Heart Outcomes Prevention Evaluation (HOPE) 2 -- Homocysteine Lowering in Stable Chronic Vascular Disease

Linda Brookes, MSc

Disclosures

July 20, 2006

Editorial Collaboration

Medscape &

Presenter: Eva M. Lonn, MD, MSc (McMaster University, Hamilton, Ontario, Canada)

Elevated blood homocysteine levels appear to be an independent marker of cardiovascular risk, but whether taking vitamins to reduce homocysteine concentrations translates into cardiovascular benefit has remained controversial. Now, 2 studies have cast further doubt on whether lowering homocysteine levels has any cardiovascular benefit at all.

The results of the Heart Outcomes Prevention Evaluation (HOPE-2) study, presented at the American College of Cardiology 55th Annual Scientific Session, showed that combined daily administration of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 for 5 years had no beneficial effects on major vascular events in a high-risk vascular disease population.[1] The HOPE-2 study was published online in The New England Journal of Medicine[2] simultaneously with the Norwegian Vitamin Trial (NORVIT), which explored the benefits of folic acid along with vitamins B6 and B12 supplementation in patients enrolled within 7 days of an acute myocardial infarction (MI). Concordant with the HOPE-2 results, the NORVIT investigators concluded that B vitamin treatment did not lower the risk of recurrent cardiovascular disease or death in these patients and found effects suggesting that this therapy might even be harmful after acute MI or coronary stenting.[3]

Background

Numerous experimental studies have shown that homocysteine increases oxidative stress, causes endothelial dysfunction and vascular injury, and enhances thrombogenicity. They have also demonstrated that there is an independent and graded association between homocysteine and cardiovascular risk. Epidemiologic studies suggest that mild-to-moderate elevations in plasma homocysteine concentrations are associated with increased risk of atherothrombotic cardiovascular disease. Simple, inexpensive, and nontoxic therapy with folic acid and vitamins B6 and B12 reduces plasma homocysteine levels by 25% to 30%. The HOPE-2 study was conducted to evaluate this therapy in patients at high risk for cardiovascular events by determining whether reducing homocysteine levels would reduce the long-term risk of MI, stroke, or death. HOPE-2 was the largest trial worldwide completed to date to measure clinical events associated with a reduction of homocysteine levels following treatment with folate and other B vitamins.

Patients and Treatment

HOPE-2 was a double-blind, placebo-controlled trial enrolling 5522 patients from 145 medical centers in 13 countries in North and South America and Europe between January and December 2000. Patients were men or women aged ≥ 55 years with chronic stable vascular disease (coronary, cerebrovascular, or peripheral vascular) or diabetes with ≥ 1 additional risk factor(s) for atherosclerosis.[4] Background folate fortification was an important enrollment difference between the countries:

  • ~70% of the study patients were enrolled in Canada and the United States, both of which have mandatory folate fortification of food

  • ~30% of patients were enrolled from countries in Western Europe, Slovakia, and Brazil, which do not have mandatory folate fortification of food.

The majority of patients (70%) were men, mean age was 69 years, 85% had a history of coronary artery disease, 15% had previous stroke or transient ischemic attack, 55% had hypertension, 40% had diabetes, 64% had dyslipidemia, and 10% reported current smoking. Mean blood pressure at baseline was 139/77 mm Hg. Most of the patients were overweight or obese, but their lipid levels were well controlled. Most were taking appropriate pharmacologic secondary-prevention interventions, including aspirin or antiplatelet drugs, beta-blockers, lipid-lowering drugs, and angiotensin-converting enzyme (ACE) inhibitors.

Patients were randomized to a single combination pill consisting of folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg once daily or to matching placebo, and were followed for 5 years.

Effects on Homocysteine Levels

At baseline, mean total homocysteine concentration was 12.2 micromol/L (1.6 mg/L) in both groups and differed by geographical region, with participants from countries without folate fortification having higher homocysteine and lower folate levels. By 2 years, homocysteine levels had decreased in the active treatment group, but had risen in the placebo group. Thereafter, levels remained almost constant and at study end were 12.9 micromol/L (1.7 mg/L) in the active treatment group vs 13.2 micromol/L (1.8 mg/L) in the placebo group, a difference of 3.2 micromol/L (0.4 mg/L).

Primary Outcome

No effect of supplementation with folic acid and vitamins B6 and B12 was seen on the primary study outcome, a composite of cardiovascular death, MI, and stroke, compared with placebo (Table 1). Fewer patients in the active treatment group had a stroke, but there were no differences between groups with regard to the other components of the primary composite outcome, or with respect to deaths from any cause.

