services (DHHS) guidelines now recommend that all people infected with HIV, regardless of CD4 cell count, begin ART.² The evidence for this recommendation comes largely from the START³ and TEMPRANO⁴ trials, which found that early initiation of ART significantly reduces morbidity and mortality associated with HIV. In addition, the HPTN 052 study concluded that early ART is associated with a 93% lower risk of viral transmission in serodiscordant heterosexual couples.⁵ The DHHS guidelines do note that when initiating ART, it is important to appropriately educate patients on the benefits of treatment and address strategies to optimize adherence.² (For more on factors to consider when selecting an initial HIV regimen, see Table 1.²) On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but it should never be withheld unless the risks clearly outweigh the benefits. Ideally, ART should be initiated as soon as possible after the initial diagnosis of HIV.

The DHHS guidelines divide treatment options into 3 categories²:

• Recommended regimens are backed by randomized controlled trials that show optimal and durable virologic efficacy, they have favorable tolerability and toxicity profiles, and they are easy to use.
• Alternative regimens have less or lower quality supporting data than recommended regimens. Although they are effective and may be optimal for certain individual patients, they have potential disadvantages and/or limitations in certain populations.
• Other regimens have limited supporting data, reduced virologic activity, a higher pill burden, more drug interactions, and greater toxicity.

Currently Recommended First-Line Therapies

An antiretroviral regimen for a treatment-naive patient should consist of 2 NRTIs in combination with a third active antiretroviral drug from one of 3 drug classes. These include: an INSTI, a boosted PI, or, in some situations, an NNRTI. The DHHS guidelines panel currently recommends 6 different ART combinations as first-line treatment in treatment-naive patients (Table 2).²

INSTI-Based Regimens

Dolutegravir/abacavir/lamivudine (Triumeq). Approved by the FDA as a single-tablet regimen in 2014, the combination of dolutegravir/abacavir/lamivudine has proven to be highly effective and well-tolerated in many clinical trials.^6-9 However, before this regimen is started, patients must be screened for the HLA-B*5701 allele, which predicts hypersensitivity to abacavir.¹⁰ Assessing patients’ risk for cardiovascular disease is also advised because some data suggest that abacavir may increase the risk of cardiovascular events, although this remains controversial.²

Dolutegravir is generally well-tolerated with minimal adverse effects (≥ 2% incidence of headache and insomnia) and toxicity.¹¹ Dolutegravir/abacavir/lamivudine should be taken 2 hours before or 6 hours after taking antacids or laxatives, sucralfate, and oral supplements with iron or calcium. However, it may be taken with calcium or iron supplements if it is also taken with food.¹¹ Dolutegravir increases levels of metformin about 2-fold, so patients should not take more than 1000 mg/d of this oral hypoglycemic agent.¹¹

• Dolutegravir plus tenofovir disoproxil fumarate/ emtricitabine (Tivicay plus Truvada). The combination
  of dolutegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine is administered as 2 pills per day. Because tenofovir disoproxil fumarate can cause proximal renal tubular dysfunction, phosphate wasting, and decreased bone mineral density (BMD), avoid prescribing it for patients with underlying renal dysfunction (creatinine clearance [CrCl] <50 mL/min) and prescribe it cautiously for patients with hypertension or diabetes who are at increased risk of renal disease. Emtricitabine is generally safe and well tolerated, but the dose should be reduced in patients with renal insufficiency, which would preclude the use of this fixed-dose combination.¹²
• Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya). The newer 4-drug combination of elvitegravir/ cobicistat/tenofovir alafenamide/emtricitabinethat was approved by the FDA in November 2015,¹³ contains the more recently approved form of tenofovir, which can be used in patients who have a CrCl as low as 30 mL/min. Compared to formulations containing tenofovir disoproxil fumarate, the newer tenofovir alafenamide formulation achieves higher intracellular levels in CD4 lymphocytes (but not in renal tubular cells). This allows for a lower dose of the drug and a smaller tablet size with co-formulation. It does not appear to cause kidney problems or loss of BMD as can be seen with tenofovir disoproxil fumarate.¹⁴ This newer single-tablet regimen may be best suited for older patients with HIV or those with comorbidities such as hypertension or diabetes.
• Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (Stribild). The FDA approved the combination of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine as a single-tablet regimen in 2012. The integrase inhibitor, elvitegravir, requires boosting with the CYP3A inhibitor, cobicistat, and should be taken with food.¹⁵ Two clinical trials demonstrated the superior efficacy of elvitegravir compared to a boosted PI and NNRTI-based regimen.^16,17 Elvitegravir is generally well tolerated, but sometimes causes dyspepsia, nausea, or diarrhea.¹⁵ Similar to dolutegravir, it should not be taken concurrently with certain supplements—in this case, those containing aluminum, calcium, iron, magnesium, or zinc.¹⁵ Because it contains tenofovir disoproxil fumarate as an active agent, it should not be used in patients with a CrCl of <70 mL/min.¹⁵ Cobicistat inhibits tubular secretion of creatinine, so it may produce an elevation in serum creatinine without actually affecting glomerular function. Cobicistat may also cause drug-drug interactions with certain antiarrhythmics, sedative-hypnotics, and erectile dysfunction agents, and is contraindicated with some statins, anticonvulsants, and ergot derivatives.¹⁸
• Raltegravir plus tenofovir disoproxil fumarate/emtricitabine (Isentress plus Truvada). The combination of the integrase inhibitor raltegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine has been recommended by the DHHS as first-line therapy for approximately 5 years. The recommendation is based mainly on data from the STARTMRK trial, a phase III non-inferiority trial that followed more than 500 patients for 5 years and concluded that raltegravir/ tenofovir/emtricitabine has superior efficacy with fewer drug-related adverse effects than efavirenz/tenofovir/emtricitabine.¹⁹ The overall pill burden with this regimen is 3 tablets per day. Although highly effective, the main drawbacks of raltegravir are that it must be dosed twice daily (which may be less preferable if adherence is a concern) and the genetic barrier to resistance is lower than that of the other 2 approved integrase inhibitors. In May 2017, FDA approved a new 1,200 mg once-daily version of raltegravir as an alternative to the twice daily regimen.²⁰ Adverse effects and toxicities (except the renal and bone effects due to tenofovir disoproxil fumarate mentioned earlier) and drug interactions with this regimen are infrequent. Raltegravir can be taken with or without food. Concurrent use of antacids that contain aluminum or magnesium may reduce absorption of raltegravir and so should be avoided.²¹

PI-Based Regimen

Darunavir (Prezista) and ritonavir (Norvir) plus tenofovir disoproxil fumarate/emtricitabine (Truvada). PIs were once the key component of all ART regimens; however, boosted darunavir is now the only PI-based regimen currently recommended as first-line therapy. It is taken as 3 tablets once daily. If the co-formulation with cobicistat is used, just 2 tablets daily are required. One advantage with darunavir with either of the boosting agents is that it does not appear to cause insulin resistance or dyslipidemia as occurs with older PIs, such as indinavir and lopinavir.² The boosting agents do, however, increase the likelihood of drug-drug interactions. As with all PIs, darunavir has a very high genetic barrier to resistance, which is important in patients for whom adherence is a concern.

