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NDT Advance Access originally published online on November 14, 2007
Nephrology Dialysis Transplantation 2008 23(2):645-653; doi:10.1093/ndt/gfm485
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease—results of the renal Hope-2 study{dagger}

Johannes F. E. Mann, Patrick Sheridan, Matthew J. McQueen, Claes Held, J. Malcolm O. Arnold, George Fodor, Salim Yusuf, Eva M. Lonn on behalf of the HOPE-2 investigators

Department of Medicine, Munich General Hospitals and KfH Kidney Centre, Munich Germany and Department of Medicine, McMaster University, Hamilton, Ontario, Canada

Correspondence to: J. F. E. Mann, MD, Professor of Medicine, Department of Nephrology & Hypertension, Schwabing General Hospital, Kolner Platz 1, Munchen 80804 Germany. Email: johannes.mann{at}kms.mhn.de



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Acknowledgements
 References
 
Background. Elevated plasma homocysteine levels are reported to be associated with higher rates of vascular diseases. Plasma homocysteine increases in chronic kidney disease (CKD) and could contribute to the increased cardiovascular risk in CKD.

Methods. Participants aged 55 years or older with CKD, defined as estimated GFR<60 ml/min and at high cardiovascular risk, were randomly assigned to the combination of folic acid, 2.5 mg, vitamin B6, 50 mg and vitamin B12, 1 mg (n = 307) or placebo (n = 312) daily for 5 years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction and stroke.

Results. Mean baseline plasma homocysteine was 15.9 ± 7.3 µmol/l in the active treatment group and 15.7 ± 5.7 µmol/l in placebo group and decreased to 11.9 ± 3.3 µmol/l (P < 0.001) on active treatment (15.5 ± 4.5 on placebo). Primary outcome events occurred in 90 participants (29.3%) on active therapy and in 80 (25.6%) on placebo (relative risk, 1.19; 95% confidence interval, 0.88–1.61; P = 0.25). There were no significant treatment benefits on death from cardiovascular causes (1.24; 0.84–1.83), myocardial infarction (1.10; 0.76–1.61) and stroke (1.00; 0.54–1.85). More participants in the active treatment group were hospitalized for heart failure (1.98; 1.21–3.26; P = 0.007) and for unstable angina (1.70; 1.02–2.83; P = 0.04). Incidence of primary outcome increased with decreasing GFR.

Conclusions. Active treatment with B vitamins lowered homocysteine levels in participants with CKD but did not reduce cardiovascular risk.

Keywords: clinical trial; homocysteine; myocardial infarction; stroke



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Acknowledgements
 References
 
People with all stages of chronic kidney disease (CKD) have a markedly elevated risk for cardiovascular disease [1–3] that is especially evident in people with known cardiovascular disease [4]. This risk has been attributed to many potential causes [1,5], including hyperhomocysteinaemia. In experimental studies homocysteine causes oxidative stress, direct endothelial injury and enhanced thrombogenicity [6–8]. Epidemiological studies generally show an independent and graded association between homocysteine and cardiovascular risk [9–13].

In people with CKD, plasma homocysteine levels tend to increase with decreasing glomerular filtration rate (GFR) [14,15] and may reach high levels in end-stage renal disease [16,17]. The relationship between plasma homocysteine and cardiovascular risk with renal insufficiency was mainly investigated in end-stage renal disease; inconsistent associations were reported, in part depending on adjustments for confounding factors such as indices of malnutrition and of inflammation [16–19]. There are few data before the terminal stage of renal insufficiency. Recent reports in people with moderate degrees of renal insufficiency indicate that higher plasma concentrations of homocysteine were not associated with cardiovascular risk after adjusting for GFR [19–21].

Daily supplementation with 0.5–5 mg of folic acid typically lowers plasma homocysteine concentrations by ~25% in people with and without renal insufficiency. Vitamin B12 supplementation of ≥ 0.4 mg/day has additive effects and vitamin B6 supplements may be particularly important in lowering homocysteine post-methionine loading [21–24]. However, several recent prospective trials, without reference to underlying renal disease, excluded a substantial effect of homocysteine lowering with folic acid on cardiovascular outcomes [25]. Two prospective trials examined the effect of folic acid in people with end-stage renal disease with neutral results [26,27]. There are no similar trials in earlier stages of renal insufficiency to our knowledge.

