VITAL: Vitamin D, omega-3 fail to reduce major CV events, cancer


JoAnn E. Manson

CHICAGO — In the large-scale VITAL trial, neither omega-3 nor vitamin D supplements for primary prevention reduced major CV events or development of invasive cancers compared with placebo over 5 years of follow-up.

The 25,871-patient, placebo-controlled trial had a 2×2 factorial design, by which patients were randomly assigned vitamin D3 (cholecalciferol) 2,000 IU per day and omega-3 fatty acids 1 g per day, each compared with placebo.

VITAL had two primary endpoints: major CV events, defined as a composite of MI, stroke or death from CV causes, and invasive cancer of any type. Patients were followed for a median of 5.3 years.

In the omega-3 part of the trial, a major CV event occurred in 386 patients assigned omega 3 supplementation vs. 419 assigned placebo (HR = 0.92; 95% CI, 0.8-1.06) and invasive cancer was diagnosed in 820 patients assigned omega-3 vs. 797 assigned placebo (HR = 1.03; 95% CI, 0.93-1.13), JoAnn E. Manson, MD, DrPH, FAHA, chief of the division of preventive medicine, Brigham and Women’s Hospital, and professor of medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, reported at the American Heart Association Scientific Sessions.

In the vitamin D part of the trial, a major CV event occurred in 396 patients assigned omega-3 supplementation vs. 409 assigned placebo (HR = 0.97; 95% CI, 0.85-1.12) and invasive cancer was diagnosed in 793 patients assigned omega-3 vs. 824 assigned placebo (HR = 0.96; 5% CI, 0.88-1.06).

Deeper dive

Findings from secondary and non-prespecified analyses may prompt further scrutiny.

In the omega-3 analysis, supplementation and placebo yielded no differences in secondary cancer endpoints that included site-specific cancers and death from cancer.

When the researchers examined individual components of the primary composite CV endpoint, risk for MI was 28% lower with omega-3 supplementation compared with placebo (HR = 0.72; 95% CI, 0.59-0.9), with the greatest reductions observed in subgroups with low dietary dish intake (< 1.5 servings per week) and in black participants compared with non-Hispanic white participants. Manson also noted that non-prespecified analyses showed reductions in PCI, fatal MI and total CHD, including MI, coronary revascularization and CHD death with omega-3 supplementation. Further, exploratory analysis excluding the first 2 years of follow-up hinted at a higher but not significant incidence of cancer in the omega-3 group, but no greater incidence of cancer-related death.

In the vitamin D analysis, supplementation did not yield a lower incidence of total cancer-related deaths or breast, colorectal or prostate cancers compared with placebo. A post hoc analysis of cancer-related deaths highlighted a possible benefit in total cancer mortality when early follow-up data were excluded. Subgroup analysis based on BMI suggest that normal-weight patients who received vitamin D had a lower incidence of cancer compared with those who received placebo. The aforementioned secondary CV events and deaths from any cause were not significantly different with vitamin D or placebo, or in any subgroups.

No significant adverse events emerged during follow-up, including risk for hypercalcemia with vitamin D, increased bleeding with omega-3 or gastrointestinal symptoms with either agent.

Trial details

“This is the first large-scale randomized trial of fish oil in a primary prevention, usual-risk population, and one of the largest trials of vitamin D,” Manson said during the press conference.

Patients enrolled were free from CVD and cancer, excluding non-melanoma skin cancer, at baseline. The mean age at baseline was 67 years and 51% were women. In total, 5,016 (20.2%) of the 25,000-plus patients were black, “for whom the question of effectiveness of vitamin D is particularly relevant because their cutaneous synthesis of vitamin D in response to solar radiation is lower than that in persons in other racial or ethnic groups,” the researchers wrote in The New England Journal of Medicine simultaneous publication.

Baseline mean serum total 25-hydroxyvitamin D level was 30.8 ng/mL; 12.7% of patients had levels < 20 ng/dL. Mean plasma omega-3 index was 2.7% in both groups.

The vitamin D was provided by Pharmavite and the fish oil by Pronova BioPharma and BASF.

Adherence — defined as the percentage of patients who reported taking at least two-thirds of the trial capsules — exceeded 80% in both analyses.

‘Timely and relevant’

Use of dietary supplements in the U.S. is common, with NHANES 1999-2012 data showing that more than half of U.S. adults consumed dietary supplements, John F. Keaney Jr., MD, from the University of Massachusetts Medical School, Worcester, and Clifford J. Rosen, MD, from the Maine Medical Center Research Institute, Scarborough, wrote in an accompanying NEJM editorial.

“In the past decade, the number of persons who supplemented their diets with fish oil increased by a factor of 10 and with vitamin D by a factor of 4. But any long-term health benefits from these products remain in doubt,” Keaney and Rosen wrote. “Hence, the results from [VITAL] … are both timely and relevant.”

In the context of other research, Manson noted at the press conference that the observed lack of benefit of vitamin D supplementation for CV outcomes in VITAL is consistent with other vitamin D trials. Moreover, the omega-3 findings are in line with those from the recent ASCEND trial, which, as Cardiology Today previously reported, demonstrated no effect of omega-3 fatty acids on primary prevention in a population with CVD and diabetes.

During a discussion of the trial, Jane Armitage, FRCP, FFPH, from the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, who was one of the ASCEND investigators, called VITAL a well-conducted study that was large, ethnically diverse and balanced between men and women.

“This primary result that universal supplementation in this primary prevention population has not been shown to be beneficial, and I think this is a robust result. These other results need to be seen as hypothesis-generating … [and] we need to be cautious in our interpretation,” Armitage said.

Several ancillary studies of the VITAL trial are underway, Manson said, and will shed further light on supplementation using higher doses in high-risk populations as well as for diabetes, cognitive function, autoimmune disorders, hypertension and more. – by Katie Kalvaitis

References:

Manson JE, et al. LBS.01 – Late Breaking Clinical Trials: Answers to Critical Questions in Cardiovascular Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Manson JE, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809944.

Manson JE, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1811403.

Keaney JF, Rosen CJ. N Engl J Med. 2018;doi:10.1056/NEJMe1814933.

Disclosures: VITAL was supported by the NIH. Manson reports she received grants from the NIH, nonfinancial support from BASF, Pharmavite, Pronova BioPharma and Quest Diagnostics during the conduct of the study. Armitage was chief investigator of the ASCEND trial; she reports she received research grants to the University of Oxford from Abbott, Bayer, Mylan and Solvay. Keaney and Rosen report no relevant financial disclosures.

JoAnn E. Manson

CHICAGO — In the large-scale VITAL trial, neither omega-3 nor vitamin D supplements for primary prevention reduced major CV events or development of invasive cancers compared with placebo over 5 years of follow-up.

The 25,871-patient, placebo-controlled trial had a 2×2 factorial design, by which patients were randomly assigned vitamin D3 (cholecalciferol) 2,000 IU per day and omega-3 fatty acids 1 g per day, each compared with placebo.

VITAL had two primary endpoints: major CV events, defined as a composite of MI, stroke or death from CV causes, and invasive cancer of any type. Patients were followed for a median of 5.3 years.

In the omega-3 part of the trial, a major CV event occurred in 386 patients assigned omega 3 supplementation vs. 419 assigned placebo (HR = 0.92; 95% CI, 0.8-1.06) and invasive cancer was diagnosed in 820 patients assigned omega-3 vs. 797 assigned placebo (HR = 1.03; 95% CI, 0.93-1.13), JoAnn E. Manson, MD, DrPH, FAHA, chief of the division of preventive medicine, Brigham and Women’s Hospital, and professor of medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, reported at the American Heart Association Scientific Sessions.

In the vitamin D part of the trial, a major CV event occurred in 396 patients assigned omega-3 supplementation vs. 409 assigned placebo (HR = 0.97; 95% CI, 0.85-1.12) and invasive cancer was diagnosed in 793 patients assigned omega-3 vs. 824 assigned placebo (HR = 0.96; 5% CI, 0.88-1.06).

Deeper dive

Findings from secondary and non-prespecified analyses may prompt further scrutiny.

In the omega-3 analysis, supplementation and placebo yielded no differences in secondary cancer endpoints that included site-specific cancers and death from cancer.

When the researchers examined individual components of the primary composite CV endpoint, risk for MI was 28% lower with omega-3 supplementation compared with placebo (HR = 0.72; 95% CI, 0.59-0.9), with the greatest reductions observed in subgroups with low dietary dish intake (< 1.5 servings per week) and in black participants compared with non-Hispanic white participants. Manson also noted that non-prespecified analyses showed reductions in PCI, fatal MI and total CHD, including MI, coronary revascularization and CHD death with omega-3 supplementation. Further, exploratory analysis excluding the first 2 years of follow-up hinted at a higher but not significant incidence of cancer in the omega-3 group, but no greater incidence of cancer-related death.

