John W. Eikelboom

Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials

BACKGROUNDnThe optimum duration of prophylaxis against venous thromboembolism after total hip or knee replacement is uncertain. Our primary objective was to establish the efficacy of extended-duration prophylaxis on symptomatic venous thromboembolic events.nnnMETHODSnWe identified randomised trials comparing extended-duration prophylaxis using heparin or warfarin with placebo or untreated control in patients undergoing elective total hip or knee replacement by searching electronic databases (MEDLINE, EMBASE), references from retrieved articles, and abstracts from conference proceedings, and by contact with pharmaceutical companies and investigators. Two reviewers independently extracted data on study design, symptomatic and symptomless venographic venous thromboembolism, death, and bleeding outcomes. Results from individual trials were combined with the Mantel-Haenszel method.nnnFINDINGSnNine studies met our inclusion criteria (3999 patients), eight with low molecular weight heparin, and one with unfractionated heparin. Extended-duration prophylaxis for 30-42 days significantly reduced the frequency of symptomatic venous thromboembolism (1.3% vs 3.3%, OR 0.38; 95% CI 0.24-0.61, numbers needed to treat [NNT]=50), with no statistical evidence of heterogeneity (x(2) test, p=0.69). There was a greater risk reduction in patients undergoing hip replacement (1.4% vs 4.3%, 0.33; 0.19-0.56, 34) compared with knee replacement (1.0% vs 1.4%, 0.74; 0.26-2.15, 250). A significant reduction in symptomless venographic deep vein thrombosis was also observed (9.6% vs 19.6%, 0.48; 0.36-0.63, 10). There was no increase in major bleeding but extended-duration prophylaxis was associated with excess minor bleeding (3.7% vs 2.5%, 1.56; 1.08-2.26, numbers needed to harm [NNH]=83).nnnINTERPRETATIONnAmong patients undergoing total hip or knee replacement, extended-duration prophylaxis significantly reduces the frequency of symptomatic venous thromboembolism. The reduction in risk is equivalent to about 20 symptomatic events per 1000 patients treated.

The evolving role of direct thrombin inhibitors in acute coronary syndromes.

The central role of thrombin in the initiation and propagation of intravascular thrombus provides a strong rationale for direct thrombin inhibitors in acute coronary syndromes (ACS). Direct thrombin inhibitors are theoretically likely to be more effective than indirect thrombin inhibitors, such as unfractionated heparin or low-molecular-weight heparin, because the heparins block only circulating thrombin, whereas direct thrombin inhibitors block both circulating and clot-bound thrombin. Several initial phase 3 trials did not demonstrate a convincing benefit of direct thrombin inhibitors over unfractionated heparin. However, the Direct Thrombin Inhibitor Trialists Collaboration meta-analysis confirms the superiority of direct thrombin inhibitors, particularly hirudin and bivalirudin, over unfractionated heparin for the prevention of death or myocardial infarction (MI) during treatment in patients with ACS, primarily due to a reduction in MI (odds ratio, 0.80; 95% confidence interval, 0.70 to 0.91) with little impact on death. The absolute risk reduction in the composite of death or MI at the end of treatment (0.8%) was similar at 30 days (0.7%), indicating no loss of benefit after cessation of therapy. Supportive evidence for the superiority of direct thrombin inhibitors over heparin derives from the recently reported Hirulog and Early Reperfusion or Occlusion (HERO)-2 randomized trial with ST-segment elevation ACS, which demonstrated a similar benefit of bivalirudin over heparin for the prevention of death or MI at 30 days (absolute risk reduction 1.0%), again primarily due to a reduction in MI during treatment (odds ratio, 0.70; 95% confidence interval, 0.56 to 0.87), with little impact on death. Further evaluation of hirudin and bivalirudin in the antithrombotic management of patients with ACS is warranted.

