American Journal of Kidney Diseases
Volume 51, Issue 4 , Pages 549-553, April 2008

Approaching the End of the Homocysteine Hype?

  • Gere Sunder-Plassmann, MD

      Affiliations

    • Medical University Vienna, Vienna, Austria
    • Corresponding Author InformationAddress correspondence to Gere Sunder-Plassman, MD, Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria.
    • ,
  • Wolfgang C. Winkelmayer, MD, ScD

      Affiliations

    • Harvard Medical School, Boston, Massachusetts
    • ,
  • Manuela Födinger, MD

      Affiliations

    • Medical University Vienna, Vienna, Austria

Article Outline

 

The following is a commentary on Jamison RL, Hartigan P, Kaufman JS, et al: Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease. A randomized controlled trial. JAMA 298:1163-1170, 2007.

Homocysteine is a sulfur-containing amino acid that occupies an important role in 1-carbon metabolism and nucleotide synthesis. Excess homocysteine is exported from the cell and can be measured in plasma. Increased plasma total homocysteine (tHcy) concentration is a sensitive marker of folate and cobalamin deficiency.1 Factors that determine tHcy concentration include genetic, physiological, and lifestyle characteristics, as well as various diseases and drugs. In the era of food fortification with folic acid, cobalamin deficiency and impairment of kidney function are the most important determinants of plasma tHcy levels.

During the last decades, several retrospective and prospective studies showed associations between increased tHcy concentrations and increased rates of cardiovascular (CV) events in the general population.2 However, in patients with chronic kidney disease (CKD), results of prospective studies were inconclusive: some found increased risk of CV outcomes in subjects with greater tHcy concentrations,3 whereas other studies found an inverse association of CV disease (CVD) risk with increasing plasma tHcy concentrations4 or no such associations.5

However, several experimental studies supported the concept of vascular damage induced by homocysteine and provided yet another rationale for intervention studies aimed at decreasing CV risk through a therapeutic decrease in tHcy concentrations.6 Specifically, clinical trials were designed to provide evidence that tHcy-lowering therapy with folic acid and B vitamins may improve CVD outcomes.

In the September 12, 2007, issue of the Journal of the American Medical Association, Jamison et al7 presented such a trial and showed that folic acid, together with vitamin B6 and vitamin B12, failed to decrease mortality and CV outcomes in patients with advanced CKD.7

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What did This Important Study Show? 

In a double-blind, randomized, and controlled multicenter trial (the Homocysteine Study), 2,056 patients aged 21 or older (98% men) from 36 US Department of Veterans Affairs medical centers who had advanced CKD (stages 4, 5, and 5D) and increased tHcy concentrations (>15 μmol/L) were randomly assigned to receive either a daily capsule containing 40 mg of folic acid, 100 mg of pyridoxine hydrochloride (vitamin B6), and 2 mg of cyanocobalamin (vitamin B12) or placebo.7 Recruitment for the study lasted from September 2001 to October 2003, and median follow-up was 3.2 years. A total of 1,024 patients (379 patients with CKD stage 5D, 645 patients with stage CKD 4 or 5) were assigned to placebo, and 1,032 patients (372 patients with CKD stage 5D, 660 patients with CKD stage 4 or 5) were randomly assigned to the vitamin intervention arm.

Sample size calculation for that study was based on an estimated 3-year mortality rate of 28% and adjusted for a 7% loss to follow-up. In a population initially supposed to be composed of 78% patients with CKD stage 4 or 5 and 22% patients with CKD stage 5D, 2,006 patients were needed to detect a postulated 17% decrease in all-cause mortality (from 27.9% to 23.2% at 3 years) with statistical power of 80%. Prespecified secondary outcomes included myocardial infarction, stroke, amputation, a composite of death and the 3 aforementioned outcomes, plasma tHcy concentrations at 3 months after treatment, and thrombosis of a vascular access in dialysis patients.8 In the published analysis, the investigators also assessed time to initiation of dialysis therapy in patients with CKD stage 4 or 5, not a prespecified end point.

