Key Points
- This trial of patients with acute myocardial infarction (AMI) and impaired left ventricular (LV) systolic function found that dapagliflozin significantly improved clinical and cardiometabolic outcomes compared with placebo.
- There was no significant difference in clinical events rates, which were low in both groups.
- The innovative registry-based clinical trial design helped facilitate efficient patient recruitment and outcomes ascertainment.
Patients with AMI are at higher risk for subsequent adverse cardiometabolic events. SGLT2 inhibitors (SGLT2i) have demonstrated benefit in prior randomized control trials in reducing major adverse cardiovascular and renal events in patients with diabetes or heart failure, irrespective of left ventricular ejection fraction (LVEF). Whether the SGLT2i dapagliflozin might prevent the development of subsequent clinical heart failure or other adverse cardiometabolic events in patients with recent AMI and newly impaired LVEF is unknown.
On November 11, 2023 the results of Dapagliflozin in Myocardial Infarction without Diabetes or Heart Failure (DAPA-MI) were presented at AHA Scientific Sessions 2023 with simultaneous publication in the NEJM Evidence. This industry-sponsored, multicenter, parallel-group, registry-based, randomized, double-blind, placebo-controlled phase 3 trial (R-RCT), compared dapagliflozin 10mg with placebo among patients who with recent AMI (within 10 days) and impaired LV systolic function (but without cardiogenic shock) on the primary hierarchical composite of death, heart failure hospitalization, non-fatal MI, atrial fibrillation or flutter, new onset diabetes, NYHA functional class, and weight loss. Patients with known diabetes, heart failure, or eGFR <20 mL/min/1.73m2 were excluded. The innovative pragmatic R-RCT design integrated existing national clinical registries in Sweden and the UK with the trial database to facilitate recruitment, randomization, blinding, and data collection (both baseline demographics as well as outcome ascertainment).1
It should be noted that the initial endpoint chosen for the study was a composite of cardiovascular death or heart failure, however during the trial the number of outcome was substantially lower than anticipated and so in February 2023 it was modified to a hierarchal (win ratio) composite outcome approach including the cardiometabolic metrics listed above.
The trial enrolled 4017 patients, of whom 2019 were assigned to dapagliflozin and 1998 to placebo. The two groups were well balanced in key demographic and baseline characteristics. The median time from hospital admission to random assignment was 3 days. The mean age was 62,9 years in both groups, with approximately 20% of the patients being female and the majority (~70%) from Sweden with the rest from UK. About 9% had a prior MI. The majority of the patients (72%) presented with ST elevation MI and LV ejection fraction was below 50% in the majority of participants (73.2%). More than 90% received aspirin, P2Y12 inhibitors, ACE inhibitors, beta blockers, and statins, indicating appropriate background guideline directed medical therapy, though only 23% were treated with aldosterone receptor antagonists.
The analysis of the primary hierarchical composite outcome resulted in significantly more wins for dapagliflozin than for placebo (win ratio, 1.34; 95% confidence interval [CI], 1.20 to 1.50; P<0.001). The win ratio outcome was mainly driven by the added cardiometabolic outcomes. When the weight loss outcome was removed from the primary endpoint, the benefits of dapagliflozin were attenuated but still statistically significant (win ratio 1.20 (95% CI 1.01,1.40; p = 0.015). The composite of time to cardiovascular death/hospitalization for heart failure occurred in 50/2019 (2.5%) patients assigned to dapagliflozin and 52/1998 (2.6%) patients assigned to placebo (hazard ratio, 0.95; 95% CI, 0.64 to 1.40). The rates of other cardiovascular events were low, with differences between the groups not reaching nominal statistical significance. No safety concerns were identified. Patients on dapagliflozin had greater weight loss and lower rates of incident diabetes. There was no difference in the secondary outcomes of time to first occurrence of cardiovascular death or hospitalization for heart failure or major adverse cardiovascular events (MI, stroke, or CV death). The benefits were consistent across subgroups and no new safety concerns were identified.
Professor Stefan James of Uppsala University, Sweden, concluded: “In patients with AMI and impaired LV systolic function, without prior diabetes or chronic heart failure, dapagliflozin demonstrated significant benefit with regards to improvement in cardiometabolic outcomes compared with placebo…Clinical event rates were low with no significant difference between randomized groups.”
References
- James S, Erlinge D, Storey RF, et al. Rationale and design of the DAPA-MI trial: Dapagliflozin in patients without diabetes mellitus with acute myocardial infarction. Am Heart J. 2023. Published onlineAugust 25, 2023. https://doi.org/10.1016/j.ahj.2023.08.008.