Homocysteine and stroke

During the past year epidemiological studies have linked elevated plasma total homocysteine concentrations with an increased risk of ischaemic stroke because of arterial disease. Laboratory studies have further explored the mitogenic effects of total homocysteine on vascular smooth muscle, and cytotoxic and thrombophilic effects on vascular endothelium. Also, a clinical trial has shown that lowering total homocysteine by means of multivitamin therapy decreases the rate of abnormal exercise electrocardiography tests. However, it remains to be determined whether lowering total homocysteine prevents hard clinical outcome events, such as stroke and other serious vascular events. An alternative explanation for the observed association between elevated total homocysteine and stroke is a confounding effect of factors associated with hyperhomocysteinaemia (e.g. cigarette smoking, renal impairment, an atherogenic diet, cystine deficiency, folate deficiency) or perhaps even the acute vascular events themselves, whereby the tissue damage temporarily increases total homocysteine levels. The results of ongoing clinical trials in stroke patients to determine the impact of multivitamin therapy on recurrent stroke and other serious vascular events are awaited.

Measurement of soluble P-selectin and soluble CD40 ligand in serum and plasma.

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Failure of aspirin to prevent atherothrombosis : potential mechanisms and implications for clinical practice

Aspirin (acetylsalicylic acid) reduces the odds of serious atherothrombotic vascular events and death in a broad category of high risk patients by about one-quarter. The mechanism is believed to be inhibition of thromboxane biosynthesis by inactivation of platelet cyclo-oxygenase-1 enzyme. However, aspirin is not that effective; it still fails to prevent the majority of serious vascular events. Mechanisms that may account for the failure of aspirin to prevent vascular events include non-atherothrombotic causes of vascular disease, non-adherence to aspirin therapy, an inadequate dosage, alternative ‘upstream’ pathways of platelet activation (e.g. via stimulation of the ADP, collagen or thrombin receptors on platelets), aspirin-insensitive thromboxane biosynthesis (e.g. via monocyte cyclo-oxygenase-2), or drugs that interfere with the antiplatelet effects of aspirin. Genetic or acquired factors may further modify the inhibitory effects of aspirin on platelets (e.g. polymorphisms involving platelet-associated proteins, increased platelet turnover states).Identification and treatment of the potential causes of aspirin failure could prevent at least another 20% of serious vascular events (i.e. over and above those that are currently prevented by aspirin). There is currently no role for routine laboratory testing to measure the antiplatelet effects of aspirin. Clinicians should ensure that patients at high risk of atherothrombosis (>3% risk over 5 years) are compliant with aspirin therapy and are taking the correct dosage (75–150 mg/day). Patients who cannot tolerate aspirin, are allergic to aspirin, or have experienced recurrent serious atherothrombotic events whilst taking aspirin, should be treated with clopidogrel, and patients with acute coronary syndromes benefit from the combination of clopidogrel plus aspirin. Future research is required to standardize and validate laboratory testing of the antiplatelet effects of aspirin and to identify treatments that can both improve these laboratory measures and reduce the risk of future atherothrombotic events.

Prevention of coronary heart disease with aspirin and clopidogrel: efficacy, safety, costs and cost-effectiveness

Atherothrombotic coronary artery disease is the single most common cause of death worldwide and a growing public health problem. Platelets play a central role in the pathogenesis of atherothrombosis and are therefore commonly targeted by one or more antiplatelet drugs as part of primary and secondary atherothrombosis prevention strategies. Aspirin reduces the risk of serious vascular events (myocardial infarction, stroke or cardiovascular death) by ∼ 20% in a broad range of high-risk patients and remains the first-line antiplatelet drug because of its relative safety, low cost and cost-effectiveness. Compared with aspirin alone, clopidogrel reduces the risk of serious vascular events by ∼ 10% and the combination of aspirin and clopidogrel reduces the risk by ∼ 20% in patients with non-ST-segment elevation acute coronary syndrome. Clopidogrel has a similar safety profile to aspirin but clopidogrel tablets are substantially more expensive. However, the incremental cost-effectiveness ratio of clopidogrel compared with aspirin is favourable, particularly in high-risk patients and is intermediate compared with a range of other effective therapeutic strategies for the treatment of coronary heart disease. Clopidogrel should be considered as a replacement for aspirin in patients who are allergic to aspirin, cannot tolerate aspirin, have experienced a recurrent atherothrombotic vascular event whilst taking aspirin and are at very high absolute risk of a serious vascular event (e.g., > 20%/year). The combination of clopidogrel and aspirin should be considered in patients with non-ST-segment elevation acute coronary syndrome or undergoing percutaneous coronary intervention.