Adverse effects of the PIs may include nausea, vomiting, and diarrhea, all of which are typically mild and selflimiting.²² Co-formulation of darunavir with cobicistat, tenofovir alafenamide, and emtricitabine is in phase III studies. Projected to be available in 2018, it will provide yet another daily STR option.²³

The Addition of Fixed-Dose Tenofovir Alafenamide/Emtricitabine

In July 2016, the DHHS panel made some additions to their guidelines to reflect the FDA approval of 3 fixed-dose combination products that contain tenofovir alafenamide. Specifically, the combination of tenofovir alafenamide and emtricitabine is recommended for use with the integrase inhibitors—dolutegravir or raltegravir. It is also recommended in combination with ritonavir-boosted darunavir.

DHHS "Alternative" And "Other" Regimens

The DHHS guidelines also include “alternative” (Table 3) and “other” regimens (available at http://aidsinfo.nih.gov/guidelines) that may be used when first-line regimens may not.² These second-line options are very effective, but have some possible clinical disadvantages or limitations. They are also less well supported by data from clinical trials. However, in certain situations, depending on an individual patient’s comorbidities, inability to tolerate one of the preferred regimens, or personal preferences, an alternative regimen may be the optimal choice.

Under the category of alternative regimens, the panel has included tenofovir alafenamide and emtricitabine in combination with the NNRTI efavirenz or with ritonavir or cobicistat-boosted atazanavir or darunavir.

The third group or “other” regimens have reduced virologic activity, increased toxicity, and even more limited data from clinical trials. Generally, medications from the DHHS “alternative” and “other” categories should be prescribed in consultation with an HIV specialist.

The Future of Art

The currently available drugs are highly effective in fully suppressing HIV and allowing for immune recovery and clinical stability for most patients. Life expectancy for patients living with HIV is estimated to be approaching that of uninfected adults—provided they remain on ART.²⁴ As a way to further simplify ART, current clinical trials are looking at 2-drug regimens including an integrase inhibitor with an NRTI, an INSTI, or an NNRTI, or a PI with one NRTI.^25,26 This approach could further reduce pill burden and toxicity and substantially decrease the cost of long-term treatment.²⁷ Also on the horizon are long-acting injectable antiretroviral drugs that will likely be available for clinical use in the next 2 to 3 years.^28,29

CASE:  At the 2-week follow-up visit, you discuss with Mr. G that his CD4+ count is 390 cells/mm3, his HIV RNA level is 32,450 copies/mL, and his HIV genotype test showed no antiviral drug resistance. Explaining that all patients with HIV should be treated with antiviral therapy regardless of CD4+ count, you recommend that Mr. G begin taking fixed-dose tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat (Stribild), noting that it is one of the regimens recommended by the DHHS national treatment guidelines. You provide a patient handout that discusses dosing and adverse effects, including nausea and headache. The patient’s pharmacy was contacted and it was determined that Mr. G’s co-pay for the drug would be $50, which he found acceptable.

In addition, you discuss the importance of good adherence to this medication, and instruct Mr. G to contact the office via phone or patient portal for any concerns or questions that arise after starting the medication. Lastly, you advise him to return in 4 weeks for follow-up blood testing, including viral load monitoring, and additional care, if needed, and strongly recommend that he begin using condoms regularly.

Click here to read the digital edition.

CASE:  James G, age 43, recently had blood work performed for a life insurance policy, and his human immunodeficiency virus (HIV) test came back positive. At a follow-up office visit, Mr. G reports having anonymous male sexual partners when traveling to New York on business and rarely using condoms. His last HIV test was “about 4 years ago.” He is otherwise in good health, takes no regular medications, and is not married.

Having recently completed a primary care CME program on HIV disease, you order a CD4/T-cell count, an HIV RNA (viral load) test, and an HIV genotype drug resistance test on Mr. G, along with other baseline lab work, including a complete blood count, chemistry panel, and hepatitis panel. You schedule a follow-up visit with Mr. G in 2 weeks when all of the lab results will be available so that you can discuss his plan of care.

A diagnosis of HIV has moved from being a fatal disease to that of a chronic condition that can be effectively managed with combination antiretroviral therapy (ART) regimens over an almost normal lifespan. As a result, the role of the primary care practitioner in the ongoing care of patients with HIV has grown and will continue to do so, making knowledge of these drug combinations vital.

20 Years Have Changed Everything

Combination ART has existed since 1996 when the first protease inhibitors (PIs) were approved by the U.S. Food and Drug Administration (FDA). Prior to this, treatment was limited to mono or dual therapy with nucleoside reverse transcriptase inhibitors (NRTIs). These agents provided some short-term clinical benefit, but didn’t significantly improve patient survival and ultimately failed due to viral resistance.1

Since the approval of zidovudine (AZT) in 1987, the FDA has approved more than 25 drugs in 6 different classes for the treatment of HIV disease.² These include the NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs), PIs, a fusion inhibitor (FI), a CCR5 antagonist, and, more recently, integrase strand transfer inhibitors (INSTIs). In addition, 2 drugs, cobicistat and ritonavir, are used solely to improve or “boost” the pharmacokinetic profiles of several antiretroviral drugs.²

Most of these newer agents are more potent, have a higher genetic barrier to resistance, and a longer halflife than their predecessors. Moreover, many are less toxic and thus more tolerable than older drugs. With the progressive development and approval of singletablet regimens (STRs) that contain 3 or 4 drugs, the majority of patients with HIV in the United States now take just one pill per day to treat their infection, facilitating far greater medication adherence.

Initiation of Antiretroviral Therapy

The U.S. Department of Health and Human Services (DHHS) guidelines now recommend that all people infected with HIV, regardless of CD4 cell count, begin ART.² The evidence for this recommendation comes largely from the START³ and TEMPRANO⁴ trials, which found that early initiation of ART significantly reduces morbidity and mortality associated with HIV. In addition, the HPTN 052 study concluded that early ART is associated with a 93% lower risk of viral transmission in serodiscordant heterosexual couples.⁵ The DHHS guidelines do note that when initiating ART, it is important to appropriately educate patients on the benefits of treatment and address strategies to optimize adherence.² (For more on factors to consider when selecting an initial HIV regimen, see Table 1.²) On a case-by-case basis, ART may be deferred because of clinical and/or psychosocial factors, but it should never be withheld unless the risks clearly outweigh the benefits. Ideally, ART should be initiated as soon as possible after the initial diagnosis of HIV.

The DHHS guidelines divide treatment options into 3 categories²:

• Recommended regimens are backed by randomized controlled trials that show optimal and durable virologic efficacy, they have favorable tolerability and toxicity profiles, and they are easy to use.
• Alternative regimens have less or lower quality supporting data than recommended regimens. Although they are effective and may be optimal for certain individual patients, they have potential disadvantages and/or limitations in certain populations.
• Other regimens have limited supporting data, reduced virologic activity, a higher pill burden, more drug interactions, and greater toxicity.

