China Stroke Primary Prevention Trial - CSPPT

Contribution To Literature:

The CSPPT trial suggests that oral folic acid supplementation with enalapril may be superior to enalapril alone in the primary prevention of stroke in patients with hypertension.

Description:

The goal of the trial was to assess the efficacy of folic acid supplementation in the primary prevention of stroke in patients with hypertension.

Study Design

Patients were randomized in a 1:1 ratio to receive either a fixed-dose combination of enalapril 10 mg/folic acid 0.8 mg daily (n = 10,348) or enalapril 10 mg daily alone (n = 10,354). They were stratified by MTHFRC677T genotypes (CC, CT, or TT).

Patient population:

  • Total number of enrollees: 20,702
  • Duration of follow-up: 4.5 years
  • Mean patient age: 60 years
  • Percentage female: 59%
  • Percentage diabetics: 3%
  • Current smokers: 23%
  • Homocysteine levels: 12.5 micromol/L
  • Vitamin B12: 379 pg/ml; vitamin B12 deficiency: 1.5%
  • MTHFRC677T polymorphisms: CC 27.3%, CT 49.2%, TT 23.5%

Inclusion criteria:

  • Age 45-75 years
  • Ambulatory hypertension
  • Adherent and tolerant of enalapril

Exclusion criteria:

  • History of physician-diagnosed stroke, myocardial infarction, heart failure, coronary revascularization, or congenital heart disease

Principal Findings:

This trial was terminated early due to significant benefit. The primary outcome, first stroke, for enalapril/folic acid vs. enalapril: 2.7% vs. 3.4%, hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.68-0.93; p = 0.003; number needed to treat (NNT) = 141. The strongest benefit was observed in patients with lower baseline folate levels (<5.6 ng/ml) (2.8% vs. 4.6%, HR 0.61), especially in patients with CC and CT genotype.

Secondary outcomes:

  • Ischemic stroke: 2.2% vs. 2.8%, p = 0.002
  • Hemorrhagic stroke: 0.56% vs. 0.6%, p = 0.71
  • Cardiovascular death/myocardial infarction (MI)/stroke: 3.1% vs. 3.9%, p = 0.002
  • MI: 0.24% vs. 0.23%, p = 0.89

Renal outcomes: Progression to chronic kidney disease (CKD) for enalapril/folic acid vs. enalapril: 2.1% vs. 2.5%, HR 0.81, 95% CI 0.64-1.02. Rapid decline in glomerular filtration rate (GFR): 6.1% vs. 6.6%, HR 0.92, 95% CI 0.8-1.06; annual decline in GFR: 1.28 vs. 1.42%, p = 0.02.

Interpretation:

The results of this trial indicate that oral folic acid supplementation with enalapril is superior to enalapril alone in the primary prevention of stroke in patients with hypertension. Although this trial was conducted in a Chinese population, this is a landmark finding that may change clinical practice globally. These results may be especially pertinent in countries/areas were fortification of food with folic acid is not a common practice, and where baseline folate levels are low. Earlier trials with folate supplementation have shown mostly negative results, but that may be partially explained by the fact that they typically included patients with existing cardiovascular disease, and were conducted in areas where baseline folate levels are higher (such as in the United States).

The effect on progression to CKD was marginal, and may at least partially be related to better hypertension control.

References:

Xu X, Qin X, Li Y, et al., on behalf of the Investigators of the Renal Substudy of the China Stroke Primary Prevention Trial (CSPPT). Efficacy of Folic Acid Therapy on the Progression of Chronic Kidney Disease: The Renal Substudy of the China Stroke Primary Prevention Trial. JAMA Intern Med 2016;176:1443-50.

Huo Y, Li J, Qin X, et al., on behalf of the CSPPT Investigators. Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in China: The CSPPT Randomized Clinical Trial. JAMA 2015;313:1325-35.

Editorial Comment: Stampfer M, Willett W. Folate Supplements for Stroke Prevention: Targeted Trial Trumps the Rest. JAMA 2015;313:1321-2.

Clinical Topics: Prevention, Hypertension

Keywords: ACC Annual Scientific Session, Primary Prevention, Stroke, Folic Acid, Enalapril, Hypertension, Myocardial Infarction, Genotype, China, Kidney Failure, Chronic


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