Comparison of Sacubitril/Valsartan vs. Ramipril in Acute Myocardial Infarction: WIN-Ratio Analysis
The PARADISE-MI trial compared Sacubitril/Valsartan and Ramipril in patients with acute myocardial infarction. The primary outcome of cardiovascular death, heart failure hospitalization, or outpatient heart failure showed no significant difference between the two treatments. Detailed event rates and cumulative incidence were also reported, indicating a comparable efficacy profile for both medications.
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SACUBITRIL/VALSARTAN VERSUS RAMIPRIL FOR PATIENTS WITH ACUTE MYOCARDIAL INFARCTION: WIN-RATIO ANALYSIS OF THE PARADISE-MI TRIAL Otavio Berwanger (MD; PhD) Director -Academic Research Organization (ARO) Hospital Israelita Albert Einstein Sao Paulo-SP, Brazil for the PARADISE-MI Committees, National Leaders and Investigators
Disclosures Dr. Otavio Berwanger Dr Berwanger received research grants from: AstraZeneca, Pfizer, Novartis, Amgen, BMS, Servier, and Bayer
Steering Committee Marc Pfeffer (Chair), Eugene Braunwald, Christopher B. Granger, Lars Kober, Douglas Mann, Aldo P. Maggioni, John J.V. McMurray, Jean L. Rouleau, Scott D. Solomon, Philippe Gabriel Steg National Lead Investigators Clinical Events Committee Eldrin Lewis (Chair), Ebrahim Barkoudah, Simon Correa-Gaviria, Abdel Brahimi, Jon Cunningham, Peter Finn, Howard Hartley, Karola Jering, Finnian R. Mc Causland, Martina M. McGrath, Muthiah Vaduganathan, Chau Duong, Renee Mercier, Anthonette Roach, Barbara Saunders- Correa, Amanda Wivagg, David Charytan, Jacob Joseph Alberto Fernandez , Argentina Marc Claeys, Belgium Jean-Francois Tanguay, Canada Maja Cikes, Croatia Saila Vikman, Finland Gerasimos Filippatos, Greece Offer Amir, Israel Peter van der Meer, Netherlands John Anonuevo, Philippines Jo o Morais, Portugal David Sim Kheng Leng, Singapore Martin Studencan, Slovakia Julio Nu ez Villota Spain Hsien-Li Kao, Taiwan Mark Petrie, United Kingdom Roxana Mehran, United States Carmine De Pasquale, Australia Dirk von Lewinski , Austria Otavio Berwanger, Brazil Yaling Han, China Petr Widimsk , Czech Republic Morten Schou, Denmark Gabriel Steg, France Bela Merkely, Hungary Michele Senni, Italy Lars Gullestad, Norway Grzegorz Opolski, Poland Dragos Vinereanu , Romania Ivo Petrov, Bulgaria Alberto Jose Cadena Bonfanti, Colombia Ulf Landmesser, Germany Prafulla Kerkar, India Jorge Carrillo-Calvillo, Mexico Alberto Jose Cadena Bonfanti, Peru Myeong-Chan Cho, Republic of Korea Olga Barbarash, Russian Federation Mpiko Ntsekhe, South Africa Angioedema Committee Allen Kaplan (Chair), Nancy Brown, Bruce Zuraw Christina Christersson, Sweden Tiziano Moccetti, Switzerland Songsak Kiatchoosakun, Thailand Mehmet Birhan Yilmaz, Turkey Azfar Zaman, United Kingdom Cara East, United States Freny Mody, United States Data Safety Monitoring Committee Henry Dargie (Chair), Robert Foley, Gary Francis, Michele Komajda, Stuart Pocock Novartis Independent Statistician Brian Claggett Yinong Zhou, Katherine Carter, Margaret Wernsing, Denise Ott, Jim Gong, Yi Wang, Abhijeet Kulkarni, Siva Ponugumati, Ghionul Ibram, Raghava Ramesh Narayana, Marty Lefkowitz, Sven Godtfredsen
PARADISE-MI Primary Outcome CV death, first HF hospitalization or outpatient HF (adjudicated) Ramipril 373 events, 7.4 per 100 pt-years Sacubitril/valsartan 338 events, 6.7 per 100 pt-years HR 0.90 (95% CI, 0.78-1.04) p = 0.17 Patients at risk, n Ramipril Sacubitril/valsartan Pfeffer M et al. N Engl J Med. 2021;385:1845-1855
Total (first and recurrent) CEC Adjudicated Primary Events Investigator Reported Primary Endpoint 30 0.30 Mean Cumulative Events per 100 Patients 25 0.25 Ramipril 516 events, 10.8 per 100 pt-years Ramipril 539 events, 10.1 per 100 pt-years Cumulative Incidence 20 0.20 15 0.15 Sacubitril/valsartan 452 events, 8.4 per 100 pt-years Sacubitril/valsartan 443 events, 9.1 per 100 pt-years 10 0.10 5 0.05 RR* 0.79 (95% CI, 0.65-0.97) p = 0.02 HR 0.85 (95% CI, 0.75-0.96) p = 0.01 0 0.00 2 2.5 2 2.5 0 0.5 1 1.5 3 0 0.5 1 1.5 3 Years since Randomization Years since Randomization *Rate ratio derived from negative binomial regression with Weibull baseline intensity function Pfeffer M et al. Circulation. 2022;145:87-89
