POINT: Should New Drug Development in Heart Failure Focus on Patients Discharged From an Acute Heart Failure Admission? Lessons From Recent Studies

Abstract

Over 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 (1McMurray JJ Packer M Desai AS Gong J Lefkowitz MP Rizkala AR Rouleau JL Shi VC Solomon SD Swedberg K Zile MR PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure.N Engl J Med. 2014; 371 (Sep 11): 993-1004Crossref PubMed Scopus (0) Google Scholar, 2Packer M Anker SD Butler J Filippatos G Pocock SJ Carson P Januzzi J Verma S Tsutsui H Brueckmann M Jamal W Kimura K Schnee J Zeller C Cotton D Bocchi E Böhm M Choi DJ Chopra V Chuquiure E Giannetti N Janssens S Zhang J JR Gonzalez Juanatey Kaul S HP Brunner-La Rocca Merkely B Nicholls SJ Perrone S Pina I Ponikowski P Sattar N Senni M Seronde MF Spinar J Squire I Taddei S Wanner C F; Zannad EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.N Engl J Med. 2020; 383 (Oct 8): 1413-1424Crossref PubMed Scopus (2009) Google Scholar, 3Anker SD Butler J Filippatos G Ferreira JP Bocchi E Böhm M Brunner-La Rocca HP Choi DJ Chopra V Chuquiure-Valenzuela E Giannetti N Gomez-Mesa JE Janssens S Januzzi JL Gonzalez-Juanatey JR Merkely B Nicholls SJ Perrone SV Piña IL Ponikowski P Senni M Sim D Spinar J Squire I Taddei S Tsutsui H Verma S Vinereanu D Zhang J Carson P Lam CSP Marx N Zeller C Sattar N Jamal W Schnaidt S Schnee JM Brueckmann M Pocock SJ Zannad F Packer M EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction.N Engl J Med. 2021; 385 (Oct 14): 1451-1461Crossref PubMed Scopus (0) Google Scholar). 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. This delay also has substantial financial implications for the pharmaceutical companies developing new interventions for HF. First, chronic HF studies typically enroll thousands of patients each followed for years and cost tens of millions of dollars to perform. Second, the delay in the time to market for a new drug reduces the time the drug can be marketed under patent protection. Each year of delay may translate into billions of dollars of financial loss. Third, and possibly most importantly, many effective drugs may never have been developed because the operational and financial burden of these mega studies can be prohibitive, particularly for smaller companies. Smaller, more effective studies for HF drug development are therefore needed. In the last 2 years, 5 studies exploring new and old drugs that were started and rapidly up titrated after an acute HF (AHF) admission were presented and published. First, the SOLOIST-WHF study (4Bhatt 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 Investigators. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure.N Engl J Med. 2021; 384 (Jan 14): 117-128Crossref PubMed Scopus (0) Google Scholar) examined a sodium-glucose cotransporter (SGLT) inhibitor prescribed within 3 days of discharge from an AHF admission. With only 1,200 patients followed for a median of 9 months, the study demonstrated a reduction in the 6-month risk of first HF readmission or cardiovascular (CV) death from 25.3% in the placebo arm to 18.6% in the Sotaglifozin arm. A recent analysis presented at the 2022 American Heart Association Scientific Sessions (5Pitt B Bhatt DL Szarek M 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 Ezekowitz JA Sun F Davies MJ s Verma Kosiborod MN Steg G Presented as a Late breaking clinical study at AHA.2022Google Scholar) showed very large early effects at 30 and 90 days, with hazard ratios (HRs) of 0.49 and 0.54, respectively (!). This finding was supported by shorter-term outcomes in the EMPULSE study comparing empagliflozin with placebo (6Voors 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 (Mar): 568-574Crossref PubMed Scopus (164) Google Scholar). With only 530 AHF patients enrolled, a secondary analysis has shown that empagliflozin reduced by 35% the risk of HF readmission or death through 100 days from about 20% in control with a HR of 0.65. Of note, both the SOLOIST-WHF and EMPULSE studies enrolled patients regardless of ejection fraction (EF) and found no interaction