HERB-CHF: Hawthorne Extract Randomized Blinded Chronic Heart Failure Trial

HERB-CHF: Hawthorne Extract Randomized Blinded Chronic Heart Failure Trial
Presenter: Keith Aaronson, MD, MS, University of Michigan Cardiovascular Center (Ann Arbor)
The results of the Hawthorne Extract Randomized Blinded Chronic Heart Failure Trial (HERB-CHF) have failed to demonstrate that the use of herbal extract hawthorn in patients with mild-to-moderate chronic heart failure (HF) is beneficial in patients already receiving standard concomitant medical therapy.
Hawthorn in Medicine
The small, fruit-bearing tree, hawthorn (Crataegus monogyna), found in East Asia, Eastern North America, and Europe, is used in Chinese, European, Japanese, and Native American traditional medicine and is currently being evaluated for the treatment of HF in conventional medicine. The active constituents in hawthorn leaves, flowers, and berries include 2 groups of polyphenolic compounds: flavonoids and oligomeric proanthocyanidins (OPCs). Importantly, the plant contains no cardiac glycosides. Pharmacologic activities attributed to the flavonoids and/or OPCs include angiotensin-converting enzyme (ACE) inhibition, type-III/IV phosphodiesterase inhibition, Na/K ATPase activity, antioxidant activity, and decreased production and release of histamine, prostaglandins, leukotrienes, and inhibition of neutrophil elastase.
WS 1442 is an ethanolic extract (46.6:1) of hawthorn leaves with flowers produced by Dr. Willmar Schwabe, GmbH and Co (Karlsruhe, Germany), standardized to contain 18.75% OPCs. It is available in Germany as Crataegutt novo 450. Pharmacologic actions of WS 1442 reported in preclinical studies include cAMP-independent positive inotropism, coronary vasodilation, peripheral vasodilation, protection against ischemia-induced ventricular arrhythmias, and anti-inflammatory properties.
Studies with large doses have not identified any acute or chronic toxicities. Clinical trials with hawthorn extract in more than 1500 HF patients to date have reported improved exercise measures, increased left ventricular ejection fraction (LVEF), and largely favorable hemodynamics. However, these trials have been in patients who were mainly New York Heart Association (NYHA) Class II, often with well-presented LVEF, on background therapy consisting of a diuretic, sometimes digoxin, rarely an ACE inhibitor, and never a beta-blocker. Mortality and important surrogates were not evaluated.
HERB-CHF Trial
HERB-CHF, a randomized, double-blind, placebo-controlled, parallel-group trial, was designed to determine the effect of WS1442 (450 mg twice daily) vs placebo, each in addition to standard medical therapy, in patients with chronic mild to moderately severe HF. A total of 120 patients were enrolled, all meeting the following inclusion criteria:
All the patients were on standard HF therapy: ACE inhibitor, beta-blocker, digoxin (unless contraindicated or not tolerated), and diuretic as needed. They were required to perform 6-min walk test twice over 1-4 weeks and walk 150-450 m at each visit. Follow-up was 6 months, with visits at baseline, 3 months, and 6 months.
Primary outcome was the 6-min walk test, based on the standard deviation of the change in walk distance over 6 months of 75 m, with major secondary outcomes of patient-assessed quality of life (7-point scale) and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) score. Other secondary outcomes were LVEF (radionuclide ventriculography) and peak VO2, norepinephrine, C-reactive protein, tumor necrosis factor, and 8-isoprostane (not presented).
Results
A total of 57 and 54 patients, respectively, completed 6 months of follow-up. There were 3 deaths in the placebo group and 6 in the hawthorn group, none related to the study drug.
No effect of hawthorn was seen on the primary outcome, the 6-min walk distance (Table 1). This result persisted after analysis by LVEF (≤ 40% or > 40%) (P = .19).
Table 1. Primary and Secondary Outcomes
LVEF = left ventricular ejection fraction; MLHFQ = Minnesota Living with Heart Failure Quesionnaire
No effects of hawthorn were seen on either quality-of-life endpoint (Tables 1 and 2), or when adjusted for LVEF.
