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BMJ. 1999 January 30; 318(7179): 328.
PMCID: PMC1114792

Intravenous β blockade in acute myocardial infarction

Doubts exist about external validity of trials of intravenous β blockade
K L Woods, Professor of therapeutics
Department of Medicine and Therapeutics, Leicester University, Leicester Royal Infirmary, Leicester LE2 7LX ; ku.oc.dnomaid@sdoow.tnek
D Ketley, Associate director for research and development

Editor—Owen’s perception that intravenous β blockers are less commonly given after acute myocardial infarction in the United Kingdom than elsewhere1 is confirmed by data from the European secondary prevention study.2 Clinical management was examined in a representative sample of over 4000 patients admitted to hospital with confirmed acute myocardial infarction in 11 European regions. Intravenous β blockade was given to 13% of patients overall, but this proportion varied from 0.5% (United Kingdom) to 54% (Sweden) in the regional samples. This 100-fold range, larger than the range for any other treatment or procedure studied, is particularly striking for an aspect of management that has been subjected to at least 28 randomised trials in over 27 000 patients.

Variation in practice on this scale has important messages for proponents of evidence based medicine and cannot be explained by lack of awareness on the part of clinicians. The key issue is the generalisability of the evidence from trials in highly selected low risk patients. In the largest trial, the first international study of infarct survival, fewer than a third of patients admitted to coronary care units were considered to have been eligible for randomisation.3 The primary end point of vascular mortality in the first week was low in both the atenolol and control groups (3.9% v 4.6%; P<0.04). The pooled estimate of treatment effect on one week mortality in all available trials remains of borderline significance, and definition of the relevant patient group is even more difficult when meta-analysis is used.

No evidence from clinical trials exists to indicate whether intravenous β blockade would be more or less beneficial in haemodynamically compromised patients or those with hypotension induced by thrombolytics. All observational data are invalidated by the confounding of treatment selection and haemodynamic status. The highly significant increase in the use of inotropic support seen after treatment with atenolol in the first international study of infarct survival gives grounds for caution.

The observed variation in practice probably reflects the widely differing judgment of clinicians on the external validity of the published trials of intravenous β blockade. For long term oral β blockade the evidence is stronger and patient selection less problematic. Correspondingly, use of this treatment was more common in the European study (46% at six months after discharge) and rather more consistent between regional samples (range 27-72%).


1. Owen A. Intravenous β blockade in acute myocardial infarction. BMJ. 1998;317:226–227. . (25 July.) [PMC free article] [PubMed]
2. Woods KL, Ketley D, Lowy A, Agusti A, Hagn C, Kala R, et al. β Blockers and antithrombotic treatment for secondary prevention after acute myocardial infarction. Towards an understanding of factors influencing practice. Eur Heart J. 1998;19:74–79. [PubMed]
3. ISIS-1 Collaborative Group. Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. Lancet. 1986;ii:57–66. [PubMed]
1999 January 30; 318(7179): 328.

Case for intravenous β blockade for patients given thrombolysis is still uncertain

Peter F Ludman, Consultant cardiologist

Editor—The debate about the value of acute β blockade in myocardial infarction is interesting, partly because of the lack of randomised data in the “thrombolytic era.”1-1 Owen’s statement that evidence for the use of intravenous β blockade is “even more overwhelming” than in the prethrombolytic era is not supported by the studies that he references in his editorial1-1 or by the world literature.

The thrombolysis in myocardial infarction (TIMI) II-B study is the only randomised comparison in patients receiving thrombolysis.1-2 The effect of acute intravenous metoprolol versus deferred oral metoprolol (started at 6-8 days) was assessed in 1434 patients who had been treated for acute myocardial infarction with recombinant tissue-type plasminogen activator. Though this was a relatively small study, the results are widely recognised to have been disappointing. There was no benefit in left ventricular function and no reduction in mortality. Furthermore, the incidence of myocardial rupture was not reduced. Though the incidence of recurrent chest pain and of reinfarction fell (18.8% v 24.1%; P<0.02 and 2.7% v 5.1%, P=0.02; respectively), this difference was not maintained at one year follow up. It should be emphasised that the GISSI-2 (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardio-2) trial, which Owen cites, was not a randomised comparison but a description of what happened to two very different groups of patients; it should not be used as evidence for either safety or efficacy.

The case for intravenous β blockade in patients who do not receive reperfusion treatment is secure, but for those treated with thrombolysis or primary angioplasty the data are far from overwhelming.


1-1. Owen A. Intravenous β blockade in acute myocardial infarction. BMJ. 1998;317:226–227. . (25 July.) [PMC free article] [PubMed]
1-2. Roberts R, Rogers WJ, Mueller HS, Lambrew CT, Diver DJ, Smith HC, et al. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) II-B study. Circulation. 1991;83:422–437. [PubMed]
1999 January 30; 318(7179): 328.

In one health district, only 0.2% eligible for intravenous β blockade received it

Kevin Hardy, Consultant physician
Sarah O’Brien, Research nurse

Editor—Owen discusses how rarely intravenous β blockade is used in trials in acute myocardial infarction in Britain,2-1 citing the fourth international study of infarct survival (ISIS-4) trial, in which intravenous β blockade was given to only 5% of patients enrolled in Britain compared with 30% of those enrolled in Italy and the United States.2-2 He says that this is consistent with anecdotal evidence that few British hospitals routinely use intravenous β blockade in acute myocardial infarction. We agree.

We have recently concluded a retrospective study examining routine clinical care of patients with acute myocardial infarction in St Helens and Knowsley Health District. For three periods of four months in successive years (1994-6) we have complete data on use of intravenous β blockers in acute myocardial infarction and contraindications to this treatment for 717 of 989 patients. Altogether, 285 of these 717 patients had contraindications to intravenous β blockade: asthma, chronic obstructive pulmonary disease, acute left ventricular failure, severe hypotension, or severe bradycardia. Of the remaining 432 patients eligible for intravenous β blockade, only one received it; 205 received thrombolysis and presumably therefore had even more to gain from intravenous β blockade (it was not indicated for over half whether they received thrombolysis or not).

Our data strongly support Owen’s impression that many eligible patients in Britain are being denied a lifesaving treatment at the time of acute myocardial infarction.


2-1. Owen E. Intravenous β blockade in acute myocardial infarction. BMJ. 1998;317:226–227. . (25 July.) [PMC free article] [PubMed]
2-2. Sleight P. What happened to intravenous atenolol in acute myocardial infarction? Cardiology. 1994;85(suppl 1):13–17. [PubMed]

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