Persistent Reduction of Mortality for Five Years After One Year of Acebutolol Treatment Initiated During Acute Myocardial Infarction

doi:10.1016/S0002-9149(96)00820-X

The American Journal of Cardiology

Volume 79, Issue 5, 1 March 1997, Pages 587-589

https://doi.org/10.1016/S0002-9149(96)00820-X Get rights and content

Abstract

The APSI trial was a randomized placebo-controlled trial designed to assess the efficacy of 1 year of treatment by acebutolol in high-risk patients who had survived an acute myocardial infarction. At 1 year there was a statistically significant 48% relative reduction in total mortality (p = 0.019) in favor of acebutolol. In 1995 a long-term mortality survey was undertaken through an administrative inquiry and contacts with investigators. The vital status of 586 of the 607 (96.5%) patients enrolled was known at the cutoff date and all these patients were followed up for at least 5 years. During follow-up (in-trial and post-trial period), 74 deaths (24.8%) occurred in the acebutolol group and 96 (31.1%) in the placebo group (p = 0.10). No difference between the 2 groups was observed for the number of deaths that occurred after the end of the trial: 55 deaths (19.6%) among the 281 survivors in the acebutolol group and 59 deaths (21.7%) (p = 0.70) among the 272 survivors in the placebo group. The annual hazard rate (annual death rate), calculated year by year using the actuarial method, was significantly different (p <0.01) only for the first year and was not significantly different thereafter. Thus, the initial benefit obtained in 1 year of treatment by acebutolol lasts for 5 years.

The APSI trial was a randomized placebo-controlled trial designed to assess the efficacy of 1-year treatment by acebutolol in high-risk patients who had survived an acute myocardial infarction. The present long-term mortality survey shows that the initial benefit conferred by acebutolol during the first year after myocardial infarction treatment is maintained for 5 years.

Section snippets

Methods

The protocol has been described elsewhere.[5]Briefly, high-risk patients were selected using a prediction function in 44 French hospitals. After selection, the patients were admitted to the trial ≤22 days after the myocardial infarction and were treated and followed up for 1 year. The protocol was approved by an Ethics Committee and the patient consent was obtained.

The present follow-up study was not planned in the protocol, but the data recorded were sufficient to enable the vital status of

Follow-Up

The vital status on the cutoff date was obtained for 586 of the 607 patients (96.5%) enrolled in APSI. The number of patients lost to follow-up was not statistically different between the groups (acebutolol: 15 of 298, 5.0%; placebo: 6 of 309, 1.9%, p = 0.06, chi-square test).

The follow-up time for the last patient enrolled in April 1987 was 5.12 years. The first patient enrolled in December 1988 was followed 7.6 years. The median duration of follow-up was 6 years (5 years after the end of the

Discussion

It is important to note that these results concern only the long-term effect of 1 year of treatment by β-blocking drug immediately following acute myocardial infarction. The controlled intervention was only applied during the trial period, but after this period we cannot rule out the possibility that patients in both groups received β blockers. Also, an unknown number of patients in the acebutolol group probably stopped taking the drug. The influence of these unknown treatments on the survival

Acknowledgements

We acknowledge all the investigators who participated in the APSI trial. The comprehensive list of the members of the APSI group was published in the appendix of the study presenting the trial results.[5]We are grateful to the reviewers for the useful comments and suggestions.

The study was supported by a grant from SPECIA Pharmaceuticals, Paris, France.

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There are more references available in the full text version of this article.