Objectives The aim of the present analysis was to provide an additional perspective into understanding the effects of sacubitril/valsartan in patients with acute myocardial infarction by considering simultaneously: 1. (the more serious events are given a higher priority and are analyzed first) The Hierarchy of Outcomes 2. The Totality of the Evidence (including multiple domains of endpoints) Events that were confirmed + events that were not confirmed by the CEC Committe Win Ratio Method
AMI (0.5-7 days with LVEF 40% and/or pulmonary congestion) PLUS any risk enhancer Age 70 years eGFR <60 Diabetes Prior MI Atrial fibrillation LVEF < 30% Killip class III STEMI without reperfusion Major Exclusions: Prior HF Clinical instability eGFR <30 Ramipril Sacubitril/Valsartan No run-in Target 5 mg BID Target 97/103 mg BID double-blind active-controlled N=2831 N=2830 Event driven: 711 primary endpoints Median follow-up: 23 months ITT principle Primary Endpoint: CV death, HF hospitalization, outpatient development of HF Jering, Eur J Heart Fail. 2021
5,669 patients from 495 Sites in 41 Countries (December 9, 2016 March 16, 2020; last follow-up on December 31, 2020)
Event Classification CEC (+) EVENTS Events that met CEC committee definitions, including: Site-reported events with adequate and complete source documentation to meet standardized study definitions Events not reported by the sites, but which were identified and confirmed through triggered events, review of adverse events and hospital admissions, or screening of laboratory data CEC (-) EVENTS Events that did not meet CEC committee definitions, including: Site-reported events that were not confirmed for missing or incomplete source documentation, insufficient signs, and symptoms and/or no qualifying intravenous treatment to characterize episodes of heart failure, or other reasons that prevented events from meeting pre-specified study definitions. CEC = clinical events classification
Principal Outcome The principal analysis was a hierarchical composite outcome analyzed in the order of: 1. CV Death - CEC (+) 2. CV Death - CEC (-) 3. First HF Hospitalization - CEC (+) 4. First HF Hospitalization - CEC (-) 5. First Outpatient Development of HF - CEC (+) 6. First Outpatient Development of HF - CEC (-) CEC = clinical events classification
We hypothesized that the inclusion of both CEC (+) and CEC (-) events in the principal hierarchical composite outcome could be informative for several reasons, including: It is likely that a proportion of CEC (-) events did represent true outcomes (events declined by lack or insufficient documentation to meet strict CEC Committee definitions). Additional information provided by CEC (-) events may improve the generalizability of the results by more closely resembling the clinical judgment applied by clinicians in routine practice By using all available trial information, this approach, closer to clinical practice, allows a more complete and comprehensive assessment of the comparison between the two treatment arms on different outcomes. Considering both types of events in the same hierarchical composite outcome may increase the statistical power to reliably detect potential treatment effects Fatal events and CEC (+) events were given a higher priority and were analyzed before CEC (-) events. CEC = clinical events classification
Statistical Analysis Unmtached Win Ratio1,2 Principal Outcome* Outpatient HF CV Mortality HF Hospitalization Sacubitril/valsartan wins Sacubitril/valsartan wins Sacubitril/valsartan wins Patient in the ramipril group has a Patient in the ramipril group develops outpatient HF first Patient in the ramipril group dies from a CV cause first HF hospitalization first Tie Tie Tie Comparison of patients from each group Both patients have a HF hospitalization on the same day or neither of the patients have a HF Hospitalization Both patients develop outpatient HF on the same day or If neither of the patients develop outpatient HF Both patients die from a CV cause on the same day or neither of the patients die from a CV cause Ramipril wins Ramipril wins Ramipril wins Patient in the ramipril group has a Patient in the sacubitril/valsartan group develops outpatient HF first Patient in the sacubitril/valsartan group dies from a CV cause first HF hospitalization first * Hierarchical Order 1. CV Death CEC (+) 2. CV Death CEC (-) 3. HF Hospitalization CEC (+) 4. HF Hospitalization - CEC (-) 5. Outpatient HF CEC (+) 6. Outpatient HF CEC (-) 1. 2. Pocock S et al. Eur Heart J. 2012;33:176-8 Redfors B et al. Eur Heart J. 2020;41:4391-4399 CV = cardiovascular; HF = heart failure
