Color Atlas and Synopsis of Electrophysiology, 1st Ed.

62. PREVENTION OF SUDDEN DEATH: NONISCHEMIC CARDIOMYOPATHY

Khaled Awad, MD, and Andrew E. Epstein, MD, FAHA, FACC, FHRS

CASE PRESENTATION

A 37-year-old woman presented with 3 weeks of worsening exertional dyspnea and orthopnea. On evaluation, a nonischemic dilated cardiomyopathy (NIDCM) was diagnosed. The left ventricular ejection fraction (LVEF) was 33%. An ECG showed sinus rhythm with left bundle branch block (LBBB), QRS duration 130 ms, and a normal PR interval. Nonsustained ventricular tachycardia (NSVT) was recorded on monitoring. The patient was treated with a β-receptor blocker, an angiotensin converting enzyme inhibitor (ACEI), and spironolactone and referred to for implantable cardioverter defibrillator (ICD) implantation. Is this appropriate?

DISCUSSION

NICDM may result from viral infection, autoimmune or inflammatory disease, genetic or metabolic disorders, tachycardia (so-called tachycardia-mediated cardiomyopathy), or causes that are not readily apparent, and most are therefore labeled idiopathic. Regardless of cause, after any reversible cause is treated, most patients with NIDCM are treated with similar therapies including diuretics, β-receptor blockers, ACEIs, angiotensin receptor blockers (ARBs), aldosterone antagonists, and often an ICD sometimes combined with the capability for biventricular pacing. The prevalence of NIDCM as compared to ischemic cardiomyopathy has not been completely characterized but ranges from 2% to 13% in the ambulatory setting and up to 50% in large clinical trials.1-3

The patient presented has a newly diagnosed NIDCM. The Device-Based Therapy Guidelines from the American College of Cardiology, American Heart Association, and Heart Rhythm Society detail indications for ICD implantation in patients with NIDCM.4 The primary class I indication is for patients who have an LVEF ≤35% and NYHA class II or III heart failure. Class II implantation indications are for those with unexplained syncope and “significant LV dysfunction” (class IIa indication), those who are outpatients awaiting transplantation (class IIa indication), and those with an LVEF ≤35% but who have NYHA functional class I heart failure (class IIb indication). These recommendations are based heavily on the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial5 and the Sudden Cardiac Death and Heart Failure Trial (SCD-HeFT),3 and implicit in the recommendations is that patients have been treated with optimal medical therapy (OMT).

DEFINITE enrolled patients with NICDM, NYHA class I-III heart failure, LVEF<36%, and premature ventricular complexes or NSVT on monitoring.5 All patients received OMT and randomized to OMT alone versus OMT with an ICD. The primary end point was death from any cause. The patients were well treated, 86% received ACEIs, and 85% received β-receptor blockers. The mean LVEF was 21%. Although the primary end point was not reached, albeit with a trend to benefit from an ICD (P = 0.08), there was an 80% reduction in sudden death from arrhythmia (P = 0.006) (Figure 62-1).

Images

FIGURE 62-1 Kaplan–Meier estimates of death from any cause (A) and sudden death from arrhythmia (B) among patients who received standard OMT and those who received an ICD. For the ICD group, as compared with the standard therapy group, the hazard ratio for death from any cause was 0.65 (95% confidence interval, 0.40 to 1.06) and the hazard ratio for sudden death from arrhythmia was 0.20 (95% confidence interval, 0.06 to 0.71). Reproduced with permission from Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004;May 20; 350(21):2151-2158.

SCD-HeFT included patients with NIDCM, NYHA class II-III heart failure, and an LVEF ≤35%.3 Randomization was between OMT, OMT with amiodarone, or OMT with an ICD. The primary end point was death from any cause. The median LVEF was 25%, and as in DEFINITE, the patients were well-treated medically. Compared to OMT, the addition of an ICD decreased the risk of death by 23%. Notably, patients on amiodarone experienced increased early mortality within the first year (Figure 62-2).

Images

FIGURE 62-2A Kaplan–Meier estimates of death from any cause in SCD-HeFT. Compared to OMT alone, ICD therapy resulted in a reduction in the primary end point of all-cause mortality (hazard ratio = 0.77). Note the curves continue to separate throughout the follow-up period of up to 5 years consistent with continued benefit drawn from ICD therapy. Reproduced with permission from Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;Jan 20;352(3):225-237.

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FIGURE 62-2B Kaplan–Meier estimates of death from any cause for patients with NIDCM in SCD-HeFT.3 The benefit derived from ICD therapy in patients with NIDCM was no different from those with ischemic cardiomyopathy. Reproduced with permission from Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;Jan 20;352(3):225-237.

