Kevin A. Schulman

Efficacy and Safety of Exercise Training in Patients With Chronic Heart Failure: HF-ACTION Randomized Controlled Trial

CONTEXT Guidelines recommend that exercise training be considered for medically stable outpatients with heart failure. Previous studies have not had adequate statistical power to measure the effects of exercise training on clinical outcomes. OBJECTIVE To test the efficacy and safety of exercise training among patients with heart failure. DESIGN, SETTING, AND PATIENTS Multicenter, randomized controlled trial of 2331 medically stable outpatients with heart failure and reduced ejection fraction. Participants in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) were randomized from April 2003 through February 2007 at 82 centers within the United States, Canada, and France; median follow-up was 30 months. INTERVENTIONS Usual care plus aerobic exercise training, consisting of 36 supervised sessions followed by home-based training, or usual care alone. MAIN OUTCOME MEASURES Composite primary end point of all-cause mortality or hospitalization and prespecified secondary end points of all-cause mortality, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or heart failure hospitalization. RESULTS The median age was 59 years, 28% were women, and 37% had New York Heart Association class III or IV symptoms. Heart failure etiology was ischemic in 51%, and median left ventricular ejection fraction was 25%. Exercise adherence decreased from a median of 95 minutes per week during months 4 through 6 of follow-up to 74 minutes per week during months 10 through 12. A total of 759 patients (65%) in the exercise training group died or were hospitalized compared with 796 patients (68%) in the usual care group (hazard ratio [HR], 0.93 [95% confidence interval {CI}, 0.84-1.02]; P = .13). There were nonsignificant reductions in the exercise training group for mortality (189 patients [16%] in the exercise training group vs 198 patients [17%] in the usual care group; HR, 0.96 [95% CI, 0.79-1.17]; P = .70), cardiovascular mortality or cardiovascular hospitalization (632 [55%] in the exercise training group vs 677 [58%] in the usual care group; HR, 0.92 [95% CI, 0.83-1.03]; P = .14), and cardiovascular mortality or heart failure hospitalization (344 [30%] in the exercise training group vs 393 [34%] in the usual care group; HR, 0.87 [95% CI, 0.75-1.00]; P = .06). In prespecified supplementary analyses adjusting for highly prognostic baseline characteristics, the HRs were 0.89 (95% CI, 0.81-0.99; P = .03) for all-cause mortality or hospitalization, 0.91 (95% CI, 0.82-1.01; P = .09) for cardiovascular mortality or cardiovascular hospitalization, and 0.85 (95% CI, 0.74-0.99; P = .03) for cardiovascular mortality or heart failure hospitalization. Other adverse events were similar between the groups. CONCLUSIONS In the protocol-specified primary analysis, exercise training resulted in nonsignificant reductions in the primary end point of all-cause mortality or hospitalization and in key secondary clinical end points. After adjustment for highly prognostic predictors of the primary end point, exercise training was associated with modest significant reductions for both all-cause mortality or hospitalization and cardiovascular mortality or heart failure hospitalization. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00047437.

A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST).

This trial evaluated the effects of epoprostenol on patients with severe left ventricular failure. Patients with class IIIB/IV congestive heart failure and decreased left ventricular ejection fraction were eligible for enrollment if angiography documented severely compromised hemodynamics while the patient was receiving a regimen of digoxin, diuretics, and an angiotensin-converting enzyme inhibitor. We randomly assigned 471 patients to epoprostenol infusion or standard care. The primary end point was survival; secondary end points were clinical events, congestive heart failure symptoms, distance walked in 6 minutes, and quality-of-life measures. The median dose of epoprostenol was 4.0 ng/kg/min, resulting in a significant increase in cardiac index (1.81 to 2.61 L/min/m2), a decrease in pulmonary capillary wedge pressure (24.5 to 20.0 mm Hg), and a decrease in systemic vascular resistance (20.76 to 12.33 units). The trial was terminated early because of a strong trend toward decreased survival in the patients treated with epoprostenol. Chronic intravenous epoprostenol therapy is not associated with improvement in distance walked, quality of life, or morbid events and is associated with an increased risk of death.

Ethical and Scientific Implications of the Globalization of Clinical Research

In recent years, the number of clinical trials conducted in the United States has declined, and the majority of study sites are now outside the United States, with marked growth of research in developing countries. The authors discuss the implications of the globalization of clinical research and make recommendations about how to address the challenges that have emerged.

