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| Name | Class |
|---|---|
| Anhui Medical University | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Enalapril/folic acid | Experimental | A fixed combination drug is given. The dose is fixed in enalapril 10 mg / folic acid 0.8 mg per day. |
|
| Enalapril | Active Comparator | Enalapril maleate 10 mg per day is given |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Enalapril/folic acid | Drug | Enalapril/folic acid, (10mg enalapril/0.8mg folic acid)/tablet, taken orally and once daily for a maximum of 5 years. Combination with other anti-hypertension drugs are allowed. |
| Measure | Description | Time Frame |
|---|---|---|
| First attack of symptomatic stroke ( ischemic or hemorrhagic) | Patients are followed-up every 3 months. All endpoint outcomes are assessed by the Endpoint Adjudication Committee of the study. | during the trial period |
| Measure | Description | Time Frame |
|---|---|---|
| Composite major cardiovascular events | during the trial period | |
| All-cause death | during the trial period | |
| First attack of ischemic stroke and resultant death |
| Measure | Description | Time Frame |
|---|---|---|
| Malignant tumors | during the trial period |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Yong Huo, M.D. | The First Hospital, Beijing University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Anqing Branch, Anhui Institute of Biomedical Research | Anqing | Anhui | 246000 | China | ||
| Lianyungang Center for Advanced Research in Cardiovascular Diseases |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 17544768 | Background | 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):1876-1882. doi: 10.1016/S0140-6736(07)60854-X. | |
| 9178790 | Background | Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom 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 Luis 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. doi: 10.1001/jama.1997.03540460039030. |
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| ID | Term |
|---|---|
| D000075222 | Essential Hypertension |
| D006973 | Hypertension |
| D020521 | Stroke |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
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| ID | Term |
|---|---|
| D004656 | Enalapril |
| D005492 | Folic Acid |
| ID | Term |
|---|---|
| D004151 | Dipeptides |
| D009842 | Oligopeptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
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|
| Enalapril maleate | Drug | Enalapril, 10mg/tablet, taken orally once daily for a maximum of 5 consecutive years. Combination with other anti-hypertension drugs are allowed. |
|
|
| during the trial period |
| First attack of hemorrhagic stroke and resultant death | during the trial period |
| Myocardial infarction and resultant death | during the trial period |
| Lianyungang |
| Jiangsu |
| 222003 |
| China |
| 15947278 | Background | 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. doi: 10.1161/01.STR.0000169946.31639.af. Epub 2005 Jun 9. |
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| D002493 |
| Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D011622 |
| Pterins |
| D011621 | Pteridines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |