REGROUP trial: Major adverse cardiac events results similar for endoscopic vein harvesting compared to open vein harvesting for CABG

There were no significant differences in major adverse cardiac events for endoscopic vein harvesting compared to open vein harvesting for CABG, according to Randomized Endovein Graft Prospective (REGROUP) results presented at Scientific Sessions 2018 in Chicago.

In the intent-to-treat, two-arm, parallel design, multicenter study, 1,150 people in 16 Veterans Health Administration centers were randomized to endoscopic vein harvesting or open (non-endoscopic) vein harvesting, with a median follow-up of 2.78 years.

Of the two surgical methods for CABG, “endoscopic vein harvesting is minimally invasive and only requires a small incision,” said Marco Zenati, MD, MSc, professor of surgery at Harvard Medical School in Cambridge, Massachusetts. “But from the provider, it requires a steep learning curve to become an expert.”

In REGROUP, the harvesting operation needed to be done on pump on the arrested heart, “and, crucially, the endoscopic harvest had to be performed by an expert, with excess of 100 EVH cases,” Zenati said.
The trial had to be large enough for a meaningful primary outcome of major adverse cardiac events: a composite of all-cause mortality, non-fatal myocardial infarction or repeat revascularization, Zenati said. Off-pump CABG patients were excluded. The characteristics of patients were balanced in both study arms.

The rates of major adverse cardiac events for endoscopic versus open harvest were 13.9 percent vs. 15.5 percent, P=0.47, primary outcome, with fewer leg wound healing problems associated with the minimally invasive method.

“We also saw a trend toward fewer recurrent events after the endoscopic approach,” said Zenati, who is also chief of cardiothoracic surgery at Boston Healthcare System and associate surgeon at Brigham and Women’s Hospital.

Longer-term follow-up and additional studies that include graft patency data are needed, he said.

Further studies are needed to establish standards for harvester expertise to ensure the safety of patients and effectiveness of the procedure.

PIONEER-HF: Sacubitril/valsartan reduced cardiovascular biomarker in patients with reduced ejection fraction hospitalized for acute decompensated heart failure

Compared to enalapril, sacubitril/valsartan was associated with a greater reduction in the biomarker N-terminal pro-brain natriuretic peptide and re-hospitalization for heart failure, according to a study presented at Scientific Sessions 2018 in Chicago.

PIONEER-HF (Angiotensin Receptor-Neprilysin Inhibition in Patients Hospitalized With Acute Decompensated Heart Failure) — a prospective, multicenter, double-blind, randomized, active-controlled trial — compared the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (n = 440) with enalapril (n = 441) in hemodynamically stabilized patients with acute heart failure and reduced ejection fraction.

Presenter Eric Velazquez, MD, professor of medicine in cardiology at Yale University School of Medicine in New Haven, Connecticut, said guideline-directed therapy for acute decompensated heart failure has been limited despite accounting for more than 1 million hospitalizations annually in the United States.

The current standard of care includes decongestion with diuretics and hemodynamic support with vasodilators and inotropes.

Study drug doses were titrated over eight weeks following in-hospital initiation of treatment. The titration algorithm was based on systolic blood pressure and aimed at target doses of sacubitril/valsartan 97/103 mg twice daily or enalapril 10 mg twice daily.

Researchers evaluated a biomarker surrogate of efficacy, safety, tolerability and clinical outcomes.

Key entry criteria included an SBP of at least 100 millimeters of mercury and no symptomatic hypotension, no increase in intravenous diuretics, no IV vasodilators and no IV inotropes within the prior 24 hours.

The primary endpoint was the proportional change in NT-proBNP from baseline to the mean of weeks four and eight. NT-proBNP is a biomarker of neurohormonal activation, hemodynamic stress and subsequent cardiovascular events.

Safety endpoints included worsening renal function, symptomatic hypotension, hyperkalemia and angioedema.

Exploratory clinical outcomes were:

  • Serious clinical composite: death, re-hospitalization for HF, left ventricular assist device or listing for cardiac transplant
  • Expanded composite: serious composite plus addition of HF medication, unplanned outpatient IV diuretics or a greater than 50 percent increase in dose

At baseline, about a third of patients had no prior HF diagnosis; 25-30 percent were women; and 36 percent self-identified as African-American.

