You are here
American Heart Association Scientific Sessions 2019
This year’s American Heart Association (AHA) annual meeting in Philadelphia, held from November 16 to 18, hosted 16,000 cardiology professionals. The review below features key sessions highlighted in press briefings, with particular emphasis on major trials in heart failure and ischemia.
The Colchicine Cardiovascular Outcomes Trial (COLCOT)
- Jean-Claude Tardif, MD, Montreal Heart Institute, Montreal, Canada
“Colchicine 0.5 mg/day significantly reduces the risk of first and total ischemic cardiovascular events compared to placebo in patients with a recent myocardial infarction,” Dr. Tardif concluded in an AHA press briefing.
The search for an available anti-inflammatory treatment that may reduce the risk of atherosclerotic events in patients with coronary artery disease was stimulated by experimental and clinical evidence delineating the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent anti-inflammatory medication currently indicated for gout and pericarditis. COLCOT, a randomized, double-blind, placebo-controlled, multinational clinical trial, was conducted in patients with a recent myocardial infarction to evaluate both colchicine’s effects on cardiovascular outcomes and its long-term safety and tolerability.
COLCOT investigators enrolled 4,745 patients (mean age, 61 years; 19% female) at 167 clinical sites who had experienced a myocardial infarction within the last 30 days followed by any percutaneous revascularization procedure. Nearly all patients were receiving background therapy with aspirin (99%), a second antiplatelet agent (98%), and a statin (99%). They were randomized to colchicine (0.5 mg daily) or placebo, with all receiving standard medical care, including intensive statin therapy. The primary outcome was time from randomization to a first event (cardiovascular mortality, resuscitated cardiac arrest, nonfatal myocardial infarction, nonfatal stroke, or urgent hospitalization for angina requiring coronary revascularization).
The 42-month cumulative incidence for the primary intention-to-treat composite efficacy endpoint was 5.5% for colchicine and 7.1% for placebo (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.61–0.96; P = 0.02). In addition to this 23% reduction in first ischemic cardiovascular events, there was a 34% reduction in total cardiovascular events. In a per-protocol analysis, the hazard ratio was 0.71 (0.56–0.90), with a P value of 0.004 for first cardiovascular events. All of the individual endpoint components favored colchicine numerically but without statistical significance.
Dr. Tardif reported a small increase in pneumonias (0.8% for colchicine versus 0.4% for placebo). Overall, adverse event rates were low. Further research is needed to assess the benefits of colchicine in other high-risk patients, he noted, emphasizing that COLCOT results apply to patients who have recently suffered a myocardial infarction.
“These landmark results provide confirmation that inflammation management reduces cardiovascular risk,” said AHA discussant Aruna Pradhan, MD, of Harvard Medical School in Boston. He added that COLCOT demonstrates a successful repurposing of a broadly available and relatively safe generic drug for a new application.
Safety and Efficacy of Inclisiran in Patients With ASCVD and Elevated LDL Cholesterol—Results From the Phase 3 ORION-10 Trial
- R. Scott Wright, MD, Mayo Clinic, Rochester Minnesota
“Inclisiran potentially offers a novel treatment for LDL [low-density lipoprotein] cholesterol that may influence medication adherence in routine clinical practice,” Dr. Wright stated after presenting results of ORION-10 at an AHA press briefing. Despite aggressive treatment with statins and other lipid-lowering strategies, he noted, atherosclerotic cardiovascular disease remains the leading cause of death globally.
While ezetemibe and monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9), in multiple treatment guidelines, are adjunctive strategies, statins and ezetimibe require daily dosing and a PCSK9-inhibiting monoclonal antibody is administered through twice-monthly injections. “There is a need for options with less frequent dosing to improve adherence and compliance,” Dr. Wright said, pointing out that phase 2 ORION-1 findings suggested that inclisiran has the potential to safely reduce low-density lipoprotein-cholesterol (LDL-C) by more than 50%.
The phase 3 ORION-10 trial assessed inclisiran efficacy and safety in patients with stable atherosclerotic cardiovascular disease and elevated LDL-C (70 mg/dL or higher) on maximal oral statin doses. ORION-10 investigators enrolled 1,561 subjects from 145 U.S. sites. Eighty percent were receiving high-intensity statins and 10% were on ezetimibe. Mean baseline LDL-C was 110 mg/dL.