Sustained Homocysteine-Lowering Effect over Time of Folic Acid-Based Multivitamin Therapy in Stroke Patients despite Increasing Folate Status in the Population

Background and Aims: It is uncertain what impact increasing voluntary folate fortification may be having on the statistical power of randomized trials testing the homocysteine hypothesis of atherothrombosis. The objective of this study was to determine whether there has been a change in folate status between 1998 and 2002 in stroke patients randomized into the VITAmins TO Prevent Stroke (VITATOPS) Study at a single center in Perth, Australia, and what impact this may have had on the magnitude of the homocysteine-lowering effect achieved over time with folic acid-based multivitamin therapy. Methods: We conducted a randomized, double-blind, placebo-controlled study involving 285 patients with stroke or transient ischemic attack who were recruited between 1998 and 2002 and randomized to long-term folic acid 2.0 mg/day, pyridoxine 25 mg/day and cobalamin 0.5 mg/day (active VITATOPS medication) or placebo. Fasting plasma total homocysteine, red cell folate, serum cobalamin and serum pyridoxine levels were measured at baseline and 6 months, and the change in blood levels over 4 time quartiles and differences in levels between the two randomized treatments were examined. Results: Between 1998 and 2002, there was a significant rise in baseline mean red cell folate levels over 4 time quartiles among the entire stroke cohort (723.3, 780.1, 922.6 and 1,023.7 nmol/l in the first, second, third and fourth quartiles, respectively; p < 0.0001), but this was not associated with a spontaneous reduction in mean baseline total homocysteine levels during the same time period (12.7, 14.3, 12.1 and 12.8 µmol/l in the first, second, third and fourth quartiles, respectively; p = 0.55). The homocysteine-lowering effect of the active VITATOPS trial medication at 6 months after randomization also did not change significantly between 1998 and 2002 (difference between randomized groups: –4.1, –4.1, –3.1 and –3.6 µmol/l in the first, second, third and fourth quartiles, respectively; p = 0.56). Conclusions: The homocysteine-lowering effect of the active VITATOPS trial medication has not attenuated significantly in the past 5 years despite increasing voluntary fortification of foods with folic acid as reflected by a progressive rise in baseline folate status. These data suggest that in the continuing absence of a program of mandatory folate fortification of food in populations served by centers participating in the VITATOPS trial, the study will remain adequately powered to test the homocysteine-lowering hypothesis for which it was designed.

Recurrent palmar–plantar erythrodysaesthesia following high-dose cytarabine treatment for acute lymphoblastic leukemia

Abstract: Palmar–plantar erythrodysaesthesia (PPE) is an uncommon cutaneous complication of cytotoxic chemotherapy which generally presents as a painful erythema involving the palms and soles. It has been suggested that PPE caused by cytarabine does not recur with subsequent cytarabine re‐challenge. We report a patient with recurrent, increasingly severe episodes of PPE, ultimately complicated by a severe bullous eruption, following successive cycles of high‐dose cytarabine for the treatment of acute lymphoblastic leukaemia. Contrary to previous recommendations, our experience cautions against the further use of high‐dose cytarabine in patients who develop PPE, and is a timely reminder of the potential toxicity of this agent, which is now increasingly being used as first‐line treatment in the management of haematologic malignancies.

Thromboprophylaxis practice patterns in hip fracture surgery patients: experience in Perth, Western Australia.

Background: u2003International guidelines recommend that all patients undergoing hip fracture surgery receive specific thromboprophylaxis. The purpose of the present study was to examine current thromboprophylaxis practice patterns in patients undergoing hip fracture surgery at Royal Perth Hospital.