  • For the primary endpoint of percent change in NT-proBNP, the reduction was 29 percent greater with sacubitril/valsartan (CI 19 percent, 37 percent; P<0.0001). There were no significant differences in safety events between the sacubitril/valsartan and enalapril treatment groups.
  • For the serious composite clinical endpoint, the event rate for sacubitril/valsartan was 9.3 percent versus 16.8 percent, which was statistically significantly lower (HR 0.54; 95 percent CI 0.37, 0.79; P=0.001).
  • Of the exploratory clinical endpoints, only re-hospitalization for HF was statistically significantly different between treatment groups: 8 percent in the sacubitril/valsartan group versus 13.8 percent in the enalapril group (HR 0.56; P=0.005). There were no statistically significant interactions in subgroup analyses of the primary endpoint or the serious composite endpoint.

Larry Allen, MD, professor of medicine in cardiology at the University of Colorado School of Medicine in Aurora, said sacubitril/valsartan use may be low due to clinical inertia.

He also noted that the median age of 62 years of the study participants was 10 years younger than the typical HF population and that relatively few patients with Stage D HF were included because of the exclusion criteria.

“In a post-PIONEER world, one of the great things about this study is that it keeps it simple,” Allen said. “This simpler algorithm for inpatient and subsequent outpatient HR rRF management is better for both clinicians and patients. It also reinforces the importance and safety of aggressive guideline-determined medical therapy in most patients.”

BRIDGE trial suggests quality improvement interventions may increase use of evidence-based therapies

The BRIDGE Cardiovascular Prevention Cluster Randomized Trial found that a multifaceted quality improvement educational intervention significantly increased the use of evidence-based therapies for cardiovascular disease in a low- and middle-income setting.

Otavio Berwanger, MD, PhD, director of the Research Institute HCor at Heart Hospital in Sao Paulo, Brazil, presented the results of BRIDGE CV, a multifaceted intervention to narrow the evidence-based gap in the treatment of high cardiovascular risk patients.

Although large-scale, randomized trials have established the efficacy of antiplatelet therapy, statins, ACE inhibitors and ARBs for the management of high-risk cardiovascular disease, adopting these modalities in practice is suboptimal, particularly in low- and middle-income settings, which account for up to 80 percent of the global CVD burden. Quality improvement interventions have rarely been evaluated in these settings.

BRIDGE CV enrolled 1,619 stable patients with high-risk, established CV disease, including prior coronary artery disease, prior stroke or symptomatic peripheral artery disease from 40 clusters of outpatient clinics from tertiary hospitals or primary care units in Brazil. Clusters were randomly assigned to a multifaceted QI intervention (18 clusters, 726 patients) or to routine care (22 clusters, 893 patients). Allocation to the interventions was concealed and adjudication of the endpoints was blinded.

Patients in both groups had screening and randomization visits as well as additional visits at one, six and 12 months. The primary endpoint of the study was adherence to antiplatelet therapy, statins and ACE inhibitors or ARBs at 12 months in an all-or-none approach.

In addition to the primary endpoint, secondary endpoints at 12 months included:

  • Individual components of the primary endpoint
  • Percentage of eligible patients with LDL below 70 mg/dL and below 50 mg/dL
  • Adherence to high-dose statins by patients with no contraindications
  • Adherence to beta-blockers in patients after myocardial infarction
  • Combined endpoint of CV mortality, non-fatal MI, or non-fatal stroke, and control of risk factors such as hypertension, diabetes or smoking cessation

The QI intervention was based on behavioral marketing. The first intervention included three steps.

  1. In a pre-physician visit, a case manager evaluated each patient using a one-page form with four colored sections to capture anti-hyperlipidemic, anti-diabetic, anti-platelet and anti-hypertensive medications. Case managers were trained in treatment guidelines. Care gaps, such as lack of recommended medical treatment, were noted with stickers
  2. Established reminders and physician prompting before the physician visit.
  3. During the physician visit, a similar four-colored, one-page decision support tool summarized treatment guidelines to facilitate the intervention. During the discussion, Berwanger said guidelines are “great, but they are complicated and long documents,” hence the use of a one-page summary.

During the second part of the intervention, audit and feedback reports were generated monthly for individual measures, such as lipid levels and medication use, as well as for the all-or-none adherence to antiplatelet therapy, ACE inhibitors/ARBs and
statins. Information on lifestyle modification was provided for patients.

