JoAnne M. Foody

Thiazolidinediones, Metformin, and Outcomes in Older Patients With Diabetes and Heart Failure: An Observational Study

Background—Insulin-sensitizing drugs of the thiazolidinedione class and metformin are commonly prescribed to treat diabetes in patients with heart failure despite strong warnings from the Food and Drug Administration against this practice. Whether this results in adverse outcomes is unknown. Methods and Results—We conducted a retrospective cohort study of 16 417 Medicare beneficiaries with diabetes discharged after hospitalization with the principal discharge diagnosis of heart failure. The association between antidiabetic drug prescriptions and outcomes was assessed in multivariable hierarchical Cox proportional hazards models, with adjustment for patient, physician, and hospital variables and accounting for the clustering of patients within hospitals. The primary outcome of the study was time to death due to all causes. Secondary outcomes included time to readmission for all causes or for heart failure. Crude 1-year mortality rates were lower among the 2226 patients treated with a thiazolidinedione (30.1%) or the 1861 treated with metformin (24.7%) compared with that among the 12 069 treated with neither insulin-sensitizing drug (36.0%, P=<0.0001 for both comparisons). In multivariable models, treatment with the thiazolidinediones (hazard ratio [HR] 0.87, 95% CI 0.80 to 0.94) or metformin (HR=0.87, 95% CI 0.78 to 0.97) was associated with significantly lower risks of death. There was no association with treatment with sulfonylureas (HR=0.99, 95% CI 0.91 to 1.08) or insulin (HR=0.96, 95% CI 0.88 to 1.05) and mortality. Admissions for all causes did not differ with either insulin sensitizer. There was a higher risk of readmission for heart failure with thiazolidinedione treatment (HR 1.06, 95% CI 1.00 to 1.09) and a lower risk with metformin treatment (HR 0.92, 95% CI 0.92 to 0.99). Conclusions—This observational study suggests that thiazolidinediones and metformin are not associated with increased mortality and may improve outcomes in older patients with diabetes and heart failure. Randomized trials are warranted to corroborate these findings.

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: Executive Summary A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons

WRITING COMMITTEE MEMBERS* Stephan D. Fihn, MD, MPH, Chair†; Julius M. Gardin, MD, Vice Chair*‡; Jonathan Abrams, MD‡; Kathleen Berra, MSN, ANP*§; James C. Blankenship, MD*\; Apostolos P. Dallas, MD*†; Pamela S. Douglas, MD*‡; JoAnne M. Foody, MD*‡; Thomas C. Gerber, MD, PhD‡; Alan L. Hinderliter, MD‡; Spencer B. King III, MD*‡; Paul D. Kligfield, MD‡; Harlan M. Krumholz, MD‡; Raymond Y.K. Kwong, MD‡; Michael J. Lim, MD*\; Jane A. Linderbaum, MS, CNP-BC¶; Michael J. Mack, MD*#; Mark A. Munger, PharmD*‡; Richard L. Prager, MD#; Joseph F. Sabik, MD***; Leslee J. Shaw, PhD*‡; Joanna D. Sikkema, MSN, ANP-BC*§; Craig R. Smith, Jr, MD**; Sidney C. Smith, Jr, MD*††; John A. Spertus, MD, MPH*‡‡; Sankey V. Williams, MD*†

Core Components of Cardiac Rehabilitation/Secondary Prevention Programs: 2007 Update A Scientific Statement From the American Heart Association Exercise, Cardiac Rehabilitation, and Prevention Committee, the Council on Clinical Cardiology; the Councils on Cardiovascular Nursing, Epidemiology and Prevention, and Nutrition, Physical Activity, and Metabolism; and the American Association of Cardiovascular and Pulmonary Rehabilitation

The American Heart Association and the American Association of Cardiovascular and Pulmonary Rehabilitation recognize that all cardiac rehabilitation/secondary prevention programs should contain specific core components that aim to optimize cardiovascular risk reduction, foster healthy behaviors and compliance to these behaviors, reduce disability, and promote an active lifestyle for patients with cardiovascular disease. This update to the previous statement presents current information on the evaluation, interventions, and expected outcomes in each of the core components of cardiac rehabilitation/secondary prevention programs, in agreement with the 2006 update of the American Heart Association/American College of Cardiology Secondary Prevention Guidelines, including baseline patient assessment, nutritional counseling, risk factor management (lipids, blood pressure, weight, diabetes mellitus, and smoking), psychosocial interventions, and physical activity counseling and exercise training.

