- Email: [email protected]
The Cardiac Insufficiency Bisoprolol Study II
Although the greatest effect in CIBISII occurred in patients with coronary heart disease, the 32% reduction in mortality refers to the whole group treated with bisoprolol with no heterogeneity of effect across several prespecified subgroups, including different aetiologies. Although the lack of heterogeneity of effect also encompassed patients with class IV heart failure, we did point out that more data in certain groups, especially those with severe heart failure and also in elderly patients, is needed. The results of CIBIS-II, coupled with the combined previous experience provides a substantial, if not entirely complete, evidence base with which to inform routine clinical practice. The onus is now on those who have lingering doubts about  blockers to provide as secure an evidence base on which to base their reservations. It is indeed becoming difficult to ignore the invitation provided by the results of robust clinical trials, such as CIBIS-II, to begin the process of applying an evidence-based approach to the treatment of heart failure. *Henry J Dargie, Philippe Lechat, on behalf of the CIBIS-II Investigators University of Glasgow , Glasgow G12 8QQ
Sir—CIBIS-II 1 shows a substantial reduction in all-cause mortality in patients with mild-to-moderate heart failure given bisoprolol. The CIBIS-II investigators ascribe the greater part of this effect to a reduction in the incidence of sudden and unknown causes of death presumed to reflect a reduction in sudden cardiac death. Their findings seem to reflect those of the US Carvedilol Study Group,2 despite bisoprolol’s lack of ␣1 and 2 adrenoceptor antagonistic effects. Metoprolol seems similarly effective although definitive reports are awaited. Retrospective reviews tend to treat -blockers as a homogeneous class, which may not be the case. The lowest common denominators of bisoprolol, carvedilol, and metoprolol in terms of pharmacodynamics and pharmacokinetics are 1 adrenoceptor antagonism and a moderate or greater degree of lipophilicity, respectively. This same -blocker profile characterises those -blockers that reduce the incidence of sudden cardiac death in the settings of hypertension3 and acute myocardial infarction and the postinfarction period.4 Central to the pathophysiology of sudden cardiac death is the concept of autonomic activation—ie, sympathetic
THE LANCET • Vol 353 • April 17, 1999
hyperactivity and reciprocal parasympathetic hypoactivity. The use of a -blocker that will mitigate against the effects of circadian sympathetic activation should have profound effects not only on the rate of sudden cardiac death, but also on the full range of acute coronary syndromes. Liphophilic -blockers cross the blood-brain barrier, whereas hydrophilic -blockers do not. Although the peripheral anti-ischaemic actions of 1 adrenoceptor antagonism undoubtedly contributed to the reduced absolute mortality in CIBIS-II, a component of the reduction may have been due to central site of action leading to reduced autonomic activation. Caution is needed in any extrapolation of results for -blockers. Carvedilol, for example, does not produce 1 adrenoceptor upregulation. Skomedal and colleagues5 showed that activation of the ␣1 adrenoceptor can produce positive inotropic effects similar to those of the 1 adrenoceptor in failing human myocardium. The direct vasodilating action of bisoprolol may thus be superior to the indirect ␣-blocking mechanism of carvedilol. -blockers have been consistently underused in heart disease, mainly because of the fear of clinical deterioration due to their negative inotropic effects. The protocols used in CIBIS-II and the other major mortality trials are laborious and reliant on specialist supervision. Their adoption will have major implications in terms of time for phyicians who see patients with heart failure. It should also be remembered that the postulated advantages of non-selective versus 1 selective and vasodilating over non-vasodilating -b l o c k e r s remain largely theoretical. The more established agents may thus be just as efficacious. *G A Drummond, I B Squire Department of Clinical Pharmacology, Division of Medicine and Therapeutics, Leicester University, Leicester Royal Infirmary, Leicester LE2 7LX, UK CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol II (CIBIS-II): a randomised trial. Lancet 1999; 353: 9–13. 2 Packer M, Bristow MR, Cohn JN, et al for the US Carvedilol Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1349–55. 3 Kaplan NM. Beta blockade in the primary prevention of hypertensive cardiovascular events with focus on sudden cardiac death. Am J Cardiol 1997; 80: 20J–22J. 4 Hjalmarson A. Effects of beta blockade on sudden cardiac death during acute myocardial infarction and the postinfarction period. Am J Cardiol 1997; 80: 35J–39J.
