Confidential: For Review Only Double blind randomized controlled trial of postoperative low molecular weight heparin bridging therapy for patients who are at high risk for arterial thromboembolism (PERIOP2) Journal: BMJ Manuscript ID BMJ-2021-064134 Article Type: Research BMJ Journal: BMJ Date Submitted by the Author: 07-Jan-2021 Complete List of Authors: Kovacs, Michael; University of Western Ontario; London Health Sciences Centre, Medicine Wells, Philip; Ottawa Health Research Institute; University of Ottawa, Medicine Anderson, David; Dalhousie University, Medicine Lazo-Langner, Alejandro; University of Western Ontario, Medicine Bates, Shannon; McMaster University, Medicine Blostein, Mark; McGill University, Hematology Kahn, Susan; McGill University Schulman, Sam; McMaster University, Division of Hematology and Thromboembolism, Department of Medicine Sabri , Elham; Ottawa Hospital Research Institute, Clinical Epidemiology Program Ramsay, Timothy; Ottawa Health Research Institute Yeo, Erik; University of Toronto, Medicine Rodger, Marc; McGill University, Medicine Keywords: anticoagulation, thromboembolism, bridging https://mc.manuscriptcentral.com/bmj BMJ
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Confidential: For Review OnlyDouble blind randomized controlled trial of postoperative
low molecular weight heparin bridging therapy for patients who are at high risk for arterial thromboembolism
(PERIOP2)
Journal: BMJ
Manuscript ID BMJ-2021-064134
Article Type: Research
BMJ Journal: BMJ
Date Submitted by the Author: 07-Jan-2021
Complete List of Authors: Kovacs, Michael; University of Western Ontario; London Health Sciences Centre, MedicineWells, Philip; Ottawa Health Research Institute; University of Ottawa, MedicineAnderson, David; Dalhousie University, MedicineLazo-Langner, Alejandro; University of Western Ontario, MedicineBates, Shannon; McMaster University, MedicineBlostein, Mark; McGill University, HematologyKahn, Susan; McGill UniversitySchulman, Sam; McMaster University, Division of Hematology and Thromboembolism, Department of MedicineSabri , Elham; Ottawa Hospital Research Institute, Clinical Epidemiology ProgramRamsay, Timothy; Ottawa Health Research InstituteYeo, Erik; University of Toronto, MedicineRodger, Marc; McGill University, Medicine
1. Kearon C, Hirsh J. Management of anticoagulation before and after elective surgery. N Engl J Med 1997; 336(21):1506-1511
2. Baron TH, Kamath PS, McBane RD. Management of antithrombotic therapy in patients undergoing invasive procedures. N Engl J Med 2013;368:2113-24.
3. Douketis JD, Spyropoulos AC, Spence FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. [published correction appears in Chest. 2012;141(4):1129]. Chest. 2012;141(2)(suppl):e326S-e350S.doi:10.1778/chest.11-2298
4. Spyropoulos AC, Al-Badri A, Sherwood MW, et al. Periprocedural management of patients receiving a vitamin k antagonist or a direct oral anticoagulant requiring an elective procedure or surgery. J Thromb Haemost. 2016;14(5):875-885. doi:10.1111/jth.13305
5. Dunn AS, Spyropoulos AC, Turpie AG. Bridging therapy in patients on long-term oral anticoagulants who require surgery: The Prospective Peri-operative Enoxaparin Cohort Trial (PROSPECT). J Thromb Haemost. 2007;5(11):2211-2218. doi:10.111/j.1538-7836.2007.02729.x
6. Kovacs MJ, Kearon C, Rodger M, et.al. A Single Arm Study of Bridging Therapy with Low Molecular Weight Heparin for Patients at Risk for Arterial Embolism Who Require Temporary Interruption of Warfarin. Circulation 2004;110:1658-1663.
7. 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;164:1319-26.