Heart Rate Recovery after Submaximal Exercise Testing as a Predictor of Mortality in a Cardiovascularly Healthy Cohort

We previously reported on the prognostic importance of heart rate recovery after symptom-limited exercise in an intermediate-risk group of patients who were referred for exercise testing with thallium single-photon emission computed tomography in a tertiary-care center (1). It is unknown, however, whether these findings can be generalized to healthy adults undergoing submaximal exercise. Our goal was to examine heart rate recovery as a predictor of long-term mortality in a population-based cohort of adults without evidence of cardiovascular disease who underwent submaximal exercise testing. All-cause mortality was the outcome of interest because of its relevance and its objective and unbiased nature (2). Methods The study cohort was derived from the Lipid Research Clinics Prevalence Study, the selection of which has been described in detail elsewhere (3-6). Briefly, that study was designed to determine the prevalence of lipid abnormalities among North Americans. Of the 68 317 population-based persons recruited from 10 primary care centers, those with lipid abnormalities (approximately 10% of the population) and an additional randomly selected 15% were invited to undergo more extensive investigation (3). Of the 13 852 who appeared for this second visit, 8681 underwent exercise testing. Reasons for exclusion from exercise testing included resting systolic blood pressure less than 90 or greater than 200 mm Hg, resting diastolic blood pressure greater than 120 mm Hg, inability to complete a treadmill test on the basis of physician examination, or participant request (5, 6). To assure selection of a cardiovascularly healthy asymptomatic cohort similar to that in previous population-based studies (7), persons were excluded if they were younger than 30 years of age (n=131 [2%]); were taking -blockers, digoxin, antiarrhythmic agents, or nitrates (n=356 [4%]); had a history of cardiovascular disease (defined as previous heart surgery or history of angina, myocardial infarction, claudication, stroke, previous vascular surgery, congenital disease, or arrhythmia) (n=2413 [28%]); or were unable to reach stage 2 of exercise (n=1620 [19%]). Before testing, participants underwent a detailed medical and family history that elicited information about medical conditions, alcohol use, smoking, education level, socioeconomic status, exercise habits, and medications. Lipid profiles were obtained in all patients. The treadmill exercise protocol used was the Bruce or modified Bruce protocol (5, 6). Participants exercised until they attained at least 85% to 90% of their age- and fitness-predicted maximum heart rate for 1 minute or until fatigue or medical contraindications to continued exercise were observed. Data on symptoms, heart rate, and blood pressure were collected and electrocardiography was done before exercise, at the end of each stage, immediately after exercise, and 2 minutes into recovery. Estimated workload, expressed in metabolic equivalents, was based on total treadmill time. Chronotropic response during exercise was assessed by using the chronotropic indexthe ratio of heart rate to metabolic reserve usedduring stage 2 of exercise (8, 9). We used a cutoff value (0.86) that maximized the log-rank chi-square statistic (10). Immediately after exercise, participants were helped to chairs, and recovery data were obtained. Heart rate recovery was defined as the change from peak heart rate to that measured after 2 minutes of recovery (that is, heart rate recovery=heart ratepeak heart rate2-min recovery). An abnormal value for heart rate recovery was determined by finding the maximum value for the log-rank chi-square test statistic for all possible cutoff points between the 10th and 90th percentiles (10); this turned out to be 42 beats/min or less. This cutoff value differed from and could not be validly compared to that of our previous study (1) because 2-minute values (rather than 1-minute values) were used and because exercise was submaximal, not symptom-limited. We also considered indexing the 2-minute heart rate recovery by the maximum heart rate, but this resulted in a substantially lower maximum log-rank chi-square value (44 compared with 77). Mean follow-up time was 12 years. The primary end point was all-cause mortality, which was determined through annual telephone interviews with study participants or their families or employers. Cause of death was assessed by review of death certificates and interviews of physicians or next of kin (6). If the patient could not be contacted, registries were searched for mortality information. For assessment of vital status, follow-up was 100% complete. All analyses were performed by using version 6.12 of the SAS statistical package (SAS Institute, Inc., Cary, North Carolina). For descriptive purposes, patients were divided into two groups based on heart rate recovery. Continuous variables are presented as the mean