INFLUENCE OF POSTOPERATIVE ANTICOAGULANT TREATMENT ON PATIENT SURVIVAL AFTER FEMOROPOPLITEAL VEIN BYPASS SURGERY

797

INFLUENCE OF POSTOPERATIVE

Patients and Methods

ANTICOAGULANT TREATMENT ON PATIENT SURVIVAL AFTER FEMOROPOPLITEAL VEIN BYPASS SURGERY

recruited for the study. All patients had chronic arterial occlusive

E. WENZL1 G. KRETSCHMER1 P. POLTERAUER1 M. SCHEMPER1* L. MARÇOSI2 H. EHRINGER2 E. MINAR2 1st Clinic

and Angiology Unit, 1st Clinic of Medicine2 University of Vienna, Austria.

of Surgery1

Summary

To examine whether

anticoagulants given

after autologous saphenous bypass surgery influenced patient survival 119 patients who received such a graft for obliterative arterial disease were recruited for a controlled clinical trial. Patients were randomly assigned to start, in the second postoperative week, phenprocoumon (60 patients) or no treatment (59 patients). The median duration of survival for all patients was greater than 60 months, and the 75%-quartile was 39·0 (SE of the median 3·9) months. 10 patients died in the treated group and 20 in the control group. The treated group had a greater probability of survival (p<0·023, Breslow; p<0·043, Mantel). Graft occlusions occurred in 11 patients in the treatment group and in 17 controls. When these patients were excluded from the analysis, the difference in probability of survival between the two groups remained significant (p<0·009, Breslow;

p<0·013, Mantel). Introduction ALTHOUGH bypass grafting with autologous saphenous vein has for many years been a standard method for treating femoral or popliteal artery occlusions, there is still uncertainty as to whether and what measures should be instituted postoperatively to prevent re-occlusion.1,2 Retrospective univariate and covariate analyses of our clinical data did not reveal an influence of anticoagulant treatment on graft patency, althoug a favourable effect was apparent in controlled clinical trials.4Our retrospective and covariate analyses did show, though, that anticoagulants significantly prolonged the lives of patients who had undergone femoropopliteal saphenous vein bypass for peripheral arterial occlusive disease.6 We have thus investigated the possible influence of anticoagulants on postoperative patient survival in a controlled randomised clinical trial. *Present address: Department of Biomathematics, University of Texas SCC, Houston, Texas 77030, USA.

3.

Bendl BJ, Graham JH

New concepts on the origin of squamous cell carcinomas of the skin: solar (senile) keratosis with squamous cell carcinoma—a clinicopathologic and histochemical study Proc Natl Cancer Conf 1971, 6: 471-88 4. Montgomery H, Dorffel J. Verruca senilis und keratoma senilis Arch Dermatol Syph 1932, 166: 286-87 5. Mackie R. Tumours of the skin. In Rook A, Wilkinson DS, Ebling FJG,

eds. Textbook of dermatology. Oxford. Blackwell, 1986. 2375-478. Metastastic squamous cell carcinoma of the skin. In. Epstein E, ed. Controversies in dermatology Philadelphia : Saunders 1984: 134-37 7. Nixon RDL, Dorevitch AP, Marks R Squamous cell carcinoma of the skin: accuracy of clinical diagnosis and outcome on follow-up in Australia. Med J Aust 1986; 144:

6.

Morgan RJ.

235-39. 8 Marks R, Foley P, Goodman G, Hage BH, Selwood TS solar keratoses the case for conservative management

Spontaneous remission of Br JDermatol 1986;

115:

649-55 9 Ponsford

MW, Goodman G, Marks R. The prevalence and accuracy of diagnosis of non-melanotic skin cancer in Victoria Aust JDermatol 1983, 24: 79-82 guide. New York McGraw-Hill, 1983

10. SPSSX user’s

119

patients aged

not more

than 75 years

(mean 63-1)

were

disease at the femoropopliteal level and underwent elective surgery. Patients were staged pre-operatively according to Fontaine’s classificationA standard venous bypass was established with autologuos saphenous vein. Patients were randomly assigned to one of two groups--60 patients (treatment group) to receive phenprocoumon as anticoagulant, from the second postoperative week until death or reocclusion; and 59 patients to serve as untreated controls. Patients were followed-up as outpatients every 3 months during the first year and twice a year thereafter or at shorter intervals when required. The results of surgery were assessed clinically. Particular attention was paid to compliance with treatment and satisfactory stabilisation of coagulation, by monitoring prothrombin time (Quick value) and ’Hepatoquick’ (Boehringer, Ingelheim, FRG), or Thrombotest (’Nycomed’, Immuno AG, Vienna, Austria) results and modifying treatment if necessary. The goals were 15 to 25 % for Quick value, 10 to 20 % for hepatoquick, and 5 to 12% for thrombotest.

