Susan I. O’Shea

Randomized controlled trial of supervised patient self‐testing of warfarin therapy using an internet‐based expert system

Summary.  Background: Increased frequency of prothrombin time testing, facilitated by patient self‐testing (PST) of the International Normalized Ratio (INR) can improve the clinical outcomes of oral anticoagulation therapy (OAT). However, oversight of this type of management is often difficult and time‐consuming for healthcare professionals. This study reports the first randomized controlled trial of an automated direct‐to‐patient expert system, enabling remote and effective management of patients on OAT. Methods: A prospective, randomized controlled cross‐over study was performed to test the hypothesis that supervised PST using an internet‐based, direct‐to‐patient expert system could provide improved anticoagulation control as compared with that provided by an anticoagulation management service (AMS). During the 6 months of supervised PST, patients measured their INR at home using a portable meter and entered this result, along with other information, onto the internet web page. Patients received instant feedback from the system as to what dose to take and when the next test was due. During the routine care arm, patients attended the AMS at least every 4–6 weeks and were dosed by the anticoagulation pharmacist or physician. The primary outcome variable was the difference in the time in therapeutic range (TTR) between both arms. Results: One hundred and sixty‐two patients were enrolled (male 61.6%, mean age 58.7 years), and 132 patients (81.5%) completed both arms. TTR was significantly higher during PST management than during AMS management (median TTR 74% vs 58.6%; z=5.67, P < 0.001). Conclusions: The use of an internet‐based, direct‐to‐patient expert system for the management of PST improves the control of OAT as compared with AMS management.

Hypercoagulable states and antithrombotic strategies in recurrent vascular access site thrombosis

Vascular access site thrombosis is a major cause of morbidity in patients receiving hemodialysis. The role of hypercoagulable states in recurrent vascular access site thrombosis remains poorly understood. Data are limited regarding systemic anticoagulation to improve access graft patency, because of concern about hemorrhagic complications. We determined the prevalence of hypercoagulable states and clinical outcome (thrombotic and hemorrhagic) after initiation of antithrombotic therapy in a series of patients with recurrent vascular access site thrombosis. We evaluated 31 patients who had sustained 119 thrombotic events that resulted in vascular access graft failure during the year before evaluation. Sixty-eight percent of patients tested had elevated concentrations of antibody to anticardiolipin or topical bovine thrombin, and 18% of patients tested had heparin-induced antibodies. More than 90% of patients had elevated factor VIII concentration, 62% had elevated fibrinogen concentrations, and 42% had elevated C-reactive protein concentrations. Twenty-nine patients were given antithrombotic therapy: 13 with warfarin sodium, 12 with unfractionated heparin (UFH), and 11 with low molecular weight heparin (LMWH). Seven patients received more than one antithrombotic agent, sequentially. Nineteen patients have had no thrombotic events since beginning antithrombotic therapy (10 with warfarin, 3 with UFH, 6 with LMWH). Mean follow-up was 8.6 months (median, 7 months). Eight patients sustained 10 bleeding complications (5 with warfarin, 3 with UFH, and 2 with LMWH). In conclusion, hypercoagulable states are common in patients with recurrent vascular access site thrombosis. Antithrombotic therapy may increase vascular access graft patency, but is associated with significant risk for hemorrhage. Prospective studies are needed to evaluate the role and safety of antithrombotic agents in improving vascular access graft patency.

The reliability of point‐of‐care prothrombin time testing. A comparison of CoaguChek S ® and XS ® INR measurements with hospital laboratory monitoring

The development of point‐of‐care (POC) testing devices enables patients to test their own international normalized ratio (INR) at home. However, previous studies have shown that when compared with clinical laboratory values, statistically significant differences may occur between the two methods of INR measurement. The aim of this study was to evaluate the accuracy of the CoaguChek S® and XS® POC meters relative to clinical laboratory measurements. As part of a randomized, crossover patient self‐testing (PST) study at Cork University Hospital, patients were randomized to 6 months PST or 6 months routine care by the anticoagulation management service. During the PST arm of the study, patients measured their INR at home using the CoaguChek S® or XS® POC meter. External quality control was performed at enrolment, 2 months and 4 months by comparing the POC measured INR with the laboratory determined value. One hundred and fifty‐one patients provided 673 paired samples. Good correlation was shown between the two methods of determination (r = 0.91), however, statistically significant differences did occur. A Bland–Altman plot illustrated good agreement of INR values between 2.0 and 3.5 INR units but there was increasing disagreement as the INR rose above 3.5. Eighty‐seven per cent of all dual measurements were within the recommended 0.5 INR units of each other. This study adds to the growing evidence that POC testing is a reliable and safe alternative to hospital laboratory monitoring but highlights the importance of external quality control when these devices are used for monitoring oral anticoagulation.

Managing oral anticoagulation therapy: improving clinical outcomes. A review

Many physicians are reluctant to prescribe oral anticoagulation therapy (OAT) because of the fear of haemorrhagic complications. Changes in patient health, lifestyle or diet and other drugs can alter the effectiveness of oral anticoagulants. These potential interferences, added to the fact that each individual has a different reaction to these drugs, requires that therapy is monitored regularly. This article aims to review those strategies which help to achieve optimal anticoagulation control and improve the outcomes of OAT. Relevant articles were identified through a search of MEDLINE and included publications reporting on intensity of anticoagulation, the initiation of therapy and the role of pharmacogenetics, the transition from primary to secondary care, management by specialized clinics using decision support software and home‐testing. Implementation of these strategies would increase the use of oral anticoagulants by physicians and offers the potential to improve patient safety and reduce adverse events.

