Europ.J.clin. Pharmacol. 9, 387-392 (1976) © by Springer-Verlag 1976

Arwin ® in Peripheral Arterial Circulatory Disorders: Controlled Multicentre Trials G. K. Wolf Institut ffir Medizinische Dokumentation, Statistik und Datenverarbeitung Universit~t Heidelberg, Heidelberg, Federal Republic of Germany

Received:

May 6, 1975, accepted:

September

23,

der

1975

Summary. The effect of Arwin ® on peripheral arterial occlusive disease has been studied in two multicentre trials. In the first, in cases of severe peripheral arterial circulatory disorders of the lower extremities with permanent rest pain (stages III and I I I + IV according to Fontaine) Arwin ® had a better intravenous therapeutic effect %han anticoagulant treatment. A further trial was done to investigate whether subcutaneous administration of Arwin ® would have an effect superior to classical conservative therapy with vasodilator drugs in this type of disease. The results were assessed by sequential analysis. Arwin ® was again shown to be a much better treatment. Problems of medical documentation and statistics are discussed in relation to the value of sequential analysis. Key words: Defibrinogenisation, peripheral medical statistics, sequential analysis.

Arwin ® contains a thrombin-!ike proteolytic enzyme derived from the venom of the Malayan pit viper (Agkistrodon rhodostoma) as active principle. The split product of fibrinogen produced by this enzyme can polymerize at a sufficiently high concentration, but cross linkage and stabilization, as in the physiological formation of fibrin, do not take place. The split products are eliminated from the blood by the endogenous fibrinolytic system (I). Thus, Arwin ® is a product which used appropriately makes possible a controlled reduction in fibrinogen concentration. This involves a corresponding decrease in the coagulability of the blood, as wel~ as a reduction in blood viscosity (2,3,4). In thrombotic processes and in subacute and chronic peripheral arterial disease the vascular wall and the viscosity of the blood may be regarded potentially as points of therapeutic attack. Arwin® could be expected to be of therapeutic value since it has effects at both these sites. The following report is of two con-

arterial disease,

clinical

trial design,

trolled therapeutic studies. The first was to test whether Arwin ® possessed any therapeutic activity greater than simple anticoagulant treatment. In addition to demonstrating any beneficial effect of Arwin ®, the study was also designed to show if the reduction of viscosity was in any way relevant to the therapeutic effect. A second trial was required to show whether the effect of Arwin ® was better than conventional therapy which acts on the vascular wall. Both studies were designed from the beginning as multicentre studies and the simultaneous investigations in several hospitals made special demands on the planning, e.g. the experimental arrangement was tested first in a pilot study. Special emphasis was placed on ensuring randomization in the clinic and on analysis of questionnaires. Even in the pilot study the questionnaires were designed in such a way that essential problems were raised repeatedly in different ways. Thus, questions were asked if vascular disorder of stage III was present, and if there was pain at