Table 1. Primary Outcome and All-Cause Death
Active Group
(n = 2758)
Placebo Group
(n = 2764)
RR 95% CI P
Cardiovascular death,
MI, stroke (%)
18.8 19.8 0.95 0.84-1.07 .41
Cardiovascular death (%) 10.0 10.5 0.96 0.81-1.12 .59
MI (%) 12.4 12.6 0.98 0.85-1.14 .82
Stroke (%) 4.0 5.3 0.75 0.59-0.97 .03
All-cause death (%) 17.0 17.2 0.99 0.88-1.13 .94
CI = confidence interval; MI = myocardial infarction; RR = relative risk

Prespecified subgroup analysis showed no difference in treatment effects by gender, age, fortified/nonfortified regions, homocysteine levels (including levels as high as ≥ 19.7 micromol/L/2.7 mg/L), creatinine levels, baseline risk levels, or use of aspirin, cholesterol-lowering drugs, or ACE inhibitors.

Secondary Outcomes

Secondary outcomes -- including total ischemic events (a composite of death from cardiovascular causes, MI, stroke, unstable angina, and revascularization), hospitalization for heart failure, and need for revascularization -- were unaffected by active treatment (Table 2). The rate of hospitalization for unstable angina was increased by 24% in the active treatment group compared with the placebo group.

Table 2. Secondary Outcomes: Cardiovascular
Active Group
(n = 2758)
Placebo Group
(n = 2764)
RR 95% CI P
Total ischemic events (%) 32.6 32.2 1.03 0.94-1.13 .37
Unstable angina (%) 9.7 7.9 1.24 1.04-1.49 .02
Heart failure (%) 7.3 6.3 1.18 0.96-1.44 .12
Revascularization (%) 16.6 15.3 1.10 0.96-1.26 .16
CI = confidence interval; RR = relative risk
Other Outcomes

There were no differences between the 2 groups with regard to incidence of cancer or deaths due to cancer, nor were any differences seen in the incidence of transient ischemic attacks, venous thromboembolic events, or fractures between the 2 groups (Table 3).

Table 3. Other Outcomes (%)
Active Group
(n = 2758)
Placebo Group
(n = 2764)
RR 95% CI P
Transient ischemic attack 4.7 4.3 1.11 0.87-1.42 0.42
Venous thromboembolism 1.3 1.4 0.96 0.61-1.50 0.86
Fracture 8.9 8.5 1.06 0.88-1.26 0.55
CI = confidence interval; RR = relative risk
Conclusions

This study of folic acid in conjunction with vitamins B6/B12 supplementation should be regarded as neutral, rather than negative, Dr. Lonn stressed. She suggested that one of the reasons for the neutral findings of the study may be that the strength of the association between homocysteine and cardiovascular risk based on retrospective and cross-sectional studies has been overestimated. "This highlights once again that epidemiology sends very important signals, as does basic science, which is quite strong for homocysteine, but to treat patients we actually need randomized trials," she stressed.

The nominal beneficial effect on stroke and an apparently potentially harmful effect on unstable angina seen in HOPE-2 need to be interpreted with caution in the light of the overall neutral effect on the primary or other endpoints, she emphasized, noting that neither the Vitamin Intervention for Stroke Prevention (VISP)[5] nor the NORVIT trial (reviewed next) showed a harmful effect on coronary heart disease or a beneficial effect on stroke. Dr. Lonn recommends that the effect on stroke should be further explored in patients living in regions without mandatory folate food fortification.

NORVIT

The NORVIT trial was a multicenter, prospective, randomized, double-blind, placebo-controlled evaluation of B vitamin therapy in patients with acute MI in Norway. (Norway does not have mandatory folate fortification of food.) The trial included 3749 men and women who had had an acute MI within 7 days before randomization. Patients were randomly assigned, in a 2 x 2 factorial design, to receive 1 of 4 daily treatments:

  1. Folic acid 0.8 mg, vitamin B12 0.4 mg, and vitamin B6 40 mg;

  2. Folic acid 0.8 mg and vitamin B12 0.4 mg;

  3. Vitamin B6 40 mg; or

  4. Placebo.

During a median follow-up of 40 months, the mean total homocysteine level was lowered by 27% among patients given folic acid plus vitamin B12, but such treatment had no significant effect on the primary study endpoint, a composite of recurrent MI, stroke, and sudden death due to coronary artery disease (RR 1.08; 95% CI, 0.93-1.25; P = .31). Treatment with vitamin B6 was not associated with any significant benefit, but in the group given folic acid, vitamin B12, and vitamin B6, there was a trend toward an increased risk (RR 1.22; 95% CI, 1.00-1.50; P = .05).

