Focused Monitoring After Heart Failure Trials

Cardiovascular death and hospitalization for heart failure (HF) are prevailing end points in randomized controlled trials (RCTs) in patients who have HF with reduced ejection fraction (HFrEF). The low incidence of cardiovascular death and hospitalization in recent RCTs contrasts with the 5-year mortality rate of 75.5% and readmission risk of 48.5% among hospitalized HFrEF patients, indicating enrollment of stable New York Heart Association (NYHA) class II-III patients.1McMurray J.J.V. Solomon S.D. Inzucchi S.E. et al.DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction.N Engl J Med. 2019; 381: 1995-2008Crossref PubMed Scopus (4069) Google Scholar,2Packer M. Anker S.D. Butler J. et al.EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure.N Engl J Med. 2020; 383: 1413-1424Crossref PubMed Scopus (2806) Google Scholar However, inclusive enrollment in RCTs may yield incomplete therapeutic information. A well-tolerated and effective therapy for stable HFrEF was 8 years later found to be poorly tolerated and ineffective in advanced HFrEF.3Mann D.L. Givertz M.M. Vader J.M. et al.LIFE Investigators. Effect of treatment with sacubitril/valsartan in patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial.JAMA Cardiol. 2022; 7: 17-25Crossref PubMed Scopus (0) Google Scholar,4Vader J.M. Givertz M.M. Starling R.C. et al.LIFE Investigators. Tolerability of sacubitril/valsartan in patients with advanced heart failure: analysis of the LIFE trial run-in.JACC Heart Fail. 2022; 10: 449-456Crossref PubMed Scopus (0) Google Scholar Extension of HFrEF RCTs to 5 years will delay drug approval and clinical use. Further, extension of HFrEF RCTs will increase the expense of drug development and HF direct costs. A pragmatic approach of focused monitoring of patients for 3 to 5 years after completion of conclusive RCTs is a viable and informative alternative to extension of HFrEF trials. The present viewpoint elucidates the rationale behind focused monitoring and proposes an outline for focused monitoring after completion of conclusive RCTs in HFrEF. The proposed approach is similar to the continued access protocol for left ventricular (LV) assist devices. The Cooperative North Scandinavian Enalapril Survival Study (Consensus) randomized 254 patients with cardiomegaly and New York Heart Association (NYHA) functional class IV to enalapril or placebo. The study was terminated after 6 months because angiotensin-converting enzyme inhibition (ACEI) with enalapril reduced mortality by 50% (95% CI, 34% to 67%). Thereafter, all study patients were followed up for 10 years and 80% received enalapril.5Swedberg K. Kjekshus J. Snapinn S. Long-term survival in severe heart failure in patients treated with enalapril: ten year follow-up of CONSENSUS I.Eur Heart J. 1999; 20: 136-139Crossref PubMed Scopus (194) Google Scholar Only 5 of the 254 patients were alive at the 10-year follow-up. The Kaplan-Meier survival curves overlapped at 5 to 6 years, independent of enalapril therapy.5Swedberg K. Kjekshus J. Snapinn S. Long-term survival in severe heart failure in patients treated with enalapril: ten year follow-up of CONSENSUS I.Eur Heart J. 1999; 20: 136-139Crossref PubMed Scopus (194) Google Scholar Limited enrollment and high mortality hinder interpretation of the CONSENSUS data. Despite a striking early effect on mortality, enalapril was beneficial for only a few years. Three years of ACEI with enalapril reduced mortality by 16% compared with placebo in the Studies of Left Ventricular Dysfunction–Treatment Arm (SOLVD-T). Thereafter, all patients in the SOLVD-T received enalapril and were followed up for 9.4 years to assess long-term survival with enalapril.6Jong P. Yusuf S. Rousseau M.F. Ahn S.A. Bangdiwala S.I. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study.Lancet. 2003; 361: 1843-1848Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar At a median follow-up of 12.4 years, 21% of patients who received enalapril from initial randomization and 20% of patients who received enalapril after 3 years of placebo were alive.6Jong P. Yusuf S. Rousseau M.F. Ahn S.A. Bangdiwala S.I. Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study.Lancet. 2003; 361: 1843-1848Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar Hence, postponing enalapril therapy for 3 years had a minimal effect on long-term mortality in the SOLVD-T cohort. The SOLVD follow-up data hint at a waning benefit of long-term ACEI. Similarly, long-term ACEI does not seem to benefit patients with advanced chronic kidney disease. Renal dysfunction or requirement of renal replacement therapy in advanced chronic kidney disease progressed regardless of ACEI.7Bhandari S. Mehta S. Khwaja A. et al.STOP ACEi Trial Investigators. Renin-angiotensin system inhibition in advanced chronic kidney disease.N Engl J Med. 2022; 387: 2021-2032Crossref PubMed Scopus (0) Google Scholar After 2 single-blind run-in periods with enalapril and sacubitril/valsartan, the Prospective Comparison of ARNi With ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) randomized 8442 patients with adequately treated HFrEF in NYHA class II to III to sacubitril/valsartan or enalapril. The executive committee terminated the study after a follow-up of 27 months because the hazard ratio was 0.80 (95% CI, 0.71 to 0.89) for cardiovascular mortality and 0.79 (95% CI, 0.71 to 0.89) for HF hospitalization in support of angiotensin receptor-neprilysin inhibition (ARNi) with sacubitril/valsartan. Apparently, there was no extended follow-up of patients after completion of the PARADIGM-HF study. However, the LCZ696 in Hospitalized Advanced Heart Failure (LIFE) trial that explored the tolerability, efficacy, and safety of sacubitril/valsartan in patients who had HFrEF with recent NYHA class IV reported noteworthy findings.3Mann D.L. Givertz M.M. Vader J.M. et al.LIFE Investigators. Effect of treatment with sacubitril/valsartan in patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial.JAMA Cardiol. 