COUNTERPOINT: the Seductive Trap of Relying on Exaggerated Effects in Short-Term Heart Failure Trials to Predict Benefits and Risks in Patients With Long-Term Disease

Abstract

A new drug for heart failure is typically evaluated in a trial of 2000-4000 patients with stable chronic heart failure (designated as “chrHF”) who are randomized to placebo or active treatment, which is added to all established treatments for the disease. Patients are generally followed for a median of 10-28 months for cardiovascular death or hospitalization for heart failure and for long-term safety. In the accompanying paper,1Cotter G, Davison B. Should new drug development in heart failure focus on patients discharged from the hospital with an acute heart failure admission? Lessons from recent studies. J Card Fail (this issue)Google Scholar Cotter and Davison propose that new heart failure drugs be evaluated in short-term trials of patients recently hospitalized for acute heart failure (designated as “postAHF”). Based on assumptions that postAHF patients have a higher event rate and are more responsive to drug therapy, they propose that a trial of 500-1000 postAHF patients for 3-6 months could reliably discern a 35% reduction in the risk of a major heart failure event (P<0.05). This proposal raises serious questions and concerns. PostAHF patients are more likely than chrHF patients to experience a major heart failure event during the months following admission, in part because many are not receiving all recommended treatments for heart failure. In STRONG-HF, only 50% of postAHF patients were receiving an inhibitor of the renin-angiotensin system, and <40% were receiving a beta-blocker. Thus, a postAHF trial is likely to test the new drug in the absence of recommended background therapy with foundational drugs, a situation that cannot inform the true incremental value of any new agent. Furthermore, in a separate paper, Cotter and Davison2Cotter G Davison B Acute heart failure is a remitting-relapsing disorder and not a step towards advanced heart failure: Implications for decongestion therapy.Eur J Heart Fail. 2023 May; : 22https://doi.org/10.1002/ejhf.2916Crossref Google Scholar have argued that postAHF and chrHF patients represent distinctly different groups of individuals. They claim that most postAHF patients are minimally symptomatic and have a remitting-relapsing disorder that does not progress to class III/IV chronic heart failure. If this perspective were true, a trial in postAHF patients would not be relevant to the evaluation of any new drug that is intended to slow the progression of heart failure. Cotter and Davison1Cotter G, Davison B. Should new drug development in heart failure focus on patients discharged from the hospital with an acute heart failure admission? Lessons from recent studies. J Card Fail (this issue)Google Scholar exaggerate the difference in the event rates between postAHF and chrHF patients, suggesting that the risk of cardiovascular death or hospitalization for heart failure is 20% after two years in chrHF patients and 20% after 6 months in postAHF patients — a 4-fold difference in rates. However, the annual event rate was 21.0% in the chrHF patients in EMPEROR-Reduced3Packer M Anker SD Butler J Filippatos G Ferreira JP Pocock SJ Carson P Anand I Doehner W Haass M Komajda M Miller A Pehrson S Teerlink JR Brueckmann M Jamal W Zeller C Schnaidt S Zannad F Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced Trial.Circulation. 