The effect of clinical trials on treatment in myocardial infarction
Article first published online: 25 DEC 2001
1999 Blackwell Science Ltd
Journal of Internal Medicine
Volume 245, Issue 1, pages 1–3, January 1999
How to Cite
Wilhelmsen, L. (1999), The effect of clinical trials on treatment in myocardial infarction. Journal of Internal Medicine, 245: 1–3. doi: 10.1046/j.1365-2796.1999.00431.x
- Issue published online: 25 DEC 2001
- Article first published online: 25 DEC 2001
The acute and long-term management of myocardial infarction has been revolutionized during the last 25 years, and has become based upon evidence from clinical trials rather than beliefs. In the area of evidence-based medicine, we tend to think that treatment is based upon results of clinical trials, but the evidence is not as simple as that. It is important to stress the importance of applying beneficial treatments to an appropriate number of patients, as well as avoiding treatments with negative effects. There is a large potential benefit to a large number of patients of even moderate percentage treatment effects [ 1]. In spite of the vast literature on trials, rather little is known about the translation process from the trial to clinical practice. Chalmers [ 2] reported the impact of controlled trials on the practice of medicine. He provided several examples of clear-cut trial results that did not alter clinical practice. However, evidence for effects of clinical trials on clinical practice has also been provided [ 3, 4]. The latter author stated that scientific findings, awareness of knowledge by physicians, marketing, public knowledge and product features all influenced the uptake of new treatments into practice or their abolition. In this issue of the journal, Miettinen et al. [ 5] report on trends in the treatment of Finnish patients with myocardial infarction during 1986–92. There was an increase in the use of thrombolytic treatment and antiplatelet agents prior to the event, during hospitalization and at discharge. The use of beta-blockers and intravenous nitrates also increased. More male than female patients were treated with these agents. The use of calcium-channel blockers decreased during the study period. The results are consistent with several other reports. It has been interesting to see what has happened during more recent years. The present study shows clear-cut changes of treatment practices within a relatively short period. In other studies, it has also been found that treatment may vary markedly between different countries [ 6, 7].
In the Finnish study, thrombolytic treatment was used in single centres even before the large trials were published, but in general these trials rapidly increased the use of thrombolytics [ 8, 9], and the increase continued between 1989 and 1992. It is interesting that thrombolytic therapy was used at least as often in the small local health care centres as in large central or university hospitals. This finding mirrors the accumulating knowledge that the treatment can also be applied in small units if pertinent indications and contraindications are applied.
The use of intravenous nitrates during hospitalization increased markedly between 1986 and 1992 most probably based upon the positive overview of several rather small trials published in 1988 [ 10].
Interestingly, the Finnish study also showed a significant increase in the use of beta-blockers both during hospitalization and at discharge, even though two trials had indicated positive acute effects much earlier [ 11, 12]. Long-term, small positive trials with beta-blockers were published at the beginning of the 1970s [ 13], whereas large, convincingly positive trials began to be published later [ 14], followed by an overview in 1985 [ 15].
The European Secondary Prevention Study Group have looked at several treatment modalities, as well as the use of coronary angiography in 11 European countries [ 6, 7]. A method was developed to look at not only real use but also shortfall in the use of various treatments. Shortfall was defined as the percentage of patients who had indications and no contraindications to treatment, but who were still not treated according to preset criteria. Marked differences between regions in the use of thrombolytics and beta-blockers have been published.
It is interesting to see the rapid acceptance of antiplatelet agents, mostly aspirin, with an increase during hospitalization from 34 to 82% between 1986 and 1992 and a similar increase in discharge use in the Finnish study. This most probably mirrors the positive results of the ISIS-2 trial published in 1988 [ 9]; thus, we see a rapid acceptance of trial results
On the other hand, the use of calcium-channel blockers decreased and the authors claim that this may have been due to a meta-analysis indicating no significant beneficial effect, or even a slight negative effect [ 16].
It is interesting to see the rapid increase in the use of ACE inhibitors (not measured in 1986); about one-fifth of the patients received this type of treatment in 1992, even before the publication of the positive trial results from the SAVE trial [ 17]. Thus, emerging results from trials with intermediate end-points, such as left ventricular ejection fraction, and the belief in the overall positive effect of this type of treatment were already affecting treatment practices before definitive trial results from hard end-points were available.
The authors also found a markedly increased use of revascularization procedures, primarily in North Karelia followed by Kuopio, but not so impressive in Turku-Loimaa. Especially in this context it has been interesting to see more recent figures against the background of the marked increase in this procedure that we found in Göteborg, Sweden, between 1993 and 1995 [ 18]. Still, this increase is not based upon particularly positive trials in infarct patients.
Lamas et al. [ 19] published an interesting analysis of the SAVE trial which randomized patients between January 1987 and January 1990. They were able to show that treatment with aspirin before and after myocardial infarction and calcium antagonists was clearly related to the publication of positive and more questionable trial results, respectively. This would indicate a much better impact of clinical trial results on treatment nowadays than reported by Chalmers [ 2] in 1974, at least in the USA.
The Finnish paper does not list the types of antiarrhythmic agents that were used. In 1989, 27% of patients in hospital received that type of treatment, decreasing to 16% during hospitalization in 1992. At discharge, 8, 6 and 5% in the years 1986, 1989 and 1992, respectively, received antiarrhythmic therapy. There was a decline in the use both in hospital and at discharge, which may be reflected by the results of the Cardiac Arrhythmia Suppression Trial [ 20, 21]. Still, these figures may be seen as high due to the overall negative effects on mortality of most antiarrhythmic drugs [ 22].
It is tempting to accept clinical trial results as being the reason for changing treatment practices, but it is not as simple as that. The rapid inclusion of aspirin into the therapeutic armamentarium may well be due to the strongly positive trial results, but why did the use of beta-blockers take so long? One explanation may be that many beta-blocker trials were of questionable statistical significance, and it took time for the medical community to accept the value, especially in acute myocardial infarction, where the use is still increasing in several coronary care units. A general conclusion from these findings is that it is extremely important to launch clinical trials which are statistically powered to give convincing results and change medical practice if indicated. However, the still changing practices regarding beta-blocker use may point towards a stronger benefit from large convincing trials like ISIS-2 (aspirin) than overviews of many smaller trials. Because of the relatively high mortality and recurrence rate, as well as the great number of patients suffering from myocardial infarction, it is important to adopt positive (as well as to avoid negative) trial results. Relative effects as moderate as around 15% have important potential impact on number of lives saved [ 1].
- 1Secondary prevention of coronary heart disease: drug intervention and life-style modification. In: Marmot M, Elliott P, eds. Coronary Heart Disease Epidemiology. From Aetiology to Public Health. Oxford: Oxford University Press, 1992; 399 416.& .
- 5Mähönen M on behalf of the FINMONICA Myocardial Infarction Register Group Trends in the treatment of patients with myocardial infarction and coronary revascularization procedures in Finland during 1986–92: the FINMONICA Myocardial Infarction Register Study. J Intern Med 1999; 245: 11 20 (this issue)., , , , ,
- 8Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; 1: 397 402.
- 9ISIS-2 Second International Study of Infarct Survival Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349 60.
- 12ISIS-1 (First International Study of Infarct Survival) Collaborative Group Randomised trial of intravenous atenolol among 16027 cases of suspected acute myocardial infarction. ISIS-1. Lancet 1986; 2: 57 66.
- 22Antiarrhythmic treatment strategies. In: Pitt B, Julian D, Pocock S, eds. Clinical Trials in Cardiology. London: WB Saunders, 1997; 291 308..
Received 19 April 1998; accepted 2 June 1998.