8. Spyropoulos AC, Douketis JD, Gerotziafas G, et al. Subcommittee on Control of Anticoagulation of the SSC of the ISTH. Periprocedural antithrombotic and bridging therapy: recommendations for standardized reporting in patients with arterial indications for chronic oral anticoagulant therapy. J Thromb Haemost. 2012;10(4):692-694. doi:10.1111/j.1538-7836.2012.04630.x
9. Siegal D, Yudin J, Kaatz S, et al. Periprocedural heparin bridging in patients receiving vitamin K antagonists: systematic review and meta-analysis of bleeding and thromboembolic rates. Circulation. 2012 Sep 25;126(13):1630-9. Doi: 10.1161/CIRCULATIONAHA.112.105221.
10. Douketis JD, Spyropoulos AC, Kaatz S, et al: BRIDGE Investigators. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med.
11. Rodger M, Bredseon C, Wells PS, et al. Cost-effectiveness of low-molecular-weight heparin and unfractionated heparin in treatment of deep vein thrombosis. CMAJ 1998; 159(8):931-938.
12. Douketis JD, Spyropoulos AC, Duncan J, et al. Perioperative management of patient with atrial fibrillation receiving a direct oral anticoagulant. JAMA Intern Med. 2019;179(11):1469-1478. Doi:10.1001/jamaintermed.2019.2431
Variable (N =650) (N =821) P ValueWarfarin treatment
Pre-procedure time not taking warfarin No. of patients with data 650 821 No. of days, Mean (SD) 5.13 (0.66) 5.11 (0.55) 0.6095Pre-procedure INR INR > 1.7 (Day -1)-no.(%) 11 (1.70) n=648 9 (1.10) n=817 0.3289Vitamin K 2 mg given -no.(%) 7 (1.08) n=650 7 (0.85) n=819 0.6633INR 1.5 - 1.7 (Day -1)-no.(%) 34 (5.25) n=648 43 (5.26) n=817 0.989Vitamin K 1 mg given -no.(%) 32 (4.92) n=650 42 (5.13) n=819 0.8583Different dose of Vitamin K given (Day-1)-no.(%) 5 (0.77) n=650 2 (0.24) n=818 0.252INR repeated on the day of procedure (Day 0)-no.(%) 131 (20.15) 128 (15.59) 0.0225
Post-procedure dose No. of patients for whom warfarin was resumed 645 (99.23) 814 (99.15) 0.8598
No. of patients for whom warfarin was resumed on post-op day (Day 0) 564/645 (87.44) 752/814 (92.38)No. of patients for whom warfarin was resumed the next post-op day (Day ≥1) 81/645 (12.56) 62/814 (7.62) 0.0016
Mean no. dose (for patients resumed on Day 0) 8.68 (3.54) n=564 8.62 (3.80) n=752 0.7678Mean no. dose (for patients resumed on Day ≥1) 7.51 (2.94) n=81 7.84 (2.79) n=62 0.4946
Low-molecular-weight heparin or placebo Pre-procedure dose
No. of patients with data 648 819 Average dose received over the three days- Mean (SD) 13508.95 (4896.02) 13484.27 (4136.75) 0.9183Receive LMWH dose Day -3 no. (%) 640 814 Dose for Day -3, Mean (SD) 16288.90 (10026.09) 15979.85 (6361.39) 0.4968Receive LMWH dose Day -2 no. (%) 646 815 Dose for Day -2, Mean (SD) 15919.90 (7471.38) 16028.91 (8076.44) 0.7894Receive LMWH dose Day -1 no. (%) 643 817 Dose for Day -1, Mean (SD) 8342.88 (2211.01) 8458.54 (4088.84) 0.4901Post-OP LMWH, N (%) Patients who started LMWH post op on Day +1 630 (96.92) 789 (96.10)Patients who started LMWH post op on day +2 or later 11 (1.69) 18 (2.19)Patients who did not receive LMWH 9 (1.38) 14 (1.71)
0.6962
