UvA-DARE (Digital Academic Repository) Diagnostic and therapeutic management of venous and arterial disease Bernardi, E. Publication date 2003 Link to publication Citation for published version (APA): Bernardi, E. (2003). Diagnostic and therapeutic management of venous and arterial disease. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. 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UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:27 Sep 2021 CHAPTERR 10 ANTITHROMBOTICC DRUGS IN THE PRIMARY MEDICALL MANAGEMENT OF INTERMITTENT CLAUDICATION N AA META-ANALYSIS Girolamii B, Bernardi E, *Prins MH, tten Cate JW, Prandoni P, *Hettiarachchii R, Marras E, Stefani PM, Girolami A, fBüller HR Thrombosiss Haemostasis 1999;81:715-722 Fromm the Institute of Medical Semiotics, University Hospital of Padua, Italy; thee *Department of Clinical Epidemiology, and the tCentre for Haemostasis, Thrombosis,, Atherosclerosis and Inflammation Research, Academic Medical Centre,, University of Amsterdam, the Netherlands Thee 1st and 2nd authors equally contributed to thee work and writing of the paper Summary y Backgroundd - There is no consensus on the efficacy of the antithrombotic drugss available for patients with intermittent claudication. Methodss - A Medline and manual search was used to identify relevant publi- cations.. Uncontrolled or retrospective studies, double reports or trials without clinicall outcomes were excluded. Included studies were graded as level 1 (ran- domisedd and double- or assessor-blind), level 2 (open randomised), or level 3 (non-randomisedd comparative). Mortality, cerebro- or cardiovascular events, amputations,, arterial occlusions or number of revascularisation procedures per- formedd in the lower limbs, pain-free and total walking distance, ankle brachial indexx and calf blood flow, were the main outcomes considered. When feasible, endd of treatment results, either continuous or binary, were combined with appropriatee statistical methods. Resultss - Mortality was significantly decreased by ticlopidine compared to placeboo (common OR, 0.68; 95% CI, 0.49 to 0.95); clopidogrel decreased vas- cularr events in comparison to aspirin (OR, 0.76; 95% CI, 0.63 to 0.92) in level 155 5 11 studies. Arterial occlusions and the number of revascularisation procedures performedd were statistically significantly decreased by aspirin and ticlopidine, respectively.. A small but statistically significantly improvement in pain free walk- ingg distance was determined by picotamide, indobufen, low molecular weight heparins,, sulodexide and defibrotide, in small studies. Conclusionss - Clopidogrel and ticlopidine do reduce clinically important events inn patients with intermittent claudication and could be added to the primary medicall treatment of these patients. The use of aspirin in these patients cannot bee based on direct evidence, but only on analogy with coronary and cerebral atherosclerosis,, where it has documented efficacy. Other antithrombotic drugs weree not properly evaluated in patients with intermittent claudication. Introduction n Intermittentt claudication and the underlying peripheral arterial disease is a commonn invalidating disorder of the Western society. In males, the prevalence approximatess 5% in males over 50 years of age, while the incidence raises from 0.2%% per year at the age of 501-2 to 1 % per year among those older than 65.3 Moreover,, in patients with peripheral arterial disease, total mortality is increased inn comparison to the general population, mainly due to an augmented risk of vascularr death.24 Sincee platelets and thrombosis play a central role in the atherosclerotic process, itt is reasonable to evaluate the usefulness of antithrombotic, and in particular antiplatelett drugs, as a primary treatment in these patients. Even more so, since itt is well documented that patients with coronary atherosclerosis do benefit fromm antiplatelet therapy.5 Moreover, in patients with peripheral arterial disease whoo have undergone a revascularisation procedure, aspirin improves patency, whilee a beneficial effect on mortality is likely.6 Finally, the role of antithrombot- icc drugs in the primary medical treatment of peripheral arterial obstructive dis- easee is still debated.7 Therefore, we performed a meta-analysis to evaluate the evidencee on the effectiveness of antithrombotic drugs, whose action in pre- ventingg clot formation is primarily a consequence of antiplatelet or anticoagu- lantt effects, in patients with intermittent claudication with regard to walking distance,, vascular events and mortality. Materialss and Methods WeWe performed a Medline search on English-language medical literature (1976 - Junee 1998), supplemented by manual searches on references of pertinent 156 6 reviewss and articles, to identify studies on intermittent claudication (key words: atherosclerosis,, intermittent claudication, peripheral vascular diseases). Studiess were eligible for inclusion if they evaluated primary treatment of inter- mittentt claudication in patients at stage II of disease according to Fontaine8 withh antithrombotic drugs, independently of their design. Studies regarding selectedd populations (hypertensive, dislipidaemic, diabetic patients), or evalu- atingg merely analgesic treatment, were not considered. The quality of this selec- tionn process was evaluated on a random sample of one hundred articles analysedd by three independent operators (BG, EB, MHP), achieving a Kappa rangingg from 0.90 to 0.95. Studies were excluded if uncontrolled, retrospec- tive,, duplicating other published material or not adequately defining or assess- ingg at least one of the following outcomes: pain-free or total walking distance, anklee brachial index, calf blood flow, number of lower limb arterial occlusions, numberr of revascularisation procedures performed in the arteries of the lower limbss (angioplasty, bypass graft, endarterectomy, thromboendarterectomy), numberr of amputations in the lower limbs, cerebro- or cardiovascular events (stroke,, myocardial infarction) or mortality. Included trials were graded by two independentt observers (BC, EB) as level 1 (randomised, double-blind or with blindd assessment of the outcome), level 2 (other randomised trials) or level 3 (non-randomisedd comparative studies). Level 3 studies were considered only if levell 1 data were not available. Dataa from included studies were extracted by two independent observers (BG, EB)) using a standardised form and summarised in tabular format. Since our pur- posee was to give a quantitative summary estimate of treatment effect, the cri- teriaa used for inclusion in the final summary measure of effectiveness was that thee report enabled direct extraction or derivation of a difference in effect betweenn the treatment groups and its common standard deviation (continuous outcomee measures) or of the exact proportion of the outcome events in each groupp (binary outcome measures). Whenever possible, outcome data, expressedd as means and standard deviations or as proportions, were combined usingg appropriate meta-analytical statistical procedures.910 Only results obtainedd at the end of the treatment period were compared, provided that baselinee values for the (continuous) outcomes considered were comparable amongg studies. The statistical advisability of combining the results of different trialss was estimated by means of a statistical heterogeneity test, which apprais- ess whether differences in treatment effect over individual trials are consistent withh natural variation around a constant effect. Results were expressed as (com- mon)) differences of the means or as (common) odds ratios, with 95% confi- 157 7 dencee interval (95% Cl). In case of disagreement at any step of the meta-ana- lyticall process, consensus was reached by adding a third observer (MHP). Results s Outt of 60 potentially eligible studies, 3 were uncontrolled,1113 2 were double reportss 1415 of other publications,1617 and 1 did not evaluate clinical outcomes.18 Thus,, 54 studies were further evaluated. Among these, 44 assessed the efficacy off an active drug in comparison with placebo or no treatment (Table i);16171960 Tablee 1 - Studies on the efficacy of antithrombotic drugs in the primary medical treat- mentment of intermittent claudication Author r Level l Sample e Runn in Activee Drug Duration n * * t t t t Regimenn § II I Aspirinn ( Dipyridamole) Schoop,, 1983 ,9T* 1 1 200/100 0 -- 990 0 5y y Hess,, 1985 20 ft 1 1 160/80 0 -- 990 0 33 m n Roztocil,, 1989 $$ 1 1 34/35 5 -- 1200 0 iy y Mannarino,19911 " §§ 2 2 10/10 0 Yes s 330 0 66 m Belcaro,, 1991 " 3 3 57/22 2 -- 1000 0 iy y Dipyridamole e Libretti,, 1986 ,6 1 1 27/27 7 -- 2255 Hu 66 m Ticlopidine e Aukland,, 1982 ^ 33/32 2 11 m, p 500 0 iy y Cloarec,,