TOPCAT
The most recent trial, TOPCAT, built upon earlier smaller trials, investigated another HF-REF-proven treatment.23 TOPCAT randomised 3,445 patients 50 years or older and LVEF >45 % to spironolactone 30 to 45 mg/day or placebo. The trial was not quite positive: the primary composite endpoint was reduced from 20.4 % to 18.6 % (HR 0.89 95 % CI 0.77–1.04; p=0.138) and HF hospitalisations reduced from 14.2 % to 12.0 % (HR 0.83, 95 % CI 0.69-0.99; p=0.04). Yet again a negative trial, but in its pattern not dissimilar to VAL-HEFT. Interestingly in what was both a pre-specified analysis and using a variable that was actually stratified for at randomisation (ensuring the likelihood of good balance between placebo and active) in those patients who qualified for TOPCAT on the basis of an elevated NP level (BNP ≥100 pg/ml or NT-proBNP ≥360 pg/ ml) there was a highly significant 35 % reduction in the primary endpoint. In the elevated NP group there were 78 primary events in 490 patients (15.9 %) compared with 116 events in 491 placebo patients (23.6 %, HR 0.65, 95 CI 0.49–0.87; p=0.003)24 entirely consistent with what has been seen in HF-REF with spironolactone or eplerenone.
The Long-term Effect of Trials that Excluded Heart Failure with Preserved Ejection Fraction
We have seen that the major trials have largely been restricted to HF-REF patients. HF-PEF trials should be able to duplicate these results. This has not happened partly because of restricted funding. Some trials (e.g. I-PRESERVE) have recruited very slowly and have been funded publically rather than by a corporate sponsor where funding is usually more generous. Consider the case of the beta-blocker carvedilol. Carvedilol is now off-patent in most developed countries so further company sponsorship of large expensive trials is unlikely. The sponsors did however pay for three trials, the US Carvedilol program,25 Copernicus and COMET.26 None of these trials included HF-PEF patients. Where resources for trials are limited it seems a tragedy that the third major trial for this agent instead of recruiting the half of all HF that had been totally ignored instead targeted a question of only marginal scientific value, whether carvedilol was superior to a non-proven formulation of another beta-blocker, non-slow-release metoprolol. We cannot, sadly, depend on sponsors studying patient populations of need, they focus where their drug will look best and avoid the more difficult or uncertain areas. If we had recruited patients with HF irrespective of LVEF in a slightly enlarged Copernicus trial and performed subanalyses of HF-PEF and HF-REF we would be in a much stronger position today. It is hard to avoid the conclusion we should investigate27–29 and treat HF-PEF as rigorously as their HF-REF counterparts.