Christianne L. Roumie

Comparative Effectiveness of Sulfonylurea and Metformin Monotherapy on Cardiovascular Events in Type 2 Diabetes Mellitus: A Cohort Study

BACKGROUND The effects of sulfonylureas and metformin on outcomes of cardiovascular disease (CVD) in type 2 diabetes are not well-characterized. OBJECTIVE To compare the effects of sulfonylureas and metformin on CVD outcomes (acute myocardial infarction and stroke) or death. DESIGN Retrospective cohort study. SETTING National Veterans Health Administration databases linked to Medicare files. PATIENTS Veterans who initiated metformin or sulfonylurea therapy for diabetes. Patients with chronic kidney disease or serious medical illness were excluded. MEASUREMENTS Composite outcome of hospitalization for acute myocardial infarction or stroke, or death, adjusted for baseline demographic characteristics; medications; cholesterol, hemoglobin A1c, and serum creatinine levels; blood pressure; body mass index; health care utilization; and comorbid conditions. RESULTS Among 253 690 patients initiating treatment (98 665 with sulfonylurea therapy and 155 025 with metformin therapy), crude rates of the composite outcome were 18.2 per 1000 person-years in sulfonylurea users and 10.4 per 1000 person-years in metformin users (adjusted incidence rate difference, 2.2 [95% CI, 1.4 to 3.0] more CVD events with sulfonylureas per 1000 person-years; adjusted hazard ratio [aHR], 1.21 [CI, 1.13 to 1.30]). Results were consistent for both glyburide (aHR, 1.26 [CI, 1.16 to 1.37]) and glipizide (aHR, 1.15 [CI, 1.06 to 1.26]) in subgroups by CVD history, age, body mass index, and albuminuria; in a propensity score-matched cohort analysis; and in sensitivity analyses. LIMITATION Most of the veterans in the study population were white men; data on women and minority groups were limited but reflective of the Veterans Health Administration population. CONCLUSION Use of sulfonylureas compared with metformin for initial treatment of diabetes was associated with an increased hazard of CVD events or death. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality and the U.S. Department of Health and Human Services.

Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years: A Randomized Clinical Trial

IMPORTANCE The appropriate treatment target for systolic blood pressure (SBP) in older patients with hypertension remains uncertain. OBJECTIVE To evaluate the effects of intensive (<120 mm Hg) compared with standard (<140 mm Hg) SBP targets in persons aged 75 years or older with hypertension but without diabetes. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial of patients aged 75 years or older who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). Recruitment began on October 20, 2010, and follow-up ended on August 20, 2015. INTERVENTIONS Participants were randomized to an SBP target of less than 120 mm Hg (intensive treatment group, n = 1317) or an SBP target of less than 140 mm Hg (standard treatment group, n = 1319). MAIN OUTCOMES AND MEASURES The primary cardiovascular disease outcome was a composite of nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes. All-cause mortality was a secondary outcome. RESULTS Among 2636 participants (mean age, 79.9 years; 37.9% women), 2510 (95.2%) provided complete follow-up data. At a median follow-up of 3.14 years, there was a significantly lower rate of the primary composite outcome (102 events in the intensive treatment group vs 148 events in the standard treatment group; hazard ratio [HR], 0.66 [95% CI, 0.51-0.85]) and all-cause mortality (73 deaths vs 107 deaths, respectively; HR, 0.67 [95% CI, 0.49-0.91]). The overall rate of serious adverse events was not different between treatment groups (48.4% in the intensive treatment group vs 48.3% in the standard treatment group; HR, 0.99 [95% CI, 0.89-1.11]). Absolute rates of hypotension were 2.4% in the intensive treatment group vs 1.4% in the standard treatment group (HR, 1.71 [95% CI, 0.97-3.09]), 3.0% vs 2.4%, respectively, for syncope (HR, 1.23 [95% CI, 0.76-2.00]), 4.0% vs 2.7% for electrolyte abnormalities (HR, 1.51 [95% CI, 0.99-2.33]), 5.5% vs 4.0% for acute kidney injury (HR, 1.41 [95% CI, 0.98-2.04]), and 4.9% vs 5.5% for injurious falls (HR, 0.91 [95% CI, 0.65-1.29]). CONCLUSIONS AND RELEVANCE Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01206062.

