. 2012 Apr;1(1):13–32. doi: 10.1177/2048872612438805

Table 3.

Major studies investigating pharmacological adjuncts to primary percutaneous coronary intervention

Study	Patients	Mechanism of cardioprotection	Therapeutic strategy	Results
Anti-inflammatory agents
Granger et al. (2003)⁷¹ (COMMA)	960 patients	Pexelizumab is an anti-inflammatory antibody which has been reported to reduce MI size by binding to and inhibiting the C5 component of complement pathway	Intravenous pexelizumab 2 mg/kg bolus only given prior to PPCI. Or bolus followed by 0.05 mg/kg/h infusion for 24 h	No difference in primary endpoint of AUC CK-MB
	All STEMI			However, the 90-d mortality rate was significantly lower with pexelizumab bolus plus infusion (1.8% vs. 5.9% with placebo, p=0.014)
	<6 h			Therefore, APEX-MI planned
	All TIMI flow
	Collaterals included
Armstrong et al. (2007)⁷² (APEX-MI)	5745 patients		Intravenous pexelizumab 2 mg/kg bolus given over 10 min prior to PPCI followed by 0.05 mg/kg/h infusion for 24 h	No difference in primary endpoint of 30 day death (pexelizumab 4.1% vs. 3.9% placebo)
	All STEMI
	<6 h
	All TIMI flow
	Collaterals included
Atar et al. (2009)⁷³ (F.I.R.E.)	232 patients	FX06 is a cleavage product of fibrin which inhibits inflammation by preventing the activation of endothelial VEcadherin	IV bolus of FX06 (200 mg) immediately prior to guidewire crossing obstruction and then repeated 10 min later	No difference in MI size by CMR at 5 days or 4 months
	All STEMI	Animal studies report MI reduction with FX06		No difference in MI size by tropinin
	<6 h
	All TIMI flow
	Collaterals included
Adenosine
Ross et al. (2005)⁷⁴ (AMISTAD II)	2118 patients	Adenosine has been reported to protect the heart in experimental studies by activating pro-survival kinases and anti-inflammatory mechanism	Intravenous infusion of adenosine 50 or 70 µg/kg/min for 3 h. Started after PPCI	No difference in primary endpoint of primary end point was new CHF beginning <24 h after randomization, or the first re-hospitalization for CHF, or death from any cause within 6 months
	Ant STEMI	However, whether it was effective at reperfusion was inconclusive		Subsequent post-hoc analysis suggested that in patients presenting within 3.17 h there was a beneficial effect with adenosine
	<6 h			Experimental evidence inconclusive
	All TIMI flow
	Collaterals included
Glucose insulin potassium (GIK) therapy
Mehta et al. (2005)⁷⁵ (CREATE-ECLA)	20,201 patients	GIK therapy reported in experimental studies to limit MI size via the activation of pro-survival kinases	IV infusion of GIK (25% glucose, 50U/l insulin, 80 mEq/lof potassium to be infused at a rate of 1.5 ml/kg/h) for 24 h. Started after reperfusion in majority of patients	No difference in 30 d mortality (9.7% placebo vs. 10.0% GIK)
	All STEMI	Initial promising clinical studies		Majority of patients treated by thrombolysis and not PPCI
	Most patients received thrombolysis			GIK administered prior to reperfusion in only 1437 patients
	<12 h
	All TIMI flow
	Collaterals included
Nicorandil
Kitakaze et al. (2007)³⁴ (J-WIND)	545 patients	Nicorandil is an anti-anginal which is also known to limit MI size via the activation of the mitochondrial KATP channel and the release of nitric oxide, both of which are known mediators of IPost	IV bolus of nicorandil (0.067 mg/kg) followed by infusion at 1.67 µg/kg/min for 72 h. Started after PPCI	No difference in MI size or LVEF
	All STEMI			Nicorandil was given after PPCI
	<12 h			Inconclusive whether nicorandil administered at reperfusion was protective in experimental studies
	All TIMI flow
	Collaterals included
Erythropoietin
Ferriario et al. (2009)⁷⁶	30 patients	EPO is a haemopoietic cytokine which is also known to limit MI size at reperfusion via the intracellular activation of the RISK pathway (a known mediator of IPost)	IV EPO 33,000 iU prior to PPCI repeated 24 and 48 h later	30% reduction in 120 h AUC CK-MB but no difference in MI size using CMR at 3 days and 6 months
