Bob Marshall, MD, MPH, MISM, FAAFP

ILLUSTRATIVE CASE

Ms. M is a 76-year-old woman with well-­controlled type 2 diabetes mellitus for 10 years and well-controlled mild hypertension. She is otherwise healthy, and her mother lived to age 95. Ms. M has never smoked, has no previous history of vascular/cardiovascular disease, and drinks 1 glass of wine 2 to 3 times per week. Based on the American College of Cardiology (ACC) calculator, she was started on atorvastatin years ago. Is continued use of the medication of any benefit at her current age?

The 2018 American Heart Association (AHA)/ACC/Multi-Society cholesterol guidelines do not provide primary prevention recommendations for those older than age 75 years.³ Up to age 75, the guidelines recommend that patients with type 2 diabetes and a low-density lipoprotein cholesterol (LDL-C) level ≥ 70 mg/dL, as well as those without diabetes but with an LDL-C ≥ 70 mg/dL and a 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥ 10%, be started on medium-intensity statin therapy.

A 2018 consensus panel review of the current literature, sponsored by the National Institute on Aging and the National Heart, Lung, and Blood Institute, concluded that there was insufficient evidence regarding the benefits and harms of statins in older adults, especially those with comorbidities, and that there was a paucity of evidence about statin therapy outcomes (both adverse and beneficial) relevant to older adults.⁴

A review of all guidelines published since 2013 revealed that only the United Kingdom’s 2014 National Institute for Health and Care Excellence (NICE) guideline provides a strong, risk-based recommendation for initiating primary prevention with statins in patients > 75 years old.⁵ These recommendations are based on the QRISK2 calculator (which has since been updated to the QRISK3), which assigns everyone ages > 75 years a > 10% 10-year risk score. This provides a universal statin indication for anyone in the 76-to-84 age range.⁶

Both the ACC/AHA and US Preventive Services Task Force guidelines clearly state that there are too few data and inadequate evidence in people older than 75 for a strong, risk-based statin recommendation.⁵ The Canadian Cardiovascular Society guideline takes a similar stance, emphasizing that the recommended Framingham risk model is not well validated in people > 75 years.⁵

STUDY SUMMARIES

Two different looks at statin use in the elderly

A retrospective cohort study (N = 46,864; median follow-up, 5.6 years) examined whether statin treatment is associated with a reduction in atherosclerotic disease and mortality in old and very old adults with and without type 2 diabetes.¹ Patients were enrolled from a large, anonymized national database in Spain. The researchers looked only at first-time users of statins and those without a statin prescription within the past 18 months.

Statin therapy seems to provide no benefit to patients ages > 75 years without ASCVD or in patients ages ≥ 85 years without ASCVD, regardless of type 2 diabetes status.

Patients with previous ASCVD, type 1 diabetes, previous lipid-lowering treatment, dementia, cancer, or paralysis were excluded, as were those who were in residential care, were on dialysis, or had received an organ transplant. Patients were stratified by age (75-84 years and ≥ 85 years), diabetes status (with or without type 2 diabetes), and statin use (nonuser or new user).

Continue to: Results

Results. For patients with type 2 diabetes, the risk of ASCVD (a composite of coronary heart disease and stroke) was lower among those who took statins than among those who did not in the 75-to-84 group (hazard ratio [HR] = 0.76; 95% confidence interval [CI], 0.65-0.89; 1-year number needed to treat [NNT] = 164). Among those who took statins, there was also lower all-cause mortality (HR = 0.84; 95% CI, 0.75-0.94; 1-year NNT = 306). In those ages ≥ 85 years with diabetes, the statin group did not have a lower risk of ASCVD (HR = 0.82; 95% CI, 0.53-1.26) or all-cause mortality (HR = 1.05; 95% CI, 0.86-1.28).

For patients ages 75 to 84 years without diabetes, there was no difference in risk between groups for ASCVD (HR = 0.94; 95% CI, 0.86–1.04) or all-cause mortality (HR = 0.98; 95% CI, 0.91-1.05). In those ages ≥ 85 years without diabetes, there was also no difference between groups for ASCVD (HR = 1; 95% CI, 0.80-1.24) or for all-cause mortality (HR = 1; 95% CI, 0.90-1.11).

A 2019 meta-analysis of randomized controlled trials (RCTs) (n = 134,537) and RCT summary data (n = 12,705) evaluated the safety and efficacy of statin therapy in patients ages ≥ 55 years.² In the group of patients ages > 75 years (n = 14,483; median follow-up, 4.9 years), each 1 mmol/L reduction in LDL-C was associated with significant decreased risk for major vascular events (risk ratio [RR] = 0.82; 95% CI, 0.70-0.95) and for major coronary events (RR = 0.82; 95% CI, 0.70-0.96).

In subgroup analysis by the presence or absence of previous vascular disease, there was a decreased risk per 1 mmol/L LDL-C reduction of major vascular events in patients with previous vascular disease (RR = 0.85; 95% CI, 0.73-0.98); however, there was not a significant effect in patients without previous vascular disease (RR = 0.92; 95% CI, 0.73-1.16).

WHAT’S NEW

Statins may be unnecessary in older adults without ASCVD or T2DM

Statin therapy reduces the risk of ASCVD and mortality in patients ages 75 to 84 with type 2 diabetes and in patients > 75 years with known vascular disease. However, statin therapy seems to provide no benefit in patients ages > 75 years without ASCVD or in patients ages ≥ 85 years without ASCVD, regardless of type 2 diabetes status.

Continue to: CAVEATS

CAVEATS

Retrospective cohort design leaves cause and effect equivocal

Even though the first study was large (with more than 46,000 patients) and the median follow-up was 5.6 years, it was a retrospective cohort study. While there is clearly an association between statin therapy and reduced ASCVD and all-cause mortality in patients with diabetes ages 75 to 84 years, cause and effect cannot be unequivocally stated. However, the meta-analysis, which included RCTs, confirms the benefit of statins in secondary prevention for older patients.

The cohort study did not look at adverse effects from statin therapy in this age group, but the data from the 2019 meta-analysis did not reveal any significant risk of myopathy.

CHALLENGES TO IMPLEMENTATION

Guidelines are lacking and discontinuing meds requires discussion

The lack of supporting guidelines to treat this age group with statins remains the largest barrier to implementation. Many patients may already be taking a statin, so a discussion about discontinuing medication will need to be initiated.

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Ms. M is a 76-year-old woman with well-­controlled type 2 diabetes mellitus for 10 years and well-controlled mild hypertension. She is otherwise healthy, and her mother lived to age 95. Ms. M has never smoked, has no previous history of vascular/cardiovascular disease, and drinks 1 glass of wine 2 to 3 times per week. Based on the American College of Cardiology (ACC) calculator, she was started on atorvastatin years ago. Is continued use of the medication of any benefit at her current age?

The 2018 American Heart Association (AHA)/ACC/Multi-Society cholesterol guidelines do not provide primary prevention recommendations for those older than age 75 years.³ Up to age 75, the guidelines recommend that patients with type 2 diabetes and a low-density lipoprotein cholesterol (LDL-C) level ≥ 70 mg/dL, as well as those without diabetes but with an LDL-C ≥ 70 mg/dL and a 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥ 10%, be started on medium-intensity statin therapy.

A 2018 consensus panel review of the current literature, sponsored by the National Institute on Aging and the National Heart, Lung, and Blood Institute, concluded that there was insufficient evidence regarding the benefits and harms of statins in older adults, especially those with comorbidities, and that there was a paucity of evidence about statin therapy outcomes (both adverse and beneficial) relevant to older adults.⁴

A review of all guidelines published since 2013 revealed that only the United Kingdom’s 2014 National Institute for Health and Care Excellence (NICE) guideline provides a strong, risk-based recommendation for initiating primary prevention with statins in patients > 75 years old.⁵ These recommendations are based on the QRISK2 calculator (which has since been updated to the QRISK3), which assigns everyone ages > 75 years a > 10% 10-year risk score. This provides a universal statin indication for anyone in the 76-to-84 age range.⁶

Both the ACC/AHA and US Preventive Services Task Force guidelines clearly state that there are too few data and inadequate evidence in people older than 75 for a strong, risk-based statin recommendation.⁵ The Canadian Cardiovascular Society guideline takes a similar stance, emphasizing that the recommended Framingham risk model is not well validated in people > 75 years.⁵

STUDY SUMMARIES

Two different looks at statin use in the elderly

A retrospective cohort study (N = 46,864; median follow-up, 5.6 years) examined whether statin treatment is associated with a reduction in atherosclerotic disease and mortality in old and very old adults with and without type 2 diabetes.¹ Patients were enrolled from a large, anonymized national database in Spain. The researchers looked only at first-time users of statins and those without a statin prescription within the past 18 months.

Statin therapy seems to provide no benefit to patients ages > 75 years without ASCVD or in patients ages ≥ 85 years without ASCVD, regardless of type 2 diabetes status.

Patients with previous ASCVD, type 1 diabetes, previous lipid-lowering treatment, dementia, cancer, or paralysis were excluded, as were those who were in residential care, were on dialysis, or had received an organ transplant. Patients were stratified by age (75-84 years and ≥ 85 years), diabetes status (with or without type 2 diabetes), and statin use (nonuser or new user).