In the vitamin D analysis, supplementation did not yield a lower incidence of total cancer-related deaths or breast, colorectal or prostate cancers compared with placebo. A post hoc analysis of cancer-related deaths highlighted a possible benefit in total cancer mortality when early follow-up data were excluded. Subgroup analysis based on BMI suggest that normal-weight patients who received vitamin D had a lower incidence of cancer compared with those who received placebo. The aforementioned secondary CV events and deaths from any cause were not significantly different with vitamin D or placebo, or in any subgroups.

PAGE BREAK

No significant adverse events emerged during follow-up, including risk for hypercalcemia with vitamin D, increased bleeding with omega-3 or gastrointestinal symptoms with either agent.

Trial details

“This is the first large-scale randomized trial of fish oil in a primary prevention, usual-risk population, and one of the largest trials of vitamin D,” Manson said during the press conference.

Patients enrolled were free from CVD and cancer, excluding non-melanoma skin cancer, at baseline. The mean age at baseline was 67 years and 51% were women. In total, 5,016 (20.2%) of the 25,000-plus patients were black, “for whom the question of effectiveness of vitamin D is particularly relevant because their cutaneous synthesis of vitamin D in response to solar radiation is lower than that in persons in other racial or ethnic groups,” the researchers wrote in The New England Journal of Medicine simultaneous publication.

Baseline mean serum total 25-hydroxyvitamin D level was 30.8 ng/mL; 12.7% of patients had levels < 20 ng/dL. Mean plasma omega-3 index was 2.7% in both groups.

The vitamin D was provided by Pharmavite and the fish oil by Pronova BioPharma and BASF.

Adherence — defined as the percentage of patients who reported taking at least two-thirds of the trial capsules — exceeded 80% in both analyses.

‘Timely and relevant’

Use of dietary supplements in the U.S. is common, with NHANES 1999-2012 data showing that more than half of U.S. adults consumed dietary supplements, John F. Keaney Jr., MD, from the University of Massachusetts Medical School, Worcester, and Clifford J. Rosen, MD, from the Maine Medical Center Research Institute, Scarborough, wrote in an accompanying NEJM editorial.

“In the past decade, the number of persons who supplemented their diets with fish oil increased by a factor of 10 and with vitamin D by a factor of 4. But any long-term health benefits from these products remain in doubt,” Keaney and Rosen wrote. “Hence, the results from [VITAL] … are both timely and relevant.”

In the context of other research, Manson noted at the press conference that the observed lack of benefit of vitamin D supplementation for CV outcomes in VITAL is consistent with other vitamin D trials. Moreover, the omega-3 findings are in line with those from the recent ASCEND trial, which, as Cardiology Today previously reported, demonstrated no effect of omega-3 fatty acids on primary prevention in a population with CVD and diabetes.

PAGE BREAK

During a discussion of the trial, Jane Armitage, FRCP, FFPH, from the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, who was one of the ASCEND investigators, called VITAL a well-conducted study that was large, ethnically diverse and balanced between men and women.

“This primary result that universal supplementation in this primary prevention population has not been shown to be beneficial, and I think this is a robust result. These other results need to be seen as hypothesis-generating … [and] we need to be cautious in our interpretation,” Armitage said.

Several ancillary studies of the VITAL trial are underway, Manson said, and will shed further light on supplementation using higher doses in high-risk populations as well as for diabetes, cognitive function, autoimmune disorders, hypertension and more. – by Katie Kalvaitis

References:

Manson JE, et al. LBS.01 – Late Breaking Clinical Trials: Answers to Critical Questions in Cardiovascular Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Manson JE, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809944.

Manson JE, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1811403.

Keaney JF, Rosen CJ. N Engl J Med. 2018;doi:10.1056/NEJMe1814933.

Disclosures: VITAL was supported by the NIH. Manson reports she received grants from the NIH, nonfinancial support from BASF, Pharmavite, Pronova BioPharma and Quest Diagnostics during the conduct of the study. Armitage was chief investigator of the ASCEND trial; she reports she received research grants to the University of Oxford from Abbott, Bayer, Mylan and Solvay. Keaney and Rosen report no relevant financial disclosures.

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