Download PDF
Thromb Haemost 1992; 68(01): 001-006
DOI: 10.1055/s-0038-1656307
Original Article
Schattauer GmbH Stuttgart

Extra-Cranial Bleeding and Other Symptoms due to Low Dose Aspirin and Low Intensity Oral Anticoagulation

T W Meade
The MRC Epidemiology and Medical Care Unit and British Heart Foundation Cardiovascular Epidemiology Research Group, Wolfson Institute of Preventive Medicine, The Medical College of St Bartholomew’s Hospital, London, United Kingdom
,
P J Roderick
The MRC Epidemiology and Medical Care Unit and British Heart Foundation Cardiovascular Epidemiology Research Group, Wolfson Institute of Preventive Medicine, The Medical College of St Bartholomew’s Hospital, London, United Kingdom
,
P J Brennan
The MRC Epidemiology and Medical Care Unit and British Heart Foundation Cardiovascular Epidemiology Research Group, Wolfson Institute of Preventive Medicine, The Medical College of St Bartholomew’s Hospital, London, United Kingdom
,
H C Wilkes
The MRC Epidemiology and Medical Care Unit and British Heart Foundation Cardiovascular Epidemiology Research Group, Wolfson Institute of Preventive Medicine, The Medical College of St Bartholomew’s Hospital, London, United Kingdom
,
C C Kelleher
The MRC Epidemiology and Medical Care Unit and British Heart Foundation Cardiovascular Epidemiology Research Group, Wolfson Institute of Preventive Medicine, The Medical College of St Bartholomew’s Hospital, London, United Kingdom
› Author Affiliations
Further Information

Publication History

Received 02 January 1992

Accepted 06 February 1992

Publication Date:
03 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Data from the early stages of the thrombosis prevention trial (TPT) have been used to establish and quantify the risk of extracranial bleeding due to low dose aspirin (75 mg) and low intensity oral anticoagulation with warfarin (international normalised ratio, INR, 1.5) singly or in combination, in men aged between 45 and 69 who are at high risk of ischaemic heart disease (IHD). The design of the trial is factorial, the four treatments being combined low dose aspirin and low intensity anticoagulation (WA), low intensity anticoagulation alone (W), low dose aspirin alone (A) and double placebo treatment (P). The trial is being carried out through the Medical Research Council’s General Practice Research Framework, with participating practices throughout the United Kingdom. Results are based on the first 3,667 men entered. The risk of major gastrointestinal bleeding due to active treatment is probably about 1 in 500 man-years of treatment, there currently being no difference between the three active regimes (WA, W, A). Intermediate and minor bleeding episodes occur more frequently with WA than with W or A on their own, the excess being mainly due to minor nose bleeds and bruises. In turn, both W and A on their own cause more such minor episodes than placebo treatment, P. There is no evidence that any of the three active regimes increases the risk of peptic ulceration, nor do they increase reports of indigestion. Aspirin increases reports of constipation and reduces reports of blurred vision. Minor bleeding occurs less frequently in smokers than in non-smokers but is not influenced by age. The antithrombotic regimes used are feasible and acceptable. So far, combined treatment and treatment with warfarin alone are not associated with more frequent serious hazards than low dose aspirin on its own, a regime that is increasingly used in clinical practice. The results provide a measure of reassurance for further trials of low intensity oral anticoagulation with warfarin alone or in combination with low dose aspirin.

 