between EF and treatment effect. Third, the PIONEER-HF study randomized a mere 881 patients with reduced EF to sacubitril/valsartan or enalapril and followed them for 60 days after an AHF admission (7Morrow 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 (May 7): 2285-2288Crossref PubMed Scopus (105) Google Scholar). In a secondary analysis the use of sacubitril/valsartan was associated with a relative 39% reduction in 8-week risk of CV death or HF readmission compared to enalapril (15.2% enalapril vs. 9.2% sacubitril/valsartan). The much smaller PARAGLIDE study (8Mentz RJ Ward JH Hernandez AF Lepage S Morrow DA Sarwat S Sharma K Starling RC Velazquez EJ Williamson KM Desai AS Zieroth S Solomon SD Braunwald E Investigators PARAGLIDE-HF Angiotensin-Neprilysin Inhibition in Patients With Mildly Reduced or Preserved Ejection Fraction and Worsening Heart Failure.J Am Coll Cardiol. 2023; (May 11:S0735-1097(23)05429-3. Epub ahead of print. PMID: 37212758)Crossref PubMed Google Scholar) which compared sacubitril/valsartan with valsartan in only 466 patients with AHF and higher EF followed for 5.9 months (IQR: 2.8-13.9 months), failed to demonstrate a statistically significant effect on an endpoint of CV death or HF events. Finally, in the STRONG-HF study (9Mebazaa A Davison B Chioncel O Cohen-Solal A Diaz R Filippatos G Metra M Ponikowski P Sliwa K Voors AA Edwards C Novosadova M Takagi K Damasceno A Saidu H Gayat E Pang PS Celutkiene J Cotter G. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial.Lancet. 2022; (Nov 4:S0140-6736(22)02076-1)Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar), AHF patients who were not treated with full doses of GDMT were randomized prior to discharge to either usual care (UC) or high intensity care (HIC) in which GDMT (mostly ACEi or ARBs, BBs and MRAs) were up-titrated to 100% of recommended doses within 2 weeks of discharge. The study was stopped after only 1,078 patients had been randomized following a recommendation of the data safety and monitoring board. The 180-day risk of HF readmission or all-cause death was 15.2% in the HIC versus 23.3% in UC, with a risk ratio of 0.66. All these studies taken together suggest that post AHF studies differ from chronic HF studies in two important aspects. First, the event rate. In PARADIGM-HF (1McMurray JJ Packer M Desai AS Gong J Lefkowitz MP Rizkala AR Rouleau JL Shi VC Solomon SD Swedberg K Zile MR PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure.N Engl J Med. 2014; 371 (Sep 11): 993-1004Crossref PubMed Scopus (0) Google Scholar) it took about 2 years to reach an event rate of 26% in the enalapril arm. In the PIONEER-HF study (7Morrow 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 (May 7): 2285-2288Crossref PubMed Scopus (105) Google Scholar) about 15% of patients had a similar endpoint in just 8 weeks. The same trends were observed in the empagliflozin program. The event rate in the EMPEROR-Reduced study was 24.7% in the control arm at 2 years (2Packer M Anker SD Butler J Filippatos G Pocock SJ Carson P Januzzi J Verma S Tsutsui H Brueckmann M Jamal W Kimura K Schnee J Zeller C Cotton D Bocchi E Böhm M Choi DJ Chopra V Chuquiure E Giannetti N Janssens S Zhang J JR Gonzalez Juanatey Kaul S HP Brunner-La Rocca Merkely B Nicholls SJ Perrone S Pina I Ponikowski P Sattar N Senni M Seronde MF Spinar J Squire I Taddei S Wanner C F; Zannad EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.N Engl J Med. 2020; 383 (Oct 8): 1413-1424Crossref PubMed Scopus (2009) Google Scholar). In EMPEROR-Preserved the control arm event rate was 17.1% at 3 years (3Anker SD Butler J Filippatos G Ferreira JP Bocchi E Böhm M Brunner-La Rocca HP Choi DJ Chopra V Chuquiure-Valenzuela E Giannetti N Gomez-Mesa JE Janssens S Januzzi JL Gonzalez-Juanatey JR Merkely B Nicholls SJ Perrone SV Piña IL Ponikowski P Senni M Sim D Spinar J Squire I Taddei S Tsutsui H Verma S Vinereanu D Zhang J Carson P Lam CSP Marx N Zeller C Sattar N Jamal W Schnaidt S Schnee JM Brueckmann M Pocock SJ Zannad F Packer M EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction.N Engl J Med. 2021; 