Special Article
Increased survival with β-blockers: Importance of ancillary properties

https://doi.org/10.1016/S0033-0620(97)80039-4Get rights and content

To assess the relative importance of ancillary properties (ie, intrinsic sympathomimetic activity (ISA), β1-selectivity, membrane stabilizing activity, and lipophilicity) in the effect of β-blockers on mortality, a meta-analysis of all available secondary and primary prevention trials was performed. Seventy-one trials evaluating the effect on mortality after myocardial infarction (MI) were identified. The overall relative risk (RR) of mortality during β-blocker treatment versus placebo was 0.89 (95% confidence interval [CI] 0.84–0.93), with a trend according to time of intervention: very early intervention RR 0.94 (95% CI 0.87–1.01), early intervention RR 0.91 (95% CI 0.81–1.01), and late intervention RR 0.80 (95% CI 0.73–0.88). Results were similar or even more marked for the end points one-week mortality, reinfarction, and sudden death. β1-selectivity, lipophilicity, absence of membrane stabilizing property, and absence of ISA were associated with a greater risk reduction compared with β-blockers with the opposite ancillary property. When the effect of the three most frequently used β-blocking drugs (atenolol, metoprolol, and propranolol) were compared, the drug with the combination of ancillary properties showing the most pronounced beneficial effects (metoprolol) had the most marked effect on survival. A similar trend was observed when the five published primary prevention trials comparing β-blockers and diuretics in patients with hypertension were considered, but the number of studies was too low to allow for definite conclusions. We conclude that β-blockade after MI leads to a substantial reduction in mortality. The so-called ‘class-effect’ of β-blockers, however, can be questioned, because ancillary properties appear to play an important role in the efficacy of these drugs.

References (139)

  • AhlmarkG et al.

    Reduction of sudden deaths after myocardial infarction

    Lancet

    (1974)
  • NorrisRM et al.

    Protective effect of propranolol in threatened myocardial infarction

    Lancet

    (1978)
  • YusufS et al.

    Effect of atenolol on recovery of the electrocardiographic signs of myocardial infarction

    Lancet

    (1979)
  • AndersenMP et al.

    Effect of alprenolol on mortality among patients with definite or suspected acute myocardial infarction. Preliminary results

    Lancet

    (1979)
  • WilcoxRG et al.

    Randomised placebo-controlled trial comparing oxprenolol with disopyramide phosphate in immediate treatment of suspected myocardial infarction

    Lancet

    (1980)
  • HjalmarsonÅ et al.

    Effect on mortality of metoprolol in acute myocardial infarction. A double-blind randomised trial

    Lancet

    (1981)
  • JulianDG et al.

    Controlled trial of sotalol for one year after myocardial infarction

    Lancet

    (1982)
  • PowellCE et al.

    Blocking of inhibitory adrenergic receptors by a dichloro analog of isoproterenol

    J Pharmacol Exp Ther

    (1958)
  • ClarkWG et al.

    Goth's Medical Pharmacology

  • HamptonJR

    Secondary prevention of acute myocardial infarction with beta-blocking agents and calcium antagonists

    Am J Cardiol

    (1990)
  • BaberNS et al.

    Beta-blockers in the treatment of myocardial infarction

    Br Med J

    (1980)
  • HjalmarsonÅ

    Beta blocking agents: Current status in the prevention of sudden coronary death

    Ann NY Acad Sci

    (1982)
  • BaberNS et al.

    Confidence in results of beta-blocker postinfarction trials

    Br Med J

    (1982)
  • LieKI et al.

    Beta-blockade and acute myocardial infarction

    Eur Heart J

    (1983)
  • SleightP

    Interventions during and after myocardial infarction

    Postgrad Med J

    (1983)
  • TuriZG et al.

    The use of β-blockers after myocardial infarction

    JAMA

    (1983)
  • WilhelmsonC et al.

    Beta blockers in ischemic heart disease

    Am J Cardiol

    (1983)
  • MaySG

    A review of acute-phase beta-blocker trials in patients with myocardial infarction

    Circulation

    (1983)
  • BassanMM et al.

    Improved prognosis during long-term treatment with beta-blockers after myocardial infarction: Analysis of randomized trials and pooling of results

    Cardiol Clin Care

    (1984)
  • YusufF et al.

    Beta-blockade during and after myocardial infarction: an overview of the randomized trials

    Prog Cardiovasc Dis

    (1985)
  • FrishmanW et al.

    Use of beta-adrenergic blocking agents after myocardial infarction

    Postgrad Med

    (1985)
  • Randomized trial of intravenous atenolol among 16027 cases of suspected acute myocardial infarction: ISIS-1

    Lancet

    (1986)
  • DepelchinP et al.

    Secondary prevention after myocardial infarction: Effects of beta blocking agents and calcium antagonists

    Cardiovasc Drugs Ther

    (1988)
  • HeldP et al.

    Early intravenous beta-blockade in acute myocardial infarction

    Cardiology

    (1989)
  • FurbergCD et al.

    Diuretic agents versus beta-blockers: Comparison of effects on mortality, stroke, and coronary events

    Hypertension

    (1989)
  • GoldsteinS

    Review of beta-blocker myocardial infarction trials

    Clin Cardiol

    (1989)
  • SinghBN

    Advantages of beta blockers versus antiarrhythmic agents and calcium antagonists in secondary prevention after myocardial infarction

    Am J Cardiol

    (1990)
  • KjekshusJK

    Importance of heart rate on determining beta blocker efficacy in acute and long-term acute myocardial infarction intervention trials

    Am J Cardiol

    (1986)
  • ShintonRA et al.

    A meta-analysis of mortality and coronary prevention in hypertensive patients treated with beta-receptor blockers

    J Hum Hypertens

    (1990)
  • FogariR et al.

    Beta-blockers and primary cardioprotection in hypertension

    Drugs Exp Clin Res

    (1990)
  • WikstrandJ

    Primary prevention with β-blockade in patients with hypertension: Review of results and clinical implications

    J Cardiovasc Pharmacol

    (1990)
  • HjalmarsonÅ et al.

    Myocardial infarction: Effects of beta-blockade

    Circulation

    (1991)
  • WikstrandJ et al.

    β-blockade in the primary prevention of coronary heart disease in hypertensive patients. Review of present evidence

    Circulation

    (1991)
  • WikstrandJ

    Primary prevention with metoprolol in hypertensive patients

    Progr Hypertens

    (1991)
  • AntmanEM et al.

    A comparison of results of meta-analysis of randomized controlled trials and recommendations of clinical experts. Treatments for myocardial infarction

    JAMA

    (1992)
  • LauJ et al.

    Cumulative meta-analysis of therapeutic trials for myocardial infarction

    N Engl J Med

    (1992)
  • OlssonG et al.

    Metoprolol induced reduction in postinfarction mortality: Pooled results from five double-blind randomized trials

    Eur Heart J

    (1992)
  • BeardK et al.

    Management of elderly patients with sustained hypertension

    Br Med J

    (1992)
  • HeldP

    Effects of beta-blockers on ventricular dysfunction after myocardial infarction: tolerability and survival effects

    Am J Cardiol

    (1993)
  • YusufS et al.

    Primary and secondary prevention of myocardial infarction and strokes. An update of randomly allocated, controlled trials

    J Hypertens

    (1993)
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