SD. Differences between groups were compared by using the Student t-test, Wilcoxon rank-sum test, and chi-square test, as appropriate. Heart rate recovery was related to all-cause mortality by using univariable and multivariable Cox regression analyses. Stratified analyses were performed on prespecified subgroups according to age, sex, exercise patterns, smoking, cholesterol level, resting blood pressure and heart rate, chronotropic response to exercise, and medication use. Logarithmic and quadratic transformations and potential interactions were assessed for improvement of fit; the strata option of PROC PHREG was used to allow for accurate estimation of main effects relative risks. The Cox proportional-hazards assumption was confirmed by inspection of log (log [survival]) curves. Attributable risk was calculated as P (RR 1)/[P (RR 1) + 1], where P is prevalence and RR is relative risk. The estimated actuarial survival rate for the population was estimated on the basis of data from 1985 U.S. life tables (11). According to the policy at our institution, this research was considered exempt from institutional review board approval because it used existing, publically available data. In addition, the data were recorded in such a manner that participants could not be identified directly or through identifiers linked to them. Results Baseline and Exercise Characteristics A total of 5234 adults met all inclusion criteria. The median value for heart rate recovery was 49 beats/min (25th and 75th percentiles, 39 and 59 beats/min). An abnormal heart rate recovery of 42 beats/min or less was seen in 1715 participants (33%). Baseline and exercise characteristics of the study participants according to heart rate recovery are summarized in Table 1. Table 1. Baseline and Exercise Characteristics according to Heart Rate Recovery after Exercise Heart Rate Recovery and Mortality During 12 years of follow-up, 325 patients (6.2%) died. According to U.S. life tables, the actuarial predicted death rate was 7%. Abnormal heart rate recovery was strongly predictive of death (10% compared with 4% among participants with normal heart rate recovery; relative risk, 2.58 [95% CI, 2.06 to 3.20]) (P<0.001). The sensitivity, specificity, and positive and negative predictive values of an abnormal heart rate recovery for prediction of death over 12 years were 54%, 69%, 10%, and 96%, respectively. Of the participants who died, 116 (36%) were thought to have died of cardiovascular causes. An abnormal heart rate recovery was even more strongly predictive of cardiovascular death than of death in general (4% compared with 1%; relative risk, 3.06 [CI, 2.10 to 4.44]) (P<0.001). Results of analyses stratified by age, sex, chronotropic response to exercise, regular exercise, smoking, resting hemodynamics, cholesterol level, and use of vasodilator medication are shown in Table 2. Abnormal heart rate recovery was predictive of death in all subgroups except participants taking vasodilators. Table 2. Association of Abnormal Heart Rate Recovery with Mortality according to Prespecified Subgroups Multivariable Cox Regression Analyses After adjustment for age, sex, body mass index, ethnicity, resting systolic blood pressure, use of vasodilators, exercise habits, physical fitness, smoking, diabetes, lipid profiles, ST-segment response, resting heart rate, chronotropic index, and educational and socioeconomic status and after consideration of interaction terms, a slower decrease in heart rate remained predictive of death (adjusted relative risk, 1.55 [CI, 1.22 to 1.98]) (P<0.001 by chi-square test). The adjusted attributable risk for death related to abnormal heart rate recovery was 15% (CI, 7% to 24%). Abnormal heart rate recovery was also predictive of cardiovascular death after adjustment for potential confounders and interactions (adjusted relative risk, 1.95 [CI, 1.11 to 3.42]) (P=0.02). Discussion Heart rate recovery after submaximal exercise was a powerful predictor of mortality in a population-based cohort of adults without clinically evident cardiovascular disease, even after we adjusted for multiple, potentially confounding factors. These findings confirm the results of our previous study (1) and expand them by demonstrating the prognostic importance of heart rate recovery in healthy persons undergoing submaximal, as opposed to symptom-limited, exercise testing. Heart rate recovery may therefore be a clinically relevant predictor of risk among patients undergoing screening exercise testing. Furthermore, because an abnormal heart rate recovery accounted for 15% of deaths, this measure may be useful for insurance underwriting assessments. It has been suggested that the link between heart rate recovery and mortality may be related to vagal tone and physical fitness (12). We also noted an association between fitness levels and recovery heart rate; participants with abnormal heart rate recovery were less likely to exercise regularly and to participate in strenuous exercise (Table 1). It should be noted that heart rates d