Implications for Homocysteine Lowering

In an editorial accompanying publication of the HOPE-2 homocysteine study and NORVIT in The New England Journal of Medicine,[6] Joseph Loscalzo, MD, PhD (Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts), says that the consistency among the results of VISP, HOPE-2, and NORVIT "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 results also raise the question as to whether the failure of homocysteine-lowering therapy to reduce the rates of cardiovascular events suggests that the homocysteine hypothesis is incorrect, and if so, whether homocysteine may be a surrogate for another, related atherogenic factor. Dr. Loscalzo notes the abundant evidence "in vitro and in vivo that homocysteine is an atherogenic determinant that promotes oxidant stress, inflammation, thrombosis, endothelial dysfunction, and cell proliferation." Second, if homocysteine is an atherogenic determinant, vitamin therapy might have other, potentially adverse effects that offset its homocysteine-lowering benefit. Dr. Loscalzo suggests 3 mechanisms by which this might be possible:

  1. Folic acid might promote cell proliferation in the atherosclerotic plaque.

  2. Use of folic acid and vitamin B12 in the setting of mild hyperhomocysteinemia might alter the methylation potential in vascular cells, resulting in a change in the cell phenotype that promotes the development of plaque.

  3. By increasing the methylation potential, treatment with folic acid and vitamin B12 might increase the concentration of asymmetric dimethylarginine, which inhibits nitric oxide synthase and is associated with an increased risk of 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," Dr. Loscalzo believes. He urges further exploration of the relations among the intermediates in this metabolic pathway and their association with atherothrombotic mediators and suggests that, in the meantime, alternative approaches to reducing homocysteine concentrations, such as enhancing the conversion of homocysteine to cysteine in the liver or enhancing the urinary excretion of the amino acid, should be considered.

Ongoing Trials of Homocysteine Lowering for Prevention of Cardiovascular Disease

Several other clinical trials of the effect of homocysteine lowering on vascular events are still ongoing, and the results are awaited with interest. The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), a multicenter trial being coordinated at the University of Oxford in the United Kingdom, has randomized 12,064 MI survivors in a 2 x 2 factorial design to more intensive vs standard cholesterol-lowering treatment (simvastatin 80 mg or 20 mg daily, respectively) and separately to homocysteine lowering with a daily dose of folic acid 2 mg plus vitamin B12 1 mg or matching placebo.[7] The primary outcome is the incidence of the first major vascular events, defined as nonfatal MI, coronary death, stroke, or arterial revascularization.

The study of VITAmins TO Prevent Stroke (VITATOPS) is a secondary stroke prevention trial being carried out in Australia, Europe, South America, and the United States to determine whether the addition of vitamin supplements (vitamin B12 500 mcg, vitamin B6 25 mg, folate 2 mg) to best medical/surgical management (including modification of risk factors) will reduce the combined incidence of recurrent vascular events (stroke, MI) and vascular death in patients with recent stroke or transient ischemic attack.[8] Patients presenting within 7 months of stroke (ischemic or hemorrhagic) or transient ischemic attack (eye or brain) were randomized in a double-blind fashion to receive multivitamins or matching placebo as 1 tablet daily. The primary outcome event is the composite event of stroke, MI, or death from any vascular cause, whichever occurs first. VITATOPS aimed to recruit and follow up on 8000 patients.

References
  1. Lonn EM, Yusuf S; The HOPE-2 Investigators. Homocysteine lowering in stable chronic vascular disease: The Heart Outcomes Prevention Evaluation (HOPE-2 trial). Program and abstracts from the American College of Cardiology 55th Annual Scientific Session. Late-Breaking Clinical Trials II. Abstract 411-6.

  2. The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354. Published online before print on March 12, 2006

  3. Bønaa KH, Njølstad I, Ueland PM, et al; for the NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006;354. Published online before print on March 12, 2006

  4. Lonn E; The HOPE-2 Investigators. Rationale, design and baseline characteristics of a large, simple, randomized trial of combined folic acid and vitamins B6 and ± 2 in high-risk patients: The Heart Outcomes Prevention Evaluation (HOPE)-2 trial. Can J Cardiol. 2006;22:47-53. Abstract

  5. 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. Abstract

  6. Loscalzo J. Homocysteine trials -- Clear outcomes for complex reasons. N Engl J Med. 2006;354. Published online before print on March 12, 2006.

  7. MacMahon M, Kirkpatrick C, Cummings CE, et al. A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH). Nutr Metab Cardiovasc Dis. 2000;10:195-203. Abstract

  8. VITATOPS Trial Study Group. The VITATOPS (Vitamins to Prevent Stroke) Trial: rationale and design of an international, large, simple, randomised trial of homocysteine-lowering multivitamin therapy in patients with recent transient ischaemic attack or stroke. Cerebrovasc Dis. 2002;13:120-126. Abstract

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