Socio-demographic and Clinical Characteristics
The socio-demographic and clinical characteristics of participants by treatment group are shown in . There were no differences between treatment groups for any demographic or clinical characteristics. However, despite the entry requirement of an LVEF ≤ 40% measured during a clinically-indicated study within the previous 12 months (see above), the baseline radionuclide ventriculogram performed after study randomisation detected an LVEF > 40% in 38 of the study participants. Since the baseline assessment of LVEF occurred after randomisation, we were not able to exclude these patients.
Socio-demographic and clinical characteristics of the study population by treatment group
Of the 120 patients who were randomised into the HERB CHF trial, 60 were assigned to placebo and 60 to Crataegus Special Extract WS 1442. One hundred and eleven patients completed all six months of the study. In the placebo group three patients did not complete the study; one died due to HF, one had severe pneumonia and one had a United Network for Organ Sharing (UNOS) status 1 heart transplant. In the Crataegus Special Extract WS 1442 group six patients did not complete the study: three patients died, one due to aplastic anaemia and two due to HF; of the other three patients: one patient developed Grave’s disease; one developed thyomas and one had a UNOS status 1 heart transplant.
Progression of Heart Failure
Progression of HF occurred in 46.6% (28/60) of Crataegus Special Extract WS1442 patients and 43.3% (26/60) of placebo patients. This reflects no difference in the incidence of the primary outcome between the groups (p=0.86) (). The odds ratio of HF progression was 1.14 (95% CI = 0.56, 2.35) for Crataegus Special Extract WS1442 compared to placebo. Evaluating each component of the combined endpoint separately, Crataegus Special Extract WS1442 resulted in nominally more HF deaths (3.3%, 2/60 vs. 1.6%, 1/60) and HF hospitalisations (18.3%, 11/60 vs. 10.0%, 6/60) but less frequent need for increased diuretic (25.0%, 15/60 vs. 31.6%, 19/60) compared to placebo.
Heart failure progression endpoints in the Crataegus Special Extract WS 1442 and placebo groups for the 120 patients in the HERB CHF trial.
The Kaplan-Meier curve for Crataegus Special Extract WS1442 and placebo (.) showed a crossing pattern that could indicate changing hazards over time. We consequently performed a non-proportional Cox regression analysis using a time by treatment interaction that demonstrated the risk of HF progression between the two groups changed significantly through time (p = 0.047). The non-proportional Cox model demonstrated that patients in the Crataegus Special Extract WS1442 group were 3.9 times (95% CI = 1.1, 13.7: p = 0.035) more likely to experience a HF progression event at baseline than the placebo group. The hazard ratio (HR) for the Crataegus Special Extract WS1442 group decreased through time, so that at six months (182 days) Crataegus Special Extract WS1442 did not increase progression (HR = 0.63, 95% CI = 0.29, 1.47: p = 0.72) compared to the placebo group. In a similar fashion, when adjusted for baseline NYHA functional class, peak oxygen consumption, LVEF, Heart Failure Survival Score, and ACE inhibitor use, as well as the time by treatment interaction, the risk of having a HF progression event at baseline in the Crataegus Special Extract WS1442 group increased to HR = 6.4 (95% CI = 1.5, 26.5: p = 0.011) times greater than the placebo group. At six months (182 days), after adjustment, Crataegus Special Extract WS1442 again no longer increased progression (HR = 0.41, 95% CI = 0.14, 1.18: p = 0.64) compared to the placebo group.
Figure 2 Kaplan-Meier plot of the effect of Crataegus Special Extract WS 1442 versus placebo on progression of heart failure in patients in the HERB CHF trial. Crataegus Special Extract WS 1442 had no effect on the rate of heart failure progression (hazard ratio (more ...)
We conducted the same analyses on the subgroup of 68 participants with LVEF 35%. Results in this subgroup of patients were similar to those observed for the whole group. Progression of HF occurred in 51.5% (17/33) of Crataegus Special Extract WS1442 patients and 42.9% (15/35) of placebo patients. This difference reflects a non-significant increase in the primary endpoint of 13% (p=0.48) in the Crataegus Special Extract WS1442 group. The odds ratio of HF progression was 1.42 (95% CI = 0.55, 3.69: p = 0.48) for Crataegus Special Extract WS1442 compared to placebo.
Kaplan-Meier analysis also demonstrated the possibility that the risk of having HF events appeared to change through time between the two groups. A non-proportional Cox regression analysis indicated that time by treatment interaction was not significant (p = 0.13). When adjusted for baseline peak oxygen consumption, cause of HF, serum sodium, and ACE inhibitor use, the risk of having a HF progression event in the Crataegus Special Extract WS1442 group was HR = 3.2 (95% CI = 1.3, 8.3: p = 0.02) times higher than in the placebo group.