388

p e r m a n e n t rest. The t h e r a p e u t i c e f f e c t was d o c u m e n t e d by asking if rest pain had d i s a p p e a r e d , if a n a l g e s i c s w e r e no longer used, and if i m p r o v e m e n t o c c u r red; the latter was d e f i n e d in an acc o m p a n y i n g letter as d i s a p p e a r a n c e of rest pain. STUDY I: M E T H O D P a t i e n t s in w h o m a p e r i p h e r a l a r t e r i a l c i r c u l a t o r y d i s o r d e r of stage III acc o r d i n g to Fontaine, i.e. p e r m a n e n t rest pain, had b e e n d i a g n o s e d from the a p p r o p r i a t e c l i n i c a l signs w e r e the t a r g e t p o p u l a t i o n of the study. T r e a t m e n t was i n t e n d e d to p r o d u c e c o m p l e t e d i s a p p e a r a n c e of the p e r m a n e n t rest pain. S u b j e c t i v e i m p r o v e m e n t s w h i c h did not r e a c h this goal, and i n c r e a s e d blood flow w i t h o u t this t h e r a p e u t i c success w e r e j u d g e d as failure. P a t i e n t s w e r e i n c l u d e d in the study if they f u l f i l l e d c e r t a i n r e q u i r e m e n t s : they had to agree to e x p e r i m e n t a l emp l o y m e n t of both forms of t r e a t m e n t in the study, i.e. A r w i n ® or heparin, and there had to be some c h a n c e of success w i t h both types of therapy. P a t i e n t s in w h o m s u r g i c a l o p e r a t i o n for r e m o v a l of b l o o d c l o t was i n d i c a t e d w e r e excluded. P a t i e n t s who had r e c e i v e d s t r e p t o k i n a s e could not be i n c l u d e d in the study b e c a u s e of their f r e q u e n t lack of c i r c u l a t i n g p l a s m i n o g e n , w h i c h is a c o n t r a i n d i c a t o n to Arwin®. O t h e r types of p a t i e n t e x c l u d e d w e r e those w i t h any risk of h a e m o r r h a g e , severe h y p e r t e n s i o n , shock, p r e g n a n c y , neoplasm, c a r d i a c i n s u f f i c i e n c y or r e c e n t m y o c a r d i a l infarction, or w h o had a pace-maker. In o r d e r to o b t a i n g r e a t e r homog e n e i t y p a t i e n t s w e r e d i v i d e d into 3 strata; they w e r e d i v i d e d by sex and for m a l e s also a c c o r d i n g to age, the age limit b e t w e e n the 2 g r o u p s of m a l e s was t a k e n as the 56th birthday. Any r e m a i n i n g i n h o m o g e n e i t y b e t w e e n patients was e l i m i n a t e d by s t r i c t randomi z a t i o n w i t h i n the strata. R a n d o m i z a tion was done by use of r a n d o m numbers. For a l l o c a t i o n to a t r e a t m e n t g r o u p sealed envelopes containing information on the m o d e of t r e a t m e n t w e r e used. In order to a v o i d any bias the e n v e l o p e s were o p e n e d only after all the abovem e n t i o n e d c r i t e r i a had been satisfied. In this w a y two fully c o m p a r a b l e groups of p a t i e n t s were generated, one to be t r e a t e d w i t h A r w i n ® and the o t h e r w i t h heparin. One g r o u p r e c e i v e d A r w i n ® a c c o r d i n g to the f o l l o w i n g scheme: on the Ist day 4 units of A r w i n ® / k g of body w e i g h t for 8 hours, as a slow drip i n f u s i o n in an inert solution, or by m e a n s of an in-

