View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector JACC Vol. 24, No. 5 November 1, 1994:llfil-8 to treatment with II clinical event rate In patients who undergo coronary artery bypass surgery, the been associated with superior early and late patency rates of internal mammary artery is considered to be the bypass internal mammary artery grafts. One year after operation, 76% conduit of choice. There is evidence (l-4) that, compared with to 93% of vein grafts are open and at the end of 10 years only saphenous vein grafts, internal mammary artery grafts improve 41% to 63% remain patent (1, 5-7). The yearly attrition rate long-term survival and decrease the incidence of recurrent increases from 2% for the 2nd to 7th postoperative year to 5% angina and cardiac events. This beneficial clinical outcome has over the next 5 years (5). In contrast, l-year and IO-year patency rates of internal mammary artery grafts are 88% to 96% and 69% to 83%, respectively (1,6,7). Early vein graft From the Department of Cardiology, University Hospital, Groningen, The occlusion is frequently due to thrombosis and probably intimal Netherlands: *Departmentof Cardiac Surgery,St. Antonius Hospital,Nieuwegein, The Netherlands; TDepartmentof Cardiology,University Hospital, Basel, Switzer- hyperplasia, whereas progressive atherosclerosis of the graft is land; $Department of Cardiac Surgery, Medical Center De Klokkenberg and the main determinant of late occlusion (5,6,8). Atherosclerosis BDcpartmentof Cardiolou, Ignatius Hospital, Breda, The Netherlands, and /De- has rarely been o!xerved in internal mammary artery grafts partment of Cardiology,Academic Medical Center, Amsterdam,The Netherlands. #A complete list of CABADASinvestigators has been publishedin Reference 11. (5,6). This study was supported by Grant 86.078from The NetherlandsHeart Foundation, It has been demonstrated persuasively (930) that patency The Hague and by funds from Dr. Karl Thomae GmbH, Biberach an der Riss. of vein grafts at 1 year is improved by antiplatelet drclgs. Germany; Boehringerlngelheim BV, Alkmaar,The Netherlands:and the Interuni- versity CardiologyInstitute of Tbe Netherlands, Utrecht. Whether these or other antithrombotic drugs have fc similar Manuscript received July 6,1993; revised manuscript received May 18.1994, favorable effect on internal mammary artery grafts iS not accepted June 2,1994. known. To compare the effects of various antithrombotic drug ass for correspondence: Dr. Jan van der Meer, Thoraxcenter, Univer- sity Hospital, P.O. Box 30.001,9700RB Groningen, The Netherlands. regimens in patients who had received internal mammary 01994 by the American College of Cardiology 073%1097/94/57.0n JAW Vol 24. No. 5 1182 VANDEK MEER ET AL. ANTlTHROMBOTIC AGENTS AFTER ARTERIAL BYPASS GRAFTING November 1, 1994:1181-S artery grafts, we analyzedthe data derived from CABADAS prothrombin times at a target range of international normal- (Prevention of Coronary Artery Bypass Graft &!usion by ized ratio (INR) between 2.8 and 4.8. Antiplatelet drugs, &pifin, Dipyridamole and Acenocoumaro!/Phenprocoumon unless assigned, were not allowed. Acetaminophen was pro- study) (11). The primaryobjective of this prospective,random- vided as a substitute for aspirin as analgesic. ized clinical trial was a comparison of the efficacy and safety Surgery. lnterna! mammary artery grafts were imp!anted of I) a low dose of aspirin, 2) a low dose of aspirin plus according to the routine techniques of each participating d@idamo!e, and 3) oral anticoagulantagents in the preven- hospital. The decision to use these grafts was made by the tion of vein graft occlusionduring the 1st year after coronary surgeon before randomization.Internal mammary artery grafts bypass surgery. Aspirin and aspirin plus dipyridamolewere were single (one distal anastomosis)or sequential (more than compared in a placebo-controlled,double-blind design. Oral one distal anastomosis),and free graftswere used occasionally. anticoagulantagents were evaluated in a third open treatment The lumen of the grafted coronary artery was measured by arm because of logisticreasons associated with the necessary calibrated probes at the xteriotomy site and as distally as l&~rctrary control for dose adjustments in patients receiving possible. Endnterectomy was performed at the discretion of these drugs, More than half of the patients received internal the surgeonif coronaryarteries were mammary artery grafts in addition to vein grafts. This sub- administeredduring oFration, was group was the subject of the present study. sulfateat the end of the pr~ed~~e unlessthe i intraaortic balloon pump required prolonged heparinizntion. Total postoperativeblood loss through chest tubes and any requiredblood transfusionswere recorded. ieats. From July 1987through August 1990,948 Fo!