Comparative Clinical Efficacy and Tolerability of Oxerutins and _Horse

Chestnut Extract in Patients with Chronic Venous Insufficiency

Dieter Rehna, Markus Unkaur a, Peter Kleinb, Volker Jost c, and Peter W Liicker c

Zyma GmbH, Medizin und Entwicklung a, Munich, Datenservice Honig h, Rohrbach,

and Arbeitskreis Klinische Arzneimittelpriifungen (AKP)C, Griinstadt (Germany)

Summary

Oxerutins (O-(�-hydroxyethyl)rutosides, HR, Venoruton®) and horse chestnut extract (HCE) are active
principles of first priority for the pharmacological treatment of chronic venous insufficiency (CVI). The
efficacies of both compounds were shown in numerous, double-blind, randomized, placebo controlled
clinical trials. Besides the direct comparison of the two compounds the aim of the study was to investigate
the initial dose/maintenance dose concept for HR. 137 female, postmenopausal patients with CVI II
finished the study according to protocol. Following one week placebo run-in the patients were treated
either with I 000 mg/d HR, 600 mg/d HCE or I 000 mg/d for 4 weeks and than with 500 mg/d HR
within the initial dose/maintainance dose concept for 12 weeks and observed for further 6 weeks. A main
confirmative criterion was the volume reduction of the leg. Subjective criteria were descriptively evaluated.
HR (1000 mg/d) was proven to be equivalent or better, reducing the leg volume (AUB0_18) by -5273 ±
11418 ml· d compared to -3187 ± 10842 ml· d under HR (1000 mg/d and 500 mg/d), and -3004 ± 7429
ml · d under HCE-treatment. Both compounds exhibit a substantial carry-over effect. The maintenance
posology of HR is able to stabilize the therapeutic obtained under initial dose conditions.

Zusammenfassung

Vergleich der klinischen Wirksamkeit und Vertriig/ichkeit von Oxerutinen und Roj3kastanien-Extrakt
bei Patienten mit chronischer venoser Insuffizienz
Oxerutine (O-(�-Hydroxyethyl)rutoside, HR, Venoruton®) und Ro8kastaniensamenextrakt (HCE) sind
die Wirkstoffe der Wahl zur medikamentosen Behandlung der chronischen Veneninsuffizienz. In zahlrei­
chen, doppelblinden, randomisierten, Plazebo-kontrollierten klinischen Studien wurde die odemprotektive
Wirkung dieser l?,eiden Wirkstoffe belegt. Neben dem Vergleich der beiden Wirkstoffe hinsichtlich ihrer
therapeutischen Aquival�pz war es <las Ziel dieser Studie, das Initial- und Erhaltungsdosierungskonzept
fiir HR einer klinischen Uberpriifung an 137 postmenopausalen Patientinnen mit CVI II zu unterziehen.
Die Studie wurde nach einem doppelblinden Design mit zufiilliger Zuordnung der Patientinnen zu den drei
Behandlungsgruppen iiber 19 Wochen (1 Woche Plazebo-Run-in, 12 Behandlungswochen und 6 Wochen
Nachbeobachtung) durchgefiihrt. HR wurde mit I 000 mg/d und Ro8kastaniensamenextrakt mit 600 mg/d
dosiert. Fiir die Initial- und Erhaltungsdosierungsgruppe wurden fiir die .�rsten 4 Wochen 1000 mg/d und
danach 500 mg/d dosiert. Konfirmatives Hauptzielkriterium (einseitige Aquivalenzfragestellung) war die
Abnahme des Beinvolumens in Form der Flache unter der Kurve iiber die Studiendauer, welches mittels
validierter Wasserverdrangungsmethode gemessen wurde. Die subjektiven Kriterien wurden deskriptiv
ausgewertet. In allen Behandlungsgruppen wurde in der Behandlungsphase <las Beinvolumen signifikant
und relevant reduziert. HR erwiesen sich als mindest�ns aquivalent oder besser im Vergleich zu Ro8-
kastaniensamenextrakt. Die AUB0_18, d. h. die Odemreduktion iiber die Studiendauer betrug
-5273 ± 11 418 ml· d nach Behandlung mit 1000 ml/d HR, -3187 ± 10 842 ml· d unter dem Initial- und
Erhaltungskonzept mit HR und -3004 ± 7429 ml · d unter Behandlung mit HCE. Beide Wirkstoffe
besitzen einen Carry-over-Effekt. Mittels Erhaltungsdosierung kann bei HR der mit der Initialdosierung
erzielte therapeutische Erfolg stabilisiert werden.

