Thrombolysis for Acute Myocardial Infarction: Drug Review

David K. Cundiff

Disclosures
In This Article

AMI Registries

The modern reperfusion era of coronary care ushered in intracoronary and then intravenous thrombolysis, aspirin, and percutaneous coronary interventions for AMI. Overall hospital mortality from AMI declined from 29% in the 1960s to 21% in the 1970s to 16% in the 1980s, to about 10% in the 1990s.[22,23,24]However, the increased public awareness of cardiac symptoms and higher rate of hospitalization of patients with milder AMI cases may account for most or all of the reduction in hospital mortality.

If thrombolytic therapy partly accounts for the decline in AMI mortality in the past 30 years, data from AMI registries, adjusted for the known poor prognostic factors, should show significant survival improvement in patients receiving thrombolysis. In the registry of 12,331 patients with AMI in Seattle, after adjusting for age, no significant reduction in mortality could be attributed to the use of thrombolysis or angioplasty.[22] Unfortunately, the AMI mortality adjusted for risk factors with and without thrombolysis in this registry was not published and is not available from the authors.

In a study of 7864 Medicare fee-for-service patients aged 65 years or older with AMI, Thiemann and colleagues[62] found that among patients aged 76 to 86 years, thrombolytic therapy significantly increased the 30-day mortality (hazard ratio, 1.38; 95% confidence interval [CI], 1.12 to 1.71; P = .003). The 3% survival advantage in the patients receiving thrombolysis in the 65- to 75-year-old group is questionable because of differences in baseline characteristics of those who did and didn't receive thrombolytics. Patients getting thrombolysis had less diabetes mellitus (22.3% vs 31.2 , P < .001), congestive heart failure (4.4% vs 13.5%, P < .001), and prior coronary events (21.7% vs 37.5 %, P < .001). Men in the 65- to 75-year-old group had no significant survival advantage with thrombolysis (hazard ratio, 1.00; CI, 0.72 to 1.39).[62]

The NRMI is a prospective, observational, phase 4 study sponsored and owned by Genentech, Inc. (San Francisco, California). It examines practice patterns and resource utilization in the treatment of AMI and monitors the in-hospital safety experience of the use of t-PA (made by Genentech). NRMI-1 covers the years 1990-1993 and NRMI-2 begins in 1994. NRMI-1 shows an unadjusted hospital mortality of 13.1% vs 5.9% for AMI patients not taking and taking thrombolytics respectively.[23]

The significance of this difference is highly questionable since the patients not receiving thrombolytics were at much higher risk because of baseline characteristics, especially age. The average age of the thrombolytic group and the nonthrombolytic group were 60.6 and 68.3, respectively. Of patients younger than 60 years old, 50% received thrombolytics, and of those 60 years old or older, only 28% got thrombolytics. Buried in the discussion section of one NRMI study, Rogers and colleagues[23] stated, "Although thrombolytic therapy was probably life-saving in many instances, it is likely that selection of lower-risk patients for thrombolysis was the primary factor explaining the lower mortality rate."

In NRMI-2, covering the years 1994 to 1997, the overall in-hospital mortality rate in those AMI patients eligible for thrombolytic reperfusion therapy was 7.9%. Patients who received reperfusion therapy again had a lower unadjusted mortality rate compared with eligible patients who did not (5.7% vs 14.8%, respectively). However, thrombolytic therapy-eligible patients who did not get treatment again included more high-risk patients such as the elderly, women, and patients with congestive heart failure, anterior-wall myocardial infarctions, strokes, or diabetes. For instance, for patients more than 75 years old, the mortality was 4.5 times the mortality of those younger than 75 years. However, the chance of patients older than 75 years receiving thrombolytics was 40% of that of younger patients.[25] The NRMI-2 authors again did not publish a comparative mortality rate adjusted for the known risk factors.

The only report that Genentech has issued from the NRMI-2 concerning age and severity of disease-adjusted mortality excluded 90% of the 691,995 patients on whom they received data.[63] Reasons for excluding patients included the following:

  1. Use of thrombolytics other than t-PA (n = 80,990)

  2. Receiving a second dose of t-PA (n = 1241)

  3. Transfer into or out of a reporting hospital (n = 258,231)

  4. Lack of ST elevation (n = 237,877)

  5. History of stroke (n = 6026)

  6. Time from symptom onset to hospital arrival either not recorded or > 12 hours (n = 25,820)

  7. Time to t-PA > 12 hours (n = 699)

  8. Contraindications to thrombolytics checked on the report form (n = 13,514)

  9. Bundle branch blocks (number not stated)

Considering that patients in categories 4, 5, 6, 7, and 8 on this list should not have received fibrinolysis, this means that an unknown portion of 283,936/691,995 (41%) of the registry patients may have inappropriately received thrombolytics. The rate of thrombolysis treatment for patients without AMI may be considerably higher than documented in the EMERAS (11%) and LATE (7%) studies.

[16,17]

Given the 1% mortality of thrombolytic therapy, this is potentially a very serious problem.

Demonstrating the importance of selecting patients for therapy, investigators who were probably partial to angioplasty used the same NRMI-2 database to show a superior AMI survival outcome with angioplasty compared with thrombolytic therapy (2.4% vs 6.6% mortality, respectively; odds ratio, 0.44; 95% CI, 0.33 to 0.60).[64,65]

Given the need to adjust for risk factors, the published registry statistics do not support the efficacy of thrombolytics in reducing AMI mortality.

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