PERIOP 2 - A Safety and Effectiveness of LMWH vs Placebo Bridging Therapy for Patients on Long Term Warfarin Requiring Temporary Interruption of Warfarin.

Summary

The purpose of the study is to determine the effectiveness and safety of LMWH postoperative bridging therapy (standard of care) versus postoperative placebo bridging therapy (experimental arm)for patients with mechanical heart valves or atrial fibrillation or atrial flutter who are at high risk for stroke when warfarin is temporarily interrupted for a procedure.

Timeline

Start

2006-12

Primary completion

2019-03

Completion

2020-12

Publications

• Background Tu JV, Gong Y. Trends in treatment and outcomes for acute stroke patients in Ontario, 1992-1998. Arch Intern Med. 2003 Feb 10;163(3):293-7. doi: 10.1001/archinte.163.3.293.
• Background Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med. 1997 May 22;336(21):1506-11. doi: 10.1056/NEJM199705223362107. No abstract available.
• Background Vongpatanasin W, Hillis LD, Lange RA. Prosthetic heart valves. N Engl J Med. 1996 Aug 8;335(6):407-16. doi: 10.1056/NEJM199608083350607. No abstract available.
• Background Cannegieter SC, Rosendaal FR, Briet E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation. 1994 Feb;89(2):635-41. doi: 10.1161/01.cir.89.2.635.
• Background White RH, McKittrick T, Hutchinson R, Twitchell J. Temporary discontinuation of warfarin therapy: changes in the international normalized ratio. Ann Intern Med. 1995 Jan 1;122(1):40-2. doi: 10.7326/0003-4819-122-1-199501010-00006.
• Background Kovacs MJ, Rodger M, Anderson DR, Morrow B, Kells G, Kovacs J, Boyle E, Wells PS. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism. A randomized, double-blind, controlled trial. Ann Intern Med. 2003 May 6;138(9):714-9. doi: 10.7326/0003-4819-138-9-200305060-00007.
• Background Madura JA, Rookstool M, Wease G. The management of patients on chronic Coumadin therapy undergoing subsequent surgical procedures. Am Surg. 1994 Jul;60(7):542-6; discussion 546-7.
• Background Eckman MH, Beshansky JR, Durand-Zaleski I, Levine HJ, Pauker SG. Anticoagulation for noncardiac procedures in patients with prosthetic heart valves. Does low risk mean high cost? JAMA. 1990 Mar 16;263(11):1513-21.
• Background Katholi RE, Nolan SP, McGuire LB. The management of anticoagulation during noncardiac operations in patients with prosthetic heart valves. A prospective study. Am Heart J. 1978 Aug;96(2):163-5. doi: 10.1016/0002-8703(78)90080-7.
• Background Stein PD, Alpert JS, Copeland J, Dalen JE, Goldman S, Turpie AG. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest. 1995 Oct;108(4 Suppl):371S-379S. doi: 10.1378/chest.108.4_supplement.371s. No abstract available.
• Background Douketis JD, Crowther MA, Cherian SS, Kearon CB. Physician preferences for perioperative anticoagulation in patients with a mechanical heart valve who are undergoing elective noncardiac surgery. Chest. 1999 Nov;116(5):1240-6. doi: 10.1378/chest.116.5.1240.
• Background Dunn AS, Turpie AG. Perioperative management of patients receiving oral anticoagulants: a systematic review. Arch Intern Med. 2003 Apr 28;163(8):901-8. doi: 10.1001/archinte.163.8.901.
• Background Douketis JD, Johnson JA, Turpie AG. Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: assessment of a standardized periprocedural anticoagulation regimen. Arch Intern Med. 2004 Jun 28;164(12):1319-26. doi: 10.1001/archinte.164.12.1319.
• Background Spandorfer JM, Lynch S, Weitz HH, Fertel S, Merli GJ. Use of enoxaparin for the chronically anticoagulated patient before and after procedures. Am J Cardiol. 1999 Aug 15;84(4):478-80, A10. doi: 10.1016/s0002-9149(99)00341-0.
