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Professor of Medicine and Radiology
Department of Medicine
Tufts University School of Medicine
Chief, Division of Cardiology
Tufts Medical Center
James Udelson, MD, has disclosed that he has performed contracted research for Cytokinetix and he has received consulting fees from Cardurion, LivaNova, and Merck.
At the 2021 American College of Cardiology (ACC) Annual Meeting, we saw new data on several therapies for patients across the spectrum of heart failure (HF). Here’s my take the most influential studies.
Beta-Blockers in HFpEF
Beta-blockers—including carvedilol, metoprolol succinate, and bisoprolol—are foundational therapies for patients with HF and reduced ejection fraction (HFrEF), with strong evidence for improved outcomes, including mortality. The use of beta-blockers in patients with HF and preserved ejection fraction (HFpEF) remains unproven. A new study from the large Swedish SWEDE-HF registry used data from more than 14,000 patients with HFpEF to identify almost 7000 learners for a propensity matched analysis of long-term outcomes, comparing patients who received beta-blockers to those who did not. Propensity matching is a method to minimize—at least in part—demographic and clinical differences in populations from an observational database in which some patents are treated with a certain medication for clinical purposes and not randomized. In this registry for instance, patients may be on beta-blockers to control heart rate in atrial fibrillation, for underlying coronary artery disease, or for other reasons.
In the propensity matched cohorts, the authors found no difference in the long-term outcomes of cardiovascular mortality and HF hospitalizations among patients receiving vs not receiving beta-blockers. In subgroup analyses, it appeared that men may benefit from beta-blockers, but women do not. I suspect this finding is not likely to be a true finding, as it is one of many subgroups analyzed in a study whose primary analysis was neutral, and it is not plausible pathophysiologically.
Although propensity matched analyses or other similar analytic approaches for assessing therapeutic effects in observational databases are not as strong as randomized trials, they do provide some insight in the absence of trials, and it is unlikely we will see of beta-blockers in patients with HFpEF. In the past, when we thought of HFpEF simply as “diastolic heart failure,” there was a pathophysiologic train of thought that slowing the heart rate would be useful to prolong diastolic filling time and allow more time for left atrial decompression, thereby improving dyspnea. However, several studies have now shown this hypothesis to be incorrect. For example, a randomized trial of ivabradine to slow the heart rate resulted in diminished peak VO2 on cardiopulmonary exercise testing compared with placebo. Thus, given the evidence from previous small trials and the current registry study, my opinion is that beta-blockers have no place in the treatment of patients with HFpEF, unless needed for another indication.
Safety and Efficacy of Soluble Guanylate Cyclase Stimulators
Translational as well as human studies suggest that the pathophysiology of both HFpEF as well as HFrEF may involve deficiency in the nitric oxide–soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate signaling pathway. Augmentation of this pathway may be a therapeutic target and several agents that act to stimulate sGC activity have been developed and studied in randomized trials in patients with HFpEF or HFrEF, including vericiguat, riociguat, and praliciguat.
In a systematic review and meta-analysis, Moghaddam and colleagues assessed the safety and efficacy of sGC stimulators across the spectrum of patients with HF. They identified 8 randomized trials involving more than 6500 patients with HFrEF or HFpEF, and one trial of patients with WHO type 2 pulmonary hypertension, that is, secondary to left-sided HF. They found that sGC stimulators had no impact on cardiovascular or all-cause mortality, but there was signal of improvement in HF hospitalizations. Adverse events were similar in patients receiving sGC stimulators or control, although there was a slightly higher incidence of hypotension in the sGC stimulator group.
These results are dominated by the large VICTORIA trial in patients with HFrEF, as that trial contributed approximately 80% of the patients in this analysis. In the VICTORIA trial, the composite endpoint of cardiovascular mortality or HF hospitalizations was favorably affected, driven by a reduction on HF hospitalizations. Based on the VICTORIA trial findings, vericiguat was recently FDA approved for this patient population. The individual trials in patients with HFpEF were focused on symptom and function endpoints and were rigorously neutral. Thus, it would not be appropriate to use the results of this pooled analysis to apply the results to patients beyond those studied in VICTORIA. At this point, vericiguat can be considered for treatment of patients with HFrEF with a recent episode of worsening HF, consistent with its indication.