Risks Associated With Statin Therapy A Systematic Overview of Randomized Clinical Trials

Background— Although statins reduce the risk of cardiovascular events, concerns about adverse effects may deter physicians from prescribing these agents. We performed a systematic overview of randomized statin trials to quantify the risks of musculoskeletal, renal, and hepatic complications associated with therapy. Methods and Results— Major statin trials were identified by electronic search of the MEDLINE database from 1966 to December 2005. We included English language reports of adults with documented hyperlipidemia; double-blind, random allocation of ≥100 patients to statin monotherapy versus placebo; and reports of myalgia, creatine kinase elevations, rhabdomyolysis, transaminase elevations, and discontinuation due to adverse events. Among 74 102 subjects enrolled in 35 trials (follow-up range, 1 to 65 months), statin therapy (excluding cerivastatin) did not result in significant absolute increases in risks of myalgias (risk difference/1000 patients [RD], 2.7; 95% CI, −3.2 to 8.7), creatine kinase elevations (RD, 0.2; 95% CI, −0.6 to 0.9), rhabdomyolysis (RD, 0.4; 95% CI, −0.1 to 0.9), or discontinuation due to any adverse event (RD, −0.5; 95% CI, −4.3 to 3.3). The absolute risk of transaminase elevations was significantly higher with statin therapy (RD, 4.2; 95% CI, 1.5 to 6.9). Conclusions— On the basis of data available from published clinical trials, statin therapy is associated with a small excess risk of transaminase elevations, but not of myalgias, creatine kinase elevations, rhabdomyolysis, or withdrawal of therapy compared with placebo. Further study is necessary to determine whether the results from these published clinical trials are similar to what occurs in routine practice, particularly among patients who are older, have more severe comorbid conditions, or receive higher statin doses than most patients in these clinical trials.

Lipid Treatment Assessment Project 2: A Multinational Survey to Evaluate the Proportion of Patients Achieving Low-Density Lipoprotein Cholesterol Goals

Background— Information about physicians’ adherence to cholesterol management guidelines remains scant. The present survey updates our knowledge of lipid management worldwide. Methods and Results— Lipid levels were determined at enrollment in dyslipidemic adult patients on stable lipid-lowering therapy in 9 countries. The primary end point was the success rate, defined as the proportion of patients achieving appropriate low-density lipoprotein cholesterol (LDL-C) goals for their given risk. The mean age of the 9955 evaluable patients was 62±12 years; 54% were male. Coronary disease and diabetes mellitus had been diagnosed in 30% and 31%, respectively, and 14% were current smokers. Current treatment consisted of a statin in 75%. The proportion of patients achieving LDL-C goals according to relevant national guidelines ranged from 47% to 84% across countries. In low-, moderate-, and high-risk groups, mean LDL-C was 119, 109, and 91 mg/dL and mean high-density lipoprotein cholesterol was 62, 49, and 50 mg/dL, respectively. The success rate for LDL-C goal achievement was 86% in low-, 74% in moderate-, and 67% in high-risk patients (73% overall). However, among coronary heart disease patients with ≥2 risk factors, only 30% attained the optional LDL-C goal of <70 mg/dL. In the entire cohort, high-density lipoprotein cholesterol was <40 mg/dL in 19%, 40 to 60 mg/dL in 55%, and >60 mg/dL in 26% of patients. Conclusions— Although there is room for improvement, particularly in very-high-risk patients, these results indicate that lipid-lowering therapy is being applied much more successfully than it was a decade ago.