f u s i o n pump. F r o m the 2nd to 7th day i n c l u s i v e 2 a m p o u l e s (= 70 units) of Arwin ® were slowly injected intravenously in the m o r n i n g and the evening. Control patients received heparin 15000 units s u b c u t a n e o u s l y twice a day for 7 days, or at least a dose suff i c i e n t to e n s u r e that the t h r o m b i n time at the end of the t r e a t m e n t p e r i o d was still twice its i n i t i a l value. Thus, the d u r a t i o n of t r e a t m e n t was 7 days in all cases. D o u b l e - b l i n d c o n d i t i o n s could not be a t t a i n e d b e c a u s e special therapeutic observations were necessary in each group. The f o l l o w i n g l a b o r a t o r y tests w e r e p e r f o r m e d b e f o r e and i m m e d i a t e l y after t e r m i n a t i o n of treatment: ESR, hemoglobin, h e m a t o c r i t , leucocyte, e r y t h r o cyte and t h r o m b o c y t e count, d i f f e r e n t i a l b l o o d count, u r i n e tests for protein, g l u c o s e and sediment; s e r u m GPT and CPK, a l k a l i n e p h o s p h a t a s e , b i l i r u b i n , creatinine, uric acid, urea and total c h o l e s t e r o l ; total p r o t e i n and serum electrophoresis. I m m e d i a t e l y b e f o r e a d m i n i s t r a t i o n of Arwin®, or of h e p a r i n to the c o n t r o l group, each p a t i e n t u n d e r w e n t a short s t a n d a r d i z e d e x a m i n a t i o n . This i n c l u d e d e n q u i r y w h e t h e r rest pain was still present, if a n a l g e s i c s had been consumed (analgesics were c o n f i n e d to F o r t r a l and D o l a n t i n ) , and e v a l u a t i o n of skin c i r c u l a t i o n by its colour. B l o o d was taken for d e t e r m i n a t i o n of fibrinogen level a c c o r d i n g to Clauss, and for m e a s u r e m e n t of w h o l e b l o o d v i s c o s i t y . The t h e r a p e u t i c r e s u l t was e v a l u a t e d i m m e d i a t e l y after t e r m i n a t i o n of t r e a t m e n t and only those cases w e r e r e g a r d e d as s u c c e s s f u l in w h o m rest pain had d i s a p p e a r e d c o m p l e t e l y d e s p i t e disc o n t i n u a t i o n of the a n a l g e s i c medication. All d a t a o b t a i n e d w e r e r e c o r d e d on the q u e s t i o n n a i r e p r e p a r e d a c c o r d i n g to the p i l o t study and i m m e d i a t e l y a f t e r w a r d s it was a n a l y s e d s t a t i s t i c a l l y . It was p l a n n e d to stop the study as soon as the e f f e c t i v e n e s s of the t h e r a p y had been d e t e r m i n e d by m e a n s of s e q u e n t i a l b i n o m i a l test w i t h c l o s e d d e s i g n acc o r d i n g to A r m i t a g e (5). P a i r i n g for the s t a t i s t i c a l a n a l y s i s was done in such a w a y that each A r w i n ® p a t i e n t was c o m p a r e d w i t h a h e p a r i n p a t i e n t t r e a t e d in the same test centre, who b e l o n g e d to the same s t r a t u m and who was next in date of admission. The slight r e s i d u a l d i f f e r e n c e in time was b a l a n c e d by r a n d o m i z a t i o n . The limits of the s e q u e n t i a l statistical a n a l y s i s w e r e fixed in such w a y that the p r o b a b i l i t y of an e-error (superior e f f e c t d e s p i t e lack of any difference) was at m o s t 5% (~=0.O5) in a two sided test. The test was also

389

b a s e d on the a s s u m p t i o n that the success r a t i o e x p e c t e d w i t h h e p a r i n adm i n i s t r a t i o n for I w e e k a c c o r d i n g to c l i n i c a l e x p e r i e n c e w o u l d not e x c e e d 5% and that the s u c c e s s r a t i o after A r w i n s u f f i c i e n t to j u s t i f y the t h e r a p e u t i c e f f o r t w o u l d have to be at least 30%. The latter m i n i m u m s u p e r i o r i t y was to be found w i t h a c e r t a i n t y of at least 95% (I-6=0.95).