2022; 7: 17-25Crossref PubMed Scopus (0) Google Scholar In the LIFE trial, 355 patients underwent an unblinded run-in period with sacubitril/valsartan and thereafter were to be randomized to sacubitril/valsartan + placebo vs valsartan + placebo. The duration of the LIFE study was 24 weeks, and the end point was the area under the curve for the ratio of N-terminal pro-brain-type natriuretic peptide compared with baseline. During the run-in period, 73 patients (18%) did not tolerate sacubitril/valsartan, with systolic blood pressure decreasing to less than 90 mm Hg and serum creatinine level increasing to more than 2 mg/dL.4Vader J.M. Givertz M.M. Starling R.C. et al.LIFE Investigators. Tolerability of sacubitril/valsartan in patients with advanced heart failure: analysis of the LIFE trial run-in.JACC Heart Fail. 2022; 10: 449-456Crossref PubMed Scopus (0) Google Scholar Compared with valsartan, sacubitril/valsartan did not lower N-terminal pro-brain-type natriuretic peptide levels or improve the clinical composite of number of days alive, number of days out of hospital, and freedom from HF events. Thus, ARNi with sacubitril/valsartan did not benefit patients with HFrEF in NYHA class IV. Owing to a marked systolic blood pressure reduction, sacubitril/valsartan may worsen renal function or cause renal injury in patients who have HFrEF with borderline systolic blood pressure.4Vader J.M. Givertz M.M. Starling R.C. et al.LIFE Investigators. Tolerability of sacubitril/valsartan in patients with advanced heart failure: analysis of the LIFE trial run-in.JACC Heart Fail. 2022; 10: 449-456Crossref PubMed Scopus (0) Google Scholar In brief, ARNi with sacubitril/valsartan may not exert consistent effects throughout the course of HFrEF. The approval of ACEI for HF preceded that of β-adrenergic receptor blockade (BARB) with carvedilol or metoprolol succinate by 15 to 20 years. Hence, 90% to 95 % of patients with HF who participated in RCTs of BARB were receiving ACEI. The effects of carvedilol and metoprolol on LV remodeling result from months of BARB and years of ACEI. Both ACEI and BARB enhance ejection fraction (EF) and delay the progression of LV remodeling. During long-term administration of ACEI or ARNi and BARB, EF may increase to near normal values. Patients who have HF with improved EF have a better clinical outcome than their counterparts with reduced EF. However, these patients remain symptomatic and are as likely to be hospitalized for HF as are patients with preserved EF. Improved EF is not enduring as it declines in 30% to 40% of patients with improved EF within 2 to 4 years.8Gulati G. Udelson J.E. Heart failure with improved ejection fraction: is it possible to escape one's past?.JACC Heart Fail. 2018; 6: 725-733Crossref PubMed Scopus (33) Google Scholar Thus, full appraisal of therapy in patients with HFrEF may require a longer follow-up than that of current RCTs even when the initial response appears favorable. Patients with HF who participate in a conclusive RCT should be followed up for 3 to 5 years after completion of the trial. The aim is to ensure that the intervention remains tolerated and beneficial when HF progresses. Follow-up after conclusive HF RCTs may include the following.(1)Management of therapy among patients at completion of the trial: how many patients continue to receive the trial's intervention in the active arm of the trial and chose to receive it in the control arm? The reason(s) that led patients to discontinue or decline the trial's intervention.(2)All patients who participated in the trial will be contacted 3 months after completion of the trial and every 6 months thereafter. Hospitalization and reason(s) for hospitalization will be noted as well as any therapeutic changes and adverse effects. Special emphasis will be given to discontinuation of the trial's intervention and possible adverse effects. Patients will be asked whether they feel better, worse, or the same than at completion of the trial or at the prior contact. When available, recent laboratory data including levels of serum urea nitrogen, creatinine, brain natriuretic peptides, and troponin will be recorded.(3)Past and current reports indicate that the cumulative mortality of HF is about 50% at 5 years.9Taylor C.J. Ryan R. Nichols L. Gale N. Hobbs F.R. Marshall T. Survival following a diagnosis of heart failure in primary care.Fam Pract. 2017; 34: 161-168PubMed Google Scholar A follow-up of 3 to 5 years after completion of conclusive therapeutic HF trials may assess whether the clinical improvement noted at trials' completion endures 5 to 7 years after randomization. The clinical and therapeutic information collected every 6 months will be recorded at the last follow-up contact. In brief, a focused follow-up for 3 to 5 years after completion of conclusive, randomized, controlled, heart failure trials may be a practical and inexpensive approach to determine the long-term clinical effects of a novel therapy. Further, while providing valuable therapeutic information, the 3- to 5-year follow-up will not delay use of an approved therapy. The authors report no competing interests. Author Contributions: Dr Le Jemtel—Conceptualization, original draft, review editing; Dr Samson—Conceptualization, original draft, review editing.