Adjunctive Use of Direct Thrombin Inhibitors in Patients Receiving Fibrinolytic Therapy for Acute Myocardial Infarction

The direct thrombin inhibitors hirudin and bivalirudin inhibit both fluid-phase and clot-bound thrombin. These agents have been extensively studied in clinical trials in comparison with intravenous unfractionated heparin (UFH), as adjuncts to fibrinolytic therapy for ST-elevation myocardial infarction (STEMI) and in percutaneous coronary intervention (PCI), and they are currently undergoing further evaluation in patients with non-ST elevation acute coronary syndromes (NSTEACS).In angiographic trials there were trends for patients treated with hirudin to be more likely to achieve Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow at 90 minutes than patients treated with UFH (65% versus 57% in TIMI-5; 41% versus 33% in Hirudin for the Improvement of Thrombolysis [HIT]-4; statistically nonsignificant differences in both trials). In Montréal Heart Institute trials and the multicenter Hirulog® and Early Reperfusion or Occlusion (HERO)-1 trial the use of bivalirudin was associated with an increased incidence of TIMI grade 3 flow (85% versus 31%, p = 0.006; and 48% versus 35%, p = 0.02, respectively). These studies used streptokinase as the fibrinolytic agent except in TIMI-5 where alteplase was used.The initial clinical outcomes studies (Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes [GUSTO]-IIA and TIMI-9A) were discontinued early because of a high incidence of intracerebral bleeding (∼1.8%). Patients in these studies had either STEMI or NSTEACS, and thus not all were treated with fibrinolytic therapy. These studies were recommenced as GUSTO-IIB and TIMI-9B, using lower dosages of hirudin (0.1 mg/kg bolus + 0.1 mg/kg infusion for 96 hours). Neither TIMI-9B nor GUSTO-IIB showed an improvement in efficacy (death or reinfarction) or an increase in bleeding with hirudin. However, in the 1015 patients with STEMI treated with streptokinase in GUSTO-IIB, there was a 40% reduction in the combined incidence of death or myocardial infarction at 30 days (8.6% versus 14.4%, odds ratio [OR] 0.57, 95% confidence interval [CI] 0.38–0.87, p = 0.004).In the HERO-2 trial, 17 073 patients receiving streptokinase for STEMI were randomized to receive either bivalirudin (0.25 mg/kg bolus and 0.5 mg/kg infusion for 12 hours followed by 0.25 mg/kg) or UFH (5000IU bolus and 800–1000 IU/h infusion titrated to an activated partial thromboplastin time [APTT] of 50–75 seconds) for a total of 48 hours. Thirty-day mortality was similar in both groups (10.8% with bivalirudin versus 10.9% with UFH, OR 0.99, 95% CI 0.90–1.09, p = 0.85). There was a 30% reduction in the incidence of reinfarction before 96 hours (1.6% with bivalirudin versus 2.3% with UFH, OR 0.70, 95% CI 0.56–0.87, p = 0.001). Patients treated with bivalirudin had significantly more moderate bleeding (1.4% versus 1.1% with UFH, OR 1.32, 95% CI 1.0–1.74, p = 0.05).In a meta-analysis of patients with STEMI in the Direct Thrombin Inhibitor Trialists’ collaboration, direct thrombin inhibitors were found to reduce the rate of reinfarction at 30 days (3.9% versus 4.8% with UFH, OR 0.80, 95% CI 0.71–0.90, p < 0.001), but did not reduce mortality (9.1% versus 9.0%, OR 1.02, 95% CI 0.94–1.11, p = 0.68) or the combined incidence of death/reinfarction at 30 days (11.8% versus 12.4%, OR 0.95, 95% CI 0.88–1.02, p = 0.18). There was no increase in major bleeding or intracerebral bleeding with direct thrombin inhibitor therapy.In conclusion, direct thrombin inhibitors reduce reinfarction, but not mortality, in patients with STEMI treated with fibrinolytic therapy. The major benefit of direct thrombin inhibitors appears to be in patients undergoing PCI, particularly after STEMI.