Mattias Wieloch

Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA

AIMS In anticoagulation treatment with warfarin, the risk of thrombo-embolic events must be weighed against the risk of bleeding. Time in therapeutic range (TTR) is an important tool to assess the quality of anticoagulation treatment, and has been shown to correlate with less bleeding and thrombo-embolic complications. AuriculA, the Swedish national quality registry for atrial fibrillation and anticoagulation, is used for follow-up and dosage control of warfarin. This is the first report of TTR in AuriculA and, in a subgroup of two centres, bleeding and thrombo-embolic complications during 2008. METHODS AND RESULTS Prothrombin complex (International normalized ratio) values from 18 391 patients in 67 different centres were analysed. The mean (SD) age was 70 (12) years. The main indications for warfarin treatment were: atrial fibrillation (64%), venous thromboembolism (19%), and heart valve dysfunction (13%). Time in therapeutic range for all patients was 76.2%. The mean weekly dose of warfarin decreased with age and TTR increased with age. In 4273 patients from two centres in AuriculA, the frequency of major bleedings and venous/arterial thrombo-embolism were 2.6 and 1.7% and for atrial fibrillation, 2.6 and 1.4%, per treatment year, respectively. A correlation between age and the risk of major bleeding (P< 0.001), but not thrombo-embolic complications (P= 0.147), was seen. CONCLUSION Compared with prospective randomized trials of warfarin treatment, TTR in the AuriculA population was higher. Complications were low, probably due to the organization of anticoagulation treatment in Sweden. Use of the AuriculA dosing programme could have contributed to the results by keeping dosing regimens consistent over all centres.

Triple antithrombotic therapy following an acute coronary syndrome: prevalence, outcomes and prognostic utility of the HAS-BLED score.

AIMS The aim of this study was to evaluate the prevalence of triple antithrombotic therapy (TT) (warfarin, aspirin and clopidogrel) in patients following an acute coronary syndrome (ACS), the bleeding risk compared to double antiplatelet therapy (DAPT) (aspirin and clopidogrel) and evaluate the accuracy of the HAS-BLED risk score in predicting serious bleeding events in TT patients. METHODS AND RESULTS We retrospectively identified all ACS patients on TT upon discharge from the Coronary Care Unit at Skane University Hospital between 2005 and 2010. TT patients were compared to age- and sex-matched control patients discharged with DAPT. Major bleeding was defined in accordance with the HAS-BLED derivation study. A total of 2,423 patients were screened, of whom 159 (6.6%) were on TT. The mean age was 67.2 (±0.9) years. The most common indication for TT was atrial fibrillation (n=63, 39.6%) followed by apical akinesia (n=60, 37.8%), and the mean duration of TT was 3.7 (±0.3) months. Upon termination of TT, warfarin was discontinued in 82 (52.2%) patients and clopidogrel in 57 (36.3%) patients. The cumulative incidence of spontaneous bleeding events was significantly higher with TT compared to DAPT at one year (10.2% vs. 3.2%; p=0.01). The HAS-BLED score significantly predicted spontaneous bleeding events in TT patients (area under the receiver operating characteristic [ROC] curve 0.67; 95% CI=0.54-0.79; p=0.048). CONCLUSIONS TT was relatively common following acute coronary syndrome and was associated with a threefold increase in major bleeding compared to DAPT at one year. The HAS-BLED risk score predicted bleeding events with moderate accuracy.

Comparison and evaluation of a Point-of-care device (CoaguChek XS) to Owren-type prothrombin time assay for monitoring of oral anticoagulant therapy with warfarin

BACKGROUND The standardized test used for evaluating the effect of warfarin is the prothrombin time (PT) which is measured and expressed in international normalized ratio (INR). Regular control of treatment intensity is required since inappropriate dosage increases the risk for complications. Portable point-of-care analytical instruments for measurement of capillary whole blood PT have been available for the last decades. The purpose of this study was to compare and evaluate INR values obtained by the point-of-care device CoaguChek XS, to Owren PT in a hospital setting. MATERIALS AND METHODS In 397 warfarin-treated patients, capillary whole blood was analyzed with the CoaguChek XS and the results were compared to analysis of venous plasma samples with the Owren PT assay. To study reproducibility and rule out preanalytical errors, a subgroup of 152 patients had two capillary blood samples analyzed with the CoaguChek XS. RESULTS In 397 patients, with a median age(+/-2SD) of 69.0(50-88) years, there was a positive correlation between results from the CoaguChek XS and the Owren-type PT assay (r=0.94;p<0.001) and concordance of 88.2%. The mean INR difference (S.D) was 0.02 (0.22). Comparison of the 152 double samples analyzed with the CoaguChek XS, produced a positive correlation of 0.99; p<0.001. CONCLUSIONS The CoaguChek XS presents reproducible, highly comparable results with Owren PT at therapeutic levels of INR. The CoaguChek XS seems to produce better results than the earlier CoaguChek S, probably due to a new method of PT measurement where levels of fibrinogen and haematocrit do not affect the outcome.