2021; 143: 326-336Crossref PubMed Scopus (151) Google Scholar and 37.8% in the postAHF patients in VICTORIA4Lam CSP Giczewska A Sliwa K Edelmann F Refsgaard J Bocchi E Ezekowitz JA Hernandez AF O'Connor CM Roessig L Patel MJ Pieske B Anstrom KJ Armstrong PW VICTORIA Study GroupClinical outcomes and response to vericiguat according to index heart failure event: insights from the VICTORIA trial.JAMA Cardiol. 2021; 6: 706-712Crossref PubMed Scopus (29) Google Scholar — a < 2-fold difference. Based on their incorrect projections, Cotter and Davison1Cotter G, Davison B. Should new drug development in heart failure focus on patients discharged from the hospital with an acute heart failure admission? Lessons from recent studies. J Card Fail (this issue)Google Scholar claim that chrHF trials require ≈10,000 patients treated for 3-4 years (i.e., ≈35,000 patient-years), while postAHF trials would require only 500-1000 patients treated for 3-6 months (≈300 patient-years). If true, the difference between the two approaches represents an extraordinary >100-fold difference in patient-years of exposure. Yet, they suggest that reducing the amount of patient data by 99% would still yield a reliable result. These depictions are not valid. EMPEROR-Reduced studied 3730 chrHF patients (median 16 months), P<0.001 (primary endpoint),3Packer M Anker SD Butler J Filippatos G Ferreira JP Pocock SJ Carson P Anand I Doehner W Haass M Komajda M Miller A Pehrson S Teerlink JR Brueckmann M Jamal W Zeller C Schnaidt S Zannad F Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced Trial.Circulation. 2021; 143: 326-336Crossref PubMed Scopus (151) Google Scholar whereas VICTORIA studied 5050 postAHF patients (median 11 months), P=0.02 (primary endpoint).4Lam CSP Giczewska A Sliwa K Edelmann F Refsgaard J Bocchi E Ezekowitz JA Hernandez AF O'Connor CM Roessig L Patel MJ Pieske B Anstrom KJ Armstrong PW VICTORIA Study GroupClinical outcomes and response to vericiguat according to index heart failure event: insights from the VICTORIA trial.JAMA Cardiol. 2021; 6: 706-712Crossref PubMed Scopus (29) Google Scholar The patient-years of exposure to achieve a compelling result in chrHF patients was similar to that needed to achieve a borderline result in the postAHF trial. Furthermore, the SOLOIST-WHF trial (in postAHF patients) planned for the enrollment of 4000 patients over 3 years.5Bhatt DL Szarek M Steg PG Cannon CP Leiter LA McGuire DK Lewis JB Riddle MC Voors AA Metra M Lund LH Komajda M Testani JM Wilcox CS Ponikowski P Lopes RD Verma S Lapuerta P Pitt B SOLOIST-WHF Trial InvestigatorsSotagliflozin in patients with diabetes and recent worsening heart failure.N Engl J Med. 2021; 384: 117-128Crossref PubMed Scopus (756) Google Scholar No registrational trial of postAHF patients that was powered for major heart failure events has ever planned for <4000 patients, and no such trial truncated follow-up at 6 months.5Bhatt DL Szarek M Steg PG Cannon CP Leiter LA McGuire DK Lewis JB Riddle MC Voors AA Metra M Lund LH Komajda M Testani JM Wilcox CS Ponikowski P Lopes RD Verma S Lapuerta P Pitt B SOLOIST-WHF Trial InvestigatorsSotagliflozin in patients with diabetes and recent worsening heart failure.N Engl J Med. 2021; 384: 117-128Crossref PubMed Scopus (756) Google Scholar,6Packer M Double vision: replicating a trial showing a survival benefit.JACC Heart Fail. 2017; 5: 232-235Crossref PubMed Scopus (8) Google Scholar Cotter and Davison1Cotter G, Davison B. Should new drug development in heart failure focus on patients discharged from the hospital with an acute heart failure admission? Lessons from recent studies. J Card Fail (this issue)Google Scholar claim that postAHF trials will be smaller and shorter because drugs reduce the risk of major heart failure events by 35% in postAHF patients, but by only 20% in chrHF patients. However, their belief