Adverse Events With SGLT2 Inhibitors
Sodium-glucose cotransporter 2 (SGLT2) inhibitors (namely, dapagliflozin, empagliflozin, and sotagliflozin) have demonstrated favorable impact on HF outcomes, including cardiovascular death and HF hospitalization. Although the agents were generally well tolerated in large, randomized, placebo-controlled trials, individual trials sometimes showed an imbalance of adverse events such as a slightly higher rate of fractures and amputations in the SGLT2 inhibitor arm. The overall rates of such events were very low, and it was hard to know whether the findings were simply due to chance or were of clinical relevance.
One way to understand such an issue is with meta-analysis. In a new study, Taha and colleagues pooled 62 large SGLT2 inhibitor randomized trials involving more than 90,000 patients, including persons with diabetes and those with HF with or without diabetes. Approximately two thirds of participants received SGLT2 inhibitors and one third received placebo. The authors found that adverse events associated with the use of SGLT2 inhibitors included diabetic ketoacidosis (<1% risk) and infections, driven by genital infections. In particular, there was no evidence of an increased risk of bone fractures or amputations, which had been of concern from some of the individual trials, nor of hypoglycemia. From the data presented, it did not appear that any specific agent within the class had differential effects on the reported adverse events.
These data help to inform discussions with patients about the use of this important new class of agents for persons with diabetes and/or HF. In particular, the elevated risk of genital infections calls for counseling about genital hygiene and early recognition and treatment.
Which Patients Benefit Most From SGLT2 Inhibitors?
As previously mentioned, SGLT2 inhibitors have shown a consistent favorable impact on outcomes in patients with HF, including cardiovascular death and HF hospitalization. With any new class of efficacious therapies, we ask if certain patients benefit more or less, or tolerate differentially, so that we can target therapies to those most likely to benefit.
In another systematic review and meta-analysis of SGLT2 inhibitors in HF, Cardoso and colleagues identified 15 studies involving more than 20,000 patients with HF, in which subgroup analyses had been performed and could be analyzed. In the overall groups, the expected finding of a favorable impact on the major outcomes of cardiovascular mortality or HF hospitalizations was confirmed, as was a reduction on all-cause mortality. Of interest, among approximately 15% of patients with HFpEF, SGLT2 inhibitors were associated with reductions in cardiovascular mortality or HF hospitalizations. This is intriguing while we await the major results of the dapagliflozin and empagliflozin HFpEF randomized trials.
The authors examined many subgroups of the data, including by sex, age, race, kidney function, symptomatic NYHA class, and ejection fraction, but found no signal of a differential effect among any subgroup. The authors conclude that favorable effects of SGLT2 inhibitors in HF are seen across all subgroups examined.
These results are entirely consistent with previous clinical trials across all other major guideline-directed medical therapies in patients with HF (in HFrEF) performed during the past 3 decades. In trials of renin–angiotensin system agents including sacubitril/valsartan, evidence-based beta-blockers, and mineralocorticoid antagonists, no subgroup has been identified in the large randomized outcome trials that has shown differential benefit, and we essentially treat everyone similarly. This appears to be the case as well with the newest entrant into the foundational therapies, the SGLT2 inhibitors. Despite much discussion of personalized therapeutic targeting, in patients with HFrEF, therapy is very impersonal! Nonetheless, this approach has resulted in a breathtaking reductions in morbidity and mortality for patients with HF. With the addition of SGLT2 inhibitors to our treatment armamentarium, these impressive trends should continue.
Which new data from ACC are you most excited about? Answer the polling question and join the conversation by posting in the discussion section.
For more detail on these and other studies from ACC 2021, download Capsule Summaries of all the key data.