The two intervention groups were generally well matched for baseline characteristics, with a median age of about 65 years; 63 percent were male, and about half had a previous MI. Cluster baseline characteristics were also well balanced.

The intervention significantly improved the primary endpoint (complete adherence to statins, anti-platelet therapy and ACEi or ARB at 12 months, with 73.5 percent complete adherence in the intervention group versus 58.7 percent in the control group (P=0.01).

The intervention also significantly improved the secondary endpoints of statin adherence, with 93.6 percent adherence in the intervention group versus 81.7 percent in the control group (P<0.01). It also improved adherence to anti-platelet therapy, with 94 percent in the intervention group versus 86.3 percent in the control group (P<0.01). Smoking cessation also significantly improved after the intervention.

There were no significant differences between treatment groups for adherence to ACEi or ARB, use of high-dose statins, use of beta-blockers post-MI, LDL less than 70 mg/dL, blood pressure below 140/90 millimeters of mercury, systolic blood pressure less than 120 mm Hg, or HbA1c ≤7.0 percent in patients with diabetes. There was no significant difference between groups in major adverse cardiovascular events.

In a subgroup analysis, there was better adherence to statins, anti-platelet therapy and ACEi or ARB in teaching units than in non-teaching units (P=0.02). Berwanger speculated that the personnel in teaching units might be more motivated to use the intervention tools.

He concluded that the tools tested in the trial could be used to develop QI programs to maximize the use of evidence-based interventions to manage the care of patients with established CVD, particularly in limited resource settings.

Trial to improve adherence to evidence-based stroke, TIA treatments yields mixed results

A multifaceted quality intervention didn’t significantly increase the composite adherence score for use of evidence-based therapies for acute ischemic stroke and transient ischemic attack patients, according to results presented Saturday in a Late-Breaking Clinical Science session.

Maria Julia Machline Carrion, MD, MHS, PhD, coordinator of the Bridge-Stroke Project at Heart Hospital in Sao Paulo, Brazil, presented results of BRIDGE stroke, a cluster randomized quality improvement trial conducted in Argentina, Brazil and Peru.

However, when using a more conservative all-or-none approach of complete adherence, the QI intervention improved adherence to evidence-based therapies and significantly increased the use of thrombolysis and smoking cessation education.

The uptake of interventions with established efficacy for managing patients with AIS and TIA has been suboptimal, particularly in low- and middle-income countries, and there are few robust QI trials in these settings, Carrion said.

The trial enrolled patients in 36 clusters that were randomly assigned to the multifaceted QI intervention (19 clusters with 817 patients) or to a control group following routine practice (17 clusters with 807 patients).

Clusters were hospitals with 24/7 emergency departments, central nervous system imaging capability and the ability to administer tissue plasminogen activator (Rt-PA). It included 1,624 consecutive patients with AIS or TIA who were admitted within 24 hours of the onset of symptoms.

The primary endpoint was a composite adherence score to 10 in-hospital quality measures, including early antithrombotics, Rt-PA within therapeutic window, deep vein thrombosis prophylaxis, door-to-needle time of less than 60 minutes, screening for dysphagia, assessment for rehabilitation, antithrombotics at discharge, anticoagulants for atrial fibrillation or flutter, statins for LDL greater than 100 mg/dL or not documented and smoking cessation education.

The secondary endpoints included complete adherence to 10 in-hospital quality measures, Rt-PA in patients admitted within 24 hours, antihypertensives, DTNT less than 45 minutes and 90-day clinical events (mortality, disability and stroke recurrence).

The QI intervention included the use of a colored wristband for patient identification and a printed poster of reminders that the patients should receive special care. A therapeutic plan/algorithm for care management included recommendations of evidence-based therapies for these patients.

Trained nurse case managers ensured all components of the QI intervention were used. Educational materials containing evidence-based recommendations were also provided. Periodic feedback reports were generated on adherence to quality measures.

Patient baseline characteristics were well matched between intervention and control groups. The majority of patients had AIS as a diagnosis. At baseline, intervention clusters were somewhat more likely to have a stroke unit, although all clusters in both groups had a stroke protocol available.