Economic evaluation of a randomized controlled trial of pharmacist‐supervized patient self‐testing of warfarin therapy

The increase in numbers of patients requiring oral anti‐coagulation testing in outpatient clinics has focused attention on alternative flexible systems of anti‐coagulation management. One option is pharmacist led patient self‐testing (PST) of international normalised ratio (INR) levels. PST has demonstrated improvements in anti‐coagulation control, but its cost‐effectiveness is inconclusive. This study reports the first cost‐effectiveness evaluation of a randomized controlled trial of an automated direct‐to‐patient expert system, enabling remote and effective management of patients on oral anti‐coagulation therapy.

A multi-dose pharmacokinetic study of dalteparin in haemodialysis patients

Low-molecular-weight heparins undergo renal elimination, and therefore the proper dosing in hemodialysis (HD) patients is unclear. It was the objective of this study to evaluate the pharmacokinetic (PK) parameters of dalteparin in patients receiving chronic HD for end-stage renal disease. We performed a multidose PK study with prophylactic doses of dalteparin in twelve HD patients. Dalteparin 5,000 IU was administered subcutaneously daily for four consecutive days, with HD performed on day 2 and day 4. Anti-factor Xa activity was determined daily and at multiple blood samples after the 3rd and 4th dose. Eleven of 12 patients completed the study. The mean (range) PK parameters determined after the 4th dose were as follows: i) maximum concentration (Cmax ) was 0.31 IU/ml (0.06 to 0.55 IU/ml); ii) time to Cmax was 3.55 hours (2.59 to 4.96 hr); iii) area under the curve was 3.24 IU*hr/ml (0.64 to 6.44 IU*hr/ml); iv) half-life was 3.82 hr (2.03 to 9.63 hr); and v) trough anti-factor Xa activity 0.04 IU/ml (0.02 to 0.08 IU/ml). No major bleeding was observed. In general, patients with lower body weight exhibited a higher Cmax . From this pilot PK study, we have determined initial PK parameters for dalteparin in HD patients. Although a standard prophylactic dose was used, we found that in this patient population differences in body weight influenced the Cmax. Future studies to evaluate the PK parameters of dalteparin in patients receiving chronic HD may have to use weight-based dosing and will need to be performed over a longer period of time.

Venous Thromboembolism in Patients With Myeloma: Incidence and Risk Factors in a “Real-World” Population

Myeloma has a well-described association with venous thromboembolism (VTE). There are few dedicated studies investigating the incidence and risk factors. Many assessment scores have been suggested to estimate the risk of VTE in patients with cancer but these have been validated in solid organ tumors. The records of patients with myeloma attending a university hospital between January 2007 and December 2012 were reviewed to investigate the incidence of VTE and the associated risk factors. In all, 217 patients with a mean (standard deviation) age at diagnosis of 65 (12) years were included. Of 217 patients, 12% had an episode of VTE, 69% received at least 1 immunomodulatory agent, and 95% had low or intermediate risk of VTE according to the Khorana score. Venous thromboembolism was a frequent occurrence in this cohort. Patients had many risk factors for VTE but no one was predictive. As myeloma outcomes continue to improve, a dedicated prospective study is warranted to investigate the most appropriate thromboprophylaxis strategy.

Plasma Thrombin Generation and Sensitivity to Activated Protein C Among Patients With Myeloma and Monoclonal Gammopathy of Undetermined Significance

The etiology of the prothrombotic state in myeloma has yet to be definitively characterized. Similarly, while recent evidence suggests that patients with monoclonal gammopathy of undetermined significance (MGUS) may also be at increased risk of thrombosis, the magnitude and the etiology of this risk have also yet to be defined. The present study aims to characterize patterns of plasma thrombin generation and sensitivity to the anticoagulant activity of activated protein C (APC) at the time of initial diagnosis of myeloma and in response to therapy in comparison to that observed among patients with MGUS and matched, healthy volunteers. Patients presenting with newly diagnosed/newly relapsed myeloma (n = 8), MGUS (n = 8), and matched healthy volunteers (n = 8) were recruited. Plasma thrombin generation was determined by calibrated automated thrombography. Peak thrombin generation was significantly higher in patients with myeloma (383.4 ± 33.4 nmol/L) and MGUS (353.4 ± 16.5 nmol/L) compared to healthy volunteers (276.7 ± 20.8 nmol/L; P < .05). In the presence of APC, endogenous thrombin potential was significantly lower in control plasma (228.6 ± 44.5 nmol/L × min) than in either myeloma (866.2 ± 241.3 nmol/L × min, P = .01) or MGUS plasma (627 ± 91.5 nmol/L × min, P = .003). Within the myeloma cohort, peak thrombin generation was significantly higher at diagnosis (353.2 ± 15.9 nmol/L) than following completion of the third cycle of therapy (282.1 ± 15.2 nmol/L; P < .005). Moreover, sensitivity to APC increased progressively with each cycle of chemotherapy. Further study of the etiology and evolving patterns of hypercoagulability among patients with these conditions is warranted and may have future implications for thromboprophylaxis strategies.