Biomedical subjects

Mark A Crowther

Publications and source records attributed to Mark A Crowther.

65 records · Page 4Linked to original sources

PubMed2003

New anticoagulants: current status and future potential.

Arterial and venous thrombosis are a major cause of morbidity and mortality. Anticoagulants are a cornerstone of treatment in patients with these disorders. The two most frequently used anticoagulants, heparin and warfarin, have pharmacological and/or biophysical limitations that make them difficult to use in day-to-day clinical practice. Development of new anticoagulants, which were designed to overcome these limitations, has been facilitated by an increased understanding of the coagulation cascade, the advent of molecular modeling and structure-based drug design, and the realization that the treatment of thrombosis and its complications consumes billions of dollars in annual healthcare expenditures. New anticoagulants target various steps in the coagulation pathway. Coagulation is triggered by the factor VIIa/tissue factor complex and propagated by factors Xa and IXa, together with their activated cofactors, factor Va and VIIIa, respectively. Thrombin, the final effector in coagulation, then converts soluble fibrinogen into insoluble fibrin, the major matrix protein of the clot. New anticoagulation drugs that target each of these clotting enzymes have been developed. This review will focus on those drugs in more advanced stages of clinical evaluation. These include inhibitors of initiation of coagulation (tissue factor pathway inhibitor, nematode anticoagulant peptide and active-site blocked factor VIIa), inhibitors of propagation of coagulation (active-site blocked factor IXa, antibodies against factor IX/IXa, fondaparinux sodium, direct factor Xa inhibitors, protein C derivatives and soluble thrombomodulin), and thrombin inhibitors (hirudin, bivalirudin, argatroban and ximelagatran).

Animals↗

PubMed2002

Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial.

BACKGROUND: Excessive anticoagulation due to warfarin use is associated with hemorrhage. Subcutaneously administered vitamin K has not been evaluated for the treatment of warfarin-associated coagulopathy, yet it is widely used. OBJECTIVE: To show that oral vitamin K is more effective than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. DESIGN: Randomized, controlled trial. SETTING: Two teaching hospitals. PATIENTS: Patients with an international normalized ratio (INR) between 4.5 and 10.0. INTERVENTION: Warfarin therapy was withheld, and 1 mg of vitamin K was given orally or subcutaneously. MEASUREMENTS: The primary outcome measure was the INR on the day after administration of vitamin K. Secondary outcome measures were hemorrhage and thrombosis during a 1-month follow-up period. RESULTS: 15 of 26 patients receiving oral vitamin K and 6 of 25 patients receiving subcutaneous vitamin K had therapeutic INRs on the day after study drug administration (P = 0.015; odds ratio, 4.32 [95% CI, 1.13 to 17.44]). CONCLUSION: Oral vitamin K lowers INR more rapidly than subcutaneous vitamin K in asymptomatic patients who have supratherapeutic INR values while receiving warfarin.

Administration, Oral↗

PubMed2002

Short-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of prospective studies investigating symptomatic outcomes.

BACKGROUND: The prevalence of asymptomatic deep vein thrombosis diagnosed by venography after hip or knee replacement remains high despite 7 to 10 days of anticoagulant prophylaxis. However, the risk of symptomatic events in such patients is unclear. We performed a meta-analysis to provide reliable estimates of the risk of symptomatic venous thromboembolism occurring within 3 months of hip or knee replacement in patients who received short-duration (7-10 days) anticoagulant prophylaxis. METHODS: The MEDLINE, EMBASE, and Cochrane databases were searched from January 1993 to March 2001, supplemented by a manual search of bibliographies and conference abstracts, to identify prospective studies of patients undergoing hip or knee replacement who received short-duration prophylaxis (ie, 7-10 days of fixed-dose low-molecular-weight heparin or adjusted-dose warfarin, with a target international normalized ratio of 2.0-3.0). Studies were classified as clinical outcome studies if the outcome was symptomatic venous thromboembolism or as venographic outcome studies if the outcome was asymptomatic deep vein thrombosis diagnosed after bilateral venography. RESULTS: There were 4 clinical outcome studies with 6089 patients who had 3 months of follow-up, and 13 venographic outcome studies with 7080 patients who had venography 7 to 10 days after surgery. In clinical outcome studies, the 3-month incidence of nonfatal venous thromboembolism was 3.2% (95% confidence interval [CI], 2.0%-4.4%), and the 3-month incidence of fatal pulmonary embolism was 0.10% (95% CI, 0.02%-0.20%). The postprophylaxis incidence of nonfatal venous thromboembolism was 2.2% (95% CI, 1.4%-3.0%), and the incidence of fatal pulmonary embolism was 0.05% (95% CI, 0%-0.12%). The postprophylaxis incidence of symptomatic venous thromboembolism was higher after hip than after knee replacement (2.5% vs 1.4%; P=.02). In venographic outcome studies, the prevalence of deep vein thrombosis (total and proximal) was higher after knee than after hip replacement (total: 38.8% vs 16.4%; P<.001; proximal: 7.6% vs 3.8%; P<.001). CONCLUSIONS: In patients who undergo hip or knee replacement and receive short-duration anticoagulant prophylaxis, symptomatic nonfatal venous thromboembolism will occur in about 1 of 32 patients and fatal pulmonary embolism will occur in about 1 of 1000 patients within 3 months of the surgery. Although the prevalence of asymptomatic deep vein thrombosis is more than 2-fold higher after knee replacement than after hip replacement 7 to 10 days after surgery, in the subsequent 3 months, symptomatic venous thromboembolism is more likely to occur after hip replacement.

