Biopharmaceutical medicines bring tremendous benefit to millions of patients worldwide. However, it is an unfortunate but immutable fact that no biologically active drug is free from the possibility of causing adverse reactions in certain individuals who are genetically and/or environmentally susceptible. Drugs for cardiac diseases or conditions of clinical concern are expected to affect the heart, having a mechanism of action that brings therapeutic benefit via advantageous changes to a patient’s biology and physiology. Drugs for all other diseases, i.e., non-cardiac drugs, are not intended to affect the heart, but it is extremely important that appropriate investigations are conducted during its development to ensure that a new drug will not have an unacceptable risk of cardiac side effects.  These investigations are part of the science of cardiac safety.

The heart’s normal electrical activity is responsible for its regular beating pattern, and for its facilitation of an appropriate supply of blood and hence oxygen for all bodily tissues.  In contrast, various abnormal patterns of electrical activity, called dysrhythmias, can occur. Atrial (“upper chamber”) dysrhythmias include atrial flutter and atrial fibrillation.  During atrial flutter, the atria contract in a regular but very rapid pattern. During atrial fibrillation (AFib), not only is the beating rapid but the pattern is irregular. At least 30 million people worldwide carry a diagnosis of AFib, and many more are likely to have undiagnosed, subclinical AFib.  Ventricular (“lower chamber”) dysrhythmias include premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation.  Premature ventricular contractions can often be felt as a ‘skipped’ heartbeat.  Ventricular tachycardia is a pattern of typically regular but rapid heart rate that often leads to inefficient pumping of blood into the arterial system.  Ventricular tachycardia can deteriorate to ventricular fibrillation, the major underlying cause of sudden cardiac death. This occurs when individual heart muscle cells contract in a totally disorganized fashion, resulting in the heart’s inability to pump blood around the body.

Of particular interest in the field of cardiac safety is a specific ventricular dysrhythmia known as Torsades de Pointes (Torsades), which was first identified by the French cardiologist François Dessertenne in 1966. Torsades is characteristically associated with QT interval prolongation. The figure below provides a stylistic representation of an ECG waveform that illustrates both the QT interval, the time (measured in milliseconds) between the onset of the QRS complex and the off-set of the T-wave, and QT interval prolongation.

qt interval

While drug-induced Torsades is rare, it can be fatal. Therefore, since 2005, there have been cardiac safety regulatory requirements for the evaluation of a new drug’s propensity to prolong the QT interval.   Both nonclinical (animal) and clinical (human) investigations are conducted.  The clinical trials conducted involve the extremely careful recording and analysis of ECGs to look for any evidence of drug-induced QT prolongation. The degree (if any) to which the drug prolongs the QT interval will be reported to regulatory agencies, along with all other efficacy and safety data, when applying for marketing approval.

Regulatory approval decisions are made at the public health level: the drug must be judged to have a favorable benefit-risk balance for the predominance of members of the population with the disease or clinical condition of concern, i.e., the population for which it is intended.   If a drug is approved due to compelling evidence of efficacy and general safety, but regulators also wish to convey that the drug has a small QT prolongation liability, such information is placed in the drug’s prescribing information. Physicians then decide if the medication has a favorable benefit-risk balance for their patients on a case-by-case basis by taking multiple clinical considerations into account.  Clinical risk factors for the occurrence of Torsades include female sex, structural heart disease, metabolic and electrolyte abnormalities (particularly lower than desirable levels of potassium and magnesium), taking more than one QT-prolonging drug, and increased drug exposure due to impaired metabolism and/or clearance associated with hepatic or renal insufficiency.  A drug that prolongs the QT interval to a small extent may therefore be deemed an acceptable treatment option for a patient without any of these risk factors, but deemed unacceptable for a patient with many of them: in the latter case, the physician would investigate other treatment options.

In conclusion, while it is clearly the case that we must treat illness and disease to the greatest extent we can, the science of cardiac safety reminds us that it is also a public health imperative to do everything we can to eliminate preventable cardiac adverse reactions while also providing optimal therapeutic benefit.