In May 2006, the Data and Safety Monitoring Board recommended that the study be stopped because the required number of primary end points had been reached. At 3 months, a significant 26% decrease in plasma tHcy concentrations was observed in the intervention group (−0.8 mg/L [−6.2 μmol/L], from 3.2 ± 1.0 mg/L [24 ± 7.7 μmol/L] at baseline), whereas no significant change was present in the placebo group (−0.05 mg/L [−0.4 μmol/L], from 3.3 ± 1.3 mg/L [24.2 ± 9.8 μmol/L] at baseline). In contrast to the tHcy-lowering effect of high-dose folic acid and B vitamins, there was no effect of treatment on the primary study end point, all-cause mortality (hazard ratio, 1.04; 95% confidence interval [CI], 0.91 to 1.18). Overall, there were 884 deaths: 448 (43.4%) in the intervention group and 436 (42.6%) in the placebo group, representing an annual mortality rate of 11.8% versus 10.0%, respectively. Hazard ratios with 95% CIs for primary and secondary outcomes are listed in Table 1.

Table 1. Primary and Secondary Outcomes of the Homocysteine Study
No. (%) of Patients With an EventHazard Ratio (95% CI)P
Vitamin Group (n = 1,032)Placebo Group (n = 1,024)
All-cause mortality448 (43)436(43)1.04(0.91-1.18)0.6
Myocardial infarction (fatal and nonfatal)129(13)150(15)0.86(0.67-1.08)0.2
Stroke (fatal and nonfatal)37(4)41(4)0.90(0.58-1.40)0.6
Amputation60(6)53(5)1.14(0.79-1.64)0.5
Composite523(51)525(51)0.99(0.88-1.12)0.9
Dialysis in CKD stage 4 or 5365(55)340(53)1.07(0.92-1.24)0.4
Access thrombosis in CKD stage 5D166(24)163(23)1.01(0.81-1.25)0.97

Abbreviation: CKD, chronic kidney disease.

Adapted with permission from Jamison et al.7

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How Does This Study Compare With Prior Studies? 

Several other studies of vitamin intervention on homocysteine concentrations in patients with CKD were completed or are underway. Of note, these studies varied considerably in the composition and dose of the vitamin arms. Regarding this, an important study by Bostom et al9 suggested that increased tHcy plasma concentrations in dialysis patients may respond better to greater doses of folic acid (15 mg/d) and B vitamins than usually prescribed in the non-CKD population. More extreme doses of folic acid (30 or 60 mg) had no additional tHcy-lowering effect compared with 15 mg in dialysis patients enrolled in The Vienna Multicenter Study.10

In northern California, Wrone et al11 randomly assigned 510 patients with CKD stage 5D to receive a multivitamin together with different doses of folic acid, but a placebo group was not included. During a median follow-up of 2 years, patients randomly assigned to receive 5 or 15 mg/d of folic acid experienced similar rates of mortality, CV events, and access thrombosis compared with those who received 1 mg of folic acid.11

The Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in Chronic Renal Failure12 randomly assigned 315 patients (CKD stages 4, 5, and 5D) to 15 mg of folic acid or placebo and failed to show an effect on progression of carotid artery intima-media thickness (difference, 0.01 mm/y; CI, −0.01 to 0.03; P = 0.4) or the incidence of CV events (hazard ratio, 0.98; 95% CI, 0.66 to 1.47) after a median observation time of 3.6 years.12

Most recently, Mann et al13 presented data from a secondary analysis of the Heart Outcomes Prevention Evaluation (HOPE)-2 trial. In that trial, 5,522 high-risk patients were randomly assigned to receive a daily combination pill containing folic acid, 2.5 mg; vitamin B6, 50 mg; and vitamin B12, 1 mg or placebo. In 3,310 patients randomly selected from the full study population, serum samples were collected and serum creatinine was measured in a central laboratory. A total of 619 patients had an estimated glomerular filtration rate less than 60 mL/min/1.73 m2 (<1 mL/s/1.73 m2) and were included in this post hoc analysis. After a median observation time of 5 years, active treatment did not decrease the risk of the primary outcome (composite of death from CVD, myocardial infarction, and stroke; relative risk, 1.19; 95% CI, 0.88 to 1.61; P = 0.2), but increased the risk of hospitalization for heart failure (relative risk, 1.98; 95% CI, 1.21 to 3.26; P = 0.007) or unstable angina (relative risk, 1.70; 95% CI, 1.02 to 2.83; P = 0.04).13

Enrollment for some other large tHcy-lowering studies (Folic Acid for Vascular Outcome Reduction In Transplantation [FAVORIT] trial study population, 4,000 kidney transplant recipients14); the Prospective Intervention Study from Magdeburg With Vitamins (PRISMAVIT) trial (study population, 650 patients with CKD stage 5D; Jutta Dierkes, Germany, personal communication, October 2007); the Vitamins To Prevent Stroke (VITATOPS) trial (study population, 8,000 patients with cerebrovascular disease15); the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH; study population, 12,064 myocardial infarction survivors16) was completed recently, and their results are being awaited with interest.