Key words CAS 7085-55-4· Horse chestnut· Oxerutins· Venoruton®, clinical studies· Venous insuffi­
ciency, chronic

Arzneim.-Forsch./Drug Res. 46 (I), 483-487 (1996)

Arzneim.-Forsch./Drug Res. 46 (I), Nr. 5 (1996)

Rehn et al. - Oxerutins and horse chestnut extract 483
1. Introduction
Chronic venous insufficiency (CVI) is a very common
disease and represents a major medical and socio-eco­
nomic problem. A relevant part of the population in
Western Europe is suffering from CVI, which is pro­
gressively disabling or altering patients' quality of life [l,
2]. Besides compression therapy the systemic pharma­
cological treatment is widely used to manage the symp­
toms of CVI, e.g. leg oedema, tired legs, etc. According
to this symptomatic objective of the pharmacological
treatment drugs with proven anti-exsudative and oed­
ema protective efficacy are mainly used, e.g. oxerutins,
horse chestnut extract. Although numerous randomized,
double-blind, placebo controlled clinical studies have
been performed in the last two decades showing clinical
efficacy of these drugs [3, 4, 5], the value of the treat­
ment is not fully recognized or even controversely dis­
cussed. But in the general physician's and special phle­
bologist's practice the use of these drugs is well accepted
and acknowledged [6, 7, 8].
The process of revalidation of drugs was carried out
with different priorities with regard to indications, com­
missions for chemical or phytochemical drugs, etc. This
has led to the curious situation that the horse chestnut
extract revalidation process was finished in early I 994
leading to a monography stating the pharmacological
activities and clinical efficacy [9] whereas for oxerutins
the revalidation process did not come to an advanced
state. As the revalidation process was legally stopped ac­
cording to the 5th Amendment of the German Drug
Law it was meaningful to compare the two leading
pharmacological principles with regard to its clinical ef­
ficacy and tolerability using state of the art scientific and
formal methods, e.g. GCP etc.
Additionally there was a second, scientific objective for
this study. It is known that treatment with oxerutins re­
sults in a remarkable carry-over effect on leg volumes
and other symptoms of CVI [10, 11]. As CVI is a disease
requesting continuous treatment it was interesting
whether an initial/maintenance dose posology, i.e. treat­
ment start with a higher loading dose and continuation
of treatment with a lower maintenance dose, does meet
the demands under therapeutical conditions.
2. Subjects, material and methods
2.1. Drugs
2.1.1. Oxerutins
Oxerutins (O-(�-hydroxyethyl)rutosides) are a standardized
mixture of hydroxyethyl derivatives of rutin of which the tri-
7,3' ,4' -hydroxyethylrutoside (tri-HR or troxerutin, CAS 7085-
55-4) is the quantitatively major component - around 38 %.
Several recent studies have shown that other components of
oxerutins, in particular the di-7,4' -hydroxyethylrutoside (di­
HR) and the mono-7-hydroxyethylrutoside, are more effective
than tri-HR on experimental models of free radical scavenging
[12-15] and microvascular permeability [16, 17]. Also clinical
criteria such as leg volumes and subjective symptoms were more
effectively improved by oxerutins compared to troxerutin [18].
Oxerutins were used for the study as commercially available film
tablets containing 500 mg oxerutin/film tablet (Venoruton®
intens; batch No. 93044)1l.
2.1.2. Horse chestnut extract
The semen of horse chestnut contains a mixture of triterpen
glycosides named aescin. This mixture is used for standardiza­
tion of the extract. In experimental models aescin was proven
to have anti-exsudative and anti-oedematuous activity like the
oxerutins. It decreases the permeability of vessel walls for low
I) Manufacturer: Zyma GmbH, Munich (Germany).
molecular proteins, water, and electrolytes. The monography [6]
states as clinical indication the treatment of symptoms of CVl
as leg oedema, tired, heavy legs, etc. for extracts in sustained
release formulations.
Horse chestnut extract was used for the study as capsules con­
