Implantable Cardioverter Defibrillators as Primary Prevention for Non-Ischaemic Cardiomyopathy: Should the DANISH trial change clinical practice?

Dr Ahran Arnold MBBS BSc MRCP

NIHR Academic Clinical Fellow, Imperial College London

Specialist Registrar in Cardiology, Imperial College Healthcare NHS Trust

Background

Implantable Cardioverter-Defibrillators (ICDs) carry a class I indication for implantation to prevent sudden cardiac death (SCD) in patients with symptomatic Heart Failure who have a Left Ventricular Ejection Fraction (LVEF) less than 35% despite optimal medical therapy^[1]. However there has been a long held suspicion among the heart failure and arrhythmia communities that the efficacy of primary prevention ICDs in heart failure of non-ischaemic aetiology is lower than that of ischaemic aetiology. This is borne out in disparity of level of evidence supporting the recommendations: B for non-ischaemic aetiology compared to A for ischaemic cardiomyopathy^[1].

DANISH - “Defibrillator Implantation in Patients with Nonischaemic Systolic Heart Failure”

The DANISH trial, published in September 2016 in the New England Journal of Medicine, has ignited the debate with its finding that prophylactic ICDs in non-ischaemic cardiomyopathy do not result in reduced mortality in a large randomized controlled trial (RCT)^[2]. Recruitment took place between 2008 and 2014 at five centres and 1,116 patients were randomized to ICD or medical therapy in a 1:1 fashion. Median age was 64 (56-72) in the ICD group and mean LVEF was 25% (IQR 20-30). Over 90% of patients were on beta-blockers and ACE-inhibitors, whilst just under 60% were taking mineralocorticoid antagonists (MRA). 58% of patients also received a left ventricular lead as part of Cardiac Resynchronization Therapy (CRT).^[2]

Median follow up was 5.5 years and the primary outcome was all-cause mortality, which was not significantly different between ICD and medical therapy (HR 0.87, confidence interval (CI) 0.68-1.12, p=0.28). When considering secondary outcomes, there was also no significant difference in cardiovascular death (HR 0.77, CI 0.57-1.05, p=0.10) but ICDs were associated with a significant reduction in Sudden Cardiac Death (HR 0.5, CI 0.31-0.82, p=0.005). Of note the total event rate for the primary outcome was 22.4% (rate of all-cause mortality in all patients), which is an annualized rate of around 4% per year, which is lower than older RCTs in the same population.^[2]

Previous RCTs in the non-Ischaemic population

The controversy regarding the efficacy of prophylactic ICDs to reduce mortality in non-ischaemic cardiomyopathy may originate from the lack of individual trials showing benefit of ICDs. Of the 5 primary prevention RCTs (CAT 2002^[3], AMIOVERT 2004^[4], DEFINITE 2004^[5], COMPANION 2004^[6], SCD-HeFT 2005^[7]) that included patients with non-ischaemic cardiomyopathy only COMPANION showed a significant reduction in all-cause mortality for non-ischaemic patients. This analysis was not included in the original analysis but has been determined from the kaplan-meier curves in the original publication by Shun-Shin et al in recent meta-analysis^[8]. SCD-HeFT showed a trend towards benefit for all-cause mortality but did show a reduction in SCD.

When these trials (excluding COMPANION, whose non-ischaemic population had not yet been analysed) were meta-analysed by Desai et al^[9] there does appear to be a clear reduction in all-cause mortality (HR 0.69, CI 0.55-0.87, P = 0.002). This forms the basis for the recommendation for implantation in the non-ischaemic population in international guidelines. It was felt that the lower event rate in the non-ischaemic population may have resulted in these trials being underpowered individually but collectively show the benefit of ICDs.

Meta-analysis including DANISH

Shun-shin et al have meta-analysed the aforementioned non-ischaemic primary prevention ICD trials along with DANISH and their analysis of the data from COMPANION. They find that when the negative finding of DANISH is combined with the 5 previous trials, the benefit of ICD over medical therapy persists (HR 0.76, CI 0.64-0.90, p=0.001). There was a low level of I² heterogeneity with this result. This indicates that the DANISH finding falls within the expected result from previous data.^[8]

Should DANISH change practice?

The inevitable question is whether or not the negative result from DANISH should change implantation practice for patients with non-ischaemic cardiomyopathy. The DANISH authors, along with an accompanying editorial by McMurray, argue that the improvement in medical therapy for heart failure has reduced the risk of death over time. There is a massive difference in the rates of beta blockade, ACE-I and MRA prescription rates across the trials (4% of CAT, 2002, patients were on beta blockers compared to 92% in DANISH, 2016) and newer pharmacological agents such as Neprilysin inhibitors (Entresto) may further reduce event rates in the future.

However, it should be considered that, even prior to DANISH, it has been understood that individually underpowered trials need to be combined to understand the true benefit of an intervention in question and this was the case for non-ischaemic cardiomyopathy. The addition of DANISH to the data set does not, on the face of it, change the summary meta-analysed result that ICDs benefit.

There are a few other considerations that may influence decision making. MADIT-RIT^[10], along with other similar trials, have demonstrated that longer detection times and higher thresholds for delivering ICD therapy (shocks and ATP, anti-tachycardia pacing) reduce mortality when compared to traditional programming. These programming settings are now widely applied and are thus improving the efficacy of ICDs. The supplementary appendices of DANISH indicate that programming during the trial did changed as these trials were published during recruitment for DANISH, however it is not clear what proportion of patients in DANISH had MADIT-RIT style programming in place and for how long.

Regarding cost-effectiveness, an economic evaluation of DANISH as an individual trial may increase the cost per QALY of implantation to a value above accepted willingness-to-pay thresholds but using the meta-analysed efficacy, the cost-effectiveness is likely to remain similar – so the question rests, again, on whether we accept DANISH as an individual trial with modern medical therapy or view it in the context of previous similar trials.

Furthermore, there is ongoing work into new ways to improve the ICD efficacy/safety profile and novel predictors of ventricular arrhythmia in heart failure that may result in better patient selection. So just as medical therapy is acquiring new agents into its pantheon, ICD therapy is also improving, so an inexorable march to lower event rates through improved medical therapy eliminating the benefit of ICD therapy should not be assumed.

References

1. Priori, S.G., et al., 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J, 2015. 36(41): p. 2793-867.
2. Kober, L., et al., Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure. N Engl J Med, 2016. 375(13): p. 1221-30.
3. Bansch, D., et al., Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation, 2002. 105(12): p. 1453-8.
4. Strickberger, S.A., et al., Amiodarone versus implantable cardioverter-defibrillator:randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia--AMIOVIRT. J Am Coll Cardiol, 2003. 41(10): p. 1707-12.
5. Kadish, A., et al., Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med, 2004. 350(21): p. 2151-8.
6. Bristow, M.R., et al., Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med, 2004. 350(21): p. 2140-50.
7. Bardy, G.H., et al., Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure.N Engl J Med, 2005. 352(3): p. 225-37.
8. Shun-shin M, Z.S., Cole G, Howard J, Whinnett Z, Francis D, Implantable cardioverter defibrilators for primary prevention of death in left ventricular dysfunction with and without ischaemic heart disease: a meta-analysis of 8567 patients in the 11 trials. European Heart Journal, 2017. 0: p. 1-10.
9. Desai, A.S., et al., Implantable defibrillators for the prevention of mortality in patients with nonischemic cardiomyopathy: a meta-analysis of randomized controlled trials. Jama, 2004. 292(23): p. 2874-9.
10. Moss, A.J., et al., Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med, 2012. 367(24): p. 2275-83.