	All STEMI	Large animal studies inconclusive
	<6 h
	All TIMI flow
	Collaterals included
Suh et al. (2010)⁷⁷	57 patients		IV EPO 50 iU/kg prior to PPCI	No beneficial effects on MI size (assessed by 72 h AUC CK-MB and CMR at 4 days)
	Ant STEMI
	<12 h
	TIMI 0 flow
	Collaterals included
Ozawa et al. (2010)⁷⁸ (EPO-AMI-1)	36 patients		IV EPO epoetin-beta 12,000 iU after (within 24 h) PPCI	Increase in LVEF at 6 months
	STEMI
	<24 h
	All TIMI flow
	Collaterals included
Voors et al. (2010)⁷⁹ (HEBE-III)	529 patient		IV EPO epoetin-alpha 60,000 iU after (within 3 h) PPCI	No difference in primary endpoint of LVEF at 6 weeks
	STEMI			No difference in MI size (AUC CK-MB or tropinin T)
	<12 h			More major adverse cardiac events occurred with EPO
	All TIMI flow
	Collaterals included
Tanaguichi et al. (2010)⁸⁰ (EPOC-AMI)	35 patients		IV EPO epoetin-alpha 6000 iU after (within 3 h) PPCI repeated 24 and 48 h later	Improvement in LVEF and smaller MI size at 4 days and 6 months by SPECT
	STEMI
	<12 h
	All TIMI flow
	Collaterals included
Ott et al. (2010)⁸¹ (REVIVAL-3)	138 patients		IV EPO epoetin-beta 33,000 iU immediately after PPCI repeated 24 and 48 h later	No difference in LVEF at 6 months assessed by CMR (primary endpoint)
	STEMI			No difference in MI size (5 days and 6 month CMR)
	<12 h
	All TIMI flow
	Collaterals included
Ludman et al. (2011)⁸²	52 patients		IV EPO epoetin-beta 50,000 iU prior to PPCI repeated 24 h later	No difference in MI size at 3 days using CMR and troponin T
	All STEMI			Doubling of incidence of MVO on CMR
	<12 h
	All TIMI flow
	No collaterals
Rao et al. (2011) (REVEAL, unpublished)	138 patients		IV EPO epoetin-beta 60,000 iU immediately after PPCI repeated 24 and 48 h later	No difference in MI size on CMR within 6 days and 3 months
	STEMI			Trend to increased adverse events in patients over 70 years old
	<8 h
	All TIMI flow
	Collaterals included
Protein kinase C-δ inhibitor
Bates et al. (2008)⁸³ (DELTA-MI)	154 patients	A drug which is known to limit MI size by inhibiting the pro-apoptotic protein kinase, PKC-δ. This mechanism also contributes to IPost	Intracoronary KAI-9803 (delcasertib) at different doses (0.05, 0.5, 1.25 and 5.0 mg) administered in two divided doses prior to and after PPCI	Safe, efficacy not primary endpoint but non-significant reductions in MI size by CK-MB and SPECT
	Ant STEMI
	<6 h
	All TIMI flow
	No collaterals
Lincoff et al. (2011) (PROTECTION-AMI, unpublished)	1083 patients		Intravenous KAI-9803 (delcasertib) at different doses 50, 150, and 450 mg/h) for 24 h started prior to PPCI	No difference on primary endpoint of infarct size as assessed by CK-MB AUC
	Ant/Inf STEMI			Takes 5–30 min to reach steady state after infusion begun
	<6 h
	All TIMI flow
	No collaterals
Atorvastatin
Kim et al. (2010)⁸⁴ STATIN STEMI	171 patients	A variety of pleiotropic effects including MI size reduction via the direct intracellular activation of the RISK pathway (a known mediator of IPost)	Atorvastatin 80 mg versus atorvastatin 10 mg prior to PPCI	No effect on primary endpoint of (death, MI, revasc)
	STEMI			No difference in MI size (CKMB max)
	<12 h			Improved myocardial perfusion (blush grade, STR)
	All TIMI flow
	No collaterals

AUC, area under the curve; CHF, congestive heart failure; CK, creatine kinase; CMR, cardiac MRI; EPO, erythropoietin; IPost, ischaemic postconditioning; LVEF, left ventricular ejection fraction; MI, myocardial infarct; MVO, microvascular obstruction; PPCI, primary percutaneous coronary intervention; SPECT, single photon emission CT; STEMI, ST-segment elevation MI; STR, ST-segment resolution; TIMI, thrombolysis in myocardial infarction.