National Patterns of Use and Effectiveness of Angiotensin-Converting Enzyme Inhibitors in Older Patients With Heart Failure and Left Ventricular Systolic Dysfunction

Background—Although ACE inhibitors are underprescribed for heart failure, factors associated with their use are not well described. Furthermore, the effectiveness of ACE inhibitors has been questioned in some populations, potentially contributing to underuse. Our objectives were to assess the correlates of ACE inhibitor use and the relationship between ACE inhibitor prescription and mortality in older patients with heart failure. Methods and Results—We studied a national sample aged ≥65 years who had survived hospitalization for heart failure between April 1998 and March 1999 or July 2000 and June 2001, restricting the analysis to patients with left ventricular systolic dysfunction and without a documented contraindication to use of ACE inhibitors (n=17 456). Factors associated with ACE inhibitor prescription at discharge and the relationship between ACE inhibitor prescription and death within 1 year were assessed with hierarchical logistic models. Secondary analyses assessed therapeutic substitution with angiotensin receptor blockers (ARBs). ACE inhibitors were prescribed to only 68% of this ideal cohort, and 76% received either an ACE inhibitor or an ARB. Patient, physician, and hospital factors were weak predictors of prescription, except for serum creatinine (RR for 133 to 221 &mgr;mol/L=0.87, 95% CI 0.85 to 0.89; RR for ≥222 &mgr;mol/L=0.53, 95% CI 0.49 to 0.57 compared with ≤132 &mgr;mol/L). ACE inhibitor prescription was associated with lower crude 1-year mortality (33.0% versus 42.1%, P<0.001), lower risk of death after adjustment (RR 0.86, 95% CI 0.82 to 0.90), and lower mortality regardless of patient gender, age, race, or serum creatinine level. Conclusions—ACE inhibitors were widely underprescribed despite evidence of a favorable impact on survival in a broad range of patients with heart failure. These results emphasize the importance of ongoing efforts to translate clinical trial results into practice.

Statins and Mortality Among Elderly Patients Hospitalized With Heart Failure

Background— Small studies suggest that statins may improve mortality in patients with heart failure (HF). Whether these results are generalizable to a broader group of patients with HF remains unclear. Our objective was to evaluate the association between statin use and survival among a national sample of elderly patients hospitalized with HF. Methods and Results— A nationwide sample of 61 939 eligible Medicare beneficiaries ≥65 years of age who were hospitalized with a primary discharge diagnosis of HF between April 1998 and March 1999 or July 2000 and June 2001 was evaluated. The analysis was restricted to patients with no contraindications to statins (n=54 960). Of these patients, only 16.7% received statins on discharge. Older patients were less likely to receive a statin at discharge. Patients with hyperlipidemia and those cared for by a cardiologist or cared for in a teaching hospital were more likely to receive a statin at discharge. In a Cox proportional hazards model that took into account demographic, clinical characteristics, treatments, physician specialty, and hospital characteristics, discharge statin therapy was associated with significant improvements in 1- and 3-year mortality (hazard ratio, 0.80; 95% CI, 0.76 to 0.84; and hazard ratio, 0.82; 95% CI, 0.79 to 0.85, respectively). Regardless of total cholesterol level or coronary artery disease status, statin therapy was associated with significant differences in mortality. Conclusions— Our data demonstrate that statin therapy is associated with better long-term mortality in older patients with HF. This study suggests a potential role for statins as an adjunct to current HF therapy. Randomized clinical trials are required to determine the role of these agents in improving outcomes in the large and growing group of patients with HF.