Investigators randomized them 1:1 to inclisiran sodium 300 mg or placebo, administered at day 1, day 90, day 270, and day 450. The coprimary endpoints were the percentage change from baseline in LDL-C at day 510 and the time-adjusted average percentage change from baseline in LDL-C between day 90 up to day 540.
Relative to placebo, lowering of LDL-C with inclisiran was highly significant (P < 0.0001), with a 58% and 52% (observed/imputed [accounting for missing data]) reduction at day 510. Time-averaged LDL-C reductions from day 90 to 540 were 56% and 54%, respectively (observed/imputed) (P < 0.00001).
Over 18 months of follow-up, Dr. Wright said, the inclisiran safety profile was similar to placebo in this high-risk cardiovascular disease population. While injection-site pain was most common, use of a prefilled syringe in cycles 3 and 4 reduced its incidence to 1% versus 0.1% for placebo. Serious adverse event rates were similar (26.3% for placebo versus 22.4% for inclisiran), with discontinuation rates of 2.2 and 2.4% for placebo and inclisiran, respectively.
The effects of inclisiran on other lipid parameters such as high-density lipoprotein-cholesterol, triglycerides, and lipoprotein(a), and the impact of infrequent dosing on patient adherence, remain as unanswered questions, commented AHA discussant Karol E. Watson, MD, PhD, from the University of California at Los Angeles. She added: “Finding medications that are both effective and that can enhance patient adherence will improve outcomes.”
International Study of Comparative Health Effectiveness With Medical and Invasive Approaches–Chronic Kidney Disease (ISCHEMIA-CKD): Primary Results
- Sripal Bangalore, MD, MHA, New York University School of Medicine, New York, New York
“Overall, an initial invasive strategy did not demonstrate a reduced risk of clinical outcomes as compared with an initial conservative strategy,” Dr. Bangalore concluded in an AHA press briefing on results from ISCHEMIA-CKD, the largest trial of invasive versus conservative strategy in patients with advanced chronic kidney disease (CKD) and stable ischemic heart disease.
Systematic exclusion of patients with advanced CKD, a cohort at markedly increased risk of cardiovascular events, has been the rule in prior strategy trials comparing optimal medical therapy with or without revascularization in patients with stable ischemic heart disease, Dr. Bangalore noted. To determine whether a routine invasive approach added to optimal medical therapy improves outcomes in this population, the National Heart, Lung, and Blood Institute–funded randomized ISCHEMIA-CKD trial was conducted. It compared the effect on long-term clinical outcomes of an initial invasive strategy (coronary angiography and optimal revascularization with either percutaneous coronary intervention or coronary artery bypass graft surgery, if feasible) plus optimal medical therapy versus a conservative strategy of optimal medical therapy alone, with coronary angiography and revascularization reserved for failure of optimal medical therapy.
ISCHEMIA-CKD investigators enrolled 777 subjects, randomizing 388 to an invasive strategy and 389 to a conservative one. All had advanced CKD, defined as an estimated glomerular filtration rate (GFR) of less than 30 mL/min/1.73 m2 or dialysis. The primary ISCHEMIA-CKD outcome was time to a composite of death or nonfatal myocardial infarction. Median age was 63 years (31% female). Fifty-three percent were on dialysis. In the other 47%, the baseline CKD stage was 4 in 86% and 5 in 14%. All had at least moderate ischemia on stress testing. Fourteen percent had estimated GFRs of less than 15 mL/min/1.73 m2 among those not on dialysis (15% invasive strategy, 13% conservative strategy). Risk factor management with various agents was generally similar between the invasive and conservative groups, Dr. Bangalore said.
The three-year primary combined death or myocardial infarction endpoint was reported at rates of 36.7% and 36.4% for the conservative and invasive strategies, respectively (HR, 1.01; 95% CI, 0.79–1.29; P = 0.95). The respective rates for the secondary combined endpoint of death, myocardial infarction, hospitalization for unstable angina or heart failure, or resuscitated cardiac arrest were 39.7% and 38.5% (HR, 1.01; 95% CI, 0.79–1.29; P = 0.93). Procedural myocardial infarctions were higher (HR, 2.03; P = NS) in the invasive group, and spontaneous myocardial infarctions were more common in the conservative group (HR, 0.72; P = NS). At four years, unstable angina was more common in the conservative group (HR, 0.15; P = 0.09) and heart failure was more common in the invasive group (HR, 1.47; P = 0.31). Although uncommon, the stroke rate (less than 30 days post-procedure) was significantly higher in the invasive strategy group (HR, 3.76; P = 0.004).
