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European Journal of Heart Failure 2000 2(4):431-437; doi:10.1016/S1388-9842(00)00109-4
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© 2000 European Society of Cardiology

Survival and Prognosis: Investigation of Crataegus Extract WS 1442 in congestive heart failure (SPICE) — rationale, study design and study protocol

Christian J.F. Holubarscha,*, Wilson S. Coluccib, Thomas Meinertzc, Wilhelm Gausd and Michal Tenderae

a Medizinische Klinik und Poliklinik, Abt. Innere Medizin III – Kardiologie und Angiologie Hugstetter Str. 55, D-79106 Freiburg, Germany
b Cardiology Department, Boston Medical Center 88 E Newton Street, Boston, MA 02118, USA
c Universitätskrankenhaus Eppendorf Medizinische Klinik, Abt. für Kardiologie, Martinistr 52, D-20246 Hamburg, Germany
d Universität Ulm, Abt. Biometrie und Medizinische Dokumentation Schwabstr. 13, D-89075 Ulm-Donau, Germany
e 3rd Division of Cardiology, Silesian School of Medicine Ziolowa 47, PL-40-635 Katowice, Poland

* Corresponding author. Tel.: +49-761-2703401; fax: +49-761-2703611. E-mail address: holubarsch{at}mm31.ukl.uni_freiburg.de (C.J. Holubarsch).


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Statistics and sample...
 4. Discussion
 Notes
 References
 
SPICE is the first, international, randomized, placebo-controlled, double-blind study to investigate the influence of the herbal drug Crataegus Special Extract WS 1442 (hawthorn leaves with flowers) on mortality of patients suffering from congestive heart failure.

Background: In vitro and experimental animal studies have suggested the following pharmacological modes of action of standardized Crataegus extracts: (1) cAMP-independent positive inotropy; (2) peripheral and coronary vasodilation; (3) protection against ischemia-induced ventricular arrhythmias; (4) antioxidative properties; and (5) anti-inflammatory effects.

Study design: In this randomized, placebo-controlled, double-blind, international trial (approximately 120 investigational centers in seven European countries), up to 2300 patients with congestive heart failure, New York Heart Association class II and III and markedly impaired left ventricular function, will be enrolled and treated over a period of 24 months. During this time patients receive either two film-coated tablets of 450 mg of the Special Extract WS 1442 standardized to 84.3 mg of oligomeric procyanidines or matched placebo per day in addition to standard therapy for congestive heart failure, such as diuretics, digoxin or digitoxin, β-adrenoceptor blockers and angiotensin-converting-enzyme inhibitors. The primary outcome variable is the combined endpoint of cardiac death, non-lethal myocardial infarction, and hospitalization due to progression of heart failure. Secondary outcome variables are total mortality, exercise duration, echocardiographic parameters, quality of life as well as pharmacoeconomic parameters. The first patient was included in October 1998. The trial is expected to be completed at the end of 2002.

Received February 23, 2000; Revised June 1, 2000; Accepted June 20, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Statistics and sample...
 4. Discussion
 Notes
 References
 
Evidence-based medicine is increasingly recognized and accepted by societies and authorities, and thereby becomes especially important in diseases associated with chronic symptoms and high mortality. Digitalis, which has been prescribed for patients with congestive heart failure (CHF) for over 200 years, is a very good example: only recently, clinical evidence for efficacy of the compound has been brought about [1,2]. However, a compound which improves symptoms must not necessarily be of benefit regarding life expectancy, it even may increase mortality [3,4]. Therefore, a digitalis mortality trial had been performed, which demonstrated a mortality equivalent to placebo [5].

