Biomedical subjects
Publications and source records attributed to Mark A Crowther.
Patients with antiphospholipid syndrome can suffer recurrent thrombosis that is very difficult to manage. Recent research has demonstrated that high-intensity anticoagulation is not superior to standard therapy. Basic questions about the nature and treatment of this syndrome remain unanswered.
A randomized, blinded study in 30 patients was undertaken. This study found that low dose oral vitamin K was more effective than placebo when used to correct the INR in patients who are discontinuing warfarin. Larger studies will be required to determine if the use of oral vitamin K, for example in patients who are temporarily discontinuing warfarin to undergo interventional procedures, is safe and effective.
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Asymptomatic elevation of the international normalized ratio (INR) is a common problem associated with hemorrhage. Evidence from randomized controlled trials supports the use of low-dose oral vitamin K therapy as a treatment that promptly reduces the INR. Vitamin K given orally is more effective than subcutaneous vitamin K injection, and as effective as intravenous administration when INR values are compared 24 hours after administration. A 1.0-mg vitamin K dose is likely most appropriate for patients with INR values between 4.5 and 10. The fear of over-correction of the INR has limited the widespread use of vitamin K; however, our review suggests that this occurs infrequently when small doses are administered orally.
BACKGROUND: Patients with mechanical heart valves (MHV) require temporary interruption of warfarin when undergoing invasive procedures. Current guidelines addressing this subject are discordant because there is no high quality evidence to support any single management strategy. We tested the hypothesis that there is significant practice variation amongst clinicians caring for patients with MHV who require temporary cessation of their warfarin therapy. METHODS: A survey describing 4 hypothetical patients with mechanical heart valves was distributed to all clinicians attending an anticoagulation specialty meeting. For each scenario, the attendee was given several choices for preoperative and postoperative anticoagulation management. Information about each respondent's profession, specialty and the frequency with which they make perioperative anticoagulation recommendations was also collected. RESULTS: Three hundred twenty-four of 650 surveys were returned. In each of the case scenarios, a majority of respondents selected subcutaneous low molecular weight heparin (LMWH) or subcutaneous unfractionated heparin (UH) as the preferred pre- and postoperative anticoagulant. Significant variation in practice was noted: for none of the questions was a single strategy selected by greater than 80% of respondents. CONCLUSION: Expert clinicians differ in their perioperative management strategies for patients with MHV who require interruption of warfarin. Although subcutaneous LMWH/UH was the treatment of choice in all scenarios, the lack of consensus found in our survey highlights the need for randomized controlled clinical trials of peri-procedural anticoagulant therapy. This survey of anticoagulation experts reveals that there is significant practice variation in scenarios where temporary interruption of warfarin is necessary in patients with mechanical heart valves. Despite discordant guidelines and a lack of high-quality data to support any strategy, a majority of the respondents surveyed would use low molecular weight heparin (or subcutaneous unfractionated heparin) to anticoagulate patients with mechanical heart valves during the peri-operative period.
BACKGROUND: Low-dose oral vitamin K effectively returns an international normalized ratio (INR) between 4.5 and 10.0 to an INR of 2.0-3.0 within 24 h in about 70% of patients. However, the efficacy of oral vitamin K for the treatment of higher INR values has only been studied in one small randomized trial. Treatment of markedly prolonged INR values with low-dose oral vitamin K is attractive because it has the potential to greatly simplify the management of such patients. METHODS: In our tertiary care anticoagulation clinic patients with an INR of more than 10 were managed as outpatients with simple warfarin withdrawal and, where feasible, low-dose (2 mg) oral vitamin K. Only patients with additional complications such as bleeding or unexplained symptoms were admitted to hospital. RESULTS: Eighty-five patients had 89 episodes of an INR value of more than 10.0. Fourteen patients were admitted to the hospital for management. In the other 75 episodes patients were managed as outpatients by warfarin withdrawal. In 24 episodes patients did not receive vitamin K. In 51 episodes patients were also given oral vitamin K. None of the patients given oral vitamin K experienced bleeding requiring medical intervention (95% confidence interval (CI) 0-6%). In contrast there were three clinically important bleeding episodes amongst the patients managed with simple warfarin withdrawal (95% CI 0-34%). Patients given vitamin K were also more likely to have an INR<5 by day 3 than those managed by withdrawal of warfarin alone. Two patients admitted to hospital and given intravenous vitamin K at higher doses became temporarily refractory to anticoagulation while there were no such complications in those treated with low-dose oral vitamin K. CONCLUSION: Low-dose (2 mg) oral vitamin K, coupled with temporary warfarin discontinuation, appears to be a safe and effective treatment for severe warfarin associated coagulopathy in non-bleeding patients.
