UpStreAm doxycycline in ST-eLeVation myocArdial infarction – targetinG infarct hEaling and ModulatIon (SALVAGE-MI trial)

Abstract Background and Aims Experimental studies demonstrate protective effects of doxycycline on myocardial ischemia-reperfusion injury. The trial investigated whether doxycycline administered prior to reperfusion in patients presenting with ST-elevation myocardial infarction (STEMI) reduces infarct size (IS) and ameliorates adverse left ventricular (LV) remodeling. Methods In this randomized, double-blind, placebo-controlled trial, patients presenting with STEMI undergoing primary percutaneous coronary intervention (PPCI) were randomized to either intravenous doxycycline or placebo prior to reperfusion followed by 7-days of oral doxycycline or placebo. The primary outcome was final IS adjusted for area-at-risk (fIS/AAR) measured on two cardiac magnetic resonance scans ∼6 months apart. Results Of 103 participants, 50 were randomized to doxycycline and 53 to placebo and were matched for age (59 ± 12 vs. 60 ± 10 years), male sex (92% vs. 79%), diabetes mellitus (26% vs. 11%) and left anterior descending artery occlusion (50% vs. 49%), all p > 0.05. Patients treated with doxycycline had a trend for larger fIS/AAR (0.79 [0.5-0.9] vs. 0.61 [0.47-0.76], p = 0.06), larger fIS at 6 months (18.8% [12-26] vs. 13.6% [11-21], p = 0.08), but similar acute IS (21.7% [17-34] vs. 19.4% [14-27], p = 0.19) and AAR (26% [20-36] vs. 24.7% [16-31], p = 0.22) compared to placebo. Doxycycline did not ameliorate adverse LV remodeling (%Δend-diastolic volume index, 1.1% [-3.8-8.4] vs. -1.34% [-6.1-5.8], p = 0.42) and was independently associated with larger fIS (regression coefficient = 0.175, p = 0.03). Conclusion Doxycycline prior to PPCI neither reduced IS acutely or at 6 months nor attenuated adverse LV remodeling. These data raise safety concerns regarding doxycycline use in STEMI for infarct modulation and healing.