There was no significant difference in composite adherence score between the intervention group (85.3%) and the control group (77.8%; intraclass correlation coefficient, 0.32). Complete adherence to in-hospital quality measures was 49.2 percent in the intervention group and 25.2 percent in the control group (population average odds ratio = 2.59; 95% CI, 1.05-6.1; ICC = 0.25).

Of the in-hospital quality measures assessed, only Rt-PA use within the therapeutic window and smoking cessation education were statistically significantly better in the intervention group than in the control group (55.0% versus 39.9%, P=0.01; and 72.1% versus 48.5%, P=0.04, respectively).

BRIDGE stroke may be a “first step in quality improvement in Latin America,” said Carrion, who suggested tailoring interventions to each location. “The other component that is very important from my end is the audit and feedback system.”

Results from DECLARE trials show drug may reduce CV death or hospitalizations for HF patients with Type 2 diabetes

The SGLT-2 inhibitor dapagliflozin met one primary composite endpoint with a statistically significant reduction in heart failure hospitalization or cardiovascular death versus placebo, according to results presented in a Late-Breaking Clinical Trial session at Scientific Sessions 2018 in Chicago.

The Dapagliflozin Effect on Cardiovascular Events-TIMI 58 (DECLARE) trial showed that dapagliflozin also met the primary safety endpoint of non-inferiority for major adverse cardiovascular events. However, the other primary composite endpoint of major adverse cardiovascular events wasn’t met.

DECLARE is a phase 3, double-blind, randomized, cardiovascular outcomes trial in 17,160 patients with Type 2 diabetes and multiple cardiovascular risk factors (n = 10,186) or established cardiovascular disease (n = 6,974).

The trial evaluated the effects of 10 mg dapagliflozin (n = 8582) daily versus placebo (n = 8,578) in 33 countries with a median follow-up of 4.2 years.

Stephen D. Wiviott, MD, senior investigator with the Thrombolysis in Myocardial Infarction Study Group and cardiovascular medicine specialist at Brigham and Women’s Hospital in Boston, presented the DECLARE results.

Enrollment criteria included diagnosis of Type 2 diabetes and established atherosclerotic cardiovascular disease including ischemic heart disease, cerebrovascular disease or peripheral artery disease (secondary prevention subgroup) or multiple risk factors for ASCVD (primary prevention subgroup). The latter group included men age >55 and women age >60 who had at least one additional risk factor such as dyslipidemia, hypertension or current tobacco use.

There were no significant differences in baseline characteristics or medication use between treatment arms, said Wiviott, who is also associate professor of medicine at Harvard Medical School in Boston. Medications were as expected in the trial patient population and included glucose-lowering therapies and cardiovascular therapies.

In the primary safety outcome analysis, dapagliflozin:

  • Met the prespecified endpoint for non-inferiority to placebo for MACE (P<0.001).
  • Didn’t result in a lower rate of MACE (8.8%) versus placebo (9.4%) (HR 0.93; CI 0.84-1.03; P=0.17 for superiority).
  • Reduced cardiovascular death or hospitalization for heart failure (4.9%) versus placebo (5.8%) (HR 0.83; CI 0.73-0.95; P=0.005 for superiority.

Because both primary endpoints weren’t met, Wiviott said the secondary endpoints have to be considered exploratory.

All-cause mortality wasn’t statistically significantly different between treatment groups. However, for the first renal composite endpoint of a 40-percent decrease in estimated glomerular filtration rate, end-stage renal disease, or renal or cardiovascular death, there were fewer events in the dapagliflozin group (4.3%) than in the placebo group (5.6%) (HR 0.76; CI 0.67-0.87; P<0.001).

Dapagliflozin was safe and generally well tolerated, with an increase in genital infections and diabetic ketoacidosis, no difference in amputation, stroke or fracture, and decreased hypoglycemia and bladder cancer, Wiviott said.

There were significantly more treatment-emergent serious adverse events in the dapagliflozin group (34.1%) versus placebo (36.2%; P<0.001), although treatment-emergent adverse events leading to drug discontinuation were higher in the dapagliflozin group (8.1%) than with placebo (6.9% P=0.01).