Crataegus Special Extract WS 1442,1 a standardized dry extract from hawthorn leaves with flowers, is used for the treatment of mild heart failure. WS 1442 contains flavonoids including hyperoside, vitexin rhamnoside, rutin, and vitexin, and is standardized to a constant content of oligomeric procyanidines (18.75%). Although the exact mode of pharmacological action of WS 1442 is unknown, a number of mechanisms have been suggested: (1) For Crataegus extracts in vitro experiments in isolated Langendorff heart preparations have documented a positive inotropic effect [6,7]. In isolated single adult rat myocytes, Crataegus increased the extent of shortening in a dose-dependent manner [8]. Furthermore, Brixius et al. [9] and Münch et al. [10] showed a positive inotropic effect of WS 1442 in human left ventricular muscle preparations obtained from explanted failing hearts. In addition, these authors clearly demonstrated a digitalis-like effect on the Na+/K+-ATPase in human cardiac muscle tissue and excluded an effect on cyclic AMP [9,10]. Quite recently, a dose-dependent effect of WS 1442 on extent of shortening was demonstrated in isolated right atrial and left ventricular failing and non-failing human myocytes [11]. These pharmacological data correlate well with an improvement of exercise parameters and decrease of heart failure symptoms in controlled clinical trials [12,13]. (2) Standardized Crataegus extracts have mild vasodilating properties as shown both in experimental [14] and clinical studies [15]. This effect, in combination with its positive inotropic action, may explain the increase in ejection fraction in patients with congestive heart failure New York Heart Association class II (NYHA II) treated with WS 1442 [16,17]. (3) Anti-ischemic properties of standardized Crataegus extracts may also come into play because the drug was shown to increase coronary blood flow in a dose-dependent manner [14]. (4) Anti-oxidative and anti-inflammatory properties of WS 1442 may improve endothelial dysfunction, prevent lipid-oxidation and protect myocardium during ischemia and reperfusion [18,19]. (5) Crataegus may also protect from arrhythmias triggered by ischemia and reperfusion: Krzeminski and Chatterjee [20] demonstrated in a rat ischemia-reperfusion model a dramatic reduction in mortality, ventricular fibrillation and tachycardia.

The SPICE (Survival and Prognosis: Investigation of Crataegus Extract WS 1442 in CHF) trial was planned and designed to investigate the efficacy and safety of Crataegus Special Extract WS 1442 in patients suffering from congestive heart failure NYHA class II–III and markedly impaired left ventricular function. This syndrome is characterized by symptoms, progression of the disease and high mortality. Therefore, to prove the efficacy and safety of WS 1442 for this disease, the combined endpoint of cardiac mortality (sudden cardiac death, death due to progressive heart failure, fatal myocardial infarction), non-fatal myocardial infarction and hospitalization because of progression of heart failure (overt heart failure, supraventricular or ventricular tachyarrhythmias related to heart failure, acute coronary syndromes, survived cardiac arrest) was chosen as primary outcome variable. The trial was approved by the appropriate Independent Ethics Committees. Legal and ethical requirements and current scientific standards (German Drug Law, ICH-Guidelines, Declaration of Helsinki) are adhered to.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Statistics and sample...
 4. Discussion
 Notes
 References
 
2.1. Study design
SPICE is a randomized, multicenter, double-blind, placebo-controlled, international clinical trial which is being conducted in Bulgaria, the Czech Republic, Germany, Latvia, Lithuania, Poland, and Slovenia. In approximately 120 participating centers, patients with diagnosed heart failure NYHA II–III and reduced left ventricular ejection fraction (see below) will receive either WS 1442 or placebo in addition to conventional standard therapy of chronic heart failure. Patients are eligible for randomization if their left ventricular function is markedly impaired according to a Wall Motion Index of 1.2 or less. After a 4-week placebo run-in period eligible patients are followed up for 24 months. Visits are scheduled for day –28, day 0 (randomization), month 3, 6, 9, 12, 15, 18, 21 and month 24.

2.2. Patients
Male and female patients aged over 18 years with clinical signs of chronic heart failure can be screened for participation in the trial. Patients with heart failure of different etiologies may be included: ischemic heart disease, idiopathic dilated cardiomyopathy, hypertensive heart disease with left ventricular dilatation. However, patients must not suffer from chronic heart failure based on a primary hemodynamically significant valvular disease. For eligibility patients have to conduct a symptom-limited bicycle stress test starting with 25 W workload with an increase of 25 W step every 2 min. Performance of this test at visit 1 (start of placebo run-in phase) and visit 2 (end of placebo run-in phase) must not differ markedly, i.e. the exercise duration at visits 1 and 2 must be at least 2 min and must not exceed 12 min; furthermore, the difference of exercise duration between visit 1 and 2 must not deviate by more than 1 min in either direction. Patients eligible for randomization have an echocardiographically proven impaired left ventricular function with a Wall Motion Index equal to or less than 1.2 (see below). Inclusion and exclusion criteria are listed in detail in Table 1.