Effects of exercise training on health status in patients with chronic heart failure: HF-ACTION randomized controlled trial.

CONTEXT Findings from previous studies of the effects of exercise training on patient-reported health status have been inconsistent. OBJECTIVE To test the effects of exercise training on health status among patients with heart failure. DESIGN, SETTING, AND PATIENTS Multicenter, randomized controlled trial among 2331 medically stable outpatients with heart failure with left ventricular ejection fraction of 35% or less. Patients were randomized from April 2003 through February 2007. INTERVENTIONS Usual care plus aerobic exercise training (n = 1172), consisting of 36 supervised sessions followed by home-based training, vs usual care alone (n = 1159). Randomization was stratified by heart failure etiology, which was a covariate in all models. MAIN OUTCOME MEASURES Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary scale and key subscales at baseline, every 3 months for 12 months, and annually thereafter for up to 4 years. The KCCQ is scored from 0 to 100 with higher scores corresponding to better health status. Treatment group effects were estimated using linear mixed models according to the intention-to-treat principle. RESULTS Median follow-up was 2.5 years. At 3 months, usual care plus exercise training led to greater improvement in the KCCQ overall summary score (mean, 5.21; 95% confidence interval, 4.42 to 6.00) compared with usual care alone (3.28; 95% confidence interval, 2.48 to 4.09). The additional 1.93-point increase (95% confidence interval, 0.84 to 3.01) in the exercise training group was statistically significant (P < .001). After 3 months, there were no further significant changes in KCCQ score for either group (P = .85 for the difference between slopes), resulting in a sustained, greater improvement overall for the exercise group (P < .001). Results were similar on the KCCQ subscales, and no subgroup interactions were detected. CONCLUSIONS Exercise training conferred modest but statistically significant improvements in self-reported health status compared with usual care without training. Improvements occurred early and persisted over time. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00047437.

Delivering affordable cancer care in high-income countries

The burden of cancer is growing, and the disease is becoming a major economic expenditure for all developed countries. In 2008, the worldwide cost of cancer due to premature death and disability (not including direct medical costs) was estimated to be US

Randomized Trial of Warfarin, Aspirin, and Clopidogrel in Patients With Chronic Heart Failure: The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) Trial

895 billion. This is not simply due to an increase in absolute numbers, but also the rate of increase of expenditure on cancer. What are the drivers and solutions to the so-called cancer-cost curve in developed countries? How are we going to afford to deliver high quality and equitable care? Here, expert opinion from health-care professionals, policy makers, and cancer survivors has been gathered to address the barriers and solutions to delivering affordable cancer care. Although many of the drivers and themes are specific to a particular field-eg, the huge development costs for cancer medicines-there is strong concordance running through each contribution. Several drivers of cost, such as over-use, rapid expansion, and shortening life cycles of cancer technologies (such as medicines and imaging modalities), and the lack of suitable clinical research and integrated health economic studies, have converged with more defensive medical practice, a less informed regulatory system, a lack of evidence-based sociopolitical debate, and a declining degree of fairness for all patients with cancer. Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (eg, value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. A radical shift in cancer policy is also required. Political toleration of unfairness in access to affordable cancer treatment is unacceptable. The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies.

Relationship Between Cardiac Rehabilitation and Long-Term Risks of Death and Myocardial Infarction Among Elderly Medicare Beneficiaries

Background— Chronic heart failure remains a major cause of mortality and morbidity. The role of antithrombotic therapy in patients with chronic heart failure has long been debated. The objective of this study was to determine the optimal antithrombotic agent for heart failure patients with reduced ejection fractions who are in sinus rhythm. Methods and Results— This prospective, randomized clinical trial of open-label warfarin (target international normalized ratio of 2.5 to 3.0) and double-blind treatment with either aspirin (162 mg once daily) or clopidogrel (75 mg once daily) had a 30-month enrollment period and a minimum of 12 months of treatment. We enrolled 1587 men and women ≥18 years of age with symptomatic heart failure for at least 3 months who were in sinus rhythm and had left ventricular ejection fraction of ≤35%. The primary outcome was the time to first occurrence of death, nonfatal myocardial infarction, or nonfatal stroke. For the primary composite end point, the hazard ratios were as follows: for warfarin versus aspirin, 0.98 (95% CI, 0.86 to 1.12; P=0.77); for clopidogrel versus aspirin, 1.08 (95% CI, 0.83 to 1.40; P=0.57); and for warfarin versus clopidogrel, 0.89 (95% CI, 0.68 to 1.16; P=0.39). Warfarin was associated with fewer nonfatal strokes than aspirin or clopidogrel. Hospitalization for worsening heart failure occurred in 116 (22.2%), 97 (18.5%), and 89 (16.5%) patients treated with aspirin, clopidogrel, and warfarin, respectively (P=0.02 for warfarin versus aspirin). Conclusion— The primary outcome measure and the mortality data do not support the primary hypotheses that warfarin is superior to aspirin and that clopidogrel is superior to aspirin.