Specific adverse events that were higher in the dapagliflozin group than with placebo included diabetic ketoacidosis (0.3% versus 0.1% ; P=0.02) and genital infection (0.9% versus 0.1%; P<0.001). These are known adverse events to be associated with dapagliflozin. Hypoglycemia was lower with dapagliflozin than with placebo (0.7% versus 1.0%; P=0.02) as was cancer of the bladder (0.3% versus 0.5%; P=0.02).

There were no statistically significant differences between treatments for amputation, fracture, symptoms of volume depletion, urinary tract infection, Fournier’s gangrene, malignancy event or hepatic event.

Wiviott concluded that these data extend the benefit of SGLT-2 inhibition to a broader population of patients for primary and secondary prevention.

DECLARE was well conducted and stands out for the large proportion of patients with risk factors but without established atherosclerotic cardiovascular disease, said discussant Javed Butler, MD, MPH, MBA, Patrick H. Lehan Chair in Cardiovascular Research and chair of the Department of Medicine and professor of Medicine and Physiology at the University of Mississippi in Oxford.

Controlling the risk factors of HbA1c, smoking, LDLc, blood pressure and albuminuria reduced the risks of acute myocardial infarction and stroke in patients with Type 2 diabetes, but didn’t reduce the incidence of heart failure, Butler said.

“Anything that reduces the risk of heart failure is a welcome addition,” he said.

“Type 2 diabetes patients similar to those in trials of SGLT-2 inhibitors should be prescribed drugs to reduce the risk of heart failure regardless of their effect on MACE outcomes,” Butler said. For those patients with no risk factors or with heart failure, more data are needed.

Yoga may have potential for cardiac rehab in low- and middle-income settings

Yoga-based cardiac rehabilitation may have potential in post-myocardial infarction patients compared with enhanced standard care, according to a multicenter randomized controlled trial in India.

Presented during a Late-Breaking Clinical Trial session at Scientific Sessions 2018 in Chicago, the two primary outcomes of Yoga-based Cardiac Rehabilitation (Yoga-CaRe) were:

  • Time to occurrence of first cardiac event (composite of death, nonfatal MI and stroke) and emergency cardiac admissions
  • Quality of life at 12 weeks

Secondary outcomes included return to pre-infarct daily activities, smoking cessation and compliance to prescribed medications at 12 weeks, said Dorairaj Prabhakaran, MD, DM, executive director at the Center for Chronic Disease Control in New Delhi, India.

To be included in Yoga-CaRe, participants had to be within 14 days of acute myocardial infarction and willing and able to attend the complete cardiac rehabilitation program, Prabhakaran said. Participants self-reporting a current practice of yoga for more than three hours a week were excluded.

The yoga-based intervention was structured similar to cardiac rehabilitation programs and included lifestyle, meditation, breathing and yoga training sessions by trained yoga instructors for 13 weeks followed by self-practice at home.

The control group received ESC from a nurse or other member of the cardiac care team individually or in groups for five sessions.

The two treatment groups — 1,970 evaluable patients in Yoga-CaRe and 1,989 evaluable patients in ESC — were well-matched for baseline characteristics such as revascularization and cardiac medications. Median age was 53.4 years, which is typical for a cardiac event in the Indian population. Women represented only about 14 percent of the trial patients.

There were no statistically significant differences between the groups for the first co-primary outcome of death, non-fatal MI, non-fatal stroke or emergency cardiovascular hospitalizations.

Less than half the number of events occurred compared with the original assumption, so the study was underpowered. However, in patients who completed 10 or more Yoga-CaRe sessions, the incidence of cardiovascular events was significantly lower than those in the control group (HR 0.54; CI 0.38, 0.76; log rank test, P<0.0001).

For the second co-primary outcome, the mean change in EQ-5D VAS score, a measure of self-reported quality of life from baseline to three months was 9.2 in the ESC group versus 10.7 in the Yoga-CaRe group (P=0.002). It remained significant after adjusting for baseline covariates, risk profiles and treatments at discharge.

Yoga-based cardiac rehabilitation is safe, feasible, improves quality of life and encourages return to pre-infarct activities, Prabhakaran said. It has the potential to be an alternative to conventional cardiac rehabilitation programs and to address the unmet needs of patients in low- and middle-income countries for low-cost, culturally acceptable and effective cardiac rehabilitation, Prabhakaran said.

