Table 1

Considerations for administration of infarct limiting treatments in acute myocardial infarction

Clinical scenario	Treatment rationale	Choice of agent	Implications for trial
Patient at risk of acute myocardial infarction, eg, unstable angina.	Pre-ischaemic pretreatment to limit infarct size.	“Preconditioning” mimetics, eg, adenosine and selective receptor agonists, K_ATP channel openers. Other anti-ischaemic agents, eg, Na/H exchange inhibitors.	Several agents are protective if administered before coronary occlusion. Clinically, timing of bolus treatment would be difficult. Continuous pretreatment over an indefinite period before infarction is the only feasible approach. For trial purposes, only a limited number of unstable angina patients would be available.
Patient presents with evolving myocardial infarction. Reperfusion treatment is indicated.	(a) Intra-ischaemic treatment to limit ongoing ischaemic injury is dependent on access of drug to the ischaemic risk zone through either residual flow in the infarct related artery, a cyclical pattern of thrombosis (“stuttering ischaemia”) or a degree of collateral flow,	Anti-ischaemic agents must have access to the risk zone during the early ischaemic period.	Drug access to the ischaemic risk zone would be unpredictable. Some patients may benefit (eg, if there is some residual flow) but because of inherent variability in effective dosing of the risk zone, large numbers would be required to show statistical benefit. Not an ideal scenario for a clinical trial. Potential benefit of adenosine in AMISTAD may be via an anti-ischaemic effect since experimental evidence for an effect at reperfusion is conflicting.
	(b) Pre- or perireperfusion treatment to limit reperfusion injury.	A few clinically tested agents, eg, insulin and magnesium, may act predominantly in this mode. Experimental agents which attenuate reperfusion injury include various inhibitors of apoptosis.	Reperfusion injury may contribute 25–50% of final infarct size. Unless treatment is very potent, large numbers would be required to detect benefit. Reperfusion injury occurs early and timing of treatment is critical. Administration after reperfusion will reveal little or no effect, cf magnesium in LIMIT-2 and ISIS-4 trials.

In all cases, prompt reperfusion is the prequisite for tissue salvage. In a trial, any benefit would have to be beyond that attributable to reperfusion treatment alone.