The Beta-Blocker Story: Getting It Right

By John Malcolm Cruickshank, MD

The idea of using beta-blockers as a treatment for ventricular fibrillation occurred to James Black over 60 years ago. He developed propranolol and cimetidine, among other pharmacologic agents, work for which he won the Nobel Prize in 1988. Beta-blockers were reported to lower blood pressure by Brian Pritchard in 1964, and he and John Cruickshank wrote Beta-blockers in Clinical Practice, a major early text on the subject, shortly thereafter in 1967. The role of beta-blockers has expanded over the years, as they have demonstrated their efficacy for treating several conditions affecting cardiovascular health. This booklet, The Beta-Blocker Story, offers an update on the role of beta-blockers in cardiovascular medicine.

KEY FEATURES

The role of beta-blockers is reviewed in the treatment of the following conditions:

• Ischemic heart disease
• Post-myocardial infarction
• Heart failure
• Dysrhythmias
• Hypertension

• Language: English
• Publisher: PMPH USA, Ltd.
• Release date: Jul 12, 2017
• ISBN: 9781607959519

John Malcolm Cruickshank, MD

John Malcolm Cruickshank, MD is an Independent Cardiovascular Consultant in London, United Kingdom.

Book preview

Preface

A whole sixty years has gone by since James Black first had the idea that an antiadrenaline agent might be beneficial in reducing the ischemic heart muscle’s demand for oxygen, and thus reduce the risk of ventricular fibrillation. Of course, beta-blockers (propranolol) were the result. For these original ideas, James Black was to receive a Nobel Prize and a knighthood.

In 1964, propranolol was noted to possess not only antianginal properties but also lowered blood pressure (Brian Prichard). In 1987, the beta-blocker story was laid out by Cruickshank JM and Prichard BNC, in a 1000-page tome entitled Beta-blockers in Clinical Practice (with a Foreword by Sir James Black).

This booklet The Beta-blocker Story: Getting it Right is a brief update of the role of beta-blockers in cardiovascular medicine in 2017.

Introduction

Beta-blockers (BBs) have been available to the medical profession for over 50 years. Their beneficial role in the treatment of ischemic heart disease and post-myocardial infarct is not questioned (though BBs with intrinsic sympathomimetic activity [ISA] have little benefit on post-myocardial infarction). Likewise, their beneficial role in the treatment of systolic heart failure (low ejection fraction) is not questioned, though (as with post-myocardial infarction) the benefit is confined to BBs without ISA.

It is in the field of hypertension that BBs have come under fire, based mainly on meta-analyses and Guideline Committees (JNC-8), that do not take age into account.

This booklet aims to review the role of BBs in: (a) ischemic heart disease (b) post-myocardial infarction (c) heart failure (d) dysrhythmias, and (e) hopes to throw some light upon the area of hypertension and BBs, particularly the vital role of the sympathetic nervous system (and its surrogate, resting heart rate) in diastolic (± systolic) hypertension in the younger/middle-aged subject, and treatment implications.

CHAPTER 1

Ischemic Heart Disease and the Post-myocardial Infarction Period

1. Beta-Blockers and the Post-myocardial Infarction Period

a) Early Intervention (Intravenous Followed by Oral)

ISIS-1 (1), in 16,105 acute (within 24 hours) myocardial infarction (MI) cases involved intravenous followed by oral atenolol (100 mg daily), versus randomized control, for one week, and resulted in a significant 15% reduction in in-hospital cardiovascular deaths (mainly due to prevention of cardiac rupture) in the atenolol group.

The large COMMIT trial (2) in 45,852 patients, was a study comparing placebo with intravenous (IV), followed by oral metoprolol given for one month in patients with a recent (within 24 hours) myocardial infarction (MI) (where, unlike ISIS-1, thrombolysis had been given). There was no reduction in the risk of death, but reinfarction and ventricular fibrillation were significantly reduced by 18% and 16% respectively by metoprolol. However, the benefit was counterbalanced by a 30% increase in the risk of cardiogenic shock. Pain-relief (3), and reduction in infarct-size (4), have been observed following intravenous BB. Thus, postacute MI, IV beta-blockade should be administered only if hemodynamic conditions are stable.

b) Late Intervention With Oral Beta-Blockade (2–28 Days Post-MI)

An overview of such studies is shown in Figure 1.1 (5). BBs without intrinsic sympathomimetic activity (ISA) effected an approximate 30% reduction in mortality. This was apparent for both non-selective and relatively beta-1 selective agents; thus beta-1 blockade is the active ingredient. BBs with ISA (with a lesser fall in heart rate—see later) effected only non-significant reductions in mortality.

Nebivolol is a recent BB with beta-3 ISA (6), acting via the L-arginine/nitric oxide (NO) pathway (7), with antioxidant properties (8). In the post-infarction period, L-arginine (compared to randomized placebo) increased the risk of death significantly (P > 0.01) over a six-month period (9). Likewise, a meta-analysis of antioxidant supplements (vitamins A, E, and beta-carotene) for primary and secondary prevention of death, indicated that these agents were associated with significant increases in mortality (10). Thus, nebivolol (as with other BBs with ISA) may not be a wise choice of BB in the post-infarction period.

Fig. 1.1 Secondary prevention of post-myocardial death by oral β-blockade. The possession of intrinsic sympathomimetic activity (ISA) reduces the efficacy of β-blockers (5). Used with permission from Elsevier.

2. Beta-Blockers and Angina Pectoris/Chronic Ischemia

a) Pain Relief and Effort Tolerance

A BB without ISA, for example, nadolol, compared to placebo, reduced episodes of pain and (glyceryl trinitrate) GTN consumption by about 30%, and increased exercise-time and total work by 25 to 30% (11) (Figure 1.2). Propranolol was significantly superior to the dihydropyridine calcium blocker nifedipine in reducing the number of anginal episodes (12). Highly beta-1 selective bisoprolol was similar to verapamil in improving effort tolerance (13). Thus beta-1 blockade is the active antianginal ingredient.

BBs with ISA (lesser falls in heart rate) are inferior to those without ISA in reducing the number of angina attacks (14).

b) Silent Ischemia and Total Ischemic Burden; Survival Aspects

Silent ischemia has a prognosis as poor as painful ischemia, being closely related to ventricular fibrillation and sudden death (15). Thus, suppression of silent ischemia has important implications. BBs with ISA are less effective in reducing heart rate, and are thus less effective than BBs without ISA in reducing daytime painful and