Three components of cardiac rehabilitation — stress reduction, exercise and lifestyle changes such as smoking cessation and healthier diet — could be addressed by yoga.

There are questions about whether Yoga-CaRe could apply to populations that are older, female or with more severe cardiac disease, according to discussant Vera Bittner, MD, MSPH, section head of General Cardiology, Prevention and Imaging in the Division of Cardiovascular Disease at the University of Alabama at Birmingham.

Patients in the ESC group had fewer contacts with study staff than the yoga group and didn’t have a physical activity intervention, so it is not known if they would have benefited from more contacts and physical activity. Only 53 percent of the yoga group completed at least 10 sessions, and Bittner wondered if adherence would have been worse outside of a clinical trial setting.

Other questions remain to be addressed, such as the potential for yoga to be integrated into existing treatment protocols, and whether it can be applied to other health care settings and populations.

REDUCE-IT finds medication added to statins reduces risks among patients with high triglycerides

Primary results from the REDUCE-IT study found that supplemental icosapent ethyl, a prescription medication approved to reduce triglycerides ≥ 500 mg/dL, significantly reduced the risk of important cardiovascular events by 25 percent. This includes a 31 percent reduction in myocardial infarction, a 28 percent reduction in stroke and a 20 percent reduction in death due to cardiovascular causes in statin-treated men and women with hypertriglycemia.

“We hope REDUCE-IT will transform the care of millions of patients worldwide,” said Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital in Boston, who presented the findings at Scientific Sessions 2018 in Chicago.

REDUCE-IT randomized more than 8,000 patients with well-controlled LDL-cholesterol on statins for secondary or primary prevention who had triglycerides between 135-500 mg/dL to icosapent ethyl versus placebo and followed them for an average five years.

Previous trials of low-dose triglycerides have shown no CV benefit. However, the JELIS trial, in which Japanese hypercholesterolemic patients received low-dose (1.8 g/day) eicosapentaenoic acid, suggested a 19 percent CV risk reduction. “That led us to the REDUCE-IT trial,” Bhatt said.

Icosapent ethyl is a highly purified ethyl ester of EPA available by prescription that lowers triglyceride levels and also has anti-oxidative, anti-inflammatory and other potentially anti-atherogenic properties. Bhatt and his colleagues sought to evaluate whether icosapent ethyl would reduce ischemic events in patients at elevated cardiovascular risk concurrently treated with statins.

In the international, multicenter, prospective, randomized, double-blinded, placebo-controlled, parallel group trial of stable statin therapy, study subjects took 4 grams/day of icosapent ethyl or placebo. That dose was chosen because it has been tested and is used most commonly, Bhatt said.

Inclusion criteria for REDUCE-IT was broad: men and women ≥ 45 years with established cardiovascular disease or ≥ 50 years with diabetes in combination with one additional risk factor for cardiovascular disease. Fasting triglycerides levels ≥ 150 mg/dL and < 500 mg/dL were required. LDL-cholesterol levels needed to be > 40 mg/dL and ≤ 100 mg/dL, with patients on statin therapy (± ezetimibe) for ≥ 4 weeks before the LDL-cholesterol and triglyceride qualifying measurements for randomization.

Although icosapent ethyl was well tolerated, study subjects experienced a small but significant risk of atrial fibrillation. “That side effect might have worried me, but we saw a 28 percent reduction in stroke, which is the worst thing that AFib could do,” Bhatt said. “I wouldn’t not use icosapent ethyl in a REDUCE-IT population because of the risk of AFib.” Bhatt cautioned, however, that icosapent ethyl should not be confused
with OTC omega-3 supplements. Most OTC omega-3 supplements contain DHA and EPA, and they are not highly purified, he said. Patients shouldn’t think they can take an over-the-counter omega-3 supplement and receive the same potent benefit of prescription icosapent ethyl, Bhatt said.

Despite the demonstrated clinical benefits of lowering LDL-C with statins, significant residual cardiovascular risk remains for statin-treated patients.

REDUCE-IT has the potential to offer a new standard of care for patients with elevated triglycerides at increased cardiovascular risk despite statin therapy.

In an initial smartphone poll in Saturday’s session, 65 percent of participants said they don’t regularly prescribe triglyceride lowering drugs in high-risk patients with moderate hypertriglyceridemia (200-500 mg/dL). After Bhatt’s REDUCE-IT presentation, 89 percent indicated they would.

