Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT)

doi:10.1016/S0140-6736(96)01109-9

The Lancet

Volume 348, Issue 9025, 17 August 1996, Pages 423-428

https://doi.org/10.1016/S0140-6736(96)01109-9 Get rights and content

Summary

Background

Bleeding is the most serious complication of the use of oral anticoagulation in the prevention and treatment of thromoboembolic complications. We studied the frequency of bleeding complications in outpatients treated routinely in anticoagulation clinics.

Methods

In a prospective cohort from thirty-four Italian anticoagulation clinics, 2745 consecutive patients were studied from the start of their oral anticoagulation (warfarin in 64%, acenocourmarol in the rest). The target anticoagulation-intensity was low (international normalised ratio [INR] ≤2·8) in 71% of the patients and high (> 2·8) in the remainder. We recorded demographic details and the main indication for treatment and, every 3·4 months, INR and outcome events. Such events included all complications (bleeding, thrombosis, other), although only bleeding events are reported here, and deaths. We divided bleeding into major and minor categories.

Findings

43% of the patients were women. Nearly three-fifths of the patients were aged 60·79; 8% were over 80. The main indication for treatment was venous thrombolism (33%), followed by non-ischaemic heart disease (17%). Mean follow-up was 267 days. Over 2011 patient-years of follow-up, 153 bleeding complications occurred (7·6 per 100 patient-years). 5 were fatal (all cerebral haemorrhages, 0·25 per 100 patient-years), 23 were major (1·1), and 125 were minor (6·2). The rate of events was similar between sexes, coumarin type, size of enrolling centre, and target INR. The rate was higher in older patients: 10·5 per 100 patient-years in those aged 70 or over, 6·0 In those aged under 70 (relative risk 1·75, 95% CI 1·29–2·39, p<0·001). The rate was also higher when the indication was peripheral and/or cerebrovascular disease than venous thromboembolism plus other indications (12·5 vs 6·0 per 100 patient-years) (1·80, 12–2·7, p <0·01), and during the first 90 days of treatment compared with later (11·0 vs 6·3, 1·75, 1·27–2·44, p <0·001). A fifth of the bleeding events occurred at low anticoagulation intensity (INR < 2, rate 7·7 per 100 patient-years of follow-up). The rates were 4·8, 9·5, 40·5, and 200 at INRs 2·0–2·9, 3–4·4, 4·5–6·9, and over 7, respectively (relative risks for INR>4 5, 7·91, 5·44–11·5, p<0·0001).

Interpretation

We saw fewer bleeding events than those recorded in other observational and experimental studies. Oral anticoagulation has become safer in recent years, especially if monitored in anticoagulation clinics. Caution is required in elderly patients and anticoagulation intensity should be closely monitored to reduce periods of overdosing.

Introduction

Oral anticoagulant therapy is increasingly used for the prevention and treatment of thromboembolic complications of vascular disease.¹ Bleeding is the most important complication. In a review of observational studies,² average annual rates of fatal, major, and major/minor bleeding were 0·8, 4·9, and 15%, respectively. In another review,³ bleeding rates ranged from 0 to 4·8% for fatal bleeding and from 2·4 to 8·1% for major bleeding. Reliable data are lacking on the true frequency of complications in patients on oral anticoagulants because of methodological limitations.⁴ Many studies were done before the introduction of the international normalised ratio system (INR) for prothrombin time (PT),5, 6 or calculated INR retrospectively. Most studies that used the INR system were in highly selected patients. The few observational studies were either retrospective or descriptive, and were not in a clearly defined inception cohort (ie, followed up in one clinic from start of treatment).4, 7 Observational studies that included an inception cohort were retrospective and did not use INR⁸ or selected patients.⁹

We have prospectively assessed the rate of bleeding complications in outpatients monitored from the beginning of oral anticoagulation.

Section snippets

Centres

This study was done in thirty-four centres of the Italian Federation of Anticoagulation Clinics. Each centre is required to: give extensive instructions to all new patients enrolled; follow-up patients by INR; fix the date for next visit and meanwhile prescribe daily anticoagulant dose; monitor changes in patients' habits, diet, and co-medication, illnesses, bleeding complications and scheduled surgical or invasive procedures; and take part in external laboratory quality-control.

Design and patients

This was an

Results

2745 patients (43% female) were included (table 1). Twenty-five centres enrolled under 100 cases, and nine enrolled over 100. In the centres that enrolled over 100 patients, the number of anticoagulated patients not included in the study (second anticoagulation course, anticoagulation started after 30 days, geographic inacccessibility) ranged from 6 to 11 % of the patients included. The anticoagulant drug used was warfarin in 1752 (63·8%) and acenocoumarol in the remaining 993 (36·2%) patients.

Discussion

We were able to estimate haemorrhagic risk complications during oral anticoagulation in outpatients monitored by INR in specialist anticoagulation clinics. The results reflect the normal practice of Italian centres. The rate of fatal, major, and minor bleeding events was 0·25, 1·1, and 6·2 per 100 patient-years of follow-up, respectively. These figures are lower than the average annual frequencies of bleeding (0·8, 4·9, and 15 per 100 patient-years for fatal, major, and major/minor bleeding,

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During a median follow-up of 3.3 years, 395 patients experienced a recurrent VTE. The 1- and 5-year cumulative incidences of recurrence were 2.9% (95% CI: 1.8-4.6) and 11.4% (95% CI: 8.7-14.8), respectively, in those with a D-dimer concentration of ≤1900 ng/mL and 5.0% (95% CI, 4.0-6.1) and 18.3% (95% CI: 16.2-20.6), respectively, in those with a D-dimer concentration of >1900 ng/mL, respectively. In patients with unprovoked VTE, the 5-year cumulative incidence was 14.3% (95% CI: 10.3-19.7) in the ≤1900-ng/mL category, and 20.2% (95% CI: 17.3-23.5) in the >1900-ng/mL category.
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A retrospective follow-up study was done on 154 individuals starting from June 2018 to June 2019 on adult patients who had completed their anticoagulant therapy at the University of Gondar specialized and comprehensive hospital. They were selected using a systematic random sampling technique among all patients who had completed their anticoagulant therapy which is heparin, warfarin, or both. A retrospective data after the initiation of anticoagulant therapy was collected. The data collection was conducted from July 1 to August 30, 2019. Bivariable and multivariable logistic regression was used to identify factors. Variables with p < 0.05 were considered statistically significant.
Out of 154 patients who received anticoagulant therapy during the study period, more than half 83 (53.9%) of the participants were female, and the mean age of participants was 54.8 ± 21.1 years. A quarter of patients, 38 (24.7%), 95% CI (17.8, 31.6) who had been on anticoagulant therapy experienced bleeding complications. Being female (AOR = 6.12, 95% CI: 1.81, 20.71, P = 0.004) Aspirin use (AOR = 7.71, 95% CI: 2.24, 26.53, P = 0.001), type of anticoagulant (AOR = 4.94, 95% CI: 1.58, 15.49, P = 0.006), and number of co-morbidities(AOR = 4.99, 95% CI: 1.47, 16.95, P = 0.010) were found to be significantly associated with hemorrhagic complications.
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ArticlesBleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT)

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Centres

Design and patients

Results

Discussion

Am J Med

Am J Med

Am J Med

Mayo Clin Proc

Am J Med

J Clin Epidemiol

Drug Therapy: oral anticoagulant drugs

N Engl J Med

Haemorrhagic complications of anticoagulant treatment

Chest

Bleeding complications in oral anticoagulant therapy-an analysis of risk factors

Arch Intern Med

33rd Report. Geneva: WHO

Tech Rep Ser

ICSH/ICTH recommendations for reporting prothrombin time in oral anticoagulant control

Thromb Haemost

Risk factors for complications of chronic anticoagulation: a multicentre study

Ann Intern Med

A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism

N Engl J Med

A computerized regulation of dosage in oral anticoagulant therapy

Res Clin Lab

Articles
Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT)