Clinical trials, FDA updates further progress of lowering CVD risk

BOSTON — Ongoing and late-breaking clinical trials throughout 2017 have made progress on CVD risk reduction and affected clinical practice, according to a presentation at the Cardiometabolic Health Conference in Boston.

Diabetes

Researchers for the CANVAS trial reviewed CV and renal outcomes in patients who were assigned canagliflozin (Invokana, Janssen) vs. placebo, Jay S. Skyler, MD, MACP, associate director of the Diabetes Research Institute and professor of medicine in pediatrics and psychology at University of Miami, said during the presentation.

After 6 years, patients assigned canagliflozin had a lower percentage of the primary outcome, which was nonfatal MI, CV death or nonfatal stroke (HR = 0.86; 95% CI, 0.75-0.97) vs. those assigned placebo. HF hospitalization (HR = 0.67; 95% CI, 0.52-0.87) was also lower in patients assigned canagliflozin compared with those assigned placebo. The incidence of lower-extremity amputations was higher in the canagliflozin group (HR = 1.97; 95% CI, 1.41-2.75).

The DEVOTE trial analyzed CV outcomes in patients with type 2 diabetes who were treated with insulin degludec (Tresiba, Novo Nordisk) vs. insulin glargine (Lantus, Sanofi). There was no difference in incidence of nonfatal MI, nonfatal stroke and CV death in patients assigned insulin degludec vs. insulin glargine (HR = 0.91; 95% CI, 0.78-1.06).  However, rates of severe hypoglycemia (RR = 0.7; 95% CI, 0.48-0.76) and nocturnal severe hypoglycemia (RR = 0.47; 95% CI, 0.31-0.73) were less with insulin degludec.

When analyzing the effects of acarbose in the ACE trial, there was no difference in the occurrence of the 5-point primary outcome, which included CV death, nonfatal MI, nonfatal stroke, unstable angina hospitalization and HF hospitalization, in patients assigned acarbose or placebo (HR = 0.98; 95% CI, 0.86-1.11). Rates of the secondary outcome (HR = 0.95; 95% CI, 0.81-1.11) and CVD death (HR = 0.89; 95% CI, 0.71-1.11) were also similar, although the occurrence of new-onset diabetes was higher in patients assigned placebo.

In the TOSCA-IT trial, there was no difference in the rate of nonfatal MI, all-cause death, urgent coronary revascularization or nonfatal stroke in patients assigned metformin and sulphonylurea vs. metformin and pioglitazone (HR = 0.96; 95% CI, 0.74-1.26). The incidence of the key secondary outcome, including fatal and nonfatal MI, major leg amputation, fatal and nonfatal stroke, sudden death or revascularization was also similar in both groups (HR = 0.88; 95% CI, 0.65-1.21).

Patients in the EXSCEL trial who were assigned exenatide (Bydureon, AstraZeneca) had a lower incidence of the primary composite CV outcome (HR = 0.91; 95% CI, 0.83-1) and all-cause mortality (HR = 0.86; 95% CI, 0.77-0.97) compared with patients assigned placebo.

These studies have led to label changes for empagliflozin (Jardiance, Boehringer Ingelheim) and liraglutide (Victoza, Novo Nordisk) to treat patients with type 2 diabetes.

“These were both important label changes which tell us that we do now have diabetes drugs which have great cardiovascular benefit,” Skyler said.

Hypertension

In a study published in the European Journal of Preventive Cardiology, Barbara A. Yankey, PhD, of Georgia State University in Atlanta, and colleagues found that patients who reported marijuana use had an increased risk for hypertension mortality, which was also affected by the duration of use. Patients who reported recreational marijuana use had CV adverse events, although the results must be investigated further, Keith C. Ferdinand, MD, FACC, FAHA, professor of medicine at Tulane University School of Medicine and Cardiology Today Editorial Board Member, said during the presentation

In the SPYRAL HTN-OFF MED study, patients in the renal denervation group had greater changes of systolic and diastolic BP vs. the sham control group.

Ihab Hajjar, MD, MS, associate professor of medicine and neurology at Emory University School of Medicine, and colleagues found that patients aged at least 70 years who achieved a systolic BP of 120 mm Hg or lower did not have worsening cognitive outcomes.