in a larger treatment effect in postAHF trials is based — not on the postAHF setting — but on the very small number of events observed during early phase of a trial, yielding unstable estimates with wide confidence intervals. (Notably, they do not provide confidence intervals for most of the effect sizes.) The small numbers of events in a short-term trial or early in a long-term trial yield exaggerated nonreplicable results (Table 1), whether the setting is chrHF or postAHF.6Packer M Double vision: replicating a trial showing a survival benefit.JACC Heart Fail. 2017; 5: 232-235Crossref PubMed Scopus (8) Google Scholar The early effect of empagliflozin in the chrHF patients in EMPEROR-Reduced at 12 days was exaggerated (hazard ratio [HR] 0.42 [0.19-0.92]) due to the small number of events (< 30);3Packer M Anker SD Butler J Filippatos G Ferreira JP Pocock SJ Carson P Anand I Doehner W Haass M Komajda M Miller A Pehrson S Teerlink JR Brueckmann M Jamal W Zeller C Schnaidt S Zannad F Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced Trial.Circulation. 2021; 143: 326-336Crossref PubMed Scopus (151) Google Scholar the early estimate was far larger than the more precise estimate in the same trial (HR 0.75 [0.65-0.86]), based on >800 events. In fact, the early effect in chrHF patients in EMPEROR-Reduced exceeded the early effect of empagliflozin in the postAHF EMPULSE trial at 90 days (HR 0.69 [0.45-1.08]), based on only ≈80 events.3Packer M Anker SD Butler J Filippatos G Ferreira JP Pocock SJ Carson P Anand I Doehner W Haass M Komajda M Miller A Pehrson S Teerlink JR Brueckmann M Jamal W Zeller C Schnaidt S Zannad F Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced Trial.Circulation. 2021; 143: 326-336Crossref PubMed Scopus (151) Google Scholar,7Voors AA Angermann CE Teerlink JR Collins SP Kosiborod M Biegus J Ferreira JP Nassif ME Psotka MA Tromp J Borleffs CJW Ma C Comin-Colet J Fu M Janssens SP Kiss RG Mentz RJ Sakata Y Schirmer H Schou M Schulze PC Spinarova L Volterrani M Wranicz JK Zeymer U Zieroth S Brueckmann M Blatchford JP Salsali A Ponikowski P The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial.Nat Med. 2022; 28: 568-574Crossref PubMed Scopus (164) Google ScholarTable 1Comparison of Treatment Effect Sizes in Short-Term Analyses Based on Few Events vs Long-Term Analyses Based on Substantial Numbers of EventsEvents and treatment effects during observation periods ≤ first 3-6 monthsEvents and treatment effectsduring full-length trialsNumber of eventsHazard ratio (95% CI)Number of eventsHazard ratio (95% CI)Carvedilol vs placebo13Packer M Bristow MR Cohn JN Colucci WS Fowler MB Gilbert EM Shusterman NH The effect of carvedilol on morbidity and mortality in patients with chronic heart failure, US Carvedilol Heart Failure Study Group.N Engl J Med. 1996; 334: 1349-1355Crossref PubMed Scopus (0) Google Scholar,14Packer M Coats AJ Fowler MB Katus HA Krum H Mohacsi P Rouleau JL Tendera M Castaigne A Roecker EB Schultz MK DeMets DL Carvedilol Prospective Randomized Cumulative Survival Study GroupEffect of carvedilol on survival in severe chronic heart failure.N Engl J Med. 2001; 344: 1651-1658Crossref PubMed Scopus (2793) Google Scholar< 60 deaths during 6 months0.35 (0.20-0.61) P<0.001>300 deaths (median 10 months)0.65 (0.52-0.81) P<0.001Vesnarinone vs placebo15Feldman AM Bristow MR Parmley WW Carson PE Pepine CJ Gilbert EM Strobeck JE Hendrix GH Powers ER Bain RP et al.Effects of vesnarinone on morbidity and mortality in patients with heart failure, Vesnarinone Study Group.N Engl J Med. 1993; 329: 149-155Crossref PubMed Scopus (0) Google Scholar,16Cohn JN Goldstein SO Greenberg BH Lorell BH Bourge RC