Folate Supplementation in HTN May Lower Risk for First Stroke

Deborah Brauser

March 16, 2015

SAN DIEGO, CA — After years of negative trials from Western researchers examining folic-acid supplementation for prevention of cardiovascular events, researchers from China are reporting significantly positive results from use of the substance[1].

As part of the Joint Symposium of the Chinese Society of Cardiology and the American College of Cardiology (ACC) here at the American College of Cardiology (ACC) 2015 Scientific Sessions, Dr Yong Huo (Peking University First Hospital, Beijing, China) presented study results that were simultaneously published in the Journal of the American Medical Association.

The China Stroke Primary Prevention Trial (CSPPT), which included more than 20 000 adults with hypertension but without a history of MI, showed that daily treatment of 10-mg enalapril plus 0.8 mg of folic acid for 4.5 years reduced the risk of first stroke (the primary outcome) by 21% compared with taking enalapril alone.

The folic-acid/enalapril group also showed significant risk reduction in first ischemic stroke and a composite of cardiovascular events, but not in hemorrhagic stroke or MI.

Huo, who is also the current president of the Chinese Society of Cardiology, told meeting attendees that he thinks the results could be generalizable.

"We believe these findings are universal. They're applicable not only to the Chinese population but also populations throughout the world, including the United States," he said.

Alarming Trend

Dr Yong Huo

Huo noted that "cerebrovascular diseases are the leading cause of death" in China, whereas they make up the number-four spot in the US. In addition, although the US has seen decreasing mortality rates for cardiovascular disease and stroke over the past 5 decades, China's mortality rates for these conditions have increased—especially over the past 2 decades.

"There is an urgency in understanding this alarming upward trend of stroke in China and to develop cost-effective strategies to halt and reverse the trend," said Huo.

He added that because folate deficiency occurs in 20% to 60% of individuals in China (vs just 0.06% of those in the US), the investigators conducted the study to test the hypothesis that folic acid added to enalapril could reduce stroke.

A total of 20 702 individuals between the ages of 45 and 75 (mean age 60 years; 59% women) participated in the CSPPT, which was conducted from May 2008 to August 2013. All participants had hypertension and no history of MI or stroke.

After a 3-week run-in of oral 10-mg enalapril taken daily to make sure the participants were tolerant of the drug and practicing adherence, they were randomly assigned to either continue receiving oral enalapril (n=10 354) or to receive single pills containing both folic acid and enalapril (n=10 348).

While first stroke was the primary outcome, secondary outcomes included MI, first hemorrhagic stroke, first ischemic stroke, and a composite of adverse cardiovascular events, which encompassed MI, stroke, cardiovascular death, and all-cause death.

After a median of 48 months of treatment, efficacy differences between the groups were found to be significant and to exceed "the boundary of the prespecified stopping rule," leading to early termination of the trial by the data and safety monitoring board.

Results at the participants' last visit showed that a first stroke occurred in 2.7% of the folic-acid/enalapril group compared with 3.4% of the enalapril-only group (hazard ratio [HR] 0.79; 95% CI 0.68–0.93; P=0.003).

The combination group also had significant risk reduction in first ischemic stroke (2.2% vs 2.8% for the enalapril-only group; HR 0.76; P=0.002) and composite cardiovascular events (3.1% vs 3.9%, respectively; HR 0.80; P=0.002).

The groups did not differ significantly in risks for hemorrhagic stroke or all-cause deaths. There were also no between-group differences in frequency of any adverse events.

"Amazingly Important"

After the presentation, session moderator Dr Heather L Gornik (Cleveland Clinic, OH) called this "an amazingly important study."

"As an American vascular doctor, I've seen that all these trials for [folic acid] for vascular disease in a more Western population have been negative," she said to meeting attendees.

Later, she reiterated to heartwire from Medscape that most of the folic-acid-supplementation studies have been very disappointing.

"But this really shows that in a Chinese population, there are things that can be done in addition to blood-pressure control to prevent stroke. It opens up a whole new area of investigation," said Gornik.

Dr Heather L Gornik

In an accompanying editorial[2], Drs Meir Stampfer and Walter Willett (Brigham and Women's Hospital and Harvard Medical School, Boston, MA) echoed Gornik's enthusiasm.

"The trial by Huo et al has important implications for stroke prevention worldwide. Although the trial participants all had hypertension, it is likely that the results would apply to normotensive persons, although the absolute effect would be smaller," write the editorialists.

They add that "ideally" food sources would provide effective levels of folate, but that isn't always possible.

"This study seems to support fortification programs where feasible, and supplementation should be considered where fortification will take more time to implement," they conclude.

Huo has received grants from the National Major Scientific and Technological Special Project and nonfinancial support from Shenzhen AUSA. Disclosures for the coauthors are listed on the journal website. Stampfer, Willett, and Gornik report they have no relevant financial relationships.

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