VITAL trial considers omega-3 fatty acids, vitamin D in CV protection and cancer mortality

Marine omega-3 fatty acids may provide a cardioprotective role, while vitamin D3 supplementation appears to benefit cancer mortality, according to principal results from the National Institutes of Health-funded VITamin D and OmegA-3 TriaL.

Results of the more than five-year large clinical trial were presented by JoAnn E. Manson, MD, DrPH, in the Late-Breaking Clinical Trial session, “The VITamin D and OmegA-3 TriaL (VITAL): Principal Results for Vitamin D and Omega-3 Fatty Acid Supplementation in the Primary Prevention of Cardiovascular Disease and Cancer.” It was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute.

VITAL is one of only two large, randomized clinical trials of vitamin D for the prevention of cancer, heart disease and stroke — and the only such trial in a racially and ethnically diverse study population. Similarly, it’s the only large trial of fish oil supplements in a generally healthy population.

“This was a look at both the independent and joint effects of the intervention,” said Manson, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital and a Michael and Lee Bell Professor of Women’s Health at Harvard Medical School in Boston.

The study involved 25,871 U.S. adults (men age ≥50 and women age ≥55) who didn’t have a history of heart disease, cancer or stroke. Participants took daily dietary supplements of vitamin D3 (2000 IU daily) or marine omega-3 fatty acids (Omacor® fish oil, one gram daily). The trial was administered by Brigham and Women’s Hospital.

VITAL, which was a 2×2 factorial randomized, double-blind, placebo-controlled study, examined both the benefits and risks of the dietary supplements given to participants.

The omega-3 fatty acid component of the trial studied the primary endpoints of major CVD events, a composite of myocardial infarction, stroke and CVD mortality, as well as total invasive cancer, Manson said. Secondary endpoints included individual components of major CVD, other vascular events, site-specific cancers and cancer mortality.

During a median 5.3 years of treatment, the one gram of omega-3 daily supplementation participants received was associated with a significant 28 percent reduction in total MI, as well as significant reductions in fatal MI, percutaneous coronary intervention and total coronary heart disease. There was no significant reduction in stroke or CVD mortality.

Also, MI was 40 percent lower in participants who ate less than one-and-a-half servings of fish per week and 53 percent lower in those eating fish less than once per month. African-Americans experienced the greatest risk reduction in the study, regardless of dietary fish intake or cardiovascular risk factor status.

“The reduction in total MI was of a comparable or greater magnitude than that for aspirin or statins in primary prevention,” Manson said. “This supports a possible cardioprotective role for n-3 fatty acids in a usual-risk setting, especially among those with cardiovascular risk factors or low fish intake and in African-Americans.”

Manson said further research is needed to determine the people who may be most likely to derive a net benefit from supplementation.

Conversely, while vitamin D3 supplementation didn’t significantly reduce cardiovascular events or incidence of total cancer, Manson said it appeared to have benefits for cancer mortality. Findings include:

  • Total cancer mortality dropped 17 percent, which became a significant 25 percent reduction in preplanned analyses after exclusion of early follow-up.
  • In subgroup analyses, normal-weight participants experienced 24 percent and 42 percent treatment-associated reductions in cancer incidence and mortality, respectively.
  • Overweight and obese participants didn’t benefit.
  • Vitamin D didn’t significantly reduce all-cause mortality. A two-year, post-intervention follow-up is ongoing to capture latency effects of the study agents and increase statistical power to assess endpoints.

“The findings indicate that high-dose vitamin D does not lower the risk of developing cancer or cardiovascular disease in generally healthy men and women, although it suggests that it may lower the risk of cancer death,” Manson said. “Although our study shows that a vitamin D dose of 2000 IU per day is well tolerated, with few if any side effects, the results do not strongly support the initiation of high-dose vitamin D for prevention of cancer or cardiovascular disease in healthy patients who already meet vitamin D requirements for bone health.”

Despite widespread reports of quality control in the dietary supplement industry, the vitamin D and fish oil supplements used in the VITAL study underwent extensive quality control testing to ensure that they contained the correct nutrients in the correct doses,
were free from contaminants, arrived fresh to participants and remained shelf-stable for at least 18 months thereafter, Manson said.