BACKGROUND: Patients who are receiving warfarin therapy require frequent blood testing to monitor the intensity of anticoagulation. Although previous studies suggest that capillary blood monitoring of the international normalize ratio (INR) is rapid and reliable, patient preferences for the method of blood drawing have not been investigated. METHODS: We performed a randomized controlled trial of patients attending an anticoagulation clinic in which patients were randomly allocated to undergo capillary or venous INR monitoring. Patient satisfaction with the outpatient visit, pain associated with blood drawing, and time spent in the clinic were assessed for each patient. RESULTS: Sixty patients were studied. Using a 10-point visual analogue scale to quantify patient satisfaction (0-very satisfied; 10-very dissatisfied), patients expressed a strong preference for capillary INR monitoring over venous INR monitoring (1.64 vs. 4.45; P < 0.001). Using a 10-point visual analogue scale to quantify pain with blood sampling (0-no pain; 10-very painful), patients who underwent capillary INR testing had less pain than venous INR testing (0.83 vs. 2.23; P < or = 0.004). Patients spent, on average, 33 fewer minutes in the clinic with capillary INR testing than venous INR testing (P < 0.001). DISCUSSION: Our findings support the routine use of capillary blood testing, using a portable monitor, for the management of patients in outpatient anticoagulation clinics.
Patients with antiphospholipid antibodies (APLA) are at risk of arterial thromboembolism (ATE) or venous thromboembolism (VTE). The true strength of the association between APLA and first TE is unknown as there are no prospective studies of a large, well-characterized inception cohort of matched patients with and without APLA. Thus, evidence-based treatment recommendations for primary prophylaxis of TE in such patients cannot be made. Optimal therapy of patients with recent TE and APLA remains controversial; although there is no doubt that some such patients have a malignant hypercoagulable state characterized by resistance to "usual intensity" anticoagulation; recent evidence suggests that most such patients are adequately treated with "usual therapy". After warfarin discontinuation, such patients appear to be at increased risk of recurrent TE, as demonstrated in a series of studies of discontinuation of secondary TE prophylaxis in patients with APLA and venous TE (VTE). Because of this increased risk of recurrent TE, after anticoagulants are discontinued, most "experts" recommend extended duration therapeutic dose warfarin for such patients. This paper will briefly review this evidence.
The optimal perioperative anticoagulation management in patients on warfarin therapy is poorly defined because of the lack of randomized trials. Because guidelines are heterogeneous, we hypothesized that treatment strategies are not uniform in clinical practice. During the Annual Meeting of the Italian Federation of Anticoagulation Clinics, a questionnaire with four different clinical scenarios was distributed. Two scenarios described the cases of patients with a mechanical heart valve in the mitral position and additional risk factors for systemic embolism, one undergoing major surgery (case 1) and one undergoing minor surgery (case 3). Two scenarios described patients with an aortic mechanical heart valve, one undergoing major surgery (case 2) and one minor surgery (case 4). Different preoperative and postoperative management options were offered. Treatment options for all scenarios were the same. Of the 300 questionnaires distributed, 72 were returned (24%). Outpatient full-dose low molecular weight heparin (LMWH) was the most selected strategy in the preoperative phase. It was chosen by 90.3% of participants in case 3, 87.5% in case 1, 62.5% in case 2, and 52.8% in case 4. In the postoperative phase, full-dose LMWH remained the most selected option for cases 1 (75%) and 3 (70.8%), whereas low-dose LMWH was selected by the majority for cases 2 (50%) and 4 (61.1%). Even among expert clinicians, the management of perioperative anticoagulation is heterogeneous. In particular, the definition of risk categories and the optimal intensity of antithrombotic drugs remain to be assessed by well-designed prospective studies.
Low molecular weight heparins (LWMH) are the preferred initial treatment for many thromboembolic disorders but are renally excreted and relatively contraindicated in patients with renal failure because of concerns of increased bleeding risks. The purpose of this study was to evaluate the safety and efficacy of LMWH compared with unfractionated heparin (UFH) for preventing thrombosis of the extracorporeal dialysis circuit. Studies were identified with the use of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and FirstSearch; reference lists were reviewed; and pharmaceutical companies were contacted. Randomized, controlled trials that compared an LMWH with another anticoagulant during hemodialysis in patients with ESRD and reported at least one of bleeding, extracorporeal circuit thrombosis, or anti-Xa levels were chosen. Two reviewers independently extracted data on methodologic quality, study design, clinical outcomes, and anti-Xa levels. Seventeen trials were included in this systematic review, 11 of which were included in the meta-analysis. It was found that LMWH did not significantly affect the number of bleeding events (relative risk, 0.96; 95% confidence interval [CI], 0.27 to 3.43), bleeding assessed by vascular access compression time (weighted mean difference, -0.87; 95% CI, -2.75 to 1.02), or extracorporeal circuit thrombosis (relative risk, 1.15; 95% CI, 0.70 to 1.91) as compared with UFH. LMWH seem to be as safe as UFH in terms of bleeding complications and as effective as UFH in preventing extracorporeal circuit thrombosis. However, inferences from these trials assessing anticoagulation for patients who undergo hemodialysis will continue to be weak until larger, more rigorous randomized trials are conducted.