Continue to: Results

Results. For patients with type 2 diabetes, the risk of ASCVD (a composite of coronary heart disease and stroke) was lower among those who took statins than among those who did not in the 75-to-84 group (hazard ratio [HR] = 0.76; 95% confidence interval [CI], 0.65-0.89; 1-year number needed to treat [NNT] = 164). Among those who took statins, there was also lower all-cause mortality (HR = 0.84; 95% CI, 0.75-0.94; 1-year NNT = 306). In those ages ≥ 85 years with diabetes, the statin group did not have a lower risk of ASCVD (HR = 0.82; 95% CI, 0.53-1.26) or all-cause mortality (HR = 1.05; 95% CI, 0.86-1.28).

For patients ages 75 to 84 years without diabetes, there was no difference in risk between groups for ASCVD (HR = 0.94; 95% CI, 0.86–1.04) or all-cause mortality (HR = 0.98; 95% CI, 0.91-1.05). In those ages ≥ 85 years without diabetes, there was also no difference between groups for ASCVD (HR = 1; 95% CI, 0.80-1.24) or for all-cause mortality (HR = 1; 95% CI, 0.90-1.11).

A 2019 meta-analysis of randomized controlled trials (RCTs) (n = 134,537) and RCT summary data (n = 12,705) evaluated the safety and efficacy of statin therapy in patients ages ≥ 55 years.² In the group of patients ages > 75 years (n = 14,483; median follow-up, 4.9 years), each 1 mmol/L reduction in LDL-C was associated with significant decreased risk for major vascular events (risk ratio [RR] = 0.82; 95% CI, 0.70-0.95) and for major coronary events (RR = 0.82; 95% CI, 0.70-0.96).

In subgroup analysis by the presence or absence of previous vascular disease, there was a decreased risk per 1 mmol/L LDL-C reduction of major vascular events in patients with previous vascular disease (RR = 0.85; 95% CI, 0.73-0.98); however, there was not a significant effect in patients without previous vascular disease (RR = 0.92; 95% CI, 0.73-1.16).

WHAT’S NEW

Statins may be unnecessary in older adults without ASCVD or T2DM

Statin therapy reduces the risk of ASCVD and mortality in patients ages 75 to 84 with type 2 diabetes and in patients > 75 years with known vascular disease. However, statin therapy seems to provide no benefit in patients ages > 75 years without ASCVD or in patients ages ≥ 85 years without ASCVD, regardless of type 2 diabetes status.

Continue to: CAVEATS

CAVEATS

Retrospective cohort design leaves cause and effect equivocal

Even though the first study was large (with more than 46,000 patients) and the median follow-up was 5.6 years, it was a retrospective cohort study. While there is clearly an association between statin therapy and reduced ASCVD and all-cause mortality in patients with diabetes ages 75 to 84 years, cause and effect cannot be unequivocally stated. However, the meta-analysis, which included RCTs, confirms the benefit of statins in secondary prevention for older patients.

The cohort study did not look at adverse effects from statin therapy in this age group, but the data from the 2019 meta-analysis did not reveal any significant risk of myopathy.

CHALLENGES TO IMPLEMENTATION

Guidelines are lacking and discontinuing meds requires discussion

The lack of supporting guidelines to treat this age group with statins remains the largest barrier to implementation. Many patients may already be taking a statin, so a discussion about discontinuing medication will need to be initiated.

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Ms. M is a 76-year-old woman with well-­controlled type 2 diabetes mellitus for 10 years and well-controlled mild hypertension. She is otherwise healthy, and her mother lived to age 95. Ms. M has never smoked, has no previous history of vascular/cardiovascular disease, and drinks 1 glass of wine 2 to 3 times per week. Based on the American College of Cardiology (ACC) calculator, she was started on atorvastatin years ago. Is continued use of the medication of any benefit at her current age?

The 2018 American Heart Association (AHA)/ACC/Multi-Society cholesterol guidelines do not provide primary prevention recommendations for those older than age 75 years.³ Up to age 75, the guidelines recommend that patients with type 2 diabetes and a low-density lipoprotein cholesterol (LDL-C) level ≥ 70 mg/dL, as well as those without diabetes but with an LDL-C ≥ 70 mg/dL and a 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥ 10%, be started on medium-intensity statin therapy.

A 2018 consensus panel review of the current literature, sponsored by the National Institute on Aging and the National Heart, Lung, and Blood Institute, concluded that there was insufficient evidence regarding the benefits and harms of statins in older adults, especially those with comorbidities, and that there was a paucity of evidence about statin therapy outcomes (both adverse and beneficial) relevant to older adults.⁴

A review of all guidelines published since 2013 revealed that only the United Kingdom’s 2014 National Institute for Health and Care Excellence (NICE) guideline provides a strong, risk-based recommendation for initiating primary prevention with statins in patients > 75 years old.⁵ These recommendations are based on the QRISK2 calculator (which has since been updated to the QRISK3), which assigns everyone ages > 75 years a > 10% 10-year risk score. This provides a universal statin indication for anyone in the 76-to-84 age range.⁶

Both the ACC/AHA and US Preventive Services Task Force guidelines clearly state that there are too few data and inadequate evidence in people older than 75 for a strong, risk-based statin recommendation.⁵ The Canadian Cardiovascular Society guideline takes a similar stance, emphasizing that the recommended Framingham risk model is not well validated in people > 75 years.⁵

STUDY SUMMARIES

Two different looks at statin use in the elderly

A retrospective cohort study (N = 46,864; median follow-up, 5.6 years) examined whether statin treatment is associated with a reduction in atherosclerotic disease and mortality in old and very old adults with and without type 2 diabetes.¹ Patients were enrolled from a large, anonymized national database in Spain. The researchers looked only at first-time users of statins and those without a statin prescription within the past 18 months.

Statin therapy seems to provide no benefit to patients ages > 75 years without ASCVD or in patients ages ≥ 85 years without ASCVD, regardless of type 2 diabetes status.

Patients with previous ASCVD, type 1 diabetes, previous lipid-lowering treatment, dementia, cancer, or paralysis were excluded, as were those who were in residential care, were on dialysis, or had received an organ transplant. Patients were stratified by age (75-84 years and ≥ 85 years), diabetes status (with or without type 2 diabetes), and statin use (nonuser or new user).

Continue to: Results

Results. For patients with type 2 diabetes, the risk of ASCVD (a composite of coronary heart disease and stroke) was lower among those who took statins than among those who did not in the 75-to-84 group (hazard ratio [HR] = 0.76; 95% confidence interval [CI], 0.65-0.89; 1-year number needed to treat [NNT] = 164). Among those who took statins, there was also lower all-cause mortality (HR = 0.84; 95% CI, 0.75-0.94; 1-year NNT = 306). In those ages ≥ 85 years with diabetes, the statin group did not have a lower risk of ASCVD (HR = 0.82; 95% CI, 0.53-1.26) or all-cause mortality (HR = 1.05; 95% CI, 0.86-1.28).

For patients ages 75 to 84 years without diabetes, there was no difference in risk between groups for ASCVD (HR = 0.94; 95% CI, 0.86–1.04) or all-cause mortality (HR = 0.98; 95% CI, 0.91-1.05). In those ages ≥ 85 years without diabetes, there was also no difference between groups for ASCVD (HR = 1; 95% CI, 0.80-1.24) or for all-cause mortality (HR = 1; 95% CI, 0.90-1.11).

A 2019 meta-analysis of randomized controlled trials (RCTs) (n = 134,537) and RCT summary data (n = 12,705) evaluated the safety and efficacy of statin therapy in patients ages ≥ 55 years.² In the group of patients ages > 75 years (n = 14,483; median follow-up, 4.9 years), each 1 mmol/L reduction in LDL-C was associated with significant decreased risk for major vascular events (risk ratio [RR] = 0.82; 95% CI, 0.70-0.95) and for major coronary events (RR = 0.82; 95% CI, 0.70-0.96).

In subgroup analysis by the presence or absence of previous vascular disease, there was a decreased risk per 1 mmol/L LDL-C reduction of major vascular events in patients with previous vascular disease (RR = 0.85; 95% CI, 0.73-0.98); however, there was not a significant effect in patients without previous vascular disease (RR = 0.92; 95% CI, 0.73-1.16).

WHAT’S NEW

Statins may be unnecessary in older adults without ASCVD or T2DM

Statin therapy reduces the risk of ASCVD and mortality in patients ages 75 to 84 with type 2 diabetes and in patients > 75 years with known vascular disease. However, statin therapy seems to provide no benefit in patients ages > 75 years without ASCVD or in patients ages ≥ 85 years without ASCVD, regardless of type 2 diabetes status.

Continue to: CAVEATS

CAVEATS

Retrospective cohort design leaves cause and effect equivocal

Even though the first study was large (with more than 46,000 patients) and the median follow-up was 5.6 years, it was a retrospective cohort study. While there is clearly an association between statin therapy and reduced ASCVD and all-cause mortality in patients with diabetes ages 75 to 84 years, cause and effect cannot be unequivocally stated. However, the meta-analysis, which included RCTs, confirms the benefit of statins in secondary prevention for older patients.

The cohort study did not look at adverse effects from statin therapy in this age group, but the data from the 2019 meta-analysis did not reveal any significant risk of myopathy.

