After 6 months of therapy with the combination drug sacubitril/valsartan (S/V; Entresto, Novartis), one quarter of primary prevention patients with left heart failure and an implantable cardioverter defibrillator (ICD) had a left ventricular ejection fraction (LVEF) > 35% with no arrhythmic events, an observational study shows.
S/V treatment was already known to be associated with an increase in LVEF, lead author Federico Guerra, MD, of the Marche Polytechnic University in Ancona, Italy, told theheart.org | Medscape Cardiology.
“The main new message” is that up to 6 months after starting treatment, nearly one in four patients no longer had an indication for ICD implant, he said. Although the treatment lowered the risk of arrhythmic events over the 6-month period, it did not eliminate it, with 5.3% of patients experiencing an arrhythmia.
The results were presented at the virtual congress of the European Heart Rhythm Association.
In the Effect of Sacubitril/Valsartan on Left Ventricular Ejection Fraction and Their Potential Impact on Implantable Cardioverter Defibrillator Implant Rates for Primary Prevention of Sudden Cardiac Death study (SAVE-ICD; NCT03935087) the primary aim was to assess how many patients receiving S/V according to current guidelines for 6 months improved enough not to be candidates for primary prevention with an ICD.
This multicenter, Italian study enrolled 230 consecutive, unselected patients 18 years and older, who had heart failure, left systolic dysfunction with baseline LVEF < 35%, and had a single-chamber (37%), dual-chamber (55.2%), or subcutaneous (7.8%) ICD for primary prevention of sudden cardiac death. “We wanted to make an observational study as close as possible to real practice,” Guerra said.
Mean LVEF was 28.3% ± 5.6%. Mean age of patients was 64.3 years, 73.9% were male, and the large majority had NYHA class II (55.2%) or III (42.6%) heart failure. At enrollment, 68.3% were receiving S/V 24 mg/26 mg twice daily, and the rest 49 mg/51 mg twice daily.
At 6 months of follow-up, the mean absolute increase in LVEF was 3.9%. Four patients (1.7%) had died, all of end-stage heart failure. Among the 230 patients, 57 (24.8%) achieved an LVEF > 35%.
Based on this finding, the investigators hypothesized that for every 100 heart failure patients with LVEF ≤ 35% and no previous arrhythmic event for ≥ 6 months, treatment with S/V could avoid an ICD implant in 25.
Rapid treatment with S/V ”could prevent ICD implantation in a good part of our patients with significant cost savings to the system,” Guerra said, calculating about €461,500 in costs avoided.
Predictors of LVEF Change
Most patients (58.8%) had an absolute increase in LVEF > 3%, with just over half of them in the 3%-5% range and the rest about evenly divided between the 6%-10% and > 10% range.
Among several variables investigated, two were independent predictors of LVEF change. A dose of S/V > 24 mg/26 mg twice daily was a positive predictor of LVEF improvement, with a hazard ratio (HR) of 2.81 (95% CI, 1.2 – 6.60; P = .018).
The other was baseline LVEF, with an HR of 0.88 (95% CI, 0.83 – 0.93; P < .001) for an LVEF increase of +1 standard deviation in LVEF percentage, meaning that baseline LVEF was a negative predictor of improvement.
Twelve (5.3%) out of the 226 patients alive at 6 months had one or more ventricular arrhythmia episodes that incurred appropriate ICD therapies: nine had a single episode leading to one shock, two had two episodes treated with two shocks, and one had one episode treated with anti-tachycardia pacing.
Guerra said the main adverse effect with S/V is hypotension, and 12% of patients in the study needed dose reductions. The main study limitation is that it was observational and should be confirmed by further investigation, possibly using better echocardiographic predictors beyond LVEF, he noted. Plus, the window of opportunity during heart failure during which S/V may be effective to sufficiently improve the condition still needs to be determined.
A Potential Dilemma
In light of this study and others showing that S/V can sufficiently improve left ventricular function in a significant minority of patients who may then no longer have an indication for an ICD for primary prevention, the question arises of what to do when it is time to replace the generator.
Guerra said the procedure itself could expose a patient to the risk of a pocket infection, but not replacing the unit may put the patient at risk in case of an arrhythmia. “We’ve never been in this kind of situation,” he said. “This is not an easy decision because there’s no evidence on what kind of path to follow.”
Commenting on the findings for theheart.org | Medscape Cardiology, Elena Arbelo, MD, PhD, Hospital Clinic of Barcelona and University of Barcelona, Spain, said her main criticism of the study is that it lacked a control group.
“It’s difficult to reach any conclusion or trust any of the observations in this study, if you have no competitor…so we don’t even know if patients with similar characteristics without this medication would have similar responses,” she said. Her recommendation is for a study with a control group and longer follow-up.
She would consider it ill-advised not to continue ICD therapy even if the LVEF improves above 35%. “The design of the study does not allow us to be able to say this,” she said. “And I think it’s kind of a dangerous message, especially if you consider that the follow-up is only 6 months, and even during the first 6 months they have some patients with ventricular arrhythmia.”
Also commenting for theheart.org | Medscape Cardiology, Paulus Kirchhof, MD, director of the Department of Cardiology at the University Heart and Vascular Center UKE Hamburg, Germany, reiterated Guerra’s point that taking into account other parameters beside LVEF may provide a better basis for deciding which patients may require an ICD.
“We currently apply very crude criteria for the indication for an implanted defibrillator, and they are crude by necessity because we try to predict single-life threatening events which will not occur in everyone, but we want to protect everyone that may be at risk,” he said. “There is a lot of work going on testing whether there are better methods to assess the sudden death risk or the need for defibrillators in patients with heart failure, including MRI imaging [or] including analysis of electrical potentials of various sorts.”
He would advise against “basing a decision for complex intervention of implantation for a defibrillator…on a binary decision on a single parameter, ejection fraction.” Furthermore, the study was observational, and there was no information on whether patients had been on optimal medical therapy, a requirement before receiving an ICD.
The study did not receive any specific funding from commercial, public, or nonprofit entities. Guerra has reported receiving fees/research grants from Actelion, Bayer, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, and Sanofi. Arbelo has reported no relevant financial relationships. Kirchhof has reported receiving support for basic, translational, and clinical research projects from the European Union, the British Heart Foundation, the Leducq Foundation, the Medical Research Council (UK), the German Centre for Cardiovascular Research, and from several drug and device companies active in atrial fibrillation, from which he has received honoraria in the past but not in the last 3 years. He is listed as inventor on two patents held by the University of Birmingham.
European Heart Rhythm Association Congress 2020. Presented online March 29-31, 2020.