385 (Oct 14): 1451-1461Crossref PubMed Scopus (0) Google Scholar). In the EMPULSE study the control event rate was about 20% at 3 months (6Voors 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 (Mar): 568-574Crossref PubMed Scopus (164) Google Scholar). These comparisons suggest that in studies of patients treated by current guidelines, event rates in the control arm of about 20% can be achieved by conducting post AHF studies with fixed follow up of 6 months, rates that are similar to those that will be seen in chronic HF studies after 2-3 years if patients are treated according toc current guidelines. Second, the effect size. In the above-mentioned chronic HF studies the treatment effects on endpoints of death or HF readmission were in the range of 0.75 – 0.88 with an average of 0.8. In the post AHF studies for the same interventions the HRs ranged from 0.49 – 0.78 with an average of 0.65. Some studies allow direct comparison of effects in patients recently admitted and not. In the VICTORIA trial (10Lam 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 Study Group VICTORIA Clinical Outcomes and Response to Vericiguat According to Index Heart Failure Event: Insights From the VICTORIA Trial.JAMA Cardiol. 2021; 6 (Jun 1): 706-712Crossref PubMed Scopus (29) Google Scholar) the effect of vericiguat versus placebo in 5,050 chronic HF patients on CV death or HF hospitalization showed a non-significant gradient from lowest in patients randomized during a HF admission to highest in those never hospitalized for HF (interaction p=0.09). On the other hand, a post-hoc analysis of the PARAGON-HF study (11Vaduganathan M Claggett BL Desai AS Anker SD Perrone SV Janssens S et al.Prior Heart Failure Hospitalization, Clinical Outcomes, and Response to Sacubitril/Valsartan Compared With Valsartan in HFpEF.J Am Coll Cardiol. 2020; 75: 245-254Crossref PubMed Scopus (68) Google Scholar), with a non-significant effect overall, showed a gradient of the effect of sacubitril/valsartan. In 4,796 patients with HF and higher EF, the lowest absolute effect on CV death or total HF hospitalizations was observed in patients never hospitalized for HF and highest in patients enrolled within 30 days of a HF hospitalization (interaction p=0.05). A pooled analysis of the PARAGLIDE-HF and PARAGON-HF studies (12Vaduganathan M Mentz RJ Claggett BL Miao ZM Kulac IJ Ward JH Hernandez AF Morrow DA Starling RC Velazquez EJ Williamson KM Desai AS Zieroth S Lefkowitz M McMurray JJV Braunwald E Solomon SD. Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: a pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF.Eur Heart J. 2023; (May 21: Epub ahead of print. PMID: 37210743)Crossref Google Scholar) demonstrated with only 1,088 patients with a recent AHF admission a benefit of sacubitril/valsartan over valsartan on CV death or HF events (rate ratio [RR] 0.78; 95% confidence interval [CI] 0.61-0.99; P=0.042) but when adding the whole range of HF patients enrolled in PARAGON-HF – both recently admitted and not recently admitted – it took 5,262 patients to reach statistical significance due to a lower event rate and a lower RR (0.86; 95% CI: 0.75-0.98; P=0.027). Another recent example of difficulties related to enrolling patients further from an AHF admission has been observed in the GALACTIC-HF study examining the effects of Omecamtiv mecarbil in patients with HF (13Teerlink JR Diaz R Felker GM McMurray JJV Metra M Solomon SD Adams KF Anand I Arias-Mendoza A Biering-Sørensen T Böhm M Bonderman D Cleland JGF Corbalan R Crespo-Leiro MG Dahlström U Echeverria LE Fang JC Filippatos G Fonseca C Goncalvesova E Goudev AR Howlett JG Lanfear DE Li J Lund M Macdonald P Mareev V Momomura SI O'Meara E Parkhomenko A Ponikowski P Ramires FJA Serpytis P Sliwa K Spinar J Suter TM Tomcsanyi J Vandekerckhove H Vinereanu D Voors AA Yilmaz MB Zannad F Sharpsten L Legg JC Varin C Honarpour N Abbasi SA Malik FI Kurtz CE Investigators GALACTIC-HF Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.N Engl J Med. 2021; 384 (Jan 14): 105-116Crossref PubMed Scopus (282) Google Scholar). Although the study, that