Anticoagulants↗

PubMed2002

Elevated cardiac troponin levels in patients with submassive pulmonary embolism.

BACKGROUND: Cardiac troponins are reliable markers of myocardial injury that are being used increasingly in patients presenting with undifferentiated chest pain or dyspnea to diagnose an acute coronary syndrome. If elevated cardiac troponin levels also occur in patients with pulmonary embolism because of right ventricular dilation and myocardial injury, such patients could be misdiagnosed. We performed a prospective cohort study to determine the prevalence of elevated cardiac troponin I (cTnI) levels in patients with submassive pulmonary embolism. METHODS: Consecutive patients with objectively confirmed submassive pulmonary embolism and no previous history of ischemic heart disease, other cardiac disease, or renal insufficiency were included. Creatine kinase and cTnI levels were measured within 24 hours of clinical presentation on 2 occasions 8 to 12 hours apart. RESULTS: Of 24 patients with submassive pulmonary embolism, 5 (20.8%) had elevated cTnI levels of 0.4 microg/L or higher (95% confidence interval, 7.1-42.2%). One of these patients had a cTnI level higher than 2.3 microg/L that was suggestive of myocardial infarction. CONCLUSION: Pulmonary embolism should be considered in the differential diagnosis of patients presenting with undifferentiated chest pain or dyspnea and an elevated cardiac troponin level.

Adult↗

PubMed2002

Mechanisms responsible for the failure of protamine to inactivate low-molecular-weight heparin.

Protamine is unable to completely reverse the anticoagulant effect of the low-molecular-weight heparins (LMWH), a fact of clinical importance given the rapid increase in use of LMWH in clinical practice. This investigation sought to determine the mechanism by which LMWH were able to resist protamine-mediated inactivation. Affinity fractionation of LMWH by passage through a protamine column, with subsequent determination of molecular mass and sulphate charge density, demonstrated that the protamine-resistant fraction in LMWH is an ultra-low-molecular-weight fraction with low sulphate charge density. This group of molecules was not found in unfractionated heparin, even when species of similar molecular mass were compared. We then determined that different commercially available LMWH varied in their ability to be neutralized by protamine, and that this variability correlated with the total sulphate content of the LMWH. We conclude that reduced sulphate charge, not molecular mass, is the principle reason that protamine is unable to fully inactivate LMWH. Furthermore, different LMWH vary in their ability to be neutralized by protamine, suggesting that product-specific recommendations for neutralization might be developed.

Anticoagulants↗

PubMed2002

Low-intensity warfarin is ineffective for the prevention of PTFE graft failure in patients on hemodialysis: a randomized controlled trial.