Currently Recommended First-Line Therapies

An antiretroviral regimen for a treatment-naive patient should consist of 2 NRTIs in combination with a third active antiretroviral drug from one of 3 drug classes. These include: an INSTI, a boosted PI, or, in some situations, an NNRTI. The DHHS guidelines panel currently recommends 6 different ART combinations as first-line treatment in treatment-naive patients (Table 2).²

INSTI-Based Regimens

Dolutegravir/abacavir/lamivudine (Triumeq). Approved by the FDA as a single-tablet regimen in 2014, the combination of dolutegravir/abacavir/lamivudine has proven to be highly effective and well-tolerated in many clinical trials.^6-9 However, before this regimen is started, patients must be screened for the HLA-B*5701 allele, which predicts hypersensitivity to abacavir.¹⁰ Assessing patients’ risk for cardiovascular disease is also advised because some data suggest that abacavir may increase the risk of cardiovascular events, although this remains controversial.²

Dolutegravir is generally well-tolerated with minimal adverse effects (≥ 2% incidence of headache and insomnia) and toxicity.¹¹ Dolutegravir/abacavir/lamivudine should be taken 2 hours before or 6 hours after taking antacids or laxatives, sucralfate, and oral supplements with iron or calcium. However, it may be taken with calcium or iron supplements if it is also taken with food.¹¹ Dolutegravir increases levels of metformin about 2-fold, so patients should not take more than 1000 mg/d of this oral hypoglycemic agent.¹¹

• Dolutegravir plus tenofovir disoproxil fumarate/ emtricitabine (Tivicay plus Truvada). The combination
  of dolutegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine is administered as 2 pills per day. Because tenofovir disoproxil fumarate can cause proximal renal tubular dysfunction, phosphate wasting, and decreased bone mineral density (BMD), avoid prescribing it for patients with underlying renal dysfunction (creatinine clearance [CrCl] <50 mL/min) and prescribe it cautiously for patients with hypertension or diabetes who are at increased risk of renal disease. Emtricitabine is generally safe and well tolerated, but the dose should be reduced in patients with renal insufficiency, which would preclude the use of this fixed-dose combination.¹²
• Elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (Genvoya). The newer 4-drug combination of elvitegravir/ cobicistat/tenofovir alafenamide/emtricitabinethat was approved by the FDA in November 2015,¹³ contains the more recently approved form of tenofovir, which can be used in patients who have a CrCl as low as 30 mL/min. Compared to formulations containing tenofovir disoproxil fumarate, the newer tenofovir alafenamide formulation achieves higher intracellular levels in CD4 lymphocytes (but not in renal tubular cells). This allows for a lower dose of the drug and a smaller tablet size with co-formulation. It does not appear to cause kidney problems or loss of BMD as can be seen with tenofovir disoproxil fumarate.¹⁴ This newer single-tablet regimen may be best suited for older patients with HIV or those with comorbidities such as hypertension or diabetes.
• Elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (Stribild). The FDA approved the combination of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine as a single-tablet regimen in 2012. The integrase inhibitor, elvitegravir, requires boosting with the CYP3A inhibitor, cobicistat, and should be taken with food.¹⁵ Two clinical trials demonstrated the superior efficacy of elvitegravir compared to a boosted PI and NNRTI-based regimen.^16,17 Elvitegravir is generally well tolerated, but sometimes causes dyspepsia, nausea, or diarrhea.¹⁵ Similar to dolutegravir, it should not be taken concurrently with certain supplements—in this case, those containing aluminum, calcium, iron, magnesium, or zinc.¹⁵ Because it contains tenofovir disoproxil fumarate as an active agent, it should not be used in patients with a CrCl of <70 mL/min.¹⁵ Cobicistat inhibits tubular secretion of creatinine, so it may produce an elevation in serum creatinine without actually affecting glomerular function. Cobicistat may also cause drug-drug interactions with certain antiarrhythmics, sedative-hypnotics, and erectile dysfunction agents, and is contraindicated with some statins, anticonvulsants, and ergot derivatives.¹⁸
• Raltegravir plus tenofovir disoproxil fumarate/emtricitabine (Isentress plus Truvada). The combination of the integrase inhibitor raltegravir plus fixed-dose tenofovir disoproxil fumarate and emtricitabine has been recommended by the DHHS as first-line therapy for approximately 5 years. The recommendation is based mainly on data from the STARTMRK trial, a phase III non-inferiority trial that followed more than 500 patients for 5 years and concluded that raltegravir/ tenofovir/emtricitabine has superior efficacy with fewer drug-related adverse effects than efavirenz/tenofovir/emtricitabine.¹⁹ The overall pill burden with this regimen is 3 tablets per day. Although highly effective, the main drawbacks of raltegravir are that it must be dosed twice daily (which may be less preferable if adherence is a concern) and the genetic barrier to resistance is lower than that of the other 2 approved integrase inhibitors. In May 2017, FDA approved a new 1,200 mg once-daily version of raltegravir as an alternative to the twice daily regimen.²⁰ Adverse effects and toxicities (except the renal and bone effects due to tenofovir disoproxil fumarate mentioned earlier) and drug interactions with this regimen are infrequent. Raltegravir can be taken with or without food. Concurrent use of antacids that contain aluminum or magnesium may reduce absorption of raltegravir and so should be avoided.²¹

PI-Based Regimen

Darunavir (Prezista) and ritonavir (Norvir) plus tenofovir disoproxil fumarate/emtricitabine (Truvada). PIs were once the key component of all ART regimens; however, boosted darunavir is now the only PI-based regimen currently recommended as first-line therapy. It is taken as 3 tablets once daily. If the co-formulation with cobicistat is used, just 2 tablets daily are required. One advantage with darunavir with either of the boosting agents is that it does not appear to cause insulin resistance or dyslipidemia as occurs with older PIs, such as indinavir and lopinavir.² The boosting agents do, however, increase the likelihood of drug-drug interactions. As with all PIs, darunavir has a very high genetic barrier to resistance, which is important in patients for whom adherence is a concern.

Adverse effects of the PIs may include nausea, vomiting, and diarrhea, all of which are typically mild and selflimiting.²² Co-formulation of darunavir with cobicistat, tenofovir alafenamide, and emtricitabine is in phase III studies. Projected to be available in 2018, it will provide yet another daily STR option.²³

The Addition of Fixed-Dose Tenofovir Alafenamide/Emtricitabine

In July 2016, the DHHS panel made some additions to their guidelines to reflect the FDA approval of 3 fixed-dose combination products that contain tenofovir alafenamide. Specifically, the combination of tenofovir alafenamide and emtricitabine is recommended for use with the integrase inhibitors—dolutegravir or raltegravir. It is also recommended in combination with ritonavir-boosted darunavir.

