Shakespeare, in Romeo and Juliet, refers to the proverb, “A cat has nine lives. For three he plays, for three he strays, and for the last he stays.”
TOPCAT is back again, having randomized its first patient with heart failure with preserved ejection fraction (HFpEF) almost 10 years ago for its treatment with spironolactone (SPIRO), a mineralocorticoid receptor antagonist.
HFpEF is a poorly described clinical entity as well as an elusive therapeutic topic. Clinically, it encompasses individuals who develop clinical heart failure with normal ejection fraction but with a number of associated precipitating events, including hypertension, arrhythmia, and often underlying pulmonary disease. A number of drugs, including beta-blockers and renin angiotensin-converting enzyme inhibitors, have been studied with variable and unconvincing results. Guideline committees have wrestled with advice for the treatment of HFpEF issue for a number of years. SPIRO, which has been shown to be effective in heart failure with reduced ejection fraction, seemed to be a likely candidate for its treatment. Many of the heart failure gurus had great expectation that TOPCAT would prove its benefit.
The first report of the results of TOPCAT in 2014 indicated that there was no benefit associate with SPIRO therapy tested in the 3,445 patients randomized in 244 sites around the world ( N Engl J Med. 2014 Apr 10;370[15]:1383-92 ). A subsequent analysis of data carried out in 2015 reported a striking regional difference in the outcome of patients randomized in the 1,767 patients in the Americas, compared with the 1,678 randomized in Russia and Georgia ( Circulation. 2015 Jan 6;131[1]:34-42 ). In the Americas, there was an 18% decrease in the primary event of death and heart failure rehospitalization (3.6% in the SPIRO vs. 4.9% in the placebo; hazard ratio, 0.82; P = .026). There was essentially no difference in the groups randomized in Russia and Georgia, which had a 1.6% placebo event rate.
And now in 2016, at the recent meeting of the Heart Failure Society of America, we were informed that there was no detectable level of blood canrenone, a metabolite of SPIRO, in 30% of the 66 randomized patients in Russia and Georgia, compared with 3% of the patients randomized in the Americas (Cardiology News. Oct 2016. p 8). These data tend to confirm that the patients randomized in Russia and Georgia were either undertreated or not treated. In fact, after examination of the baseline characteristics of the two groups it is possible that many of the patients may not have had heart failure at all.
So what are we left with? One thing that is clear is that the management of TOPCAT was flawed and constitutes an example of how not to run an international clinical trial. Can we make any conclusion about the benefit of SPIRO? TOPCAT initially was powered for over 3,515 patients and 630 events in order to achieve a 85% benefit. The current analysis has now narrowed the population down to 1,787 patients with 522 events with an 18% decrease (P = .02) in the primary end point. During the mean follow-up of 3.3 years there was a placebo mortality of 4.9%, which is impressive in the setting of concomitant beta-blocker and renin angiotensin-converting enzyme inhibitor therapy. The only significant adverse observation was a threefold occurrence in hyperkalemia (potassium greater than 5.5 mmols/L) in the 25.2% in the Americas group treated with SPIRO, compared with the Russian-Georgian patients
Unfortunately the answer is not entirely clear. We all know who HFpEF patients are when they walk into the clinic but identifying them for a clinical trial has been difficult if not impossible. As for me, I will choose to treat their hypertension aggressively (not an easy task) and prevent or suppress their arrhythmias. In that project I will use beta-blockers and SPIRO to prevent their next heart failure episode and hope for the best.
Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.