CHALLENGES TO IMPLEMENTATION

Guidelines are lacking and discontinuing meds requires discussion

The lack of supporting guidelines to treat this age group with statins remains the largest barrier to implementation. Many patients may already be taking a statin, so a discussion about discontinuing medication will need to be initiated.

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Blanche is a 54-year-old overweight woman who has had type 2 diabetes mellitus (T2DM) for 5 years. She has been optimized on both metformin (1000 mg bid) and exenatide (2 mg weekly). While taking these medications, her hemoglobin A1C (HbA1C) has dropped from 11.2 to 8.4, and her body mass index (BMI) has declined from 35 to 31. However, she is still not at goal. You decide to start her on long-acting basal insulin. She has limited income, and she currently spends $75/month for her metformin, exenatide, atorvastatin, and lisinopril. What insulin do you prescribe?

The Centers for Disease Control and Prevention (CDC) reported that the prevalence of diabetes in the United States was 9.4% (30.3 million people) in 2015.² Among those affected, approximately 95.8% had T2DM.² The same report estimated that 1.5 million new cases of diabetes (6.7 per 1000 persons) were diagnosed annually among US adults ≥ 18 years of age, and that about $7900 of annual medical expenses for patients diagnosed with diabetes was directly attributable to diabetes.²

In the United States, neutral protamine Hagedorn (NPH) insulin was the most commonly used intermediate- to long-acting insulin until the introduction of the long-acting insulin analogs (insulin glargine in 2000 and insulin detemir in 2005).³ Despite being considerably more expensive than NPH insulin, long-acting insulin analogs had captured more than 80% of the total long-acting insulin market by 2010.⁴ The market share for NPH insulin dropped from 81.9% in 2001 to 16.2% in 2010.⁴

While the newer insulin analogs are significantly more expensive than NPH insulin, with higher corresponding out-of-pocket costs to patients, researchers have had a difficult time demonstrating greater effectiveness or any definitive differences in any long-term outcomes between NPH and the insulin analogs. A 2007 Cochrane review comparing NPH insulin to both glargine and detemir showed little difference in metabolic control (as measured by HbA1C) or in the rate of severe hypoglycemia. However, the rates of symptomatic, overall, and nocturnal hypoglycemia were statistically lower with the insulin analogs.⁵

A 2015 retrospective observational study from the Veterans Health Administration (N = 142,940) covering a 10-year period from 2000 to 2010 found no consistent differences in long-term health outcomes when comparing the use of long-acting insulin analogs to that of NPH insulin.^3,6

STUDY SUMMARY

Study compares performance of basal insulin analogs to that of NPH

This retrospective, observational study included 25,489 adult patients with T2DM who were enrolled in Kaiser Permanente of Northern California, had full medical and prescription coverage, and initiated basal insulin therapy with either NPH or an insulin analog between 2006 and 2015.

This study makes a strong case for a different approach to initial basal insulin therapy for patients with T2DM who need insulin for glucose control.

The primary outcome was the time from basal insulin therapy initiation to a hypoglycemia-related emergency department (ED) visit or hospital admission. The secondary outcome was the change in HbA1C level within 1 year of initiation of basal insulin therapy.

Continue to: Per 1000 person-years...

Per 1000 person-years, there was no significant difference in hypoglycemia-related ED visits or hospital admissions between the analog and NPH groups (11.9 events vs 8.8 events, respectively; between-group difference, 3.1 events; 95% confidence interval [CI], –1.5 to 7.7). HbA1C reduction was statistically greater with NPH, but most likely not clinically significant between insulin analogs and NPH (1.26 vs 1.48 percentage points; between group difference, –0.22%; 95% CI, –0.09% to –0.37%).

WHAT’S NEW?

No clinically relevant differences between insulin analogs and NPH

This study revealed that there is no clinically relevant difference in HbA1C levels and no difference in patient-focused outcomes of hypoglycemia-related ED visits or hospital admissions between NPH insulin and the more expensive insulin analogs. This makes a strong case for a different approach to initial basal insulin therapy for patients with T2DM who need insulin for glucose control.

CAVEATS

Demographics and less severe hypoglycemia might be at issue

This retrospective, observational study has broad demographics (but moderate under-representation of African-Americans), minimal patient health care disparities, and good access to medications. But generalizability outside of an integrated health delivery system may be limited. The study design also is subject to confounding, as not all potential impacts on the results can be corrected for or controlled in an observational study. Also, less profound hypoglycemia that did not require an ED visit or hospital admission was not captured.

CHALLENGES TO IMPLEMENTATION

Convenience and marketing factors may hinder change

Insulin analogs may have a number of convenience and marketing factors that may make it hard for providers and systems to change and use more NPH. However, the easy-to-use insulin analog pens are matched in availability and convenience by the much less advertised NPH insulin pens produced by at least 3 major pharmaceutical companies. In addition, while the overall cost for the insulin analogs continues to be 2 to 3 times that of non-human NPH insulin, insurance often covers up to, or more than, 80% of the cost of the insulin analogs, making the difference in the patient’s copay between the 2 not as severe. For example, patients may pay $30 to $40 per month for insulin analogs vs $10 to $25 per month for cheaper versions of NPH.^7,8

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Blanche is a 54-year-old overweight woman who has had type 2 diabetes mellitus (T2DM) for 5 years. She has been optimized on both metformin (1000 mg bid) and exenatide (2 mg weekly). While taking these medications, her hemoglobin A1C (HbA1C) has dropped from 11.2 to 8.4, and her body mass index (BMI) has declined from 35 to 31. However, she is still not at goal. You decide to start her on long-acting basal insulin. She has limited income, and she currently spends $75/month for her metformin, exenatide, atorvastatin, and lisinopril. What insulin do you prescribe?

The Centers for Disease Control and Prevention (CDC) reported that the prevalence of diabetes in the United States was 9.4% (30.3 million people) in 2015.² Among those affected, approximately 95.8% had T2DM.² The same report estimated that 1.5 million new cases of diabetes (6.7 per 1000 persons) were diagnosed annually among US adults ≥ 18 years of age, and that about $7900 of annual medical expenses for patients diagnosed with diabetes was directly attributable to diabetes.²

In the United States, neutral protamine Hagedorn (NPH) insulin was the most commonly used intermediate- to long-acting insulin until the introduction of the long-acting insulin analogs (insulin glargine in 2000 and insulin detemir in 2005).³ Despite being considerably more expensive than NPH insulin, long-acting insulin analogs had captured more than 80% of the total long-acting insulin market by 2010.⁴ The market share for NPH insulin dropped from 81.9% in 2001 to 16.2% in 2010.⁴

While the newer insulin analogs are significantly more expensive than NPH insulin, with higher corresponding out-of-pocket costs to patients, researchers have had a difficult time demonstrating greater effectiveness or any definitive differences in any long-term outcomes between NPH and the insulin analogs. A 2007 Cochrane review comparing NPH insulin to both glargine and detemir showed little difference in metabolic control (as measured by HbA1C) or in the rate of severe hypoglycemia. However, the rates of symptomatic, overall, and nocturnal hypoglycemia were statistically lower with the insulin analogs.⁵

A 2015 retrospective observational study from the Veterans Health Administration (N = 142,940) covering a 10-year period from 2000 to 2010 found no consistent differences in long-term health outcomes when comparing the use of long-acting insulin analogs to that of NPH insulin.^3,6

STUDY SUMMARY

Study compares performance of basal insulin analogs to that of NPH

This retrospective, observational study included 25,489 adult patients with T2DM who were enrolled in Kaiser Permanente of Northern California, had full medical and prescription coverage, and initiated basal insulin therapy with either NPH or an insulin analog between 2006 and 2015.

This study makes a strong case for a different approach to initial basal insulin therapy for patients with T2DM who need insulin for glucose control.

The primary outcome was the time from basal insulin therapy initiation to a hypoglycemia-related emergency department (ED) visit or hospital admission. The secondary outcome was the change in HbA1C level within 1 year of initiation of basal insulin therapy.

Continue to: Per 1000 person-years...

Per 1000 person-years, there was no significant difference in hypoglycemia-related ED visits or hospital admissions between the analog and NPH groups (11.9 events vs 8.8 events, respectively; between-group difference, 3.1 events; 95% confidence interval [CI], –1.5 to 7.7). HbA1C reduction was statistically greater with NPH, but most likely not clinically significant between insulin analogs and NPH (1.26 vs 1.48 percentage points; between group difference, –0.22%; 95% CI, –0.09% to –0.37%).

WHAT’S NEW?

No clinically relevant differences between insulin analogs and NPH

This study revealed that there is no clinically relevant difference in HbA1C levels and no difference in patient-focused outcomes of hypoglycemia-related ED visits or hospital admissions between NPH insulin and the more expensive insulin analogs. This makes a strong case for a different approach to initial basal insulin therapy for patients with T2DM who need insulin for glucose control.

CAVEATS

Demographics and less severe hypoglycemia might be at issue

This retrospective, observational study has broad demographics (but moderate under-representation of African-Americans), minimal patient health care disparities, and good access to medications. But generalizability outside of an integrated health delivery system may be limited. The study design also is subject to confounding, as not all potential impacts on the results can be corrected for or controlled in an observational study. Also, less profound hypoglycemia that did not require an ED visit or hospital admission was not captured.

