Many effective drugs have been developed to prevent and treat cardiovascular diseases. Certain drugs have striking benefits to reduce death and disability. The vast majority are widely prescribed by practitioners.
But there is one exception: beta-blockers.
Beta-blockers inhibit the effects of activation of the sympathetic nervous system on an important receptor (the beta-adrenergic receptor). By doing so, they protect the heart from overstimulation. They were first synthesized in the early 1960s by Sir James Black, who (in 1988) won the Nobel Prize in Medicine for his groundbreaking role in their development.
Beta-blockers have been widely prescribed for the treatment of a broad spectrum of cardiovascular diseases. Initially, they were used to control certain rhythm disturbances of the heart and to reduce the frequency of anginal attacks in patients with coronary artery disease. Then they became one of the main treatments for hypertension. Subsequently, they were routinely prescribed to patients who had survived a heart attack in order to prevent a second event. Finally, they were given to patients with heart failure to prevent death and disease progression.
No other class of drugs in cardiovascular medicine has such a broad list of clinical indications. And for many years, the drugs were exceptionally popular.
But over the last decade, the use of beta-blockers has experienced a major decline. Currently, these drugs are infrequently used for cardiac arrhythmias, because other interventions have supplanted them. They are sparsely prescribed for exertional angina, because most patients with angina now undergo a revascularization procedure. They are no longer popular for the treatment of hypertension, because other drugs are often more effective and better tolerated. And many physicians neglect to prescribe beta-blockers following a heart attack, perhaps because we no longer understand their role in the modern era, where efforts are focused to maintain coronary artery patency. In nearly all indications for their original use, the prescribing of beta-blockers has plummeted.
Because they are generic, beta-blockers are no longer promoted by the pharmaceutical industry. Last year, AstraZeneca sold all European rights to its iconic beta-blocker metoprolol, presumably because the annual sales of the drug had dropped to a mere $110 million annually.
There is only one therapeutic area in which the role of beta-blockers remains paramount — heart failure.
That is incredibly ironic, since for most of the past five decades, physicians were told to avoid the use of beta-blockers in patients with heart failure who had impaired ventricular function. That belief was wrong.
Studies in the 1970s by investigators in Sweden challenged the prohibition against the use of beta-blockers in heart failure. Led by Finn Waagstein and Karl Swedberg, these reports suggested that beta-blockers produced dramatic results in patients whose hearts were damaged, because they were susceptible to further injury as a result of being stimulated by their own sympathetic nervous system. These promising results were ignored by mainstream cardiology for years.
The tide began to turn in the late 1980s and early 1990s. Several small trials showed improvements in pump function when beta-blockers were given to patients with heart failure whose contractile function was impaired. Then, several large-scale clinical trials (reported from 1996-2001) demonstrated that beta-blockers reduced the risk of death, the frequency of hospitalizations, and prevented disease progression. The magnitude of the benefit was unexpectedly large, and the results across trials were amazingly consistent. (I had the incredible privilege of leading two of these trials, published in the New England Journal of Medicine in 1996 and 2001.)
In fact, in some patients with heart failure, beta-blockers actually led to a normalization of heart function, which was sustained for years. In 2018, beta-blockers are arguably our most effective drug for the treatment of heart failure in patients with a reduced ejection fraction.
So in the 1960s, physicians were told NEVER to prescribe beta-blockers for heart failure. Now, 50 years later, the treatment of heart failure is one of the primary reasons that beta-blockers are still used in cardiovascular medicine.
It is a great story, but there is a catch.
Despite overwhelming evidence of efficacy, most patients with heart failure do not receive proper doses of beta-blockers in clinical practice. There is no good reason for the lack of prescribing. There is no dispute about their efficacy. Patients with heart failure typically tolerate them very well. And they are not expensive. (The beta-blockers used for heart failure are all generic.)
Yet, a large proportion of patients with heart failure are not being treated with beta-blockers, even though they are life-saving. Heart failure specialists prescribe them enthusiastically, but most patients with heart failure are not treated by specialists. In primary care, beta-blockers are not consistently used. In one survey, only one-third of patients with heart failure received these drugs.
To make matters worse, even when patients are treated with beta-blockers, the drugs are often prescribed in low doses — despite considerable evidence that higher doses produces better results and are strongly preferred.
What proportion of patients with heart failure are receiving beta-blockers at appropriate doses? I do not know. But I fear that the number may be less than 20%.
Sounds bad? It is bad. But the situation is even worse than you think.
There is one group of patients with heart failure who are being deprived of beta-blockers entirely — even though they are treated by specialists in cardiology.
Sadly, some children develop heart failure. For most, it results from a genetic condition, a viral infection or after the treatment of cancer. Many children with a cardiomyopathy would benefit from treatment with a beta-blocker. These drugs are considered accepted therapy in children, but typically, pediatric cardiologists do not prescribe beta-blockers to children with cardiomyopathy.
Why not? In 2007, a small trial reported that beta-blockers did not work in children, but it enrolled only 157 patients and treated them for only 8 months. However, to show dramatic benefits in adults with heart failure, the trials needed to enroll tens of thousands of patients who were treated for many years. That kind of evidence does not exist with beta-blockers in children. Yet, children with heart failure routinely receive other drugs (e.g., digitalis, diuretics, and ACE inhibitors), even though none of them have ever been evaluated in a pediatric clinical trial.
The story of beta-blockers in cardiovascular medicine is unique. Fifty years after their introduction, they remain the cornerstone of treatment for a life-threatening cardiovascular disorder — and deservingly so. But physicians are not financially incentivized to prescribe drugs, and drug companies have no reason to advertise the use of low-cost off-patent versions. As a result, millions of people with heart failure who would benefit from beta-blockers do not receive them in an appropriate way.
The generic form of the beta-blocker carvedilol costs about $3 per month. If properly used, it would save about 100,000 lives in the U.S. each year.
Ever see commercials for it on television? Nope.
Packer recently consulted for Actavis, Akcea, Amgen, AstraZeneca, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Novo Nordisk, Pfizer, Sanofi, Synthetic Biologics, and Takeda. He chairs the EMPEROR Executive Committee for trials of empagliflozin for the treatment of heart failure. He was previously the co-PI of the PARADIGM-HF trial and serves on the Steering Committee of the PARAGON-HF trial, but has no financial relationship with Novartis.