Hemorrhagic Complications of Anticoagulant and Thrombolytic Treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

doi:10.1378/chest.08-0674

Chest

Volume 133, Issue 6, Supplement, June 2008, Pages 257S-298S

https://doi.org/10.1378/chest.08-0674 Get rights and content

This article about hemorrhagic complications of anticoagulant and thrombolytic treatment is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Bleeding is the major complication of anticoagulant and fibrinolytic therapy. The criteria for defining the severity of bleeding vary considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist (VKA)-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that VKA therapy, targeted international normalized ratio (INR) of 2.5 (range, 2.0-3.0), is associated with a lower risk of bleeding than therapy targeted at an INR > 3.0.

The risk of bleeding associated with IV unfractionated heparin (UFH) in patients with acute venous thromboembolism is < 3% in recent trials. This bleeding risk may increase with increasing heparin dosages and age (> 70 years). Low-molecular-weight heparin (LMWH) is associated with less major bleeding compared with UFH in acute venous thromboembolism. Higher doses of UFH and LMWH are associated with important increases in major bleeding in ischemic stroke. In ST-segment elevation myocardial infarction, addition of LMWH, hirudin, or its derivatives to thrombolytic therapy is associated with a small increase in the risk of major bleeding, whereas treatment with fondaparinux or UFH is associated with a lower risk of bleeding.

Thrombolytic therapy increases the risk of major bleeding 1.5-fold to threefold in patients with acute venous thromboembolism, ischemic stroke, or ST-elevation myocardial infarction.

Section snippets

VKAs

The increase in risk of major bleeding in patients treated with VKA compared to controls is low in well-controlled patients. In the pooled analysis of the first five trials with warfarin in atrial fibrillation the annual rate of major bleeding was 1.0% in control patients vs 1.3% in patients treated with warfarin.⁹ The annual rate of intracranial hemorrhage (ICH) was 0.1% in controls and 0.3% in patients treated with warfarin.⁹ In a metaanalysis of trials with different durations of VKA therapy

Initial Therapy

Initial Thrombolytic Therapy vs Anticoagulant Therapy Alone in Patients With Acute DVT or PE: Metaanalyses have combined the results of the mostly small RCTs that have compared various thrombolytic regimens with anticoagulant therapy alone in patients with acute DVT.

In patients with acute DVT, Watson and Armon²⁰² estimated the RR for “significant bleeding” (excludes very minor bleeding and ICH) to be 1.7 (95% CI, 1.04–2.9) with use of thrombolytic therapy (Table 4).²⁰² There were 2 (0.6%) ICHs

OVERALL COMPARISONS

So far there is no anticoagulant agent that, across all indications, is safe regarding major hemorrhage. Comparisons between different drugs may yield different RRs depending on the selected intensity of treatment, concomitant or antecedent anticoagulant, antiplatelet or thrombolytic drugs, characteristics of the patient population, and also the condition that is being treated, as in the following examples:

LMWH is safer than UFH in the treatment of acute VTE, but UFH appears safer than LMWH as

CONFLICT OF INTEREST DISCLOSURES

Dr. Schulmandiscloses having received grant monies from Physicians Services Inc Foundation, and unrestricted educational grants from Leo Pharmaceuticals and Bayer. He serves on advisory committees for Sanofi-Aventis, Bayer, Boehringer Ingelheim, AstraZeneca, Octapharma, and CLS Behring.

Dr. Levinereveals no real or potential conflicts of interest or commitment.

Dr. Beythreveals no real or potential conflicts of interest or commitment.

