ICDs Do Not Reduce Mortality in Patients With HF Not Caused by Coronary Artery Disease: DANISH

ROME, Italy—Prophylactic implantable cardioverter defibrillator (ICD) therapy with or without cardiac resynchronization therapy (CRT) in patients with nonischemic systolic heart failure does not lower the risk of death when compared with usual care, according to the results of a new study.

“We failed to show that we could prolong life in everyone in the trial,” Lars Køber, MD (Rigshospitalet University Hospital, Copenhagen, Denmark), the lead researcher of the Danish Study to Assess the Efficacy of ICDs in Patients with Nonischemic Systolic Heart Failure on Mortality (DANISH) study, said today during a press conference at the European Society of Cardiology (ESC) Congress 2016 in Rome, Italy.

During a median follow-up of 5.6 years, death from any cause occurred in 21.6% of 556 patients treated with the ICD and in 23.4% of 560 patients managed with optimal medical therapy, a nonsignificant difference. Cardiovascular mortality was also unaffected by the addition of ICD therapy. There was a reduction in the risk of sudden cardiac death observed in the ICD arm (4.3% vs 8.2%; P = 0.005), which was a secondary endpoint, and shows “the ICD does what it can,” according to researchers.    

The study, in which 58% of patients in both arms were treated with cardiac resynchronization therapy (CRT), was published today in the New England Journal of Medicine to coincide with the ESC presentation.  

Might Lead to Increased Use in Denmark

Speaking with the media, Køber said Denmark has been a bit of an outlier in terms of ICD use for nonischemic systolic heart failure. He said evidence supporting the indication and clinical recommendations for ICD use in this population has largely been based on small-to-medium sized trials and subgroup analyses of larger studies. As such, they did “not believe” the evidence and limited their use of ICDs in nonischemic heart failure. 

Ironically, despite the negative results, the DANISH trial might lead to an increase in ICD use in Denmark, specifically in younger patients, said Køber. In the trial, investigators did observe a statistically significant 36% reduction in all-cause mortality among patients younger than 68 years. 

Mary Norine Walsh, MD (St. Vincent Heart Center, Indianapolis, IN), who was not involved in the study, told TCTMD there has always been a hint that patients with nonischemic heart failure differ from those with heart failure caused by coronary artery disease. To date, though, there has not been any definitive evidence these patients should not have a defibrillator. 

“I think this study, which was well done, will add to what we’re able to say to our patients, particularly those that are older,” said Walsh. “The older patients [in the DANISH trial] didn’t appear to benefit as much as the younger patients so this is another piece of data we can use when we’re trying to make a decision.” 

Although prophylactic ICD implantation in patients with nonischemic heart failure did not provide a survival advantage over medical therapy with ACE inhibitors, angiotensin receptor blockers (ARBs), and beta blockers, Walsh said ICDs will likely remain part of the discussion in these patients, particularly in the United States where there is the risk for lawsuits and the guidelines currently provide a strong recommendation. 

To TCTMD, Walsh said she will tell patients with nonischemic systolic heart failure that “a really well done study casts doubt on whether you will benefit [from an ICD].”   

For John McMurray, MD (University of Glasgow, Scotland), who wrote an editorial accompanying the study, the DANISH results likely represent the most optimistic evaluation of benefit of ICD therapy in patients with nonischemic heart failure who receive evidence-based therapy. In the present study, approximately 73% of all deaths in the control arm were attributed to cardiovascular causes, which is “one of the lowest proportions ever described in a trial involving patients with heart failure.” Patients enrolled in clinical trials are usually younger than those in the community, have fewer comorbid conditions, and as a result, have a relatively higher risk of death from cardiovascular causes. 

“Consequently, the absolute benefit of ICDs in a typical and well-treated population with heart failure might be small,” writes McMurray. 

Strong Recommendations From Guidelines

The DANISH investigators explain there is strong evidence ICDs decrease the risk of sudden cardiac death in patients with systolic heart failure and reduced ejection fraction caused by coronary artery disease, but the data are much weaker in support of ICD use in patients with a nonischemic heart-failure etiology. To date, there are only very limited data from randomized clinical trials showing a statistically significant effect of ICD therapy in patients with nonischemic heart failure.

The American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend ICD therapy for primary prevention of sudden cardiac death in selected patients with nonischemic dilated cardiomyopathy or ischemic heart disease who are at least 40 days out from an MI, left ventricular ejection fractions < 35%, and NYHA class II or III symptoms despite guideline-recommended medical therapy (class I, level of evidence A).

In contrast with the ACC/AHA recommendations, which make no differentiation between ischemic and nonischemic heart failure, ICD implantation in the European Society of Cardiology guidelines is a class IB recommendation for patients with nonischemic heart failure. 

Mariell Jessup, MD (University of Pennsylvania, Philadelphia), who was involved in drafting the ESC and ACC/AHA heart failure guidelines, said ICD use is higher in the US than in Europe. The European guidelines were recently updated, and specifically noted the weaker evidence for ICD use in patients with heart failure not caused by coronary artery disease. Although the ESC updated their heart-failure guidelines related to the use of ICDs, the ACC/AHA do not have any plans to update their guidelines anytime soon, she said.

For Frank Ruschitzka, MD (University of Zurich, Switzerland), who, with Jessup, chaired the morning press conference announcing the results, there is no need to rush to alter the clinical guidelines on the basis of this one study. Both sets of guidelines factor in patient age, focusing on the patients most likely to benefit from ICD therapy. For example, the IB recommendation from the ESC states ICDs should be used only in patients “expected to live substantially longer than one year,” he said. In DANISH, the ICD reduced the risk of sudden cardiac death, which would be beneficial in a young patient at low risk of death from other cardiovascular causes, he suggested. 

Patients who receive an ICD are typically at a higher risk of major device-related complications such as systemic infections or endocarditis, pneumothorax, cardiac perforation, and pocket revisions due to pain, among others. In the DANISH study, device-related infection occurred in 4.9% of patients who received the ICD and in 3.6% of patients in the control group, a nonsignificant difference. 

Sources:

•  Køber L, Thune JJ, Nielsen JC, et al. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med. 2016;Epub ahead of print.
•  McMurray JJ. The ICD in heart failure—time for a rethink. N Engl J Med. 2016;Epub ahead of print.

Disclosures:

• Køber reports no conflicts of interest related to the DANISH study. He reports receiving personal fees from Sanofi and Novartis outside this trial.
• McMurray reports nonfinancial and other support from Cardiorentis AG, Amgen, Novartis, Oxford University/Bayer, GlaxoSmithKline, Theracos, AbbVie, AstraZeneca, Kidney Research UK/Kings College Hospital, London/Vifor Fresenius Pharma, and other support from DalCor, Pfizer, Merck, and Bristol-Myers Squibb. 

Related Stories:

•  US and European Heart Failure Guidelines Advocate Use of Two New Therapies
•  Heart Failure Still a Problem but Less of a Burden on Acute MI Patients
•  CMR Can Accurately Diagnose Cause of Heart Failure