Jaski BE Gottlieb SO McGrew 3rd, F DeMets DL White BG A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators.N Engl J Med. 1998; 339: 1810-1816Crossref PubMed Scopus (580) Google Scholar< 50 deaths during 6 months0.38 (0.20-0.62) P=0.002> 800 deaths (median 10 months)1.22 (1.05-1.42) P=0.02Sacubitril/valsartan vs enalapril11Packer M McMurray JJ Desai AS Gong J Lefkowitz MP Rizkala AR Rouleau JL Shi VC Solomon SD Swedberg K Zile M Andersen K Arango JL Arnold JM Bělohlávek J Böhm M Boytsov S Burgess LJ Cabrera W Calvo C Chen CH Dukat A Duarte YC Erglis A Fu M Gomez E Gonzàlez-Medina A Hagège AA Huang J Katova T Kiatchoosakun S Kim KS Kozan Ö Llamas EB Martinez F Merkely B Mendoza I Mosterd A Negrusz-Kawecka M Peuhkurinen K Ramires FJ Refsgaard J Rosenthal A Senni M Sibulo Jr, AS Silva-Cardoso J Squire IB Starling RC Teerlink JR Vanhaecke J Vinereanu D Wong RC PARADIGM-HF Investigators and Coordinators. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.Circulation. 2015; 131: 54-61Crossref PubMed Scopus (503) Google Scholar< 60 heart failure events during first 30 days0.60 (0.38-0.94) P=0.027> 2000 heart failure events (median 27 months)0.80 (0.73-0.87) P<0.001Empagliflozin vs placebo3Packer M Anker SD Butler J Filippatos G Ferreira JP Pocock SJ Carson P Anand I Doehner W Haass M Komajda M Miller A Pehrson S Teerlink JR Brueckmann M Jamal W Zeller C Schnaidt S Zannad F Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced Trial.Circulation. 2021; 143: 326-336Crossref PubMed Scopus (151) Google Scholar< 30 heart failure events during first 12 days0.42 (0.19-0.92) P=0.029> 800 heart failure events (median 16 months)0.75 (0.65-0.86) P<0.001Dapagliflozin vs placebo (EF≤40%)10Berg DD Jhund PS Docherty KF Murphy SA Verma S Inzucchi SE Køber L Kosiborod MN Langkilde AM Martinez FA Bengtsson O Ponikowski P Sjöstrand M Solomon SD McMurray JJV Sabatine MS Time to clinical benefit of dapagliflozin and significance of prior heart failure hospitalization in patients with heart failure with reduced ejection fraction.JAMA Cardiol. 2021; 6: 499-507Crossref PubMed Scopus (78) Google Scholar< 50 heart failure events during first 28 days0.51 (0.28-0.94) P=0.03≈ 900 heart failure events (median 18 months)0.74 (0.65-0.85) P<0.001Dapagliflozin vs placebo (EF>40%)8Vaduganathan M Claggett BL Jhund P de Boer RA Hernandez AF Inzucchi SE Kosiborod MN Lam CSP Martinez F Shah SJ Desai AS Hegde SM Lindholm D Petersson M Langkilde AM McMurray JJV Solomon SD Time to clinical benefit of dapagliflozin in patients with heart failure with mildly reduced or preserved ejection fraction: a prespecified secondary analysis of the DELIVER randomized clinical trial.JAMA Cardiol. 2022; 7: 1259-1263Crossref PubMed Scopus (11) Google Scholar< 50 heart failure events during first 13 days0.45 (0.20-0.99) P=0.046> 1100 heart failure events (median 2.3 years)0.82 (0.73-0.92) P<0.001Sotagliflozin vs placebo5Bhatt DL Szarek M Steg PG Cannon CP Leiter LA McGuire DK Lewis JB Riddle MC Voors AA Metra M Lund LH Komajda M Testani JM Wilcox CS Ponikowski P Lopes RD Verma S Lapuerta P Pitt B SOLOIST-WHF Trial InvestigatorsSotagliflozin in patients with diabetes and recent worsening heart failure.N Engl J Med. 2021; 384: 117-128Crossref PubMed Scopus (756) Google Scholar,9Pitt B Bhatt DL Szarek M Sun F Davies MJ Steg PG The effect of the dual SGLT1 and 2 inhibitor sotagliflozin on cardiovascular mortality and hospital readmission rates for heart failure at 30 and 90 days post discharge in patients with type 2 diabetes hospitalized for worsening heart failure in the SOLOIST-WHF trial.Circulation. 