~ow-us.After discharge front the !r ta!. follow-up underwentelective aortocoronaty bypasssurgery visits were scheduled at 3-month intervals coronary an- with saphenous vein grafts for treatment of disablingangina giography at 1 year after operation. A questionnaire was were entered into the trial by 10 participatinghospitals. The addressedto the cardiologist1 year after operation if a patient present study group contained 494 of these patients who had been withdrawnfrom the trial. At follow-upvisits, clinical received internal mammaty artery grafts in addition to vein and !&oratory data were collected and an ~lectro~drdiogram grafts. Exclusioncriteria have been described in detail previ- (ECG) w corded. Compliancewas assessedby pi!!count in ously (11) and included age >70 years; unstable angina or both aspi roups. Prothrombin time was measured regularly myocardia!infarction <2 and <7 days before operation,respec- in patients who received oral anticoagulant agents. Coronary tiveb previousor concurrentcardiac operation; need for contin- angiographywas not performed 1 year after oFration if it had ued antithromboticdrug therapy; increased risk of bleeding; been done for medical reasons ~3 months previously or if known allew or intoleranceto the trial medication;impaired previous angiography already showed vein graft occlusion, a renalor hepaticfunctian; concomitant severe disease, and allero primary end paint of the vein graft patency study. to contrast agent impedingability to repat coronaryangiogra- Angiogmphic end points. Internal mammary artery grafts phy. The use of previouslyprescribed antiplatelet drugs or ora! were visualizedby selective injection.A graft was classifiedas anticoagulantagents had to be discontinued814 and ~5 days, undefined if selective injectionfailed for technical reasons and respectively,&fore spention. All patients!!ave informed written no retrograde filling of the graft with contrast agent at coro- taco! was approvedby the ethicseommittee of nary angiographywas demonstrated. A graft was defined as occluded if occlusion was visualizedat selective injection. A Shyly medication, Patients were randomly allocated to distal anastomosiswas defined as occluded if contrast agent receive either aspirin plus dipyridamole placebo, aspirin plus failed to flow from the graft into the grafted artery. If a dipyridamole,or oral anticoagulantagents. They were assigned sequentialgraft was occluded at its origin, all associateddistal to one of these drug regimenson the day before operation by anastomoses were considered occluded unless a retrograde the pharmacist of the participating hospital, according to a flowof contrast agent from the grafted artery into the graft was randomizationlist provided by the study coordinatingcenter. demonstrated. Patientswere stratifiedby center, Treatment was started either Angiograms were reviewed by independent experienced before (dipyridamole,oral anticoagulant agents) or after (as- cardiologists,members of the angiographyclassification com- pirin) operation. Dipyridamolewas administered by intnve- mittee who had no knowledge of the patient’s group assign- nOUsinfusion (5 mg&gbody weight per 24 h) from 8 PM on the ment, and a consensus was reached. day before operation until midnight after operation and was C!!ru?ealend points. Myocardia!infarction, thromboembo- continued orally in a slow release form (200 mg twice daily). lism, major bleeding and death were primary clinical end Treatment with aspirin (50 mg once daily) was started at points. Myocardia!infarction was diagnosed accordingto ECG midnight after operation; the first dose was administered criteria. Thromboembolism was established by appropriate through a nasogastrictube. Ora! anticoagulanttreatment was techniques. Bleeding was defined as major if life-threatening started on the day before operation and continued on the 1st or fatal and if blood transfusion or a repeat operation was postoperative day. The dose of oral anticoagulant agents, necessary. Death was classified as cardiac, due to throm- either acenocoumaro! or phenprocoumon, was adjusted to bosis, due to bleeding or due to other causes, according to JAW Vol. 24, No. 5 VAN DER MEER ET AL. 1883 November 1. 1994:1181-8 ANFITMROIbfBOTiC AGENTS AFTER ARTERIAL BYPASS GRAFl-ING ings. SecQnda~clinical en rent angina, heart failure and o the left anterior coronary artery; 86% of sequential grafts were placed to a incidence events (secondary end diagonal branch and then to the left anterior descending equally distributed among the groups. operation to angiographywas 372 days grams were not availablein 65 patients because of death (n = 6) withdrawal from the