• Background Kovacs MJ, Kearon C, Rodger M, Anderson DR, Turpie AG, Bates SM, Desjardins L, Douketis J, Kahn SR, Solymoss S, Wells PS. Single-arm study of bridging therapy with low-molecular-weight heparin for patients at risk of arterial embolism who require temporary interruption of warfarin. Circulation. 2004 Sep 21;110(12):1658-63. doi: 10.1161/01.CIR.0000142859.77578.C9. Epub 2004 Sep 13.
• Background Ferreira I, Dos L, Tornos P, Nicolau I, Permanyer-Miralda G, Soler-Soler J. Experience with enoxaparin in patients with mechanical heart valves who must withhold acenocumarol. Heart. 2003 May;89(5):527-30. doi: 10.1136/heart.89.5.527.
• Background Omran H, Hammerstingl C, Schmidt H, von der Recke G, Paar WD, Luderitz B. A prospective and randomized comparison of the safety and effects of therapeutic levels of enoxaparin versus unfractionated heparin in chronically anticoagulated patients undergoing elective cardiac catheterization. Thromb Haemost. 2003 Aug;90(2):267-71. doi: 10.1160/TH02-10-0159.
• Background Tinmouth AH, Morrow BH, Cruickshank MK, Moore PM, Kovacs MJ. Dalteparin as periprocedure anticoagulation for patients on warfarin and at high risk of thrombosis. Ann Pharmacother. 2001 Jun;35(6):669-74. doi: 10.1345/aph.10305.
• Background POLLER L, THOMSON J. EVIDENCE FOR
• Background Grip L, Blomback M, Schulman S. Hypercoagulable state and thromboembolism following warfarin withdrawal in post-myocardial-infarction patients. Eur Heart J. 1991 Nov;12(11):1225-33. doi: 10.1093/eurheartj/12.11.1225.
• Background Palareti G, Legnani C, Guazzaloca G, Frascaro M, Grauso F, De Rosa F, Fortunato G, Coccheri S. Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants--a prospective study. Thromb Haemost. 1994 Aug;72(2):222-6.
• Background Valles J, Aznar J, Santos T, Villa P, Fernandez A. Platelet function in patients with chronic coronary heart disease on long-term anticoagulant therapy: effect of anticoagulant stopping. Haemostasis. 1993 Jul-Aug;23(4):212-8. doi: 10.1159/000216877.
• Background Raskob GE, Durica SS, Morrissey JH, Owen WL, Comp PC. Effect of treatment with low-dose warfarin-aspirin on activated factor VII. Blood. 1995 Jun 1;85(11):3034-9.
• Background Genewein U, Haeberli A, Straub PW, Beer JH. Rebound after cessation of oral anticoagulant therapy: the biochemical evidence. Br J Haematol. 1996 Feb;92(2):479-85. doi: 10.1046/j.1365-2141.1996.d01-1499.x.
• Background Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet. 1996 Sep 7;348(9028):633-8.
• Background Weitz JI. Low-molecular-weight heparins. N Engl J Med. 1997 Sep 4;337(10):688-98. doi: 10.1056/NEJM199709043371007. No abstract available.
• Background Kovacs MJ, Weir K, MacKinnon K, Keeney M, Brien WF, Cruickshank MK. Body weight does not predict for anti-Xa levels after fixed dose prophylaxis with enoxaparin after orthopedic surgery. Thromb Res. 1998 Aug 1;91(3):137-42. doi: 10.1016/s0049-3848(98)00083-8.
• Background Cohen M, Demers C, Gurfinkel EP, Turpie AG, Fromell GJ, Goodman S, Langer A, Califf RM, Fox KA, Premmereur J, Bigonzi F. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med. 1997 Aug 14;337(7):447-52. doi: 10.1056/NEJM199708143370702.
• Background Low-molecular-weight heparin during instability in coronary artery disease, Fragmin during Instability in Coronary Artery Disease (FRISC) study group. Lancet. 1996 Mar 2;347(9001):561-8.
• Background Levine M, Gent M, Hirsh J, Leclerc J, Anderson D, Weitz J, Ginsberg J, Turpie AG, Demers C, Kovacs M. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996 Mar 14;334(11):677-81. doi: 10.1056/NEJM199603143341101.
