Bolus fibrinolysis: risk, benefit, and opportunities.

Fibrinolytic therapy for acute ST-segment elevation myocardial infarction has made a major contribution to the care of thousands of patients worldwide.1 Over the past decade, there have been tremendous advances in the care of such patients, including an enhanced assessment of both the risks of the infarction and the potential for complicating intracranial hemorrhage (ICH), more effective reperfusion strategies, and commensurate improvements in the approach to primary angioplasty and stenting.2–4 Recently, a metaanalysis of phase III megatrials involving several different fibrinolytic agents used for acute myocardial infarction suggested that agents administered as a bolus are associated with an excess risk of ICH.5 The advantages of long-acting, third-generation fibrinolytic agents administered as a simple, singleor double-bolus injection are substantial when compared with prior agents that require sustained infusions and are often introduced by a bolus, with or without a step-down infusion. Within contemporary emergency departments, physicians and nurses are required to deal with a growing and increasingly complicated array of available therapies, not only for acute coronary syndromes, but for many other conditions as well. These demands are often accented by resource constraints; hence, simple bolus fibrinolytic regimens are a welcome innovation for those healthcare workers on the front lines, and such regimens are less likely to engender medication errors. However, the relationship between fibrinolytic dosing errors and morbidity and mortality is complex. Thus, whereas a higher frequency of modest dosing errors was identified after therapy with recombinant tissue-type plasminogen activator (rt-PA) than with tenecteplase (TNK-tPA) in the Assessment of the Safety of a New Thrombolytic (ASSENT) 2 study and 30-day mortality was also higher with incorrect dosing of rt-PA in this study, the excess mortality was evident whether patients received rt-PA or rt-PA placebo.6 This analysis emphasizes the important role of confounding factors in the ascertainment of causal relationships. Notwithstanding these findings, the implications for more general use outside a clinical trial may be different. In this regard, medication errors were noted to occur in 15% of the National Registry of Myocardial Infarction population with administration of the weight-adjusted 90-minute step-down infusion of rt-PA after its initial bolus.7,8 Excessive rt-PA dosing was associated with a 49% increase in the incidence of ICH after adjustment for relevant baseline covariants.7 When ICH complicates fibrinolytic therapy, the implications are often devastating, with approximately two-thirds of patients dying and two-thirds of the survivors experiencing important residual disability. Unfortunately, the symptoms that permit recognition of complicating ICH develop some hours after the completion of current fibrinolytic therapy, and modification of their administration regimen is not a feasible remedy to circumvent this problem. It is well recognized that the difference in properties between the fibrinolytic agents currently in general use has a substantial impact on their efficacy and safety. Hence, whereas rt-PA administered over 90 minutes in a bolus and step-down infusion produces superior early coronary patency, improved preservation of left ventricular function, and enhanced survival when compared with streptokinase, it is also associated with a higher ICH rate, especially in elderly patients.9,10 From its beginnings in the early Thrombolysis in Myocardial Infarction (TIMI) experience, dosing of rt-PA was found to be critical as it relates to the risk of ICH; hence, an unacceptably high rate of 1.89% was found with the 150-mg dose, leading to a reduction in the dose to 100 mg and a decline in ICH to 0.54%.11 A similar experience occurred in the TIMI 10B Phase II evaluation of the triple substitution mutant of rt-PA (ie, TNK-tPA).12 These 3 modifications of TNK-tPA confer a diminished plasma clearance rate, a higher resistance to plasminogen activator inhibitor-1 inhibition, and more pronounced fibrin specificity. In the TIMI 10B study, 886 patients with acute ST-segment elevation myocardial infarction presenting within 12 hours were randomized in a non–weight-adjusted fashion to receive either a single bolus of 30 or 50 mg of TNK-tPA versus accelerated rt-PA. Because of a concerning early rate of ICH (3 of the first 78 patients; ie, 3.8% at 50 mg), the 50-mg dose