2022 Oct 30; 146 (Abstract): A10209Google Scholar< 50 heart failure events during first 30 days0.48 (0.27-0.88) P=0.015> 300 heart failure events (median 9 months)0.71 (0.51-0.99) P<0.05Flosequinan vs placebo17Packer M Narahara KA Elkayam U Sullivan JM Pearle DL Massie BM Creager MA Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure, Principal Investigators of the REFLECT Study.J Am Coll Cardiol. 1993; 22: 65-72Crossref PubMed Scopus (110) Google Scholar,18Packer M Pitt B Rouleau JL Swedberg K DeMets DL Fisher L Long-term effects of flosequinan on the morbidity and mortality of patients with severe chronic heart failure: primary results of the PROFILE trial after 24 years.JACC Heart Fail. 2017; 5: 399-407Crossref PubMed Scopus (28) Google Scholar< 10 deaths during first 3 months≈0.30 P> 0.10> 400 deaths (median 10 months)1.39 (1.15-1.67) P<0.001Trials that base estimates on <10-60 events routinely yield exaggerated estimates of a treatment effect, reporting a 40%-70% reduction in risk with exceptionally wide confidence intervals, often with an upper bound close to or > 1.0. However, when the same drugs are evaluated in the same or follow-up trials that based estimates on a meaningful number of events (i.e., 300-2000 events), the estimates of a treatment effect are far more precise, and the magnitude of benefit decreases to a 15-30% reduction in risk or the drug is shown to have a significant adverse effect, i.e., a 20-40% increase in risk of death (e.g., vesnarinone and flosequinan). Heart failure events typically refers to a composite of cardiovascular death or hospitalization for heart failure. The sotagliflozin trial enrolled postAHF patients. Abbreviations: EF=ejection fraction. Open table in a new tab Trials that base estimates on <10-60 events routinely yield exaggerated estimates of a treatment effect, reporting a 40%-70% reduction in risk with exceptionally wide confidence intervals, often with an upper bound close to or > 1.0. However, when the same drugs are evaluated in the same or follow-up trials that based estimates on a meaningful number of events (i.e., 300-2000 events), the estimates of a treatment effect are far more precise, and the magnitude of benefit decreases to a 15-30% reduction in risk or the drug is shown to have a significant adverse effect, i.e., a 20-40% increase in risk of death (e.g., vesnarinone and flosequinan). Heart failure events typically refers to a composite of cardiovascular death or hospitalization for heart failure. The sotagliflozin trial enrolled postAHF patients. Abbreviations: EF=ejection fraction. Similarly, because of the small number of events, the early effect of dapagliflozin in DELIVER (HR 0.45 [0.20-0.99] was exaggerated compared with the more precise effect during long-term treatment (HR 0.82 [0.73-0.92]).8Vaduganathan M Claggett BL Jhund P de Boer RA Hernandez AF Inzucchi SE Kosiborod MN Lam CSP Martinez F Shah SJ Desai AS Hegde SM Lindholm D Petersson M Langkilde AM McMurray JJV Solomon SD Time to clinical benefit of dapagliflozin in patients with heart failure with mildly reduced or preserved ejection fraction: a prespecified secondary analysis of the DELIVER randomized clinical trial.JAMA Cardiol. 2022; 7: 1259-1263Crossref PubMed Scopus (11) Google Scholar Similar exaggerations have been reported in SOLOIST-WHF and in DAPA-HF (Table 1).9Pitt B Bhatt DL Szarek M Sun F Davies MJ Steg PG The effect of the dual SGLT1 and 2 inhibitor sotagliflozin on cardiovascular mortality and hospital readmission rates for heart failure at 30 and 90 days post discharge in patients with type 2 diabetes hospitalized for worsening heart failure in the SOLOIST-WHF trial.Circulation. 