5,669 Randomized Patients Ineligible and no drug N = 4 Ineligible and no drug N = 4 Validly Randomized Patients N = 5,661 Ramipril 5 mg bid N = 2831 Sacubitril/valsartan 97/103 mg bid N = 2830 Vital status unknown n = 9 Vital status unknown n = 4 Median duration of follow-up 23 months Median duration of follow-up 23 months Average dose (at 4 months) 3.8 (1.8) mg bid Average dose (at 4 months) 139.2 (74.9) mg bid
Baseline Characteristics Ramipril N = 2831 64 (11) 25 17 / 1 / 76 excluded 16 5 65 42 21 13 72 (23) Sacubitril/Valsartan N = 2830 64 (12) 23 17 / 1 / 75 excluded 16 4 65 43 22 14 72 (22) Characteristic Age (years), mean (SD) Female sex (%) Race Asian/Black/Caucasian (%) Prior heart failure Prior MI (%) Prior stroke (%) Hypertension (%) Diabetes (%) Smoking (%) Atrial fibrillation / flutter (%) eGFR (ml/min/1.73m2), mean (SD)
Ramipril N = 2831 Sacubitril/Valsartan N = 2830 Index MI STEMI / NSTEMI (%) Reperfusion (PCI / lytics) (%) Location Anterior / inferior (%) Time to randomization (days), mean (SD) LVEF (%), mean (SD) Killip class II (%) Medications at baseline: Dual antiplatelet therapy (%) Beta blocker (%) Aldosterone antagonist (%) Statin (%) ACEi/ARB (%) 76 / 24 89 (88 / 4) 68 / 19 4.3 (1.8) 36 (9) 56 76 / 24 89 (88 / 5) 68 /18 4.3 (1.7) 37 (10) 57 92 85 41 94 78 92 85 42 95 78
Principal Composite Outcome Total patient pairs N=8,011,730 Contribution to number of wins (%) CV Death CEC (+) events Wins Ties Losses N=406,389 36.9% N=459,367 N=7,145,974 CV Death CEC (-) events Ties Losses N=5,418 Wins N=11,843 0.7% N=7,128,713 1stHF Hospitalization CEC (+) events Ties Losses N=339,064 Wins 29.8% N=6,429,969 N=359,680 1stHF Hospitalization CEC (-) events Ties Wins Losses N=163,511 14.7% N=6,085,579 N=180,879 1stOutpatient HF CEC (+) events Wins N=72,590 Ties Losses N=63,692 5.8% N=5,949,297 1stOutpatient HF CEC (-) events Wins Losses N=101,428 Ties 12.1% N=181,408 N=5,666,461 Total wins: 1,265,767 Total losses: 1,079,502 Estimated unmatched win ratio* = 1.17 (95% CI,1.03 to 1.33; P=0.015)
Total Wins Total Losses Win Ratio (95% CI) P value Sacubitril/ valsartan (N = 2830) Sensitivity Analyses Ramipril (N = 2831) 1.17 CV death, Total HF hospitalization, Total OHF CEC(+),CEC(-) CEC (+),CEC(-) CEC (+),CEC(-) 1,323,611 1,128,785 (1.03 to 1.33) P=0.01 = 1.15 (95% CI, 1.02 to 1.31; P = 0.024) (1.02 to 1.31) P=0.024 1.15 All-cause death, 1stHF hospitalization, 1stOHF CEC(+),CEC(-) CEC(+),CEC(-) CEC(+),CEC(-) 1,313,868 1,138,813 CV death*, 1stHF hospitalization*, 1stOHF* CEC(+),CEC(-) CEC(+),CEC (-) CEC(+),CEC(-) 1.17 1,124,299 958,051 (1.02 to 1.35) P=0.025 1.11 814,484 CV death, 1st HF hospitalization, 1stOHF 907,147 (0.96 to 1.30) P=0.16 CEC(+) CEC(+) CEC(+) CV= cardiovascular, HF= heart failure, OHF= outpatient heart failure * Events during the first year of follow-up
Interpretation The present analysis may help to better understand although not change the neutral primary results of the PARADISE-MI trial. By simultaneously considering the hierarchy of outcomes and the totality of trial evidence across multiple domains of endpoints, these findings provide an additional perspective into understanding the effects of sacubitril/valsartan in patients with acute myocardial infarction. The sensitivity analyses using alternative definitions of the hierarchical composite outcome showed results similar to those of the principal analysis, except for analysis restricted to CEC (+) events (although the magnitude and directionality of the analysis were similar). Given the post-hoc nature of the analysis, our findings should be considered exploratory or hypothesis generating.
Conclusion In summary, in this post-hoc win ratio analysis of the PARADISE-MI trial, sacubitril/valsartan was superior to ramipril among high-risk survivors of myocardial infarction. This study provides an example of how the win ratio approach may be as a useful adjunct to the conventional time-to-first event analysis for trials with composite outcomes, especially where ranking of the clinical importance of the different types of events is considered relevant.
