Cardiovascular disease remains the most common cause of morbidity and mortality in persons with CKD. This increased risk along with the high prevalence of hyperhomocysteinemia, the expected infrequency of treatment with supplemental folic acid, and the previously-demonstrated ability to “normalize” tHcy levels in renal transplant recipients with combined folic acid, vitamin B12 and vitamin B6 treatment makes kidney transplant recipients an especially suitable population in which to test the effects of lowering homocysteine.
In order to test this hypothesis we recruited a large sample of stable kidney transplant recipients who are at high risk of CVD. Most of the participants had either Stage 2 or 3 CKD based on the MDRD Study formula. Moreover nearly forty percent had a diagnosis of diabetes, another important risk factor for CVD, exceeding the estimate used in the original power calculation (35%). As expected, a history of cardiovascular disease was more prevalent among the FAVORIT participants with diabetes than among those without diabetes (29% and 13%, respectively). Thus the trial appears to be well poised to accrue a sufficient number of events to address the primary hypothesis of whether homocysteine lowering in stable kidney transplant recipients will significantly reduce arteriosclerotic cardiovascular disease. We are aware of the results of nine tHcy-lowering clinical trials evaluating the potential reduction of cardiovascular disease outcomes among various patient populations 5-13
and none have shown a beneficial effect. However, each of these trials had limitations including failure to normalize tHcy levels, 8, 12, 13
the impact of folic acid fortification in folate “sensitive” non-CKD populations 5, 9, 11
or medication drop-ins who used up to 1 mg/day of folic acid 8
which may have reduced study power.
One recently reported trial of homocysteine lowering in approximately 2,000 ESRD or stage 4 CKD patients, the Homocysteinemia in Kidney and End Stage Renal Disease (HOST) study, reported that even a very high dose B-vitamin regimen for tHcy-lowering (40 mg/day folic acid, 100 mg/day B6, and 2 mg/day B12) failed to reduce crude all-cause mortality during a median of 3.2 years of follow-up. However, there was a trend for fewer myocardial infarctions in the actively treated group compared to placebo. 8
In comparison, a subgroup analysis of participants with CKD (GFR <60 ml/min) in the Heart Outcomes Prevention Evaluation 2 (HOPE-2) Study failed to show a beneficial effect of homocysteine lowering on cardiovascular risk. 14
While the limited or lack of statistical power to detect CVD event rate changes of 20% in the preliminary CKD patient trials, and even the larger HOST trial are clear (see ), we investigated whether the considerably larger non-CKD patient trial cohorts might also have been inadequately powered based on their now reported control event rates. Only two 5, 9
of the five 5-7, 9, 11
large trials completed in predominantly non-renal populations, HOPE-2 9
and Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), 5
remained well-powered (i.e., >=85%) to detect a 20% reduction in CVD events with active treatment, based on the actual control group event rate. None of the trials are well-powered to detect a 10% or 15% reduction in CVD events. Furthermore, the mean tHcy concentration at baseline in HOPE-2 was only 12.1 μmol/L, and was reduced by just 2.4 μmol/L with active treatment. 9
Comparable data from WAFACS reveal an initial level of 12.2 μmol/L, which was only reduced by 2.2 μmol/L with active treatment. 5
In contrast, the Norwegian Vitamin trial (NORVIT) participants had slightly higher baseline tHcy concentrations (13.1 μmol/L), and achieved a greater absolute reduction (3.5 μmol/L), but when the actual control group event rate was considered, the study lacked adequate statistical power to detect a 20% reduction in CVD event rates. 7
The Cambridge Heart Antioxidant Study-2 (CHAOS-2), 6
and to a lesser extent the Vitamin Intervention for Stroke Prevention trial (VISP),11
may have also suffered from the combined effects of these limitations. In contrast, at screening, FAVORIT participants have a mean tHcy level of 17.1 μmol/L in comparison to a range of baseline levels of 11.2-13.4 μmol/L in these recently completed trials of patients without CKD. 5-7, 9, 11
We have previously shown that 15-17
subsequent to chronic exposure to cereal grain flour products fortified with folic acid, long-term kidney transplant recipients with mild hyperhomocysteinemia who were similar to participants enrolled in FAVORIT, still experienced a nearly one-third (5.0-5.5 μmol/L) decrease during treatment with a folic acid, B12, and B6 regimen, and 50% of these participants maintained their tHcy concentrations below 12 μmol/L. A similar reduction in tHcy of 5-6 μmol/L is expected among the FAVORIT participants receiving the high dose multivitamin. Thus, we anticipate that both the higher observed tHcy levels and expected greater impact of tHcy-lowering vitamin therapy may enhance the likelihood of the FAVORIT study showing a reduction of CVD risk compared to previous studies.
The FAVORIT trial has several potential limitations. As we have shown there are important differences in several baseline CVD risk factors by country that could impact the observed event rate. However, these risk factor differences are not in the same direction. For example, among participants in Brazil, mean BMI is lower whereas mean blood pressure is higher than among participants in the U.S. Additionally, the within-country sample sizes are large and this heterogeneity may increase the generalizability of the findings. Many important, albeit tertiary, research questions will be addressed through analyses stratified by country or within the U.S. subgroup. Another limitation of the baseline data is that history of disease was taken from patient report and medical records without verification or classification using standardized definitions as is being done prospectively with the myocardial infarction, stroke, resuscitated sudden death, and cardiovascular death components of the FAVORIT primary endpoint. While this is a limitation for cross-sectional baseline analyses, it will not affect the validity of the primary trial objective. We also acknowledge that renal function is estimated instead of measured GFR. However data are provided based on two well-established prediction equations 21, 28
for comparison with other scientific literature and clinical practice. However, these equations have not been uniformly validated in kidney transplant recipients with stable renal function. Finally, caution should be exercised if generalizing CKD among RTRs to CKD among other patient groups.
FAVORIT has a number of strengths. The sample size of 4,110 chronic stable renal transplant recipients is large. The planned period of follow-up (4.5 to 9 years) is long. This duration of follow-up may detect a lag in treatment effect, a focus not considered in most previous clinical trials. Screening data confirm that baseline tHcy levels are higher than in trials conducted among non-CKD populations. Finally, with the projected FAVORIT event rate for CVD among the control group, the trial appears to be adequately powered to discern even a moderate 20% reduction in events (if achieved) with active tHcy-lowering treatment. Since FAVORIT includes participants with predominantly stage 2 and stage 3 CKD the findings will provide important information on the clinical benefit of tHcy-lowering with B-vitamin therapy among this group and may indicate a low-cost intervention for the general CKD population.