5
Skomedal T, Borthne K, Halfdan A, Geiran O, Osnes J. Comparison between alpha-1 adrenoceptor-mediated and beta adrenoceptor mediated inotropic components elicited by Norepinephrine in failing human ventricular muscle. J Pharmacol Exp Therap 1997; 280: 721–29.
Sir—The beneficial effect of blockers in moderate to severe left ventricular dysfunction is reported by the CIBIS-II investigators.1 However, they also reported more admissions to hospital for stroke in the bisoprolol group than in the placebo group (31 vs 16, p=0·04). They did not explain this unexpected result in their discussion, nor if this increased rate of stroke occurred predominantly among patients with a very low ejection fraction. Their study group consisted of patients with the New York Heart Association functional class IV. It is well known that a very low ejection fraction may result in left-ventricle thrombus formation leading to increased risk of stroke, and some clinicians recommend treatment of these patients with anticoagulation therapy.2 We propose a theory for this unexpected finding. Cardioversion of atrial fibrillation to sinus rhythm may result in an embolic stroke without This proper anticoagulation. 3 phenomenon occurs because of thrombus formation in the uncontracted left atrium, while restoration of atrial contraction may result in thrombi release and stroke.3 If one can make an analogy to the left ventricle, thrombi can be formed in patients with severe dilated or ischaemic cardiomyopathy, while improvement of left-ventricular contraction by use of -blocking agents may result in thrombi release and embolic stroke. We, therefore, suggest assessment of the beneficial effects of anticoagulation in the subgroup of patients with severe left-ventricular dysfunction when starting  blockers. *Amit Segev, Yoseph A Mekori Department of Medicine B, Meir Hospital, Kfar-Saba 44281, Sackler School of Medicine, Tel-A viv University, Tel-A viv, Israel (e-mail: [email protected])
1
1
CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 3 5 3 : 9–13. 2 Guidelines for the evaluation and management of heart failure. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 1995; 2 6 : 1376–98. 3 Management of patients with atrial fibrillation. A statement for healthcare professionals. From the subcommittee on Electrocardiography and Electrophysiology, American Heart Association. Circulation 1996; 9 3 : 1262–77.
1361
Sir—CIBIS-II 1 shows a substantial reduction in all-cause mortality in patients with mild-to-moderate heart failure given bisoprolol. The CIBIS-II investigators ascribe the greater part of this effect to a reduction in the incidence of sudden and unknown causes of death presumed to reflect a reduction in sudden cardiac death. Their findings seem to reflect those of the US Carvedilol Study Group,2 despite bisoprolol’s lack of ␣1 and 2 adrenoceptor antagonistic effects. Metoprolol seems similarly effective although definitive reports are awaited. Retrospective reviews tend to treat -blockers as a homogeneous class, which may not be the case. The lowest common denominators of bisoprolol, carvedilol, and metoprolol in terms of pharmacodynamics and pharmacokinetics are 1 adrenoceptor antagonism and a moderate or greater degree of lipophilicity, respectively. This same -blocker profile characterises those -blockers that reduce the incidence of sudden cardiac death in the settings of hypertension3 and acute myocardial infarction and the postinfarction period.4 Central to the pathophysiology of sudden cardiac death is the concept of autonomic activation—ie, sympathetic
THE LANCET • Vol 353 • April 17, 1999
