Thrombolysis for Acute Myocardial Infarction: Drug Review

David K. Cundiff

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In This Article

The "Open-Artery Hypothesis" and the "Illusion of Perfusion"

The open-artery hypothesis of Kim and Braunwald[3] states that early reperfusion of an IRA would be associated with reduced myocardial necrosis, improved left ventricular function, and reduced mortality. However, the literature has shown that survival is not well linked to preserving left ventricular function,[3] and in randomized trials, thrombolysis long after irreversible myocardial necrosis has occurred still seems to be associated with survival benefit.[3] Therefore, part or all of any supposed survival benefit associated with thrombolytic drugs is not due to reperfusing an occluded IRA.

Recent clinical research also reveals another paradox in the theory that thrombolytic therapy works by opening obstructed IRAs. Lincoff and Topol[4] found that the high patency rates reported with thrombolytic therapy (up to 85% at 90 minutes) are not really happening. Angiographic data after infusion of thrombolytics give only an "imperfect snapshot" of the dynamic of a thrombotic coronary artery causing an AMI. The high number of "patent" culprit coronary lesions achieved with thrombolysis include: (1) vessels not occluded at baseline, (2) those that spontaneously achieve patency, and (3) those successfully acted upon by thrombolytic drugs. By analysis of the thrombolytic literature, these authors determined that fewer than 25% of patients have demonstrable improvement in perfusion due to thrombolysis after considering the following factors:

  1. The lesser rate of patency at the more critical time of 60 minutes after infusion of thrombolytic agents;

  2. Patency redefined as brisk angiographic flow rather than brisk angiographic flow or functionally inadequate delayed flow (ie, on the Thrombolysis in Myocardial Infarction [TIMI] angiographic flow assessment scale, TIMI 3 only, not TIMI 2 + TIMI 3)[5,6,7];

  3. The "no flow" phenomenon or the incidence of lack of myocardial perfusion despite patency;

  4. The occurrence of intermittent patency; and

  5. Reocclusion.

In their analysis of angiographic studies in patients treated with thrombolysis, Lincoff and Topol also found that mortality benefit from thrombolysis is disproportionately high in comparison with the very modest improvements in left ventricular function (ie, 2% to 3% increased ejection fractions). This suggests that the mortality reduction is not linked to the speed of reperfusion or to greater salvage of myocardium.

[4]

The authors concluded, "clinical and experimental data clearly demonstrate a sobering deterioration of benefit derived from coronary recanalization that is not early, not rapid, with incomplete reflow, with critical residual stenoses, unaccompanied by tissue-level reperfusion, diminished by cyclical patency or frank reocclusion, or possibly negated by reperfusion injury. The 'open artery hypothesis' that prognosis is improved by restoration of infarct artery patency has not and cannot truly be tested until optimal reperfusion becomes a practical reality."[4]

Further problems with the clinical validation of the theoretical basis of thrombolysis came from a study by Ohman and colleagues,[8] showing the relationship of AMI survival and patency of the IRA at 90 minutes after thrombolysis. Relatively little difference exists between patency rates of patients who survive (71%) compared with those who die in the first 24 hours (59%) or those who die after 24 hours (45%). Survivors overall did have a higher chance of patency than those who died (P = .002). However, as noted by Lincoff and Topol, thrombolysis accounts for a relatively small amount of the difference in patency rates of all patients, survivors and those who die. The fact that 29% of AMI survivors who received thrombolytics still have an occluded IRA at 90 minutes while about half who die have a patent IRA at 90 minutes argues strongly against the "open-artery hypothesis."

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