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Editorials

Drug treatment in heart failure

BMJ 1998; 316 doi: https://doi.org/10.1136/bmj.316.7131.567 (Published 14 February 1998) Cite this as: BMJ 1998;316:567

Lowering heart rate may reduce mortality

  1. Richard P Steeds, Research registrar,
  2. Kevin S Channer, Consultant cardiologist
  1. Department of Cardiology, Royal Hallamshire Hospital, Sheffield S10 2JF

    Heart failure is a clinical syndrome in which the heart fails to maintain an adequate output to vital organs. The responses to the resultant low blood pressure and underperfusion of organs include activation of the renin-angiotensin system with retention of salt and water, structural change of the heart and blood vessels with altered arterial compliance, and increased sympathetic drive. These result in an increase in heart rate, peripheral resistance, and myocardial contractility. Although these compensatory mechanisms are effective in the short term, they eventually become harmful. The adverse compensatory activation of the renin-angiotensin system can be modified by inhibitors, which improve symptoms and reduce mortality. Is the long term sympathetic overdrive that occurs as a consequence of heart failure also harmful?

    The effect of adrenergic stimulation on the myocyte is to increase contractility and improve cardiac function. This should be a beneficial effect, yet all clinical trials of positively inotropic drugs have either failed to improve symptoms or have increased mortality in heart failure. The long list of drugs includes the phosphodiesterase inhibitors,1 dopaminergic inodilators with β adrenoceptor stimulating properties,2 β adrenoceptor agonists,3 and quinolone based inotropes.4 If positive inotropic drugs seem harmful, could reduction in other indices of sympathetic activity be beneficial?

    Increased heart rate is known to be an indicator of poor outcome in congestive heart failure.5 Trials of low dose β adrenergic blockers from as early as 1975 have shown improvements in functional class, exercise capacity on treadmill testing, and ejection fraction on radionuclide scanning in patients with dilated cardiomyopathy.6 Carvedilol, a non-selective β blocker with antagonist activity at α1 receptors, improves ejection fraction and ventricular dimensions, albeit without improvement in exercise capacity. There are indications that it may improve mortality in chronic heart failure,7 but some questions remain, including how to select the patients who might benefit. The reduction in death rate found with carvedilol is consistent with results from using metoprolol8 and bisoprolol9 to treat heart failure of idiopathic origin, and with subgroup analysis of patients with heart failure after myocardial infarction.10 β adrenergic receptor antagonists consistently lower heart rate in the failing heart independent of aetiology.

    Angiotensin converting enzyme inhibitors and β blockers share a specific therapeutic effect—a reduction in heart rate.11 The fall in heart rate with angiotensin converting enzyme inhibitors is not shared by other vasodilators such as minoxidil and flosequinon, which produce reflex tachycardia and have an adverse effect on outcome in heart failure.12 A reduction in mortality from heart failure was found with a combination of the vasodilator drugs hydralazine and isosorbide dinitrate, which does not substantially alter heart rate. However, when this combination was compared with enalapril, the enalapril treated group showed a further reduction in mortality, from 13% to 9%, in association with a fall in heart rate in the first year.13 Could this bradycardiac effect add to the clinical benefit derived from other actions of angiotensin converting enzyme inhibitors in heart failure?

    Short acting calcium antagonists produce a relative tachycardia and may worsen heart failure, increasing the risk of death in patients with left ventricular dysfunction. The only dihydropyridine calcium antagonist that does not affect heart rate, amlodipine, has no adverse effect on mortality.14 Amiodarone causes a reduction in heart rate when used to treat heart failure and may reduce mortality depending on the population studied.15 The decrease in mortality may depend on the size of the reduction in heart rate, which seems to improve the therapeutic efficacy of amiodarone in heart failure.16

    There is, therefore, an association between a reduction in heart rate and those drug treatments that may be successful in heart failure. It seems unlikely that a decreased heart rate in itself is responsible for the improved outcome: two drugs seem to contradict the possible benefits of reduced heart rate and serve to show that there may be more important underlying influences. Xamoterol is a partial agonist at the β1 adrenoceptor which improves symptoms and effort tolerance in mild heart failure but which is associated with increased mortality in severe disease.17 Although it causes a small fall in heart rate, xamoterol moderately increases myocardial contractility and, in addition, has 43% of the activity of a full agonist when changes in heart rate are used to assess intrinsic sympathomimetic activity. This supports the concept that positive inotropism with sympathetic stimulation is damaging in heart failure. By comparison, digoxin is a positive inotrope which reduces heart rate, and recent evidence has shown it to have no impact on mortality.18 Xamoterol has sympathomimetic activity, whereas digoxin increases parasympathetic outflow.19 Is the adverse effect of positive inotropy outweighed by the benefits of a reduced heart rate and parasympathetic stimulation? Drug treatment in heart failure with β blockers and angiotensin converting enzyme inhibitors increases indices of parasympathetic activity and reduces sympathetic drive,20 but this does not apply to all interventions. Alteration of heart rate by interference with autonomic drive may be only part of the story.

    Drugs that increase the force of contraction of the failing heart result in increased mortality, and we believe that there should be a halt on further development in this direction. Further studies are needed to establish whether increasing cardiac vagal tone improves mortality.

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