By Connor Emdin
August 1, 2017
Heart failure is the cause of more than one million hospital admissions in the United States annually1 and is a leading cause of death worldwide.2 Heart failure with reduced ejection fraction (HFrEF), characterized by EF typically <40%, is observed in approximately 50% of individuals with heart failure1 and is associated with an elevated risk of sudden cardiac death due to ventricular arrhythmia.3 While implantable cardioverter-defibrillators (ICD) can reduce the risk of sudden death, substantial risk remains and implantation itself is expensive and associated with risks including infection, and device misfiring.1,4 Therefore identifying the patient population who will gain most benefit from ICD implantation is of considerable interest.
Over the past twenty years, several landmark clinical trials have demonstrated reduced mortality with the use of angiotensin converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers and mineralocorticoid receptor antagonists in HFrEF1. The data is increasingly applied in clinical practice, with more than 70% of heart failure patients discharged from United States hospitals prescribed a beta-blocker and an ACE-inhibitor or ARB.5
In a recent study published in the New England Journal of Medicine, a group of investigators, led by Li Shen and John McMurray of Glasgow University, examined whether greater use of evidence-based medications for HFrEF has lowered the risk of sudden cardiac death.6 They hypothesized that a reduced incidence of sudden cardiac death may attenuate the benefit of ICDs for prevention of sudden cardiac death in HFrEF.
The investigators aimed to pool results from all large (>1000 patients) randomized trials that were conducted in HFrEF populations over the past 19 years and that included an adjudicated cause of death. From 22 eligible trials, they were able to obtain individual patient-level data from 12 trials, which were included in the current study. Using data from 40,195 patients with HFrEF, they examined whether the risk of sudden cardiac death was associated with calendar year, having adjusted for treatment groups within each trial.
RALES, which investigated the use of mineralocorticoid inhibition in HF, was initiated in 1995. Patients in this study had an annual rate of sudden cardiac death of 6.5% (Table). This rate fell throughout the study period, to 3.3% in the last randomized trial included, PARADIGM-HF, for which randomization was performed in 2009. When adjusted for randomized group, risk of sudden death in HFrEF declined by 44% over the 19-year period (hazard ratio 0.56 CI 0.33 to 0.93; p=0.03). Results were similar when sudden death at 90 days after randomization was examined; cumulative rates declined from 2.4% (95% CI 1.6 to 3.1) in the earliest trial to 1.0% (95% CI 0.8 to 1.3) in the most recent trial
Table. Annual rate of sudden death by trial and year of randomization.
|Trial||Number of Participants||Year of Randomization||Annual Rate of Sudden Death % (95% confidence interval)|
Interestingly, the proportion of sudden deaths relative to overall mortality did not change over time, indicating that these changes reflect declining overall mortality in the HF population. The authors suggest that the decline in rates of sudden cardiac death observed in the study are evidence that increased use of evidence-based medication in HFrEF has lowered the rate of sudden cardiac death. They speculate that intensive use of evidence-based medication may attenuate some of the benefits of ICDs for HFrEF patients, as the risk of sudden death has fallen so markedly in recent years.
These are encouraging data, but there are several important considerations. This was an observational analysis of heavily-monitored patients enrolled in randomized trials, and some of the decrease in sudden cardiac death may be due to changes in the characteristics of the patients enrolled, rather than the effect of use of evidence-based medications. Furthermore, this study does not provide any evidence that implantable cardioverter-defibrillators are less effective in HFrEF patients who are at lower risk of sudden cardiac death, and a separate study would be needed to definitively answer this question.
Despite these limitations, the lower rates of sudden death observed in recent years lends further support to greater use of evidenced-based medications for patients with HFrEF. This is particularly important considering the low rates of ACE-inhibitor, beta-blocker and mineralocorticoid antagonist use for HFrEF observed in many US hospitals. 7
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-e327. doi:10.1161/CIR.0b013e31829e8776.
- Callender T, Woodward M, Roth G, et al. Heart failure care in low- and middle-income countries: a systematic review and meta-analysis. Byass P, ed. PLoS medicine. 2014;11(8):e1001699. doi:10.1371/journal.pmed.1001699.
- McMurray JJV. Clinical practice. Systolic heart failure. N Engl J Med. 2010;362(3):228-238. doi:10.1056/NEJMcp0909392.
- 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. doi:10.1056/NEJMoa043399.
- Hernandez AF, Greiner MA, Fonarow GC, et al. Relationship between early physician follow-up and 30-day readmission among Medicare beneficiaries hospitalized for heart failure. JAMA : the journal of the American Medical Association. 2010;303(17):1716-1722. doi:10.1001/jama.2010.533.
- Shen L, Jhund PS, Petrie MC, et al. Declining Risk of Sudden Death in Heart Failure. N Engl J Med. 2017;377(1):41-51. doi:10.1056/NEJMoa1609758.
- Allen LA, Fonarow GC, Liang L, et al. Medication Initiation Burden Required to Comply With Heart Failure Guideline Recommendations and Hospital Quality Measures. Circulation. 2015;132(14):1347-1353. doi:10.1161/CIRCULATIONAHA.115.014281.
Connor Emdin is a post-doctoral research fellow in Sek Kathiresan’s lab at the Broad, specializing in the genetics of cardiovascular disease. He completed his doctorate in cardiovascular epidemiology at the University of Oxford from 2009-2013.