Table 1

Recent attempts to reduce MI size in reperfused patients presenting with STEMI

Clinical study	Therapeutic intervention (patient population)	N	Main outcomes	Mechanism of cardioprotection potential reasons for neutral results
Therapeutic hypothermia
Erlinge et al10 CHILL-MI	IV 600 to 2000 mL cold saline and endovascular cooling prior to PPCI for 1h to cool to 34.7°C	120	No effect on primary end point of MI size (CMR at 4 days) Delays reperfusion by 9 min	Experimental studies show that mild hypothermia, induced before reperfusion reduced MI size. The reasons for the neutral study are unclear but may relate to: 20%–27% of patients had TIMI flow of > 0 before PPCI Only 76% of patients had a temperature of <35°C at reperfusion Interestingly, post-hoc sub-group analysis revealed that patients presenting early (<4 h) with anterior STEMI had a smaller MI/AAR
Nichol et al11 VELOCITY	Peritoneal hypothermia to cool to 34.7°C	57	No effect on primary end point of MI size (CMR at 3–5 days) Delays reperfusion by 15 min Increase in stent thrombosis	The reasons for the neutral study may relate to: The study being underpowered. Out of 26 patients in the hypothermia arm, 6 had TIMI flow of >1 prior to PPCI and <50% achieved a temperature of <34.9°C at the time of PPCI
Targeting mitochondrial function
Lincoff et al12 PROTECTION-AMI	IV delcasertib infusion for 2.5 h (LAD/RCA STEMI)	1010	No effect on primary end point of AUC CK-MB	Peptide inhibitor of delta-protein kinase C a major mediator of the mitochondrial apoptotic pathway which has been reported in animal studies to reduce MI size when administered prior to reperfusion.The reasons for the neutral study is unclear but may relate to: 30%–40% of patients had TIMI flow of >1 before PPCI. Intravenous delcasertib may take up to 30 min to reach steady state and therefore may not have been effective at reperfusion Lack of signs of toxicity raised the question of whether the dose used was sufficient
Atar et al13 MITOCARE	IV bolus of TRO40303 prior to angioplasty (All-comer STEMI, TIMI <1)	163	No effect on primary end point of 72 h AUC CK-MB/Troponin-T	This drug is an indirect inhibitor of the mitochondrial permeability transition pore which has been reported in animal studies to reduce MI size when administered prior to reperfusion.The reason for the neutral study is unclear but may relate to: Relatively small MI size compared with previous studies Groups were not well balanced (higher initial mean CK, less patients with TIMI 0 pre-PPCI and more patients with TIMI 0/1 post PPCI, older age by 4 years in the TR040303 group) Concerns that the dose used may not have been correct
Chakrabarti et al14 EMBRACE-STEMI	IV infusion (75 min) of Bendavia started 15 min before reperfusion (LAD STEMI, TIMI 0)	118	No effect on the primary end point of 72 h AUC CK-MB	A mitochondria-targeting peptide which has been reported in animal studies to reduce MI size when administered prior to reperfusion. The reason for the neutral study is unclear but may be because the study was underpowered. Full study results are awaited.
Nitric oxide signalling
Siddiqi et al15 (NIAMI)	IV sodium nitrite (70 µmol) over 5 min prior to PPCI (All-comer STEMI, TIMI<1)	229	No effect on the primary end point of 72 h AUC CK-MB	The reason for the neutral study is unclear but may relate to the route of drug administration and the fact that >90% of patient had received GTN prior to reperfusion
Jones et al16 NITRITE	IC sodium nitrite (1.8 μmol) bolus prior to angioplasty (All-comer STEMI)	80	No effect on the primary end point of MI size (as % LV mass) (on 6–8 days CMR)	The reason for the neutral study is unclear but may relate to patient selection as post-hoc subgroup analysis revealed reduced MI size in patients with LAD STEMI
NOMI NCT01398384	Inhaled nitric oxide at 80 ppm for 4 h initiated prior to PPCI	248	No effect on the primary end point of MI size (as % of LV mass) on CMR (48–72 h)	The reason for the neutral study is unclear but may relate to patient selection (post-hoc subgroup analysis revealed reduced MI size in patients with LAD STEMI) and prior dosing with IC/IV GTN as patients who were GTN-naïve, there was a reduction in MI size

AUC, area under curve; CK-MB, creatine kinase myocardial band; CMR, cardiovascular MRI; GTN, glyceryl trinitrate; IC, intracoronary; IV, intravenous; LAD, left anterior descending artery; MI, myocardial infract; PPCI, primary percutaneous coronary intervention; RCA, right coronary artery; STEMI, ST-segment elevation myocardial infarction; TIMI, Thrombolysis in MI.