“Overall, an initial invasive strategy did not demonstrate a reduced risk of clinical outcomes as compared with an initial conservative strategy,” Dr. Bangalore concluded.
“Based on the results of ISCHEMIA-CKD, I will generally not go ‘searching’ for ischemia and coronary artery disease in most severe and end-stage chronic kidney disease patients, absent marked or unacceptable angina, and will treat them with medical therapy alone,” said AHA discussant Glenn N. Levine, MD, of the Baylor College of Medicine.
International Study of Comparative Health Effectiveness With Medical and Invasive Approaches–ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) Primary Report of Quality of Life Outcomes
- John A. Spertus, MD, MPH, Saint Luke’s Mid America Heart Institute, Kansas City, Missouri
Significant angina control and quality of life benefits were conferred by an invasive strategy as compared with a conservative strategy only among those patients experiencing daily, weekly, or monthly angina, but not among those without angina symptoms, according to ISCHEMIA results. The National Heart, Lung, and Blood Institute–funded ISCHEMIA trial revealed minimal quality of life benefits in this latter group. Its main analysis compared clinical outcomes in patients with stable coronary artery disease and moderate-to-severe ischemia who were randomized to an early invasive strategy versus those treated with optimal medical therapy. The invasive strategy did not reduce the primary composite outcome of cardiovascular death, myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, or resuscitated out-of-hospital cardiac arrest (adjusted HR, 0.93, P = 0.34).
All patients, Dr. Spertus said in an AHA press briefing, received aggressive, evidence-based antianginal and secondary prevention therapies over a mean 3.5 years of follow-up. The invasive strategy included cardiac catheterization and either percutaneous coronary intervention or coronary artery bypass graft surgery to achieve optimal revascularization, if possible, while in the conservative strategy, only those subjects who failed optimal medical therapy were eligible to undergo cardiac catheterization and revascularization.
Disease-specific health status was assessed with the seven-item Seattle Angina Questionnaire (SAQ) prior to randomization and at 1.5, three, six, and every six months thereafter. The primary quality of life endpoint was the SAQ Summary Score. Median age among the 4,617 subjects was 65 years; 23% were female.
For the 35% of patients with no baseline angina, the probability of remaining angina-free at three months was identical for the invasive and conservative groups. For patients with weekly angina, however, the likelihood of remaining angina-free in the conservative group was 15% compared with 45% in the invasive strategy group, with a number needed to treat of only 3. Differences favoring an invasive strategy were generally large, as well, in patients with less frequent (monthly) symptoms, but not in nearly or entirely asymptomatic patients.
However, Dr. Spertus recommended: “In patients with angina, shared decision-making should occur to align treatment with patients’ goals and preferences.”
The Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure Trial (DAPA-HF): Results in Nondiabetic Patients
- John McMurray, MD, BHF Cardiovascular Research Centre, University of Glasgow & Queen Elizabeth University Hospital, Glasgow, United Kingdom
An analysis of DAPA-HF results among patients without type-2 diabetes addressed this question: “Given that SGLT2 inhibitor benefits may be glucose-independent, can SGLT2 inhibitors be used to treat patients without type-2 diabetes?” It showed, Dr. McMurray said in an AHA press briefing, that when added to standard therapy, dapagliflozin reduced the risk of worsening heart failure events and cardiovascular death, and improved symptoms in patients with heart failure with reduced ejection fraction, both with and without type-2 diabetes.
The sodium-glucose cotransporter 2 inhibitor dapagliflozin, in prior research, has been shown to prevent the development of heart failure in patients with type-2 diabetes. In DAPA-HF, investigators randomized 2,371 patients to placebo and 2,373 to dapagliflozin 10 mg once daily. Mean age was approximately 66 years (77% male), with a mean left ventricular ejection fraction of 31%. Nearly half had prior heart failure hospitalizations. All were receiving standard heart failure therapy for New York Heart Association class II–IV heart failure with a left ventricular ejection fraction at or below 40% and N-terminal pro b-type natriuretic peptide (NT-proBNP) of at least 600 pg/mL2. The primary endpoint was the composite of cardiovascular death, heart failure hospitalizations, and urgent heart failure visits.
