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Xin Xu,MD, PhD; Xianhui Qin, MD, PhD; Youbao Li, MD; Danhua Sun, MD; JunWang, MD; Min Liang, MD; BinyanWang, MD, PhD; Yong Huo, MD; Fan Fan Hou, MD, PhD; for the investigators of the Renal Substudy of the China Stroke Primary Prevention Trial (CSPPT)
JAMA Intern Med. doi:10.1001/jamainternmed.2016.4687 Published online August 22, 2016.
Free Full text available today and tomorrow at this link (courtesy JAMA)
Related Editorial in JAMA Int Med
Background
Hyperhomocysteinemia has been linked to vascular disease, albuminuria and CKD in observational studies; but interventional studies have shown no benefit or even harmful effects on renal outcomes. Interestingly, the premise of this study rests on a few things. Firstly, the thermolabile mutation of MTHFR C677T gene which has been linked with hyperhomocysteinemia is very common in China. Secondly, food fortification with folate is not as routine and widespread as in the Western world. This lead to the main CSPPT trial, done in just over 20,000 patients, which reported a beneficial effect of enalapril + folic acid compared to enalapril alone, in 2013.
The renal sub-study (sponsored by Shenzhen AUSA Pharmed Co. Ltd, Shenzhen, China) was aimed to examine the effects of combination of Enalapril and Folic acid with Enalapril alone in slowing down the renal function decline in the CSPPT participants belonging to populations without folic acid fortification. The renal substudy included patients without severe CKD (GFR < 30) at baseline, or with missing GFR, hence 'only' about 15,000 patients.
Methods
CSPPT was a randomized, double bind controlled trial conducted in 32 centers of Jiangsu and Anhui provinces of China from May 2008 to August 2013 with inclusion of patients with age 45 to 75 years and hypertension without history of stroke or congenital or coronary heart disease. The renal sub study included the patients from Jiangsu province and excluded patients with eGFR <30 ml/min/1.73 m2 BSA, or missing GFR.
The trial was conducted in 3 phase,s namely screening where eligibility of participants was assessed with physical examination and laboratory investigations, which was followed by a 3 week run in phase to judge tolerance to Enalapril 10 mg/day with simultaneous genotyping for MTHFR C677T gene. In the treatment phase, participants were randomly assigned to one of the two double-blind treatment groups stratified by MTHFR C677T genotypes. One group received a daily oral dose of one Enalapril-Folic acid tablet and the other group received a daily oral dose of 10 mg Enalapril(10mg).
The primary endpoint was progression of CKD defined as
- a decrease in eGFR of ≥30% and to a level of < 60 mL/min/1.73m2 if the baseline eGFR was ≥60 mL/min/1.73m2,
- or a decrease in eGFR of ≥50% if the baseline eGFR was < 60 mL/min/1.73m2;
- or ESRD
Secondary endpoints were a composite of primary endpoint and all-cause mortality, rapid decline in eGFR and annual rate of relative decline in eGFR.
Intention to treat and per protocol set analyses were done with patients meeting inclusion criteria and the compliant subset respectively. The trial protocol itself is available in the supplementary material
Results
Overall, 15 104 Chinese adults with a mean age of 60 years were recruited; median follow up was 4.4 years.
Table 1 from Xu et al, JAMA INt Med, 2016
There were 164 and 132 primary events in the Enalapril group and the Enalapril–Folic acid group respectively with a 21% risk reduction (OR 0.79; 95%CI, 0.62-1.00) in the latter group.
Table 3 from Xu et al, JAMA Int Med 2016
The secondary outcomes seemed to be in favor of Folic acid treatment group as well.
There was an interesting effect modification: Among the participants with CKD at baseline, folic acid therapy resulted in significant reduction in the risks for the primary event with OR 0.44(CI, 0.26-0.75); but among those without CKD at baseline it made no difference.
Table 4 from Xu et al, JAMA Int Med 2016
The thermolabile mutation of MTHFR C677T gene did not alter the outcomes despite showing biggest reduction in Serum homocysteine levels, in the other subgroup analyses
Figure 1 from Xu et al, JAMA Int Med 2016
Discussion
This study had a more than adequate population size and a good design with demonstration of significant reduction in risk of CKD progression with folic acid treatment
Limitations include:
- The primary outcome was relative soft (30% fall in GFR, and to a level < 60 if baseline > 60; 50% fall to < 30 if GFR 30-60), not the usual doubling of creatinineor GFR < 15/ESRD as is usually reported
- The study population also seemed to be at low risk of progressing
- There was no data on hard outcomes (ESRD)
- the biggest challenge is of its generalizability to a population where folic acid fortification is common.
- Stroke was the only vascular event - apart from CKD in this study to be prevented. If hyperhomocystinemia is the pathway, all vascular disease should potentially benefit?