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Oral Iloprost in the Treatment of Thromboangiitis Obliterans (Buerger's Disease): a Double-Blind, Randomised, Placebo-Controlled Trial

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Oral Iloprost in the Treatment of Thromboangiitis Obliterans (Buerger's Disease): a Double-Blind, Randomised, Placebo-Controlled Trial Eur J Vasc Endovasc Surg 15, 300-307 (1998) Oral Iloprost in the Treatment of Thromboangiitis Obliterans (Buerger's Disease): a Double-blind, Randomised, Placebo-controlled Trial The European TAO Study Group Objectives: To assess efficacy and tolerability of two dosages of the oral prostacyclin analogue iloprost versus placebo in thromboangiitis obliterans (TAO). Design: Placebo-controlled, double-blind, study; TAO patients randomised to iloprost 100, 200 pg, or placebo bid for 8 weeks, with 6 months' follow-up. Methods: Three-hundred and nineteen TAO patients with rest pain, trophic lesions (or both)from 23 clinics in six European countries. Primary endpoint: total healing of most important lesion. Secondary endpoint: relief of rest pain without need of analgesics. Combined endpoint: alive without major amputation, no lesions, no rest pain, no use of analgesics. Results: Total healing of lesions was not significantly different between treatment groups at any time point. For relief of rest pain without need of analgesics, low dose (LD) iloprost was significantly more effective than placebo at end of follow-up (placebo 49%; LD iloprost 63%; p=O.020). This also applied to the combined endpoint (placebo 35%; LD iloprost 50%; p = 0.016). High dose iloprost (HD) failed to show significant treatment effects over placebo. Conclusions: Iloprost LD was significantly more effective than placebo for relief of rest pain without need of analgesics and for a combined endpoint, at 6 months offollow-up, whilst both iloprost doses showed no significant effects vs. placebo on total healing of lesions. Key Words: Thromboangiitis obliterans (TAO, Buerger's disease); Trophic lesions; Ischaemic rest pain; Iloprost; Efficacy; Safety. Introduction symptoms in these patients has been iloprost, a prosta- cyclin analogue that stimulates blood flow and has Thromboangiitis obliterans (TAO), also known as vasodilatory and platelet inhibitory action. 15 In a pre- Buerger's disease, is a non-atherosclerotic in- vious double-blind trial, 133 patients with TAO were flammatory obliterative disease of the small and randomly selected to receive either intravenous ilo- medium sized arteries. 1-6 This disease occurs pre- prost or aspirin. 7 Analysis showed that 63% of patients dominantly in young Caucasian men who are heavy treated with iloprost were entirely free of ischaemic smokers ~-6 but all races and both sexes can present rest pain, compared with 28% of patients treated with with TAO. 4-6 aspirin at the end of the 28-day treatment period Cessation of smoking is the most important step (p<0.05 in favour of iloprost). Also, ischaemic ulcers in the management of TAO. 2'4-4 There is much un- healed completely in 35% of the study group, com- certainty on the efficacy of the numerous drugs (vaso- pared with only 13% in the control group. At 6 months, dilating agents, anticoagulants, non-steroidal anti- the overall response rate (combined pain relief and/ inflammatory drugs) assessed in the treatment of this or ulcer healing) was 88% in the group given iloprost disorder. ~4 Calcium channel blockers have occasion- vs. 21% in the group given aspirin (p<0.05 in favour ally been reported to reduce both the frequency and of iloprost). severity of Raynaud attacks in TAO patients. 1 How- A major drawback to intravenous use of iloprost ever, no placebo-controlled, double-blind studies have is the need for hospitalisation of patients. An oral been performed with these drugs. formulation of iloprost (iloprost clathrate extended- The most promising drug treatment to improve release capsules) has now been developed, which would allow treatment on an outpatient basis and for longer periods of time. Studies in human volunteerss and in patients with either peripheral atherosclerosis9 Please address all correspondence to: M. Verstraete, Centre for Molecular and Vascular Biology,Campus Gasthuisberg, Herestraat or TAO 1° have demonstrated that doses from 50 gg up 49, B-3000 Leuven,Belgium. to 200 gg taken twice daily show an acceptable safety 1078-5884/98/040300+08 $12.00/0 © 1998 W.B. Saunders CompanyLtd. Oral Iloprost in Thromboangiitis Obliterans (TAO) 301 and tolerability profile. The aim of the present trial or placebo). From day 2 onwards patients had to take was to investigate the effectiveness of oral iloprost in two capsules of their medication twice daily (200 gg the treatment of TAO patients with rest pain with or iloprost per day, 400 gg iloprost per day or placebo). without trophic lesions. Apart from the lower dose on day 1 a change of dosage was not permitted during the trial. In case of intolerance to the trial medication during the first 4 days of treatment, study medication was discontinued Materials and Methods and the patient was withdrawn from this study and transferred to a complementary open trial. The trial was a randomised, placebo-controlled, During the 8-week treatment period the use of drugs double-blind study conducted in 22 centres in six aimed for the treatment of TAO (e.g. aspirin, pen- countries: Bulgaria, Poland, Portugal, Greece, France toxiphylline, naftidrofuryl, dextran, loftyl), as well as and Israel (see appendix for list of investigators). intravenous heparin and oral anticoagulants were not permitted. Drugs for the treatment of concomitant diseases, subcutaneous heparin, local wound and limb Patients care (including local debridement or amputation), anti- biotics and physical procedures (e.g. positional ex- To be considered for the trial, patients had to fulfil all ercise, slow walking, body heating, hyperbaric oxygen) of the following criteria: age under 50 years, current were permitted. smoker or history of smoking, angiographic criteria compatible with TAO with typical arteriographic find- Treatment phase and follow-up ings, e.g. skip lesions below the popliteal artery and/ or corkscrew collaterals (Martorell's sign) or direct Patients were hospitalised at least during the first collaterals below the knee in the absence of ath- week of treatment. Blood pressure and heart rate were erosclerotic lesions (based on an aortoarteriogram measured hourly for 4 h after each administration of which had to be performed within 5 years before entry medication. At the end of week 1 the patients could into the trial) and current or history of superficial be discharged from the hospital and continue the trial thrombophlebitis or vasospastic symptoms. as out-patients but had to return on weeks 2, 4 and 6 Patients were excluded from the study if they had for a clinic visit. At the end of week 8 (end of treatment), diabetes mellitus, treated or untreated hypertension a closing examination and the assessments scheduled (systolic BP>160 mmHg/diastolic BP>95 mmHg), for this visit were performed and documented. The hypercholesterolaemia (>260 mg/dl), atrial fibrillation following variables were evaluated at each visit: num- (or other known causes of arterial embolism) and ber of trophic lesions and healing of the most important sympathectomy within the last 3 weeks of entering lesion determined at baseline, assessment of rest pain the study. Oral anticoagulants had to be stopped 1 and consumption of analgesics, blood pressure and week before randomisation. Additionally, all TAO heart rate, Doppler pressures, ECG, haematology, patients had to have rest pain, ischaemic lesions of the thromboplastin and prothrombin times, clinical chem- extremities, (or both) of sufficient severity to require istry and urine dipstick, smoking habits, superficial hospitalisation and specific treatment. thrombophlebitis and vasospastic symptoms (Ray- naud phenomenon), blood sampling for compliance check, adverse events, concomitant medication, as well as interventions, including major and minor am- Randomisation and drug administration putations and revascularisations. This examination had to be carried out for all patients who had been Patients satisfying the criteria for selection and who randomised, even if the study drug was terminated gave their written informed consent were randomly prematurely. assigned to one of three treatment groups: 200 gg After the end of treatment, patients were followed iloprost per day, 400 gg iloprost per day, or matching up for a further 6 months. Examinations were per- placebo. The iloprost capsules contained either 50 gg formed after 1 month, 3 months, and 6 months. or 100 #g iloprost and were taken twice daily, in the morning and afternoon, for 8 weeks. The interval Endpoints between the morning and afternoon dose was 5 h. On day 1, all patients received one capsule twice Primary efficacy endpoint was the number of patients daily (100 gg iloprost per day, 200 gg iloprost per day with total healing of the trophic lesion judged as most Eur J Vasc Endovasc Surg Vo115, April 1998 302 The European TAO Study Group important by the investigator at baseline (ulcer or input as non-healing. Due to the multiple comparisons gangrene/necrosis). The most important lesion was of the two iloprost groups and placebo, a Bonferroni regarded as healed only if the physician's assessment correction of the type I error of significance (~) was was graded as "totally healed". applied. The corrected ~ was 0.025. The analysis was The two following endpoints were applicable to based on the "intent-to-treat" population (ITT) for all patients: secondary endpoint was the number of patients with lesions at baseline. patients with relief of rest pain without need for The same strategy has been used for the secondary analgesics in patients with rest pain at baseline. A efficacy endpoint, the number of patients with total patient was totally relieved of rest pain if the intensity relief of rest pain without need for analgesics for of rest pain was judged as "no pain" and no analgesics patients with rest pain at baseline. Additional variables were used. for efficacy were analysed using a Mantel-Haenszel A combined endpoint, including the two major test for dichotomous variables or an extended Mantel- symptoms of TAO, i.e. trophic lesions and rest pain, Haenszel test with modified ridit scores for ordinal as well as major amputations (above the ankle), was parameters.
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