Elsevier

Heart & Lung

Volume 43, Issue 4, July–August 2014, Pages 358-362
Heart & Lung

Care of Adults and Infants with Pulmonary Disorders
Higher dose of warfarin for patients with pulmonary embolism complicated by obstructive sleep apnea hypopnea syndrome

https://doi.org/10.1016/j.hrtlng.2014.04.005Get rights and content

Abstract

Background

The concomitant prevalence of obstructive sleep apnea hypopnea syndrome (OSAHS) and pulmonary embolism (PE) is strikingly high, and therefore we studied the patients with PE to determine whether those who had OSHAS required greater warfarin doses to achieve a therapeutic international normalized ratio (INR).

Methods

By using computer tomographic pulmonary angiography or pulmonary angiography, we identified and recruited 97 patients with PE and all underwent polysomnography. Warfarin was initiated at a dose of 3 mg/day and modified to adjust the INR to the range of 2.0–3.0.

Results

OSAHS patients (n = 32) required a significantly higher dose of warfarin than their non-OSAHS counterparts (5.01 mg vs 3.61 mg, P < .001). This difference still existed between the two groups after adjusting for covariates (achieved INR value and weight). Logistic analysis suggested that OSAHS was an independent risk factor for high dose warfarin (OR 5.715, P < .001). On admission, OSAHS patients had a lower mean value of INR and prothrombin time but higher plasminogen (PLG) activity compared to non-OSAHS patients. Other coagulation indices were not significantly different between the two groups. Except for the PLG activity (r = .273, P = .026), the correlation between the warfarin dose and the baseline coagulating indices wasn't significant.

Conclusions

Our findings indicate that factors associated with OSAHS, such as hypercoagulation, may explain the need for higher doses of warfarin in treating patients with PE.

Introduction

The overall prevalence of obstructive sleep apnea hypopnea syndrome (OSAHS) in the general population is between 1.2%–4.5% in females and 3.1%–7.5% in males.1 However, the under-recognition of OSAHS among patients admitted for coronary heart disease is astonishingly high. For example, it was reported that the prevalence of OSAHS among acute coronary syndrome patients was 69%, with 34% of them having severe OSAHS (apnea–hypopnea index (AHI) > 30).2 In our previous study, the concomitant prevalence of OSAHS and PE was very high. Also, the patients with PE complicated by OSAHS had a significantly younger mean age of onset of disease and a higher incidence of obesity and diabetes than patients without OSAHS. Aggressive treatment was needed for them because of more lung segment involvement and lower partial pressure of oxygen in arterial blood.3 OSAHS may cause a pathologic prothrombotic state which could possibly promote the development of venous thromboembolic disease.4, 5, 6, 7, 8 The potential association between OSAHS and PE has already been discovered by several studies.9, 10, 11 Obesity, which is closely related to the occurrence of OSAHS and has a significant effect on its severity, may also aggravate the prothrombotic state and increase the risk of thrombosis.12

PE is thought to account for 5%–10% of deaths in hospitalized patients.13 If untreated, approximately one third of those who survive an initial PE die of a future embolic episode. Anticoagulant treatment plays a pivotal role in the management of patients with PE. Warfarin, still the most commonly used anticoagulation agent, should be initiated during the early phase of treatment with heparin, and the dose of warfarin should be adjusted to achieve an optimal international normalized ratio (INR). The anticoagulant effectiveness of warfarin is associated with non-genetic factors (including sex, age, and body weight) and genetic factors.14, 15

However, according to our knowledge, no data are available on the coagulation of patients who have PE complicated by OSAHS. Generally, OSAHS patients tend to have higher weight and more risks of hypercoagulation due to factors such as sedentary behavior, increased hematocrit (HCT) levels,16 slower blood viscosity,17 and increased platelet activity,18 all of which tend to permit more aggressive anticoagulation. We tested the hypothesis that having untreated OSHAS would be associated with the need for a higher dose of warfarin to achieve a therapeutic INR.

Section snippets

Study subjects

This prospective study was performed between June 2012 and May 2013. Ninety-seven identified patients with PE were recruited consecutively. The inclusion criteria were patients who have been diagnosed of PE and agreeing to participate in the study. Exclusion criteria were: 1. Patients unable or unwilling to participate or to provide consent; 2. Patients younger than 18 or older than 80, and pregnant women; 3. Patients diagnosed with malignant tumor, connective tissue disease, and heart failure

Clinical characteristics

As shown in Table 1, OSAHS group versus non-OSAHS group had more male patients, with a much higher body mass index (BMI), body weight, and triglyceride level. For the patients in our study, 78.13% of OSAHS patients had hypertension, while the incidence was 55.39% for non-OSAHS patients. Although arterial PO2 was similar for the two groups, the OSAHS group had a much higher arterial PCO2 compared to the arterial PCO2 of the non-OSAHS. There was no significant difference between the two groups in

Discussion

According to our knowledge, this is the first study to verify that OSAHS constitutes an independent factor for high warfarin dose when PE is present and treated without thrombolysis. OSAHS, a prothrombotic risk factor,20 was detected among patients who have PE at strikingly high rates.10, 11 Screening of OSAHS may affect the treatment strategies of patients with PE.

Similar to others, we found that body weight was significantly associated with warfarin dosage; obese patients required higher

Study limitations

Several shortcomings should be mentioned in our study. First and foremost, when the dose of warfarin was compared between OSAHS and non-OSAHS patients, weight, one of the most important influential factors, was adjusted. However, it was very hard to adjust for other potential factors concomitant with overweight, such as hypertension, diabetes, hyperlipemia, hyperuricemia, reduced physical exercise, etc, which made deviation almost inevitable. Secondly, a few people with AHI ≥5 events/hour, but

Conclusions

To treat PE, the OSAHS group required a comparatively higher dose of warfarin to achieve an INR of 2.0–3.0. This difference still exists after adjusting for weight and achieved INR value. The more severe the OSAHS was, the higher the dose of warfarin that was possibly needed. OSAHS patients had relatively high hypercoagulation states, but hypercoagulation was not an important reason for a higher warfarin dose for them. Many genetic and non-genetic factors may determine warfarin dose.

Acknowledgment

This study is supported by Beijing Project of Science and Technology (Z101107050210044).

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