Post-procedure dose No. of patients with dose given 641 807 No. of doses, Mean (SD) 5.56 (2.11) 5.37 (1.96) 0.0819Average Dose per day, Mean (SD) 9523.51 (5479.98) 8663.02 (5271.28) 0.0025No. of patients when LMWH started post-op Day +1 630 789 No. of doses when LMWH started post-op Day +1, Mean (SD) 5.57 (2.11) 5.38 (1.94) 0.0778Average dose per day when LMWH started post-op Day +1, Mean (SD) 9433.13 (5462.90) 8688.34 (5277.13) 0.0094No. of patients when LMWH started post-op Day ≥ 2 11 18 No. of doses when LMWH started post op Day ≥ 2, Mean (SD) 4.91 (1.70) 5.11 (2.85) 0.8334Average dose per day when LMWH started post op Day ≥ 2, Mean (SD) 14700.00 (3755.38) 7553.33 (5022.53) 0.0004
Low Risk patients who received post-op LMWH dose 284 287 No. of doses- Low bleeding risk, Mean (SD) 5.52 (1.99) 5.49 (2.15) 0.8399Average dose per day- Low bleeding risk, Mean (SD) 15142.15 (3223.94) 15255.99 (3166.79) 0.6012Patients had >5000 per day, N (%) (Fisher’s Exact Test) 281 (98.60) 283 (98.61) 1
High Risk patients who received post-op LMWH dose 356 520 No. of doses- High bleeding risk, Mean (SD) 5.54 (2.19) 5.31 (1.85) 0.0494Average dose per day- High bleeding risk, Mean (SD) 5046.64 (684.82) 5024.21 (567.77) 0.6106Patients had >5000 per day, N (%) (Fisher’s Exact Test) 2 (0.56) 3 (0.58) 1Aspirin treatment – no./total no.(%) 167 (25.69) 193 (23.51) 0.3332Anti-platelet medication 173 (26.62) 204 (24.85) 0.4406No. of patients have stop day reported for anti-platelet medication 149 190 Interruption ≥ 7 days before procedure 122 (81.88) 163 (85.79)Interruption < 7 days before procedure 27 (18.12) 27 (14.21) 0.3288
ASA Restarted post procedure 123 (86.01) n=143 150 (85.23) n=176 0.8423Total days until ASA resumed, Mean (SD) 9.08 (2.86) n=123 10.13 (5.69) n=150 0.049
*Major thromboembolism: i.e. any one of first seven secondary outcomes: ischemic stroke, or TIA or symptomatic MI, or peripheral embolism, or valve thrombosis, or venous thromboembolism (PE or DVT) or vascular death.** With or without atrial fibrillation
Informed consent, Patients aged >18 Patients with a prosthetic mechanical heart valve
or Patients with atrial fibrillation or atrial flutter and a major risk factor (previous TIA or
stroke, high blood pressure, diabetes, aged >75, moderate/severe left ventricle dysfunction)
Who are receiving long-term oral anticoagulation and require elective non-cardiac surgery or an invasive procedure with reversal of their anticoagulant therapy.
Exclusion Criteria
Evidence of active bleeding within last 30 days prior to stopping warfarin. Platelet count <100 x 109/L. Spinal or neurosurgery. Life expectancy less than 3 months. Calculated creatinine clearance <30 ml/min Patients requiring cardiac surgery. Multiple prosthetic (mechanical)valves or Starr-Edwards valve or
prosthetic(mechanical) valve with a history of stroke or TIA History of heparin induced thrombocytopenia (HIT)
Ischemic Stroke Sudden onset of a neurological deficit that persists for more than 24 hours and involves one or more of the following: Hemiparesis: involving the face, arm and/or leg unilaterally Hemisensory loss; involving face, arm and/or leg unilaterally Speech impairment; (i.e. Aphasia) Visuo-spatial impairment Visual loss (monocular or binocular) Two or more of the following symptoms which suggest
vertebrobasilar involvement:o (a) incoordination/ataxia, o (b) cranial nerve abnormality, o (c) dysarthria,o (d) dysphagia, o (e) vertigo, o (f) reduction/loss of consciousness, o (g) diplopia
Objective and persistent (more than one week) worsening of a previous deficit or worsening associated with an appropriate new finding on CT scan or MRI.