Linking Inpatient Clinical Registry Data to Medicare Claims Data Using Indirect Identifiers

Background— For patients with coronary heart disease, exercise-based cardiac rehabilitation improves survival rate and has beneficial effects on risk factors for coronary artery disease. The relationship between the number of sessions attended and long-term outcomes is unknown. Methods and Results— In a national 5% sample of Medicare beneficiaries, we identified 30 161 elderly patients who attended at least 1 cardiac rehabilitation session between January 1, 2000, and December 31, 2005. We used a Cox proportional hazards model to estimate the relationship between the number of sessions attended and death and myocardial infarction (MI) at 4 years. The cumulative number of sessions was a time-dependent covariate. After adjustment for demographic characteristics, comorbid conditions, and subsequent hospitalization, patients who attended 36 sessions had a 14% lower risk of death (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77 to 0.97) and a 12% lower risk of MI (HR, 0.88; 95% CI, 0.83 to 0.93) than those who attended 24 sessions; a 22% lower risk of death (HR, 0.78; 95% CI, 0.71 to 0.87) and a 23% lower risk of MI (HR, 0.77; 95% CI, 0.69 to 0.87) than those who attended 12 sessions; and a 47% lower risk of death (HR, 0.53; 95% CI, 0.48 to 0.59) and a 31% lower risk of MI (HR, 0.69; 95% CI, 0.58 to 0.81) than those who attended 1 session. Conclusions— Among Medicare beneficiaries, a strong dose–response relationship existed between the number of cardiac rehabilitation sessions and long-term outcomes. Attending all 36 sessions reimbursed by Medicare was associated with lower risks of death and MI at 4 years compared with attending fewer sessions.

Cost of Cancer Care: Issues and Implications

BACKGROUND Inpatient clinical registries generally have limited ability to provide a longitudinal perspective on care beyond the acute episode. We present a method to link hospitalization records from registries with Medicare inpatient claims data, without using direct identifiers, to create a unique data source that pairs rich clinical data with long-term outcome data. METHODS AND RESULTS The method takes advantage of the hospital clustering observed in each database by demonstrating that different combinations of indirect identifiers within hospitals yield a large proportion of unique patient records. This high level of uniqueness also allows linking without advance knowledge of the Medicare provider number of each registry hospital. We applied this method to 2 inpatient databases and were able to identify 81% of 39,178 records in a large clinical registry of patients with heart failure and 91% of 6,581 heart failure records from a hospital inpatient database. The quality of the link is high, and reasons for incomplete linkage are explored. Finally, we discuss the unique opportunities afforded by combining claims and clinical data for specific analyses. CONCLUSIONS In the absence of direct identifiers, it is possible to create a high-quality link between inpatient clinical registry data and Medicare claims data. The method will allow researchers to use existing data to create a linked claims-clinical database that capitalizes on the strengths of both types of data sources.

Patterns of breast carcinoma treatment in older women: Patient preference and clinical and physician influences

Medical technology is increasingly costly in most fields of clinical medicine. Oncology has not been spared from issues related to cost, in part resulting from the tremendous scientific progress that has lead to new tools for diagnosis, treatment, and follow-up of our patients. The increasing cost of health care in general (and cancer care in particular) raises complex questions related to its effects on our economy and the citizens of our society. This article reviews the macroeconomic principles and individual behaviors that govern medical spending, and examines how cost disproportionately affects various populations. Our overall goal is to frame debate about health policy concerns that influence the clinical practice of oncology.