taining 300 mg HCE standardized to 50 mg aescin/capsule
(batch No. 90085 T).
2.1.3. Placebo
According to the double dummy procedure both for oxerutin
film tablets and horse chestnut extract capsules ident-tcally ap­
pearing placebo film tablets or capsules were used (batch Nos.
DPH 93001 and 15064).
2.2. Patients
2.2.1. Inclusion criteria
Female postmenopausal patients, maximum age of 70 years,
with uni- or bilateral CVI grade II [22] were included in the
study. Patients had corona phlebectatica paraplantaris, clinical
persistent oedema, low-grade skin alterations e.g. hypo- or hy­
perpigmentation, athrophie blanche, etc., but without severe
dermatosclerosis. Patients must have had a doppler sonography
and a phlebological status in the past 6 month.
2.2.2. Exclusion criteria
Patients with leg oedema not due to venous diseases of the legs,
aged over 70 years, women with childbearing potential, decom­
pensated cardiac insufficiency, current acute phlebitis or throm­
bosis, renal insufficiency, liver disease, and other relevant dis­
eases e.g. diabetes mellitus etc. were excluded from the parti­
cipation. Pretreatment which could potentially have influence
on the results of the study e.g. regular compression therapy
within the last 4 weeks, treatment with other venous drugs for
the last 6 weeks, use of laxatives with influence on fluid or elec­
trolyte balance within the last 8 days, treatment with theophyl­
line, diuretics, cardiac glycosides angiotensin converting enzyme
(ACE) inhibitors or calcium antagonists within the last 8 days
and changes in the postmenopausal hormone replacement ther­
apy within the last 2 months was an additional exclusion cri­
terion. As concomitant therapy all the above mentioned treat­
ment as well as compression therapy were excluded. Patient who
participated in other clinical trials within 30 previous days were
not allowed to participate.
2.3. Design
The study was carried out according a double-blind, double
dummy design with randomized allocation of the patient to the
treatment groups. Twelve centers participated in this multi­
center trial. Three different treatments were investigated: oxeru­
tins 1000 mg/d (OXl000), oxerutins 1000 mg/d (loading dose
for 4 weeks) and following 500 mg/d (OXI000-500), i.e. initial
and maintenance dose concept, and horse chestnut extract 600
mg/d (HCE).
The whole study lasted for 19 weeks. Following a 1 week pla­
cebo run-in period the drug treatment was provided for 12
weeks followed by a 6 weeks follow-up period without medical
treatment. This follow-up period served for the investigation of
the carry over effect (Fig. I).
The placebo run-in period of 1 week was choosen in order to
standardize the conditions for all treatment groups. During this
week all patients were closely screened for compliance and
could get familiar with the requirement of the participation in
the study. In addition the study personnel was trained with the
techniques used for the evaluation of the efficacy criteria, espe­
cially the water-displacement method.
treatment phase
OX 1000
�-------1' □>------
�
placebo: 6-����
, o_o:��----------�- -=-=-1� .i�=.::: -.:§
run� �
I
-----0-----0-----j
HCE
s o, T
2
•4 '
.,eeks
T
10
•t2 14 J
I',/,
':ii
Fig. I: Flow chart of the study. D Evaluation times.
_ �•u:ii--F�rsch./Drug ��•· 46 (I), Nr. 5 (1996)
2.4. Dosage and administration
The study medications were administered orally. During the 12
weeks treatment period the patient took one filmtablet and cap­
sule (containing either verum or corresponding placebo) in the
morning and in the evening after the respective meal. Compli­
ance was checked by pill count of the returned medication.
Patients suspected to have taken more than 75 % of the medica­
tion were regarded as compliant.
2.9. Advisory board
The study was accompanied by an independent scientific advis­
ory board in order to ensure today's demands for a clinical
study with regard to methodological and scientific aspects
(Prof. Dr. G. G. Belz, Wiesbaden, Prof. Dr. H. Kleinsorge,
Mannheim, Prof. Dr. W. Lehmacher, Cologne/Germany).