CHALLENGES TO IMPLEMENTATION

Convenience and marketing factors may hinder change

Insulin analogs may have a number of convenience and marketing factors that may make it hard for providers and systems to change and use more NPH. However, the easy-to-use insulin analog pens are matched in availability and convenience by the much less advertised NPH insulin pens produced by at least 3 major pharmaceutical companies. In addition, while the overall cost for the insulin analogs continues to be 2 to 3 times that of non-human NPH insulin, insurance often covers up to, or more than, 80% of the cost of the insulin analogs, making the difference in the patient’s copay between the 2 not as severe. For example, patients may pay $30 to $40 per month for insulin analogs vs $10 to $25 per month for cheaper versions of NPH.^7,8

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Blanche is a 54-year-old overweight woman who has had type 2 diabetes mellitus (T2DM) for 5 years. She has been optimized on both metformin (1000 mg bid) and exenatide (2 mg weekly). While taking these medications, her hemoglobin A1C (HbA1C) has dropped from 11.2 to 8.4, and her body mass index (BMI) has declined from 35 to 31. However, she is still not at goal. You decide to start her on long-acting basal insulin. She has limited income, and she currently spends $75/month for her metformin, exenatide, atorvastatin, and lisinopril. What insulin do you prescribe?

The Centers for Disease Control and Prevention (CDC) reported that the prevalence of diabetes in the United States was 9.4% (30.3 million people) in 2015.² Among those affected, approximately 95.8% had T2DM.² The same report estimated that 1.5 million new cases of diabetes (6.7 per 1000 persons) were diagnosed annually among US adults ≥ 18 years of age, and that about $7900 of annual medical expenses for patients diagnosed with diabetes was directly attributable to diabetes.²

In the United States, neutral protamine Hagedorn (NPH) insulin was the most commonly used intermediate- to long-acting insulin until the introduction of the long-acting insulin analogs (insulin glargine in 2000 and insulin detemir in 2005).³ Despite being considerably more expensive than NPH insulin, long-acting insulin analogs had captured more than 80% of the total long-acting insulin market by 2010.⁴ The market share for NPH insulin dropped from 81.9% in 2001 to 16.2% in 2010.⁴

While the newer insulin analogs are significantly more expensive than NPH insulin, with higher corresponding out-of-pocket costs to patients, researchers have had a difficult time demonstrating greater effectiveness or any definitive differences in any long-term outcomes between NPH and the insulin analogs. A 2007 Cochrane review comparing NPH insulin to both glargine and detemir showed little difference in metabolic control (as measured by HbA1C) or in the rate of severe hypoglycemia. However, the rates of symptomatic, overall, and nocturnal hypoglycemia were statistically lower with the insulin analogs.⁵

A 2015 retrospective observational study from the Veterans Health Administration (N = 142,940) covering a 10-year period from 2000 to 2010 found no consistent differences in long-term health outcomes when comparing the use of long-acting insulin analogs to that of NPH insulin.^3,6

STUDY SUMMARY

Study compares performance of basal insulin analogs to that of NPH

This retrospective, observational study included 25,489 adult patients with T2DM who were enrolled in Kaiser Permanente of Northern California, had full medical and prescription coverage, and initiated basal insulin therapy with either NPH or an insulin analog between 2006 and 2015.

This study makes a strong case for a different approach to initial basal insulin therapy for patients with T2DM who need insulin for glucose control.

The primary outcome was the time from basal insulin therapy initiation to a hypoglycemia-related emergency department (ED) visit or hospital admission. The secondary outcome was the change in HbA1C level within 1 year of initiation of basal insulin therapy.

Continue to: Per 1000 person-years...

Per 1000 person-years, there was no significant difference in hypoglycemia-related ED visits or hospital admissions between the analog and NPH groups (11.9 events vs 8.8 events, respectively; between-group difference, 3.1 events; 95% confidence interval [CI], –1.5 to 7.7). HbA1C reduction was statistically greater with NPH, but most likely not clinically significant between insulin analogs and NPH (1.26 vs 1.48 percentage points; between group difference, –0.22%; 95% CI, –0.09% to –0.37%).

WHAT’S NEW?

No clinically relevant differences between insulin analogs and NPH

This study revealed that there is no clinically relevant difference in HbA1C levels and no difference in patient-focused outcomes of hypoglycemia-related ED visits or hospital admissions between NPH insulin and the more expensive insulin analogs. This makes a strong case for a different approach to initial basal insulin therapy for patients with T2DM who need insulin for glucose control.

CAVEATS

Demographics and less severe hypoglycemia might be at issue

This retrospective, observational study has broad demographics (but moderate under-representation of African-Americans), minimal patient health care disparities, and good access to medications. But generalizability outside of an integrated health delivery system may be limited. The study design also is subject to confounding, as not all potential impacts on the results can be corrected for or controlled in an observational study. Also, less profound hypoglycemia that did not require an ED visit or hospital admission was not captured.

CHALLENGES TO IMPLEMENTATION

Convenience and marketing factors may hinder change

Insulin analogs may have a number of convenience and marketing factors that may make it hard for providers and systems to change and use more NPH. However, the easy-to-use insulin analog pens are matched in availability and convenience by the much less advertised NPH insulin pens produced by at least 3 major pharmaceutical companies. In addition, while the overall cost for the insulin analogs continues to be 2 to 3 times that of non-human NPH insulin, insurance often covers up to, or more than, 80% of the cost of the insulin analogs, making the difference in the patient’s copay between the 2 not as severe. For example, patients may pay $30 to $40 per month for insulin analogs vs $10 to $25 per month for cheaper versions of NPH.^7,8

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 60-year-old woman who is generally healthy except for a history of recurrent urinary tract infections presents to the emergency department with fever, hypotension, and altered mental status, meeting criteria for septic shock. During her resuscitation, supplemental oxygen is administered. Standard treatment calls for a minimum SpO₂ (saturation of peripheral oxygen) > 90%. What should your SpO₂ goal be?

Use of supplemental oxygen in the acute care of the critically ill adult is a common practice in pre-hospital, emergency department (ED), and hospitalized settings.^2,3 Despite their prevalence, guidelines about appropriate oxygen concentration and target SpO₂ levels are often conflicting or vague.^3-5

Excessive oxygen supplementation in acute illness may be harmful and cause increased risk of hypercapnic respiratory failure, delayed recognition of clinical deterioration, and oxygen toxicity.^2,6 The perception of oxygen safety persists despite these findings, and it likely contributes to the ongoing practice of liberal oxygen supplementation in the acutely ill adult.^2,7,8

STUDY SUMMARY

Liberal supplemental O₂ linked to increased mortality

The Improving Oxygen Therapy in Acute illness (IOTA) study was a systematic review and meta-analysis of 25 randomized controlled trials (RCTs) that compared liberal vs conservative oxygen strategies for acutely ill adults (N = 16,037; median age = 64 years; range = 28-76 years). Patients with sepsis, critical illness, stroke, trauma, myocardial infarction, or cardiac arrest, and patients who had emergency surgery were included. Studies were excluded if they involved patients who had chronic respiratory illness or psychiatric diseases, were receiving extracorporeal membrane oxygenation, were undergoing elective surgeries, were being treated with hyperbaric oxygen therapy, or were pregnant.

The outcomes studied were mortality (in-hospital, at 30 days, and at the longest ­follow-up) and morbidity (disability measured by the modified Rankin Scale at longest follow-up, risk of hospital-acquired pneumonia, risk of any hospital-acquired infection, and hospital length of stay).

Liberal supplemental oxygen, above an SpO₂ range of 94% to 96%, increased mortality during inpatient stays (relative risk [RR] = 1.21; 95% confidence interval [CI], 1.03-1.43; N = 15,071), at 30 days (RR = 1.14; 95% CI, 1.01-1.29; N = 15,053), and at longest follow-up (RR = 1.10; 95% CI, 1.00-1.20; N = 15,754; median = 90 days; range = 14,365 days). There was no difference in morbidity outcomes between groups.

While it’s difficult to define a specific target SpO₂ range, the number needed to harm when using a liberal oxygen approach (SpO₂ > 96%) resulting in 1 death was 71 (95% CI, 37-1000).

Continue to: WHAT'S NEW

High-quality evidence points to the dangers of liberal O₂ therapy

This comprehensive meta-analysis is the first high-quality evidence to suggest that liberal use of oxygen in acutely ill adults above a specific SpO₂ level increases all-cause mortality. Previous small RCTs and observational studies have examined the effect of liberal oxygen only on specific presenting conditions, thus making more generalizable conclusions challenging.^9-12

CAVEATS

Varied definitions of “liberal” and “conservative”

This review included studies with variable ranges of SpO₂ defined as liberal vs conservative supplementation. However, in all of these, SpO₂ above 96% was correlated with unfavorable outcomes.

This meta-analysis is the first high-quality evidence to suggest that liberal use of oxygen in acutely ill adults above a specific SpO₂ level increases all-cause mortality.

The study excluded 2 potentially important patient groups: patients with chronic respiratory diseases and pregnant patients. Increased oxygen supplementation in patients with chronic respiratory diseases in noncritical settings has been shown to be deleterious.^13-15 While this study does not address the issue of oxygen supplementation in acutely ill patients with chronic respiratory disease, use should be considered with caution. The results from this study may not be generalizable to women who are pregnant.

