Real-World HF Findings at Odds With Clinical Trials

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Which Results Should Clinicians Believe?

If clinicians consider the totality of the evidence from these two observational studies and the randomized clinical trials that they appear to contradict, we can arrive at two sound conclusions: First, it is reasonable to use RAS antagonists to control hypertension in HF with preserved ejection fraction; second, aldosterone antagonists are effective but should be used carefully and selectively in patients who have HF with reduced ejection fraction, said Dr. James C. Fang.

"Although clinical trials should remain the gold standard for testing hypotheses, observational studies bridge the gap from the scientific rigor of clinical trials to real-world experience," he said.

Dr. Fang is at University Hospitals Case Medical Center, Cleveland. He had no financial conflicts of interest. These remarks were taken from his editorial accompanying the reports by Dr. Hernandez and Dr. Lund (JAMA 2012;308:2144-6).



Two large observational "real-world" studies of two different treatments for heart failure failed to confirm the results of clinical trials of those treatments, leaving clinicians to wonder which study findings to trust, according to separate reports in the Nov. 28 issue of JAMA.

In one report, aldosterone antagonists failed to improve mortality or reduce CV readmissions in patients who had heart failure with decreased ejection fraction, after clinical trials had indicated the agents would do so. In another report, renin-angiotensin system antagonists did reduce mortality in patients who had HF with preserved ejection fraction, after clinical trials had indicated the drugs would not do so.

Dr. Andrian Hernandez

Both research groups called for additional study to clarify the discrepant results.

In the first study, investigators noted that "landmark clinical trials" had shown the aldosterone antagonists spironolactone and eplerenone cut mortality by up to 30% and readmissions for HF by nearly 40% among patients who had heart failure accompanied by reduced ejection fraction. Yet even though these drugs are now recommended for such patients, physicians have been slow to comply.

This may be due in part to uncertainty about the safety and effectiveness of aldosterone antagonists under real-world conditions, where many patients – the elderly, those with diabetes or chronic kidney disease, and those already using other medications predisposing them to hyperkalemia – fall outside the strict inclusion criteria used in clinical trial populations, said Dr. Adrian F. Hernandez of Duke Clinical Research Institute, Durham, N.C., and his associates.

Dr. Hernandez and his colleagues used data from the Get With The Guidelines–HF registry and the Medicare claims database to assess the drugs’ effectiveness in 5,887 patients aged 65 and older who had been discharged from 246 U.S. hospitals with a diagnosis of HF with decreased left ventricular ejection fraction in 2005-2009 and who were eligible for treatment with aldosterone antagonists. Only 1,070 of the study subjects received a prescription for the drugs at discharge.

After 3 years, there were no significant differences in all-cause mortality or in readmission for cardiovascular disorders between patients who were given aldosterone antagonists and patients who were not, the researchers said (JAMA 2012;308:2097-107).

On the down side, treated patients did show a higher rate of rehospitalization for hyperkalemia, usually during the first few weeks after initiating therapy with aldosterone antagonists.

This study wasn’t designed to determine why the results contradicted the "impressive benefits of aldosterone antagonist therapy" reported in "pivotal" efficacy trials as well as in a systematic review of randomized clinical trials of the therapy. But the researchers suggested that it’s possible the drugs have limited effectiveness in older patients in clinical practice, possibly because they may not adhere to treatment as well as subjects in intensely monitored clinical trials.

"Our findings highlight the importance of conducting clinical trials that can be easily generalized to real-world practice and in which the most vulnerable patient groups are well represented," Dr. Hernandez and his colleagues said.

Moreover, "developing protocols and systems that encourage optimal use and monitoring of aldosterone antagonist therapy may help to ensure that the effectiveness of this therapy in clinical practice approaches the efficacy achieved in clinical trials."

The investigators added that in their study, aldosterone antagonists did reduce the rate of rehospitalization for HF, which indicates that further study is needed to clarify the benefits and risks of therapy.

The second JAMA report involved the use of renin-angiotensin system (RAS) antagonists, which includes ACE inhibitors and angiotensin-receptor blockers, for patients who have heart failure with preserved ejection fraction. Three randomized clinical trials had concluded that the agents failed to improve outcomes in such patients, but those trials were marred by flaws such as selection bias, underpowering, and high crossover rates, said Dr. Lars H. Lund of the Karolinska Institutet, Stockholm, and his associates.

Dr. Lund and his colleagues used data from the Swedish Heart Failure Registry to examine RAS antagonists’ effectiveness in a large, unselected patient population. Their main analysis included 16,216 patients from 77 hospitals and 84 primary care outpatient clinics, of whom 77% received RAS antagonists and 23% did not.

Patients who took the drugs showed a 1-year crude survival of 86%, compared with only 69% for patients who didn’t take them. Five-year survival was 55% and 32%, respectively, the investigators said (JAMA 2012;308:2108-117).

The researchers also developed propensity scores using 43 clinically relevant variables at baseline so they could construct age-matched and propensity-matched groups of 3,329 patients who received the drugs at hospital discharge and 3,329 who did not. In this analysis, 1-year survival was 77% for the treated patients vs. 72% for the untreated, and 5-year survival was 36% vs 34%, respectively. These differences were statistically significant and confirmed that the result of the main analysis was accurate, Dr. Lund and his associates said.


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