With respect to when to consider ICD implantation in patients with NIDCM, a waiting period of at least 3 months is required. This waiting period was driven in large part by SCD-HeFT, which required a 3-month waiting period for medical therapy to be optimized,3 and since many cardiomyopathies improve with OMT. Notably, McNamara et al showed that LVEF markedly improves after recent onset heart failure in nonischemic cardiomyopathy.6 Stratified by LVEDD, those with LVEDDs <60 mm experienced a 19% improvement in the LVEF (from 27% to 45% at 6 months), for LVEDDs 60 to 70 mm, a 17% improvement in LVEF (from 23% to 40% at 6 months), and for LVEDDs >70 mm, a 13% improvement in LVEF (from 20% to 32% at 6 months). In DEFINITE, no heart failure duration was specified.5 Since the primary end point was not reached (P = 0.08), including death or resuscitated cardiac arrest, no inference can be made about timing of ICD implantation. In addition, a third study, the Cardiomyopathy Trial (CAT) also addressed primary prevention ICD implantation in patients with NIDCM.7 Patients with NIDCM, NYHA class II-III heart failure, a LVEF ≤30% and duration of heart failure ≤9 months were enrolled and randomized to OMT alone or OMT with an ICD. The trial was terminated early for futility when interim analysis indicated that with continued enrollment no survival benefit would be shown from ICD therapy added to OMT.

Although a DEFINITE substudy suggested that ICD implantation within 3 or 9 months following diagnosis provided benefit, as indicated above, the analysis violates the statistical principal that subanalyses cannot be used to draw conclusions when the overall study is negative.8

Furthermore, enrollment in SCD-HEFT required that heart failure must have been present for at least 3 months so there can be no inference made regarding early implantation from that study either.3 Also, although SCD-HeFT showed benefit from ICD therapy, the benefit became apparent only after over a year. Thus, no study supports early implantation of an ICD in patients with newly diagnosed heart failure. And for Medicare patients, the Centers for Medicare and Medicaid Services (CMS) determined that clinical trial data was adequate to conclude that an ICD is reasonable and necessary for patients with NIDCM >3 months, NYHA class II or III heart failure, and measured an LVEF ≤35% after 3 months of diagnosis if the beneficiary is receiving the ICD for primary prevention, and is enrolled in either a clinical trial or registry such as the National Cardiac Data Registry (NCDR).9 Otherwise, the waiting period is 9 months. For the reasons previously stated, ICD implantation within the first 3 months following the diagnosis of heart failure is not appropriate. This patient was followed, treated optimally, and the LVEF improved to 45%. She was not treated with an ICD.

Another point to consider is that our patient had LBBB. Multiple studies have shown that LBBB, as a marker for electrical dyssynchrony (QRS >120 ms), is associated with increased mortality and morbidity in subjects with LV systolic dysfunction.10-12 LBBB contributes to progressive pump failure and increases the risk of developing ventricular arrhythmias.13 Cardiac resynchronization therapy (CRT) via biventricular pacing has changed the paradigm in management of systolic heart failure with LV dyssynchrony (usually identified by a prolonged QRS duration, especially LBBB) allowing for direct electrical intervention to restore interventricular synchrony, which is discussed in a separate chapter of this monograph. Though more often used in Europe compared with the United States, for patients with LV dysfunction, symptomatic heart failure, and a prolonged QRS duration, using CRT alone without defibrillation (a CRT pacemaker, CRT-P) may be considered, especially in situations where an there may be reasons why ICD implantation might not be desirable after open discussion with the patient and his or her family.

Two major studies addressed CRT-P in patients with severe LV dysfunction and evidence of dyssynchrony. The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) study enrolled patients with either ischemic or nonischemic cardiomyopathy, a LVEF ≤35%, and a QRS duration ≥120 msec.1 Patients in COMPANION were randomized to OMT alone, OMT with a CRT-P, or OMT with a biventricular ICD (CRT-D). In this study, patients with CRT (CRT-P and CRT-D groups combined) experienced a 20% reduction in mortality and hospitalization from any cause. The study was terminated early because of marked reduction in the primary and secondary endpoints with CRT. Although there was a clear trend towards lower mortality in the CRT-P group, 24% in relative terms when compared to the OMT group, that was not statistically significant (P = 0.06) (Figure 62-3). Had the study not been terminated early, CRT-P could have been associated with statistically significant reduction in mortality.

