Are Primary-Prevention ICDs Still Right for Nonischemic Heart Failure? DANISH Says No

August 28, 2016

ROME, ITALY ( updated ) — With contemporary heart-failure therapies, it seems that an implantable cardioverter defibrillator (ICD) for primary prevention does not improve long-term survival in patients with nonischemic cardiomyopathy, whether or not they are also getting cardiac resynchronization therapy (CRT), suggests a major randomized trial[1].

But secondarily there was confirmation that the ICD implants do cut the risk of sudden cardiac death overall. And that they probably prolong survival in one subgroup that researchers and some observers say may represent the most appropriate population for the devices among patients with nonischemic heart failure.

In the Danish Study to Assess the Efficacy of ICDs in Patients With Nonischemic Systolic Heart Failure on Mortality (DANISH) of about 1100 symptomatic patients with an LVEF <35 on optimal meds but without coronary disease, the hazard ratio for all-cause mortality was 0.85 (95% CI 0.68–1.12) for those implanted with an ICD vs those managed with "usual clinical care." The median follow-up was 67.6 months.

But age showed a significant interaction (P=0.009) with mortality among those with an ICD. Patients younger than 59 years may have shown an ICD survival gain, according to the researchers. In a subgroup analysis, they showed a 49% drop in all-cause mortality (P=0.02).

Toward a Tailored Approach?

Dr Lars Køber

The interaction with age makes sense, according to Dr Lars Køber (Copenhagen University Hospital of Rigshospitalet, Denmark), who also presented the study here today at European Society of Cardiology (ESC) 2016 Congress.

The survival benefits of ICDs are more likely to show up in younger patients, he observed for heartwire from Medscape, because as people get older, they become more frail with a higher comorbidity burden, so that any survival gain from an ICD "drowns" in competing risks for death.

"Maybe an ICD is not what you need when you're 84," according to Køber. While the trial weakens the case for an ICD in older patients with nonischemic heart failure, it also argues for greater, selective use in the younger ones, he said. DANISH was published today in the New England Journal of Medicine with Køber as lead author.

In contrast to the all-cause-mortality primary outcome, the risk of sudden death was cut by half for the 556 ICD patients compared with the 560 patients in control group, from 8.2% to 4.3% (P=0.005).

Almost 60% of patients in both groups were on CRT. Rates of device-related infection were not significantly different across groups. About 6% of patients in the ICD group experienced inappropriate shocks.

Even though the trial was "neutral" for the primary finding of comparable all-cause mortality with or without the devices, "it would be wrong" to say it argues against primary-prevention ICDs in symptomatic nonischemic cardiomyopathy, agreed Prof Martin Cowie (Royal Brompton and Harefield NHS Foundation Trust, London, UK).

DANISH strengthens the evidence base favoring ICDs in selected patients with nonischemic HF, Cowie, who is not connected with the trial, told heartwire . While subgroup analyses should be interpreted with great caution, an ICD survival effect in the younger-age group is biologically plausible and even what would be expected, he said, concurring with Køber, because their sudden death risk—which ICDs are designed to lower—is enlarged among possible causes of death.

"For me, [the trial] is very much about the need for a tailored approach to the patient, thinking about their individual risk of sudden death vs other ways of dying." ICDs can prolong life by preventing sudden death, Cowie said, "but in that individual's overall management plan, does that make sense?"

Cowie said he hopes DANISH will encourage clinicians not to follow blanket recommendations for prophylactic ICDs in nonischemic HF patients, "but to follow a more tailored approach to the individual."

ICDs With Modern HF Therapies

In other ways, DANISH does address lingering questions about primary-prevention–device therapy in nonischemic heart failure. For example, the authors note, the seminal SCD-HeFT trial from a dozen years ago was a rare primary-prevention ICD trial to enroll lots of nonischemic patients and to show a mortality benefit for device therapy. But no one in the trial was on CRT, which has since had a huge impact on heart-failure survival.

And before that, primary-prevention ICDs came up short for all-cause mortality in the much smaller DEFINITE trial.

"The results of the DANISH trial probably represent the most optimistic estimate of the benefit of ICD therapy in patients with nonischemic heart failure who receive evidence-based treatment," according to Dr John JV McMurray (University of Glasgow, Scotland) in an accompanying editorial[2].

Patients in the trial had a low risk of sudden death, accounting for their lack of survival gain from ICD therapy, he writes. Patients with nonischemic cardiomyopathy tend to be at lower risk for sudden death and all-cause death compared with those with ischemic heart failure, the group most represented in the seminal primary-prevention ICD trials of the past 15 years.

"Second, and probably more important, the background treatment in the trial was very comprehensive." Use of ACE inhibitors or angiotensin-receptor blockers (ARBs) and beta-blockers was "almost universal," and use of aldosterone blockers approached 60%, according to McMurray. Moreover, "unlike in previous ICD trials, 58% of patients received CRT."

Whither the Guidelines?

Køber and others at the ESC sessions pointed out that the US guidelines recommend primary-prevention ICDs in low-LVEF nonischemic HF patients as strongly as ischemic-HF patients—while the ESC guidelines recommend the devices a little less strongly for nonischemics. Yet, on both sides of the Atlantic, such ICDs are even now used in only a small proportion of those who meet the indications and would presumably benefit.

So even with a neutral trial, in a cohort especially well treated for heart failure, the trial does not argue to pull back on primary-prevention ICDs in nonischemics, Dr Mariell Jessup (University of Pennsylvania, Philadelphia) told heartwire .

"ICDS were never supposed to reduce overall mortality. They reduce sudden cardiac death, that's their mechanism," noted Jessup, who was not part of the trial but played a role in developing both the US and the European primary-prevention ICD guidelines.

DANISH, she said, shows that even in nonischemic patients, "ICDs still work and were especially effective in people who weren't going to die from other comorbidities. So I would argue strongly that if you follow the guidelines, either the American or European guidelines, no country is putting in enough ICDs to prevent sudden death in patients who could expect to live more than a year."

Agreed Køber to heartwire , "In the real world, ICDs are not overused. They are not used as [extensively] as the guidelines say." He said expects the DANISH trial to spur clinicians to implant more primary-prevention ICDs in nonischemic HF patients, not fewer, due to the observed sudden-death benefit if not the survival gain in younger patients.

Prof Michel Komajda (Groupe Hospitalier Pitié-Salpêtrière, Paris, France), involved in developing the European guidelines but who isn't part of DANISH, said he would wish to incorporate the trial's results into the recently revised document. "I would add an amendment to the guidelines. Of course the primary outcome was neutral, but I feel that the reduction in sudden cardiac death, which is the primary objective of implanting an ICD, was quite significant."

DANISH was supported by grants from Medtronic, St Jude Medical, TrygFonden, and the Danish Heart Foundation. Køber reports personal fees from Sanofi and Novartis outside the submitted work. Disclosures for the coauthors are listed on the journal website. McMurray reports nonfinancial and other support from Cardiorentis, Amgen, Novartis, Oxford University/Bayer, GlaxoSmithKline, Theracos, AbbVie, AstraZeneca, and Kidney Research UK/Kings College Hospital/ViforFreseneius Pharma, and other support from DalCor, Pfizer, Merck, and Bristol-Myers Squibb outside the submitted work.

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