2022 Oct 30; 146 (Abstract): A10209Google Scholar,10Berg DD Jhund PS Docherty KF Murphy SA Verma S Inzucchi SE Køber L Kosiborod MN Langkilde AM Martinez FA Bengtsson O Ponikowski P Sjöstrand M Solomon SD McMurray JJV Sabatine MS Time to clinical benefit of dapagliflozin and significance of prior heart failure hospitalization in patients with heart failure with reduced ejection fraction.JAMA Cardiol. 2021; 6: 499-507Crossref PubMed Scopus (78) Google Scholar The early effect of sacubitril/valsartan in the chrHF patients in PARADIGM-HF at 30 days was also exaggerated (HR 0.60 [0.38-0.94]) (based on <60 events) compared with the precise effect in the same trial (HR 0.80 [0.73-0.87]), based on >2000 events.11Packer M McMurray JJ Desai AS Gong J Lefkowitz MP Rizkala AR Rouleau JL Shi VC Solomon SD Swedberg K Zile M Andersen K Arango JL Arnold JM Bělohlávek J Böhm M Boytsov S Burgess LJ Cabrera W Calvo C Chen CH Dukat A Duarte YC Erglis A Fu M Gomez E Gonzàlez-Medina A Hagège AA Huang J Katova T Kiatchoosakun S Kim KS Kozan Ö Llamas EB Martinez F Merkely B Mendoza I Mosterd A Negrusz-Kawecka M Peuhkurinen K Ramires FJ Refsgaard J Rosenthal A Senni M Sibulo Jr, AS Silva-Cardoso J Squire IB Starling RC Teerlink JR Vanhaecke J Vinereanu D Wong RC PARADIGM-HF Investigators and Coordinators. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.Circulation. 2015; 131: 54-61Crossref PubMed Scopus (503) Google Scholar Therefore, the large apparent effect of sacubitril/valsartan at 8 weeks in PIONEER (HR 0.58 [0.39-0.87]) was not related to its focus on postAHF patients, but to an estimate based on few events.12Morrow DA Velazquez EJ DeVore AD Desai AS Duffy CI Ambrosy AP Gurmu Y McCague K Rocha R Braunwald E Clinical outcomes in patients with acute decompensated heart failure randomly assigned to sacubitril/valsartan or enalapril in the PIONEER-HF trial.Circulation. 2019; 139: 2285-2288Crossref PubMed Scopus (105) Google Scholar The trials in Table 13Packer M Anker SD Butler J Filippatos G Ferreira JP Pocock SJ Carson P Anand I Doehner W Haass M Komajda M Miller A Pehrson S Teerlink JR Brueckmann M Jamal W Zeller C Schnaidt S Zannad F Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced Trial.Circulation. 2021; 143: 326-336Crossref PubMed Scopus (151) Google Scholar,5Bhatt DL Szarek M Steg PG Cannon CP Leiter LA McGuire DK Lewis JB Riddle MC Voors AA Metra M Lund LH Komajda M Testani JM Wilcox CS Ponikowski P Lopes RD Verma S Lapuerta P Pitt B SOLOIST-WHF Trial InvestigatorsSotagliflozin in patients with diabetes and recent worsening heart failure.N Engl J Med. 2021; 384: 117-128Crossref PubMed Scopus (756) Google Scholar,9Pitt B Bhatt DL Szarek M Sun F Davies MJ Steg PG The effect of the dual SGLT1 and 2 inhibitor sotagliflozin on cardiovascular mortality and hospital readmission rates for heart failure at 30 and 90 days post discharge in patients with type 2 diabetes hospitalized for worsening heart failure in the SOLOIST-WHF trial.Circulation. 2022 Oct 30; 146 (Abstract): A10209Google Scholar, 10Berg DD Jhund PS Docherty KF Murphy SA Verma S Inzucchi SE Køber L Kosiborod MN Langkilde AM Martinez FA Bengtsson O Ponikowski P Sjöstrand M Solomon SD McMurray JJV Sabatine MS Time to clinical benefit of dapagliflozin and significance of prior heart failure hospitalization in patients with heart failure with reduced ejection fraction.JAMA Cardiol. 2021; 6: 499-507Crossref PubMed Scopus (78) Google Scholar, 11Packer M McMurray JJ Desai AS Gong J Lefkowitz MP Rizkala AR Rouleau JL Shi VC Solomon SD Swedberg K Zile M Andersen K Arango JL Arnold JM Bělohlávek J Böhm M Boytsov S Burgess LJ Cabrera W Calvo C Chen CH Dukat A Duarte YC Erglis A Fu M Gomez E Gonzàlez-Medina A Hagège AA Huang J Katova T Kiatchoosakun S Kim KS Kozan Ö Llamas EB Martinez F Merkely B Mendoza I Mosterd A Negrusz-Kawecka M Peuhkurinen K Ramires FJ Refsgaard J Rosenthal A Senni M Sibulo Jr, AS Silva-Cardoso J Squire IB Starling RC Teerlink JR Vanhaecke J Vinereanu D Wong RC PARADIGM-HF Investigators and Coordinators. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure.Circulation. 2015; 131: 54-61Crossref PubMed Scopus (503) Google Scholar,13Packer M Bristow MR Cohn JN Colucci WS Fowler MB Gilbert EM Shusterman NH The effect of carvedilol on morbidity and mortality in patients with chronic heart failure, US Carvedilol Heart Failure Study Group.N Engl J Med. 1996; 334: 1349-1355Crossref PubMed Scopus (0) Google Scholar, 14Packer M Coats AJ Fowler MB Katus HA Krum H Mohacsi P Rouleau JL Tendera M Castaigne A Roecker EB Schultz MK DeMets DL Carvedilol Prospective Randomized Cumulative Survival Study GroupEffect of carvedilol on survival in severe chronic heart failure.N Engl J Med. 2001; 344: 1651-1658Crossref PubMed Scopus (2793) Google Scholar, 15Feldman AM Bristow MR Parmley WW Carson PE Pepine CJ Gilbert EM Strobeck JE Hendrix GH Powers ER Bain RP et al.Effects of vesnarinone on morbidity and mortality in patients with heart failure, Vesnarinone Study Group.N Engl J Med. 1993; 329: 149-155Crossref PubMed Scopus (0) Google Scholar, 16Cohn JN Goldstein SO Greenberg BH Lorell BH Bourge RC Jaski BE Gottlieb SO McGrew 3rd, F DeMets DL White BG A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators.N Engl J Med. 1998; 339: 1810-1816Crossref PubMed Scopus (580) Google Scholar, 17Packer M Narahara KA Elkayam U Sullivan JM Pearle DL Massie BM Creager MA Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure, Principal Investigators of the REFLECT Study.J Am Coll Cardiol. 1993; 22: 65-72Crossref PubMed Scopus (110) Google Scholar, 18Packer M Pitt B Rouleau JL Swedberg K DeMets DL Fisher L Long-term effects of flosequinan on the morbidity and mortality of patients with severe chronic heart failure: primary results of the PROFILE trial after 24 years.JACC Heart Fail. 2017; 5: 399-407Crossref PubMed Scopus (28) Google Scholar demonstrate that small numbers of events over short periods of time yield exaggerated nonreproducible estimates of a drug effect and that a focus on postAHF patients provides no advantage. Furthermore, as Cotter and Davison concede, recency of hospitalization has not enhanced the magnitude of benefit with sacubitril/valsartan, dapagliflozin, omecamtiv or vericiguat .1Cotter G, Davison B. Should new drug development in heart failure focus on patients discharged from the hospital with an acute heart failure admission? Lessons from recent studies. J Card Fail (this issue)Google Scholar,4Lam CSP Giczewska A Sliwa K Edelmann F Refsgaard J Bocchi E Ezekowitz JA Hernandez AF O'Connor CM Roessig L Patel MJ Pieske B Anstrom KJ Armstrong PW VICTORIA Study GroupClinical outcomes and response to vericiguat according to index heart failure event: insights from the VICTORIA trial.JAMA Cardiol. 2021; 6: 706-712Crossref PubMed Scopus (29) Google Scholar,10Berg DD Jhund PS Docherty KF Murphy SA Verma S Inzucchi SE Køber L Kosiborod MN Langkilde AM Martinez FA Bengtsson O Ponikowski P Sjöstrand M Solomon SD McMurray JJV Sabatine MS Time to clinical benefit of dapagliflozin and significance of prior heart failure hospitalization in patients with heart failure with reduced ejection fraction.JAMA Cardiol. 2021; 6: 499-507Crossref PubMed Scopus (78) Google Scholar,19Cunningham JW Vaduganathan M Claggett BL Kulac IJ Desai AS Jhund PS de Boer RA DeMets D Hernandez AF Inzucchi SE Kosiborod MN Lam CSP Martinez F Shah SJ McGrath MM O'Meara E Wilderäng U Lindholm D Petersson M Langkilde AM McMurray JJV Solomon SD Dapagliflozin in patients recently hospitalized with heart failure and mildly reduced or preserved ejection fraction.J Am Coll Cardiol. 