Statistical Methods The documentation system of the Austrian Society for Vascular Surgery was used to enter details of all surgical treatment procedures into a computer (180 variables per surgical intervention, more than 8000 operations since 1965). We had access to the IBM 4381 computer of the faculty of medicine. Data were stored on-line and retrieved with Statistical Analysis System (SAS) software. The use of SAS8 and the Biomedical Dixon Program BMDP-1L (Life)9 facilitated survival analysis. Patients were assigned to the two groups by adaptive

randoniisation.10 a method that allows optimum balancing of prognostic factors between groups-even for small random samples.ll Prognostic factors taken into consideration were sex, age, diabetes mellitus, blood pressure, and clinical status before surgery. The survival curves were analysed by the Kaplan-Meier method12 and differences between the two groups were checked with Breslow’s13 and Mantel’s14 tests. In 6 patients anticoagulant treatment was discontinued for various reasons: epistaxis 1, gastrointestinal haemorrhage 3, unknown cause 1, suspected cerebral stroke 1. Nevertheless, for evaluation these patients remained in the group to which they had BALANCING OF RISK FACTORS IN THE TREATMENT GROUP (TG) VERSUS CONTROL GROUP (0)

798

Fig 1-Probability of patient survival (Kaplan-Meier function) treatment (TG) and control (0) groups. Numbers above the curve (in parentheses) indicate patients numbers below indicate cumulative survival.

at

in

risk,

been assigned to originally (ie, the intention-to-treat principle).ls 1 patient, randomised to the control group, was put on phenprocoumon for cardiac reasons and had to be censored from that date on. The latest information about patients’ survival status was obtained from the Austrian Central Bureau of Statistics. To date no patient has been lost to follow-up.

Results The treatment and control groups were reasonably well matched (table). The median survival for all 119 patients was greater than 60 months, the 75% quartile being 39-0 (SE of the median [SE] 3-9) months. During follow-up 30 patients died-10 in the treatment group and 20 in the untreated group. 1 death was related to the anticoagulant treatment, most were due to patients’ underlying cardiovascular disease, and 3 (11 in the anticoagulated and 2 in the untreated group) were due to

malignancy. groups differed significantly in probability of survival (fig 1) (p < 0-023 Breslow, p < 0-043 patient The 75% Mantel). quartile for duration of survival was 68-8 for the treated patients and 33-4 (7-5) months (SE 9-8) months for the controls. Graft occlusion occurred in 28 patients—11in the anticoagulant and 17 in the control group. Patients with occluded transplants often require repeat surgery, which might be responsible for the demonstrated effect of treatment, but analysis confined to those patients whose grafts had remained patent throughout the observation period (fig 2) also showed that postoperative anticoagulant treatment had a highly significant effect on patient survival (p<0-009 Breslow, p<0-013 Mantel). The 75%-quartile for duration of survival was 68-3 (SE 33-0) months for treated patients and 26-5 (100) for controls.

The

two

Discussion Diabetes mellitus, hyperlipidaemia, hypertension, and smoking, alone or in combination, have an adverse effect on

Fig 2-Probability of patient survival (Kaplan-Meier function) in treatment (TG) and control (0) groups. Only patients with patent grafts are considered. Numbers above the curve patients at risk, numbers below indicate cumulative survival.