Effect of a Pharmacist Intervention on Clinically Important Medication Errors After Hospital Discharge: A Randomized Trial

BACKGROUND Clinically important medication errors are common after hospital discharge. They include preventable or ameliorable adverse drug events (ADEs), as well as medication discrepancies or nonadherence with high potential for future harm (potential ADEs). OBJECTIVE To determine the effect of a tailored intervention on the occurrence of clinically important medication errors after hospital discharge. DESIGN Randomized, controlled trial with concealed allocation and blinded outcome assessors. (ClinicalTrials.gov registration number: NCT00632021) SETTING Two tertiary care academic hospitals. PATIENTS Adults hospitalized with acute coronary syndromes or acute decompensated heart failure. INTERVENTION Pharmacist-assisted medication reconciliation, inpatient pharmacist counseling, low-literacy adherence aids, and individualized telephone follow-up after discharge. MEASUREMENTS The primary outcome was the number of clinically important medication errors per patient during the first 30 days after hospital discharge. Secondary outcomes included preventable or ameliorable ADEs, as well as potential ADEs. RESULTS Among 851 participants, 432 (50.8%) had 1 or more clinically important medication errors; 22.9% of such errors were judged to be serious and 1.8% life-threatening. Adverse drug events occurred in 258 patients (30.3%) and potential ADEs in 253 patients (29.7%). The intervention did not significantly alter the per-patient number of clinically important medication errors (unadjusted incidence rate ratio, 0.92 [95% CI, 0.77 to 1.10]) or ADEs (unadjusted incidence rate ratio, 1.09 [CI, 0.86 to 1.39]). Patients in the intervention group tended to have fewer potential ADEs (unadjusted incidence rate ratio, 0.80 [CI, 0.61 to 1.04]). LIMITATION The characteristics of the study hospitals and participants may limit generalizability. CONCLUSION Clinically important medication errors were present among one half of patients after hospital discharge and were not significantly reduced by a health-literacy-sensitive, pharmacist-delivered intervention. PRIMARY FUNDING SOURCE National Heart, Lung, and Blood Institute.

Trends in antibiotic prescribing for adults in the United States—1995 to 2002

AbstractCONTEXT: The impact of national efforts to limit antibiotic prescribing has not been fully evaluated. OBJECTIVES: To analyze trends in outpatient visits associated with antibiotic prescription for U.S. adults. DESIGN: Cross-sectional study of data (1995 to 2002) from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. PARTICIPANTS: Adults ≥18 years with an outpatient visit to an office-or hospital-based medical practice or to an emergency department. All visits were classified into 1 of 4 diagnostic categories: (1) acute respiratory infection (ARI)—antibiotics rarely indicated, (2) ARI—antibiotics often indicated, (3) nonrespiratory infection—antibiotics often indicated, and (4) all others. MEASUREMENTS: Trends in: (1) Proportion of outpatient visits associated with an antibiotic prescription; (2) proportion of antibiotic prescriptions that were broad spectrum; and (3) number of visits and antibiotic prescriptions per 1,000 U.S. adults ≥18 years of age. RESULTS: From 1995–1996 to 2001–2002, the proportion of all outpatient visits that generated an antibiotic prescription decreased from 17.9% to 15.3% (adjusted odds ratio [OR] 0.84, 95% confidence interval [CI] 0.76 to 0.92). The entire reduction was because of a decrease in antibiotic prescriptions associated with visits for ARIs where antibiotics are rarely indicated from 59.9% to 49.1% (adjusted OR 0.64 95% CI 0.51 to 0.80). However, the proportion of prescribed antibiotics for these visits that were classified as broad-spectrum antibiotic prescription increased from 41.0% to 76.8%. Overall outpatient visits increased from 1693 to 1986 per 1,000 adults over the 8 years studied, but associated antibiotic prescriptions changed little, from 302 to 304 per 1,000 adults. CONCLUSION: During the study period, outpatient antibiotic prescribing for respiratory infections where antibiotics are rarely indicated has declined, while the proportion of broad-spectrum antibiotics prescribed for these diagnoses has increased significantly. This trend resulted in a 15% decline in the total proportion of outpatient visits in which antibiotics were prescribed. However, because outpatient visits increased 17% over this time period, the population burden of outpatient antibiotic prescriptions changed little.