  • References

  • 1 De Wood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980; 303: 897-901
    CrossrefPubMedGoogle Scholar
  • 2 Davies MJ. Thrombosis in acute myocardial infarction and sudden death. Thrombosis and Platelets in Myocardial Ischemia. F A Divis Company; Philadelphia, PA: 1987. 10 151-159
    Google Scholar
  • 3 Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med 1984; 310: 1137-1140
    CrossrefPubMedGoogle Scholar
  • 4 Antiplatelet Trialists’ Collaboration Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988 296. 320-331
    PubMedGoogle Scholar
  • 5 Physicians’ Health Study Research Group Final report of the aspirin component of the ongoing physicians’ health study. N Engl J Med 1989 321. 129-135
    PubMedGoogle Scholar
  • 6 Peto R, Gray R, Collins R. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J 1988; 296: 313-316
    CrossrefPubMedGoogle Scholar
  • 7 RISC Group Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990 336. 827-830
    PubMedGoogle Scholar
  • 8 International Anticoagulant Review Group Collaborative analysis of long-term anticoagulant administration after acute myocardial infarction. Lancet 1970 1. 203-209
    PubMedGoogle Scholar
  • 9 Chalmers TC, Matta RJ, Smith H, Kunzler AM. Evidence favouring the use of anticoagulants in the hospital phase of acute myocardial infarction. N Engl J Med 1977; 297: 1091-1096
    CrossrefPubMedGoogle Scholar
  • 10 Armitage P. Clinical trials in the secondary prevention of myocardial infarction and stroke. Thromb Haemostas 1980; 43: 90-94
    PubMedGoogle Scholar
  • 11 Report of the Sixty Plus Reinfarction Study Research Group A double-blind trial to assess long-term oral anticoagulant therapy in elderly patients after myocardial infarction. Lancet 1980 2. 989-994
    PubMedGoogle Scholar
  • 12 Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 1990; 323: 147-152
    CrossrefPubMedGoogle Scholar
  • 13 Meade TW, Mellows S, Brozivic M. et al Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 2: 533-537
    PubMedGoogle Scholar
  • 14 Meade TW, Miller GJ, Rosenberg RD. Characteristics associated with the risk factors for thrombosis and prethrombotic state. Thrombosis in Cardiovascular Disorders. W B Saunders Company; Philadelphia, PA: 1991
    Google Scholar
  • 15 Miller GJ, Wilkes HC, Meade TW, Bauer KA, Barzegar S, Rosenberg RD. Haemostatic changes that constitute the hypercoagulable state. Lancet 1991; 338: 1079
    PubMedGoogle Scholar
  • 16 Lowe GDO. Haemostatic changes and the hypercoagulable state. Lancet 1991; 338: 1526
    PubMedGoogle Scholar
  • 17 Hull R, Hirsh J, Jay R. et al Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982; 307: 1676-1681
    CrossrefPubMedGoogle Scholar
  • 18 Francis CW, Marder VJ, McCollister EvartsC, Yaukoolbodi S. Two-step warfarin therapy. JAMA 1983; 249: 374-378
    CrossrefPubMedGoogle Scholar
  • 19 Saour JN, Sieck JO, Rahim Mamo LA, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med 1990; 322: 428-432
    CrossrefPubMedGoogle Scholar
  • 20 Powers PJ, Gent M, Jay RM. et al A randomized trial of less intense postoperative warfarin or aspirin therapy in the prevention of venous thromboembolism after surgery for fractured hip. Arch Intern Med 1989; 149: 771-774
    CrossrefPubMedGoogle Scholar
  • 21 Turpie AGG, Gunstensen J, Hirsh J. et al Randomised comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet 1988; 1: 1242-1245
    CrossrefPubMedGoogle Scholar
  • 22 Boston Area Anticoagulation Trial for Atrial Fibrillation The effect of low-dose warfarin on the risk of stroke in patients with non-rheumatic atrial fibrillation. N Engl J Med 1990 323. 1505-1511
    PubMedGoogle Scholar
  • 23 Altman R, Rouvier J, Gurfinkel E. et al Comparison of two levels of anticoagulant therapy in patients with substitute heart valves. J Thorac Cardiovasc Surg 1991; 101: 427-431
    PubMedGoogle Scholar
  • 24 Poller L, McKernan A, Thomson JM. et al Fixed minidose warfarin: a new approach to prophylaxis against venous thrombosis after major surgery. Br Med J 1987; 295: 1309-1312
    CrossrefPubMedGoogle Scholar
  • 25 Bern MM, Lokich JJ, Wallach SR. et al Very low doses of warfarin can prevent thrombosis in central venous catheters. Am Coll Physicians 1990; 112: 423-428