• Background Koopman MM, Prandoni P, Piovella F, Ockelford PA, Brandjes DP, van der Meer J, Gallus AS, Simonneau G, Chesterman CH, Prins MH. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med. 1996 Mar 14;334(11):682-7. doi: 10.1056/NEJM199603143341102.
• Background Columbus Investigators; Buller HR, Gent M, Gallus AS, Ginsberg J, Prins MH, Baildon R. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997 Sep 4;337(10):657-62. doi: 10.1056/NEJM199709043371001.
• Background Simonneau G, Sors H, Charbonnier B, Page Y, Laaban JP, Azarian R, Laurent M, Hirsch JL, Ferrari E, Bosson JL, Mottier D, Beau B. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire. N Engl J Med. 1997 Sep 4;337(10):663-9. doi: 10.1056/NEJM199709043371002.
• Background Schafer AI, Levine MN, Konkle BA, Kearon C. Thrombotic disorders: diagnosis and treatment. Hematology Am Soc Hematol Educ Program. 2003:520-39. doi: 10.1182/asheducation-2003.1.520.
• Background Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126(3 Suppl):188S-203S. doi: 10.1378/chest.126.3_suppl.188S.
• Background Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126(3 Suppl):338S-400S. doi: 10.1378/chest.126.3_suppl.338S.
• Background Kearon C, Hirsh J. Perioperative management of patients receiving oral anticoagulants. Arch Intern Med. 2003 Nov 10;163(20):2532-3; author reply 2533. doi: 10.1001/archinte.163.20.2532-b. No abstract available.
• Background Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994 Jul 11;154(13):1449-57.
• Background Crowther MA, Julian J, McCarty D, Douketis J, Kovacs M, Biagoni L, Schnurr T, McGinnis J, Gent M, Hirsh J, Ginsberg J. Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial. Lancet. 2000 Nov 4;356(9241):1551-3. doi: 10.1016/S0140-6736(00)03125-1.
• Background Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells P, Julian JA, MacKinnon B, Weitz JI, Crowther MA, Dolan S, Turpie AG, Geerts W, Solymoss S, van Nguyen P, Demers C, Kahn SR, Kassis J, Rodger M, Hambleton J, Gent M; Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Aug 14;349(7):631-9. doi: 10.1056/NEJMoa035422.
• Background Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18;349(12):1133-8. doi: 10.1056/NEJMoa035241.
• Background Wilson JT, Hareendran A, Grant M, Baird T, Schulz UG, Muir KW, Bone I. Improving the assessment of outcomes in stroke: use of a structured interview to assign grades on the modified Rankin Scale. Stroke. 2002 Sep;33(9):2243-6. doi: 10.1161/01.str.0000027437.22450.bd.
• Background van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988 May;19(5):604-7. doi: 10.1161/01.str.19.5.604.
• Background Rodger M, Bredeson C, Wells PS, Beck J, Kearns B, Huebsch LB. Cost-effectiveness of low-molecular-weight heparin and unfractionated heparin in treatment of deep vein thrombosis. CMAJ. 1998 Oct 20;159(8):931-8.
• Background Buller HR, Davidson BL, Decousus H, Gallus A, Gent M, Piovella F, Prins MH, Raskob G, van den Berg-Segers AE, Cariou R, Leeuwenkamp O, Lensing AW; Matisse Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003 Oct 30;349(18):1695-702. doi: 10.1056/NEJMoa035451.
• Kovacs MJ, Wells PS, Anderson DR, Lazo-Langner A, Kearon C, Bates SM, Blostein M, Kahn SR, Schulman S, Sabri E, Solymoss S, Ramsay T, Yeo E, Rodger MA; PERIOP2 Investigators. Postoperative low molecular weight heparin bridging treatment for patients at high risk of arterial thromboembolism (PERIOP2): double blind randomised controlled trial. BMJ. 2021 Jun 9;373:n1205. doi: 10.1136/bmj.n1205.

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Indications