enrolled 8,256 patients, met its primary endpoint of a first HF event (hospitalization or urgent visit for heart failure) or CV death after a median of 21.8 months follow-up (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). Omecamtiv is as of now not approved by the FDA. A subsequent analysis found that the treatment effect was larger in patients enrolled during an AHF admission (14Docherty KF, Claggett BL, Diaz R, Divanji P, Felker GM, Heitner SB, Kupfer S, Malik FI, Metra M, Solomon SD, McMurray JJV, Teerlink JR. The Effect Of Omecamtiv Mecarbil In Hospitalized Patients As Compared With Outpatients. Presented ACC 2022.Google Scholar) and even higher in those in patients with NTproBNP > median, reaching nominal significance with slightly more than 1,000 patients (HR = 0.75; 95% CI 0.61–0.92; estimated p=0.006). Given that a trend towards reduced mortality in Omecamtiv-treated inpatients was also observed in the AHF cohort, one can only wonder if Omecamtiv would have been approved and available to patients now if the study would have been conducted in only post AHF patients. The combination of higher event rates and potentially larger treatment effects makes post AHF studies potentially more efficient. These studies can be done with less than half the number of patients needed for a chronic HF study, and with shorter average follow up. If PARADIGM-HF had been replaced by a larger PIONEER-HF with 90-180 days follow up, a study with < 2,000 patients would have had > 90% power for the primary endpoint of HF readmission or death at an alpha of 0.001. Similar power could have been achieved in a large single EMPULSE study including both low and high EF with fewer than 2,500 patients. A theoretical comparison of power for given sample sizes in post-acute and chronic HF studies is presented in the Figure 1. The power is based on the average HRs seen in the acute and Chronic studies described above (excluding VICTORIA and GALACTIC where exact data on acute versus non acute are not available) and a control event rate of about 20%, lower than seen in recent studies due to the assumption that with almost global adaptation of ARNi and SGLT blockers, control event rates will drop. The graph suggests that < 3,000 patients enrolled in post AHF studies with a 6-month event rate of 20% will provide > 90% power for an alpha of 0.001, but it will take > 10,000 chronic HF patients treated with modern current GDMT to achieve a similar endpoint. To satisfy practical and regulatory perspectives, post-AHF studies can be performed using a more adaptive approach. Given that P-values <0.05 can be already seen with 500-1,000 patients followed for 3 months, these studies can be designed with early futility analyses after 500 -1,000 patients have 3-month follow-up, reducing the sponsor's risk. To satisfy regulatory requirements for safety data on longer exposure, patients who have reached the 6 months primary endpoint, for example, can remain in the study while other patients are recruited and even after the last patient reaches 6 months follow-up, as was the case in the SOLOIST-WHF study, which was the basis of the approval of Sotaglifozin by the FDA despite only about 9 Months median follow up (15https://www.lexpharma.com/media-center/news/2023-05-26-lexicon-announces-fda-approval-of-inpefa-sotagliflozin-for-treatment-of-heart-failureGoogle Scholar). In conclusion, targeting chronic HF patients in confirmatory mega-trials with up to 10,000 patients each and recruitment and follow-up over 3-4 years is an ineffective way to develop new interventions for HF. Unless the intervention's mechanism of action dictates otherwise, studies of new interventions in HF could be done primarily in patients with a very recent AHF admission. This is likely to be a less expensive and more efficient approach that could encourage the development of more innovative interventions and allow for good delineation of safety and differing treatment effects in post-acute versus chronic HF. Patients’ treatment would be improved both by having more treatment options and getting them earlier. Gad Cotter