Editor's Note: This Article of the Month is based on Al-Khatib, SM, Hellkamp, A, Bardy, GH et al. Survival of Patients Receiving a Primary Prevention Implantable Cardioverter-Defibrillator in Clinical Practice vs. Clinical Trials. JAMA 2013; 309: 55-62..

Summary

Primary prevention implantable cardioverter-defibrillator (ICD) therapy has shown robust mortality benefits in multiple clinical trials—most most notably the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT).^1,2 Despite early skepticism, the results of these trials have shown a persistent benefit over time.^3,4 Much attention has been focused on the highly controlled environment of the clinical trials and whether this data is generalizable to clinical practice.^5-8 This study aims to evaluate clinical trial-comparable patients registry data with similar data from the MADIT II and SCD-HeFT trials.

Methods

All patients enrolled in MADIT II (1232 patients) and all patients enrolled in SCD-HeFT and randomized to either standard-of-care medications (patients in the arm receiving amiodarone were excluded) or ICD therapy (1676 patients) were included along with all National Cardiovascular Data Registry (NCDR) ICD registry patients that met similar criteria. Mortality in the registry patients was ascertained by matching patients in the registry with the Death Master File within Social Security Administration. Excluded were NCDR patients who had a myocardial infarction within 40 days of implantation and patients implanted within 3 months of revascularization. All NCDR SCD-HeFT-type patients who exhibited New York Heart Association Class I or IV symptoms were also excluded.

Results

After exclusion of secondary prevention patients, ICD patients with cardiac resynchronization therapy and device replacements, 56,985 patients met criteria for analysis from the NCDR registry. Of these patients, 28,608 were classified as MADIT II-like, and 53,351 were SCD-HeFT-like. Within the clinical trials, randomization to an ICD arm included 742 patients from MADIT II and 829 patients from SCD-HeFT for a total of 1571 patients. The standard of care medications subgroup included 490 patients from MADIT II and 847 from SCD-HeFT, a total of 1337 patients.

Compared to the clinical trial patients, patients from the registry were noted to be older and had significantly more co-morbities both within the SCD-HeFT-like and MADIT II-like groups. Median follow-up was: 19.5 months (MADIT-II); 35.8 months (MADIT II-like registry); 46.1 months (SCD-HeFT); and 35.0 months (SCD-HeFT-like registry).

Using adjusted Cox-proportional models, there was no significant difference in survival after ICD implantation between the MADIT II and MADIT II-like (two-year mortality rates: 15.6% vs. 13.9% respectively) and the SCD-HeFT and SCD-HeFT-like patients (three-year mortality rates: 17.4% vs. 17.3% respectively). In both clinical trials, two-year and three-year mortality rates with standard-of-care medications were significantly worse (MADIT-II- 22%; SCD-HeFT- 22.4%) highlighting the strength of recommendations towards ICD therapy in at-risk populations compared to medical therapy.

Conclusions

When compared to trial data, clinical practice outcomes for ICD therapy in the primary prevention arena have yielded similar mortality benefits despite implantation in an older and more complex cohort of patients.

Perspective

The use of ICD therapy to prevent sudden death in patients with high-risk features, such as prior myocardial infarction and congestive heart failure, has produced robust mortality reductions. While the data in the protected realm of clinical trials has never been questioned, the utility and application of this data in a real-world environment has come into question, guided gently by economic pressures to reduce utilization.

What happens when we apply strict clinical trial criterion to a sicker and more "realistic" clinical practice population? The answer is a reinforcement of the benefits of ICD therapy in the prevention of sudden death.

The authors should be applauded for highlighting a major success of the electrophysiology community and the cost-efficient treatment of a lethal problem. It is now our responsibility to make sure this literature gets its due attention. We should acknowledge the difficulty of the broad application of an expensive therapy to a large population and focus our efforts on more strategic identification of high-risk patients. But, until we find a more reliable indicator of risk, the utility of ICD therapy in the prevention of sudden cardiac death should no longer be questioned.

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References

1. Moss AJ, Zareba W, Hall WJ, et al; Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346: 877-883.
2. Bardy GH, Lee KL, Mark DB et al; Sudden Cardiac Death in Heart Failure Trial Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352: 225-237.
3. Goldenberg, I, Gillespie J, Moss AJ, et al. Long-term benefit of primary prevention with an implantable Cardioverter-defibrillator: an extended 8-year follow-up study of the Multicenter Automatic Defibrillator Implantation Trial II. Circulation 2010; 122: 1265-71.
4. Bardy G, Lee K, Mark D, et al. Long-term follow-up in the Sudden Cardiac Death Heart Failure Trial (SCD-HeFT). Heart Rhythm 2012; 9:1579.
5. cardial Infarction. Direct comparison of characteristics, treatment, and outomces of patients enrolled versus patients not enrolled in a clinical trial at centers participating in the TIMI 9 trial and TIMI 9 Registry. Am Heart J 2003; 145: 109-117.
6. Walsh CR, Lloyd-Jones DM, Camargo CA Jr, Giugliano RP, O'Donnell CJ. Clinical trials of unfractionated heparin and low-molecular weight heparin in addition to aspirin for the treatment of unstable angina pectoris: do the results apply to all patients? Am J Cardiol 2000; 86:908-912.
7. Hordijik-Trion M, Lenzen M, Wijns W, et al; EHS-CR Investigators. Patients enrolled in coronary intervention trials are not representative of patients in clinical practice: results from the Euro Heart Survey on Coronary Revascularization. Eur Heart J 2006; 27:671-678.
8. Badano LP, Di Lenarda A, Bellotti P, Albanese MC, Singara G, Fioretti PM. Patients with chronic heart failure encountered in daily clinical practice are different from the "typical" patient enrolled in therapeutic trials. Ital Heart J 2003; 4:84-91.

Keywords: Death, Sudden, Cardiac, Defibrillators, Implantable, Environment, Controlled, Heart Failure, Heart, Artificial, Primary Prevention

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