hyperactivity and reciprocal parasympathetic hypoactivity. The use of a -blocker that will mitigate against the effects of circadian sympathetic activation should have profound effects not only on the rate of sudden cardiac death, but also on the full range of acute coronary syndromes. Liphophilic -blockers cross the blood-brain barrier, whereas hydrophilic -blockers do not. Although the peripheral anti-ischaemic actions of 1 adrenoceptor antagonism undoubtedly contributed to the reduced absolute mortality in CIBIS-II, a component of the reduction may have been due to central site of action leading to reduced autonomic activation. Caution is needed in any extrapolation of results for -blockers. Carvedilol, for example, does not produce 1 adrenoceptor upregulation. Skomedal and colleagues5 showed that activation of the ␣1 adrenoceptor can produce positive inotropic effects similar to those of the 1 adrenoceptor in failing human myocardium. The direct vasodilating action of bisoprolol may thus be superior to the indirect ␣-blocking mechanism of carvedilol. -blockers have been consistently underused in heart disease, mainly because of the fear of clinical deterioration due to their negative inotropic effects. The protocols used in CIBIS-II and the other major mortality trials are laborious and reliant on specialist supervision. Their adoption will have major implications in terms of time for phyicians who see patients with heart failure. It should also be remembered that the postulated advantages of non-selective versus 1 selective and vasodilating over non-vasodilating -b l o c k e r s remain largely theoretical. The more established agents may thus be just as efficacious. *G A Drummond, I B Squire Department of Clinical Pharmacology, Division of Medicine and Therapeutics, Leicester University, Leicester Royal Infirmary, Leicester LE2 7LX, UK CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol II (CIBIS-II): a randomised trial. Lancet 1999; 353: 9–13. 2 Packer M, Bristow MR, Cohn JN, et al for the US Carvedilol Study Group. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1349–55. 3 Kaplan NM. Beta blockade in the primary prevention of hypertensive cardiovascular events with focus on sudden cardiac death. Am J Cardiol 1997; 80: 20J–22J. 4 Hjalmarson A. Effects of beta blockade on sudden cardiac death during acute myocardial infarction and the postinfarction period. Am J Cardiol 1997; 80: 35J–39J.
5
Skomedal T, Borthne K, Halfdan A, Geiran O, Osnes J. Comparison between alpha-1 adrenoceptor-mediated and beta adrenoceptor mediated inotropic components elicited by Norepinephrine in failing human ventricular muscle. J Pharmacol Exp Therap 1997; 280: 721–29.
Sir—The beneficial effect of blockers in moderate to severe left ventricular dysfunction is reported by the CIBIS-II investigators.1 However, they also reported more admissions to hospital for stroke in the bisoprolol group than in the placebo group (31 vs 16, p=0·04). They did not explain this unexpected result in their discussion, nor if this increased rate of stroke occurred predominantly among patients with a very low ejection fraction. Their study group consisted of patients with the New York Heart Association functional class IV. It is well known that a very low ejection fraction may result in left-ventricle thrombus formation leading to increased risk of stroke, and some clinicians recommend treatment of these patients with anticoagulation therapy.2 We propose a theory for this unexpected finding. Cardioversion of atrial fibrillation to sinus rhythm may result in an embolic stroke without This proper anticoagulation. 3 phenomenon occurs because of thrombus formation in the uncontracted left atrium, while restoration of atrial contraction may result in thrombi release and stroke.3 If one can make an analogy to the left ventricle, thrombi can be formed in patients with severe dilated or ischaemic cardiomyopathy, while improvement of left-ventricular contraction by use of -blocking agents may result in thrombi release and embolic stroke. We, therefore, suggest assessment of the beneficial effects of anticoagulation in the subgroup of patients with severe left-ventricular dysfunction when starting  blockers. *Amit Segev, Yoseph A Mekori Department of Medicine B, Meir Hospital, Kfar-Saba 44281, Sackler School of Medicine, Tel-A viv University, Tel-A viv, Israel (e-mail: [email protected])
1
1
CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 3 5 3 : 9–13. 2 Guidelines for the evaluation and management of heart failure. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 1995; 2 6 : 1376–98. 3 Management of patients with atrial fibrillation. A statement for healthcare professionals. From the subcommittee on Electrocardiography and Electrophysiology, American Heart Association. Circulation 1996; 9 3 : 1262–77.
1361