Dr. Kearondiscloses that he has received grant monies from the

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Safety and efficacy of fixed versus variable-dose prothrombin complex concentrate for emergent reversal of vitamin K antagonists: A systematic review and meta-analysis
2024, American Journal of Emergency Medicine
Four-factor prothrombin complex concentrate (4F-PCC) is standard of care for emergent vitamin K antagonist (VKA) reversal but optimal dosing is uncertain. This meta-analysis estimated the proportion of patients treated with fixed dose (FD) 4F-PCC who achieved adequate reversal and compared safety and efficacy of FD versus weight-based dose (WB) strategies.
This review was conducted according to PRISMA guidelines. Medline and Scopus were searched and included studies evaluating FD regimens and comparing FD and WB for emergent VKA reversal. Data was pooled using random effects. Subgroup analyses examined heterogeneity. Risk of bias was assessed with Newcastle-Ottawa Scale and RoB2 score.
Twenty-three studies (n = 2055) were included with twelve (n = 1143) comparing FD versus WB. The proportion of patients achieving goal INR with FD varied depending on the INR target, being significantly higher for INR <2 (90.9%, 95% Confidence Interval (CI) 87.2, 94.06) compared to INR <1.6 (70.97%, 95%CI 65.33, 76.31). Compared to WB, FD was less likely to achieve a goal INR <1.6 (Risk Difference (RD) −13%, 95% CI −21, −4) but achieved similar reversal for a goal INR <2.0, (RD −1%, 95%CI −7, 4). There was no difference in hospital mortality (RD 4%, 95%CI −2, 9) or thrombosis (RD 0.0%, 95%CI −3, 3).
FD VKA reversal was associated with significantly lower attainment of goal INR compared to WB with lower INR targets. This did not translate to differences in hospital mortality, but these results should be interpreted cautiously in light of the observational nature of the included studies.
Determinants of Late Venous Thromboembolic Events After Acute Isolated Superficial Vein Thrombosis in Daily Practice: 12 Month Results of the INSIGHTS-SVT Study
2023, European Journal of Vascular and Endovascular Surgery
Long term incidence of symptomatic venous thromboembolism (VTE) and bleeding events in patients with superficial vein thrombosis (SVT) was investigated.
In this prospective, observational study, patients with acute SVT were treated at the discretion of the responsible physician. The primary efficacy outcome was symptomatic VTE including deep vein thrombosis (DVT), pulmonary embolism (PE), and recurrent or extending SVT. The primary safety outcome was clinically relevant bleeding, recorded at periodic clinic visits over a 12 month period.
The mean age of 872 patients with 12 month follow up was 60.6 ± 14.5 years, 64.5% were female, 80.1% had chronic venous disease (defined as chronic venous insufficiency and or varicose veins), and 41.9% had a history of VTE. They were receiving fondaparinux in 62.1% (mean duration 34.9 ± 15.7 days), low molecular weight heparin (LMWH) in 25.0% (mean duration 26.2 ± 23.2 days), any other anticoagulants in 6.2%, and no anticoagulant in 6.7%. At 12 months, 108 patients (14.3%) achieved the primary efficacy outcome. The most common VTE event was recurrent or extending SVT in 11.0%, followed by symptomatic DVT in 2.7%, symptomatic PE in 2.4%, hospitalisation due to VTE in 1.8%, and death in 1.1%. Clinically relevant bleeding events occurred in 2.1% of patients, and major bleedings in 0.3%. By drug, the rate of the primary efficacy outcome was highest in the LMWH group (22.4%) and lowest in the fondaparinux group (10.4%). In a multivariable model, patients with events between three months and 12 months were significantly more likely to have higher BMI (hazard ratio [HR] 1.06; p = .002), history of VTE (HR 2.89; p = .002), and severe systemic infections (HR 7.59; p = .006).
The risk of symptomatic VTE remained elevated over 12 months of follow up. Therefore, anticoagulation beyond 45 days may be considered in patients with risk factors. [ClinicalTrials.gov identifier: NCT02699151.]
Atrial Cardiopathy: Redefining Stroke Risk Beyond Atrial Fibrillation
2023, American Journal of Cardiology
Atrial fibrillation (AF) and ischemic stroke are dual epidemics in society, both associated with poor clinical outcomes, patient disability, and significant healthcare expenditure. The conditions are interrelated and share complex causal pathways. Risk stratification algorithms such as the CHADS₂ and CHA₂DS₂-VASc score offer predictive value in stroke and systemic embolism risk in the AF population, however, have limitations. Recent evidence suggests that an intrinsically prothrombotic atrial substrate may precede and promote AF and lead to thromboembolic events independent of the arrhythmia, allowing for a window of intervention before arrhythmia detection and development of ischemic stroke. Initial work has found incremental value in addition of parameters of atrial cardiopathy to traditional stroke risk stratification algorithms, however, requires evaluation with dedicated prospective randomized studies before use in real-world clinical practice. In this narrative review, we explore current evidence and literature on the use of measures of atrial cardiopathy in stroke risk stratification and management.