    PubMedGoogle Scholar
  • 26 Fordyce MJF, Baker AS, Staddon GE. Efficacy of fixed minidose warfarin prophylaxis in total hip replacement. Br Med J 1991; 303: 219-220
    CrossrefPubMedGoogle Scholar
  • 27 Altman R, Boulton F, Rouvier J. et al Aspirin and prophylaxis of thromboembolic complications in patients with substitute heart valves. J Thoracic Cardiovasc Surg 1976; 72: 127-129
    PubMedGoogle Scholar
  • 28 Dale J, Myhre E, Loew D. Bleeding during acetylsalicylic acid and anticoagulant therapy in patients with reduced platelet reactivity after aortic valve replacement. Am Heart J 1980; 99: 746-752
    CrossrefPubMedGoogle Scholar
  • 29 Chesebro JH, Fuster V, Elveback UR. et al Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole. Am J Cardiol 1983; 51: 1537-1541
    CrossrefPubMedGoogle Scholar
  • 30 Miller A, Lees RS. Simultaneous therapy with antiplatelet and anticoagulant drugs in symptomatic cardiovascular disease. Stroke 1985; 16: 668-675
    CrossrefPubMedGoogle Scholar
  • 31 ISIS-2 Collaborative Group Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988 2. 349-360
    PubMedGoogle Scholar
  • 32 Meade TW, Wilkes HC, Stirling Y. et al Randomized controlled trial of low dose warfarin in the primary prevention of ischaemic heart disease in men at high risk: design and pilot study. Euro Heart J 1988; 9: 836-843
    CrossrefPubMedGoogle Scholar
  • 33 Meade TW. Low-dose warfarin and low-dose aspirin in the primary prevention of ischemic heart disease. Am J Cardiol 1990; 65: 7c-11c
    CrossrefPubMedGoogle Scholar
  • 34 Pocock SJ. Clinical Trials: A Practical Approach. John Wiley & Sons Ltd; New York: 1983
    Google Scholar
  • 35 Rothman KJ, Greenland S, Walker AM. Concepts of interaction. Am J Epidemiol 1980; 112: 467-470
    CrossrefPubMedGoogle Scholar
  • 36 Cohen M, Fuster V, Chesebro JH. Unstable angina: aspirin and anticoagulant use. Curr Opinion Cardiol 1989; 4: 510-512
    CrossrefPubMedGoogle Scholar
  • 37 Prichard PJ, Kitchingman GK, Walt RP. et al Human gastric mucosal bleeding induced by low dose aspirin, but not warfarin. Br Med J 1989; 298: 493-496
    CrossrefPubMedGoogle Scholar
  • 38 Aspirin Myocardial Infarction Study Research Group A randomized, controlled trial of aspirin in persons recovered from myocardial infarction. JAMA 1980 243. 661-669
    PubMedGoogle Scholar
  • 39 UK-TIA Study Group United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: interim results. Br Med J 1988 296. 316-320
    PubMedGoogle Scholar
  • 40 The Persantine-Aspirin Reinfarction Study Research Group Persantine and aspirin in coronary heart disease. Circulation 1980 62. 449-461
    PubMedGoogle Scholar
  • 41 Buring JE, Peto R, Hennekens CH. Low-dose aspirin for migraine prophylaxis. JAMA 1990; 265: 1711-1713
    PubMedGoogle Scholar
  • 42 Boysen G, Sorensen PS, Juhler M. et al Danish very-low-dose aspirin after carotid endarterectomy trial. Stroke 1988; 19: 1211-1215
    CrossrefPubMedGoogle Scholar
  • 43 Petersen P, Boysen G, Godtfredsen J. et al Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. Lancet 1989; 1: 175-179
    CrossrefPubMedGoogle Scholar
  • 44 The SALT collaborative group Swedish aspirin low-dose trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. Lancet 1991 338. 1345-1349
    PubMedGoogle Scholar
  • 45 The Dutch TIA trial study group A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991 325. 1261-1266
    PubMedGoogle Scholar
  • 46 Gurewich V, Lipinski B, Hyde E. et al The effect of the fibrinogen concentration and the leukocyte count on intravascular fibrin deposition from soluble fibrin monomer complexes. Thromb Haemostas 1976; 36: 605-614
    PubMedGoogle Scholar
  • 47 Chooi CC, Gallus AS. Acute phase reaction, fibrinogen level and thrombus size. Thromb Res 1989; 53: 493-501
    CrossrefPubMedGoogle Scholar
  • 48 Naski MC, Shafer JA. A kinetic model for the α-thrombin-catalyzed conversion of plasma levels of fibrinogen to fibrin in the presence of antithrombin III. J Biol Chem 1991; 266: 13003-13010
    PubMedGoogle Scholar
  • 49 Hirsh J. Oral anticoagulant drugs. N Engl J Med 1991; 324: 1865-1875
    CrossrefPubMedGoogle Scholar