Meeting NewsPerspective

VITAL: Mixed findings for vitamin D, omega-3s in CVD, cancer prevention

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, but some secondary endpoints showed promising signals.

The 25,871-patient, placebo-controlled, NIH-funded trial had a 2x2 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 prespecified secondary and other 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.

In prespecified secondary analyses of the 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. The primary endpoint of major CVD events was also significantly reduced among those with low fish consumption. 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 to account for cancer latency issues. 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.

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, depression 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.

Editor's Note: This article was updated on Nov. 27, 2018 with a new headline and other changes at the request of Dr. Manson.

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, but some secondary endpoints showed promising signals.

The 25,871-patient, placebo-controlled, NIH-funded trial had a 2x2 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 prespecified secondary and other 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.

In prespecified secondary analyses of the 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. The primary endpoint of major CVD events was also significantly reduced among those with low fish consumption. 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 to account for cancer latency issues. 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.

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, depression 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.

Editor's Note: This article was updated on Nov. 27, 2018 with a new headline and other changes at the request of Dr. Manson.

    Perspective
    Martha Gulati

    Martha Gulati

    The take-home to me is that, from a primary prevention standpoint, in this older population there appears to be no role for vitamin D or fish oil supplementation. These are supplements that many people use. They are generally over-the-counter supplements that can be as cheap as $10 per month or as much as $50 or $60 per month. In my experience, I have patients who come in with a long list of supplements they take. We need to critically look at these supplements our patients are taking to determine what is safe, what is not safe, what is effective and what is not effective. To go further, I think regulating the mass marketing of multivitamins is also warranted. I hope the message is that a healthy diet may be better for you than anything else. For example, in one of the subgroups studied, those who had lower fish consumption may benefit from omega-3. This would be interesting to study further. 

    We have all been waiting for the VITAL results. The equity in gender in this study was amazing — 51% women. Twenty percent of patients were African American, too. It is important to include generally underrepresented populations to truly extrapolate the results.

    • Martha Gulati, MD, MS, FACC, FAHA
    • Division Chief of Cardiology
      University of Arizona College of Medicine – Phoenix
      Physician Executive Director for the Banner – University Medicine Heart Institute
      Editor in Chief, ACC CardioSmart
    Perspective

    The results of the VITAL trial have been eagerly awaited. Recent data have demonstrated that vitamin D supplementation does not confer significant musculoskeletal benefits for healthy, community-dwelling adults. However, many individuals continue to take vitamin D supplements in hopes that they might provide extraskeletal benefits. Recent estimates suggest that almost 20% of adults in the U.S. take a daily vitamin D supplement containing 1,000 IU or more (Rooney MR, et al. JAMA. 2017;doi:10.1001/jama.2017.4392). The results of the large VITAL study indicate that taking vitamin D 2,000 IU/day does not reduce the incidence of invasive cancer or major CVD.

    Importantly, average 25-hydroxyvitamin D concentrations, measured in a subset of the study population, were 77 nmol/L at baseline and just over 100 nmol/L on treatment. These levels exceed the targets recommended by both the Institute Of Medicine (50 nmol/L) and Endocrine Society (75 nmol/L).

    Intriguingly, vitamin D supplementation reduced cancer incidence in the subgroup of individuals with a BMI < 25 mg/kg2 — part of the prespecified secondary analyses). Additionally, in another analysis, not prespecified, where events occurring in the first 2 years of follow-up were excluded, vitamin D supplementation was associated with fewer cancer-related deaths. These findings are interesting and hypothesis-generating. However, based on the VITAL study results, I would not at this time recommend use of vitamin D supplementation for the prevention of cancer or CVD.

    • Emma Billington, BSc, MD, FRCPC
    • Clinical Assistant Professor
      Division of Endocrinology and Metabolism
      University of Calgary/Alberta Health Services

    Disclosures: Billington reports no relevant financial disclosures.

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