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  		Table 1 Inclusion and exclusion criteria

 
2.3. Study medication and concomitant medication
The investigational drug is Crataegus Special Extract WS 14422 (one film-coated tablet containing 450 mg dry extract of hawthorn leaves with flowers standardized to 84.3 mg of oligomeric procyanidines). The daily dose is 900 mg (i.e. two film-coated tablets) WS 1442 or placebo. The study drugs are identical in all aspects of their appearance.

As concomitant medication, standard drugs covering the four pharmacological strategies in the treatment of heart failure are allowed: (1) digoxin or digitoxin; (2) diuretics; (3) angiotensin-converting-enzyme inhibitors; and (4) β-adrenoceptor blockers. Calcium channel blockers, angiotensin-II-receptor blockers (except of intolerance to ACE-inhibitors, e.g. cough), class-I-antiarrhythmics, and drugs containing any other preparation of Crataegus are not allowed.

2.4. Endpoints
The primary outcome variable (Table 2) is defined as the time to first cardiac event. A cardiac event is the composite endpoint of death of cardiac cause, non-fatal myocardial infarction and hospitalization due to progression of heart failure. The distinct cardiac events are defined in Table 3. Secondary outcome variables, including measurement of quality of life and pharmacoeconomics, are also listed in Table 2.


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  		Table 2 Primary and secondary outcome variables

 


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  		Table 3 Definition of cardiac events

 
2.5. Echocardiography
Before a patient can be included into the study, a careful echocardiographic investigation has to be performed as described below and recorded on a separate video tape for each patient. This is sent immediately for evaluation to the Core Echocardiography Laboratory (CEL), a central service institution of the study. The two-dimensional echocardiographic study consists of an apical four-chamber view, an apical two-chamber view, an apical long-axis view, a parasternal long-axis view, a parasternal short-axis view at the tips of the mitral valve leaflets, and a parasternal short-axis view at mid-papillary level. An M-mode tracing of the left ventricle should be obtained using the parasternal long- or short-axis view with the ultrasonic beam directed slightly apical to the tips of the mitral valve leaflet.

The CEL estimates the wall motion index using the 16-segment model according to the American Heart Association [21]. Wall motion score value is graded as described by Berning and Steensgaard-Hansen [22]. The wall motion score value of each segment will be assessed according to the following definition: Hyperkinesia is scored a value of 3, normokinesia to a value of 2, hypokinesia to a value of 1, akinesia to a value of 0, and dyskinesia to a value of –1.

Wall motion index (WMI) is calculated by dividing the sum of the values due to the number of segments by 16 [21]. The use of a scale with descending scores corresponding to descending ventricular pump function ensures a reliable calculation of left ventricular ejection fraction (LVEF) [23]. A linear correlation between WMI and LVEF has been previously demonstrated [24]. WMIx0.3 results in a calculated LVEF value. Patients with a wall motion index ≤1.2 corresponding to left ventricular ejection fraction of approximately 35% are eligible for the study.

Left ventricular end-systolic diameter (LVESD) and left ventricular end-diastolic diameter (LVEDD) will be measured from the M-mode echocardiogram by the CEL. LVEF will be calculated by the CEL directly from the patients’ first and last study echocardiogram. Left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) will be calculated using the modified Simpson method.

Echocardiography will take place before and 6, 12 and 24 months after randomization of the patients. Follow-up echocardiographic examinations will also be recorded on a video tape, which will also be analyzed by the CEL after the patient has finished the study. This procedure guarantees central echocardiographic evaluation in a fully blinded form with respect to group assignment and follow-up time.


   3. Statistics and sample size
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Statistics and sample...
4. Discussion
 Notes
 References
 
For the primary endpoint ‘time to first cardiac event’, Kaplan–Meier survival curves will be calculated and differences between treatment groups will be assessed with the two-sided log rank test stratified for centers. The analysis will be done by intention to treat.