The Heart Outcomes Prevention Evaluation (HOPE)-2 study recently reported that combined treatment with folic acid and vitamins B6 and B12 had no effect on cardiovascular outcomes [28]. In the present post-hoc analysis we tested the hypothesis that the subgroup with moderate renal insufficiency may benefit from B vitamin treatment.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Appendix 1
 Appendix 2
 Acknowledgements
 References
 
Study design
HOPE-2 was a randomized, double-blind, placebo-controlled trial, which evaluated the effects of homocysteine-lowering B vitamins on major vascular events in a high-risk population (n = 5522). The trial design has been described previously [29]. The study was coordinated by the Population Health Research Institute, McMaster University, Canada and sponsored by the Canadian Institute of Health Research. Study drug and matching placebo were provided by Jamieson Laboratories, Canada. The study sponsors were not involved in the design, execution, analysis or reporting of the trial results. An independent Data Safety and Monitoring Board monitored the safety of the study participants and the overall quality and scientific integrity of the study. The study was approved by the ethics review boards of all participating institutions and all participants provided informed written consent.

Study population and intervention
Men and women 55 years or older with a history of vascular disease (coronary, cerebrovascular or peripheral vascular) or diabetes with additional risk factors for atherosclerosis were enrolled, irrespective of their homocysteine levels, from countries with folate food fortification (Canada and USA) and without (Brazil, Western Europe and Slovakia). Participants taking vitamin supplements containing ≥0.2 mg of folic acid were excluded. Detailed eligibility criteria have been published [29]. Participants were not stratified or excluded according to GFR.

In 3310 randomly selected participants of the entire population (n = 5522), blood samples were collected at randomization and serum creatinine was measured centrally at the core laboratory, as well as other parameters (see subsequently). Estimated glomerular filtration rate (eGFR) from the above measurements of serum creatinine was <60 ml/min in 619 participants. The latter population is the basis of the present post-hoc analysis.

Participants were randomly assigned to receive daily a combined pill containing folic acid 2.5 mg, vitamin B6 50 mg and vitamin B 12 1 mg or matching placebo.

Follow-up and laboratory evaluation
Participants were evaluated at six-monthly intervals for assessment of adherence to treatment (by interview and pill count), adverse events and clinical outcomes. Fasting blood samples were collected at randomization, at 2 years and at study end in a randomly selected subset of participants with proportional representation from countries with folate food fortification and without and with expected significant differences in dietary habits.

Plasma folate (Roche chemiluminesence method, Roche Diagnostics, Mannheim, Germany), vitamin B6 (Chromsystems kit, Instruments and Chemicals, GmbH, Munchen, Germany) and vitamin B12 levels (Immulite 2000 Analyzer, Diagnostic Products Corporation, Los Angeles, USA), were measured at randomization and at 2 years. Total plasma homocysteine levels were measured (Abbott IMX immunofluorescence method, Abbott, Missisauga, Canada) at randomization, at 2 years and at study end (average 5 years). Serum creatinine was measured centrally by the Jaffe method at randomization, at 2 years and at study end. GFR was estimated (eGFR) according to the four-variable formula developed from the Modification of Diet in Renal Disease (MDRD) study [30,31] which incorporates serum-creatinine, age, sex and race.

Trial outcomes
The primary study outcome was the composite of death from cardiovascular causes, myocardial infarction and stroke. Secondary outcomes were total ischaemic events (including death from cardiovascular causes, myocardial infarction, stroke, hospitalization for unstable angina and revascularization), total mortality, hospitalization for unstable angina, hospitalization for congestive heart failure, revascularization, cancer incidence and cancer death. Other outcomes included transient ischaemic attacks, venous thromboembolic events and fractures. All primary and secondary outcomes were centrally adjudicated. Detailed definitions of the outcome measures were published previously [28,29].

Statistical analysis
Only data from the original intention-to-treat analysis [28] were used for this report. Baseline characteristics were compared using {chi}2 tests for discrete and t-tests for continuous variables. Time-to-event by group was estimated by Cox regression. Kaplan–Meier curves were used to estimate survival and were compared by log-rank tests. The annual event rate for the primary outcome (myocardial infarction, stroke and cardiovascular death) was 5.5 and 8% for total ischaemic events (all above plus revascularizations and hospitalizations for heart failure or unstable angina), the secondary outcome with the highest event rate. Active treatment lowered plasma homocysteine by 25%; according to observational studies, this lowering can be associated with a reduction in major cardiovascular events by 30% [9–11]. On the basis of 619 participants the power to detect a 30% relative reduction in the primary outcome and in total ischaemic events by active treatment was 73% and 93%, respectively, based on an alpha level of 0.05 for a one-sided test. All analyses were done using SAS 8.2 for Unix.



