Bleeding is the major risk associated with thrombolytic therapy. Absolute and relative bleeding contraindications to thrombolytic therapy are given in Table 6. Fortunately, bleeding is usually manageable with conservative measures, only occasionally requires transfusion, and most frequently (70% of cases) occurs at sites of vascular puncture. In ISIS-3 (118), which did not require angiography, noncerebral bleeding was reported in 4.5% of patients after SK, 5.4% after APSAC, and 5.2% after tPA; hemorrhage required transfusion or was otherwise defined as "major" in only 0.9, 1.0, and 0.8% of patients, respectively. In the FTT overview experience of about 60,000 patients (110), a major bleeding event occurred in 1.1% after thrombolytic therapy compared with 0.4% after control, a small but significant difference (p < 0.00001).

Life-threatening internal hemorrhage may occur after thrombolytic therapy, of which ICH is the most important. The fatality rate with ICH is approx 60% (range 44-75%) (110,150-153), and disability is common among survivors. The risk of ICH in clinical trials has averaged about 0.5-1.0% but varies with patient characteristics, particularly advancing age, as well as the specific dose and type of the thrombolytic agent and adjunctive antithrombotic therapies (150-156). Downward adjustment of heparin doses in recent trials has helped to avoid excessive ICH risk with tPA variants (90,133). Increases in ICH associated with thrombolysis are in part offset by decreases in ischemic stroke.

The FTT meta-analysis suggested that for every 1000 patients treated with fibrinolytic agents, therapy causes 7 major noncerebral hemorrhages and 2 nonfatal, non-cerebral hemorrhages while preventing 18 deaths by 35 d (110). ISIS-3 compared various older thrombolytic regimens and reported ICH rates of 0.2% for SK, 0.55% for APSAC, and 0.66% for tPA (duteplase) (118). Respective total stroke rates were 1.04, 1.26, and 1.39% (slightly but significantly greater with tPA than SK). In the subsequent GUSTO study (96), rates of ICH were 0.54% with SK and 0.72% with accelerated tPA (alteplase), each with IV heparin. Respective total stroke rates were 1.40 and 1.55%. In a comparison of rPA and tPA, ICH rates were 0.93 and 0.87%, respectively, and total stroke rates 1.68 and 1.81% (p = NS) (75). Similar ICH rates also were found in the phase-3 comparison of TNK-tPA and tPA (0.93 vs 0.94%) (133).

Unacceptable increases in ICH and other bleeding risks have been observed with aggressive adjuvant antithrombotic regimens given together with thrombolytics. Indeed, the GUSTO-IIA, TIMI-9A, and r-Hirudin for Improvement of Thrombolysis (HIT)-III trials (157-159) were stopped prematurely and reconfigured because of excessive rates of hemorrhage, including ICH. In the subsequent trials (GUSTO-IIB, TIMI-9B), hemorrhage rates decreased to an expected and acceptable range (147,148). Downward adjustments of heparin dosing were made prior to ASSENT-II (with TNK-tPA) and InTIME-2 (with lanoteplase), as noted above (90,133,148).

In an effort to build a predictive model for ICH, Simoons et al. (155) collected information from five clinical study sources providing information on 150 patients with documented ICH after thrombolytic therapy. These were compared with 294 matched controls. A multivariate analysis identified four independent predictors for ICH: age >65 yr (OR: 2.2, CI: 1.4-3.5), weight <70 kg (OR: 2.1, CI: 1.3-3.2), hypertension on admission (OR: 2.0, CI: 1.2-3.2), and use of tPA (alteplase) compared with SK (OR: 1.6, CI: 1.0-2.5). Assuming an overall incidence of ICH of 0.75%, the model predicted incidences of ICH of0.26, 0.96, 1.32, and 2.17% for those with no, one, two, or three risk factors, respectively. For patients over 75 yr, the risk was predicted to be 1.5% with no other risk factors, climbing to 3.3% with the other two risk factors. Comparing the expected benefits of thrombolytic therapy with these predicted risks may allow the physician to individualize the selection of therapy, which might include a less aggressive thrombolytic or antithrombotic regimen or a primary PCI in those at high risk for ICH.

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