2.5. Trial. procedures 3. Results

After general medical examination, laboratory testing, and hav­ The results are presented in detail for the study popula­
ing given informed consent the patient was included in the tion subset which completed the study according to the
study. There were no other selection criteria than the defined protocol. There have not been any relevant differences
inclusion and exclusion criteria. between the per protocoll subset and the intend to treat
The volume of the more effected leg was assessed by water­ subset with regard to the study results and the conclu­
displacement at eight visits (Fig. 1). At each visit these measure­ sions drawn from it.
ment were carried out twice. In order to minimize external in­
fluences the patients were asked to come to the study center if
possible at the same time on the evaluation days. All measure­ 3.1. Demographics
ments were carried out following a 45 min temperature and In total 158 female Caucasian patients were recruited in
cardiovascular adaptation (sitting position/room temperature). order to reach the calculated sample size of 130. 155 of
The subjective symptoms i.e. tired heavy legs, sensation of ten­ them fulfilled all the study conditions and were entered
sion, and tingling sensation were evaluated at the same occa­
tions as the leg volumes by means of a 10 cm visual analogue into the intent-to-treat population as defined by the pro­
scale (VAS). Safety and tolerability of the dru �s used were as­ tocol. Three patients were excluded from the efficacy
sessed by means of clinical laboratory evaluat10ns, changes in analysis as they did not reach the treatment phase and
physical examination, and vital signs. Adverse event were asses­ only limited data of the placebo run-in phase were avail­
sed at every visit. able. 137 patients completed the study according to the
protocol. 21 patients were excluded from the per proto­
2.6. Leg volumes col subset for major protocol deviations, i.e. premature
Despite the development of sophisticated methods for the as­ discontinuation (n = 17), unsatisfactory compliance (n =
sessment of the leg volume changes, e.g. optoelectronic 1), and intake of excluded concomitant medication (n =
methods, nuclear magnetic resonance methods, the most prac­ 3).
tical method is the water displacement [19]. For this study the At baseline the three treatment groups were homogen­
geometry of the water-displacement tool was optimized, i.e.
water surface reduced, in order to reduce measuring error. The eous with regard to demographic data (age, height and
reproducibility of this method was validated and is character­ weight), vital parameters (blood pressure and heart
ized by a mean coefficient of variation of 0.14 % for a standard rate), and efficacy criteria (leg volume, l),nkle and calf
inanimate body and of 0.48 % for human subjects [20]. circumferences, and subjective symptoms). There were
no statistically significant differences between the treat­
2.7. Primary efficacy criterion and biometric considerations ment groups (Table 1).
The trial objective was a comparison of three treatments. The More than 90 % of the patients suffered from CVI in
primary efficacy criterion was the area under baseline of the both legs. The grade of severity was nearly equally dis­
baseline adjusted leg volume over time curves from day zero tributed between left and right leg. There was no rele­
until the end of the follow-up period (AUB0_18) calculated by vant difference regarding this distribution between the
means of the trapezoidal rule. Missing data were intrapolated, three treatment groups.
if possible, or the method of last value carry forward was used.
The calculation of the AUB's was based on the individual study The diagnosis of the venous disease leading to CVI
days. Baseline adjustment was carried out by calculating differ­ grade II was based on anamnestic and clinical findings
ences between leg volumes on the different evaluation times and and additional apparative examination. The phlebolog­
leg volume on day 0 (V,-V, = 0) As all patients had a one week ical status as examined by ultrasound-doppler, light