Magnitude of hemorrhagic complications and its associated factors among patients on anticoagulant therapy at University of Gondar Comprehensive and Specialized Hospital, Northwest Ethiopia
2023, Thrombosis Update
Despite the well-established effectiveness of anticoagulants, the risk of their hemorrhagic complications withheld many patients from being maintained on anticoagulant therapy. However, there is no sufficient data on the magnitude and factors associated with anticoagulant-related hemorrhagic complications in resource-constrained settings. Thus this study aimed to assess the magnitude of hemorrhagic complications and associated factors related to anticoagulant therapy among patients at the University Of Gondar Comprehensive and Specialized Hospital.
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.
Hemorrhagic complications related to anticoagulant therapy are not rare. Therefore close monitoring of coagulation profiles as well as minimization of risk factors is crucial and needs collaborated work of all health care professionals and decision-makers.
Incidence and clinical impact of bleeding events in older patients with acute venous thromboembolism
2023, Blood Advances
Older patients anticoagulated for venous thromboembolism (VTE) have an increased risk of bleeding compared with younger patients. Little is known about the clinical impact of anticoagulation-related bleeding in this growing patient group. To prospectively assess the incidence, clinical impact, and predictors of bleeding in older patients anticoagulated for VTE, we analyzed 981 patients aged ≥65 years with acute VTE in a prospective multicenter cohort. Eight-eight percent were anticoagulated with vitamin K antagonists. Outcomes were the occurrence of major bleeding (MB) or clinically relevant nonmajor bleeding (CRNMB) event during the initial anticoagulation period up to 36 months. We described the incidence and clinical impact of bleeding and examined the association between risk factors and time to a first bleeding using competing risk regression; 100 MB and 125 CRNMB events occurred during follow-up. The incidence of MB and CRNMB was 8.5 (95% confidence interval [CI], 7.0-10.4) and 13.4 events (95% CI, 11.4-15.7) per 100 patient-years, respectively. In patients with MB, 79% required hospitalization, 18% required surgical intervention, and 19% required permanent discontinuation of anticoagulation; 15% of MB were intracranial and 6% were fatal. After adjustment, active cancer (subhazard ratio [SHR], 1.81; 95% CI, 1.12-2.93) and low physical activity (SHR, 1.88; 95% CI, 1.19-2.98) were associated with MB and high risk of falls with CRNMB (SHR, 2.04; 95% CI, 1.39-3.00). Older patients anticoagulated for VTE had a high incidence of MB and CRNMB, and these bleeding episodes caused a great burden of disease. Physicians should carefully weigh the risks/benefits of extended anticoagulation in the older population with VTE.
Clinical outcomes of cancer-associated isolated superficial vein thrombosis in daily practice
2022, Thrombosis Research
Despite significant progress in the understanding of paraneoplastic deep vein thrombosis (DVT) and pulmonary embolism (PE), little is known about the outcomes of cancer-associated superficial vein thrombosis (SVT) in daily practice.
INSIGHTS-SVT was a prospective observational study on patients with acute isolated SVT. Primary outcome measure was symptomatic venous thromboembolism (VTE), a composite of DVT, PE, and SVT extension/recurrence, at 3 months. Clinically relevant bleeding was also assessed.
Of 1151 patients included, 6.7 % either had active cancer at baseline or were diagnosed with cancer during 12 months of follow-up. At 3 months, symptomatic VTE had occurred in 13.0 % and 5.4 % of cancer and non-cancer patients, respectively (HR 2.6, 95 % CI 1.3–5.0). Regarding secondary outcomes, cancer patients had increased risks of DVT and PE (HR 3.9, 95 % CI 1.3–11.8) and hospitalization due to VTE (HR 11.0, 95 % CI 2.5–49.0). The rate of clinically relevant bleeding was numerically higher in the cancer cohort (3.9 % vs 1.3 %, HR 3.1, 95 % CI 0.9–10.7). At 12 months, the primary composite outcome had occurred in 15.6 % and 11.9 % of cancer and non-cancer patients, respectively (HR 1.9, 95 % CI 1.0–3.5). After adjusting for additional risk factors, including age, history of DVT/PE and cardiovascular risk factors/diseases, the association of cancer with the primary outcome remained statistically significant.
Cancer patients with isolated SVT are at significant risk of symptomatic VTE. While most events occur within 3 months, the VTE risk remains elevated up to one year of follow-up.
ClinicalTrials.gov identifier: NCT02699151.

