Prevention Trials in Patients at Risk for Sudden Death by Hugh Calkins, MD May 15, 1999 - 300,000 people in the USA die suddenly each year. For those patients who survive, the risk for another episode of sudden death within one year may be as high as 30%. The recent AVID trial has shown that an ICD in these patients results in improved survival compared to patients treated with amiodarone or sotolol. Interest is now in developing ways to identify patients at highest risk of sudden cardiac death, and to prevent it. This is called "primary prevention." Many people do not survive a first episode, so primary prevention is the only way to go. Is Placebo Control Ethically Possible? Dr. Doug Packer from the Mayo Foundation in Rochester, Minnesota discussed the role of placebo in ICD trials. In order for a placebo to be ethical in a trial, there must be no established effective treatment for the disease. If an established therapy exists, then it must have grave risks or side effects to NOT be used. Or, both placebo and treatment groups should receive some type of effective therapy. Dr. Packer reviewed some trials showing that compliance with treatment, whether placebo or "real" treatment, means a better outcome than with patients who are not compliant. Is A Preventive ICD Possible? Dr. Andrea Natale from the University of Kentucky discussed prophylactic ICDs for patients with non-ischemic cardiomyopathy. Both the MADIT and MUSST trials showed that inducible sustained ventricular tachycardia (SVT) in heart attack patients, non-sustained ventricular tachycardia (NSVT), and low EF (less than 40%) identify patients at high risk of death. Both studies showed that ICDs in these patients increases survival compared to drug treatments, including amiodarone. She discussed other types of cardiomyopathies for which definite answers are not available. These types need trials to establish the best treatment to prevent sudden death for patients with these conditions. These include: 1) nonischemic dilated cardiomyopathy 2) hypertrophic cardiomyopathy 3) right ventricular dysplasia. In the case of nonischemic cardiomyopathies, she said that patient mortality was related to heart failure class, with a one year mortality of 5-15% for those in Class 2 heart failure, 20-50% for patients in Class 3 and 30-70% for those in Class 4 heart failure. The proportion of sudden cardiac deaths are greater for those in Class 2 and 3 than for patients in Class 4 heart failure. Class 4 patients are more likely to die an extended death from pump failure. Dr. Natale estimated the annual risk of sudden cardiac death is 2-4% in adults and 4-6% in younger patients with hypertrophic cardiomyopathy. Factors that may help identify high risk patients include family history of sudden death, prior fainting spells, NSVT and the results of an EP test. In JAMA, among 277 patients followed for 8 years, there were 45 deaths (16% mortality). The mortality in hypertrophic cardiomyopathy patients was the same as for everyone else but if patients were diagnosed with hypertrophic cardiomyopathy before the age of 20, the mortality was higher. Dr. Natale also mentioned stress arrhythmia. This is ventricular arrhythmia that happens during exercise. It affects young atheletes with right ventricular dysplasia. It remains uncertain how to best manage such patients. Primary Prevention Trials Dr. Albert Buxton from Temple University School of Medicine in Philadelphia reviewed ongoing primary prevention trials for CHF. The GESICA trial from Argentina randomized patients with severe CHF to amiodarone or placebo. This trial showed a reduction in death with amiodarone. The CHF-STAT trial, done in the USA, showed no survival benefit in patents with ischemic heart failure taking amiodarone compared to placebo. A later analysis showed that amiodarone caused a very small reduction in mortality and sudden cardiac death in CHF patients. The benefit was too small to be seen in individual studies. He reviewed several beta-blocker trials, which show a reduction in mortality and sudden death. In contrast, ACE inhibitors reduced overall mortality but appeared to have no specific benefit on reducing risk of sudden death. Identifying CHFers At Risk of Sudden Death Dr. Jeremy Ruskin from Massachusetts General Hospital reviewed factors that help identify CHF patients who are at highest risk of sudden death. In 30% of patients at risk, sudden death occurs as the first sign of heart disease. It would therefore be impossible to identify these patients ahead of time. He reviewed data on how to identify high risk patients. Results of a signal-averaged ECG, presence of NSVT, or ambient ectopy are NOT useful. On the other hand, EF, presence of ischemia, abnormal heart rate variability, EP test results in ishemic patients, and QT (or T-wave) alternans ARE useful. He discussed some economic realities about ICD use in heart failure patients. He estimated that there are now 4,000,000 CHF patients in the USA and that 400,000 patients develop CHF each year. If 10% of CHF patients are high risk and are treated with an ICD, the initial cost will be $12 billion and the further yearly cost will be $1.2 billion. Because of this overwhelming cost, we must improve methods of identifying those who truly need an ICD, develop cheaper ICDs or ration their use.