Clinical benefit of glycoprotein IIb/IIIa blockade with abciximab is independent of gender: Pooled analysis from EPIC, EPILOG and EPISTENT trials

OBJECTIVES We sought to determine the efficacy and safety of platelet glycoprotein IIb/IIIa receptor (GP IIb/IIIa) blockade with abciximab in women undergoing percutaneous coronary intervention. BACKGROUND Although gender differences in response to platelet glycoprotein IIb/IIIa receptor blockade have been described, there have been no large clinical studies to assess these differences. METHODS Outcomes were determined using meta-analysis technique. RESULTS In the pooled analysis, the primary end point of death, myocardial infarction (MI) or urgent revascularization within 30 days was reduced from 11.3% to 5.8% (p<0.001) in men and from 12.7% to 6.5% (p<0.001) in women treated with abciximab. At six months, death, MI or urgent revascularization was reduced from 14.1% to 8.3% (p<0.001) in men and 16.0% to 9.9% (p<0.001) in women receiving abciximab. At one year, mortality was reduced from 2.7% to 1.9% (p = 0.06) in men and 4.0% to 2.5% (p = 0.03) in women treated with abciximab. Major bleeding events occurred in 2.9% versus 3.0% (p = 0.96) of women and 2.7% versus 1.3% (p = 0.003) of men treated with placebo versus abciximab, respectively. Minor bleeding events occurred in 4.7% versus 6.7% (p = 0.01) of women and 2.3% versus 2.2% (p = 0.94) of men treated with placebo versus abciximab, respectively. CONCLUSIONS This pooled analysis demonstrated no gender difference in protection from major adverse outcomes with GP IIb/IIIa inhibition with abciximab. Although women had higher rates of both major and minor bleeding events with abciximab compared with men, major bleeding in women was similar with and without abciximab. There was a small increased risk of minor bleeding with abciximab in women.

National Trends in Patient Safety for Four Common Conditions, 2005–2011

BACKGROUND Changes in adverse-event rates among Medicare patients with common medical conditions and conditions requiring surgery remain largely unknown. METHODS We used Medicare Patient Safety Monitoring System data abstracted from medical records on 21 adverse events in patients hospitalized in the United States between 2005 and 2011 for acute myocardial infarction, congestive heart failure, pneumonia, or conditions requiring surgery. We estimated trends in the rate of occurrence of adverse events for which patients were at risk, the proportion of patients with one or more adverse events, and the number of adverse events per 1000 hospitalizations. RESULTS The study included 61,523 patients hospitalized for acute myocardial infarction (19%), congestive heart failure (25%), pneumonia (30%), and conditions requiring surgery (27%). From 2005 through 2011, among patients with acute myocardial infarction, the rate of occurrence of adverse events declined from 5.0% to 3.7% (difference, 1.3 percentage points; 95% confidence interval [CI], 0.7 to 1.9), the proportion of patients with one or more adverse events declined from 26.0% to 19.4% (difference, 6.6 percentage points; 95% CI, 3.3 to 10.2), and the number of adverse events per 1000 hospitalizations declined from 401.9 to 262.2 (difference, 139.7; 95% CI, 90.6 to 189.0). Among patients with congestive heart failure, the rate of occurrence of adverse events declined from 3.7% to 2.7% (difference, 1.0 percentage points; 95% CI, 0.5 to 1.4), the proportion of patients with one or more adverse events declined from 17.5% to 14.2% (difference, 3.3 percentage points; 95% CI, 1.0 to 5.5), and the number of adverse events per 1000 hospitalizations declined from 235.2 to 166.9 (difference, 68.3; 95% CI, 39.9 to 96.7). Patients with pneumonia and those with conditions requiring surgery had no significant declines in adverse-event rates. CONCLUSIONS From 2005 through 2011, adverse-event rates declined substantially among patients hospitalized for acute myocardial infarction or congestive heart failure but not among those hospitalized for pneumonia or conditions requiring surgery. (Funded by the Agency for Healthcare Research and Quality and others.).