On March 15, Prof. Huo Yong of our hospital, as the study leader, made the first official public presentation of the results of the China Stroke Prevention Study (CSPPT) at the American College of Cardiology Annual Meeting (ACC 2015). This study is the world’s first large-scale, randomized, controlled study of folic acid supplementation for stroke prevention in hypertensive patients. After a mean follow-up of 4.5 years in 20,702 Chinese patients with hypertension, it was found that supplementing folic acid with antihypertensive therapy significantly reduced the risk of first stroke by 21%. The results of the study have been published simultaneously online in the Journal of the American Medical Association (JAMA). Stroke is the leading cause of death in China, posing a serious threat to the health and quality of life of the nation. Elevated blood homocysteine/folic acid deficiency is strongly associated with stroke and can act synergistically with hypertension to further increase stroke risk. The unique genetic background and its interaction with low folate levels are important factors in the high incidence of stroke in hypertensive patients in China. The CSPPT study provides key evidence for a more cost-effective, safe and effective stroke prevention in China, and is the first post-marketing clinical study of an innovative drug in China. In the past three months, more than 90 media outlets have reported the results and implications of this study, and the fact that long-term low-dose folic acid supplementation can prevent stroke in Chinese patients with hypertension has been included in clinical guidelines and continuing education courses for physicians in the United States. How was such a far-reaching study conceived and designed? With this question in mind, I interviewed the study leader, Professor Huo Yong. The story that spans more than 20 years was recorded. Professor Huo Yong met Professor Xu Xiping in 1994 while studying in the U.S. In the 1990s, the incidence of cardiovascular and cerebrovascular diseases in China was still rising year by year, while in developed countries such as the U.S., the incidence of cardiovascular and cerebrovascular diseases had significantly decreased. How to reduce the incidence of cardiovascular and cerebrovascular diseases in Chinese patients was a frequent discussion between the two professors. During the discussion, it was found that the incidence of stroke in Chinese patients is 3-5 times higher than that of myocardial infarction, while the ratio is exactly the opposite in the United States. Is it because of the high incidence of hypertension in China? In addition, for every 10 mmHg increase in systolic blood pressure, the incidence of stroke increases by 50% in Chinese patients, but only by 10%-20% in Europe and the United States. So there must be something different between the Chinese and the European and American population that ultimately leads to the increase in stroke incidence. It became a common goal of both professors to find this cause and make a change. In 1995, after returning to China, Professor Huo Yong began to devote himself to the study of stroke risk factors. Soon, the results of the Anqing cohort study showed that plasma homocysteine (HCY) levels were 50-60% higher in the Chinese than in the US. At the same time, up to one quarter of the Chinese had mutations in the HCY metabolic genotype that resulted in elevated HCY, compared to less than 10% of such genotypes in the United States. The findings also showed that the risk of stroke increased progressively with elevated HCY. Patients with hypertension combined with high HCY can have a 3-4 fold increase in stroke risk, showing a one plus one result. Several years have passed and a result can be clearly established that elevated HCY is associated with increased stroke. In 2007, Prof. Huo Yong’s team compiled international studies on folic acid supplementation for the prevention of cardiovascular events and confirmed that folic acid supplementation can prevent stroke, especially in folic acid deficient populations such as the Chinese population. The results of the meta-analysis were published in the Lancet that year. In the same year, under the active promotion of Prof. Huo Yong’s team, the new drug Enalapril Folic Acid Tablets (Eveline) was approved for marketing in China, which is a combination of angiotensin inhibitor antihypertensive drug Enalapril 10 mg and 800 micrograms of folic acid. It is the first antihypertensive drug to include folic acid. In 2009, the Chinese Stroke Prevention Study, CSPPT, was officially opened. This study was the first large-scale clinical study designed and conducted by Chinese people in China, with a planned enrollment of 20,000 patients and a 5-year follow-up. By the fourth year of follow-up, on June 30, 2013, the sixth meeting of the Data Safety Committee reported that a significant difference in stroke incidence had emerged between the two populations studied and recommended early termination of the trial. From this time until the end of 2013, the study team organized a final outgroup follow-up for all 20,702 enrolled patients by more than 500 physicians. The final statistical results showed that there was no difference in the level of blood pressure reduction in the etanercept group, but the incidence of stroke in the etanercept group decreased by 21%, p=0.003, a very significant difference. This result has received wide attention from experts and scholars at home and abroad, and on March 15, 2015 at 10:00 am, Professor Huo Yong, as the study leader, officially announced the results of CSPPT to the public for the first time at the American College of Cardiology Annual Meeting (ACC 2015), while the study results were published online in JAMA. CSPPT has far-reaching clinical implications. Firstly, this study has demonstrated that the high incidence of stroke in the Chinese population is due to folic acid deficiency and high HCY, and the decrease in stroke incidence after folic acid supplementation has confirmed the relationship between folic acid deficiency and stroke incidence. Second, the problem of high stroke incidence in China can be addressed in a simple way. Folic acid can reduce the incidence of stroke by an additional 21% on top of the same blood pressure reduction. Some foreign experts have projected that folic acid may reduce the incidence of stroke by half. There was no requirement in this study for patients to have elevated HCY, so all patients with hypertension could benefit from folic acid supplementation. Third, this study is an overall boost to the prevention and treatment of the cardiovascular epidemic. In the 3 months since the study was published, Prof. Yong Huo’s team has received interviews from more than 90 institutions outside China. The results of this study have been written into the prevention guidelines in our group. Further dissemination studies are on the agenda. So how exactly should the results of the CSPPT study be recognized and implemented? First, folic acid supplementation is recommended in all hypertensive patients with high HCY with H hypertension and an increased proportion of TT in the folic acid metabolic phenotype. The benefit of folic acid supplementation is greater. Second, folic acid supplementation is also recommended in hypertensive patients who have already had a stroke. the CSPPT study did not enroll patients who had already had a stroke, but the Canadian study showed a 1% per year increase in stroke incidence reduction to 5% per year with universal folic acid supplementation, and there was no significant increase in the rate of reduction in non-folic acid supplemented areas in the same developed countries. Continuation of folic acid in patients who have already had an event has implications for secondary prevention. Third, drug supplementation is recommended in China. China is a vast country with great regional dietary differences and thousands of flour milling plants, making it difficult to add folic acid to flour uniformly as in North America. Chinese people like to eat cooked vegetables and lose a lot of folic acid, so dietary supplementation is too costly and ineffective. It is recommended to add it to medicines. When used in combination with antihypertensive drugs, folic acid is highly soluble and compliance is better. Fourth, it is recommended to check HCY in patients with hypertension. high HCY is an indicator of folic acid deficiency, and if it is elevated, it is more recommended to supplement folic acid, and a decrease in HCY indicates a significant effect of folic acid supplementation. Fifth, it is recommended that supplementation be given at a dose of 800-1000 mcg per day. 800-1000 mcg per day was found to be the most cost-effective supplementation in the CSPPT study, which examined different doses of folic acid supplementation. Sixth, it is recommended to focus on the safety of folic acid supplementation. Small doses of supplementation are safe, but taking large amounts over a long period of time carries the risk of promoting cell proliferation to develop tumors. People with contraindications to folic acid use should avoid taking it. In conclusion, folic acid supplementation for stroke prevention is the appropriate dose for long-term supplementation, at least up to 36 months, with a 20% and higher decrease in HCY. It is also important to emphasize that folic acid supplementation should be used for comprehensive control of stroke risk factors to obtain maximum clinical benefit.