indicate

the natural history of peripheral arterial disease.16,17 In our study the two patient groups were well matched for these factors and for preoperative clinical stage. Patients with peripheral vascular disease are prone to fatal cardiovascular events,16-18 and anticoagulants can prevent thrombus formation and hence death from embolisation, but the treatment group and the controls were well matched in terms of the presence of cardiac risk factors and the presence of arrhythmias. Many patients required further operations for occlusions of the graft and their survival could conceivably have been shortened by this complication. Such shortening could have accounted for the differences in survival between our two groups since more transplants failed in the control group. However, when patients with occluded grafts were excluded from statistical analysis, the results in favour of anticoagulant treatment became even more striking. Our conclusion thus is that anticoagulants influence patient survival irrespective of graft performance. It was tempting to assume that anticoagulants prolong the life of arteriosclerotic patients by reducing the incidence of coronary events. There is controversy over whether to prescribe anticoagulants or antiplatelet drugs after myocardial infarction.19 The trend is to give anticoagulants,2O withdrawal of which, once started, may be dangerous.21 Antiplatelet drugs have also been found to be valuable after coronary events2z but their value has not been tested in severe peripheral arterial disease requiring femoropopliteal bypass surgery. However, the possibility that patients with peripheral arterial disease have a more active coagulation system plus a less active fibrinolytic system than patients with only coronary artery disease exclusively23 may account for the effect of anticoagulants reported here. Correspondence should be addressed to Wien, Alserstrasse 4, Austria.

A-1090

G.

K., I. Chirurg. Univ. Klinik,

799

Preliminary Communication PARTIAL TRISOMY CHROMOSOME 5 COSEGREGATING WITH SCHIZOPHRENIA ANNE S. BASSETT

BARRY D.JONES

BARBARA C. McGILLIVRAY1 J. TAPIO PANTZAR1

Department of Psychiatry, Health Sciences Centre Hospital, University of British Columbia, Vancouver, B.C., Canada V6T 2A1; and Department of Medical Genetics, Grace Hospital, University of British Columbia1

Schizophrenia was associated with a distinct autosomal abnormality in two related mildly dysmorphic individuals. The finding of cosegregation of schizophrenia and a partial trisomy of chromosome 5 in the family suggests a potential location of a gene or genes linked to schizophrenia. Summary

INTRODUCTION

SCHIZOPHRENIA affects 0-5-1% of the population.1’z Although the syndrome clusters in families the inheritance pattern is complex and does not follow Mendelian models.3 Specific gene involvement has not yet been proven. We report here some findings that may point to the location of such a gene. SUBJECTS AND INVESTIGATIONS The

family studied is of Asian descent, living in Vancouver, Canada. Two members of the family have schizophrenia-a 20-year-old male college student and his 52-year-old maternal uncle. The 20-year-old proband was admitted to inpatient psychiatric care with typical symptoms of acute schizophrenia (prominent auditory hallucinations and paranoid and bizarre delusions of four weeks’ duration). He had had no change in mood and there was no alcohol or drug history. He had deteriorated in social functioning and school performance and had had prodromal symptoms for several years. He met both International Classification of Disease (ICD-94) and DSM-III-R5 criteria for schizophrenia. His psychotic symptoms resolved with Grimley RP, Obeid ML, Ashton F, Slaney G. Long term results of autogenous vein bypass grafts m femoro-popliteal arterial occlusion. Br J Surg 1979; 66: 723-26 2. Waibel P, Geering P. Spatresultate der Antikoagulation bei Rekonstruktionen wegen Verschlußkrankheit der unteren Extremitaten. JVasc Dis 1981; 10: 308-09 3. Kretschmer G, Huk J, Polterauer P, et al Der autologe Venenbypass in der Therapie der arteriellen Verschlußkrankeit der femoropoplitealen Etage: Langseitresultate. Wr Klin Wchschr 1986; 98: 830-38. 4. Schneider E, Brunner UV, Bollinger A. Medikamentose Rezidivprophylaxe nach femoropoplitealer Arterienrekonstruktion. Angio 1979; 2: 73-77 5. Kretschmer G, Wenzl E, Wagner O, et al. Influence of anti-coagulant treatment in preventing graft occlusion following saphenous vein bypass for femoro-popliteal occlusive disease. Br J Surg 1986; 73: 689-92 6 Kretschmer G, Wenzl E, Schemper M, et al. Vein bypass surgery for femoro-popliteal 1.