Until now, only 1 study in the general population suggested a beneficial effect of folic acid and vitamin intervention on CVD outcomes (Table 2). All other studies showed no such effect or even worse outcomes in the intervention group. Thus, the lack of effect of tHcy-lowering therapies in the general population (Table 2), as well as the negative results of the hitherto published studies in patients with CKD, do not suggest that the yet uncompleted studies will show a major effect of tHcy-lowering interventions on CVD outcomes.

Table 2. Results of Total Homocysteine–Lowering Trials in the General Population
Study, Reference, Journal, YearNo. of PatientsOutcomeTrial DurationRisk/Hazard Ratio (95% confidence interval)
IMPROVEMENT WITH INTERVENTION
Swiss Heart Study,17N Engl J Med, 2001205Coronary restenosis after PTCA6 mo0.52(0.32-0.86)
Swiss Heart Study,18JAMA, 2002553MACE after PTCA1 y0.68(0.48-0.96)
FACIT,19Lancet, 2007⁎818Memory (change in z score)3 y0.132(0.032-0.233)
NO EFFECT OF INTERVENTION
Liem et al,20J Am Coll Cardiol, 2003593Mortality & CVD events2 y1.05(0.63-1.75)
VISP,21JAMA, 20043,680Recurrent stroke2 y1.0(0.8-1.1)
McMahon et al,22N Engl J Med, 2006276Cognitive function (combined score)2 y−0.11(−0.2-0)
HOPE-2,23N Engl J Med, 20065,522CVD death, MI, stroke5 y0.95(0.84-1.07)
HOPE-2,24Ann Intern Med, 2007†5,522Venous thromboembolism5 y1.01(0.66-1.53)
VITRO,25Blood, 2007701Recurrent venous thromboembolism2.5 y0.84(0.56-1.26)
WORSE OUTCOME WITH INTERVENTION
Lange et al,26N Engl J Med, 2004636In-stent restenosis6 mo1.30(1.00-1.69)
NORVIT,27N Engl J Med, 20063,749MACE after MI40 mo1.22(1.00-1.50)

Abbreviations: PTCA, percutaneous transluminal coronary angioplasty; MACE, major adverse cardiovascular events; CVD, cardiovascular disease; MI, myocardial infarction; CVD, cardiovascular disease; FACIT, Folic Acid and Carotid-Intima-media Thickness trial; VISP, Vitamin Intervention for Stroke Prevention; HOPE, Heart Outcomes Prevention Evaluation; VITRO, Vitamins and Thrombosis study; NORVIT, Norwegian Vitamin trial.

⁎Secondary analysis, primary results not reported.

†Secondary analysis.

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What Should Clinicians and Researchers do? 

From the clinical point of view, tHcy-lowering therapy can be considered to have no major effect on important CVD or kidney disease outcomes. Nevertheless, some experts in the field have claimed that one should not yet abandon the Hcy pathway for potential interventions aimed at curbing CV risk.4 Our recommendation is more conservative. Folic acid alone can mask the megaloblastic anemia caused by cobalamin deficiency and thereby permit neurological dysfunction to develop and sometimes become irreversible.28 In addition, some of the aforementioned tHcy-lowering trials in the general population, as well as in patients with CKD, even showed an increased risk of CV outcomes in patients treated with folic acid and B vitamins compared with those administered placebo (Table 2 and13). We therefore do not support the opinion that decreasing homocysteine concentrations in patients with CKD is important even in the absence of trials showing the benefit of such intervention.

In summary, at present, no evidence is available that supports the concept of tHcy-lowering intervention with folic acid and B vitamins to improve CVD outcomes in the general population or patients with CKD. The study of Jamison et al7 is yet another contribution to the growing number of large randomized intervention trials that failed to show improved outcomes in patients with CKD.29, 30, 31, 32, 33, 34, 35 Thus, prevention of CKD per se moves to center stage and should have top priority on the research agenda.

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Acknowledgements 

Support: None.

Financial Disclosure: None.

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References 

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PII: S0272-6386(08)00044-9

doi:10.1053/j.ajkd.2008.01.007

American Journal of Kidney Diseases
Volume 51, Issue 4 , Pages 549-553, April 2008

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