Data from the literature [5,25] show an incidence of cardiac events with placebo of 30% within 24 months. It is assumed to reduce the event rate by 20% under treatment with WS 1442. Thus the 24-month incidence in the WS 1442 group is presumed to be 24%. For a two-sided level of significance {alpha}=0.05, a power (1–β)=0.90 and the above mentioned difference in incidence (30% vs. 24%) the sample size calculation as per Reboussin et al. [26] requires 1155 evaluable patients per group.

The study is planned in a group sequential design with two interim analyses. The first interim analysis will be done after 1/3 of the expected cardiac events are observed, the second interim analysis after 2/3, with a total of 624 events being expected throughout the study (1155 placebo patients with incidence rate 30%+1155 WS 1442 patients with incident rate 24%). According to the group sequential boundaries of the Peto-Haybittle design [27,28] the overall level of significance of {alpha}=0.05, the significance levels are 0.001 for the first and second interim analysis and 0.0494 for the final analysis. The interim analyses will be performed by an Independent Data and Safety Monitoring Committee (DSMC).

A blinded data review will be performed before the first interim analysis to re-assess the overall incidence rate of 0.27 used for sample size calculation. This rate depends strongly on the definition of cardiac events used for the combined endpoint and highly influences the required sample size. Since patients will not be observed for 24 months at the time of sample size re-calculation, the observed 12-month event rate will be extrapolated to 24 months. This will be done by multiplying by 1.4, because data from the literature [5,25] show an increase of cardiac events between 12 and 24 months of approximately 40%. Depending on the results of the data reviewed the sample size may be modified.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Statistics and sample...
 4. Discussion
Notes
 References
 
4.1. Selection of patients
In conducting a large-scale trial with patients suffering from congestive heart failure, inclusion of patients with different etiologies and different stages of congestive heart failure (NYHA I–IV) is important. In the DIG trial [5], patients with all clinical stages of congestive heart failure were recruited including NYHA I. In most patients, the stage of heart failure was judged to be NYHA I or II. Naturally, mortality and morbidity of patients with moderate heart failure is low as compared to patients being NYHA III.

Therefore, in the SPICE study, criteria for inclusion of patients were extended to careful evaluation of LV-ejection fraction. An accepted method for evaluation of LV-function is echocardiography using the 16-segment method [21,29]. This method can be used in large multicenter trials in patients with reduced LV-function, is easier to implement and less expensive as compared to radionuclide scintigraphy [23]. The installation of a Core Echocardiographic Laboratory (CEL) as a central service institution of the study increases reliability and objectivity of measurements.

4.2. Selection of endpoints
In contrast to similar studies in congestive heart failure, a composite endpoint of cardiac death, non-lethal infarction and hospitalization due to progression of heart failure has been chosen. There are at least three arguments for such a decision. Firstly, to describe both survival and quality of a life with congestive heart failure, the combination of cardiac death and the freedom from the most severe cardiac events such as hospitalization and myocardial infarction, is judged to be the most reasonable and significant parameter. Secondly, the pharmacological properties of Crataegus Special Extract WS 1442 involve benefits for treatment of myocardial failure as well as for coronary heart disease. Because more than 70% of patients with congestive heart failure suffer from coronary heart disease, the chosen combined endpoint covers the progression of heart failure per se and the progression of coronary heart disease. Thirdly, a composite endpoint delivers more events per 100 patient-years and therefore increases the power of the study.

4.3. Calculation of sample size
The calculation of sample size was based on rates of events as observed in comparable mortality trials. As a prerequisite, patients with low ejection fraction are included (see above), which is assumed to result in an event rate of 15% per year. Furthermore, a reduction of the rate of cardiovascular events of 20% or more is generally accepted.

4.4. Schedule of the trial
The first patients were entered into the study during October 1998. Up to now more than 1600 patients are included in the trial. The end of the study is expected in 2002.


   Notes
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Statistics and sample...
 4. Discussion
 Notes
References
 
1 Active substance of Crataegutt® 450 novo; manufacturer: Dr Willmar Schwabe Pharmaceuticals, Karlsruhe (Germany). Back

2 One film-coated tablet contains 450mg dry extract of hawthorn leaves with flowers (4-6.6:1; extraction solvent: ethanol 45%) standardized to 84.3mg of oligomeric procyanidines. Back


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Statistics and sample...
 4. Discussion
 Notes
 References
 

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