Vancouver IM LMR

Source paper, NEJM April 6, 2024: https://www.nejm.org/doi/full/10.1056/NEJMoa2314051

Recent VGH LMR Alex Monaghan reviewed EMPACT-MI at GIM journal club this week, see slides and notes below for a high yield review of this RCT reviewing the role of early use of empagliflozin in post acute MI patients at high risk for developing heart failure.

Slides

Summary

• Background – SGLT2 inhibitors have had a very successful run in the last few years of research), with benefits in heart failure with reduced AND preserved ejection fraction, CKD, and diabetes. But do they work to improve cardiac outcomes post myocardial infarction? Research from animal models of MI suggest some physiologically viable mechanisms, but in vivo data limited thus far.
• EMPACT MI was a multi-centre double-blinded randomized control trial across 451 sites in 22 countries
• PICO question
  • Population – Hospitalized patients with acute myocardial infarction at risk for heart failure (new reduced LVEF% or symptoms/signs of congestion or both, with additional risk factors for developing heart failure)
  • Intervention – Empagliflozin 10 mg po daily within 14 days of AMI + standard care
  • Comparator – Placebo + standard care
  • Outcome – Primary: Composite of time to first HHF, time to all-cause mortality. Secondary: Hierarchical testing of # HHF + death, # CV hosp + death, readmission + death, MI readmission + death

• Statistical analysis: Intent to treat analysis. Used a hierarchical testing method in which outcomes were tested sequentially for significance until a no-difference result was reached (to avoid issues with multiplicity).
• Results:
  • Primary outcome of time to first hospitalization or all-cause mortality no difference (8.2% empa group vs 9.1% placebo group (HR 0.90, CI 0.76-1.06, p=0.21))
  • Secondary outcomes not tested for significance as per the pre-specified hierarchical analysis.
  • There was a signal to benefit in the empagliflozin group for time to first hospitalization as well as total hospitalizations compared to placebo.
• Significance:
  • Limitations include: white men trial (despite author’s best efforts in diversifying recruitment), lower than expected primary event rates in the face of excellent revascularization + COVID + regional wars.
  • Authors speculate that failure to show difference in all-cause mortality may be related to the concept that early mortality post-AMI is due to events that may not be modulated by SGLT2 inhibition (eg mechanical complications, stent thrombosis, recurrent MI)
• Takeaway:
  • No mortality benefit shown from early SGLT2 inhibition after acute MI, but possible signal to benefit in HF hospitalizations and total number of HF hospitalizations (and in additional pre-specified secondary outcome analysis – possibly less likely to require initiation of other HF medications in the months following discharge)
  • Good safety data suggesting risks of volume depletion and AKI in use of SGLT2i post MI with other heart failure therapies are low.
  • Bottom line is that it is not wrong or unsafe to start SGLT2i early for acute MI patients at high risk for developing heart failure. There is no mortality benefit in doing this, but we are possibly decreasing relatively short-term heart failure events post discharge (which will need to be further delineated in future research)
  • Not yet included in any guidelines.
• Audience Q
  • Did the investigators tolerate any degree of renal impairment before discontinuing the drug if necessary?
    • No specific threshold noted in the protocol for tolerating GFR reduction during the trial.
    • Interestingly, in the safety data table it appears that those in the empa arm were actually less likely than placebo to have events classified as AKI/acute renal failure or volume depletion.