Transient Ischemic Attack (TIA)
A transient ischemic attack is defined for the purposes of this trial as a sudden onset of a neurological deficit lasting at least one minute but less than 24 hours. Isolated syncope was not considered a TIA unless this occurs with one or more of the following neurological symptoms suggesting vertebrobasilar involvement. Hemiparesis; involving face, arm and/or leg unilaterally Hemisensory loss; involving face, arm and/or leg unilaterally Speech impairment; (i.e. Aphasia) Visuo-spatial impairment Visual Loss (monocular or binocular) Two or more of the following symptoms:
o Incoordination/ataxia, o Cranial nerve abnormality, o Dysarthria, o Dysphasia,o Vertigo, o Reduction/loss of consciousness, o Diplopia
Myocardial Infarction At least two of:i) Ischemic chest pain,ii) EKG changes compatible with a MI (hyperacute T wave, elevated ST segment,
T wave inversion, presence of new bundle branch block, loss of R wave height, development of Q waves) OR
iii) elevation of cardiac enzymes (troponin, CK, CKMB isoenzyme, or other cardiac enzymes) to at least 2X the upper limit of the normal reference range or 3X the upper limit of normal within 48 hours after percutaneous coronary intervention (or if markers are already elevated, greater than 50% of the lowest recovery level from the index infarction
Peripheral embolism The occurrence of acute ischaemia documented by angiography or at surgical removal.
Valve Thrombosis Thrombus deposition on the valve resulting in valve dysfunction requiring reoperation or thrombolytic therapy.
Vascular Death Cardiac, cerebrovascular death excluding subarachnoid or primary intracranial haemorrhage or fatal pulmonary embolism.
Venous Thromboembolism Symptomatic deep vein thrombosis or pulmonary embolism confirmed objectively by any of compression ultrasound, ascending venogram, ventilation/perfusion lung scan, spiral CT or pulmonary angiogram.
Primary outcome events were ascertained from the time of randomisation to 90 days. The time of randomization coincided with the time of administration of the first post-operative dose of study drug (+/- 1 hour). All thromboembolic events from the time of randomisation to 90 days were similarly ascertained. All outcome events were blindly and independently adjudicated by an adjudication committee (a cardiologist, a neurologist and a specialist in thromboembolism).
The primary bleeding endpoint is major bleeding, defined by one or more of the events defined by the International Society on Thrombosis and Hemostasis.
Primary Bleeding Endpoint
Major Bleeding: All major bleed must be clinically overt and satisfies one of the following criteria: a fall in hemoglobin of 20g/L within a 24-hour period; results in transfusion of 2 units of blood within a 24-hour period; Death One of the following sites (see below)Clinically overt bleeding at a critical anatomic site Intracranial Intraspinal Intraocular Retroperitoneal, Pericardial
Fatal bleeding Bleeding that directly contributes to death (e.g. intracranial bleed) or causes clinical
deterioration leading to death (e.g. bleed associated with major organ failure or sepsis)Note: Bleeding that was asymptomatic, such as a small retroperitoneal bleed identified as an incidental
finding on computed tomography, would not qualify as a major bleed Intra-operative bleeding that is expected due to the type of surgical procedure and requires blood
transfusion of ≥ 2 units of packed red blood cells would not qualify as a major bleed