Table 2. Secondary Outcome: Patient Global Assessment
A modest relative benefit was seen with hawthorn for LVEF (Table 1). Small, nonsignificant falls were seen in systolic and diastolic blood pressure in the hawthorn group together with a small, nonsignificant increase in heart rate, contrary to findings of previous reports with hawthorn extract.
Investigators' Conclusion
The results of HERB-CHF do not provide evidence that use of hawthorn extract (WS 1442 450 mg twice daily) is asociated with functional improvement or symptomatic benefit in HF patients receiving contemporary concomitant medical therapy.
Major European Study Under Way
The Survival and Prognosis Investigation of Crataegus Extract (SPICE) trial is the first international, randomized, placebo-controlled, double-blind study to investigate the influence of the herbal drug WS 1442 on mortality of patients with congestive HF. SPICE aimed to enroll 2500 patients in NYHA Class II/III with markedly impaired LV function. Treatment consists of WS 1442 450 mg twice daily or matched placebo twice daily in addition to standard therapy such as diuretics, digoxin, beta-blockers, and ACE inhibitors. The primary outcome variable is the combined endpoint of cardiac death, nonfatal myocardial infarction, and hospitalization due to progression of HF. Secondary outcome variables are total mortality, exercise duration, echocardiographic parameters, quality of life, and pharmacoeconomic parameters. The trial results are expected to be reported in the year 2005.
References
The results of the Hawthorne Extract Randomized Blinded Chronic Heart Failure Trial (HERB-CHF) have failed to demonstrate that the use of herbal extract hawthorn in patients with mild-to-moderate chronic heart failure (HF) is beneficial in patients already receiving standard concomitant medical therapy.
Hawthorn in Medicine
The small, fruit-bearing tree, hawthorn (Crataegus monogyna), found in East Asia, Eastern North America, and Europe, is used in Chinese, European, Japanese, and Native American traditional medicine and is currently being evaluated for the treatment of HF in conventional medicine. The active constituents in hawthorn leaves, flowers, and berries include 2 groups of polyphenolic compounds: flavonoids and oligomeric proanthocyanidins (OPCs). Importantly, the plant contains no cardiac glycosides. Pharmacologic activities attributed to the flavonoids and/or OPCs include angiotensin-converting enzyme (ACE) inhibition, type-III/IV phosphodiesterase inhibition, Na/K ATPase activity, antioxidant activity, and decreased production and release of histamine, prostaglandins, leukotrienes, and inhibition of neutrophil elastase.
WS 1442 is an ethanolic extract (46.6:1) of hawthorn leaves with flowers produced by Dr. Willmar Schwabe, GmbH and Co (Karlsruhe, Germany), standardized to contain 18.75% OPCs. It is available in Germany as Crataegutt novo 450. Pharmacologic actions of WS 1442 reported in preclinical studies include cAMP-independent positive inotropism, coronary vasodilation, peripheral vasodilation, protection against ischemia-induced ventricular arrhythmias, and anti-inflammatory properties.
Studies with large doses have not identified any acute or chronic toxicities. Clinical trials with hawthorn extract in more than 1500 HF patients to date have reported improved exercise measures, increased left ventricular ejection fraction (LVEF), and largely favorable hemodynamics. However, these trials have been in patients who were mainly New York Heart Association (NYHA) Class II, often with well-presented LVEF, on background therapy consisting of a diuretic, sometimes digoxin, rarely an ACE inhibitor, and never a beta-blocker. Mortality and important surrogates were not evaluated.
HERB-CHF Trial
HERB-CHF, a randomized, double-blind, placebo-controlled, parallel-group trial, was designed to determine the effect of WS1442 (450 mg twice daily) vs placebo, each in addition to standard medical therapy, in patients with chronic mild to moderately severe HF. A total of 120 patients were enrolled, all meeting the following inclusion criteria:
Chronic HF ≥ 3 months
NYHA Class II-IV
LV systolic dysfunction (LVEF ≤ 40%) on routine clinical study ≤ 12 months
Euvolemic
Background medications (except diuretics) stable for ≥ 3 months at randomization
All the patients were on standard HF therapy: ACE inhibitor, beta-blocker, digoxin (unless contraindicated or not tolerated), and diuretic as needed. They were required to perform 6-min walk test twice over 1-4 weeks and walk 150-450 m at each visit. Follow-up was 6 months, with visits at baseline, 3 months, and 6 months.
