BLOG: A fellow’s take on the TOPCAT trial

DALLAS — A common question in medicine is: What therapies improve mortality in patients with HF with reduced ejection fraction? As a current cardiology fellow, I have “grown up” in an era in which medical students and residents are able to rapidly rattle off the many correct answers to this common question on rounds. One of my favorite questions to ask instead is: What therapies improve mortality in patients with HF with preserved ejection fraction? Unfortunately, this question has stumped medical students and HF specialists alike for many years.

As the population ages and develops predisposing comorbidities, HF with preserved ejection fraction (HFpEF) has become a growing epidemic associated with high prevalence, hospitalization and economic burden. Clinicians continue to struggle with optimal medical management of these patients, and so results from the recently completed TOPCAT trial were highly anticipated at AHA 2013.

Nisha Aggarwal Gilotra

On behalf of the TOPCAT investigators, Marc A. Pfeffer, MD, PhD, presented results at a late-breaking clinical trial session in Dallas. The international, multicenter, NHLBI-funded trial included 3,445 patients with HFpEF (mean EF, 56%; mean age, 69 years; majority NYHA Class II/III) and elevated BNP/NT-proBNP or hospitalization for HF in the last year who were randomly assigned spironolactone or placebo.

There was no difference between the spironolactone and placebo groups for the study’s primary composite endpoint of death, aborted cardiac arrest or HF hospitalization. However, there was a trend toward lower HF hospitalization in the spironolactone group (12% vs. 14.2%; p=.042). There was also a significant difference in composite primary endpoint between spironolactone and placebo groups in the 981 patients enrolled based on elevated natriuretic peptide levels (HR 0.65; p=0.003).

Interestingly, the primary endpoint rate in the placebo group was much higher at sites in the Americas when compared with sites in Russia and the Republic of Georgia. There also was a study drug attrition rate of about one-third, which in part may be due to the longer follow-up necessitated by slow initial enrollment.

Additionally, although there was neither an increase in patients requiring initiation of dialysis nor any deaths attributable to hyperkalemia, researchers reported a significantly higher incidence of hyperkalemia (≥5.5 mmol/L) and increase in creatinine in the spironolactone group. This emphasizes the need for close monitoring of patients on spironolactone in the real world, especially in patients on concomitant ACE inhibitors. We are reminded of the spike in hyperkalemia-related deaths and hospitalizations after publication of the RALES trial, which demonstrated the effectiveness of spironolactone in HF with reduced EF, or HFrEF.

Although we are left empty-handed when it comes to methods of decreasing mortality in HFpEF patients, it may be reasonable, in a closely monitored setting, to employ spironolactone to reduce HFpEF hospitalizations. Sidenote: The HF readmission debate also was in the limelight at this year’s AHA meeting. This end goal may improve patient quality of life and alleviate the economic burden that HF portends. Future investigation powered to study the effect on HF hospitalization as a primary endpoint may lend further insight.

Also, the HFpEF population is a heterogeneous population, and we may need to target therapy toward a particular subset of this population. For example, in this study, the population enrolled was based on elevated natriuretic peptide levels.

During the AHA 2013 opening session presidential address, Mariell Jessup, MD, described limitations she faced during her early career while treating patients with HFrEF. Just as she was able to eventually offer life-saving treatments to the HFrEF patients whose stories she shared with us, I hope that with the ongoing rigorous investigation in the field, I will one day be able to do the same for my HFpEF patients. And finally, trainees on rounds will be expected to have an answer to the question: What therapies improve mortality in patients with HFpEF?

Nisha Aggarwal Gilotra, MD, is a fellow in the division of cardiology at Johns Hopkins Hospital.

Disclosure: Gilotra reports no relevant financial disclosures.