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This White Paper provides a summary of presentations and discussions at a Cardiovascular Safety Outcome Trials Think Tank cosponsored by the Cardiac Safety Research Consortium, the US Food and Drug Administration, and the American College of Cardiology, held at American College of Cardiology's Heart House, Washington, DC, on February 19, 2014. Studies to assess cardiovascular (CV) risk of a new drug are sometimes requested by regulators to resolve ambiguous safety signals seen during its development or among other members of its class. Think Tank participants thought that important considerations in undertaking such studies were as follows: (1) plausibility-how likely it is that a possible signal indicating risk is real, based on strength of evidence, and/or whether a plausible mechanism of action for potential CV harm has been identified; (2) relevance-what relative and absolute CV risk would need to be excluded to determine that the drug had an acceptable benefit-to-risk balance for its use in the intended patient population; and (3) how plausibility and relevance influence the timing and approach to further safety assessment.

People who recover from cardiac arrest are at risk of suffering a recurrent episode. A subset of this group (60 to 80 percent) exhibits abnormalities in heart function during electrocardiogram (ECG) testing; these patients respond well to medication that alleviates the abnormalities. This improvement appears to prevent recurrence of cardiac arrest. The remaining 20 to 40 percent of patients show no abnormalities during ECG testing; this group is thought to be at a particularly high risk for sudden cardiac death. Seventy-one survivors of a single episode of cardiac arrest were evaluated. During testing, 26 of these patients had no inducible ECG abnormalities, such as ventricular tachycardia (abnormally rapid patterns of contraction of the ventricle). After a 16-month follow-up, 11 of the 26 patients suffered recurrent cardiac arrest, and 10 of these patients died. Analysis of the clinical data pertaining to these patients revealed that several variables were more likely to be associated with recurrent cardiac arrest. Among the 11 patients who suffered a recurrence, 55 percent had dilated cardiomyopathy (a defect in the functioning of the heart muscle), and 64 percent experienced premature ventricular contractions. Twenty-four-hour ambulatory ECG-guided therapy (wearing a portable ECG machine) did not improve the survival rate for these patients. Further studies are needed to determine the optimal treatment strategy for this high-risk group of patients. (Consumer Summary produced by Reliance Medical Information, Inc.)

Ventricular aneurysms (ballooning of the walls of the lower heart chamber) have many causes, with coronary artery disease being the cause in 75 percent of cases. Infrequently, no cause can be found; these are idiopathic cases. A case is reported of a 56-year-old woman with three idiopathic left ventricular aneurysms. For four years, prior to hospitalization, the patient had dyspnea (shortness of breath) on exertion, which was diagnosed as mild congestive heart failure. She had no other history of disorders which could contribute to ventricular tachycardia (rapid heartbeat), the symptom for which she was hospitalized. Her heart rate was 200 beats per minute (bpm), while the normal rate is 72 bpm. The initial chest X-ray showed no abnormal bulges indicative of aneurysms. Invasive imaging techniques were needed to reveal the aneurysms. Ventricular tachycardia was not responsive to drugs, and a device was implanted to restore normal heart rhythm. All previously reported cases of ventricular aneurysms were of single aneurysms, all of which were associated with arrhythmias. The study suggests this is a case of true idiopathic disease, as little or no evidence was found for known causes such as coronary artery disease, thrombi (clots), Chagas disease (a parasitic infection), or syphilis. (Consumer Summary produced by Reliance Medical Information, Inc.)