Carvedilol and Heart Failure Banging our Heads against the Textbooks

At the time, there was no solid proof that beta blockers would have beneficial effects on morbidity and mortality in heart failure, and there was an overwhelming fear that these drugs might hurt, or even kill, patients with heart failure. Leading textbooks in pharmacology,29,30 medicine,31,32 cardiology, and heart failure32-36 all warned of the potential of beta blockers to exacerbate the symptoms of heart failure and to negatively impact cardiac output (due to cardiac depressant effects) and cardiac conduction disturbances.

To compound the situation, in the compilation of beta blockers by Cruickshank and Prichard,29 while the emerging reports on the potential benefits of beta blockers in heart failure were acknowledged, there was also emphasis on the widely held belief (which is probably true in the short term) that sympathetic tone, mediated by beta receptor stimulation in the heart, is important in maintaining cardiac function in heart failure, and there were reports of cardiogenic failure and severe hypotension precipitated by some beta blockers in these patients.

Likewise, the 'bible' of pharmacology, Goodman and Gilman: The Pharmacological Basis of Therapeutics,30 the leading teaching textbook of pharmacology for the biomedical sciences, highlighted special precautions for beta blockers, including the fact that ''heart failure that may develop suddenly or slowly usually in severely compromised heart'' with the use of these drugs. Likewise, Harrison's Principals of Internal Medicine31 lists as adverse effects of beta blockers ''the precipitation of heart failure in patients whom cardiac compensation depends upon enhanced sympathetic drive,'' and in the Textbook of Medicine3 the suggestion is made that ''beta adrenoceptor blockers should not be used in patients with Asthma, COPD [chronic obstructive pulmonary disease] or congestive heart failure.''

The skepticism around the utility of beta blockers in the treatment of heart failure was further reinforced by the early termination of a clinical trial with xamoterol, a beta receptor 'partial agonist,' which is somewhat like a beta blocker, in severe heart failure due to an increase in mortality in patients taking the drug.33'34 The bias at that time against the use of carvedilol was very strong and at least one vocal opponent of the study suggested that the proposed studies were 'extreme in nature.' So strong was the bias against the use of beta blockers in heart failure that even after the utility of carvedilol had been clearly demonstrated in heart failure through large controlled phase III clinical trials, some textbooks continued to warn of their use in this disease, or recommend their use with extreme caution, and warned of the potential to worsen the status of patients with heart failure.35,36

It was against this perceived background of caution, fear, and hesitation, and the anticipation of tough regulatory hurdles (which would require the demonstration of reductions in morbidity and mortality) as well as serious commercial doubts about the return on what would be an extraordinary financial investment, that a decision needed to be made on whether to proceed with the development of carvedilol in heart failure. The stakeholders, who consisted of corporate and R&D management, as well as the core team of Discovery scientists and a few internal and external cardiologists who supported this program, faced a very tough decision indeed.

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