C. oxycantha in the formulation and dose administered in this study when added to optimum evidence based therapy did not decrease the risk of our primary outcome, clinical HF progression compared to placebo. There were, however, significantly more HF progression events at baseline in the Crataegus Special Extract WS1442 group versus the placebo group. Subgroup analysis of data from patients with LVEF ≤ 35 % demonstrated similar results, although more ill patients who received Crataegus Special Extract WS1442 were at a significantly increased risk of having a HF progression event throughout the 6 months of the study and not just at baseline.
It is unclear why patients who receive Crataegus
Special Extract WS1442 are at greater risk at baseline or if more ill throughout the entire 6 months of the study for having a HF related hospitalisation, death or increased diuretic use. Our results could well be due to chance, as this study was a secondary data analysis and had limited power due to the small sample size. The analysis in sicker patients, with an even smaller sample size, was even more limited and vulnerable to chance outcomes. Moreover, as other clinical trials examining C. oxycantha
for HF have not examined the occurrence of clinical HF events through time, we are unable to determine if this is a unique conclusion of our study or a common pattern with C. oxycantha
intake in this population. The Survival and Prognosis: Investigation of Crataegus
Extract WS 1442 in Congestive Heart Failure (SPICE) trial has recently been completed. The SPICE trial was a randomised clinical trial in nearly 3,000 HF patients with LVEF ≤ 35%, the primary endpoint was cardiac morbidity, non-fatal myocardial infarction and hospitalisation due to HF progression over 24 months. (16
) The SPICE trial used Crataegus
Special Extract WS1442 at the same dose as in our study and enrolled patients with similar baseline demographic and clinical characteristics. (17
) However, since the SPICE trial has not yet been published, only data presented orally and in the associated abstract are currently available, allowing only limited comparisons with our study data. The SPICE trial reported similar results to our study, in that there was no significant difference in HF progression between the active and placebo groups (27.9% vs. 28.9%: p = NS), although clearly our trial had a higher percentage of HF progression events (46.6% vs. 43.3%). (16
) Kaplan-Meier curves have not yet been presented for the SPICE trial, consequently it is unclear if the relative risk between the active and placebo group changed through time, and if there was an increased risk in the Crataegus
Special Extract WS1442 group at baseline or in sicker patients.
One possible explanation for the increased risk for progression of HF at baseline in the Crataegus
Special Extract WS1442 group and for patients with LVEF ≤ 35% (in the adjusted analysis) is the possibility of herb-drug interactions. As the majority of patients with HF are on several different drugs, many interactions are theoretically possible. In particular, the flavonoids in C. oxycantha
are chemically similar to other flavonoids that have demonstrated P-glycoprotein activity, which may lead to various drug-flavonoid interactions. (18
) Only one study has examined possible interactions between C. oxycantha
and a commonly administered HF medication, digoxin. This study found that Crataegus
Special Extract WS 1442 (450 mg twice daily) did not significantly alter the pharmacokinetic parameters of digoxin. (21
) Further, several flavonoids in C. oxycantha
such as the vitexin rhamnosides have been demonstrated to have low oral absorption or undergo extensive conjugation before reaching the systemic circulation. (22
) Both the negative study examining potential interactions with digoxin and the low level absorption of the main flavonoids present in C. oxycantha
diminish the potential of possible C. oxycantha
-drug interactions. It is possible that constituents other than flavonoids in C. oxycantha
may cause herb-drug interactions, but currently there is not enough information to determine whether C. oxycantha
-drug interaction led to the increased early risk of HF progression.
This study had several limitations. As with all secondary analyses this study was not designed a priori to detect HF progression events. As such, we did not have a data collection method in place to monitor changes in HF medications continuously over the six month study period. Instead we collected information about medications taken, their dose and frequency at baseline, three and six months. At three and six months, we noted if the patient’s diuretic dose was increased from their last visit. As a consequence we could have included patients who did not truly have an increased sustained diuretic dose and missed including patients with sustained increased diuretic dose. These potential misclassifications, however, should have been non-differentially spread across both groups, thus keeping the risk relationships between the two groups the same.
Another major limitation of this study is its small sample size. With 54 events in 120 patients we are able to detect relatively moderate changes in hazard ratios (2 times or greater) between the groups but not small differences. This is even more pronounced in the subgroup analyses of patients with LVEF of ≤ 35% where we have 32 events in 68 patients.
We suggest that healthcare providers use caution when considering prescribing C. oxycantha to patients with HF. Patients already taking C. oxycantha should also be observed closely for any adverse events that could be temporally related to C. oxycantha ingestion. We make these recommendations because Crataegus Special Extract WS1442, at a commonly recommended dose, significantly increased the risk for progression of HF at baseline and in the more clinically compromised patients with LVEF ≤ 35% in this study. Moreover, Crataegus Special Extract WS1442 increased risk consistently in more compromised patients with LVEF ≤ 35%.
In summary, Crataegus Special Extract WS 1442 does not reduce heart failure progression in patients who have mild to moderate HF. Crataegus Special Extract WS 1442 appears to increase the early risk of heart failure progression.