Polytetrafluoroethylene (PTFE) dialysis grafts in patients with end-stage renal disease (ESRD) are prone to thrombotic failure. The objective of this multicenter, randomized, double-blind, placebo-controlled clinical trial was to determine if warfarin reduces the risk of failure of PTFE dialysis grafts. Patients with ESRD and newly placed PTFE grafts were studied at community and academic dialysis centers in Southwestern Ontario. Patients were allocated to receive warfarin or matching placebo, with the warfarin administered to achieve a target INR of 1.4 to 1.9. Time to graft failure was the main outcome measure. A total of 107 patients (56 allocated to warfarin) were randomized. The time-to-event analysis revealed no significant difference in the likelihood of graft survival between the two groups (odds ratio, 1.76 in favor of placebo; 95% confidence interval, 0.72 to 4.34). Six major bleeds occurred in five patients allocated to warfarin compared with none in the patients who received placebo (P = 0.03). In conclusion, low-dose warfarin was associated with an excess of clinically important major bleeding in patients with ESRD enrolled in this study. Furthermore, low-intensity, monitored-dose warfarin does not appear to prolong PTFE graft survival.

Adult↗

PubMed2002

Selecting patients for home treatment of deep vein thrombosis: the problem of cancer.

BACKGROUND AND OBJECTIVES: Patients with deep vein thrombosis are selected for home treatment on the basis of their clinical and social condition. Cancer is frequently associated with venous thromboembolism and is often considered an exclusion criterion for outpatient treatment. We investigated the impact of cancer on the outpatient management of venous thrombosis. DESIGN AND METHODS: We performed a prospective, cohort study on consecutive patients with objectively documented deep vein thrombosis. All were assessed for home treatment. Hospital admission was recommended in the presence of common exclusion criteria. All patients were treated with low molecular weight heparin and warfarin. Information on previous, active, or suspected cancer was collected. Recurrent thrombosis, bleeding and mortality were documented at a 3-month follow-up. RESULTS: One hundred patients were included; 72 were entirely treated at home (mean age: 61.2 years). There were 22 patients with known cancer: 12 (55%) were managed as outpatients (16.5% of the outpatient population) and 10 were hospitalized (36% of the inpatient population), 6 because of a poor clinical condition, 4 because further investigation of their malignancy was required. The presence of cancer and the likelihood of poor compliance were the most frequent reasons cited for in-hospital treatment. Overall, event rates at 3 months were comparable to those reported in previous studies in the outpatient population and slightly higher in the inpatient population (recurrent thrombosis 1.5% and 7%; bleeding 5.5% and 10.7%; mortality 4% and 18%, respectively). INTERPRETATION AND CONCLUSIONS: Cancer was the most common reason cited for in-hospital treatment. Nevertheless, more than half of the patients with known cancer were safely and effectively treated at home.

Adult↗

PubMed2002

Anticoagulant effect at the time of epidural catheter removal in patients receiving twice-daily or once-daily low-molecular-weight heparin and continuous epidural analgesia after orthopedic surgery.

In patients who receive co-administered low-molecular-weight heparin (LMWH) and continuous epidural analgesia (CEA) after orthopedic surgery, there is concern about an increased risk of a spinal epidural hematoma. The practice of twice-daily LMWH dosing in North America might, in part, account for the greater number of epidural hematomas reports compared to Europe where once-daily LMWH is used. We performed a prospective cohort study in patients who had orthopedic surgery and received co-administered LMWH and CEA. We investigated the trough anticoagulant effect, as measured by an anti-Xa heparin level, at the time of epidural catheter removal in patients who received twice-daily or once-daily LMWH. Twenty-five patients who received enoxaparin, 30 mg twice-daily, and 25 patients who received dalteparin, 5,000 IU once-daily, had anti-Xa heparin levels measured on the second or third post-operative day at the time of epidural catheter removal. In patients who received twice-daily enoxaparin, or once-daily dalteparin, the anti-Xa heparin level was measured, on average, 10.4 h and 21.8 h, respectively, after the preceding LWMH dose. All 25 patients who received once-daily LMWH had an anti-Xa heparin level < 0.10 U/ml at the time of catheter removal. Of 25 patients who received twice-daily LMWH, the anti-Xa heparin level at the time of catheter removal was > or = 0.20 U/ml in 5 patients (P = 0.050), and > or = 0.10 U/ml in 7 patients (P = 0.009). We conclude that in patients who are receiving co-administered LMWH and CEA after orthopedic surgery, twice-daily but not once-daily LMWH administration is more likely to be associated with a clinically important anticoagulant effect at the time of epidural catheter removal.

Aged↗

PubMedDate not supplied

Elevated cardiac troponin measurements in critically ill patients.