A study published in the Journal of the American Society of Nephrology found that reducing systolic BP also decreased primary CVD outcomes and all-cause death in patients with chronic kidney disease.

“Those patients who have CKD but not patients who have end-stage renal disease may still benefit from intensive blood pressure reduction,” Ferdinand said.

When comparing patients with a systolic BP of at least 160 mm Hg and a 10-year risk less than 31.3% from the SPRINT trial with the rest of the patients from the trial, lowering BP with intensive treatment was associated with a higher incidence of all-cause death (HR = 3.12; 95% CI, 1-9.69) vs. standard treatment.

The American College of Cardiology, American Heart Association and the Heart Failure Society of America guidelines recommended that the optimal BP for those with hypertension should be less than 130/80 mm Hg, and patients with HF with reduced ejection fraction and hypertension should aim for a systolic BP less than 130 mm Hg.

 

“Intensive blood pressure reduction may have benefit in patients either at risk of heart failure or in patients who already have symptomatic heart failure,” Ferdinand said.

The American Association of Clinical Endocrinologists and the American College of Endocrinology recommends a goal of less than 130/80 mm Hg.

Updated new hypertension guidelines from the ACC/AHA and multiple additional organizations are currently pending, according to the presentation.

Antithrombotics

Deepak L. Bhatt, MD, MPH, executive director of interventional cardiology programs at Brigham and Women’s Hospital, professor of medicine at Harvard Medical School, Cardiology Today Editorial Board Member and Cardiology Today’s Intervention Chief Medical Editor, summarized two very recent trials. In the RE-DUAL PCI study published in The New England Journal of Medicine, investigators assigned patients with atrial fibrillation various doses of dabigatran (Pradaxa, Boehringer Ingelheim) after undergoing PCI. Patients assigned triple therapy of warfarin had a higher event rate compared with those assigned 110 mg (HR = 0.52; 95% CI, 0.42-0.63) or 150 mg dabigatran (HR = 0.72; 95% CI, 0.58-0.88). Major and minor bleeding from TIMI and intracranial hemorrhage was also higher in patients assigned warfarin vs. dabigatran. The time to thromboembolic event or death or unplanned revascularization was similar in both groups.

 

“If patients have AF, they should get a full dose of an anticoagulant unless there’s a good reason not to,” Bhatt said during the presentation.

When comparing very low-dose rivaroxaban (Xarelto, Janssen) with aspirin vs. without aspirin in patients with stable CVD in the COMPASS trial, patients treated with aspirin alone had a higher incidence of stroke, MI or CV death vs. patients assigned rivaroxaban with aspirin. The rates of secondary outcomes were also higher in the aspirin-alone group, though major bleeding was higher in the combination therapy arm.

 

 

Obesity

Robert H. Eckel, MD, professor of medicine in the division of cardiology and endocrinology, metabolism and diabetes; professor of physiology and biophysics; Charles A. Boettcher II Chair in Atherosclerosis at the University of Colorado Denver Anschutz Medical Center; director of the lipid clinic at University of Colorado Hospital in Aurora; past president of the AHA; and co-chair of the CMHC, discussed the various studies that focused on patients who were obese.

Dennis T. Villareal, MD, professor of endocrinology, diabetes and metabolism at Baylor College of Medicine, and colleagues analyzed the effects of aerobic exercise, resistance exercise or both in older patients who were obese and dieting.

“In the methods tested, weight loss plus combined aerobic and resistance exercise was the most effective in improving functional status of obese over adults and also preserved bone mass,” Eckel said.

 

A study published in JAMA Internal Medicine in 2017 compared the effects of alternate-day fasting with daily calorie restriction on weight and risk indicators of CVD. Patients assigned alternate-day fasting did not have greater weight loss, maintenance or cardioprotection vs. those who restricted their daily caloric intake, according to the presentation.

Another study found that, at 5 years, patients with type 2 diabetes with a BMI between 27 kg/m² and 43 kg/m² had improved outcomes with bariatric surgery and intensive medical therapy vs. those who received intensive medical therapy alone.

