Editor's Note: This article is based on Moss AJ, Schuger C, Beck CA et al. Reduction in Inappropriate Therapy and Mortality through ICD Programming. N Engl J Med 2012;36:2275-2283.

Summary

Multiple prospective clinical trials have demonstrated that implantable cardioverter-defibrillator (ICD) therapy reduces mortality in patients at risk for sudden cardiac arrest (SCA).^1-4 Current practice guidelines indicate ICD therapy for primary prevention of SCA in a variety of at-risk patients.⁵ However, device programming varied among the trials that validated primary prevention ICD therapy^3,4 and optimal programming of such ICDs remains poorly defined. This study examined the appropriateness of ICD therapy and overall mortality when "conventional," "high-rate" and "delayed" ICD programming was utilized for newly implanted primary prevention ICDs.

Methods

This study focused on 1500 patients with a primary prevention ICD indication received either a dual-chamber ICD or CRT-D (as their clinical scenario dictated) and were randomized in a 1:1:1 fashion to one of three ICD programming schemes. "Conventional" therapy utilized a 2.5-second delay at 170 – 199 beats per minute (bpm) and a 1-second delay at ≥ 200bpm. "High-rate" therapy utilized a 2.5-second delay at ≥ 200bpm. "Delayed" therapy utilized a 60-second delay at 170 – 199bpm, a 12-second delay at 200 – 249bpm and a 2.5-second delay at ≥ 250bpm. Rhythm discrimination features were active in the "conventional" 170 – 199bpm zone and in the "delayed" 170 – 199bpm and 200 – 249bpm zones. All therapy zones for each programming scheme contained anti-tachycardia pacing (ATP) followed by shock therapy if ATP did not successfully terminate the detected arrhythmia.

Ischemic and non-ischemic patients at least 21-years-of-age were enrolled. Patients were excluded if they had previously received a pacemaker, ICD or CRT device, had permanent atrial fibrillation, or if within the three months prior to enrollment had suffered a myocardial infarction or undergone coronary revascularization.

The pre-specified primary endpoint was the first occurrence of inappropriate ATP or shock therapy. An independent panel adjudicated appropriateness of all therapy delivered. Secondary endpoints included all-cause mortality and the first occurrence of syncope.

Results

Compared to conventional programming, both high-rate and delayed programming provided statistically significant reductions in the first occurrence of inappropriate therapy (hazard ratio [HR] for high-rate vs. conventional = 0.21 with a 95% confidence interval [CI] of 0.13 – 0.34, p<0.001; HR for delayed vs. conventional = 0.24, CI of 0.15 – 0.40, p<0.001). For both the high-rate and delayed programming groups, any delivery of appropriate and inappropriate ATP were significantly reduced when compared to conventional programming (conventional appropriate ATP = 111, high-rate = 38 [p<0.001], delayed = 20 [p<0.001]; conventional inappropriate ATP = 104, high-rate = 20 [p<0.001], delayed = 25 [p<0.001]). High-rate and delayed programming also significantly reduced inappropriate shock therapy (conventional inappropriate shocks = 31, high-rate = 14 [p<0.01], delayed = 15 [p<0.03]). Appropriate shock therapy was not significantly different among the three groups.

A significant reduction in all-cause mortality was observed for high-rate versus conventional programming (HR = 0.45, CI 0.24-0.85, p=0.01). Delayed programming was associated with numerically fewer mortality events when compared to conventional programming, but did not achieve statistical significance at the 95% CI (HR = 0.56, CI 0.30 – 1.02, p=0.06). Occurrence of the first episode of syncope was numerically higher but not statistically significantly different for high-rate (HR = 1.32, CI 0.71 – 2.47, p=0.39) or delayed (HR = 1.09, CI 0.58 – 2.05, p=0.80) programming compared to conventional programming.

Conclusions

In a primary prevention patient population, ICD programming that only treated arrhythmias ≥ 200bpm significantly reduced inappropriate therapy and all-cause mortality when compared to conventional programming. Programming a 60-second delay of therapy for arrhythmias of 170 – 199bpm and a 12-second delay for 200 – 249bpm significantly reduced inappropriate therapy and strongly trended toward a significant reduction in all-cause mortality compared to conventional programming. Syncope was not significantly increased in either group.

Perspective

This is the first trial to demonstrate a reduction in mortality based solely on ICD programming. An earlier, nonrandomized study showed a reduction in inappropriate ICD therapy when higher detection rates, longer arrhythmia detection windows and arrhythmia discrimination were programmed.⁶ The mortality benefit seen with the programming of the MADIT-RIT high-rate group forces us to reconsider what is optimal programming for primary prevention ICDs and the clinical impact of inappropriate and unnecessary therapy. Physicians implanting a primary prevention ICD or CRT-D should consider programming such devices with a single arrhythmia therapy zone of ≥ 200bpm with ATP followed by shock therapy.

As for reducing inappropriate and unnecessary therapy, there is evidence that ICD shocks can lead to myocardial dysfunction⁷ and heart failure progression.⁸ ICD shocks have been associated with increased mortality.⁹ The psychological effect of ICD shocks on patients can be significant, even when such therapy is appropriate.¹⁰ The clinical impact of ATP therapy is less clear. One trial comparing ATP and shocks showed a trend toward higher mortality with ATP.¹¹ Although appropriate ATP, inappropriate ATP and inappropriate shocks were all significantly reduced in MADIT-RIT's high-rate and delayed programming groups, the difference in ATP was far more significant than that for shocks. This may indicate that inappropriate ATP may be more detrimental than was previously thought.

MADIT-RIT makes a strong case for minimizing or delaying therapy in primary prevention ICDs. The statistically significant reduction in mortality and inappropriate therapy seen in the high-rate group suggests that we need a more thorough understanding of the safety and efficacy of ICD therapy, and ATP therapy in particular. ATP's ability to painlessly terminate life-threatening ventricular arrhythmias is desirable, but the large number of programmable ATP therapy variables makes defining the safest and most effective ATP programming a complex problem. MADIT-RIT was not designed to address whether inappropriate shocks or inappropriate ATP is more strongly associated with adverse events, but it does show that delivering inappropriate or unnecessary therapy of either form has mortality risk. This is clearly an area needing additional investigation to determine how ATP can best be used to extend and improve the lives of our patients.

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References

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8. Tereshchenko LG, Faddis MN, Fetics BJ et al. Transient local injury current in right ventricular electrogram after implantable cardioverter-defibrillator shock predicts heart failure progression. J Am Coll Cardiol 2009;54:822-8.
9. Poole JE, Johnson GW, Hellkamp AS et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008; 359:1009-17.
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11. Wathen MS, DeGroot PJ, Sweeney MO et al. Prospective randomized multicenter trial of empirical antitachycardia pacing versus shocks for spontaneous rapid ventricular tachycardia in patients with implantable cardioverter-defibrillators: Pacing Fast Ventricular Tachycardia Reduces Shock Therapies (PainFREE Rx II) trial results. Circulation 2004;110:2591-6.

Keywords: Death, Sudden, Cardiac, Defibrillators, Implantable, Primary Prevention

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