BACKGROUND: The clinical significance of elevated cardiac troponin (cTn) level in patients in the intensive care unit (ICU) is uncertain. We reviewed the frequency of cTn elevation and its association with mortality and length of ICU stay in these patients. METHODS: Studies were identified using MEDLINE, EMBASE, and reference list review. We included observational studies of critically ill patients that measured cTn at least once and reported the frequency of elevated cTn or outcome (mortality and length of ICU or hospital stay). We pooled the odds ratios (ORs) using the inverse variance method in studies that conducted multivariable analysis to examine the relationship between elevated cTn and mortality (adjusted analysis). We calculated the weighted mean difference in length of stay between patients with and without elevated cTn and pooled the results using the inverse variance method (unadjusted analysis). RESULTS: A total of 23 studies involving 4492 critically ill patients were included. In 20 studies, elevated cTn was found in a median of 43% (interquartile range, 21% to 59%) of 3278 patients. In adjusted analysis (6 studies comprising 1706 patients), elevated cTn was associated with an increased risk of death (OR, 2.5; 95% confidence interval [CI], 1.9 to 3.4; P < .001). In the unadjusted analysis (8 studies comprising 1019 patients), elevated cTn was associated with an increased length of ICU stay of 3.0 days (95% CI, 1.0 to 5.1 days; P = .004) and an increased length of hospital stay of 2.2 days (95% CI, -0.6 to 4.9; P = .12). CONCLUSIONS: Elevated cTn measurements among critically ill patients are associated with increased mortality and ICU length of stay. Research is needed to clarify the underlying causes of elevated cTn in this population and to examine their clinical significance.

Critical Illness↗

PubMedDate not supplied

Vitamin K for the treatment of asymptomatic coagulopathy associated with oral anticoagulant therapy.

Patients with asymptomatic elevated International Normalized Ratios (INRs) are commonly seen in practice, but there is no consensus on how best to manage this condition. Evidence suggests that low-dose (1 mg to 2.5 mg) oral vitamin K restores patients to INR values associated with a lower risk of hemorrhage more rapidly than discontinuing warfarin alone. Vitamin K therapy remains under-utilized despite evidence for its effectiveness. The studies discussed in this review suggest that vitamin K1 should be considered if rapid reductions in the INR are desired. For most rapid corrections in the INR, vitamin K should be administered by the intravenous route since it begins to reduce the INR within 8 hours. Subcutaneous vitamin K is relatively ineffective, and its use may be associated with over-correction of the INR.

Administration, Oral↗

PubMedDate not supplied

Reversing anticoagulants both old and new.

PURPOSE: Reversal of pharmacologic anticoagulation is an issue that arises when an anticoagulated patient has major bleeding or when a patient on chronic anticoagulant therapy requires urgent reversal of anticoagulation, for example, for surgery. SOURCE: We reviewed the literature to determine what strategies are available to reverse anticoagulation caused by older agents, such as warfarin or unfractionated heparin (UFH), as well as newer agents, for example, low-molecular-weight heparin, danaparoid, fondaparinux, lepirudin, and argatroban. PRINCIPAL FINDINGS: Specific "antidotes" exist for the "classic" anticoagulant agents: protamine sulfate for UFH, and vitamin K for warfarin. However, vitamin K only begins to reverse warfarin's anticoagulant effect by four to six hours, so urgent situations additionally require blood products, such as plasma (fresh frozen or cryosupermatant plasma), prothrombin complex concentrates, or, possibly, recombinant factor VIIa. A growing problem arises from the increasing use of new anticoagulants that lack specific antidotes. For example, protamine sulfate reverses only about 60% of the anti-factor Xa activity of low-molecular-weight heparin, has negligible effects on danaparoid (a mixture of anticoagulant glycosaminoglycans used to treat heparin-induced thrombocytopenia) and fondaparinux (a novel synthetic antithrombin-binding pentasaccharide with exclusive anti-factor Xa activity approved in the United States for antithrombotic prophylaxis following orthopedic surgery). The new direct thrombin inhibitors (e.g., lepirudin, bivalirudin, argatroban) also have no specific antidote. CONCLUSION: Newer anticoagulant agents generally lack specific antidotes. Thus, careful choice of an anticoagulant agent and laboratory monitoring where appropriate are needed to minimize risk of bleeding complications.

Anticoagulants↗