A critical amendment to the Meta-analysis of clinical trials comparing Thrombolysis with Primary Angioplasty

Michael Thimme*

Aventis Behring GmbH Germany, Business Unit Critical Care, Emil-v.- Behring Str., 35037 Marburg, Hessen, Germany

* Corresponding author. Tel.: +49-6421-39-4130; fax: +49-6421-39-4146
E-mail address: michael.thimme{at}aventis.com

Received 13 May 2003; accepted 20 June 2003

I refer to the publication of Zijlstra,1who compares two therapeutic concepts in the treatment of acute myocardial infarction. The author concluded that this study demonstrates the advantage of primary angioplasty vs thrombolysis. The analysis mainly focuses on outcome parameters, which of course are of utmost importance, but with a selective pooling of individual results, without addressing limitations or a potential publication bias. Some methodological issues that may affect the conclusions should be addressed:

First, the methodology of meta-analysis always bears a certain risk that important information gets lost. In this meta-analysis the author uses the data of Weaver.2These data, however, also represent a meta-analysis of several studies, and the use of secondary data is critical. Another trial used in Zijlsta’s analysis was the Prague-2 trial, published by Widimsky.3This trial was not significant in the intention-to-treat analysis. Authors in particular analyze a relatively small subgroup of 299 patients with >3h of characteristic symptoms. Although, in this subgroup primary PCI was significantly better than thrombolysis, the results should be interpreted with caution due to the limited sample size. An additional critical issue is the long delay between onset of symptoms and randomization (almost 3 hours), which appears unacceptable. However, Prague-2 represents a randomized clinical trial and only the data drawn from Weaver’s analysis2have to be excluded for methodology reasons.

Using the reported database1of 3873 patients enrolled in 10 clinical trials and focusing only on the baseline characteristic ‘previous MI’, from 1947 patients treated with primary PCI, 232 (12.05%) were reported to meet this characteristic, and from 1926 treated with thrombolysis 198 (10.17%) respectively. This 1.9% discrepancy is representing a strong trend (P=0.066, two-sided Fisher test) towards a better prognosis for the angioplasty groups. In an analysis resulting in a difference between strategies ranging between 2.8% and 2.3%, this is definitely relevant. It is even more important, as there are many more characteristics, which may have an impact on trial results (e.g. age, Killip class, location etc) than outcome parameters (mortality or composite end-point).

At the first glance not only mortality but also the adverse events rate (in the publication defined as non-fatal reinfarction and stroke) may be striking. The increased benefit observed in the respective analysis is mainly due to the reduced reinfarction rate in the PCI groups. However, this conclusion neglects the data of recent clinical trials with improved anticoagulation, e.g. the results of ASSENT-34or AMI-SK,5where also a significant reduction of reinfarction was achieved.

In summary, the presented naïve meta-analysis did not address a possible publication bias, the possible heterogeneity of individual trials and confounding prognostic factors (e.g. previous MI, delay of treatment) with their impact on the outcomes.

Primary PCI offers a highly welcomed alternative for the cardiologist to treat patients with ST-elevation myocardialinfarction. Zijlstra’s recommendation, however, appears to be premature and should be substantiated by data from large, prospective, randomized clinical trials or properly conducted meta-analyses.

References

  1. Zijlstra F. Angioplasty vs thrombolysis for acute myocardial infarction: a quantitative overview of the effects of interhospital transportation. Eur Heart J. 2003;24:21–23.[Free Full Text]
  2. Weaver WD, Simes RJ, Betriu A, for the Primary Coronary Angioplasty vs Thrombolysis Collaboration Group et al. Comparison of primary coronary angioplasty and intravenous thrombolytic therapy for acute myocardial infarction: a quantitative overview. JAMA. 1997;278:2093–2098.[Abstract]
  3. Widimsky P, Budesinsky T, Vorac D et al. for the ‘Prague‘ study group investigators. Long distance transport for primary angioplasty versus immediate thrombolysis in acute myocardial infarction: final results of the randomized national multicenter trial ‘PRAGUE-2’. Eur Heart J. 2003;24:94–104.[Abstract/Free Full Text]
  4. The Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet. 2001;358:605–613.[CrossRef][Medline]
  5. Simoons ML, Krzeminska-Pakula M, Alonso A et al. for the AMI-SK investigators. Improved reperfusion and clinical outcome with enoxaparin as an adjunctive to streptokinase thrombolysis in acute myocardial infarction. Eur Heart J. 2002;23:1282–1290.[Abstract/Free Full Text]




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