Association Between Intensification of Metformin Treatment With Insulin vs Sulfonylureas and Cardiovascular Events and All-Cause Mortality Among Patients With Diabetes

IMPORTANCE Preferred second-line medication for diabetes treatment after metformin failure remains uncertain. OBJECTIVE To compare time to acute myocardial infarction (AMI), stroke, or death in a cohort of metformin initiators who added insulin or a sulfonylurea. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort constructed with national Veterans Health Administration, Medicare, and National Death Index databases. The study population comprised veterans initially treated with metformin from 2001 through 2008 who subsequently added either insulin or sulfonylurea. Propensity score matching on characteristics was performed, matching each participant who added insulin to 5 who added a sulfonylurea. Patients were followed through September 2011 for primary analyses or September 2009 for cause-of-death analyses. MAIN OUTCOMES AND MEASURES Risk of a composite outcome of AMI, stroke hospitalization, or all-cause death was compared between therapies with marginal structural Cox proportional hazard models adjusting for baseline and time-varying demographics, medications, cholesterol level, hemoglobin A1c level, creatinine level, blood pressure, body mass index, and comorbidities. RESULTS Among 178,341 metformin monotherapy patients, 2948 added insulin and 39,990 added a sulfonylurea. Propensity score matching yielded 2436 metformin + insulin and 12,180 metformin + sulfonylurea patients. At intensification, patients had received metformin for a median of 14 months (IQR, 5-30), and hemoglobin A1c level was 8.1% (IQR, 7.2%-9.9%). Median follow-up after intensification was 14 months (IQR, 6-29 months). There were 172 vs 634 events for the primary outcome among patients who added insulin vs sulfonylureas, respectively (42.7 vs 32.8 events per 1000 person-years; adjusted hazard ratio [aHR], 1.30; 95% CI, 1.07-1.58; P = .009). Acute myocardial infarction and stroke rates were statistically similar, 41 vs 229 events (10.2 and 11.9 events per 1000 person-years; aHR, 0.88; 95% CI, 0.59-1.30; P = .52), whereas all-cause death rates were 137 vs 444 events, respectively (33.7 and 22.7 events per 1000 person-years; aHR, 1.44; 95% CI, 1.15-1.79; P = .001). There were 54 vs 258 secondary outcomes: AMI, stroke hospitalizations, or cardiovascular deaths (22.8 vs 22.5 events per 1000 person-years; aHR, 0.98; 95% CI, 0.71-1.34; P = .87). CONCLUSIONS AND RELEVANCE Among patients with diabetes who were receiving metformin, the addition of insulin vs a sulfonylurea was associated with an increased risk of a composite of nonfatal cardiovascular outcomes and all-cause mortality. These findings require further investigation to understand risks associated with insulin use in these patients.

Over-the-counter analgesics in older adults: a call for improved labelling and consumer education.

The use of analgesics increases with age and on any given day 20–30% of older adults take an analgesic medication. Over-the-counter (OTC) analgesics are generally well tolerated and effective when taken for brief periods of time and at recommended dosages. However, their long-term use, use at inappropriately high doses, or use by persons with contraindications may result in adverse effects, including gastrointestinal haemorrhage, cardiovascular toxicity, renal toxicity and hepatotoxicity. Many OTC drugs are also available through a prescription, for a broader range of indications and for longer durations of use and wider dose ranges, under the assumption that healthcare providers will help patients make safe choices about analgesics. Safe and effective use of medications is one of the greatest challenges faced by healthcare providers in medicine. More than 60% of people cannot identify the active ingredient in their brand of pain reliever. Additionally, about 40% of Americans believe that OTC drugs are too weak to cause any real harm. As a result of a recent US FDA policy, the conversion of prescription to OTC medications will result in a 50% increase of OTC medications. To reduce the risks of potential adverse effects from OTC drug therapy in older adults, we propose that the use of analgesics will be enhanced through the use of patient and healthcare provider education, as well as improved labelling of OTC analgesics. Improved labelling of OTC analgesics may help consumers distinguish common analgesic ingredients in a wide variety of preparations and facilitate informed decisions concerning the use of OTC drugs.