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Tratar con bloqueadores beta a pacientes con síndrome coronario agudo y fracción de eyección del ventrículo izquierdo preservada se asocia con menos mortalidad a largo plazo.
The scientific evidence for using beta-blockers after acute coronary syndrome stems from studies conducted in the days before coronary revascularization and in patients with ventricular dysfunction. The aim of this study was to analyze the current long-term prognostic benefit of beta-blockers in patients with acute coronary syndrome and preserved left ventricular ejection fraction.
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Beta-blocker treatment in patients with acute coronary syndrome and preserved left ventricular ejection fraction is associated with lower long-term mortality.
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Debate exists about the efficacy of β-blockers in myocardial infarction and their required duration of usage in contemporary practice.
We conducted a MEDLINE/EMBASE/CENTRAL search for randomized trials evaluating β-blockers in myocardial infarction enrolling at least 100 patients. The primary outcome was all-cause mortality. Analysis was performed stratifying trials into reperfusion-era (> 50% undergoing reperfusion or receiving aspirin/statin) or pre-reperfusion-era trials.
Sixty trials with 102,003 patients satisfied the inclusion criteria. In the acute myocardial infarction trials, a significant interaction (P_interaction = .02) was noted such that β-blockers reduced mortality in the pre-reperfusion (incident rate ratio [IRR] 0.86; 95% confidence interval [CI], 0.79-0.94) but not in the reperfusion era (IRR 0.98; 95% CI, 0.92-1.05). In the pre-reperfusion era, β-blockers reduced cardiovascular mortality (IRR 0.87; 95% CI, 0.78-0.98), myocardial infarction (IRR 0.78; 95% CI, 0.62-0.97), and angina (IRR 0.88; 95% CI, 0.82-0.95), with no difference for other outcomes. In the reperfusion era, β-blockers reduced myocardial infarction (IRR 0.72; 95% CI, 0.62-0.83) (number needed to treat to benefit [NNTB] = 209) and angina (IRR 0.80; 95% CI, 0.65-0.98) (NNTB = 26) at the expense of increase in heart failure (IRR 1.10; 95% CI, 1.05-1.16) (number needed to treat to harm [NNTH] = 79), cardiogenic shock (IRR 1.29; 95% CI, 1.18-1.41) (NNTH = 90), and drug discontinuation (IRR 1.64; 95% CI, 1.55-1.73), with no benefit for other outcomes. Benefits for recurrent myocardial infarction and angina in the reperfusion era appeared to be short term (30 days).
In contemporary practice of treatment of myocardial infarction, β-blockers have no mortality benefit but reduce recurrent myocardial infarction and angina (short-term) at the expense of increase in heart failure, cardiogenic shock, and drug discontinuation. The guideline authors should reconsider the strength of recommendations for β-blockers post myocardial infarction.
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In this regard, a metaregression analysis has shown that there was a near significant trend toward a decreased benefit of agents with ISA in patients after an MI.18,31 However, the Acebutolol et Prévention Secondaire de l'Infarctus (APSI) trial has shown that acebutolol still decreases mortality at 5 years in patients who had an MI.66 Lipophilic agents, such as propranolol, metoprolol, and nebivolol67 have the ability to cross the blood-brain barrier.
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The Norwegian Multicenter Study Group5 reported that this survival benefit was evident for at least 6 years after MI. Similar results were observed in the extended 5-year follow-up of the APSI trial.9 Large-scale observational reports have confirmed that the benefits that have been observed with β-blocker therapy in clinical trials are actually achieved in clinical practice.10-12
Multiple clinical trials have demonstrated β-blockers improving survival after myocardial infarction (MI). Patients with “bradycardia-related” contraindications to β-blockers, such as those with asymptomatic bradycardia or AV conduction abnormalities, have been excluded from clinical trials of β-blockers and continue to be excluded from post-MI β-blocker therapy in routine clinical practice. These patients tend to be elderly and have a high 1-year mortality. If β-blockers provide benefit to the post-MI patient independent of their heart rate–lowering effect, then these patients could benefit substantially from initiation of β-blocker therapy. However, in this particular group of patients, β-blockers can be safely initiated only if more severe or significant bradycardia can be prevented by pacemaker implantation. It is unclear whether adverse effects related to pacemaker implantation could also negate some or all of the hypothesized benefit of β-blocker therapy. Although β-blockers are particularly effective in the elderly, the benefit of β-blocker therapy in patients with bradycardia-related contraindications to β-blockers has not been established. The PACE-MI trial is a randomized controlled trial that will address whether β-blocker therapy enabled by pacemaker implantation is superior to no β-blocker and no pacemaker therapy after MI in patients with rhythm contraindications to β-blockers or in those who have developed symptomatic bradycardia due to β-blockers. The trial will randomize 1124 patients to standard therapy (not to include β-blockers as patients must have a contraindication to be enrolled) or standard therapy plus pacemaker implantation and β-blocker. The primary end point is the composite end point of total mortality plus nonfatal reinfarction.

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Persistent Reduction of Mortality for Five Years After One Year of Acebutolol Treatment Initiated During Acute Myocardial Infarction

Abstract

Section snippets

Methods

Follow-Up

Discussion

Acknowledgements

Progr Cardiovasc Dis

Am J Cardiol

The Beta-Blocker Pooling Project (BBPP) research group. Subgroup findings form randomized trials in post infarction patieints

Eur Heart J