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Author: Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA

Hypothetically, the vasodilation produced by inhibiting peripheral α1 receptors should make carvedilol more tolerable at initiation, as the negative inotropic effects associated with myocardial β1 receptor blockade should be offset by a reduction in afterload. But what are the consequences of α1 blockade long-term?

Evidence from several trials suggests that sympatholysis, and specifically α1 blockade, may actually be harmful in patients with heart failure.  In the first Vasodilator Heart Failure Trial (V-HeFT I), the α1 blocker prazosin failed to improve outcomes compared to either placebo or the combination of isosorbide dinitrate and hydralazine.1 Similarly, a two-fold increase in incident heart failure was observed among patients randomized to the α1 blocker doxazosin in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).2  A clinical trial of bucindolol, a non-selective beta blocker with intrinsic sympathomimetic activity and α1 antagonist effects, was terminated early because the drug failed to improve survival in patients with heart failure.3 As a result of these and other data, some have proposed that α1 stimulation may exert cardioprotective effects in patients with advanced disease.4

But if carvedilol inhibits α1 receptors, why doesn’t it have the same deleterious effects as other α1 blockers in patients with heart failure?

As it turns out, its effects on α1 receptors appear to diminish with time.

In a trial of 36 patients with heart failure randomized to carvedilol or metoprolol, carvedilol failed to produce clinically-evident α1 receptor inhibition at 4 months of therapy, as measured by changes in calf vascular conductance, vasoconstrictor response, and neuroeffector transfer function.5  In a similar study using forearm vascular resistance as a measure of vasoreactivity, acute administration of carvedilol in normal subjects produced vasodilation whereas 6 months of therapy in patients with heart failure did not.6

So what does this mean clinically?

Although the α1-mediated effects of carvedilol may make it more tolerable at initiation, the clinical significance of this has not been borne out in clinical trials. More importantly, the oft-quoted pearl that carvedilol should be preferred in those with hypertension (whether in the setting of heart failure or otherwise) should probably be re-examined. Although carvedilol is certainly an appropriate choice for beta blockade in a patient with heart failure, the expectation that it will have long-lasting antihypertensive effects as a result of α1 blockade is unlikely based on the studies to date.

 

 
Brent N. Reed, PharmD, BCPS-AQ Cardiology, FAHA

Dr. Reed is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in advanced heart failure at the University of Maryland Medical Center in Baltimore, MD. Follow him on Twitter @brentnreed

 

References

  1. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986 Jun 12;314(24):1547-52.
  2. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981-97.
  3. Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001 May 31;344(22):1659-67.
  4. Skomedal T, et al. Comparison between alpha-1 adrenoceptor-mediated and beta adrenoceptor-mediated inotropic components elicited by norepinephrine in failing human ventricular muscle. J Pharmacol Exp Ther. 1997 Feb;280(2):721-9.
  5. Kubo T, et al. Lack of evidence for peripheral alpha(1)- adrenoceptor blockade during long-term treatment of heart failure with carvedilol. J Am Coll Cardiol. 2001 Nov 1;38(5):1463-9.
  6. Hryniewicz K, et al. Comparative effects of carvedilol and metoprolol on regional vascular responses to adrenergic stimuli in normal subjects and patients with chronic heart failure. Circulation. 2003 Aug 26;108(8):971-6.
Carvedilol and Alpha Blockade: Does it Matter in the Long Run?

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