Within the patient pairs: Preference of Arwin 12

/

RESULTS A f t e r a d m i n i s t r a t i o n of A r w i n ® all the p a t i e n t s showed a c o n s i d e r a b l e d e c r e a s e in the level of fibrinogen. The initial c o n c e n t r a t i o n s of f i b r i n o g e n w e r e betw e e n 250 mg and 500 m g / I O 0 ml and after the first dose the v a l u e d e c r e a s e d b e l o w d e t e c t i o n limit of 30 m g / I O O ml. I m m e d i a t e e v a l u a t i o n of the therap e u t i c r e s u l t by m e a n s of the sequential plan (Fig. I) at the t e r m i n a t i o n of treatment showed a significant result after only 9 pairs of patients, and this led to c e s s a t i o n of the study. Of those pairs 7 p a t i e n t s showed the s u p e r i o r i t y of A r w i n ® and f a i l u r e a f t e r a d m i n i s t r a t i o n of heparin. In 2 cases n e i t h e r t r e a t m e n t led to any success. As 3 h o s p i t a l s p a r t i c i p a t e d in the trial there was a total of 10 p a t i e n t s t r e a t e d w i t h A r w i n ® and 5 w i t h h e p a r i n who c o u l d not be p a i r e d w h e n the study was term i n a t e d . T h e r a p e u t i c success was found in 7 of those p a t i e n t s t r e a t e d w i t h A r w i n ® and in none of those t r e a t e d w i t h heparin. Thus, a l t o g e t h e r the r e s u l t s were: no success in 14 p a t i e n t s on h e p a r i n and 14 s u c c e s s e s in 19 p a t i e n t s on A r w i n ®. N e g l e c t i n g the p o s s i b l e inf l u e n c e due to strata, b i n o m i a l 5%c o n f i d e n c e i n t e r v a l s for the s u c c e s s r a t i o after A r w i n ® and h e p a r i n w e r e 49% to 91% and 0% to 23%, r e s p e c t i v e l y . In r o u t i n e l a b o r a t o r y tests only 4 v a l u e s showed changes: after A r w i n ® the e r y t h r o c y t e s e d i m e n t a t i o n r e a c t i o n fell to a very low level even if it had b e e n h i g h before, w h e r e a s h e p a r i n led to a c c e l e r a t i o n . Both these r e a c t i o n s are a l r e a d y w e l l - k n o w n . F u r t h e r m o r e , treatm e n t w i t h A r w i n ® a p p e a r e d to r e s u l t in r e d u c t i o n of CPK (creatinine p h o s p h o kinase), u r e a and total serum cholesterol. However, as there were only 30 s a m p l e s in all it is p o s s i b l e that this was due to r a n d o m v a r i a t i o n . STUDY II: M E T H O D This was an a t t e m p t to d i s c o v e r w h e t h e r A r w i n ® was s u p e r i o r to the m o s t c o m m o n l y used t h e r a p y for p e r i p h e r a l a r t e r i a l blood d i s o r d e r s - R o n i c o l ® (HoffmannL a - R o c h e AG). In this c o m p a r i s o n the m a r k e d r e d u c t i o n of b l o o d c o a g u l a b i l i t y

-2

/

/

/

~,=o.o5

o.3

Number of preference

Preference_~o of heparin '~

Fig. i. Sequential evaluation of Study I. The two horizontal lines show 2 paired patients in whom no difference between modes of treatment was present

by A r w i n ® w o u l d no longer be important, only its e f f e c t in d e c r e a s i n g blood viscosity. C r i t e r i a for e x c l u s i o n and a l l o c a t i o n to p a r t i c u l a r s t r a t a w e r e as in S t u d y I. Again, s t r i c t c o m p a r a b i l i t y of p a t i e n t s r e c e i v i n g A r w i n ® or R o n i c o l ® was a c h i e v ed by a l l o c a t i o n u s i n g r a n d o m numbers. The d u r a t i o n of t r e a t m e n t w i t h A r w i n ® was 4 w e e k s and the total p e r i o d of o b s e r v a t i o n of the p a t i e n t s was 3 months. In the c o n t r o l g r o u p who r e c e i v e d R o n i c o l ®, t r e a t m e n t was c o n t i n u e d t h r o u g h out the e n t i r e p e r i o d of o b s e r v a t i o n . A r w i n ® was a d m i n i s t e r e d a c c o r d i n g to the f o l l o w i n g schedule: d u r i n g the first 4 days A r w i n ® IU/kg body w e i g h t / d a y was g i v e n s u b c u t a n e o u s l y , c h a n g e d on the 5th day A r w i n ® 4U/kg b o d y w e i g h t subc u t a n e o u s l y r e p e a t e d e v e r y 3 to 4 days. R o n i c o l ® was a d m i n i s t e r e d as u s u a l in the v a r i o u s trial centers. P a t i e n t s rec e i v e d i n f u s i o n s for I to 2 w e e k s and then the m e d i c a t i o n was c h a n g e d to oral a d m i n i s t r a t i o n . These p a t i e n t s also rec e i v e d a n t i c o a g u l a n t t h e r a p y w i t h Marcumar (Hoffman-La R o c h e AG). The t h e r a p e u t i c r e s u l t was e v a l u a t e d as in S t u d y I, b u t only for the first 4 days w e r e the tests p e r f o r m e d daily, and s u b s e q u e n t l y they were done w e e k l y up to 4 weeks, and a f t e r w a r d s monthly. Before t r e a t m e n t and after 4 w e e k s CPK, urea and total s e r u m c h o l e s t e r o l were m e a s u r e d . Also, a f t e r the m a i n t r e a t m e n t p e r i o d of 4 w e e k s the t h e r a p e u t i c re-