CHALLENGES TO IMPLEMENTATION

Reversing the tide

Liberal oxygen administration continues to be practiced in many health care settings. The main challenges to implementing the conclusions of this study are these pervasive practices.

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 60-year-old woman who is generally healthy except for a history of recurrent urinary tract infections presents to the emergency department with fever, hypotension, and altered mental status, meeting criteria for septic shock. During her resuscitation, supplemental oxygen is administered. Standard treatment calls for a minimum SpO₂ (saturation of peripheral oxygen) > 90%. What should your SpO₂ goal be?

Use of supplemental oxygen in the acute care of the critically ill adult is a common practice in pre-hospital, emergency department (ED), and hospitalized settings.^2,3 Despite their prevalence, guidelines about appropriate oxygen concentration and target SpO₂ levels are often conflicting or vague.^3-5

Excessive oxygen supplementation in acute illness may be harmful and cause increased risk of hypercapnic respiratory failure, delayed recognition of clinical deterioration, and oxygen toxicity.^2,6 The perception of oxygen safety persists despite these findings, and it likely contributes to the ongoing practice of liberal oxygen supplementation in the acutely ill adult.^2,7,8

STUDY SUMMARY

Liberal supplemental O₂ linked to increased mortality

The Improving Oxygen Therapy in Acute illness (IOTA) study was a systematic review and meta-analysis of 25 randomized controlled trials (RCTs) that compared liberal vs conservative oxygen strategies for acutely ill adults (N = 16,037; median age = 64 years; range = 28-76 years). Patients with sepsis, critical illness, stroke, trauma, myocardial infarction, or cardiac arrest, and patients who had emergency surgery were included. Studies were excluded if they involved patients who had chronic respiratory illness or psychiatric diseases, were receiving extracorporeal membrane oxygenation, were undergoing elective surgeries, were being treated with hyperbaric oxygen therapy, or were pregnant.

The outcomes studied were mortality (in-hospital, at 30 days, and at the longest ­follow-up) and morbidity (disability measured by the modified Rankin Scale at longest follow-up, risk of hospital-acquired pneumonia, risk of any hospital-acquired infection, and hospital length of stay).

Liberal supplemental oxygen, above an SpO₂ range of 94% to 96%, increased mortality during inpatient stays (relative risk [RR] = 1.21; 95% confidence interval [CI], 1.03-1.43; N = 15,071), at 30 days (RR = 1.14; 95% CI, 1.01-1.29; N = 15,053), and at longest follow-up (RR = 1.10; 95% CI, 1.00-1.20; N = 15,754; median = 90 days; range = 14,365 days). There was no difference in morbidity outcomes between groups.

While it’s difficult to define a specific target SpO₂ range, the number needed to harm when using a liberal oxygen approach (SpO₂ > 96%) resulting in 1 death was 71 (95% CI, 37-1000).

Continue to: WHAT'S NEW

High-quality evidence points to the dangers of liberal O₂ therapy

This comprehensive meta-analysis is the first high-quality evidence to suggest that liberal use of oxygen in acutely ill adults above a specific SpO₂ level increases all-cause mortality. Previous small RCTs and observational studies have examined the effect of liberal oxygen only on specific presenting conditions, thus making more generalizable conclusions challenging.^9-12

CAVEATS

Varied definitions of “liberal” and “conservative”

This review included studies with variable ranges of SpO₂ defined as liberal vs conservative supplementation. However, in all of these, SpO₂ above 96% was correlated with unfavorable outcomes.

This meta-analysis is the first high-quality evidence to suggest that liberal use of oxygen in acutely ill adults above a specific SpO₂ level increases all-cause mortality.

The study excluded 2 potentially important patient groups: patients with chronic respiratory diseases and pregnant patients. Increased oxygen supplementation in patients with chronic respiratory diseases in noncritical settings has been shown to be deleterious.^13-15 While this study does not address the issue of oxygen supplementation in acutely ill patients with chronic respiratory disease, use should be considered with caution. The results from this study may not be generalizable to women who are pregnant.

CHALLENGES TO IMPLEMENTATION

Reversing the tide

Liberal oxygen administration continues to be practiced in many health care settings. The main challenges to implementing the conclusions of this study are these pervasive practices.

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 60-year-old woman who is generally healthy except for a history of recurrent urinary tract infections presents to the emergency department with fever, hypotension, and altered mental status, meeting criteria for septic shock. During her resuscitation, supplemental oxygen is administered. Standard treatment calls for a minimum SpO₂ (saturation of peripheral oxygen) > 90%. What should your SpO₂ goal be?

Use of supplemental oxygen in the acute care of the critically ill adult is a common practice in pre-hospital, emergency department (ED), and hospitalized settings.^2,3 Despite their prevalence, guidelines about appropriate oxygen concentration and target SpO₂ levels are often conflicting or vague.^3-5

Excessive oxygen supplementation in acute illness may be harmful and cause increased risk of hypercapnic respiratory failure, delayed recognition of clinical deterioration, and oxygen toxicity.^2,6 The perception of oxygen safety persists despite these findings, and it likely contributes to the ongoing practice of liberal oxygen supplementation in the acutely ill adult.^2,7,8

STUDY SUMMARY

Liberal supplemental O₂ linked to increased mortality

The Improving Oxygen Therapy in Acute illness (IOTA) study was a systematic review and meta-analysis of 25 randomized controlled trials (RCTs) that compared liberal vs conservative oxygen strategies for acutely ill adults (N = 16,037; median age = 64 years; range = 28-76 years). Patients with sepsis, critical illness, stroke, trauma, myocardial infarction, or cardiac arrest, and patients who had emergency surgery were included. Studies were excluded if they involved patients who had chronic respiratory illness or psychiatric diseases, were receiving extracorporeal membrane oxygenation, were undergoing elective surgeries, were being treated with hyperbaric oxygen therapy, or were pregnant.

The outcomes studied were mortality (in-hospital, at 30 days, and at the longest ­follow-up) and morbidity (disability measured by the modified Rankin Scale at longest follow-up, risk of hospital-acquired pneumonia, risk of any hospital-acquired infection, and hospital length of stay).

Liberal supplemental oxygen, above an SpO₂ range of 94% to 96%, increased mortality during inpatient stays (relative risk [RR] = 1.21; 95% confidence interval [CI], 1.03-1.43; N = 15,071), at 30 days (RR = 1.14; 95% CI, 1.01-1.29; N = 15,053), and at longest follow-up (RR = 1.10; 95% CI, 1.00-1.20; N = 15,754; median = 90 days; range = 14,365 days). There was no difference in morbidity outcomes between groups.

While it’s difficult to define a specific target SpO₂ range, the number needed to harm when using a liberal oxygen approach (SpO₂ > 96%) resulting in 1 death was 71 (95% CI, 37-1000).

Continue to: WHAT'S NEW

High-quality evidence points to the dangers of liberal O₂ therapy

This comprehensive meta-analysis is the first high-quality evidence to suggest that liberal use of oxygen in acutely ill adults above a specific SpO₂ level increases all-cause mortality. Previous small RCTs and observational studies have examined the effect of liberal oxygen only on specific presenting conditions, thus making more generalizable conclusions challenging.^9-12

CAVEATS

Varied definitions of “liberal” and “conservative”

This review included studies with variable ranges of SpO₂ defined as liberal vs conservative supplementation. However, in all of these, SpO₂ above 96% was correlated with unfavorable outcomes.

This meta-analysis is the first high-quality evidence to suggest that liberal use of oxygen in acutely ill adults above a specific SpO₂ level increases all-cause mortality.

The study excluded 2 potentially important patient groups: patients with chronic respiratory diseases and pregnant patients. Increased oxygen supplementation in patients with chronic respiratory diseases in noncritical settings has been shown to be deleterious.^13-15 While this study does not address the issue of oxygen supplementation in acutely ill patients with chronic respiratory disease, use should be considered with caution. The results from this study may not be generalizable to women who are pregnant.

CHALLENGES TO IMPLEMENTATION

Reversing the tide

Liberal oxygen administration continues to be practiced in many health care settings. The main challenges to implementing the conclusions of this study are these pervasive practices.

ACKNOWLEDGMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Ms. M, a generally healthy 55-year-old woman, was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] level of 8 ng/mL). She presents with her second episode of acute viral bronchitis in the past 6 months. She has no history of significant smoking or exposure or history of asthma and does not take respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/wk in bolus dosing—but is that your best option for the patient?

ARTIs include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common reason for ambulatory care visits, accounting for almost 120 million (about 10% of all) visits per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D is protective in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N = 10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk for bias. The Cochrane risk-for-bias tool was used to address threats to validity.

The study included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI; and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR], 0.88; number needed to treat [NNT], 33). In subgroup ­an­alysis, daily or weekly vitamin D was protective (AOR, 0.81), but bolus dosing (≥ 30,000 IU) was not (AOR, 0.97).