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Appendix 1
 Appendix 2
 Acknowledgements
 References
 
Characteristics of the participants
Six hundred and nineteen participants with eGFR <60 ml/min were recruited from January to December 2000 at 145 centres in 13 countries; and were followed up for a median 5 years; mean serum creatinine was 129.1 ± 38.0 umol/l. Of these, 307 were randomly assigned to active treatment and 312 to placebo. Baseline characteristics are shown in Tables 1 and 2 and were well balanced between the study groups.


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  		Table 1. Baseline characteristics of the participants: clinical data

 

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  		Table 2. Baseline characteristics of the participants: physical exam and laboratory data

 
Participants with renal insufficiency differed in several baseline characteristics from participants without renal insufficiency (Tables 1 and 2). The former were older, more likely to be female, had a higher baseline prevalence of hypertension, diabetes, peripheral vascular disease, cerebrovascular disease, use of antihypertensive agents, of insulin and a lower use of antiplatelet agents. Systolic blood pressure was not different while diastolic was lower. Serum levels of homocysteine, vitamin B6, triglycerides and CRP were higher and levels of HDL lower in those with renal insufficiency.

Adherence, adverse events and follow-up
Among those assigned to the active treatment group 96.2, 94.1 and 91.2% were taking the study drug at 1, 3 and 5 years, respectively. Comparable figures for the placebo group were 97.3, 93.0 and 88.1%. There were no serious adverse events related to study treatment. Median follow-up was 5 years; vital status was ascertained at study end in all but one participant.

Effects on vitamin and homocysteine levels
At 2 years post-randomization, plasma homocysteine decreased while plasma folate and vitamin B12 levels increased in the active treatment group with no significant changes in the placebo group (Table 3). Baseline levels were not different with lower folate and higher homocysteine levels in participants from non-fortified regions (data not shown; 90/619 participants were recruited in regions with no folate food fortification).


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  		Table 3. Plasma concentrations of homocysteine, at baseline, at 2 years and at 5 years, and of folate, vitamin B6 and B12 at baseline and at 2 years in participants with renal insufficiency

 
Primary outcomes and deaths from any causes
In the active treatment group 90/307 participants (29.3%) had a primary outcome compared with 80/312 (25.7%) in the placebo group (relative risk, 1.19; 95% confidence interval, 0.88–1.61; P = 0.25) (Figure 1 and Table 4). There was no significant difference in any of the components of the primary composite outcome (Table 4) and no difference in total mortality (relative risk 1.20, 95% confidence interval, 0.88–1.63; P = 0.26).


Figure 1
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  		Fig. 1. Composite primary endpoint: Kaplan–Meier estimates of the proportion of participants with renal insufficiency with the composite primary outcome in the active vitamin treatment group and the placebo group. The relative risk of the composite primary outcome in the active vitamin treatment group as compared with the placebo group was 1.19 (95% confidence interval, 0.88–1.61).

 

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  		Table 4. Outcomes in participants with renal insufficiency

 
Secondary and other outcomes
Among the pre-specified cardiovascular secondary outcomes, hospitalization for heart failure occurred in 44 (14.3%) vs 24 participants (7.7%) in the active and placebo treatment groups, respectively (relative risk 1.98, 95% confidence interval 1.21–3.26; P = 0.007) (Figure 2). Hospitalization for unstable angina was also more frequent in the active treatment group (relative risk 1.70; 95% confidence interval 1.02–2.83, P = 0.043).


Figure 2
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  		Fig. 2. Hospitalization for heart failure. Kaplan–Meier estimates of the proportion of participants with renal insufficiency with heart failure in the active vitamin treatment group and the placebo group. The relative risk of hospitalization for heart failure in the active vitamin treatment group as compared with the placebo group was 1.98 (95% confidence interval, 1.21–3.26).

 
Any ischaemic event occurred in 126 (41.0%) participants in the active treatment group and in 128 (41.0%) in the placebo group (relative risk 1.04, 95% confidence interval, 0.82–1.33; P = 0.74) (Table 4). There were no significant differences between the treatment groups in rates of revascularization, transient ischaemic attack, venous thromboembolism, fracture or incident cancers and cancer deaths (Table 4).