Oral anticoagulants are often prescribed for long-term prevention and treatment of venous or arterial thromboembolism. The only orally active anticoagulants currently available are the vitamin K antagonists. Although effective, they have a narrow therapeutic window and require routine coagulation monitoring to ensure that a therapeutic level has been achieved. Furthermore, genetic differences in metabolism and multiple food and drug interactions affect the anticoagulant response to vitamin K antagonists. These factors add to the need for routine coagulation monitoring, which is problematic for patients and physicians and costly for the healthcare system. Ximelagatran, the first oral direct thrombin inhibitor, was designed to overcome many of the drawbacks of vitamin K antagonists. Since it produces a predictable anticoagulant response, ximelagatran does not require coagulation monitoring. Phase III clinical trials have evaluated the efficacy and safety of ximelagatran for the prevention and treatment of venous thromboembolism and for the prevention of thromboembolic events in patients with atrial fibrillation. Focusing on ximelagatran, this review will discuss the appropriateness of thrombin as a target for new anticoagulants, compare and contrast direct and indirect thrombin inhibitors and describe the theoretical advantages of direct thrombin inhibitors. It will also review the pharmacology of ximelagatran, discuss the clinical trial results with ximelagatran and provide perspective on the advantages and potential limitations of ximelagatran.
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Explore the source record for details and available documents.
BACKGROUND: Many patients with the antiphospholipid antibody syndrome and recurrent thrombosis receive doses of warfarin adjusted to achieve an international normalized ratio (INR) of more than 3.0. However, there are no prospective data to support this approach to thromboprophylaxis. METHODS: We performed a randomized, double-blind trial in which patients with antiphospholipid antibodies and previous thrombosis were assigned to receive enough warfarin to achieve an INR of 2.0 to 3.0 (moderate intensity) or 3.1 to 4.0 (high intensity). Our objective was to show that high-intensity warfarin was more effective in preventing thrombosis than moderate-intensity warfarin. RESULTS: A total of 114 patients were enrolled in the study and followed for a mean of 2.7 years. Recurrent thrombosis occurred in 6 of 56 patients (10.7 percent) assigned to receive high-intensity warfarin and in 2 of 58 patients (3.4 percent) assigned to receive moderate-intensity warfarin (hazard ratio for the high-intensity group, 3.1; 95 percent confidence interval, 0.6 to 15.0). Major bleeding occurred in three patients assigned to receive high-intensity warfarin and four patients assigned to receive moderate-intensity warfarin (hazard ratio, 1.0; 95 percent confidence interval, 0.2 to 4.8). CONCLUSIONS: High-intensity warfarin was not superior to moderate-intensity warfarin for thromboprophylaxis in patients with antiphospholipid antibodies and previous thrombosis. The low rate of recurrent thrombosis among patients in whom the target INR was 2.0 to 3.0 suggests that moderate-intensity warfarin is appropriate for patients with the antiphospholipid antibody syndrome.
BACKGROUND: Warfarin is very effective in preventing recurrent venous thromboembolism but is also associated with a substantial risk of bleeding. After three months of conventional warfarin therapy, a lower dose of anticoagulant medication may result in less bleeding and still prevent recurrent venous thromboembolism. METHODS: We conducted a randomized, double-blind study, in which 738 patients who had completed three or more months of warfarin therapy for unprovoked venous thromboembolism were randomly assigned to continue warfarin therapy with a target international normalized ratio (INR) of 2.0 to 3.0 (conventional intensity) or a target INR of 1.5 to 1.9 (low intensity). Patients were followed for an average of 2.4 years. RESULTS: Of 369 patients assigned to low-intensity therapy, 16 had recurrent venous thromboembolism (1.9 per 100 person-years), as compared with 6 of 369 assigned to conventional-intensity therapy (0.7 per 100 person-years; hazard ratio, 2.8; 95 percent confidence interval, 1.1 to 7.0). A major bleeding episode occurred in nine patients assigned to low-intensity therapy (1.1 events per 100 person-years) and eight patients assigned to conventional-intensity therapy (0.9 event per 100 person-years; hazard ratio, 1.2; 95 percent confidence interval, 0.4 to 3.0). There was no significant difference in the frequency of overall bleeding between the two groups (hazard ratio, 1.3; 95 percent confidence interval, 0.8 to 2.1). CONCLUSIONS: Conventional-intensity warfarin therapy is more effective than low-intensity warfarin therapy for the long-term prevention of recurrent venous thromboembolism. The low-intensity warfarin regimen does not reduce the risk of clinically important bleeding.
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Congenital causes of venous thrombosis have gained increasing prominence with the description of the factor V Leiden mutation and the prothrombin gene mutation. More recently, the description of the association between increased levels of coagulation factors and venous thrombosis and the finding that patients with thrombophilia can harbor more than one prothrombotic state have further increased the clinical relevance of the congenital thrombophilic states. In this qualitative review, we summarize current knowledge of the congenital prothrombotic states and propose a simple classification system that divides the states into two broad groups: those associated with reduced levels of the inhibitors of the coagulation cascade and those associated with increased levels or function of the coagulation factors. The first group is less common than the second, but it is associated with a much higher risk for venous thrombosis. This review provides clinicians with an evidence-based, practical guide to the congenital prothrombotic states.