Treatment of HF in an Era of Multiple Therapies: Statement From the HF Collaboratory

Statement From the HF Collaboratory

Ankeet S. Bhatt, MD, MBA; William T. Abraham, MD; JoAnn Lindenfeld, MD; Michael Bristow, MD; Peter E. Carson, MD; G. Michael Felker, MD, MHS; Gregg C. Fonarow, MD; Stephen J. Greene, MD; Mitchell A. Psotka, MD, PHD; Scott D. Solomon, MD; Norman Stockbridge, MD, PHD; John R. Teerlink, MD; Muthiah Vaduganathan, MD, MPH; Janet Wittes, PHD; Mona Fiuzat, PHARMD; Christopher M. O'Connor, MD; Javed Butler, MD, MPH, MBA


JACC Heart Fail. 2021;9(1):1-12. 

In This Article

A Consensus Approach for Today: Comprehensive Disease-modifying Therapy

Even given limited data and the need for future research, health care providers still must make therapeutic decisions daily in routine clinical practice. We contend that until some of the aforementioned approaches are prospectively studied and the benefits and limitations are better understood, the best option is an attempt to administer comprehensive disease-modifying therapy, encompassing proven therapies at low doses initially and titrated as tolerated, to all patients with HFrEF.

Prior HF clinical trials have yielded important conclusions. First, in general, very few prior class I recommended therapies have shown clinical benefit that is convincingly dependent on a particular background therapy (i.e., that the therapy did/did not show clinical benefit based on whether patients were or were not on any given prior therapy). In the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, use of ARNI improved outcomes in patients on all background therapies, including MRAs.[26] The EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trial favored the study drug regardless of background beta-blocker and ACE inhibitor/ARB use.[9] MRA use showed similar benefit with and without use of beta-blockers in the RALES trial that enrolled only 10% of patients on beta-blockade. DAPA-HF (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) trial found similar improvements with dapagliflozin across different forms of background therapy, including ARNI.[27,28]

Second, although target doses should be sought whenever possible, data support the notion that maximally tolerated doses at less than target seem to be better than not receiving therapy. In the CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) trial, bisoprolol lowered mortality at all doses, including in >400 patients who received a maximum tolerated dose of <4 mg daily.[35] Similar findings were found with evaluations of ACE inhibitors and ARBs.[36,37] Treatment benefit of ARNI at maximum tolerated doses that were less than target doses was similar to that of target doses in a post hoc analysis.[38] Although target doses should be sought whenever possible, maximally tolerated doses at less than target seem to be better than receiving no therapy.

Third, recent evidence found significant improvement in survival (all-cause and cardiovascular) with a comprehensive strategy of concomitant use of evidence-based beta-blockers, ARNI, MRA, and SGLT2 inhibitors compared with conventional therapy with beta-blockers and ACE inhibitors/ARBs.[39] Treatment with comprehensive disease-modifying therapy was estimated to afford 1.4 additional years of life for an 80-year-old and 6.3 additional years in a 55-year-old compared with survival with conventional therapy alone. Patients treated with comprehensive medical therapy were also estimated to have significant improvements in event-free survival, suggesting reductions in HF-related morbidity. These findings highlight the potential importance of early comprehensive therapy for HFrEF.

Until generation of a more robust framework well supported by evidence, a "comprehensive therapy approach" incorporating all life-prolonging therapies should serve as the bedrock of HFrEF therapy. This approach is necessary in the current framework to ensure that patients have the greatest opportunity to benefit from the advances in discovery science. At present, treatment should at least consist of 4 therapies modifying 5 disease pathways: beta-adrenergic blockade, dual renin-angiotensin and aldosterone inhibition, neprilysin inhibition, and SGLT2 inhibition (Figure 1). It is understood that this approach is contrary to the move toward "precision medicine" and will need to be modified according to practical considerations of side effects and cost, but it is the approach that is most clearly evidenced based. Consensus documents offer important practical guidance in managing such complexities to optimize adherence, cost, and tolerability considerations. Nevertheless, this approach currently offers the best pragmatic advice based on available evidence.