Primary outcome was the 6-min walk test, based on the standard deviation of the change in walk distance over 6 months of 75 m, with major secondary outcomes of patient-assessed quality of life (7-point scale) and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) score. Other secondary outcomes were LVEF (radionuclide ventriculography) and peak VO2, norepinephrine, C-reactive protein, tumor necrosis factor, and 8-isoprostane (not presented).
Results
A total of 57 and 54 patients, respectively, completed 6 months of follow-up. There were 3 deaths in the placebo group and 6 in the hawthorn group, none related to the study drug.
No effect of hawthorn was seen on the primary outcome, the 6-min walk distance (Table 1). This result persisted after analysis by LVEF (≤ 40% or > 40%) (P = .19).
Table 1. Primary and Secondary Outcomes
| Outcome | Baseline | 6 Months | ||||
|---|---|---|---|---|---|---|
| Placebo | Hawthorn | P Value | Placebo | Hawthorn | P Value | |
| 6-min walk distance (cm) |
374 | 358 | .13 | 379 | 371 | .41 |
| MLHFQ score | 47 | 51 | .31 | 40 | 43 | .48 |
| LVEF | 35 | 36 | .59 | 33 | 37 | .04 |
No effects of hawthorn were seen on either quality-of-life endpoint (Tables 1 and 2), or when adjusted for LVEF.
Table 2. Secondary Outcome: Patient Global Assessment
| Placebo (n = 56) |
Hawthorn (n = 53) |
|||
|---|---|---|---|---|
| Markedly better | 9 | 16% | 10 | 19% |
| Moderately better | 14 | 25% | 10 | 19% |
| Mildly better | 11 | 20% | 8 | 15% |
| No change | 17 | 30% | 18 | 34% |
| Mildly worse | 4 | 7% | 4 | 8% |
| Moderately worse | 1 | 2% | 3 | 6% |
| Markedly worse | 0 | 0% | 0 | 0% |
A modest relative benefit was seen with hawthorn for LVEF (Table 1). Small, nonsignificant falls were seen in systolic and diastolic blood pressure in the hawthorn group together with a small, nonsignificant increase in heart rate, contrary to findings of previous reports with hawthorn extract.
Investigators' Conclusion
The results of HERB-CHF do not provide evidence that use of hawthorn extract (WS 1442 450 mg twice daily) is asociated with functional improvement or symptomatic benefit in HF patients receiving contemporary concomitant medical therapy.
Major European Study Under Way
The Survival and Prognosis Investigation of Crataegus Extract (SPICE) trial is the first international, randomized, placebo-controlled, double-blind study to investigate the influence of the herbal drug WS 1442 on mortality of patients with congestive HF. SPICE aimed to enroll 2500 patients in NYHA Class II/III with markedly impaired LV function. Treatment consists of WS 1442 450 mg twice daily or matched placebo twice daily in addition to standard therapy such as diuretics, digoxin, beta-blockers, and ACE inhibitors. The primary outcome variable is the combined endpoint of cardiac death, nonfatal myocardial infarction, and hospitalization due to progression of HF. Secondary outcome variables are total mortality, exercise duration, echocardiographic parameters, quality of life, and pharmacoeconomic parameters. The trial results are expected to be reported in the year 2005.
References
Aaronson K. HERB-CHF (Hawthorn Extract Randomized Blinded Chronic HF Study). Late-Breaking and Recent Clinical Trials. Presented at the 8th Annual Scientific Meeting of the Heart Failure Society of America; September 12-15, 2004; Toronto, Ontario, Canada.
Pittler MH, Schmidt K, Ernst E. Hawthorn extract for treating chronic heart failure: meta-analysis of randomized trials. Am J Med. 2003;114:665-674.
Holubarsch CJ, Colucci WS, Meinertz T. Survival and prognosis: investigation of Crataegus extract WS 1442 in congestive heart failure (SPICE) – rationale, study design and study protocol. Eur J Heart Fail. 2000;2:431-437.
Source...