In 2-step analysis, patients benefited if they had baseline circulating 25(OH)D concentrations < 10 ng/mL (AOR, 0.30; NNT, 4); had baseline circulating 25(OH)D levels of 10 to 28 ng/mL (AOR, 0.75; NNT, 15); were ages 1.1 to 15.9 (AOR, 0.59); were ages 16 to 65 (AOR, 0.79); or had a BMI < 25 (AOR, 0.82).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25(OH)D ≥ 30 ng/mL did not appear to provide benefit (AOR, 0.96). Supplementation in this population did not influence any of the secondary outcomes, ­including risk for all-cause serious adverse events (AOR, 0.98).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25(OH)D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect was noted in those who were most severely vitamin D deficient (those with circulating 25(OH)D levels < 10 ng/mL [NNT, 4] and those with circulating 25(OH)D levels 10-28 ng/mL [NNT, 15]). There was no demonstrable effect once circulating 25(OH)D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs. However, the doses studied were much lower than those commonly used (10,000 to 50,000 IU bolus), which were ineffective in reducing ARTIs in this meta-analysis. Changing from bolus dosing may prove challenging, as it is an ingrained practice for many providers.

In addition, the authors of the study suggest that one way to provide this level of vitamin D is through food fortification. But this method is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[4]:230-231).

Ms. M, a generally healthy 55-year-old woman, was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] level of 8 ng/mL). She presents with her second episode of acute viral bronchitis in the past 6 months. She has no history of significant smoking or exposure or history of asthma and does not take respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/wk in bolus dosing—but is that your best option for the patient?

ARTIs include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common reason for ambulatory care visits, accounting for almost 120 million (about 10% of all) visits per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D is protective in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N = 10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk for bias. The Cochrane risk-for-bias tool was used to address threats to validity.

The study included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI; and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR], 0.88; number needed to treat [NNT], 33). In subgroup ­an­alysis, daily or weekly vitamin D was protective (AOR, 0.81), but bolus dosing (≥ 30,000 IU) was not (AOR, 0.97).

In 2-step analysis, patients benefited if they had baseline circulating 25(OH)D concentrations < 10 ng/mL (AOR, 0.30; NNT, 4); had baseline circulating 25(OH)D levels of 10 to 28 ng/mL (AOR, 0.75; NNT, 15); were ages 1.1 to 15.9 (AOR, 0.59); were ages 16 to 65 (AOR, 0.79); or had a BMI < 25 (AOR, 0.82).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25(OH)D ≥ 30 ng/mL did not appear to provide benefit (AOR, 0.96). Supplementation in this population did not influence any of the secondary outcomes, ­including risk for all-cause serious adverse events (AOR, 0.98).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25(OH)D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect was noted in those who were most severely vitamin D deficient (those with circulating 25(OH)D levels < 10 ng/mL [NNT, 4] and those with circulating 25(OH)D levels 10-28 ng/mL [NNT, 15]). There was no demonstrable effect once circulating 25(OH)D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs. However, the doses studied were much lower than those commonly used (10,000 to 50,000 IU bolus), which were ineffective in reducing ARTIs in this meta-analysis. Changing from bolus dosing may prove challenging, as it is an ingrained practice for many providers.

In addition, the authors of the study suggest that one way to provide this level of vitamin D is through food fortification. But this method is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[4]:230-231).

Ms. M, a generally healthy 55-year-old woman, was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] level of 8 ng/mL). She presents with her second episode of acute viral bronchitis in the past 6 months. She has no history of significant smoking or exposure or history of asthma and does not take respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/wk in bolus dosing—but is that your best option for the patient?

ARTIs include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common reason for ambulatory care visits, accounting for almost 120 million (about 10% of all) visits per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D is protective in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N = 10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk for bias. The Cochrane risk-for-bias tool was used to address threats to validity.

The study included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI; and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR], 0.88; number needed to treat [NNT], 33). In subgroup ­an­alysis, daily or weekly vitamin D was protective (AOR, 0.81), but bolus dosing (≥ 30,000 IU) was not (AOR, 0.97).

In 2-step analysis, patients benefited if they had baseline circulating 25(OH)D concentrations < 10 ng/mL (AOR, 0.30; NNT, 4); had baseline circulating 25(OH)D levels of 10 to 28 ng/mL (AOR, 0.75; NNT, 15); were ages 1.1 to 15.9 (AOR, 0.59); were ages 16 to 65 (AOR, 0.79); or had a BMI < 25 (AOR, 0.82).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25(OH)D ≥ 30 ng/mL did not appear to provide benefit (AOR, 0.96). Supplementation in this population did not influence any of the secondary outcomes, ­including risk for all-cause serious adverse events (AOR, 0.98).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25(OH)D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect was noted in those who were most severely vitamin D deficient (those with circulating 25(OH)D levels < 10 ng/mL [NNT, 4] and those with circulating 25(OH)D levels 10-28 ng/mL [NNT, 15]). There was no demonstrable effect once circulating 25(OH)D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs. However, the doses studied were much lower than those commonly used (10,000 to 50,000 IU bolus), which were ineffective in reducing ARTIs in this meta-analysis. Changing from bolus dosing may prove challenging, as it is an ingrained practice for many providers.

In addition, the authors of the study suggest that one way to provide this level of vitamin D is through food fortification. But this method is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2019. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2019;68[4]:230-231).

ILLUSTRATIVE CASE

Ms. M is a 55-year-old woman who is generally healthy, but who was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D level of 8 ng/mL). She is being seen for her second episode of acute viral bronchitis in the past 6 months. She has no significant smoking or exposure history, no history of asthma, and takes no respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/week in bolus dosing, but is that your best option in this case?

Acute respiratory tract infections (ARTIs) include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common cause of ambulatory care visits, accounting for almost 120 million, or about 10% of all visits, per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D protects against ARTIs, but only in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N=10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk of bias. The Cochrane risk of bias tool was used to address threats to validity.

The review and meta-analysis included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or vitamin D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI, and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR] = 0.88; 95% confidence interval [CI], 0.81-0.96; number needed to treat [NNT] = 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR = 0.81; 95% CI, 0.72-0.91), but bolus dosing (≥ 30,000 IU) was not (AOR = 0.97; 95% CI, 0.86-1.10).

Continue to: In 2-step analysis...

This study found that low-dose daily or weekly vitamin D supplementation was protective against acute respiratory tract infections, but bolus dosing was not.

In 2-step analysis, patients benefited who: had baseline circulating 25-hydroxyvitamin D concentrations < 10 ng/mL (AOR = 0.30; 95% CI, 0.17-0.53; NNT = 4); had baseline circulating 25-hydroxyvitamin D levels of 10 to 28 ng/mL (AOR = 0.75; 95% CI, 0.60-0.95; NNT = 15); were ages 1.1 to 15.9 years (AOR = 0.59; 95% CI, 0.45-0.79); were ages 16 to 65 years (AOR = 0.79; 95% CI, 0.63-0.99); or had a body mass index < 25 (AOR = 0.82; 95% CI, 0.71-0.95).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25-hydroxyvitamin D ≥ 30 ng/mL did not appear to provide benefit (AOR = 0.96; 95% CI, 0.78-1.18). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR = 0.98; 95% CI, 0.80-1.20).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25-hydroxyvitamin D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or vitamin D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect of vitamin D supplementation on the prevention of ARTIs was noted in those who were most severely vitamin D deficient (those with circulating 25-hydroxyvitamin levels < 10 ng/mL, NNT = 4; 10-28 ng/mL, NNT = 15). There was no demonstrable effect once circulating 25-hydroxyvitamin D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs, but the doses used were much lower than the commonly used 10,000 to 50,000 IU bolus doses, which were ineffective in reducing ARTIs in the current meta-analysis. Since bolus dosing is an ingrained practice for many providers, changing this may prove challenging.

Continue to: In addition...

In addition, the authors of the study suggest that one of the ways to provide this level of vitamin D is through food fortification, but food fortification is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Ms. M is a 55-year-old woman who is generally healthy, but who was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D level of 8 ng/mL). She is being seen for her second episode of acute viral bronchitis in the past 6 months. She has no significant smoking or exposure history, no history of asthma, and takes no respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/week in bolus dosing, but is that your best option in this case?

Acute respiratory tract infections (ARTIs) include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common cause of ambulatory care visits, accounting for almost 120 million, or about 10% of all visits, per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D protects against ARTIs, but only in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N=10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk of bias. The Cochrane risk of bias tool was used to address threats to validity.

The review and meta-analysis included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or vitamin D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI, and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR] = 0.88; 95% confidence interval [CI], 0.81-0.96; number needed to treat [NNT] = 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR = 0.81; 95% CI, 0.72-0.91), but bolus dosing (≥ 30,000 IU) was not (AOR = 0.97; 95% CI, 0.86-1.10).

Continue to: In 2-step analysis...

This study found that low-dose daily or weekly vitamin D supplementation was protective against acute respiratory tract infections, but bolus dosing was not.

