Clinical trials of omega-3 fatty acid or vitamin D supplements have followed a long and winding road in search of benefits in cardiovascular (CV) disease, with wildly mixed results. But the journey may be in vain in one of cardiology’s frontier research areas, primary prevention of atrial fibrillation (AF), suggest primary results of the VITAL-Rhythm trial, presented November 13 during the American Heart Association (AHA) Scientific Sessions 2020 virtual meeting.
Neither marine-oil caps nor the vitamin D3 supplements made a difference to risk for incident AF, whether paroxysmal or persistent, over more than 5 years in the study, with more than 25,000 adults in the community. Nor did they seem to cause harm.
“To our knowledge, this is the first large-scale, long-term, randomized placebo-controlled trial to test the effect of any intervention on incident AF,” Christine M. Albert, MD, MPH, Cedars-Sinai Medical Center in Los Angeles, California, said at a media briefing on VITAL-Rhythm before her formal presentation of the trial during the conference.
Its findings, she said, don’t support the use of marine-oil caps or vitamin D3 for primary prevention of incident AF. “Fortunately, they also do not show any increased risk in atrial fibrillation for patients who are using these supplements for other indications.”
Both agents are widely taken without physician supervision for their perceived benefits, and marine-oil caps in particular — often in special prescription formulations — may be used for reducing elevated triglyceride levels and, based on the results of REDUCE-IT, cutting cardiovascular risk.
“It’s pretty clear that there’s no evidence to suggest that either of these supplements is helpful for preventing atrial fibrillation. And I think that’s clear from the evidence these investigators presented,” said Jonathan P. Piccini, MD, MHS, Duke University, Durham, North Carolina, who wasn’t part of the study.
“It’s also a little disappointing because atrial fibrillation is such a huge problem, and the inability to identify preventative strategies is a repeated theme,” he told theheart.org | Medscape Cardiology.
VITAL-Rhythm is an ancillary study within the VITAL trial, which showed no benefit from either supplement regarding risk for incident cancer or CV events, as reported at the AHA sessions 2 years ago. In fact, their effects seem sweepingly negative throughout the trial; in another ancillary study, VITAL-DKD, neither supplement helped preserve renal function over 5 years in patients with type 2 diabetes.
The participants started VITAL without a history of AF, CV disease, or cancer; they were randomly assigned to take about a gram of omega-3 fatty acids, 2000 IU vitamin D3 daily, or their placebos, in a double randomization.
VITAL and its ancillary studies collectively undercut mechanistic theories about how omega-3 fatty acid and vitamin D supplements may affect AF risk, ideas derived from epidemiologic and dietary studies. They were thought perhaps “to have direct antiarrhythmic effects on myocytes through effects on ion channels, electrical remodeling, electrical stabilizing effects, and fluidity of the cell membranes,” observed Renate B. Schnabel, MD, MSc, University Heart Center, Hamburg, Germany, at the briefing. Or such effects might be related to beneficial effects on atherosclerosis, inflammation, or ischemic heart disease, she noted.
Neither idea is likely after VITAL and VITAL-Rhythm, said Schnabel, who spoke as an invited discussant after Albert’s formal presentation at AHA 2020.
That omega-3 fatty acid supplements may not improve AF incidence or risks has also been evident from many clinical trials and observational studies. Several, including REDUCE-IT, included some evidence for increasing risk for AF with marine-oil supplement intake. That may have happened in VITAL-Rhythm as well.
“While there was no evidence that the omega-3 three fatty acids prevented atrial fibrillation, there was a signal of perhaps more atrial fibrillation in the omega-3 fatty-acids group,” said Piccini, who directs his center’s electrophysiology clinical trials program.
A sensitivity analysis limited to participants who adhered to their assigned regimens, as opposed to the main intention-to-treat (ITT) analysis, showed a nonsignificant 13% increased hazard ratio for incident AF for the marine-oil supplement group. It reached a P value of .09, which can be interpreted as a trend.
“There are a few studies that have now showed a trend or an increased incidence of arrhythmia in patients treated with omega-3 fatty acids,” Piccini noted. “I don’t think it’s definitive, but it’s certainly something to keep an eye on.”
VITAL-Rhythm included an electrocardiography (ECG) substudy, yet to be reported, that should yield more insights about any such effects of marine-oil or vitamin D supplements in the trial, Albert said at the briefing.
The ancillary study assigned its 25,119 patients (mean age, 67 years; 51% women) to take vitamin D3 at 2000 IU/day, marine-oil supplements containing omega-3 fatty acids at 840 mg per day — 460 mg eicosapentaenoic acid (EPA) plus 380 mg docosahexaenoic acid (DHA) (Omacor, Pronova BioPharma) — or their placebos in a 2 ˟ 2 randomization
Incident cases of AF were identified through annual questionnaires in which the participants self-reported whether they had received a physician diagnosis of the arrhythmia, supplemented by Centers for Medicare & Medicaid Services (CMS) claims data for AF hospital and clinical visits. Those led to a review of inpatient and outpatient records, from which AF events were adjudicated by an endpoint committee. An electrocardiogram (72.9%) or physician’s report (27.1%) confirmed the AF diagnosis as the protocol required.
By those standards, 900 incident cases were identified, for a rate of 3.6% over a median of 5.3 years. They were paroxysmal in 58.4%, persistent in 38.4%, and indeterminant in 3.1%, Albert reported.
Of the 12,542 patients assigned to marine-oil caps by ITT, 469 (3.74%) developed incident AF in the ITT analysis, compared to 431 of 12,577 (3.43%) who received placebo, for an adjusted hazard ratio (HR) of 1.09 (95% CI, 0.96 – 1.24; P = .19).
The results were similar in two sensitivity analyses, one of which omitted patients with AF who may have had symptoms before randomization and another excluding those whose incident AF was identified solely in CMS data. But in the third “on treatment” sensitivity analysis, the HR for events was 1.13 (95% CI, 0.98 – 1.30; P = .09).
Outcomes for the vitamin D randomization were nearly the same, for an HR of 1.09 (95% CI, 0.96 – 1.25; P = .19) by ITT; the results were similar in all three sensitivity analyses.
“It’s not a tremendous signal of risk,” said Piccini of the marine-oil on-treatment analysis. But it, along with consistent evidence from other studies, does give him pause. “If a patient came to me and said, Doctor, I want to take omega-3 fish oil, because I want to reduce my risk of events, as an arrhythmia doctor I would say, ‘We don’t have great evidence to do that for preventing atrial fibrillation. And there’s actually some evidence that it could mildly increase your risk of developing it.'”
For those prescribed evidence-based marine-oil therapy for other indications, he said, “I think the take-home message certainly is, if they report palpitations or other signs or symptoms that could be due to atrial fibrillation, we should be aggressive about screening for atrial fibrillation,” and making the diagnosis as appropriate. If the incident AF resolves after stopping the treatment, “maybe it’s reasonable to refrain from prescribing the medication for that patient.”
VITAL-Rhythm and VITAL are supported by multiple grants from the National Institutes of Health. Albert discloses receiving grant support from St. Jude Medical, Abbott, and Roche. Schnabel reports receiving honoraria from Bristol-Myers Squibb/Pfizer. Piccini previously disclosed receiving research grants from Abbott, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serving as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, Sanofi, Philips, and UptoDate.
American Heart Association (AHA) Scientific Sessions 2020. LBS.01 Presented November 13, 2021.