More life years and with fewer hospitalizations

A number of recent randomized trials provided evidence that newer disease-modifying therapies can extend life and reduce hospitalizations for patients with reduced ejection fraction heart failure — but what if those therapies were combined into a single, focused, disease-modifying treatment strategy?

The answer, according to Muthiah Vaduganathan, MD, MPH, Brigham and Women’s Hospital/Harvard Medical School, and colleagues, is more years of life with fewer hospitalizations during those years.

“Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2.7 additional years (for an 80-year-old) to 8.3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1.4 additional years (for an 80-year-old) to 6.3 additional years (for a 55-year-old) of survival compared with conventional therapy,” they wrote in The Lancet.

Vaduganathan and colleagues looked at data from trials of three classes of heart failure drugs — mineralocorticoid receptor antagonists (MRAs), angiotensin receptor–neprilysin inhibitors (ARNIs), and sodium/glucose cotransporter 2 (SGLT2) inhibitors — and conventional therapies: angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and β blockers.

The study authors explained that they “estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, withen projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker).”

Among the findings:

  • The imputed aggregate hazard ratio for the comprehensive disease-modifying therapy versus conventional therapy for the combined endpoint cardiovascular death or hospitalization was 0.38 (95% CIN 0.30-0.47).
  • HR for death alone was 0.50 (95% CI 0.37-0.67).
  • HR for heart failure hospitalization was 0.32 (95% CI 0.24-0.43).
  • HR for all-cause mortality was 0.53 (95% CI 0.40-0.70).

The authors noted that there are data to support both the feasibility and safety of either clustered or “near-simultaneous” initiation of these combined therapies using an aggressive, rapid up-titration strategy.

“Once these therapies become broadly available and generic, a polypill of comprehensive disease-modifying therapy might be feasibly implemented to promote effective and equitable therapy at the population level,” they added.

But there are barriers to such a strategy, including the well-recognized fact that multidrug regimens are known to increase the risk of nonadherence, often driven by increased out-0f-pocket costs.

Vaduganathan et al also cautioned that their analyses did not “dissect potential safety issues related to comprehensive therapy. However, data from pivotal clinical trials have added reassurance that optimizing therapeutic regimens can be done safely with appropriate follow-up and monitoring. For example, in PARADIGM-HF, sacubitril–valsartan resulted in less hyperkalemia and renal insufficiency than enalapril when added to background MRA therapy. Similarly, there were low rates of drug discontinuation or serious adverse events with addition of dapagliflozin to excellent background medical therapy in DAPA-HF, and these risks were similar to those observed with placebo.”

In a commentary published along with the study, Mitchell A. Psotka, MD, PhD, of Inova Heart and Vascular Institute in Falls Church, Virgina, and John R. Teerlink, MD of the Veterans Medical Center in San Francisco and UCSF, cheered the analysis, pointing out that the researchers added a valuable analysis to aid clinicians who are wading through reams of data to try to determine the best treatment for their heart failure patients.

“Drawing upon individual patient data from three randomized controlled trials of HFrEF therapies (combined total 15,880 patients enrolled; 12,329 men [78%] and 3,551 women [22%]), they estimated the long-term treatment benefits of a more comprehensive contemporary regimen compared with a less complete regimen,” they wrote. “Although β blockers and angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) have been widely, if not imperfectly, implemented in clinical practice, most patients are not treated with mineralocorticoid receptor antagonists (MRAs). In the analysis by Vaduganathan and colleagues, the use of a comprehensive contemporary regimen (β blocker, angiotensin–neprilysin inhibitor [ARNI], MRA, and SGLT2 inhibitor) reduces the hazard of cardiovascular death or admission to hospital for heart failure (hazard ratio 0.38 [95% CI 0.30-0.47]), and might lengthen life by 1-6 years, depending on the age at which treatment is initiated.”

Psotka and Teerlink pointed out that the estimates of benefits do require “multiple assumptions about therapy,” but they considered that a minor quibble because “these results provide readily understandable values for clinicians or healthcare professionals and patients and far outpace those of many approved treatments for cancer, for which additional survival is often measured in months.”

Vaduganathan and colleagues concluded that their data “support the central role of comprehensive disease-modifying pharmacological therapy to halt or delay clinical progression and extend survival in patients with HFrEF. Given incomplete uptake of well established and novel therapies, innovative and disruptive implementation strategies are urgently needed to facilitate use of combination multidrug regimens in appropriately selected patients with HFrEF. The survival benefits estimated with comprehensive disease-modifying pharmacological therapy might be important in shared therapeutic decision making and future health system valuation.”

Psotka and Teerlink echoed that assessment, adding that the “results should be broadcast to patients, caregivers, clinicians, health systems, and payers to encourage the best possible outcomes for patients.”

  1. Be aware that this analysis suggests that combining an ARNI, β blocker, MRA, and SGLT2 inhibitor in a comprehensive treatment regimen reduces the relative risk of death or hospitalization for heart failure by 62% compared with a conventional strategy of ACE or ARB and β blocker treatment.

  2. Note that the authors estimate that the therapeutic optimization strategy they describe may add years to overall survival compared to standard therapy.

Peggy Peck, Editor-in-Chief, BreakingMED™

Vaduganathan is supported by the KL2/Catalyst medical research investigator training award from Harvard Catalyst (National Institutes of Health (NIH)/National Center for Advancing Translational Sciences award UL 1TR002541) and serves on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer, Boehringer Ingelheim, Cytokinetics, and Relypsa.

Psotka reported personal fees from Amgen, Cytokinetics, and Windtree Therapeutics and grants from the US Food and Drug Administration, outside the area of work commented on here.

Teerlink reported personal fees and non-financial support from Abbott, Bayer, Boehringer-Ingelheim, EBR Systems, Medtronic, Merck, and Windtree Therapeutics; personal fees from AbbVie and AstraZeneca; grants, personal fees, and non-financial support from Amgen, Bristol-Myers Squibb, and Cytokinetics; and grants from the Department of Veterans Affairs, outside the area of work commented on here.

Cat ID: 3

Topic ID: 74,3,730,3,914,192,925