Glomerular filtration rate in patients with atrial fibrillation on warfarin treatment: A subgroup analysis from the AURICULA registry in Sweden

INTRODUCTION Numerous associations between chronic kidney disease (CKD) and atrial fibrillation (AF) have been reported and patients with CKD on anticoagulation therapy have an increased risk of bleeding. Currently, new anticoagulant agents are emerging in clinical practice, some of which are excreted by the kidneys. The proportion of AF patients on anticoagulant treatment with reduced renal function is, however, unknown. MATERIALS AND METHODS Using AURICULA, a Swedish registry for anticoagulation, estimated glomerular filtration rate (eGFR) was investigated in AF patients on warfarin treatment (n = 2,603). The study group was compared with a healthy sample from the population (n = 2,261). Two different creatinine prediction equations were used for calculating eGFR: the Lund-Malmö (LM) and MDRD Study equation. RESULTS The fraction of AF patients with eGFR <30 and <45 ml/min/1.73 m(2) were 8.1% and 22.9% with the LM and 4.3% and 16.3% with the MDRD equation, respectively, and significantly higher than corresponding values in the reference population. GFR decreased with increasing age, where 11.4% and 5.6% of AF patients aged ≥ 75 years had eGFR <30 ml/min/1.73 m(2) according to the LM and MDRD equations, respectively. CONCLUSIONS Severe renal impairment is common among AF patients on anticoagulant treatment with warfarin, especially at higher ages. Monitoring of renal function should be implemented in clinical practice for AF patients treated with new anticoagulants eliminated by the kidneys.

Estimated glomerular filtration rate is associated with major bleeding complications but not thromboembolic events, in anticoagulated patients taking warfarin.

BACKGROUND Decreased glomerular filtration rate is an established risk factor for bleeding but there are limited data on its association with bleeding risk in well-controlled anticoagulated patients taking warfarin. OBJECTIVES The aim was to investigate the relationship between glomerular filtration rate, major bleeding and thromboembolic complications in patients with tight anticoagulation control. PATIENTS/METHODS A cohort study of patients from a Swedish quality register for anticoagulation, including all the registered patients that received anticoagulation during 2008 in the anticoagulation center of Skåne University Hospital, Malmö. Key outcome measures were major bleeding and arterial or venous thrombosis during 2008. A total of 3536 patients (2875 treatment years) were included. RESULTS Total rates of 2.6 (2.0-3.2) bleeding events and 1.8 (1.3-2.3) thrombotic events per 100 treatment years were recorded (75 bleeding and 51 thromboembolic events). Data on estimated glomerular filtration rate were available in 3349 patients. Mean time in therapeutic range (international normalized ratio 2.0-3.0) was 74.5% (n=2894). Major bleeding events were significantly related to age and percentage of time with international normalized ratio >3.0 (P<0.001). Glomerular filtration rate levels <30 ml/min/1.73 m(2) were particularly associated with high risk of bleeding, especially in elderly patients. No correlation between glomerular filtration rate and thromboembolic events was seen. CONCLUSIONS With good anticoagulation control as measured by time in therapeutic range, patients had a relatively low risk for major bleeding if their renal function is normal. Despite good anticoagulation control, severely impaired kidney function is associated with a very high yearly risk of major bleeding events.

Thromboembolism, major bleeding and mortality in patients with mechanical heart valves- a population-based cohort study.

INTRODUCTION Low incidences of thromboembolism (TE) and bleeding in patients with mechanical heart valves (MHV) have previously been reported. This study assesses the incidence of and clinical risk factors predicting TE, major bleeding and mortality in a clinical setting. METHODS AND RESULTS All 546 patients undergoing anticoagulation treatment due to MHV replacement at hospitals in Malmö and Sundsvall in Sweden were monitored during 2008-2011 and the incidence of TE, major bleeding and mortality was prospectively followed. There were 398, 122 and 26 patients in the aortic group (AVR), mitral (MVR) group and the combined aortic/mitral valve group respectively. The incidence of TE was 1.8 and 2.2 per 100 patient-years in the AVR group MVR group respectively. The corresponding incidences of bleeding were 4.4 and 4.6, respectively. Independent predictor of thromboembolism was vascular disease (Odds ratio {OR}: 4.2; 95% CI: 1.0-17.4). Predictor of bleeding was previous bleeding (OR: 2.7; 95% CI: 1.4-5.3). Independent predictors of mortality was age (Hazard ratio {HR}: 1.03; 95% CI: 1.00-1.05), hypertension (HR: 2.4; 95% CI: 1.3-4.5), diabetes (HR: 2.4; 95% CI: 1.3-4.3) and alcohol overconsumption (HR: 5.2; 95% CI: 1.7-15.9). Standardized mortality/morbidity ratio for mortality and AMI was 0.99 (95% CI: 0.8-1.2) and 0.87 (95% CI: 0.5-1.2) respectively. CONCLUSION The incidence of TE and major bleeding in this unselected clinical population exceeds that of previously reported retrospective and randomized trials. Despite this, mortality is equal to that of the general population.