arteriosclerosis

Influence of different risk factors on patient survival and the importance of anticoagulant treatment Eur J Vasc Surg (in press) 7. Fontaine R, Kim M, Kieny R. Die chirurgische Behandlung der arteriellen Durchblutungsstorungen. Helv Chir Acta 1954, 21: 499-533. 8 Users guide, basics. Cary, North Carolina; SAS Institute, 1985 9 Dixon WJ, Brown MD, Engleman L, et al. BMDP: statistical software Berkley University of California Press, USA. 1983. 10 Pocock SJ, Simon R Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial Biometrics 1975; 31: 103-15. 11 Schemper M. Randomisierung fur kontrollierte Therapiestudien. Wien Klin Wchschr 1982; 94: 604-09 12 Kaplan EL, Meier P Nonparametric estimation from incomplete observations. Am J Statist Ass 1958; 53: 457-81.

low-dose neuroleptic treatment (2 mg haloperidol daily). He subsequently had residual symptoms of low motivation, blunted emotions, and poverty of speech. The proband was noted on admission to have slightly different facial features from his parents. The mother remarked he looked similar to her brother who also had schizophrenia. This maternal uncle had had first onset of social withdrawal, paranoid delusions, and auditory hallucinations without prominent mood change at age 20. The psychosis had relapsed on several occasions, responding each time to low-dose neuroleptic treatment which he continues to take (100 mg chlorpromazine daily). He still has blunted emotions and low motivation, and meets ICD-9 and DSM-III-R criteria for chronic schizophrenia. Because of the conjunction of schizophrenia and subtle dysmorphic facial features the two men were examined thoroughly for other physical abnormalities and they proved to have the following constellation of structural abnormalities and features of schizophrenia: frontal bossing; flat occiput; hypertelorism (widely spaced eyes); overfolded protuberant ears; short stature ( < 3rd percentile); mild obesity; short 4th proximal phalanx (toe); partial syndactyly fingers and toes (soft tissue fusion); left kidney abnormal on ultrasound examination, possibly duplex (left kidney absent in proband’s maternal uncle); small phallus (< 10th percentile); full syndrome of schizophrenia meeting narrowly defined classification, with onset of acute psychosis at age 20 and responsiveness to low-dose neuroleptics. Neither individual had evidence of neurological impairment or mental retardation. No other family members have similar physical features or any history of mental illness. Cytogenetic studies revealed that the two men had an extra identical unbalanced male karyotype with chromosomal material in the long arm of chromosome 1 (fig 1). Chromosome analysis of the phenotypically normal mother of the proband showed the same abnormal chromosome 1 and one chromosome 5 with a deletion in the proximal long arm. Since the size and banding pattern of the additional material inserted into chromosome 1 correspond with those of the material missing from chromosome 5, the mother seems to carry a balanced insertion (fig 2). Both the proband and his uncle have inherited the same derivative chromosome 1 from a balanced 1;5 insertion carrier parent (the parents of the uncle were not available for karyotyping)

for comparing k-samples subject to 57: 163-65. Mantel N Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1965, 50: 163-65. Pocock SJ. Clinical trials. New York Wiley, 1984: 176-84 Da Silva A, Widmer LK. Peripher arterielle Verschlußkrankheit Bern: Hans Huber, 1979. Gordon T., Kannel WB Predisposition to atherosclerosis in the head, heart and

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legs-the Framingham study JAMA 1972, 221: 661-63 18 Berkoff HA, Levine RL Management of the vascular patient with atherosclerosis. Progr Cardiovasc Dis 1987; 29: 347-68

multisystem

JRA. Anticoagulants in coronary heart disease—retrospect and prospect Lancet 1981, i: 257-62 20. Loeliger EAA, Hensen F, Kroes L, Van Dijk MN, Fekkes N, De Jonge H, Hemker HC. A double blind trial of long term anticoagulant treatment after myocardial infarction Acta Med Scand 1967; 182; 549-66 21. Sixty plus reinfarction study research group A double blind trial to assess long term oral anticoagulant therapy in elderly patients after myocardial infarction Lancet 1980; ii: 989-93 19. Mitchell

22. Klimt Ch R, Knatterud GL, Stamler J, Meier P Persantin-aspirin reinfarction study, part II Secondary coronary prevention with persantin and aspirin J Am Coll Cardiol 1986, 7: 251-69

U, Diehm C, Sieben U, et al Pravalenz und Risikofaktoren von penpher-arteneller Verschlußkrankheit und Koronarer Herzkrankheit J Vasc Dis 1987, Suppl 21: 1-46

23 Muller-Buhl