DHHS "Alternative" And "Other" Regimens

The DHHS guidelines also include “alternative” (Table 3) and “other” regimens (available at http://aidsinfo.nih.gov/guidelines) that may be used when first-line regimens may not.² These second-line options are very effective, but have some possible clinical disadvantages or limitations. They are also less well supported by data from clinical trials. However, in certain situations, depending on an individual patient’s comorbidities, inability to tolerate one of the preferred regimens, or personal preferences, an alternative regimen may be the optimal choice.

Under the category of alternative regimens, the panel has included tenofovir alafenamide and emtricitabine in combination with the NNRTI efavirenz or with ritonavir or cobicistat-boosted atazanavir or darunavir.

The third group or “other” regimens have reduced virologic activity, increased toxicity, and even more limited data from clinical trials. Generally, medications from the DHHS “alternative” and “other” categories should be prescribed in consultation with an HIV specialist.

The Future of Art

The currently available drugs are highly effective in fully suppressing HIV and allowing for immune recovery and clinical stability for most patients. Life expectancy for patients living with HIV is estimated to be approaching that of uninfected adults—provided they remain on ART.²⁴ As a way to further simplify ART, current clinical trials are looking at 2-drug regimens including an integrase inhibitor with an NRTI, an INSTI, or an NNRTI, or a PI with one NRTI.^25,26 This approach could further reduce pill burden and toxicity and substantially decrease the cost of long-term treatment.²⁷ Also on the horizon are long-acting injectable antiretroviral drugs that will likely be available for clinical use in the next 2 to 3 years.^28,29

CASE:  At the 2-week follow-up visit, you discuss with Mr. G that his CD4+ count is 390 cells/mm3, his HIV RNA level is 32,450 copies/mL, and his HIV genotype test showed no antiviral drug resistance. Explaining that all patients with HIV should be treated with antiviral therapy regardless of CD4+ count, you recommend that Mr. G begin taking fixed-dose tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat (Stribild), noting that it is one of the regimens recommended by the DHHS national treatment guidelines. You provide a patient handout that discusses dosing and adverse effects, including nausea and headache. The patient’s pharmacy was contacted and it was determined that Mr. G’s co-pay for the drug would be $50, which he found acceptable.

In addition, you discuss the importance of good adherence to this medication, and instruct Mr. G to contact the office via phone or patient portal for any concerns or questions that arise after starting the medication. Lastly, you advise him to return in 4 weeks for follow-up blood testing, including viral load monitoring, and additional care, if needed, and strongly recommend that he begin using condoms regularly.

Click here to read the digital edition.

VA Pharmacy Benefit Management Service (PBM) continually issues or revises its guidances for hematology and oncology care providers on a number of cancer care medications. Below are excerpts from recently released Criteria for Use documents. The complete documents, including the inclusion criteria, dosage and administration guidance, monitoring information, and discontinuation criteria should be consulted and can be found at www.pbm.va.gov or vaww.cmopnational.va.gov/cmop/PBM/default.aspx.

ENZALUTAMIDE (XTANDI) Criteria for Use, January 2017

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive enzalutamide.

• Brain metastases or active epidural disease
• Severe renal impairment (creatinine clearance < 30 mL/min)
• History of seizure (including febrile seizure, loss of consciousness, or transient ischemic attack within the previous 12 months, any condition predisposing to seizure: prior stroke, brain AV malformation, head trauma with loss of consciousness requiring hospitalization)
• ECOG Performance Status > 2
• Inability to swallow capsules

Issues for Consideration

• Enzalutamide is not indicated for use in women. Based on the mechanism of action, can cause fetal harm if used during pregnancy. Pregnancy Category X—use contraindicated during pregnancy. Exclude pregnancy before prescribing enzalutamide, discuss risks if pregnancy occurs, and provide contraceptive counseling.
• Use in patients taking concomitant medications that may lower the seizure threshold was not studied; caution patients about the risk of activities where the sudden loss of consciousness could cause serious harm if concomitant use cannot be avoided.
• Use in patients at risk for or with a strong history of falls: in the phase 3 clinical trial, falls or injuries from falls occurred in 4.6% of enzalutamide patients vs 1.3% of placebo patients.
• Avoid strong inhibitors of CYP2C8 (eg, gemfibrozil); if concomitant use of a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of  enzalutamide to 80 mg once daily according to the package insert.
• Co-administration with strong or moderate inducers of CYP3A4 (eg, carbamazepine, phenobarbital, phenytoin, rifampin, bosentan, efavirenz, modafinil, nafcillin, St. John’s Wort) or CYP2C8 (eg, rifampin) should be avoided if possible. If patient must be co-administered a strong CYP3A4 inducer, increase enzalutamide dose from 160 mg to 240 mg once daily.
• Drugs that are substrates of CYP3A4 (eg, alfentanil, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (eg, phenytoin, warfarin), or CYP2C19 (eg, S-mephenytoin) with a narrow therapeutic index should be avoided. If enzalutamide is co-administered with warfarin, additional INR testing should be conducted.
• Use in patients with hepatic impairment: Pharmacokinetics of enzalutamide and its metabolite were examined in volunteers with normal, Child-Pugh Class A, Child-Pugh Class B, and Child-Pugh Class C hepatic impairment. The composite AUC for enzalutamide and its metabolite after a single 160-mg dose was similar across all levels of hepatic impairment compared with normal volunteers.
• There have been postmarketing reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving enzalutamide. PRES is a neurologic disorder presenting with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual/neurological disturbances with or without associated hypertension. Diagnosis of PRES requires brain imaging, preferably by MRI. Enzalutamide should be discontinued in patients developing PRES.
• Sequencing of enzalutamide and abiraterone has been evaluated in several small retrospective analyses; the majority of the analyses are in the post chemotherapy setting. From this limited observational data, it is unclear if there is a preferred sequencing of abiraterone and enzalutamide. There is some evidence for cross-resistance. There are ongoing investigations into mechanisms of resistance to enzalutamide and abiraterone.

DARATUMUMAB (DARZALEX) Criteria for Use, January 2017

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive daratumumab.

• Patient is noncompliant with medication, follow-up, or laboratory appointments
• Patient unable or unwilling to be observed an extended period of time that may be necessary for first infusion (refer to Issues for Consideration)
• Hemoglobin < 8 g/dL; Must transfuse to hemoglobin above 8 gm/dL prior to therapy initiation
• Absolute neutrophil count (ANC) < 1,000/mm³
• Platelet count < 50,000/mm³ (< 30,000/mm³ if myeloma involvement in bone marrow > 50%)
• ECOG Performance Status > 2
• Total bilirubin > 3x the upper limit of the normal range (except for Gilbert syndrome: direct bilirubin 2x ULN) or ALT and AST > 3x ULN
• NYHA Class III or IV heart failure (refer to Issues for Consideration)
• Ongoing or active systemic infection, including active hepatitis B or C, or known HIV (refer to Issues for Consideration)
• Positive pregnancy test

Issues for Consideration

• Drug infusion time will be dependent upon patient tolerance and exposure to daratumumab. Median duration of the first infusion was ~ 7 hours in the SIRIUS trial, followed by infusion times of 4.2 and 3.4 hours, subsequently.
• Type and screen patients shortly prior to starting treatment. When the sample is provided to the blood bank, inform them that the patient will be receiving daratumumab.
• Those with NYHA Class III or IV heart failure, recent MI, conduction abnormalities, angina or arrhythmias uncontrolled by medications, were not eligible for clinical trials and may be at greater risk of cardiac complications.
• Patients with active hepatitis B, C, or HIV were excluded from clinical trials with daratumumab, therefore safety and efficacy data are unknown in these patient populations. The risk of infections was slightly higher in the daratumumab-treated arms of the comparative studies. Use of daratumumab should only be considered in those with well-controlled hepatitis B, hepatitis C, or HIV.