Referring physicians underestimate the extent of abnormalities in final reports from myocardial perfusion imaging

BackgroundIt is important that referring physicians and other treating clinicians properly understand the final reports from diagnostic tests. The aim of the study was to investigate whether referring physicians interpret a final report for a myocardial perfusion scintigraphy (MPS) test in the same way that the reading nuclear medicine physician intended.MethodsAfter viewing final reports containing only typical clinical verbiage and images, physicians in nuclear medicine and referring physicians (physicians in cardiology, internal medicine, and general practitioners) independently classified 60 MPS tests for the presence versus absence of ischemia/infarction according to objective grades of 1–5 (1 = No ischemia/infarction, 2 = Probably no ischemia/infarction 3 = Equivocal, 4 = Probable ischemia/infarction, and 5 = Certain ischemia/infarction). When ischemia and/or infarction were thought to be present in the left ventricle, all physicians were also asked to mark the involved segments based on the 17-segment model.ResultsThere was good diagnostic agreement between physicians in nuclear medicine and referring physicians when assessing the general presence versus absence of both ischemia and infarction (median squared kappa coefficient of 0.92 for both). However, when using the 17-segment model, compared to the physicians in nuclear medicine, 12 of 23 referring physicians underestimated the extent of ischemic area while 6 underestimated and 1 overestimated the extent of infarcted area.ConclusionsWhereas referring physicians gain a good understanding of the general presence versus absence of ischemia and infarction from MPS test reports, they often underestimate the extent of any ischemic or infarcted areas. This may have adverse clinical consequences and thus the language in final reports from MPS tests might be further improved and standardized.

Inflammatory biomarkers predicting prognosis in patients with acute dyspnea

Objective/Purpose The objective was to identify inflammatory biomarkers that predict risk of 90-day mortality in patients with acute dyspnea. Method We analyzed 25 inflammatory biomarkers, in plasma, in 407 adult patients admitted to the emergency department (ED) with acute dyspnea and related them to risk of 90-day mortality using Cox proportional hazard models adjusted for age, sex, oxygen saturation, respiratory rate, C-reactive protein, and Medical Emergency Triage and Treatment System–Adult score. Results Fifty patients (12%) died within 90 day from admission. Two strong and independent biomarker signals were detected: The hazard ratio (95% confidence interval) for 90-day mortality per 1-SD increment of interleukin-8 (IL-8) was 2.20 (1.67-2.90) (P = 2.5 × 10− 8) and for growth differentiation factor–15 (GDF-15) was 3.45 (2.18-5.45) (P = 1.3 × 10− 7) A Biomarker Mortality Risk Score (BMRS) summing standardized and weighted values of IL-8 and GDF-15 revealed that of patients belonging to quartile 1 (Q1) of the BMRS, only 1 patient died, whereas 32 patients died among those belonging to quartile 4. Each 1-SD increment of the BMRS was associated with a hazard ratio of 3.79 (2.50-5.73) (P = 2 × 10− 10) for 90-day mortality, and the point estimate was 13 times higher in Q4 as compared with Q1 of the BMRS (Ptrend over quartiles = 2 × 10− 6). Conclusion Interleukin-8 and GDF-15 are strongly and independently related to risk of 90-day mortality in unselected patients admitted to the ED because of acute dyspnea, suggesting that they may guide first-line physicians at the ED in risk assessment which in turn could lead to more accurate level of care and treatment intensity.

Concomitant use of dronedarone with dabigatran in patients with atrial fibrillation in clinical practice

INTRODUCTION Dronedarone is a strong P-glycoprotein inhibitor with a potential to increase bioavailability of dabigatran. We sought to measure and report plasma concentrations of dabigatran in patients with atrial fibrillation (AF) on concomitant dronedarone treatment. MATERIALS AND METHODS A cohort of 33 patients (mean age 64 years, 16 men) concomitantly treated with dabigatran at a dose of 110 mg twice a day (bid) and dronedarone at a dose of 400mg bid at the discretion of the patients cardiologist were followed prospectively. RESULTS Median trough plasma concentration of dabigatran at one week and one month after the concomitant treatment start was 102.0 (range 8-251) ng/ml and 84 (range 27-302) ng/ml respectively. Median treatment length was 13 (range 1-21) months. There was one major bleeding event (2,8% per patient-year) and no thrombotic events during a total of 35.5 patient-years. CONCLUSIONS Median trough plasma concentration of dabigatran in our study was observed to be similar to median trough plasma concentration of dabigatran at a dose of 150 mg bid without concomitant dronedarone in earlier studies with low reported rate of bleeding and thrombosis. Since concomitant treatment offers potential benefits to patients with AF, larger future trials that might refute the current contraindication are warranted.

Dabigatran in clinical practice – One-year experience at Skåne University Hospital

Dear Editors, In 2009, the pivotal RE-LY study established the oral thrombin inhibitor dabigatran to be at least as safe and effective as warfarin in preventing stroke in atrial fibrillation patients at a similar or reduced rate of major bleeding depending on dosage [1]. Dabigatran has subsequently been marketed in many countries. However, it is largely unknown how results from the carefully monitored RE-LY study extrapolate to the general clinical context. Therefore, we decided to evaluate the implementation of dabigatran treatment in patients with atrial fibrillation (AF) one year after marketing.