390

Plasma fibrinogen mg/lOOml

35C

250

150

50

|

1

I

2

....... *

3

i

4

....................

*

14

!

2t

...d...

ays

2

28

Fig. 2. Plasma fibrinogen curves during repeated subcutaneous injection of Arwin® in 13 patients in Study II

sult was a s s e s s e d for the s e q u e n t i a l analysis. A g a i n only those cases w e r e r e g a r d e d as s u c c e s s f u l in w h o m there was loss of rest pain d e s p i t e s t o p p i n g Fortral, the only a n a l g e s i c p e r m i t t e d in the study. For the s e q u e n t i a l analysis a c c o r d i n g to A r m i t a g e (5) m o r e rigorous c o n d i t i o n s were a p p l i e d in the second study. F r o m the p r e v i o u s study the success ratio of A r w i n ® could be e s t i m a t e d to be at least 50%. The success ratio after 4 weeks of t r e a t m e n t w i t h R o n i c o l ® was e s t i m a t e d from u n p u b l i s h e d clinical data to be 10%. C o n s i d e r i n g the i m p o r t a n c e of the c o n c l u s i o n it was d e c i d e d that the p r o b a b i l i t y of s-errors should be at m o s t I% (e=O.O1). A o n e - s i d e d test was applied, b e c a u s e n o n - i m p r o v e m e n t after A r w i n ® w o u l d have the same n e g a t i v e consequences for the p r e p a r a t i o n as a lower success ratio of A r w i n ® than of Ronicol®. The p r o b a b i l i t y of s-errors (missing the a b o v e - m e n t i o n e d m i n i m u m superiority) was limited to 5%. The rem a i n i n g data w e r e treated by d e s c r i p t i v e s t a t i s t i c a l m e t h o d s or either were subm i t t e d to a te~t analogous to the s e q u e n t i a l p r o c e d u r e chosen, i.e. a sign test, p a i r i n g being p e r f o r m e d a c c o r d i n g to the p r o c e d u r e p r o p o s e d by A r m i t a g e (5).

RESULTS In all the p a t i e n t s treated w i t h Arwin ® a slow d e c r e a s e in the f i b r i n o g e n level (Fig. 2) o c c u r r e d d u r i n g the initial phase of treatment, i.e. d u r i n g the first 4 days. The curves of f i b r i n o g e n level t h r o u g h o u t t r e a t m e n t showed that fibrinogen was kept at about I/3 of its initial concentration. I m m e d i a t e l y after the f i b r i n o g e n level had fallen to about 50% of the initial value, rest pain d i s a p p e a r e d from the patients treated w i t h A r w i n ®. In the p a t i e n t s t r e a t e d w i t h Ronicol ® who showed improvement, there was no a p p a r e n t r e l a t i o n to the c o m m e n c e m e n t of t r e a t m e n t (Fig. 3). A m o n g s t patients treated w i t h A r w i n ®, unlike those who r e c e i v e d Ronicol®, the c o n s u m p t i o n of a n a l g e s i c s ceased comp l e t e l y w i t h i n the t r e a t m e n t period (Fig. 4). E v a l u a t i o n of the t h e r a p e u t i c result at the end of the first t r e a t m e n t p e r i o d of 4 weeks by means of the sequential analysis showed a s i g n i f i c a n t result after 9 pairs of patients. Thus, A r w i n ® therapy a p p e a r e d superior to Ronicol ®. At the time w h e n the study was d i s c o n t i n u e d 6 p a t i e n t s w e r e still