2022; 80: 1302-1310Crossref PubMed Scopus (21) Google Scholar,20Solomon SD Claggett B Packer M Desai A Zile MR Swedberg K Rouleau J Shi V Lefkowitz M McMurray JJV Efficacy of sacubitril/valsartan relative to a prior decompensation: the PARADIGM-HF trial.JACC Heart Fail. 2016; 4: 816-822Crossref PubMed Scopus (77) Google Scholar Any proposal to base decisions on 3-6 months of data ignores the fact that heart failure drugs may exert favorable short-term, but deleterious long-term, effects. In 1993, flosequinan was approved for use in the US based on symptomatic benefits in trials of 12-16 weeks in duration.17Packer M Narahara KA Elkayam U Sullivan JM Pearle DL Massie BM Creager MA Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure, Principal Investigators of the REFLECT Study.J Am Coll Cardiol. 1993; 22: 65-72Crossref PubMed Scopus (110) Google Scholar Yet, in the PROFILE trial,18Packer M Pitt B Rouleau JL Swedberg K DeMets DL Fisher L Long-term effects of flosequinan on the morbidity and mortality of patients with severe chronic heart failure: primary results of the PROFILE trial after 24 years.JACC Heart Fail. 2017; 5: 399-407Crossref PubMed Scopus (28) Google Scholar flosequinan reduced major heart failure events during the first 3-4 months, but after 6 months, patients receiving flosequinan progressively deteriorated and had a 39% higher risk of death. The drug was withdrawn after only 6 weeks on the market. According to the new proposal, the possibility of a long-term reversal of an early drug effect would never be seriously explored. Because patients with heart failure have a life-long progressive disease, they deserve drugs that have been demonstrated to be safe and highly effective for long periods of time. Cotter and Davison1Cotter G, Davison B. Should new drug development in heart failure focus on patients discharged from the hospital with an acute heart failure admission? Lessons from recent studies. J Card Fail (this issue)Google Scholar propose to reduce the amount of efficacy and safety data by >90%. Yet, their Figure 1 still projects a need for a 3000-patient trial to achieve 90% power in the postAHF setting. It takes 3-4 years to recruit 3000 patients, but the new proposal would make decisions based on the first 500-1000 patients treated for 3 months, thus ensuring unreliable estimates and minimizing any ability to reliably discern long-term effects. The new proposal does not shorten the time needed for drug development, but it greatly limits the evidence needed to make informed judgments about the efficacy and safety of drugs for chronic heart failure. During the past three years, MP reports personal fees for consulting from Abbvie, Actavis, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, Salamandra POINT: Should new drug development in heart failure focus on patients discharged from an acute heart failure admission? Lessons from recent studies.Journal of Cardiac FailurePreviewOver more than 30 years, most drug development in heart failure (HF) has been directed towards reducing HF readmission or death in patients with chronic heart failure (1-3). These studies included thousands of patients and took many years to accomplish but permitted approval of new interventions that substantially improved HF patients’ outcomes. However, the long duration of HF mega studies leads to substantial delays in delivering these new interventions, and hence delays their implementation and uptake. Full-Text PDF Open Access