In 2-step analysis, patients benefited who: had baseline circulating 25-hydroxyvitamin D concentrations < 10 ng/mL (AOR = 0.30; 95% CI, 0.17-0.53; NNT = 4); had baseline circulating 25-hydroxyvitamin D levels of 10 to 28 ng/mL (AOR = 0.75; 95% CI, 0.60-0.95; NNT = 15); were ages 1.1 to 15.9 years (AOR = 0.59; 95% CI, 0.45-0.79); were ages 16 to 65 years (AOR = 0.79; 95% CI, 0.63-0.99); or had a body mass index < 25 (AOR = 0.82; 95% CI, 0.71-0.95).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25-hydroxyvitamin D ≥ 30 ng/mL did not appear to provide benefit (AOR = 0.96; 95% CI, 0.78-1.18). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR = 0.98; 95% CI, 0.80-1.20).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25-hydroxyvitamin D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or vitamin D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect of vitamin D supplementation on the prevention of ARTIs was noted in those who were most severely vitamin D deficient (those with circulating 25-hydroxyvitamin levels < 10 ng/mL, NNT = 4; 10-28 ng/mL, NNT = 15). There was no demonstrable effect once circulating 25-hydroxyvitamin D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs, but the doses used were much lower than the commonly used 10,000 to 50,000 IU bolus doses, which were ineffective in reducing ARTIs in the current meta-analysis. Since bolus dosing is an ingrained practice for many providers, changing this may prove challenging.

Continue to: In addition...

In addition, the authors of the study suggest that one of the ways to provide this level of vitamin D is through food fortification, but food fortification is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Ms. M is a 55-year-old woman who is generally healthy, but who was diagnosed recently with severe vitamin D deficiency (serum 25-hydroxyvitamin D level of 8 ng/mL). She is being seen for her second episode of acute viral bronchitis in the past 6 months. She has no significant smoking or exposure history, no history of asthma, and takes no respiratory medications. Standard treatment for her level of vitamin D deficiency is 50,000 IU/week in bolus dosing, but is that your best option in this case?

Acute respiratory tract infections (ARTIs) include nonspecific upper respiratory illnesses, otitis media, sinusitis (~70% viral), pharyngitis, acute bronchitis (also ~70% viral), influenza, respiratory syncytial virus, and pneumonia.^1,2 In the United States, ARTIs strain the health care system and are the most common cause of ambulatory care visits, accounting for almost 120 million, or about 10% of all visits, per year.³ In addition, ARTIs account for almost 50% of antibiotic prescriptions for adults and almost 75% of antibiotic prescriptions for children—many of which are unnecessary.^2,4

While patient and parent education, antibiotic stewardship programs, and demand management may reduce inappropriate antibiotic use and the overall burden of ARTIs on the health care system, prevention of infections is a powerful tool within the overall approach to managing ARTIs.

STUDY SUMMARY

Vitamin D protects against ARTIs, but only in smaller doses

This 2017 systematic review and meta-analysis of 25 trials (N=10,933) evaluated vitamin D supplementation for the prevention of ARTIs in the primary care setting. Individual participant data were reevaluated to reduce risk of bias. The Cochrane risk of bias tool was used to address threats to validity.

The review and meta-analysis included institutional review board–approved, randomized, double-blind, placebo-controlled trials of vitamin D₃ or vitamin D₂ supplementation of any duration and in any language. The incidence of ARTI was a prespecified efficacy outcome. Duration of the included randomized controlled trials (RCTs) ranged from 7 weeks to 1.5 years.

Outcomes. The primary outcome was an incidence of at least 1 ARTI. Secondary outcomes included incidence of upper and lower ARTIs; incidence of adverse reactions to vitamin D; incidence of emergency department visits or hospital admission or both for ARTI; use of antimicrobials for ARTI; absence from work or school due to ARTI, and mortality (ARTI-related and all-cause).

Findings. Daily or weekly vitamin D supplementation (in doses ranging from < 20 to ≥ 50 µg/d) reduced the risk for ARTI (adjusted odds ratio [AOR] = 0.88; 95% confidence interval [CI], 0.81-0.96; number needed to treat [NNT] = 33). In subgroup analysis, daily or weekly vitamin D was protective (AOR = 0.81; 95% CI, 0.72-0.91), but bolus dosing (≥ 30,000 IU) was not (AOR = 0.97; 95% CI, 0.86-1.10).

Continue to: In 2-step analysis...

This study found that low-dose daily or weekly vitamin D supplementation was protective against acute respiratory tract infections, but bolus dosing was not.

In 2-step analysis, patients benefited who: had baseline circulating 25-hydroxyvitamin D concentrations < 10 ng/mL (AOR = 0.30; 95% CI, 0.17-0.53; NNT = 4); had baseline circulating 25-hydroxyvitamin D levels of 10 to 28 ng/mL (AOR = 0.75; 95% CI, 0.60-0.95; NNT = 15); were ages 1.1 to 15.9 years (AOR = 0.59; 95% CI, 0.45-0.79); were ages 16 to 65 years (AOR = 0.79; 95% CI, 0.63-0.99); or had a body mass index < 25 (AOR = 0.82; 95% CI, 0.71-0.95).

Higher D levels are a different story. Vitamin D supplementation in people with circulating levels of 25-hydroxyvitamin D ≥ 30 ng/mL did not appear to provide benefit (AOR = 0.96; 95% CI, 0.78-1.18). Supplementation in this population did not influence any of the secondary outcomes, including risk for all-cause serious adverse events (AOR = 0.98; 95% CI, 0.80-1.20).

WHAT’S NEW

A more accurate snapshot

Previous studies of vitamin D and respiratory tract infections were mostly observational in nature. Those that were RCTs used variable doses of vitamin D, had variable baseline 25-hydroxyvitamin D levels, and employed various methods to monitor ARTI symptoms/incidence.^5-8 This is the first systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials with supplementation using vitamin D₃ or vitamin D₂ that used individual participant-level data, which gives a more accurate estimate of outcomes when compared with traditional meta-analyses.

CAVEATS

Only the most deficient benefit?

Vitamin D supplementation was safe and protected against ARTIs overall, but the greatest effect of vitamin D supplementation on the prevention of ARTIs was noted in those who were most severely vitamin D deficient (those with circulating 25-hydroxyvitamin levels < 10 ng/mL, NNT = 4; 10-28 ng/mL, NNT = 15). There was no demonstrable effect once circulating 25-hydroxyvitamin D levels reached 30 ng/mL.

CHALLENGES TO IMPLEMENTATION

Breaking tradition

The study found that both daily and weekly doses of vitamin D were effective in reducing the incidence of ARTIs, but the doses used were much lower than the commonly used 10,000 to 50,000 IU bolus doses, which were ineffective in reducing ARTIs in the current meta-analysis. Since bolus dosing is an ingrained practice for many providers, changing this may prove challenging.

Continue to: In addition...

In addition, the authors of the study suggest that one of the ways to provide this level of vitamin D is through food fortification, but food fortification is often complicated by emotional and/or political issues that could thwart implementation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with OTC medications. You suspect diverticulitis and obtain an abdominal CT scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis. How would you treat this patient?

Diverticulitis is common; each year, about 200,000 people in the United States are admitted to the hospital because of it.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized controlled trial (RCT; N = 623) found that antibiotic treatment for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by the lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, nonuniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

Watchful waiting just as effective as antibiotics

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adults in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomly assigned to receive amoxicillin-clavulanate (1,200 mg by IV qid for at least 48 hours, followed by 625 mg po tid, for 10 total days; n = 266) or to be observed (n = 262). Randomization was performed by computer, with a random varying block size and stratification by Hinchey classification and center; allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic adverse effects; and all-cause mortality.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 d vs 12 d; hazard ratio for functional recovery, 0.91). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up: complicated diverticulitis (3.8% vs 2.6%, respectively), recurrent diverticulitis (3.4% vs 3%), readmission (17.6% vs 12%), or adverse events (48.5% vs 54.5%). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 d). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

Continue to: WHAT'S NEW

WHAT’S NEW

Study looked at true patient-oriented ­outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate or requirement for percutaneous drainage.^7,8 This study is the first to look at functional return to work (a true patient-oriented outcome). And it is the only study to follow up at 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize to worse cases

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease) and are not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis may be more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[7]:435-436,438).

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with OTC medications. You suspect diverticulitis and obtain an abdominal CT scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis. How would you treat this patient?

Diverticulitis is common; each year, about 200,000 people in the United States are admitted to the hospital because of it.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized controlled trial (RCT; N = 623) found that antibiotic treatment for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by the lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, nonuniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

Watchful waiting just as effective as antibiotics

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adults in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomly assigned to receive amoxicillin-clavulanate (1,200 mg by IV qid for at least 48 hours, followed by 625 mg po tid, for 10 total days; n = 266) or to be observed (n = 262). Randomization was performed by computer, with a random varying block size and stratification by Hinchey classification and center; allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic adverse effects; and all-cause mortality.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 d vs 12 d; hazard ratio for functional recovery, 0.91). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up: complicated diverticulitis (3.8% vs 2.6%, respectively), recurrent diverticulitis (3.4% vs 3%), readmission (17.6% vs 12%), or adverse events (48.5% vs 54.5%). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 d). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

Continue to: WHAT'S NEW

WHAT’S NEW

Study looked at true patient-oriented ­outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate or requirement for percutaneous drainage.^7,8 This study is the first to look at functional return to work (a true patient-oriented outcome). And it is the only study to follow up at 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize to worse cases

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease) and are not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis may be more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[7]:435-436,438).

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with OTC medications. You suspect diverticulitis and obtain an abdominal CT scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis. How would you treat this patient?

