HOPE-2, NORVIT: No CV benefit from reducing homocysteine with folic acid and B vitamins

Susan Jeffrey

March 12, 2006

Mar 12, 2006

Atlanta, GA - Two new studies appear to have largely finished off the idea that reducing elevated homocysteine levels with folic acid and B vitamins may reduce cardiovascular events.

In one trial [ 1 ], some of the same investigators who brought evidence against cardiovascular benefit from vitamin E in the Heart Outcomes Prevention Evaluation (HOPE) trial now report data showing no effect from B-vitamin and folic-acid supplementation in preventing CV events in the second Heart Outcomes Prevention Evaluation (HOPE-2).

Dr Eva Lonn

"Because the primary study outcome is neutral, I think we have to conclude that supplementation with high-dose folic acid and vitamins B6 and B12 does not reduce major vascular events in a high-risk population with established vascular disease," Dr Eva Lonn (McMaster University, Hamilton, ON) said at a press conference here at the American College of Cardiology (ACC) 2006 Scientific Sessions, where the HOPE-2 results are being presented Monday.

While the results were neutral, Lonn added, "I think they're important, because we have been often derailed in our efforts to implement secondary prevention adequately, and the focus should be on what has been proven to work namely, a healthy lifestyle with a good intake of fruits and vegetables, exercise, and, for those who already have had an event, certain drugs such as aspirin, statins, beta blockers, and ACE inhibitors, which have proven benefit."

The second study [ 2 ], the Norwegian Vitamin Trial (NORVIT), showed no benefit from folic acid and B vitamins in patients started on treatment within seven days after an MI in preventing recurrent events. The researchers, with principal investigator Dr Kaare H B¿ naa (University of Troms¿, Norway), actually report an increase in events with the combination of folic acid and vitamins B12 and B6.

The studies are published online March 12, 2006 in the New England Journal of Medicine, released to coincide with the presentation of HOPE-2 here at the ACC meeting.

No HOPE for homocysteine hypothesis?

Observational data have suggested that high homocysteinelevels are a risk factor for cardiovascular disease, with supporting experimental work showing homocysteine causes oxidative stress, damages the endothelium, and enhances thrombogenicity, the HOPE-2 investigators write; even mild to moderate elevations have been associated with risk. This observation "is important because such increases are common and can be easily corrected with safe and inexpensive therapy." The hope had been that this safe and inexpensive therapy, folic acid and vitamins B12 and B6, would lower homocysteine levels and in turn cardiovascular events. That hope received its first blow with the results of the Vitamin Intervention for Stroke Prevention (VISP) trial [ 3 ], which failed to show a benefit from vitamin therapy in patients with a history of stroke.

HOPE-2 was a randomized, double-blind trial including 5522 patients 59 years of age or older with a history of vascular disease coronary, cerebrovascular, or peripheral arterial disease or with diabetes and at least one additional risk factor. They were recruited both from countries such as the US and Canada, where folate fortification of food is mandatory about 70% of the study population and those where it is not mandatory, including Brazil, Western Europe, and Slovakia.

Patients were randomized to receive a combined pill containing 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or placebo daily for an average of five years. The primary outcome was a composite of death from CV causes, MI, and stroke.

Mean homocysteine levels decreased by 2.4 ¿mol/L (0.3 mg/L) among those receiving the active treatment, while a slight increase of 0.8 ¿mol/L was seen in the placebo group. Despite this effective homocysteine lowering, however, no significant effect was seen on primary end-point events.

HOPE-2: Primary outcome events with folic acid, vitamin B6 and B12 supplementation vs placebo at five years

End point
Active therapy
Placebo ¿¿¿¿¿¿
Relative risk (95% CI)
Primary outcome (death from CV causes, MI, and stroke), n (%)
519 (18.8)
547 (19.8)
0.95 (0.84-1.07)

There was no benefit seen in the components of the primary end point, with the exception of stroke, where there was an absolute risk reduction of 1.3%, and a relative risk reduction of 24% with active treatment. However, in their discussion, the HOPE-2 investigators conclude that since no effect was seen on transient ischemic attacks and such an effect has not been seen in other trials, this finding is "either an overestimate of the real effect or a spurious result due to the play of chance."

They did find an increase with treatment in the number of patients who were hospitalized for unstable angina.

HOPE-2: Secondary outcomes

Active treatment
Relative risk (95% CI)
Death from CV causes, n (%)
276 (10.0)
291 (10.5)
0.96 (0.81-1.13)
MI, n (%)
341 (12.4)
349 (12.6)
0.98 (0.85-1.14)
Stroke, n (%)
111 (4.0)
147 (5.3)
0.75 (0.59-0.97)
Hospitalization for unstable angina, n (%)
268 (9.7)
219 (7.9)
1.24 (1.04-1.49)

There was no difference in outcomes in any subgroups, including those from countries with or without folate supplementation or those with higher or lower baseline homocysteine levels.

"We believe the effect on stroke may require further exploration, and a number of studies that are ongoing, especially studies that are conducted in regions without folate supplementation, may be of interest," Lonn added. Among these are SEARCH, also a secondary-prevention trial conducted in the US including 12¿000 people, and the VITATOPS study, conducted in countries without fortification and looking primarily at stroke outcomes. "I think in a few years we will have very definitive answers," Lonn said. "We already have big piece of the puzzle."

No benefit seen among those with creatinine levels above or below the median of 0.98 mg/dL.

The lack of benefit in reducing vascular events from reducing homocysteine seen in these studies is similar to results of Atherosclerosis Folic Acid Supplementation Trial (ASFAST), presented at last fall's American Society of Nephrology meeting and reported by renalwire at that time. ASFAST, a randomized trial carried out in renal units in Australia and New Zealand, showed no improvement in cardiovascular outcome from high-dose folic acid in patients with chronic renal failure.

NORVIT: Homocysteine an "innocent bystander"

A second trial in the same issue of the Journal looks at B vitamins and folic acid in reducing recurrent events in patients soon after a myocardial infarction. NORVIT, results of which were presented last fall at the European Society of Cardiology (ESC) meeting, included 3749 men and women who had had an MI in the seven days prior to randomization. They were then randomized in a 2x2 factorial design to one of four daily regimens: 0.8 mg of folic acid, 0.4 mg of vitamin B12, 40 mg of vitamin B6, or placebo. The primary end point was a composite of recurrent MI, stroke, and sudden death attributed to coronary artery disease.

Over the median follow-up of 40 months, homocysteine levels were reduced by the combination of folic acid and vitamin B12 by 27%. However, this reduction did not translate into any effect on the primary end point in that group. B6 alone did not have much effect on homocysteine levels. The combination of folic acid and both B vitamins again reduced the homocysteine levels but not the primary end point. In fact, they note, "Contrary to expectations, there was a trend toward an increased rate of events among patients receiving B vitamins, in particular the combination of folic acid, vitamin B6, and vitamin B12."

NORVIT: Primary end point

Rate ratio
95% CI
Folic acid and B 12 vs no folic acid and B 12
B 6 vs no B 6
Folic acid, B 12 , and B 6 vs placebo

To download tables as slides, click on slide logo below

"In summary, the NORVIT trial demonstrated that intervention with folic acid, with or without high doses of vitamin B6, did not lower the risk of recurrent cardiovascular disease or death after an acute myocardial infarction," B¿naa et al conclude. "Such therapy may even be harmful after acute myocardial infarction or coronary stenting and should therefore not be recommended."

"The homocysteine hypothesis is dead," B¿naa told a press conference when he presented these findings at the ESC meeting in September 2005. "Homocysteine is not a causal risk factor; it is an innocent bystander."

An "unequivocal conclusion"

In an accompanying editorial [ 4 ], Dr Joseph Loscalzo (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) writes that the consistency of the results of HOPE-2, NORVIT, and VISP in three similar, although not identical, populations "leads to the unequivocal conclusion that there is no clinical benefit of the use of folic acid and vitamin B12 (with or without the addition of vitamin B6) in patients with established vascular disease.

"The straightforward but incorrect view that folic acid can decrease homocysteine levels and thus reduce the risk of atherosclerosis effectively may be an unintended consequence of oversimplifying a complicated metabolic network," Loscalzo writes. "Further exploration of the relations among the intermediates in this metabolic pathway and their association with atherothrombotic mediators will be needed. Meanwhile, we should consider alternative approaches to reducing homocysteine concentrations, perhaps with new methods of enhancing the conversion of homocysteine to cysteine in the liver or enhancing the urinary excretion of the amino acid."


  1. The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; DOI:10.1056/NEJMoa060900. Available at: http://www.nejm.org.

  2. B¿naa KH, Nj¿lstad I, Ueland PM, et al, for the NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; DOI: 10.1056/NEJMoa055227. Available at: http://www.nejm.org.

  3. Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death. The Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;¿291:565-575.

  4. Loscalzo J. Homocysteine trials?Clear outcomes for complex reasons. N Engl J Med 2006; DOI:10.1056/NEJMe068060. Available at: http://www.nejm.org.