In both the diabetes and no-diabetes groups, Dr. McMurray reported, the hazard ratios with dapagliflozin versus placebo for the primary composite outcome were nearly identical, at 0.75 (0.63–0.90) in the diabetes group and 0.73 (0.60–0.88) in the no-diabetes group. The hazard ratios for individual components followed the same pattern of benefits for dapagliflozin at 0.79 (diabetes) and 0.85 (no diabetes) for cardiovascular death, and 0.77 (diabetes) and 0.62 (no diabetes) for worsening heart failure events.
Hazard ratios favoring dapagliflozin for combined cardiovascular death or heart failure hospitalization, a secondary endpoint, were 0.75 and 0.73 for the diabetes and no-diabetes groups, respectively. Combined total heart failure hospitalizations and cardiovascular death hazard ratios were 0.77 for diabetes and 0.73 for no diabetes. Also, worsening heart failure (sustained 50% or greater reduction in estimated GFR, end-stage renal disease, or death from renal causes) hazard ratios favoring dapagliflozin were 0.73 in the diabetes group and 0.67 in the no-diabetes group. The hazard ratios for all-cause death were 0.78 and 0.88 in the diabetes and no-diabetes groups, respectively. The primary endpoint was not affected by HbA1c levels or diabetes status, Dr. McMurray observed.
Discontinuation rates for adverse events were low and similar for the placebo and dapagliflozin groups (4.0–5.4%, NS). Serious adverse event rates between placebo and dapagliflozin groups were also similar (48.3% for placebo and 41.7% for dapagliflozin in the diabetes group; 36.9% and 34.6% in the no-diabetes group, respectively). “Dapagliflozin was well tolerated,” he said.
“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction in patients with and without type-2 diabetes,” Dr. McMurray concluded.
AHA discussant Larry A. Allen, MD, suggested that future research might address how, given the common comorbidities of heart failure patients, medical therapy should be sequenced, and what “toxicities” extreme polypharmacy might present for patients, both clinically and financially.
Effect of Treatment on the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure Trial (DAPA-HF)
- Mikhail Kosiborod, MD, Saint Luke’s Mid America Heart Institute, Kansas City, Missouri
All major components of the Kansas City Cardiomyopathy Questionnaire (KCCQ), a validated test of the heart failure patient’s perspective, were improved among patients with heart failure with reduced ejection fraction receiving dapagliflozin in the DAPA-HF trial, Dr. Kosiborod said in an AHA press briefing. The KCCQ assesses heart failure–related symptoms, physical limitations, qualify of life, and social limitations.
The KCCQ, Dr. Kosiborod noted, has a 100-point scale, with higher numbers reflecting better health status. A 5-point threshold in either direction has been established as a clinically meaningful change. DAPA-HF tested dapagliflozin 10 mg once daily versus matching placebo in 4,774 patients, with a primary endpoint of a first episode of worsening heart failure (hospitalization for heart failure or an urgent heart failure visit requiring intravenous therapy) or death from cardiovascular causes. A key secondary outcome was change from baseline to eight months in the KCCQ total symptom score (KCCQ-TSS).
Patients were stratified according to baseline KCCG-TSS tertiles: less than or equal to 65.6 (n = 1,487), 65.7–87.5 (n = 1,564), and more than 87.5 (n = 1,392). Analysis showed benefits for dapagliflozin versus placebo to persist across the three tertiles similarly (interaction P value, 0.52), with hazard ratios of 0.70, 0.77, and 0.62 for the ≤ 65.6, 65.7–87.5, and > 87.5 tertiles, respectively. Looking at separate components of the primary endpoint and death from any cause identified none without a dapagliflozin benefit.
KCCQ-TSS scores improved over time from baseline significantly through four and eight months, Dr. Kosiborod noted, as did KCCQ Clinical Summary and Overall Summary Scores (P < 0.0001 for each).
Deterioration of 5 or more points occurred more often in the placebo group (P < 0.0001). Improvements of 5 or more, 10 or more, or 15 or more points, however, occurred significantly (P < 0.001) more often in the dapagliflozin group for KCCQ Clinical Summary and Overall Summary Scores.
“Dapagliflozin offers a new approach to improving symptoms, functional limitations, and quality of life in patients with heart failure with reduced ejection fraction,” Dr. Kosiborod concluded. “Effects were substantial, with the number needed to treat ranging between 12 and 18 when compared to placebo after just eight months of treatment.”
