Brigham-Led Clinical Trials Take Center Stage at the American College of Cardiology
Top experts from the Brigham presented outcomes from some of the most-anticipated clinical trials in cardiology at the American College of Cardiology’s 70th Annual Scientific Session (ACC.21) which took place virtually May 15-17. In four late-breaking clinical trial presentations, Brigham cardiologists shared their latest findings on strategies to prevent future cardiovascular events in at-risk patient populations, results of a randomized clinical trial of a statin drug among patients critically ill with COVID-19, and more.
IL-6 Inhibitor Reduced Biomarkers of Inflammation in Patients at High Risk for Heart Attacks, Strokes
In work that builds upon and extends the potential clinical reach of the inflammatory hypothesis of heart disease, Paul M. Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention at the Brigham and the Eugene Braunwald Professor of Medicine, presented data on the IL-6 inhibitor Ziltivekimab. Ziltivekimab is a human monoclonal antibody targeting the IL-6 ligand that is being developed specifically for atherosclerosis. Ridker led RESCUE, a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the effects of ziltivekimab on multiple biomarkers of inflammation and thrombosis. The trial evaluated patients at high cardiovascular risk with chronic kidney disease (CKD) and elevated hsCRP.
In a late-breaking clinical trial presentation and in simultaneous publication in The Lancet, Ridker reported that ziltivekimab markedly reduced multiple biomarkers of systemic inflammation and thrombosis, including hsCRP, fibrinogen, SAA, sPLA2, and Lp(a). Investigators found minimal evidence of bone marrow suppression, infectious risk, hepatic toxicity, or change in atherogenic lipid levels.
“These phase II data suggest that ziltivekimab may be unique among currently available IL-6 inhibitors and strongly supports its use in future cardiovascular outcome trials,” said Ridker.
Based on the safety and efficacy results of RESCUE, a new cardiovascular outcomes trial known as ZEUS is set to launch later this year.
In a separate presentation at ACC.21, Brigham cardiologist Muthiah Vaduganathan, MD, MPH, and colleagues presented data showing that people with heart failure and kidney disease face very high risks of adverse events and death yet are infrequently treated with guideline-recommended medical therapies. Their presentation underscored the unmet clinical need for patients with CKD.
SGLT 1/2 Inhibitor Shows Benefit in Men and Women with Heart Failure with Preserved Ejection Fraction
Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC, executive director of Interventional Cardiovascular Programs at the Brigham’s Heart & Vascular Center, presented evidence on the benefits of sotagliflozin across the spectrum of ejection fraction, including heart failure with preserved ejection fraction. Sotagliflozin inhibits both SGLT1 and SGLT2. Two clinical trials, SOLOIST-WHF and SCORED, demonstrated its protective effects for patients with diabetes and worsening heart failure as well as patients with diabetes and chronic kidney disease, respectively.
Bhatt presented data showing that sotagliflozin robustly and significantly reduced the composite of total cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure across the full range of ejection fraction, including in patients with heart failure with preserved ejection fraction (HFpEF). In on-treatment analyses, sotagliflozin demonstrated a significant reduction in cardiovascular death.
“These are the first randomized data from a prespecified analysis of clinical trials to show a significant effect of a therapy on HFpEF,” said Bhatt. “Additionally, sotagliflozin demonstrated a consistent and significant benefit in women.”
Statin Drug Did Not Improve Outcomes for Patients Critically Ill with COVID-19
Behnood Bikdeli, MD, MS, a physician-investigator in the Brigham’s Cardiovascular Medicine Division, presented results from the INSPIRATION-statin trial in a late-breaking clinical trials session. INSPIRATION-S is a randomized controlled clinical trial of hospitalized critically ill patients with COVID-19. Patients were randomized to receive atorvastatin 20mg daily or a matching placebo. The study’s primary endpoint included a composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), use of extracorporeal membrane oxygenation, or all-cause death within 30 days from enrollment. Bikdeli reported no statistically significant difference between the statin intervention and placebo.
“The body’s exuberant inflammatory response is known to play a role in the acute respiratory distress syndrome (ARDS) which is seen in some cases of COVID-19,” said Bikdeli. “We hypothesized that statins, which can have anti-inflammatory and antithrombotic effects, might be beneficial in patients with severe COVID-19. While we found no statistical difference between atorvastatin and placebo, we did see intriguing hints among patients who presented within the first seven days of when symptoms first appeared, and are interested in understanding these observations further.”
Sacubitril/Valsartan Did Not Outperform an ACE Inhibitor
A late-breaking clinical trial highlighting the results of PARADISE-MI extends the Brigham’s decades-long work in the area of angiotensin converting enzyme (ACE) inhibitors, which are used during acute myocardial infarction to save lives and reduce incidence of heart failure. Marc Pfeffer, MD, PhD, Distinguished Dzau Professor of Medicine at Harvard Medical School and cardiologist at the Brigham, presented the results of PARADISE-MI. The clinical trial compared the effectiveness of the heart failure drug sacubitril/valsartan to ramipril, a proven effective ACE inhibitor, at preventing cardiovascular death, heart failure hospitalization, and outpatient development of heart failure among patients who had survived a heart attack and had left ventricular systolic dysfunction and/or pulmonary congestion. There was a high use of guideline-based therapies and procedures prior to randomization.
Pfeffer reported that sacubitril/valsartan did not significantly lower rate of cardiovascular death, heart failure hospitalization or outpatient heart failure requiring treatment. However, pre-specified observations of reductions in both investigator reports of the primary composite as well as in the total (recurrent) adjudicated events support incremental clinical benefits of sacubitril/valsartan. The safety and tolerability of sacubitril/valsartan in this patient population was comparable to that of the ACE inhibitor.
“We found sacubitril/valsartan was as safe and well-tolerated as one of the best proven ACE inhibitors, even in an acutely ill population,” said Pfeffer. “This trial is not likely going to change guidelines, but it should make physicians even more comfortable using sacubitril/valsartan in their patients with heart failure.”
Disclosures: The RESCUE trial was supported by Corvidia and Novo Nordisk. Dr. Ridker has received investigator-initiated research grants from Kowa, Novartis, Pfizer, AstraZeneca, Amarin, NHLBI, NCI. Dr. Ridker has served as a consultant to Corvidia, Novo Nordisk, Inflazome, Novartis, Amgen, Merck, Jansen, Agepha, Flame, and CiviBio. Dr. Ridker is listed as a co-inventor on patents related to the use of inflammatory biomarkers in CVD and diabetes that are no longer active.
The original sponsor of SCORED and SOLOIST was Sanofi. Sponsorship was transferred to Lexicon Pharmaceuticals as of January 30, 2020. Dr. Bhatt receives research funding paid to Brigham and Women’s Hospital from Sanofi and Lexicon for his role as the study chairman of SCORED and SOLOIST.
Dr. Pfeffer has received research grant support (through Brigham and Women’s Hospital) from Novartis; consulting fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Corvidia, DalCor, GlaxoSmithKline, NHLBI CONNECTs (Master Protocol Committee), Novartis, Novo Nordisk, Peerbridge and Sanofi; and has equity in DalCor and Peerbridge.
The INSPIRATION-S trial was funded by the Rajaie Cardiovascular Medical and Research Center. Dr. Bikdeli reports that he is a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of IVC filters.
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