Nonaspirin NSAIDs, Cyclooxygenase 2 Inhibitors, and the Risk for Stroke

Background and Purpose— There is limited information regarding the cerebrovascular safety of cyclooxygenase 2 inhibitors (coxibs) and noncoxib nonsteroidal antiinflammatory drugs (NSAIDs). We determined whether specific NSAIDs, including coxibs, are associated with risk of stroke. Methods— Retrospective cohort study among Tennessee Medicaid enrollees aged 50 to 84 years between January 1, 1999 and December 31, 2004. Noninstitutionalized persons with continuous enrollment in Medicaid and no stroke or other serious medical illness in the year before cohort entry were included. The 7 most common NSAIDs were examined: celecoxib, rofecoxib, valdecoxib, ibuprofen, naproxen, diclofenac, and indomethacin. Nonuse of NSAIDs was the reference group. Because new use is less susceptible to bias, we conducted a similar analysis confined to new users. The outcome was hospitalization for an incident cerebrovascular event: ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Results— The cohort included 336 906 persons, with 989 826 person-years of follow-up, and 4354 stroke hospitalizations. There were 4.51 strokes per 1000 person years in the nonuse group, 5.15 strokes per 1000 person years (adjusted HR 1.28, 95% CI 1.06, 1.53) with rofecoxib use, and 5.95 strokes per 1000 person years (adjusted HR 1.41, 95% CI 1.04, 1.91) with valdecoxib use. New use of rofecoxib and valdecoxib led to 6.06 (adjusted HR 1.46 95% CI 1.08, 1.98) and 6.19 (adjusted HR 1.39, 95% CI 0.74, 2.59) strokes per 1000 person years respectively. No other NSAID significantly increased the risk of incident stroke. Conclusions— Our results indicate an increased risk of stroke with current use of two highly selective coxibs, rofecoxib and valdecoxib, also shown to increase cardiovascular risk. These results also provide some reassurance about other specific NSAIDs regarding stroke risk.

Comparative effectiveness of incident oral antidiabetic drugs on kidney function.

Diabetes is a major cause of chronic kidney disease, and oral antidiabetic drugs are the mainstay of therapy for most patients with Type 2 diabetes. Here we evaluated their role on renal outcomes by using a national Veterans Administration database to assemble a retrospective cohort of 93,577 diabetic patients who filled an incident oral antidiabetic drug prescription for metformin, sulfonylurea, or rosiglitazone, and had an estimated glomerular filtration rate (eGFR) of 60 ml/min or better. The primary composite outcome was a persistent decline in eGFR from baseline of 25% or more (eGFR event) or a diagnosis of end-stage renal disease (ESRD). The secondary outcome was an eGFR event, ESRD, or death. Sensitivity analyses included using a more stringent definition of the eGFR event requiring an eGFR <60 ml/min per 1.73 m2 in addition to the 25% or more decline; controlling for baseline proteinuria thereby restricting data to 15,065 patients; and not requiring persistent treatment with the initial oral antidiabetic drug. Compared to patients using metformin, sulfonylurea users had an increased risk for both the primary and the secondary outcome, each with an adjusted hazard ratio of 1.20. Results of sensitivity analyses were consistent with the main findings. The risk associated with rosiglitazone was similar to metformin for both outcomes. Thus, compared to metformin, oral antidiabetic drug treatment with sulfonylureas increased the risk of a decline in eGFR, ESRD, or death.

Rationale and Design of the Pharmacist Intervention for Low Literacy in Cardiovascular Disease (PILL-CVD) Study

Background—Medication errors and adverse drug events are common after hospital discharge due to changes in medication regimens, suboptimal discharge instructions, and prolonged time to follow-up. Pharmacist-based interventions may be effective in promoting the safe and effective use of medications, especially among high-risk patients such as those with low health literacy. Methods and Results—The Pharmacist Intervention for Low Literacy in Cardiovascular Disease (PILL-CVD) study is a randomized controlled trial conducted at 2 academic centers—Vanderbilt University Hospital and Brigham and Womens Hospital. Patients admitted with acute coronary syndrome or acute decompensated heart failure were randomly assigned to usual care or intervention. The intervention consisted of pharmacist-assisted medication reconciliation, inpatient pharmacist counseling, low-literacy adherence aids, and tailored telephone follow-up after discharge. The primary outcome is the occurrence of serious medication errors in the first 30 days after hospital discharge. Secondary outcomes are health care utilization, disease-specific quality of life, and cost-effectiveness. Enrollment was completed September 2009. A total of 862 patients were enrolled, and 430 patients were randomly assigned to receive the intervention. Analyses will determine whether the intervention was effective in reducing serious medication errors, particularly in patients with low health literacy. Conclusions—The PILL-CVD study was designed to reduce serious medication errors after hospitalization through a pharmacist-based intervention. The intervention, if effective, will inform health care facilities on the use of pharmacist-assisted medication reconciliation, inpatient counseling, low-literacy adherence aids, and patient follow-up after discharge. Clinical Trial Registration—clinicaltrials.gov. Identifier: NCT00632021.

Non-aspirin NSAIDs, cyclooxygenase-2 inhibitors and risk for cardiovascular events–stroke, acute myocardial infarction, and death from coronary heart disease†

To determine if certain non‐steroidal anti‐inflammatory drugs (NSAIDs) are associated with increased risk of cardiovascular events: acute myocardial infarction (AMI), stroke, and death from coronary heart disease (CHD).