Effect of Treatment According to Age in the Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure Trial (DAPA-HF)
- Felipe Martinez, MD, Cordoba National University, Cordoba, Argentina
Rates of worsening heart failure events and cardiovascular death and symptoms all improved with dapagliflozin added to standard therapy across all age subgroups in the placebo-controlled DAPA-HF trial, Dr. Martinez said in an AHA press briefing. In DAPA-HF, dapagliflozin was added to other guideline-recommended therapies in patients with heart failure and reduced ejection fraction.
It is very important to understand the efficacy and safety of new treatments in all age groups, Dr. Martinez said. While in many countries the number of elderly patients with heart failure is increasing, in other geographic regions (such as Latin America, Africa, and Asia), people with heart failure are often younger than those in North America and Western Europe. He emphasized further that heart failure with reduced ejection fraction patients are often elderly and more likely to have comorbidities requiring polypharmacy, perhaps including renal disease, which may limit the use of pharmacological therapies—all giving DAPA-HF investigators further rationale for assessing the efficacy and safety of dapagliflozin according to age. More than half (57%) of patients in the trial were older than 65 years of age, and the oldest was 98.
DAPA-HF included 5,744 heart failure patients with reduced ejection fraction randomized 1:1 to placebo or dapagliflozin 10 mg given once daily. The composite of cardiovascular death, heart failure hospitalization, and urgent heart failure visits was the primary endpoint.
For the overall population in DAPA-HF, the hazard ratio for the primary endpoint with dapagliflozin compared with placebo was 0.74 (0.65–0.85, P = 0.00001) with a number needed to treat of 21. The same pattern of reduced risk persisted for all age-group subdivisions (less than 55 years, by 13%; 55–64 years, by 29%; 65–74 years, by 24%; 75 years or older, by 32%). No differences were observed for individual endpoint components (cardiovascular death, all-cause death, heart failure hospitalization/urgent visit). Clinically meaningful (at least 5 points) changes in Kansas City Cardiomyopathy Questionnaire Total Symptom Score in either direction were similar across all age divisions.
In the placebo groups, older-age renal adverse events and serious renal adverse events increased, as did doubling of serum creatinine. With advancing age, however, discontinuation of active treatment and overall serious adverse event rates (including death) did not increase.
Dr. Martinez observed, “The relative and absolute risk reductions in death and hospitalization were substantial and clinically important.” He emphasized, “The absolute benefits in older patients were large because they were at higher risk than younger patients.”
TWILIGHT-ACS: Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention for Acute Coronary Syndrome
- Usman Baber, MD, Icahn School of Medicine at Mount Sinai, New York, New York
Continued treatment with ticagrelor alone significantly lowers clinically relevant and major bleeding without increasing risk for ischemic events over one year in patients with non-ST segment–acute coronary syndromes undergoing percutaneous coronary intervention with drug-eluting stents. Patients included in TWILIGHT-ACS had all completed a three-month course of dual antiplatelet therapy with ticagrelor plus aspirin, Dr. Baber said in an AHA press briefing.
Clinical trials showing that the addition of an oral P2Y12 inhibitor to aspirin significantly lowers recurrent ischemic events compared with aspirin alone lie behind the current preference for dual antiplatelet therapy as treatment for patients with acute coronary syndromes, Dr. Baber said. While aspirin has typically served as a background agent in earlier studies, the benefits and harms of maintaining it as a long-term component of dual antiplatelet therapy in acute coronary syndromes remain unknown. Some recent studies, however, have suggested that aspirin-free strategies lower bleeding without increasing ischemic risk in selected patients. The TWILIGHT objective, therefore, was to examine the effect of antiplatelet monotherapy with ticagrelor alone versus ticagrelor plus aspirin in this population.
In a prespecified subgroup analysis of the randomized, placebo-controlled TWILIGHT trial, investigators evaluated the impact of one year of ticagrelor plus placebo (n = 2,273) versus dual antiplatelet therapy with ticagrelor plus aspirin (n = 2,341) on clinically relevant bleeding in high-risk patients successfully undergoing percutaneous coronary intervention with drug-eluting stents followed by three months of dual antiplatelet therapy with ticagrelor and aspirin. The primary endpoint was Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding. All patients had an indication of unstable angina or non-ST-elevation myocardial infarction.
