China Stroke Primary Prevention Trial

Condition(s) targeted: Primary Hypertension

Intervention: Enalapril/folic acid (Drug); Enalapril maleate (Drug)

Phase: Phase 4

Status: Completed

Sponsored by: Shenzhen Ausa Pharmed Co.,Ltd

Official(s) and/or principal investigator(s):
Yong Huo, M.D., Principal Investigator, Affiliation: The First Hospital, Beijing University

The purpose of this trial is to confirm that enalapril maleate and folic acid tablets is more effective in preventing stroke among the patients with primary hypertension when compared to enalapril maleate.

Official title: Enalapril Maleate and Folic Acid Tablets for Primary Prevention of Stroke in Patients With Hypertension: a Post-marketing, Double-blind, Randomized Controlled Trial.

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Primary outcome: First attack of symptomatic stroke ( ischemic or hemorrhagic)

Secondary outcome:

Composite major cardiovascular events

All-cause death

First attack of ischemic stroke and resultant death

First attack of hemorrhagic stroke and resultant death

Myocardial infarction and resultant death

Detailed description: Primary hypertension is the most important risk factor leading to cardiovascular events. Successful management of hypertension is a key to prevent these events. Hyperhomocysteinemia (HHcy) is another independent risk factor, especially for stroke. Our team's prospective nested case-control study of 39165 subjects in China showed that incidence of cardiovascular events (especially stroke) was strongly associated with plasma level of total homocysteine (tHcy). The coexistence of hypertension and HHcy dramatically increased the risk of stroke by 25 to 30 times as compared to the subjects without the two risk factors (Graham et al, 1997). Findings from previous and our studies clearly indicate that simultaneous control of hypertension and HHcy is pivotal in reducing cardiovascular events morbidity and mortality in China. It has been well documented that folic acid is effective in lowering the level of plasma tHcy. While controversial remains on its efficacy on preventing cardiovascular events, a study done by our team: "Efficacy of folic acid supplementation in stroke prevention: a meta-analysis" (Wang et al, 2007) provide coherent evidence that folic acid supplementation can decrease the risk of stroke by 18%, and 25% in populations where folic fortification was not issued, or used for primary prevention. C677T gene polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) is one of the genetic determinators of plasma tHcy level. Observational studies showed that individuals with TT genotype tend to have high plasma tHcy and elevated risk of cardiovascular events (Cronin et al. 2005), and folic acid supplementation led to a remarkable reduction in plasma tHcy. In short, previous studies by others and by our team have provided strong rationale for our proposed trial as detailed below. The hypothesis of the current study is that a combination of antihypertensive drug (e. g., enalapril) with folic acid is not only efficacious, but also is safe and highly cost-effective than antihypertensive (e. g., enalapril) used alone to prevent stroke in hypertensive patients. This trial will enroll 20,000 patients with primary hypertension and with known MTHFR C677T genotype. Subjects will be first stratified by genotypes, and then randomly assigned to treatment groups. The study patients will be instructed to take orally enalapril 10 mg daily or enalapril/folic acid 10mg/0. 8mg tablets daily for a maximum of 5 years. The follow-up is given every 3 months. The incidence and time of first-time stroke episode (primary endpoint) or composite cardiovascular events are used as endpoints. They will be compared by treatment groups with and without stratification by C677T gene polymorphisms. The potential interaction between treatment groups and C677T gene polymorphisms on therapeutic efficacy will also be tested. This will be the first and largest trial of this kind in Chinese population. The findings from this trial may have the potential to transform current clinical and public health findings into practice.

Minimum age: 45 Years. Maximum age: 75 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- BP≥140/90 mmHg in both of the two screening visits or currently under

anti-hypertension treatment

- 45 - 75 years old

- Successful determination of MTHFR C677T genotype

- For pre-menopausal women, agreed to use contraceptives during the trial

- Signed the written informed consent

Exclusion Criteria:

- Having a history of stroke

- Having a history of myocardial infarction

- Having a history of physician diagnosed heart failure

- Post- coronary revascularization

- Severe somatic disease such as cancer

- Secondary hypertension

- Congenital or acquired organic heart diseases

- Contraindicated to angiotensin-converting enzyme inhibitor(ACEI)

- History of ACEI adverse effects

- Currently long-term use of folic acid or vitamin B12 or vitamin B6

- Pregnant or child breastfeeding women

- Severe mental disorders

- Lab tests indicating abnormal liver or kidney function

- Unwilling to participate the trial, unwilling to change the current antihypertensive

treatment

Anqing Branch, Anhui Institute of Biomedical Research, Anqing City, Anhui 246000, China

Lianyungang Center for Advanced Research in Cardiovascular Diseases, Lianyungang, Jiangsu 222003, China

Related publications:

Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, Sun N, Liu L, Xu X. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet. 2007 Jun 2;369(9576):1876-82. Review.

Graham IM, Daly LE, Refsum HM, Robinson K, Brattström LE, Ueland PM, Palma-Reis RJ, Boers GH, Sheahan RG, Israelsson B, Uiterwaal CS, Meleady R, McMaster D, Verhoef P, Witteman J, Rubba P, Bellet H, Wautrecht JC, de Valk HW, Sales Lúis AC, Parrot-Rouland FM, Tan KS, Higgins I, Garcon D, Andria G, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. 1997 Jun 11;277(22):1775-81.

Cronin S, Furie KL, Kelly PJ. Dose-related association of MTHFR 677T allele with risk of ischemic stroke: evidence from a cumulative meta-analysis. Stroke. 2005 Jul;36(7):1581-7. Epub 2005 Jun 9.

Starting date: May 2008
Last updated: August 11, 2014