391

Within the patient pairs: t

Preference 1£ of Arwin "~

Arwin

1

+

.....

+

.....

+

"//

+

+

Ronicol

.....

÷ +

÷

~ 2

Z

"

f&

21..... days

28

Fig. 3. Development of pain in the patients in Study II. Duration of pain during observation Duration of pain outside the observation period; Continuous analgesic medication required Fort ral Ln mg j

120 100 8O

Ronicot

6O

4C 20 Arwin

¼

Ii

2'1 days 28

Fig. 4. Consumption of analgesics by the two groups in Study II

under treatment. The result in those p a t i e n t s was recorded, too, and has been i n c l u d e d in the s e q u e n t i a l analysis (dashed line in Fig. 5). These cases make the result more striking. The results in 2 p a t i e n t s could not be i n c l u d e d in the analysis since comp a r a b l e p a t i e n t s of the same s t r a t u m

-2 " :2

"/ 0

'

'Nu'mbe'rof'pref~2e~e

Preference of Ronicol

Fig. 5. Sequential evaluation of Study If. Dashed line: result if 6 additional patients are included were not available. One of these patients had b e e n t r e a t e d w i t h Arwin®, with the r e s u l t rated as failure, the other had r e c e i v e d R o n i c o l ® w i t h success. There w e r e d i f f e r e n c e s in the results of l a b o r a t o r y tests done in the various centres, i.e. CPK, u r e a and total serum cholesterol. The d i f f e r ences b e t w e e n initial and final values, however, did not show any o b v i o u s relation to place or stratum. The changes from initial values w e r e s u b j e c t e d to a d e s c r i p t i v e s t a t i s t i c a l analysis. CPK did not show any clear t e n d e n c y to change, and in b o t h treatm e n t groups values i n c r e a s e d and dec r e a s e d w i t h a p p r o x i m a t e l y the same frequency. The same a p p l i e d to the urea m e a s u r e m e n t s . Both A r w i n ® and Ronicol ® led to a m a r k e d r e d u c t i o n in total cholesterol; the m e d i a n d e c r e a s e after A r w i n ® was 35 m g / I O O ml and it was m u c h less after R o n i c o l ® - only 14 m g / 1 0 0 ml. The sign test was a p p l i e d to the d a t a after p a i r i n g a c c o r d i n g to the procedure of the s e q u e n t i a l trial and the s e e m i n g l y f a v o u r a b l e e f f e c t of A r w i n ® was shown to be due to r a n d o m change. At the end of the total o b s e r v a t i o n p e r i o d of 3 m o n t h s the r e s u l t s were: In I p a t i e n t t r e a t e d w i t h A r w i n ® a r e l a p s e was seen after i m p r o v e m e n t during t r e a t m e n t p e r i o d of 4 weeks. This also a p p l i e d to I p a t i e n t t r e a t e d w i t h R o n i c o l ® who had p r e v i o u s l y shown improvement. A m p u t a t i o n of a leg was n e c e s s a r y in a n o t h e r p a t i e n t in the R o n i c o l ® group. S u m m a r y of the r e s u l t s showed 13 failures in 13 p a t i e n t s t r e a t e d w i t h R o n i c o l ® and 11 s u c c e s s e s in 13 p a t i e n t s t r e a t e d w i t h Arwin®. If the p o s s i b l e i n f l u e n c e due to strata