ELOTUZUMAB (EMPLICITI) Criteria for Use, January 2017

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive elotuzumab.

• Patient is noncompliant with medication, follow-up, or laboratory appointments
• Patient is not a candidate for lenalidomide therapy (ie, is lenalidomide-refractory or possesses contraindications to therapy)
• Patient is not a candidate for high-dose dexamethasone therapy
• Hemoglobin < 8 g/dL; Must transfuse to hemoglobin above 8 gm/dL prior to therapy initiation
• Absolute neutrophil count (ANC) < 1,000/mm³
• Platelet count < 50,000/mm3 (< 30,000/mm³ if myeloma involvement in bone marrow > 50%)
• ECOG Performance Status > 2
• Total bilirubin > 2x the upper limit of the normal range (except for Gilbert syndrome: direct bilirubin > 2 mg/dL) or ALT and AST > 3x ULN
• NYHA Class III or IV heart failure (refer to Issues for Consideration)
• Ongoing or active systemic infection, including active hepatitis B or hepatitis C, or known HIV (refer to Issues for Consideration)
• Positive pregnancy test
• Patient intends to breastfeed during therapy

Issues for Consideration

• Those with NYHA Class III or IV heart failure, recent MI, conduction abnormalities, angina or arrhythmias uncontrolled by medications, were not eligible for clinical trials and may be at greater risk of cardiac complications.
• Patients with active hepatitis B, hepatitis C, or HIV were excluded from clinical trials with elotuzumab, therefore safety and efficacy data are unknown in these patient populations. The risk of infections (OI, fungal, viral) was greater in the elotuzumab arm vs control arm of the comparative clinical trial. Use of elotuzumab should only be considered in those with well-controlled hepatitis B, hepatitis C, or HIV.
• Disappointing response rates as monotherapy in the relapsed/refractory setting suggest that elotuzumab should be given in combination with lenalidomide and dexamethasone.
• Impact of elotuzumab/lenalidomide/dexamethasone on overall survival is not known as these data were not mature at the time ELOQUENT-2 was published.

CARFILZOMIB (KYPROLIS) Criteria for Use, December 2016

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive carfilzomib.

• Care for the oncologic disease being treated not provided by a VA or VA purchased care (eg, Choice Program, Fee Basis) oncology provider
• Patient is noncompliant with medication, follow-up, or laboratory appointments
• Hemoglobin < 8 g/dL; Must transfuse to hemoglobin above 8 g/dL prior to therapy initiation
• Absolute neutrophil count (ANC) < 1,000/mm³
• Platelet count < 50,000/mm³ (< 30,000/mm³ if myeloma involvement in bone marrow > 50%)
• ECOG Performance Status > 2
• Total bilirubin > 1.5 x the upper limit of the normal range or ALT and AST > 3 x ULN
• NYHA Class III and IV heart failure (refer to Issues for Consideration; those at risk for cardiac failure and ischemia were also excluded from clinical trials)
• LVEF < 40%
• Uncontrolled hypertension
• Grade 3 or 4 peripheral neuropathy
• Ongoing or active systemic infection, including active hepatitis B or C, or known HIV

Issues for Consideration

• A significant percentage of patients on carfilzomib develop dyspnea. This drug should be used with caution in patients with underlying lung disease. Close monitoring for worsening of dyspnea is advised.
• Risk of cardiac failure increases in those aged > 75 years; those with NYHA Class III and IV heart failure, recent MI, conduction abnormalities, angina or arrhythmias uncontrolled by medications, were not eligible for clinical trials and may be at greater risk of cardiac complications. Refer to Prescribing Information for management recommendations.
• Those aged > 75 years experienced greater toxicity than their younger counterparts.
• Patients on dialysis: administer carfilzomib after the dialysis procedure.
• Phase III evidence in heavily pretreated relapsed/refractory patients (median 5 prior regimens) of carfilzomib vs low-dose steroids ± cyclophosphamide indicates that the median overall survival is not significantly different between these treatment arms.

IXAZOMIB (NILARO) Criteria for Use, December 2016

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive ixazomib

• Care for the oncologic disease being treated not provided by a VA or VA purchased care (eg, Choice Program, Fee Basis) oncology provider
• Patient is not a candidate for lenalidomide or dexamethasone therapy
• Patient is refractory to lenalidomide or proteasomeinhibitor therapy (defined as disease progression while on treatment or within 60 days of last dose)
• Absolute neutrophil count (ANC) < 1,000/mm³
• Platelet count < 75,000/mm³
• ECOG Performance Status > 2
• Patient with CNS involvement
• Patient receiving concurrent therapy with a strong CYP3A inducer (ie, rifampin, phenytoin, carbamazepine) that cannot be discontinued
• Uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina or myocardial infarction within 6 months prior to start
• Ongoing or active systemic infection, including active hepatitis B, hepatitis C, or known HIV

Issues for Consideration

• Indirect comparisons of phase 3 data (KRd vs Rd and IRd vs Rd) show that in similar populations of pretreated relapsed, refractory myeloma patients, those receiving KRd experienced longer PFS (26.3 vs 21 months), greater CR (32% vs 12%), greater ORR (87% vs 78%) and longer duration of response (28.6 vs 20.5 months). Therefore, providers may want to consider using carfilzomib in those meeting its criteria for use.
• Ixazomib is cytotoxic. Capsules should not be opened or crushed. Waste should be considered hazardous.
• Avoid concomitant use of strong CYP3A inducers (rifampin, phenytoin, carbamazepine, and St. John’s Wort).

Click here to read the digital edition.

VA Pharmacy Benefit Management Service (PBM) continually issues or revises its guidances for hematology and oncology care providers on a number of cancer care medications. Below are excerpts from recently released Criteria for Use documents. The complete documents, including the inclusion criteria, dosage and administration guidance, monitoring information, and discontinuation criteria should be consulted and can be found at www.pbm.va.gov or vaww.cmopnational.va.gov/cmop/PBM/default.aspx.

ENZALUTAMIDE (XTANDI) Criteria for Use, January 2017

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive enzalutamide.

