Hawthorn extract for systolic HF shows no clinical effect in rare placebo-controlled test of herbal drug

March 28, 2007

New Orleans, LA - In a rare long-term placebo-controlled study of a herbal remedy's effect on clinical end points, a commercial extract of Crataegus, also called hawthorn, failed to show any incremental benefit when given with standard drug therapy to patients with chronic systolic heart failure[1][2]. The trial did suggest, however, that it's safe to use the preparation, WS-1442 (Schwabe Pharmaceuticals, Karlsruhe, Germany), in combination with ACE inhibitors, beta blockers, and other standard HF medications.

The trial, called Survival and Prognosis: Investigation of Crataegus Extract WS 1442 in CHF (SPICE), also hinted that WS-1442 may protect against cardiac death and sudden death, but effects on those secondary end points weren't consistent throughout the 24-month trial.

Dr Christian JF Holubarsch

The Crataegus extract used in SPICE is consistently manufactured with a 17% to 20% concentration of oligomeric procyanidins, which are responsible for its cardiovascular effects, Dr Christian JF Holubarsch (Median Kliniken Hospitals, Bad Krozingen, Germany) told heart wire . Holubarsch presented the results of SPICE here at the American College of Cardiology 2007 Scientific Sessions. Schwabe markets the herbal remedy predominantly in Europe but not in North America, representatives of the company said when interviewed.

Various forms of Crataegus, derived from hawthorn berries, leaves, and flowers, have been used medicinally for centuries in Europe, Asia, and other parts of the word. A sizable body of research suggests that ingestion of the extract can relax blood vessels and improve some functional measures in patients with mild heart failure [3] [4]. On the other hand, WS-1442 given for six months had no apparent effect on six-minute-walk distance in the Hawthorne Extract Randomized Blinded Chronic Heart Failure trial (HERB-CHF), which was reported at the Heart Failure Society of American 2004 Scientific Sessions [5][6].

The SPICE trial, conducted in 13 European countries, predominantly in Eastern Europe, randomized 2681 patients with NYHA class 2-3 heart failure and an LVEF <35% to receive either WS-1442 or placebo for two years. The active drug was given at 900 mg/day; all participants received standard HF drug therapy, which included diuretics in 85%, ACE inhibitors in 83%, beta blockers in 64%, glycosides in 57%, and aldosterone blockers in 39% of patients.

The herbal preparation had a neutral effect on the primary end point, a composite of sudden cardiac death, death due to progressive heart failure, fatal MI, nonfatal MI, or hospitalization due to HF progression, measured at 24 months. The rates were statistically similar, at 28% for actively treated patients and 29% for controls.

Patients taking WS-1442 showed significant relative-risk reductions in the secondary end point of cardiac mortality after six months (by 41%, p=0.009) and 18 months (by 20%, p=0.046) but not at the 12-month or 24-month follow-ups (by 18% and 10%, respectively).

The rates of adverse events and of serious adverse events were about 68% and 40%, respectively, for both groups, according to Holubarsch's report.

In a prospectively planned subgroup analysis, patients who received WS-1442 and had an LVEF from 25% to 35% showed a significantly reduced risk of sudden cardiac death from month 12 to month 24; no such signal emerged for patients with the poorest ventricular function. The protection was significantly stronger among the 70% of patients with ischemic disease, Holubarsch said, adding that the drug, therefore, is protective probably by being anti-ischemic.

Although the SPICE trial was negative for its primary end point, it was noteworthy for reliably showing that WS-1442 can be safely added to mainstream HF medications in patients with systolic heart failure, agreed observers that included Dr E Murat Tuzcu (Cleveland Clinic, OH) and Dr Salim Yusuf (McMaster University, Hamilton, ON), who officiated at Holubarsch's formal presentation of SPICE, and Dr Marc Pfeffer (Brigham and Women's Hospital, Boston, MA), who attended a subsequent media briefing on the study.

Holubarsch said he was compensated by Schwabe for his time as an investigator for the SPICE trial.

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