392

is a g a i n n e g l e c t e d , the I% b i n o m i a l c o n f i d e n c e i n t e r v a l s for the success r a t i o a f t e r A r w i n ® and R o n i c o l ® w e r e 46% to 99% and 0% to 33%, r e s p e c t i v e l y . DISCUSSION The p a t i e n t s i n c l u d e d in these studies s u f f e r e d from severe a r t e r i a l circulatory d i s o r d e r s . The s e v e r i t y of their d i s e a s e is s h o w n by the fact that success r a t i o a f t e r the c o n t r o l t h e r a p i e s a p p l i e d to the c o n t r o l g r o u p s w e r e a c t u a l l y as low as expected. In spite of this u n f a v o u r a b l e initial s i t u a t i o n and the p r e s e n c e of m a r k e d s y m p t o m s of c i r c u l a t o r y d i s e a s e A r w i n ® p r o v e d to be a h i g h l y e f f e c t i v e treatment. C o m p l e t e d i s a p p e a r a n c e of rest pain as a c r i t e r i o n for success in a nond o u b l e - b l i n d study has to be justified. This pain, however, is v e r y s e v e r e and c a n n o t r e a d i l y be ignored. In p a r t i c u lar, it is not p o s s i b l e for it to be s u p p r e s s e d by s u g g e s t i o n for a p e r i o d of 3 months, the l e n g t h of o b s e r v a t i o n in the s e c o n d study. M o r e o v e r , very c a r e f u l d o c u m e n t a t i o n of the cases w i t h m u l t i p l e r e c o r d i n g of the c r i t e r i o n of success did not show any d i s c r e p a n c i e s . It is i m p o r t a n t to realise, however, that every other criterion, too, could e i t h e r be d i s m i s s e d as s u b j e c t i v e , e.g. w a l k i n g distance, or, even if an obj e c t i v e c h a n g e in a p h y s i o l o g i c a l v a l u e w e r e detected, such as a d i f f e r e n c e in b l o o d flow, it is not c e r t a i n that it w o u l d r e p r e s e n t an e f f e c t s u f f i c i e n t for a t h e r a p e u t i c success. The first study s h o w e d that the p r o p h y l a c t i c e f f e c t of A r w i n ® a g a i n s t t h r o m b o e m b o l i s m was not the d e c i s i v e f a c t o r in its t h e r a p e u t i c success. The second study s t r e n g t h e n e d this r e s u l t as the t h e r a p e u t i c e f f e c t was q u i t e definitely maintained despite a smaller r e d u c t i o n in the f i b r i n o g e n level. The e x t e n t to w h i c h the small prophylactic action against thromboembolism of low doses a d m i n i s t e r e d s u b c u t a n e o u s l y led to t h e r a p e u t i c s u c c e s s on long t e r m a d m i n i s t r a t i o n will only be c l a r i f i e d in s p e c i a l l y d e s i g n e d studies. The d o c u m e n t a t i o n of the p a t i e n t s , w h i c h was i n t e n d e d to be r e d u n d a n t in e s s e n t i a l parts, a f f o r d e d p o s s i b i l i t y of a p p r o p r i a t e c o n t r o l s in the p r e s e n t study. If this w e r e not c a r e f u l l y employed, however, it m i g h t be that the c l i n i c i a n who c o l l e c t e d the data w o u l d s u b s e q u e n t l y have had to "correct" the r e s u l t s in i n d i v i d u a l cases. Use of r e s u l t s o b t a i n e d from c o n t r o l s to improve the m e t h o d s for later studies, as was d o n e here, was a v e r y u s e f u l procedure. S e q u e n t i a l s t a t i s t i c a l test p r o c e dures are still not used s u f f i c i e n t l y in c l i n i c a l studies. In the p r e s e n t studies, however, t h e i r e m p l o y m e n t was

