Why Has The Antiarrhythmic Drug Well Gone Dry?
We are delighted to have this post from one of the most senior cardiac electrophysiologists in the world. Dr Kowey is one of the pioneers of antiarrhythmic drug development and a brilliant teacher. This is superb and I hope he continues to contribute to Sensible Medicine. JMM
I am indebted to Dr. Mandrola for the privilege of addressing the issue of antiarrhythmic drug development. Specifically, he asked me to try to answer the question of why it has been so hard to get new drugs on the market, especially given the limitations of those available for clinical use. The last antiarrhythmic drug approved in the US was dronedarone in 2010. With a checkered clinical trial history and high cost, it has had limited use.
It is my premise that we need better therapies for our arrhythmia patients. The failure of development of new and improved antiarrhythmic drugs is yet another example of how miserably our healthcare system has failed our patients. I will deal with five important impediments.
First, modern medicine is ruled by technology. Medical students and young doctors are quickly seduced by procedures and the equipment that supports them. Pharmacology, on the other hand, is not only boring, but also complicated. I distinctly remember throwing the frisbee on the front lawn at Penn Med School during our pharmacology lectures, while being entirely captivated by all the toys cardiologists had at their disposal.
Second, doing procedures generates revenue far greater than treating patients with medication. So not only is procedural medicine perceived as more fun, but it is also lucrative. Mired in debt, graduating medical students shy away from specialties like internal medicine, endocrinology and rheumatology and gravitate toward the specialties that feature high-paying procedures. Cardiologists who train as arrhythmia specialists are incentivized to do ablation procedures and implant devices. Antiarrhythmic drugs are an afterthought.
Third, decisions about the development of new drugs and devices are made by industry. Drug companies make money for shareholders when products they develop and market are used by millions of patients. Though the number of people with AF has increased, the perception has been that most can be “cured” by catheter ablation. What drug company wants to spend a few billion dollars to develop a drug with a limited market size. Ironically, the rise in popularity of ablation has meant that more patients with AF need drug treatment at some point in their journey. Consequently, sales of older generic drugs have increased significantly
Fourth, our regulatory agencies have been misguided and are progressively more so. The people who sit in positions of authority are not clinicians. In times past, this obvious limitation was mitigated by having excellent advisory committees consisting of experienced physicians and academicians who lent their considerable wisdom to the process. Those committees no longer function at the same level, having been disbanded altogether or populated by individuals who are naïve to the science of regulatory medicine, or who have a financial interest in the products being discussed. The FDA staff, left to its own devices, has chosen to pay more attention to safety than unmet need, and have mandated large, expensive and usually unnecessary outcome trials as a condition of antiarrhythmic drug approval.
Fifth, patients want instant cures for complex diseases. They have been manipulated by medical advertising into believing that practitioners and hospitals can solve their medical problems quickly and efficiently, when in reality, cures are rare. When I explain to a patient that there may be an effective drug to palliate their arrhythmia, they immediately want to know the term of therapy, how much it will cost, and how the drug might harm them. They gravitate to procedures advertised on television for a quick fix, and one they may not need to pay for.
Most cardiac arrhythmias are the result of chronic diseases that require lifelong management. For example, the most common form of atrial fibrillation occurs in elderly patients and is caused by progressive atrial fibrosis with the development of cell disconnection. Drugs, including antiarrhythmics and anticoagulants, form an integral part of treatment paradigms for most of these patients, especially since they are frequently poor candidates for procedures due to common comorbidities.
The brutal truth is that we cure almost nothing in medicine, but we can be quite effective in helping people maintain a good quality of life. Ablation efficacy is modest, in the range of 50-60% in patients with heart disease and a persistent pattern. A well-conceived antiarrhythmic drug treatment program in which drugs are carefully titrated to clinical effect and tolerance, as a reasonable alternative for many patients. Studies of comparative efficacy and safety of ablation versus drugs are necessarily biased toward non-drug treatments. Unless sham procedures are carried out, patients know when they have an ablation and are therefore biased to feel better even if their arrhythmia continues. Furthermore, a single arrhythmia recurrence is not necessarily a “failure” since further episodes may be preempted by a simple dose or drug change.
As we learn more about the pathogenesis and genetics of cardiac arrhythmia, we hope that our colleagues in academia and industry will come up with ways of treating the disease in a targeted way to avoid the organ toxic or cardiac depressant side-effects of the drugs we currently use. In the meantime, we must continue to make drug developers and regulators aware of how dire the need is for better therapies to treat common arrhythmias that plague our patients.
Dr. Kowey is Professor of Medicine and Clinical Pharmacology at Thomas Jefferson University, Emeritus Chief of Cardiology, Lankenau Heart Institute, and the William Wykoff Smith Chair, Cardiovascular Research, Lankenau Institute for Medical Research. He is also the author of Failure to Treat: How a Broken Healthcare System Puts Patients and Practitioners at Risk.
Dr Kowey is active on Substack here
This is an outstanding article, truthful, concise, and relevant. I am a physician, but would like you to be my cardiologist.
I am reminded that 99% I do in Cardiac Surgery is palliative, not curative. All of our procedures require life long care.