Associations between homocysteine levels and cardiovascular risk in participants with renal insufficiency
Increasing levels of baseline plasma homocysteine were associated with a higher risk of the primary outcome in univariate analysis (relative risk 1.015, 95% confidence interval 0.999–1.030, P = 0.0642) and after adjusting for age, sex and treatment assignment (relative risk 1.017, 95% confidence interval 1.000–1.033, P = 0.0480) but not in multivariate analysis adjusting for age, sex, treatment assignment and the classical cardiovascular risk factors (smoking, hypertension, diabetes mellitus), previous cardiovascular disease and eGFR (relative risk 1.011, 95% confidence interval 0.991–1.032, P = 0.278) and also not after adjusting only for eGFR (relative risk 1.008; 95% confidence interval 0.989–1.027, P = 0.400).

Analysis of renal insufficiency as a risk indicator
When analysing all participants with measured serum creatinine at baseline (n = 3310), eGFR emerged as a strong predictor of risk (Figure 3). From the quintile with the highest to the quintiles with the lowest eGFR, the incidence of the primary event increased continuously from 14.0 to 26.4% (P < 0.001) and similarly for other major outcomes (P < 0.001 for CV death, stroke and total mortality).


Figure 3
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  		Fig. 3. Relationship of GFR at baseline (quintiles) with the incidence of the primary outcome (black bars), with cardiovascular death (white bars) and with total mortality (grey bars). P for trend was significant for all three outcomes with P < 0.0001. The ordinate indicates the event incidence in percentage for the trial duration. eGFR ranges of the respective quintiles: ≥90.46; 80.14–90.45; 80.13–71.38; 60.78–71.37; < 60.78 ml/min.

 
The incidence of all major outcomes was much higher in participants with renal insufficiency as compared with those without (Table 5). In multivariate analysis (Table 6), renal insufficiency remained strongly associated with the primary outcome (relative risk 1.436, 95% confidence interval 1.182–1.746, P = 0.0003), as well as plasma homocysteine (relative risk 1.018, 95% confidence interval 1.006–1.030, P = 0.0029). Separate multivariate analyses on myocardial infarction, on stroke, on cardiovascular death and on heart failure hospitalization yielded similar hazard ratios as for the primary outcome (data not shown).


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  		Table 5. Number of outcomes and event rates (in brackets) in participants with and without renal insufficiency

 

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  		Table 6. Multivariate analysis of factors that independently and significantly (P < 0.05) predict the primary outcome (cardiovascular death, myocardial infarction or stroke) in all participants with eGFR measurement (N = 3310)

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Appendix 1
 Appendix 2
 Acknowledgements
 References
 
Despite ample evidence that plasma homocysteine concentration increases with decreasing GFR [14–20] there have been few studies investigating the relationship between plasma homocysteine concentration and cardiovascular disease or mortality in people with moderate renal insufficiency i.e. stages 3–4 of CKD, defined by a GFR of 15–60 ml/min. Plasma homocysteine was not significantly associated with cardiovascular outcomes or mortality in our cohort of 619 people with moderate renal insufficiency and at high cardiovascular risk. In unadjusted analysis there was a modest effect of homocysteine—a 1–2% risk change for a 1 µmol/l change of plasma homocysteine—which was, however, not significant when adjusted for further variables. The effect of homocysteine was also no more significant if adjusted only for eGFR. To our knowledge there are only four studies, two of which are in renal transplant patients that have investigated the relationship between plasma homocysteine and ‘hard’ outcomes in pre-end-stage renal disease [20,33–35]. Data from the MDRD trial [20], involving 804 people with a GFR of 13–55 ml/min (mean 33), found no association of plasma homocysteine with fatal outcomes when adjusted for GFR. Non-fatal events were not recorded but the study exhibited a very long follow-up (mean 10 years) and an exact measurement of GFR. Two further prospective observational studies in 773 and in 227 people with a renal transplant described a positive relationship between plasma homocysteine and cardiovascular outcomes and mortality after adjustment for GFR or for serum creatinine [34,35]. Similar positive findings were reported by Jungers et al. [33] in a small cohort of 93 people with a GFR between 20–55 ml/min. Thus the findings of the renal HOPE-2 study support the notion that there is a weak relationship between plasma homocysteine levels and cardiovascular risk also in people with CKD stages 3–4. The latter relationship may, however, be fully explained by other cardiovascular risk factors and by eGFR.