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Chest

SupplementAntithrombotic and Thrombolytic Therapy, 8th ED: ACCP GuidelinesHemorrhagic Complications of Anticoagulant and Thrombolytic Treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

Section snippets

VKAs

Initial Therapy

OVERALL COMPARISONS

CONFLICT OF INTEREST DISCLOSURES

J Thromb Haemost

Lancet

Clin Ther

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Lancet

J Thromb Haemost

Lancet

Thromb Res

Eur J Vasc Endovasc Surg

Am J Med

Am J Med

Mayo Clin Proc

Am J Med

Int J Cardiol

Blood

Lancet

Ann Thorac Surg

J Thromb Haemost

J Am Coll Cardiol

J Thromb Haemost

Hemorrhagic complications of anticoagulant treatment

Chest

Hemorrhagic complications of anticoagulant treatment

Chest

Hemorrhagic complications of long-term anticoagulant therapy

Chest

Hemorrhagic complications of long-term anticoagulant therapy

Chest

Hemorrhagic complications of anticoagulant treatment

Chest

Hemorrhagic complications of anticoagulant treatment

Chest

Hemorrhagic complications of anticoagulant treatment

Chest

Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials

Arch Intern Med

Duration of anticoagulation following venous thromboembolism: a metaanalysis

JAMA

Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice?

JAMA

Outcomes in the management of atrial fibrillation: clinical trial results can apply in practice

Intern Med J

Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis

N Engl J Med

A comparison of a moderate with moderate-high intensity oral anticoagulant treatment in patients with mechanical heart valve prostheses

Thromb Haemost

Trial of different intensities of anticoagulation in patients with prosthetic heart valves

N Engl J Med

Lowering the intensity of oral anticoagulant therapy: effects on the risk of hemorrhage and thromboembolism

Arch Intern Med

Oral anticoagulation in patients after cerebral ischemia of arterial origin and risk of intracranial hemorrhage

Stroke

Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomized clinical trial

Lancet

Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study

Arch Intern Med

Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation: a multicenter, prospective, randomized trial; Japanese Nonvalvular Atrial Fibrillation-Embolism Secondary Prevention Cooperative Study Group

Stroke

A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome

N Engl J Med

Risk factors for intracranial hemorrhage in outpatients taking warfarin

Ann Intern Med

International normalized ratio increase before warfarin-associated hemorrhage: brief and subtle

Arch Intern Med

Optimal oral anticoagulant therapy in patients with mechanical heart valves

N Engl J Med

Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation

Ann Intern Med

Complications of preinjury warfarin use in the trauma patient

J Trauma Injury Infect Crit Care

A randomized trial of anticoagulants vs aspirin after cerebral ischemia of presumed arterial origin

Ann Neurol

Supplement
Antithrombotic and Thrombolytic Therapy, 8th ED: ACCP Guidelines
Hemorrhagic Complications of Anticoagulant and Thrombolytic Treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)