Dr Kaare Harald Bønaa

"The homocysteine hypothesis is dead," principal investigator Dr Kaare Harald Bønaa (University of Tromsø, Norway) told the press. "Homocysteine is not a causal risk factor; it is an innocent bystander."

NORVIT enrolled 3749 patients, age 30 to 84, from 35 Norwegian hospitals. Trial participants were randomized to one of four study groups: a combination folic-acid and vitamin-B6 group, a folic-acid-only group, a vitamin-B6 group, or placebo. Doses used for each group were 0.8 mg daily for folic acid and 40 mg daily for vitamin B6; 0.4 mg of vitamin B12 was given with the folic-acid dose. The primary end point of the trial was a combination of nonfatal and fatal MI and stroke after 3.5 years. Secondary end points included death, stroke, MI, need for PCI/CABG, and hospitalization for unstable angina.

As Bønaa reported here today, the combination of vitamin B6 and folic acid, as well as folic acid alone, effectively lowered homocysteine levels by 28% but did not have the expected beneficial effect on cardiovascular risk. At follow-up, the risk of stroke and MI was 18% in the placebo group, roughly the same as that seen in both the folic-acid-only group and the vitamin-B6-only group. By contrast, in the combination group, 23% of patients had a fatal or nonfatal stroke or MI, a statistically significant absolute increase of 5%, compared with the other treatment arms (p=0.029). No differences were seen in any of the secondary end points.

Of note, investigators also saw a trend toward an increased incidence in cancer among patients taking high-dose folic acid, a finding Bønaa said should be studied further. To heartwire, Bønaa explained that while NORVIT did not explore possible mechanisms for the increased MI/stroke risk, there are some indications from previous studies that folic acid and vitamin B6 can speed up the methylation of DNA, thereby accelerating cell growth and increasing cancer risk.

"High doses of B vitamins should not be prescribed for secondary prevention of cardiovascular disease," Bønaa concluded, adding that vitamin B6 and folic acid are sold in high doses in the US but are not as easy to obtain over the counter in Europe.

Dr Ian Graham

Dr Ian Graham (Trinity College Dublin, Ireland), who discussed the implications of NORVIT following its presentation, pointed out that although the trial's power calculations were appropriate, the study may not have been large enough to clearly establish the effects of a folic-acid/B-vitamin combination on CVD risk. Likewise, the study's 2x2 factorial design made it difficult to isolate the effects of folic acid, Graham noted. While the results raise "interesting questions" about the relationship between folic acid and cancer, this relationship is by no means clear and should thus only "signal the need for ongoing surveillance," he said.

Graham concluded, "Although lack of proof of benefit cannot prove no benefit, we cannot advocate the use of B vitamins post MI at this time, and the relationship between homocysteine and vascular disease cannot thus far be established as causal."

Dr Alexander Battler

Commenting on the study for heartwire, Dr Alexander Battler (University of Tel-Aviv, Petach-Tikva, Israel) was reluctant to agree that the homocysteine hypothesis was doomed. "This study enrolled a relatively small group of patients and it shows a certain result, but when you take all the evidence together, you can't say at this stage that the concept is proven or unproven. There may still be something behind it, perhaps particularly for patients with genetically high homocysteine, but we still need larger studies."

Of note, however, no one subgroup in NORVIT appeared to benefit from high-dose B vitamins. Indeed, patients with the highest homocysteine levels at the start of the study were more likely to experience adverse events in the high-dose combination group, as were patients with impaired renal function and patients who reported using other vitamin supplements in addition to the study medication.

The success of failed trials Dr Robert Califf By failing to show that homocysteine lowering can improve cardiovascular risk, NORVIT falls into a category of studies dubbed, by one expert, a highly successful failed trial. In an ESC session yesterday entitled "Cardiovascular clinical trials—close inspection, rear view," Dr Robert Califf (Duke Clinical Research Institute, Durham, NC) paid tribute to trials deemed failures by the sponsor. "The alternative world of failed trials for me is that most failed trials are great successes. From the perspective of patients and healthcare providers, there is no such thing as a failed trial, just additional information that should help make us better." In the case of high-dose vitamin B, some physicians have already been advising patients to take high-dose B vitamins in the hopes that lowering homocysteine levels would decrease their risk of future events; the NORVIT results should discourage such a strategy, Bønaa said. Should further studies corroborate NORVIT, high-dose vitamin B will join the time-honored tradition in cardiology of therapeutic strategies believed to be beneficial, used in patients, then proven harmful, a process also highlighted by Califf and others in yesterday's session. "Cardiology has been the leading specialty in doing clinical trials that fail—this tells us what treatments we shouldn't be giving. I wish more specialties had more failed clinical trials that were honestly reported. It would save a lot of lives and disability!" -SW