Study PersonnelPrincipal Investigators:Michael J Kovacs, Lawson Health Research Institute-London Health Science Centre (Clinical Coordinating Center), and Marc A Rodger, Ottawa Hospital Research Institute (Data Coordinating Centre)Data Safety Monitoring Board (DSMB)Mary Cushman (chair, College of Medicine Laboratory for Clinical Biochemistry Research).Kenneth Bauer (Beth Israel Deaconess Medical Center), Chris E. Holmes (University of Vermont and Fletcher Allen Health Care), George Howard (Dept. of Biostatistics School of Public Health University of Alabama at Birmingham)
Steering CommitteeMichael J. Kovacs, Marc A. Rodger, David R. Anderson, Phil S. Wells, Clive Kearon, Shannon M. Bates, Susan Kahn, Linda Vickars, Alejandro Lazo-Langner, Tim Ramsay
Lawson Health Research Institute-London Health Science Centre: Project ManagementData Management: Tim Ramsey, Michael Henley, Dong Vo (OHRI)Clinical Trial Management: Mike Henley, Dong Vo (OHRI)Clinical Trial Statistics: Tim Ramsey and Elham Sabri (OHRI)Clinical Operations: Luljeta Pallaveshi (Lead CRA), Judy Kovacs, Holly VanSpronsen, Melinda Robbins, Roweena Corpuz, Tammy Kraushaar, Anne Marie Clement, Melisa Spero, Judy Richard, Rebekah Conlon, Lisa Grey, Blaine Gallant, Naomi Bedek, Pamela Stevens, Terry Schnurr, Laurie A. Sardo, Diane Donovan, Lisa Rudd-Scott , Shannon Dodds, Michelle Zondag, Montreal Vivian Pananis, Susan Finkenbine, Barb St. Jacques, Maria Dzyuba, Martha Lenis, Sheila Kelly, India (Libie Jose, Nayan Ramesh, Anudeep Ratanala, Sunil Swamy, Sital Pawar) Research Ethics Boards (REB): HSREB Western University, Ottawa Hospital Research Ethics Boards, Hamilton Integrated Ethics Board (HIREB), Biomedical D. Research Ethics Board MUHC-Montreal General Hospital, University Health Network Research Ethics Board, Regina Qu’Appelle Research Ethic Board, India: Canara Research Ethical Committee Bendoorwell Mangalore; Institutional Ethics Committees: Care Foundation Care Convergence Centre, Deenanath Mangeshkar Hospital & Research Centre; Poona Medical Research FoundationMonitoring & Safety: Lawson Research Health Institution-LHSC (for Canada sites) and iProcess Coordinator Network (for India sites). Data cleaning and entry: Jennie Cote.Central Adjudication Committee: David Massel, Michael Nicolle and Alejandro Lazo-LangnerStudy Drug Management Pharmacy: Teresa Longfield, Sherry Weir, Tony Gyapong, Patti Gallant, Deborh Snow, Kim Bruce Payne, Diane Lourenco, Maya Biljan, Gita Sobhi, Armanda Marechal, Julie Roy, Muhammad Zyber, Jie Meng, India (S. Bagwan, Anuja N Chougule)
Enrolling Site Investigators:Canada sites:Ottawa site (518): Marc A Rodger, Phil S. Wells, Allan J. Karotovitch, Marc Carrier, LDM Duffett, Lana A. Castelluci, E Gandara, G. Le Gal, D Scarvellis, MA Forgie, CL. Conslaves, CC. Code (OHRI: Ottawa Hospital-General Campus, Ottawa Hospital); Halifax Site (439): David R Anderson, Andrea Kew, Sudeep Shivakumar, Wanda Hasegawa, Sue Robinson, Darrell White, Stephen Couban, Mary Margaret Keating (QEII Health Science Centre);
London Site (140): Michael J Kovacs, Alejandro Lazo-Langner, Martha Louzada, Kang Howson-Jan, Cyrus Hsia, Joy E Mangel, Anargyros Xenocostas, Brian Larocque (London Health Sciences Centre,140); Hamilton Site (159): Shannon M. Bates, Sam Schulman, Clive Kearon, John WA Eikelboom, Sonia Savitri Anand, Kerstin Elisabeth de Wit, Jeffrey I. Weltz, Peter L. Gross, Agnes YY Lee, Lori-Anne Linkins, Jeffrey S. Ginsberg, Frederick A. Spenser, MA Patel (Hamilton HSC – McMaster University, 89; Hamilton General Hospital,46; Hamilton HSC-Henderson,24)Montreal Site (67): Mark Blostein, Susan Solymoss, Susan Kahn (Jewish General Hospital, 56; Montreal General Hospital, 11)Toronto Site (6): Erik Yeo, William F. Brien, Anne McLeod (UHN -Toronto General Hospital,6)Regina Site (5): Patrick Duffy (Regina General Hospital, 5)