TWILIGHT investigators enrolled 7,119 patients (mean age, 64 years; 25.1% female) at 187 sites in 11 countries. Adherence to study treatments was similar in both groups. Rates of BARC 2, 3, or 5 bleeding were 7.6% in the ticagrelor plus aspirin group and 3.6% in the ticagrelor plus placebo group (HR, 0.47; 95% CI, 0.36–0.61; P < 0.001). The ticagrelor plus placebo benefit persisted across the range of risk factor strata (1–3, 4–5, 6–9). Similarly, prespecified evaluation of TIMI major, GUSTO moderate or severe, and ISTH major bleeding revealed the same pattern of benefit for ticagrelor plus placebo over ticagrelor plus aspirin. Analysis of the secondary combined endpoint of death, myocardial infarction, or stroke revealed similar rates (4.4% for ticagrelor plus aspirin versus 4.3% for ticagrelor plus placebo; P = 0.84). Among patients presenting with unstable angina or non–ST-elevation myocardial infarction, results were also similar, Dr. Baber said.
“Discontinuation of aspirin markedly reduces bleeding when stopped one to three months post-PCI and/or ACS for patients initially started on dual antiplatelet therapy,” said AHA discussant Michelle L. O’Donoghue, MD, MPH, of Harvard Medical School. She added, “The evidence to date does not indicate that stopping aspirin leads to any increase in the risk of major adverse coronary events.”
Effect of Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure
- Scott D. Solomon, MD, Brigham and Women’s Hospital, Boston
In an analysis of two pivotal heart failure trials, PARAGON-HF and PARADIGM-HF, the therapeutic effects of sacubitril/valsartan compared with a renin-angiotensin system inhibitor alone extended to patients with heart failure and mildly reduced left ventricular ejection fraction (LVEF). Benefits in women, Dr. Solomon said in an AHA press briefing, extended to a higher LVEF range than in men.
Virtually all patients respond to several classes of pharmacological therapies that have, in clinical trials, been shown to contribute to step-wise reductions in morbidity and mortality, despite the fact that heart failure with reduced ejection fraction has multiple etiologies, Dr. Solomon noted. Few options have been available for patients with ejection fractions above the “reduced” range, generally considered 40% or less. Investigators for this analysis assessed both time to first composite of cardiovascular death or heart failure hospitalization (PARADIGM primary endpoint) and the composite of total heart failure hospitalizations and cardiovascular death (PARAGON primary endpoint) across the spectrum of LVEFs.
Dr. Solomon’s pooled analysis included data from the two large outcomes trials, PARADIGM-HF and PARAGON-HF. Both compared sacubitril/valsartan to renin-angiotensin system inhibition (either enalapril or valsartan) in more than 13,000 heart failure patients from 56 countries. While PARADIGM-HF included patients with LVEFs of 40% or less, PARAGON-HF included patients with LVEFs of 45% or greater, allowing together examination of effects across the full spectrum of LVEFs.
The sacubitril/valsartan versus renin-angiotensin system inhibition comparison revealed highly significant (P < 0.001) treatment benefits with the combination. They were observed for the combined endpoint (HR, 0.84; 0.78–0.90) and its components (cardiovascular death and heart failure hospitalization each reduced by 16%, as well) in the combined trials. All death was also reduced in the combined trials with sacubitril/valsartan (by 12%, P = 0.003). For the combined endpoint, benefit was relatively consistent up until LVEFs of 52.5% to 62.5%, but disappeared above 62.5%. For the component of cardiovascular death, benefit was modest and declining above an LVEF of 42.5%.
The combined endpoint benefit disappeared at an LVEF of about 57% in men for sacubitril/valsartan versus renin-angiotensin system inhibition. In women it continued for ejection fractions up to about 67%.
Sacubitril/valsartan benefits were driven largely by gains in the below-normal range of LVEFs, Dr. Solomon noted. Also, it was heart failure hospitalizations that drove benefits in the frankly “reduced” but below normal range of LVEFs.
He concluded, “In this large, patient-level analysis of two pivotal trials, we observed overall benefit comparing sacubitril/valsartan to renin angiotensin system inhibition alone, with therapeutic benefits that extend to a higher LVEF range in women compared with men.”
Note: An abbreviated version of our coverage of the American Academy of Children and Adolescent Psychiatry meeting ran in the print edition of the December issue.