m e d i c a l l y indicated: The c o n v e n t i o n a l t r e a t m e n t of p e r i p h e r a l a r t e r i a l circ u l a t o r y d i s o r d e r s in the stage of p e r m a n e n t rest pain has been r e g a r d e d as a l m o s t i n e f f e c t i v e up to present. T h e r e f o r e , the c o n t r o l g r o u p could not be larger than a b s o l u t e l y n e c e s s a r y for s t a t i s t i c a l decision. Only a s e q u e n t i a l p r o c e d u r e m a d e it p o s s i b l e to p e r f o r m a test for s i g n i f i c a n c e a f t e r o b t a i n i n g each result. W i t h the u s u a l n o n - s e q u e n t i a l m e t h o d s it w o u l d have been n e c e s s a r y to fix the sample size in such w a y that the smallest i m p o r t a n t d i f f e r e n c e c o u l d still be r e c o g n i z e d w i t h a s u f f i c i e n t l y high p r o b a b i l i t y . T h e r e f o r e , an u n n e c e s s a r i l y large n u m b e r of p a t i e n t s w o u l d have had to have b e e n i n c l u d e d in the study in case of a m o r e e f f e c t i v e therapy. The a d v a n t a g e of the s e q u e n t i a l p r o c e d u r e was d e m o n s t r a t e d by the fact that a s t a t e m e n t on s i g n i f i c a n c e could be m a d e m o r e r a p i d l y as the r e s u l t of a g r e a t e r e f f e c t than a n t i c i p a t e d .

Acknowledgements. The study was organized by P.W. Lficker, D-6719 Bobenheim am Berg, Am Rebst6ckel. The clinical investigations were conducted by Drs. H. Hess and E. Keil-Kuri, Univ.-Poliklinik, D-8OOO M~nchen, V. Tilsner, Chirurg. Univ.-Klinik und Poliklinik, D-2OO0 Hamburg, and H. Vinazzer, A-402 Linz, Blutgerinnungslaboratorien. The investigations in study II were performed by V. Tilsner, Chirurg. Univ.-Klinik und Poliklinik, D-2000 Hamburg and H. Vinazzer, A-402 Linz, Blutgerinnungslaboratorien. Arwin® was provided by Knoll AG, Ludwigshafen, Germany. REFERENCES I. Esnouf, M.P., Tunnah, G.W.: The isolation and properties of the thrombin-like activity from Ancistrodon rhodostoma venom. Brit. J. Haemat. 13, 581-591 (1967) 2. Chien, S., Osami, S., Dellenback, PoJ., Gregeren, M.I.: Influence of fibrinogen and globulin on blood-rheo!ogy at lower shearrates: Comparison among elephant, dog and man. In: Theoretical and clinical haemorheology. Proceedings of the 2nd International Conference 1969 (eds. H.H. Hartert, A.L. Coplea), pp. 144-153. Berlin: Springer 1971 3. Ehringer, H., Dudczak, R., Lechner, K.: Therapeutische Defibrinierung mit Ancrod. Dtsch. med. Wschr. 98, 2298-2304 (1973) 4. Ehrly, A.M.: Increased blood flow by improvement of the flow properties of blood: A new concept in the treatment of vascular diseases. VIII. International Congress of Angiology, Rio de Janeiro, 24.-30. July 1972 5. Armitage, P.: SequentZal medical trials. Oxford: Blackwell 1960 Dr. G.K. Wolf Institut ffir Medizinische Dokumentation Statistik und Datenverarbeitung der Univ. Im Neuenheimer Feld 325 69 Heidelberg I Federal Republic of Germany

Arwin in peripheral arterial circulatory disorders: controlled multicentre trials.

Europ.J.clin. Pharmacol. 9, 387-392 (1976) © by Springer-Verlag 1976 Arwin ® in Peripheral Arterial Circulatory Disorders: Controlled Multicentre Tri...
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