placebo run-in prior to day 0 the leg volumes on this day were reflexion rheography (LRR) or duplex-sonography was
regarded as a reliable baseline. comparable for the three treatment groups. Out of the
For the confirmatory test of the primary efficacy criterion a
one-sided, stratified t-test appropriate for the analysis of a mul­
ticenter study according to Pleiss [21] was used. By the a priori
defined stepwise testing procedure the alpha level of 0.05 was
warranted. In the first step equivalence or superiority was con­ Table 1: Patients' characteristics.
cluded, if the hypothesis
H0: MttcE - standardised difference > Mox OXl000 OXI000-500 HCE
was rejected in favor of oxerutins (standardized difference =
1.0). If equivalence or superiority for oxerutins was concluded N 51 35 51
t-tests for superiority were carried out. For the comparison of Age (y) 58.4±9.41 62.8±7.45 59.0 ± 8.97
Weight(kg) 74.9 ± 10.8 77.5±11.35 81.2±17.11
OXl000 and HCE a sample size of 50 patients per group was Height(cm) 163.0 ± 4.69 162.1 ± 6.23 164.8±6.37
considered as sufficient (power > 0.99). For the comparison be­ BP, syst.(mmHg) 136.1±17.7 141.1 ± 19.24 137.5 ± 18.64
tween OXl000-500 and HCE a sample size of 30 patients was BP, diast.(mmHg) 81.9±8.68 85.1± 8.26 84.3 ± 8.91
calculated as sufficient (power = 0.99). Heart rate (beats/min) 71.6±7.22 73.2±6.5 74.0 ± 8.75
A total sample size of 130 patients (each 50 for the oxerutin Leg volume(ml) 2182 ± 329 2220±265 2219±452
and horse chestnut extract group and 30 for loading dose/main­ Tired, heavy legs(cm) 4.1 ± 2.9 3.8 ±2.6 3.0±2.2
tenance group) was considered to be sufficient. Tension (cm) 3.6 ± 3.0 4.0±2.8 2.8±2.3
Tingling(cm) 2.8 ± 2.7 3.1±2.6 1.9±2.2
Diagnoses•!
2.8. Ethics Pr. varicosis of superficial
veins(%) 96.6 86.5 95.2
The declaration of Helsinki and it's amendments were fully re­ Pr. varicosis of Vv.
spected. The study protocol was submitted to the responsible perforantes(%) 78 75.7 79
Ethics Committee and positively voted. The patients gave oral Primary deep venous
(in presence of a witness) or written informed consent. The insufficiency(%) 1.7 5.4 1.6
GCP-guidelines were fully respected as well as the §§ 40, 41 of Postthrombotic
the German Drug Act. syndrome(%) 15.3 21.6 12.9
�n individual dec�ding unit containing _emergency ident\fica- •J Multiple counts possible.
tion of the respective treatment was provided for each patient. ________________________
e rs 1
!��� �r:i�-,F°_ ;;�:��� �;� �.��•J::;,�,/!::?L"' 485
Table 3: VAS of subjective symptoms. Absolute values and changes are of a 4-week's 1000 mg treatment until week 12. There
presented in cm. was even a further, remarkable increase in mean volume
OXI0OO OXl000-500 HCE reduction from week 4 to 12. As the responder fraction
remained constant in this period this increase can be as­
Tired, heavy legs (cm) sociated to an increased volume reduction. This result is
Baseline value 4.1:1:2.91 3.8:1:2.6 3.0 :1:2.2 of practical socio-oeconomic significance. It opens the
Change of symptom
Week4 -1.0:1:2.5 -0.5 :1:2.1 0.8:1:2.3 possibility to treat the patients for a relatively short time
Week8 -1.2:1:3.1 -0.5:1:3.6 -0.0:1:2.2 with the higher initial dose until the desired effect is rea­
Week12 -1.3:1:3.4 -1.4:1:3.1 -0.3:1:1.9 ched and in order to speed up the onset of perceivable
Week15 -0.8 :t 3.0 -1.3 :I: 3.1 -0.2 :1: 2.1
Week18 -1.5 :t 3.0 -1.0:1:3.3 -0.2 :1: 2.5 efficacy. This level of efficacy is maintained by the re­
duced maintenance dose in an oeconomical way.
Sensation of tension (cm) As already found in earlier studies also in this study the
Baseline value 3.6 :1: 3.0 4.0 :t 2.8 2.8 :1: 2.3
Change of symptom carry-over effect of treatment with oxerutins was con­
Week4 -0.7:1:2.7 -0.5:1:2.7 0.5 :1: 2.1 firmed. Also for HCE a similar carry-over effect was
Week8 -0.7:1:3.2 -0.5:1:3.4 0.3:1:2.6 seen as in the OXl000-500 group. The carry-over is obvi­
Week12 -1.0:1:3.5 -1.4:1:3.7 -0.3:1: 2.2 ously more pronounced in theOXlO00 group. This find­
Week15 -0.8:1:3.2 -1.3:1:3.1 -0.3 :1: 2.2
Week18 -1.3:1:3.0 -1.7:1:3.3 -0.1 :1: 2.7 ing also indicates that both drugs act according to a sim­
ilar mode of action as expected from the pharmacolog­
Tingling sensation (cm) ical data.
Baseline value 2.8"'2.7 3.1:1:2.6 1.9 :1: 2.2
Change of symptom Generally it is to note that both tested drugs are able to
Week4 -0.9:1:2.2 -0.1 "'2.0 0.2 "' 2.1 achieve a mean leg volume reduction of about 100 ml
Week8 -0.9:1:2.6 --0.1:1:2.6 0.0 :1: 2.6 after 12 weeks treatment in responding patients. This is
Week12 -0.9 :1:2.5 --0.7:1:3.0 0.1 :1: 2.5
Week15 -0.9:1:2.1 -0.8:1:2.9 0.2 :1: 2.2 a therapeutic relevant amount of oedema reduction and
Week18 -I.I± 2.3 --0.7 :1: 2.8 0.8 :1: 2.8 comparable to values reported or calculated for com­
pression therapy (Wienert, V., personal communication;
[24]). The findings confirm the therapeutic value of the
pharmacological treatment of CVI and supports the cur­
(5 , 1 %) in the OXl000 group, 6 of 37 (16 ,2 %) in the rently published statements.
OXl000-500 group, and 2 of 62 (3,2 %) in the horse
chestnut group. The symptoms reported were unspecific
gastrointestinal complaints, headache and dizziness of 5. References
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Mensch Gesellschaft IO, 286 (1985) - [3] Belcaro, G., Rulo, A.,
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4. Discussion D., Amendt, K. et al., VASA 21, 188 (1992) - [5] McLennan,
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With regard to the equivalence question it may be con­ Rehn, D., Unkauf, M., Vix, J.-M., Pharm. Ztg. 27, 2152
cluded that 1000 mg oxerutins are at least equivalent or (1994) - [12] van Acker, S., Towart, R., Hiisken, B. et al., 17th
superior to horse chestnut extract in the dose accepted European Conference on Mikrocirculation, London, July 5-10
(1992) - [13] Bast, A., Jansen, F., Haenen, G., 17th European
as therapeutically active by the monography. In numer­ Conference on Mikrocirculation, London, July 5-10 (1992) -
ical terms the main efficacy criterion AUB0_18 in the [14] Rekka, E., Kourounakis, P., J. Pharm. Pharmacol. 43, 486
OXlO00 group is twice as high as in both other groups (1991)-(15] Nees, S., 17th European Conference on Mikrocir­
(p = 0 .1 ). Due to the interindividual variance of the culation, London, July 5-10 (1992)- [16] Kendall, S., Towart,
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on the 5 % level with regard to the primary criterion July 5-10 (1992) - (17] Michel, C., Blumberg, S., Clough, G.,
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W. et al., Arzneim.-Forsch./Drug Res. 43 (D, 335
seem to be based on a higher intrinsic potency but on a Diebschlag,
(1993) -(19] Marshal, M., Loew, D., Phlebology 23, 85 (1994)­
higher responder fraction of the study population. (20] Frank, J., Wienert, V., VASA, in press - [21] Fleiss, I., The
Whereas the leg volume reduction in responders is not Design and Analysis of Clinical Experiments, pp. 150 ff., Wi­
different between both groups the fraction of responders ley & Sons, New York (1986) - [22] Widmer, L. K., Stiihelin,
following therapy with OXl000 is superior to that with H. B., da Silva, A., Venen-, Arterien-Krankheiten, koronare
HCE on the 2 % level (p = 0 .0238). The subgroup of Herzkrankheiten bei Berufstatigen, Verlag Hans Huber, Bern­
responders was conservatively defined as in this chronic Stuttgart etc. (1981) -(23] Marshal, M., Dermatologie 23, 248
disease an inhibition of worsening would also be re­ (1993)
garded as therapeutic effect. Such patients were excluded
from the responders population as this information was
not available from the data.
The assumption of superiority ofOXlO00 versus 600 mg
HCE is supported by the finding that even the reduction
of leg oedema in the OXl000-500 group is equivalent to
the reduction obtained within the HCE group.
With regard to the initial dose/maintenance dose con­
cept the study has shown that a maintenance dose of Correspondence: Dr. Dieter Rehn, do Zyrna GmbH,
500 mg oxerutins is at least able to maintain the effect Zielstattstr. 40, D-81379 Miinchen (Germany)
Arzneim.-Forsch./Drug Res. 46 (I), Nr. 5 (1996)
n ...L... n♦ ,.1 /"'\ .,,._,+;... ,.. ,.,..,{ J..,.....,,. ,.J.."'"'+.n,,♦ •vt.--.,-♦ 487