• Brain metastases or active epidural disease
• Severe renal impairment (creatinine clearance < 30 mL/min)
• History of seizure (including febrile seizure, loss of consciousness, or transient ischemic attack within the previous 12 months, any condition predisposing to seizure: prior stroke, brain AV malformation, head trauma with loss of consciousness requiring hospitalization)
• ECOG Performance Status > 2
• Inability to swallow capsules

Issues for Consideration

• Enzalutamide is not indicated for use in women. Based on the mechanism of action, can cause fetal harm if used during pregnancy. Pregnancy Category X—use contraindicated during pregnancy. Exclude pregnancy before prescribing enzalutamide, discuss risks if pregnancy occurs, and provide contraceptive counseling.
• Use in patients taking concomitant medications that may lower the seizure threshold was not studied; caution patients about the risk of activities where the sudden loss of consciousness could cause serious harm if concomitant use cannot be avoided.
• Use in patients at risk for or with a strong history of falls: in the phase 3 clinical trial, falls or injuries from falls occurred in 4.6% of enzalutamide patients vs 1.3% of placebo patients.
• Avoid strong inhibitors of CYP2C8 (eg, gemfibrozil); if concomitant use of a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of  enzalutamide to 80 mg once daily according to the package insert.
• Co-administration with strong or moderate inducers of CYP3A4 (eg, carbamazepine, phenobarbital, phenytoin, rifampin, bosentan, efavirenz, modafinil, nafcillin, St. John’s Wort) or CYP2C8 (eg, rifampin) should be avoided if possible. If patient must be co-administered a strong CYP3A4 inducer, increase enzalutamide dose from 160 mg to 240 mg once daily.
• Drugs that are substrates of CYP3A4 (eg, alfentanil, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (eg, phenytoin, warfarin), or CYP2C19 (eg, S-mephenytoin) with a narrow therapeutic index should be avoided. If enzalutamide is co-administered with warfarin, additional INR testing should be conducted.
• Use in patients with hepatic impairment: Pharmacokinetics of enzalutamide and its metabolite were examined in volunteers with normal, Child-Pugh Class A, Child-Pugh Class B, and Child-Pugh Class C hepatic impairment. The composite AUC for enzalutamide and its metabolite after a single 160-mg dose was similar across all levels of hepatic impairment compared with normal volunteers.
• There have been postmarketing reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving enzalutamide. PRES is a neurologic disorder presenting with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual/neurological disturbances with or without associated hypertension. Diagnosis of PRES requires brain imaging, preferably by MRI. Enzalutamide should be discontinued in patients developing PRES.
• Sequencing of enzalutamide and abiraterone has been evaluated in several small retrospective analyses; the majority of the analyses are in the post chemotherapy setting. From this limited observational data, it is unclear if there is a preferred sequencing of abiraterone and enzalutamide. There is some evidence for cross-resistance. There are ongoing investigations into mechanisms of resistance to enzalutamide and abiraterone.

DARATUMUMAB (DARZALEX) Criteria for Use, January 2017

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive daratumumab.

• Patient is noncompliant with medication, follow-up, or laboratory appointments
• Patient unable or unwilling to be observed an extended period of time that may be necessary for first infusion (refer to Issues for Consideration)
• Hemoglobin < 8 g/dL; Must transfuse to hemoglobin above 8 gm/dL prior to therapy initiation
• Absolute neutrophil count (ANC) < 1,000/mm³
• Platelet count < 50,000/mm³ (< 30,000/mm³ if myeloma involvement in bone marrow > 50%)
• ECOG Performance Status > 2
• Total bilirubin > 3x the upper limit of the normal range (except for Gilbert syndrome: direct bilirubin 2x ULN) or ALT and AST > 3x ULN
• NYHA Class III or IV heart failure (refer to Issues for Consideration)
• Ongoing or active systemic infection, including active hepatitis B or C, or known HIV (refer to Issues for Consideration)
• Positive pregnancy test

Issues for Consideration

• Drug infusion time will be dependent upon patient tolerance and exposure to daratumumab. Median duration of the first infusion was ~ 7 hours in the SIRIUS trial, followed by infusion times of 4.2 and 3.4 hours, subsequently.
• Type and screen patients shortly prior to starting treatment. When the sample is provided to the blood bank, inform them that the patient will be receiving daratumumab.
• Those with NYHA Class III or IV heart failure, recent MI, conduction abnormalities, angina or arrhythmias uncontrolled by medications, were not eligible for clinical trials and may be at greater risk of cardiac complications.
• Patients with active hepatitis B, C, or HIV were excluded from clinical trials with daratumumab, therefore safety and efficacy data are unknown in these patient populations. The risk of infections was slightly higher in the daratumumab-treated arms of the comparative studies. Use of daratumumab should only be considered in those with well-controlled hepatitis B, hepatitis C, or HIV.

ELOTUZUMAB (EMPLICITI) Criteria for Use, January 2017

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive elotuzumab.

• Patient is noncompliant with medication, follow-up, or laboratory appointments
• Patient is not a candidate for lenalidomide therapy (ie, is lenalidomide-refractory or possesses contraindications to therapy)
• Patient is not a candidate for high-dose dexamethasone therapy
• Hemoglobin < 8 g/dL; Must transfuse to hemoglobin above 8 gm/dL prior to therapy initiation
• Absolute neutrophil count (ANC) < 1,000/mm³
• Platelet count < 50,000/mm3 (< 30,000/mm³ if myeloma involvement in bone marrow > 50%)
• ECOG Performance Status > 2
• Total bilirubin > 2x the upper limit of the normal range (except for Gilbert syndrome: direct bilirubin > 2 mg/dL) or ALT and AST > 3x ULN
• NYHA Class III or IV heart failure (refer to Issues for Consideration)
• Ongoing or active systemic infection, including active hepatitis B or hepatitis C, or known HIV (refer to Issues for Consideration)
• Positive pregnancy test
• Patient intends to breastfeed during therapy

Issues for Consideration

• Those with NYHA Class III or IV heart failure, recent MI, conduction abnormalities, angina or arrhythmias uncontrolled by medications, were not eligible for clinical trials and may be at greater risk of cardiac complications.
• Patients with active hepatitis B, hepatitis C, or HIV were excluded from clinical trials with elotuzumab, therefore safety and efficacy data are unknown in these patient populations. The risk of infections (OI, fungal, viral) was greater in the elotuzumab arm vs control arm of the comparative clinical trial. Use of elotuzumab should only be considered in those with well-controlled hepatitis B, hepatitis C, or HIV.
• Disappointing response rates as monotherapy in the relapsed/refractory setting suggest that elotuzumab should be given in combination with lenalidomide and dexamethasone.
• Impact of elotuzumab/lenalidomide/dexamethasone on overall survival is not known as these data were not mature at the time ELOQUENT-2 was published.

CARFILZOMIB (KYPROLIS) Criteria for Use, December 2016

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive carfilzomib.