India Sites: Mangalore Site (84): Mukund Kumbla, Anoop Nambiar, KP Shabnam, Abdul Khadar kasim, (Omega Hospitals, 84)Hyderabad Site (49): Guntuboina Usha Rani, Mukund Karmalkar, Sharada Kalavakolanu (CARE Hospital Hyderabad, 49) Pune Site (4): Purvez.K Grant, Nirmala Castellino, Nita Murshi, Desai Bhagyashtri Shripatrao; Shireesh Prabhakar Sathe, Bhingare Kishor Laxman (Ruby Hall Clinic, 2; Deenanath Mangeshkar Hospital, 2)
S1. Suggested Classification of Type of Surgery or Procedure
Classification of Type of Surgery or Procedure*
Minor or low-bleeding risk surgery/procedure
Non-cancer Abdominal Surgery (e.g. bowel or visceral organ resection) Cholecystectomy Hernia repair (inguinal, umbilical) Node dissection Vaginal hysterectomy Hand Surgery Skin procedure (dermatologic surgery or any other dermatologic procedure) Non-joint replacement orthopedic Line insertion (cardiac catheterization, angiogram) Dental procedure (tooth extraction) Endoscopic procedure (e.g. colonoscopy, gastroscopy, esophagoscopy, bronchoscopy without
biopsy)
Major or high-bleeding risk surgery/procedure
Cancer surgery:o GU o Head and Neck o Chest (Lung lobectomy) o Abdominal (mass removal, colectomy, etc.)o Breast (mastoidectomy, reconstruction, etc.) o Extremities
Arthroplasty Kidney biopsy Urologic Surgery Liver biopsy Prostate biopsy TURP Pacemaker Insertion/internal defibrillator insertion Abdominal hysterectomy Vascular surgery (e.g. vascular bypass, abdominal aortic aneurysm repair) Colonic polyp resection Major orthopedic surgery (e.g. hip or knee replacement)
*Note: Patients who satisfied the trial eligibility criteria were classified according to this suggested classification, although the final destination as minor/major /high bleeding risk was left to the discretion of the site investigator.
Study arm Adjudicated cause of death(SAE coded term)
No. of days to death
Dalteparin Pancreatic cancer *93Dalteparin NSSCL 85Dalteparin Lung carcinoma *98Dalteparin Mass lesion in medulla 63Dalteparin Congestive heart failure (CHF) 32Dalteparin Metastatic adenocarcinoma 14
Placebo Metastatic esophageal cancer 86Placebo Myocardial Infarction 3Placebo Metastatic cancer 86Placebo VT Storm- Lung cancer 84Placebo Myocardial Infarction 75Placebo Unknown 87Placebo Stroke 24Placebo Unknown *97Note: The number of days of surgery is computed from the day of the procedure/ randomization to 90 days follow up. *Three of the death events occurred after the 90 days of follow up.
Double blind randomized controlled trial of postoperative low molecular weight heparin bridging therapy for patients who are at high risk for arterial thromboembolism (PERIOP2)
Authors:
Michael J. Kovacs, Philip S. Wells, David R. Anderson, Alejandro Lazo-Langner, *Clive Kearon, Shannon M. Bates, Mark Blostein, Susan R. Kahn, Sam Schulman, Elham Sabri, *Susan Solymoss, Tim Ramsay, Erik Yeo, and Marc A. Rodger; for the PERIOP2 Investigators(*These authors are deceased)
Corresponding Author: Dr. Michael J. Kovacs
Corresponding Author’s address:
London Health Sciences Centre800 Commissioners Road EastRoom E6-214London, Ontario, Canada N6A 5W9
Dr. Sam Schulman has received honoraria from Alnylam, Boehringer Ingelheim, Bayer HealthCare, Daiichi Sankyo, Pfizer, and Sanofi, and research support from Boehringer Ingelheim and Octapharma.None of these have any connection with the study.
Dr. Shannon M. Bates has received consultancy fees from Leo Pharma Canada.
Dr. Philip S. Wells declares honoraria from Bayer Healthcare, Janssen, Sanofi, Medscape, Servier Canada, Pfizer, BMS, WebMd and Grant fees from Bayer Healthcare, Pfizer/BMS in the last 3 years outside the submitted work.