In a study published in JAMA Surgery in 2017, researchers found that patients who had a BMI less than 40 kg/m² before metabolic surgery had an increased rate of achieving a BMI below 30 kg/m² and have comorbidity remission. Those who underwent surgery when their BMI was at least 50 kg/m² had inferior outcomes.

Researchers from a study published in the Journal of the American College of Cardiology found that patients who were obese had an increased risk for cerebrovascular disease, CHD and HF.

“The take-home message here is the fact that some people do well with medical management for obesity and some people do poorly with surgical intervention, and I wish up front we could behaviorally know how to distinguish these groups of patients,” Eckel said.

New medications

Many clinical trials and FDA updates were made regarding the treatment of patients with cardiometabolic disease, Christie M. Ballantyne, MD, professor of medicine, chief of the section of cardiovascular research and director of the Center for Cardiovascular Disease Prevention at Baylor College of Medicine, said during the presentation.

Akcea and Ionic recently announced the submission of a new drug application for volanesorsen, and numerous phase 3 trials have been completed or are ongoing to study the effects of the treatment, including APPROACH, COMPASS, BROADEN and APPROACH Open-Level Extension.

A monthly dosing schedule for alirocumab (Praluent, Sanofi/Regeneron) was approved by the FDA, and treatment with bempedoic acid and ezetimibe was confirmed to be on a pathway that could potentially be approved by the FDA depending upon the results of a phase 3 trial.

In the ORION-1 trial, patients with high CVD risk and elevated LDL on a statin were assigned inclisiran (Alnylam/The Medicines Company) or placebo. Patients assigned inclisiran had a greater reduction of LDL vs. placebo through 240 days.

In the ORION-1 trial, patients with high CVD risk and elevated LDL on a statin were assigned inclisiran (Alnylam/The Medicines Company) or placebo. Patients assigned inclisiran had a greater increase of LDL vs. placebo through 240 days.

A focused update from the ACC on nonstatin therapies for LDL lowering includes LDL and non-HDL thresholds for the consideration of atherosclerotic CVD risk reduction. The update also recommends ezetimibe or a PCSK9 inhibitor as a nonstatin agent, and another agent can be added if needed.

 

Trials including REDUCE-IT and STRENGTH are reviewing the effects of omega-3 fatty acids in patients with CVD or high CVD risk, which are estimated to be completed in 2018 and 2019, respectively.

Various outcomes trials are in progress now analyzing the effects of PCSK9 inhibitors and anacetrapib (Merck) and canakinumab (Novartis) have shown recent positive outcomes, according to the presentation. – by Darlene Dobkowski

Reference:

Ballantyne CM, et al. FDA Update and Late Breaking Clinical Trials. Presented at: Cardiometabolic Health Conference; Oct. 4-7, 2017; Boston.

Disclosures: Ballantyne reports he receives grant/research support from Abbott Diagnostic, Amarin, Amgen, Eli Lilly, Esperion, Ionis, Novartis, Pfizer, Regeneron, Roche Diagnostic and Sanofi-Synthelabo; and consults for Abbott Diagnostics, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Esperion, Ionis, Matinas BioPharma, Merck, Novartis, Pfizer, Regeneron, Roche Diagnostic and Sanofi-Synthelabo. Eckel reports he is a consultant/independent contractor for Sanofi Regeneron. Bhatt reports he serves on an advisory board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology and Regado Biosciences; receives honoraria from Belvoir Publications, HMP Communications, Journal of the American College of Cardiology, Slack Publications and WebMD; receives research funding from Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis and The Medicines Company; receives royalties from Elsevier; serves as a site co-investigator for Biotronik, Boston Scientific and St. Jude Medical; and performs unfunded research for FlowCo, Merck, PLx Pharma and Takeda. Ferdinand reports he is a consultant/independent contractor for Amgen, Eli Lilly, Novartis, Quantum Genomics and Sanofi; and receives grant/research support from Boehringer Ingelheim. Skyler reports nor relevant financial disclosures.

 

Editor’s Note: This article was updated on Oct. 16, 2017 to correct mischaracterization of the COMPASS trial. The Editors regret the error.