• Care for the oncologic disease being treated not provided by a VA or VA purchased care (eg, Choice Program, Fee Basis) oncology provider
• Patient is noncompliant with medication, follow-up, or laboratory appointments
• Hemoglobin < 8 g/dL; Must transfuse to hemoglobin above 8 g/dL prior to therapy initiation
• Absolute neutrophil count (ANC) < 1,000/mm³
• Platelet count < 50,000/mm³ (< 30,000/mm³ if myeloma involvement in bone marrow > 50%)
• ECOG Performance Status > 2
• Total bilirubin > 1.5 x the upper limit of the normal range or ALT and AST > 3 x ULN
• NYHA Class III and IV heart failure (refer to Issues for Consideration; those at risk for cardiac failure and ischemia were also excluded from clinical trials)
• LVEF < 40%
• Uncontrolled hypertension
• Grade 3 or 4 peripheral neuropathy
• Ongoing or active systemic infection, including active hepatitis B or C, or known HIV

Issues for Consideration

• A significant percentage of patients on carfilzomib develop dyspnea. This drug should be used with caution in patients with underlying lung disease. Close monitoring for worsening of dyspnea is advised.
• Risk of cardiac failure increases in those aged > 75 years; those with NYHA Class III and IV heart failure, recent MI, conduction abnormalities, angina or arrhythmias uncontrolled by medications, were not eligible for clinical trials and may be at greater risk of cardiac complications. Refer to Prescribing Information for management recommendations.
• Those aged > 75 years experienced greater toxicity than their younger counterparts.
• Patients on dialysis: administer carfilzomib after the dialysis procedure.
• Phase III evidence in heavily pretreated relapsed/refractory patients (median 5 prior regimens) of carfilzomib vs low-dose steroids ± cyclophosphamide indicates that the median overall survival is not significantly different between these treatment arms.

IXAZOMIB (NILARO) Criteria for Use, December 2016

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive ixazomib

• Care for the oncologic disease being treated not provided by a VA or VA purchased care (eg, Choice Program, Fee Basis) oncology provider
• Patient is not a candidate for lenalidomide or dexamethasone therapy
• Patient is refractory to lenalidomide or proteasomeinhibitor therapy (defined as disease progression while on treatment or within 60 days of last dose)
• Absolute neutrophil count (ANC) < 1,000/mm³
• Platelet count < 75,000/mm³
• ECOG Performance Status > 2
• Patient with CNS involvement
• Patient receiving concurrent therapy with a strong CYP3A inducer (ie, rifampin, phenytoin, carbamazepine) that cannot be discontinued
• Uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina or myocardial infarction within 6 months prior to start
• Ongoing or active systemic infection, including active hepatitis B, hepatitis C, or known HIV

Issues for Consideration

• Indirect comparisons of phase 3 data (KRd vs Rd and IRd vs Rd) show that in similar populations of pretreated relapsed, refractory myeloma patients, those receiving KRd experienced longer PFS (26.3 vs 21 months), greater CR (32% vs 12%), greater ORR (87% vs 78%) and longer duration of response (28.6 vs 20.5 months). Therefore, providers may want to consider using carfilzomib in those meeting its criteria for use.
• Ixazomib is cytotoxic. Capsules should not be opened or crushed. Waste should be considered hazardous.
• Avoid concomitant use of strong CYP3A inducers (rifampin, phenytoin, carbamazepine, and St. John’s Wort).

Click here to read the digital edition.

VA Pharmacy Benefit Management Service (PBM) continually issues or revises its guidances for hematology and oncology care providers on a number of cancer care medications. Below are excerpts from recently released Criteria for Use documents. The complete documents, including the inclusion criteria, dosage and administration guidance, monitoring information, and discontinuation criteria should be consulted and can be found at www.pbm.va.gov or vaww.cmopnational.va.gov/cmop/PBM/default.aspx.

ENZALUTAMIDE (XTANDI) Criteria for Use, January 2017

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive enzalutamide.

• Brain metastases or active epidural disease
• Severe renal impairment (creatinine clearance < 30 mL/min)
• History of seizure (including febrile seizure, loss of consciousness, or transient ischemic attack within the previous 12 months, any condition predisposing to seizure: prior stroke, brain AV malformation, head trauma with loss of consciousness requiring hospitalization)
• ECOG Performance Status > 2
• Inability to swallow capsules

Issues for Consideration

• Enzalutamide is not indicated for use in women. Based on the mechanism of action, can cause fetal harm if used during pregnancy. Pregnancy Category X—use contraindicated during pregnancy. Exclude pregnancy before prescribing enzalutamide, discuss risks if pregnancy occurs, and provide contraceptive counseling.
• Use in patients taking concomitant medications that may lower the seizure threshold was not studied; caution patients about the risk of activities where the sudden loss of consciousness could cause serious harm if concomitant use cannot be avoided.
• Use in patients at risk for or with a strong history of falls: in the phase 3 clinical trial, falls or injuries from falls occurred in 4.6% of enzalutamide patients vs 1.3% of placebo patients.
• Avoid strong inhibitors of CYP2C8 (eg, gemfibrozil); if concomitant use of a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of  enzalutamide to 80 mg once daily according to the package insert.
• Co-administration with strong or moderate inducers of CYP3A4 (eg, carbamazepine, phenobarbital, phenytoin, rifampin, bosentan, efavirenz, modafinil, nafcillin, St. John’s Wort) or CYP2C8 (eg, rifampin) should be avoided if possible. If patient must be co-administered a strong CYP3A4 inducer, increase enzalutamide dose from 160 mg to 240 mg once daily.
• Drugs that are substrates of CYP3A4 (eg, alfentanil, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (eg, phenytoin, warfarin), or CYP2C19 (eg, S-mephenytoin) with a narrow therapeutic index should be avoided. If enzalutamide is co-administered with warfarin, additional INR testing should be conducted.
• Use in patients with hepatic impairment: Pharmacokinetics of enzalutamide and its metabolite were examined in volunteers with normal, Child-Pugh Class A, Child-Pugh Class B, and Child-Pugh Class C hepatic impairment. The composite AUC for enzalutamide and its metabolite after a single 160-mg dose was similar across all levels of hepatic impairment compared with normal volunteers.
• There have been postmarketing reports of posterior reversible encephalopathy syndrome (PRES) in patients receiving enzalutamide. PRES is a neurologic disorder presenting with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual/neurological disturbances with or without associated hypertension. Diagnosis of PRES requires brain imaging, preferably by MRI. Enzalutamide should be discontinued in patients developing PRES.
• Sequencing of enzalutamide and abiraterone has been evaluated in several small retrospective analyses; the majority of the analyses are in the post chemotherapy setting. From this limited observational data, it is unclear if there is a preferred sequencing of abiraterone and enzalutamide. There is some evidence for cross-resistance. There are ongoing investigations into mechanisms of resistance to enzalutamide and abiraterone.

DARATUMUMAB (DARZALEX) Criteria for Use, January 2017

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive daratumumab.