Others [20] have alluded to the fact that many observational studies on plasma homocysteine as a risk factor for cardiovascular outcomes did not adjust for renal function [9]. Impaired renal function is a very strong predictor of cardiovascular prognosis [1–5]. The reasons for the latter relationship are unknown and are likely independent of plasma homocysteine [20]. In any event, the data of our and other studies [20] emphasize that analysis of homocysteine as a cardiovascular risk factor must incorporate renal function as a possible confounder. Two often cited meta-analyses that examined the relationship between plasma homocysteine and cardiovascular outcomes did not adjust for renal function [11,13].

In our HOPE-2 cohort with renal insufficiency, daily administration of the combination of folic acid and vitamins B6 and B12 lowered homocysteine levels substantially, but did not reduce the incidence of the primary outcome, the composite of death from cardiovascular causes, myocardial infarction and stroke, during a mean follow-up period of 5 years. All-cause mortality was also not affected by active therapy. Those findings are consistent with the main HOPE-2 results, the Norwegian Vitamin Study in people after myocardial infarction (NORVIT, [36]), the Vitamin Intervention for Stroke Prevention study in people after a stroke (VISP, [37]) and a smaller trial in people with stable coronary heart disease from the Netherlands [38].

Our study cannot definitively exclude a small beneficial effect of folic acid and B vitamins on cardiovascular disease in renal insufficiency. First the sample size of participants with renal insufficiency may lack adequate power to detect a small to modest reduction in risk. Nevertheless such a reduction is unlikely as we did not observe any trends and no benefit was apparent in the overall study population [28]. Second, this is a post-hoc analysis with the limitations of such an analytical approach. Third, our population consisted mainly of Caucasian participants. It has been suggested that lowering of plasma homocysteine may be more effective in Asian cohorts [39]. Fourth, we tested a fixed dose combination of folic acid and vitamins B6 and B12. Fifth, we did not adjust for indices of malnutrition and inflammation such as serum albumin. Such indices confound the association of homocysteine and cardiovascular outcomes in end-stage renal disease [40]. However, such confounding has not been established in moderate renal insufficiency and is unlikely to play a major role in our population with a mean serum creatinine of 130 umol/l. In spite of these limitations, this is by far the largest interventional trial in people with pre-dialysis renal insufficiency that examined the cardiovascular effects of homocysteine lowering by vitamin supplements and the only trial with adequate power to detect substantial effects on major outcomes. Furthermore, the neutral results of HOPE-2 in participants with renal insufficiency are consistent with two similar trials in end-stage renal disease [26,27]. Only one of those trials [27] included a few participants (48 of 315) with pre-dialysis renal insufficiency and a placebo group. The other trial was exclusively done in a dialysis population and did test several doses of folic acid but no placebo [26].

The apparent increase in hospitalization for heart failure and for unstable angina on active treatment is inconsistent with the neutral findings for most other CHD outcomes evaluated and may be related to the difficulty in establishing these diagnoses in people with renal insufficiency or to the play of chance.

In conclusion, the story of homocysteine in renal insufficiency remains puzzling. The interventional data of the present study in people with renal insufficiency do not support preventive treatment with combinations of folic acid and vitamin B6 and B12 at the doses used in HOPE-2 for people with renal insufficiency and high cardiovascular risk.



   Appendix 1
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
Appendix 2
 Acknowledgements
 References
 
HOPE-2 trial investigators and responsibilities see:

Heart Outcomes Prevention Evaluation (HOPE) investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354: 1611–1618.



   Appendix 2
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
Acknowledgements
 References
 

Figure 4



   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Acknowledgements
References
 
The study was supported by a Canadian Institutes of Health Research grant (MT-15418) and by in-kind contributions of Jamieson Laboratories, Canada.

Trial Registration Number: NCT00106886 [ClinicalTrials.gov] (National Institutes of Health Registry); ISRCTN 14017017 (Canadian Institutes of Health Registry).

Conflict of interest statement. None declared.



   Notes
 
{dagger}A full listing of the HOPE-2 Investigators has been published previously (reference 29) Back



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Appendix 1
 Appendix 2
 Acknowledgements
 References
 

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Received for publication: 8. 3.07
Accepted in revised form: 26. 6.07


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