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FIGURE 62-3 Kaplan–Meier Estimates of the time to the primary endpoint of death from or hospitalization for any cause (A), the time to the secondary endpoints of death from any cause (B), the time to death from or hospitalization for cardiovascular causes (C), and the time to death from or hospitalization for heart failure (D). (A) The 12-month rates of death from or hospitalization for any cause (the primary end point) were 68% in the OMT group, 56% in the group that received CRT-P, and 56% in the group that received CRT-D. (B) The 12-month rates of death from any cause were 19% in the OMT group, 15% in the CRT-P group, and 12% in the CRT-D group. (C) The 12-month rates of death from or hospitalization for cardiovascular causes were 60% in the OMT group, 45% in the CRT-P group, and 44% in the CRT-D group. (D) The 12-month rates of death from or hospitalization for heart failure were 45% in the OMT group, 31% in the CRT-P group, and 29% in the CRT-Dgroup. P values are for the comparison with OMT. Reproduced with permission from Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;May 20;350(21):2140-2150.

The Cardiac Resynchronization-Heart Failure (CARE-HF) study compared CRT-P to OMT in patients with LVEF of ≤35%, NYHA class III or IV heart failure, a left ventricular end-diastolic dimension of at least 30 mm (indexed to height), and a QRS duration ≥120 ms. For those with QRS durations 120 to 149 ms, evidence of dyssynchrony was also required.14 This study showed marked reduction in the primary composite end point of death or cardiovascular hospitalization (39% in CRT-P group, 55% in OMT group, hazard ratio, 0.63; 95% confidence interval, 0.51 to 0.77; P < 0.001) (Figure 62-4). The relative risk reduction in mortality observed in the CARE-HF trial was not only similar to the CRT-D arm in COMPANION, but the mortality benefit was achieved without the defibrillation capabilities of the device. Indeed, in COMPANION the secondary endpoint of death or hospitalization from a cardiovascular cause (the primary endpoint in CARE-HF) was decreased only 1% by the addition of a defibrillator to CRT-P (Figure 62-3C). Thus, for patients who desire quality of life and improved longevity but do not desire an ICD, a CRT-P is completely appropriate and emphasizes the importance of discussing options and having patients share in the decision making process.15

Images

FIGURE 62-4 Kaplan–Meier estimates of the time to the primary endpoint (A), and the principal secondary end point (B) in the CARE-HF trial. The primary end point was death from any cause or an unplanned hospitalization for a major cardiovascular event, significantly decreased by CRT-P (hazard ratio, 0.63, 95% confidence interval, 0.51 to 0.77; P<0.001). The principal secondary end point was death from any cause was also decreased by CRT-P (hazard ratio, 0.64; 95% confidence interval, 0.48 to 0.85; P<0.002). Reproduced with permission from Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;April 14;352(15):1539-1549.

REFERENCES

1. Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350(21):2140-2150.

2. Follath F. Nonischemic heart failure: epidemiology, pathophysiology, and progression of disease. J Cardiovasc Pharmacol. 1999;33(Suppl 3):S31-35.

3. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352(3):225-237.

4. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008;51(21):e1-62.

5. Kadish A, Dyer A, Daubert JP, et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004;350(21):2151-2158.

6. McNamara DM, Starling RC, Cooper LT, et al. Clinical and demographic predictors of outcomes in recent onset dilated cardiomyopathy: results of the IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 study. J Am Coll Cardiol. 2011;58(11):1112-1118.

7. Bansch D, Antz M, Boczor S, et al. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy—The “Cardiomyopathy Trial (CAT). Circulation. 2002;105(12): 1453-1458.

8. Kadish A, Schaechter A, Subacius H, et al. Patients with recently diagnosed nonischemic cardiomyopathy benefit from implantable cardioverter-defibrillators. J Am Coll Cardiol. 2006;47(12):2477-2482.

9. National Coverage Determination (NCD) for Implantable Automatic Defibrillators. 2005; http://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=110&ncdver=3&bc=AAAAgAAAAAAAAA%3d%3d&. Accessed Oct 21, 2014.

10. Baldasseroni S, Opasich C, Gorini M, et al. Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure. Am Heart J. 2002;143(3):398-405.

11. Silvet H, Amin J, Padmanabhan S, et al. Prognostic implications of increased QRS duration in patients with moderate and severe left ventricular systolic dysfunction. Am J Cardiol. 2001;88(2):182-185, A186.

12. Tabrizi F, Englund A, Rosenqvist M, et al. Influence of left bundle branch block on long-term mortality in a population with heart failure. Eur Heart J. 2007;28(20):2449-2455.

13. Horwich T, Lee SJ, Saxon L. Usefulness of QRS prolongation in predicting risk of inducible monomorphic ventricular tachycardia in patients referred for electrophysiologic studies. Am J Cardiol. 2003;92(7):804-809.

14. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352(15):1539-1549.

15. Lin GA, Matlock DD. Less patient-centered care: an unintended consequence of guidelines? JAMA Intern Med. 2013;173(7):578-579.