• Patient is noncompliant with medication, follow-up, or laboratory appointments
• Patient unable or unwilling to be observed an extended period of time that may be necessary for first infusion (refer to Issues for Consideration)
• Hemoglobin < 8 g/dL; Must transfuse to hemoglobin above 8 gm/dL prior to therapy initiation
• Absolute neutrophil count (ANC) < 1,000/mm³
• Platelet count < 50,000/mm³ (< 30,000/mm³ if myeloma involvement in bone marrow > 50%)
• ECOG Performance Status > 2
• Total bilirubin > 3x the upper limit of the normal range (except for Gilbert syndrome: direct bilirubin 2x ULN) or ALT and AST > 3x ULN
• NYHA Class III or IV heart failure (refer to Issues for Consideration)
• Ongoing or active systemic infection, including active hepatitis B or C, or known HIV (refer to Issues for Consideration)
• Positive pregnancy test

Issues for Consideration

• Drug infusion time will be dependent upon patient tolerance and exposure to daratumumab. Median duration of the first infusion was ~ 7 hours in the SIRIUS trial, followed by infusion times of 4.2 and 3.4 hours, subsequently.
• Type and screen patients shortly prior to starting treatment. When the sample is provided to the blood bank, inform them that the patient will be receiving daratumumab.
• Those with NYHA Class III or IV heart failure, recent MI, conduction abnormalities, angina or arrhythmias uncontrolled by medications, were not eligible for clinical trials and may be at greater risk of cardiac complications.
• Patients with active hepatitis B, C, or HIV were excluded from clinical trials with daratumumab, therefore safety and efficacy data are unknown in these patient populations. The risk of infections was slightly higher in the daratumumab-treated arms of the comparative studies. Use of daratumumab should only be considered in those with well-controlled hepatitis B, hepatitis C, or HIV.

ELOTUZUMAB (EMPLICITI) Criteria for Use, January 2017

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive elotuzumab.

• Patient is noncompliant with medication, follow-up, or laboratory appointments
• Patient is not a candidate for lenalidomide therapy (ie, is lenalidomide-refractory or possesses contraindications to therapy)
• Patient is not a candidate for high-dose dexamethasone therapy
• Hemoglobin < 8 g/dL; Must transfuse to hemoglobin above 8 gm/dL prior to therapy initiation
• Absolute neutrophil count (ANC) < 1,000/mm³
• Platelet count < 50,000/mm3 (< 30,000/mm³ if myeloma involvement in bone marrow > 50%)
• ECOG Performance Status > 2
• Total bilirubin > 2x the upper limit of the normal range (except for Gilbert syndrome: direct bilirubin > 2 mg/dL) or ALT and AST > 3x ULN
• NYHA Class III or IV heart failure (refer to Issues for Consideration)
• Ongoing or active systemic infection, including active hepatitis B or hepatitis C, or known HIV (refer to Issues for Consideration)
• Positive pregnancy test
• Patient intends to breastfeed during therapy

Issues for Consideration

• Those with NYHA Class III or IV heart failure, recent MI, conduction abnormalities, angina or arrhythmias uncontrolled by medications, were not eligible for clinical trials and may be at greater risk of cardiac complications.
• Patients with active hepatitis B, hepatitis C, or HIV were excluded from clinical trials with elotuzumab, therefore safety and efficacy data are unknown in these patient populations. The risk of infections (OI, fungal, viral) was greater in the elotuzumab arm vs control arm of the comparative clinical trial. Use of elotuzumab should only be considered in those with well-controlled hepatitis B, hepatitis C, or HIV.
• Disappointing response rates as monotherapy in the relapsed/refractory setting suggest that elotuzumab should be given in combination with lenalidomide and dexamethasone.
• Impact of elotuzumab/lenalidomide/dexamethasone on overall survival is not known as these data were not mature at the time ELOQUENT-2 was published.

CARFILZOMIB (KYPROLIS) Criteria for Use, December 2016

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive carfilzomib.

• Care for the oncologic disease being treated not provided by a VA or VA purchased care (eg, Choice Program, Fee Basis) oncology provider
• Patient is noncompliant with medication, follow-up, or laboratory appointments
• Hemoglobin < 8 g/dL; Must transfuse to hemoglobin above 8 g/dL prior to therapy initiation
• Absolute neutrophil count (ANC) < 1,000/mm³
• Platelet count < 50,000/mm³ (< 30,000/mm³ if myeloma involvement in bone marrow > 50%)
• ECOG Performance Status > 2
• Total bilirubin > 1.5 x the upper limit of the normal range or ALT and AST > 3 x ULN
• NYHA Class III and IV heart failure (refer to Issues for Consideration; those at risk for cardiac failure and ischemia were also excluded from clinical trials)
• LVEF < 40%
• Uncontrolled hypertension
• Grade 3 or 4 peripheral neuropathy
• Ongoing or active systemic infection, including active hepatitis B or C, or known HIV

Issues for Consideration

• A significant percentage of patients on carfilzomib develop dyspnea. This drug should be used with caution in patients with underlying lung disease. Close monitoring for worsening of dyspnea is advised.
• Risk of cardiac failure increases in those aged > 75 years; those with NYHA Class III and IV heart failure, recent MI, conduction abnormalities, angina or arrhythmias uncontrolled by medications, were not eligible for clinical trials and may be at greater risk of cardiac complications. Refer to Prescribing Information for management recommendations.
• Those aged > 75 years experienced greater toxicity than their younger counterparts.
• Patients on dialysis: administer carfilzomib after the dialysis procedure.
• Phase III evidence in heavily pretreated relapsed/refractory patients (median 5 prior regimens) of carfilzomib vs low-dose steroids ± cyclophosphamide indicates that the median overall survival is not significantly different between these treatment arms.

IXAZOMIB (NILARO) Criteria for Use, December 2016

Exclusion Criteria: If the answer to ANY item below is met, then the patient should NOT receive ixazomib

• Care for the oncologic disease being treated not provided by a VA or VA purchased care (eg, Choice Program, Fee Basis) oncology provider
• Patient is not a candidate for lenalidomide or dexamethasone therapy
• Patient is refractory to lenalidomide or proteasomeinhibitor therapy (defined as disease progression while on treatment or within 60 days of last dose)
• Absolute neutrophil count (ANC) < 1,000/mm³
• Platelet count < 75,000/mm³
• ECOG Performance Status > 2
• Patient with CNS involvement
• Patient receiving concurrent therapy with a strong CYP3A inducer (ie, rifampin, phenytoin, carbamazepine) that cannot be discontinued
• Uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina or myocardial infarction within 6 months prior to start
• Ongoing or active systemic infection, including active hepatitis B, hepatitis C, or known HIV

Issues for Consideration

• Indirect comparisons of phase 3 data (KRd vs Rd and IRd vs Rd) show that in similar populations of pretreated relapsed, refractory myeloma patients, those receiving KRd experienced longer PFS (26.3 vs 21 months), greater CR (32% vs 12%), greater ORR (87% vs 78%) and longer duration of response (28.6 vs 20.5 months). Therefore, providers may want to consider using carfilzomib in those meeting its criteria for use.
• Ixazomib is cytotoxic. Capsules should not be opened or crushed. Waste should be considered hazardous.
• Avoid concomitant use of strong CYP3A inducers (rifampin, phenytoin, carbamazepine, and St. John’s Wort).

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