Diverticulitis is common; each year, about 200,000 people in the United States are admitted to the hospital because of it.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized controlled trial (RCT; N = 623) found that antibiotic treatment for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by the lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, nonuniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

Watchful waiting just as effective as antibiotics

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adults in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomly assigned to receive amoxicillin-clavulanate (1,200 mg by IV qid for at least 48 hours, followed by 625 mg po tid, for 10 total days; n = 266) or to be observed (n = 262). Randomization was performed by computer, with a random varying block size and stratification by Hinchey classification and center; allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic adverse effects; and all-cause mortality.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 d vs 12 d; hazard ratio for functional recovery, 0.91). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up: complicated diverticulitis (3.8% vs 2.6%, respectively), recurrent diverticulitis (3.4% vs 3%), readmission (17.6% vs 12%), or adverse events (48.5% vs 54.5%). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 d). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

Continue to: WHAT'S NEW

WHAT’S NEW

Study looked at true patient-oriented ­outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate or requirement for percutaneous drainage.^7,8 This study is the first to look at functional return to work (a true patient-oriented outcome). And it is the only study to follow up at 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize to worse cases

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease) and are not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis may be more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2018. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice (2018;67[7]:435-436,438).

ILLUSTRATIVE CASE

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with over-the-counter medications. You suspect diverticulitis and obtain an abdominal computed tomography (CT) scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis.

How would you treat him?

Diverticulitis is common; about 200,000 people per year are admitted to the hospital because of diverticulitis in the United States.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized control trial (RCT; N=623) found that antibiotic treatment (compared with no antibiotic treatment) for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by a lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, non-uniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

RCT finds that watchful waiting is just as effective as antibiotic Tx

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adult patients in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomized to receive IV administration of amoxicillin-clavulanate 1200 mg 4 times daily for at least 48 hours followed by 625 mg PO 3 times daily for 10 total days of antibiotic treatment (n=266) or to be observed (n=262). Computerized randomization, with a random varying block size and stratified by Hinchey classification and center, was performed, and allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic treatment adverse effects; and all-cause mortality.

Continue to: Results

This study is the first to look at functional return to work and the only study to gauge long-term outcomes with observational treatment.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 days vs 12 days; P=.15; hazard ratio [HR] for functional recovery=0.91; lower limit of 1-sided 95% confidence interval, 0.78). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up (complicated diverticulitis, 3.8% vs 2.6%, respectively; P=.377), recurrent diverticulitis (3.4% vs 3%; P=.494), readmission (17.6% vs 12%; P=.148), or adverse events (48.5% vs 54.5%; P=.221). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 days; P=.006). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

WHAT’S NEW

A study that looks at a true patient-oriented outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate, or requirement for percutaneous drainage.^7,8 This study is the first one to look at functional return to work (a true patient-oriented outcome). And it is the only study to look out to 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize findings to patients with worse forms of diverticulitis

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease), and is not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis maybe more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

Continuet to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with over-the-counter medications. You suspect diverticulitis and obtain an abdominal computed tomography (CT) scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis.

How would you treat him?

Diverticulitis is common; about 200,000 people per year are admitted to the hospital because of diverticulitis in the United States.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized control trial (RCT; N=623) found that antibiotic treatment (compared with no antibiotic treatment) for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by a lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, non-uniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

RCT finds that watchful waiting is just as effective as antibiotic Tx

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adult patients in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomized to receive IV administration of amoxicillin-clavulanate 1200 mg 4 times daily for at least 48 hours followed by 625 mg PO 3 times daily for 10 total days of antibiotic treatment (n=266) or to be observed (n=262). Computerized randomization, with a random varying block size and stratified by Hinchey classification and center, was performed, and allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic treatment adverse effects; and all-cause mortality.

Continue to: Results

This study is the first to look at functional return to work and the only study to gauge long-term outcomes with observational treatment.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 days vs 12 days; P=.15; hazard ratio [HR] for functional recovery=0.91; lower limit of 1-sided 95% confidence interval, 0.78). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up (complicated diverticulitis, 3.8% vs 2.6%, respectively; P=.377), recurrent diverticulitis (3.4% vs 3%; P=.494), readmission (17.6% vs 12%; P=.148), or adverse events (48.5% vs 54.5%; P=.221). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 days; P=.006). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

WHAT’S NEW

A study that looks at a true patient-oriented outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate, or requirement for percutaneous drainage.^7,8 This study is the first one to look at functional return to work (a true patient-oriented outcome). And it is the only study to look out to 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize findings to patients with worse forms of diverticulitis

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease), and is not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis maybe more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

Continuet to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 58-year-old man presents to your office with a 2-day history of moderate (6/10) left lower quadrant pain, mild fever (none currently), 2 episodes of vomiting, no diarrhea, and no relief with over-the-counter medications. You suspect diverticulitis and obtain an abdominal computed tomography (CT) scan, which shows mild, uncomplicated (Hinchey stage 1a) diverticulitis.

How would you treat him?

Diverticulitis is common; about 200,000 people per year are admitted to the hospital because of diverticulitis in the United States.^2,3 Health care providers typically treat diverticular disease with antibiotics and bowel rest.^2,3 While severe forms of diverticulitis often require parenteral antibiotics and/or surgery, practitioners are increasingly managing the condition with oral antibiotics.⁴

One previous randomized control trial (RCT; N=623) found that antibiotic treatment (compared with no antibiotic treatment) for acute uncomplicated diverticulitis did not speed recovery or prevent complications (perforation or abscess formation) or recurrence at 12 months.⁵ The study’s strengths included limiting enrollment to people with CT-proven diverticulitis, using a good randomization and concealment process, and employing intention-to-treat analysis. The study was limited by a lack of a standardized antibiotic regimen across centers, previous diverticulitis diagnoses in 40% of patients, non-uniform follow-up processes to confirm anatomic resolution, and the lack of assessment to confirm resolution.⁵

STUDY SUMMARY

RCT finds that watchful waiting is just as effective as antibiotic Tx

This newer study was a single-blind RCT that compared treatment with antibiotics to observation among 528 adult patients in the Netherlands. Patients were enrolled if they had CT-proven, primary, left-sided, uncomplicated acute diverticulitis (Hinchey stage 1a and 1b).¹ (The Hinchey classification is based on radiologic findings, with 0 for clinical diverticulitis only, 1a for confined pericolic inflammation or phlegmon, and 1b for pericolic or mesocolic abscess.⁶) Exclusion criteria included suspicion of colonic cancer by CT or ultrasound (US), previous CT/US-proven diverticulitis, sepsis, pregnancy, or antibiotic use in the previous 4 weeks.¹

Observational vs antibiotic treatment. Enrolled patients were randomized to receive IV administration of amoxicillin-clavulanate 1200 mg 4 times daily for at least 48 hours followed by 625 mg PO 3 times daily for 10 total days of antibiotic treatment (n=266) or to be observed (n=262). Computerized randomization, with a random varying block size and stratified by Hinchey classification and center, was performed, and allocation was concealed. The investigators were masked to the allocation until all analyses were completed.¹

The primary outcome was the time to functional recovery (resumption of pre-illness work activities) during a 6-month follow-up period. Secondary outcomes included hospital readmission rate; complicated, ongoing, and recurrent diverticulitis; sigmoid resection; other nonsurgical intervention; antibiotic treatment adverse effects; and all-cause mortality.

Continue to: Results

This study is the first to look at functional return to work and the only study to gauge long-term outcomes with observational treatment.

Results. Median recovery time for observational treatment was not inferior to antibiotic treatment (14 days vs 12 days; P=.15; hazard ratio [HR] for functional recovery=0.91; lower limit of 1-sided 95% confidence interval, 0.78). Observation was not inferior to antibiotics for any of the secondary endpoints at 6 and 12 months of follow-up (complicated diverticulitis, 3.8% vs 2.6%, respectively; P=.377), recurrent diverticulitis (3.4% vs 3%; P=.494), readmission (17.6% vs 12%; P=.148), or adverse events (48.5% vs 54.5%; P=.221). Initial hospitalization length of stay was shorter in the observation group (2 vs 3 days; P=.006). The researchers conducted a 24-month telephone follow-up, but no differences from the 12-month follow-up were noted.¹

WHAT’S NEW

A study that looks at a true patient-oriented outcome

Previous studies of treatment options for acute uncomplicated diverticulitis looked at short-term outcomes, or at readmission, recurrence, and surgical intervention rate, or requirement for percutaneous drainage.^7,8 This study is the first one to look at functional return to work (a true patient-oriented outcome). And it is the only study to look out to 24 months to gauge long-term outcomes with observational treatment.

CAVEATS

Can’t generalize findings to patients with worse forms of diverticulitis

It is worth noting that the findings of this study apply only to the mildest form of CT-proven acute diverticulitis (those patients classified as having Hinchey 1a disease), and is not generalizable to patients with more severe forms. Not enough patients with Hinchey 1b acute diverticulitis were enrolled in the study to reach any conclusions about treatment.

Various guidelines issued outside the United States recommend antibiotics for uncomplicated diverticulitis; however, the American Gastroenterological Association (AGA) indicates that antibiotics should be used selectively.^1,9,10 This recommendation was based on an emerging understanding that diverticulitis maybe more inflammatory than infectious in nature. The AGA guideline authors acknowledge that their conclusion was based on low-quality evidence.⁹

Continuet to: CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to implementing this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.