Marc A. Rodger

Excluding Pulmonary Embolism at the Bedside without Diagnostic Imaging: Management of Patients with Suspected Pulmonary Embolism Presenting to the Emergency Department by Using a Simple Clinical Model and D-Dimer

Pulmonary embolism is a relatively common disease, with an estimated annual incidence in the United States of 23 cases diagnosed per 100 000 persons (1). More than 50% of cases are undiagnosed. Untreated pulmonary embolism has a high mortality, although risk for death is reduced significantly with anticoagulation (2). Because the clinical signs and symptoms of pulmonary embolism are not specific, timely diagnostic testing must be done to confirm the diagnosis. Ventilation-perfusion lung scanning is the most common imaging procedure for suspected pulmonary embolism. However, the result is frequently nondiagnostic, and additional testing is needed to confirm a diagnosis. Patients presenting to the emergency department with suspected pulmonary embolism present a challenge, particularly if diagnostic testing is not immediately available. We recently validated a simple model (3), which we incorporated into a diagnostic algorithm, to classify pretest probability of pulmonary embolism by using clinical findings along with results on electrocardiography and chest radiography. We had not tested our model or the diagnostic algorithm in an emergency department setting. Another diagnostic test, d-dimer assay, may be useful in patients with suspected pulmonary embolism, but experience with this test to exclude pulmonary embolism diagnoses in an emergency department has been limited [4]. In the current study, we used a diagnostic algorithm based on our clinical model and a non-enzyme-linked immunosorbent d-dimer assay in patients presenting to emergency departments with suspected pulmonary embolism. We sought to 1) demonstrate the safety of excluding the diagnosis of pulmonary embolism in an emergency department using diagnostic algorithms that were based on pretest probability and d-dimer assay results and 2) confirm the reliability of the pretest probability clinical model and d-dimer testing for pulmonary embolism in an emergency department. Methods Patients Data for this study were collected from September 1998 to September 1999 at four participating medical centers in Canada: The Ottawa Civic Hospital, Ottawa, Ontario; the London Health Sciences Centre, London, Ontario; the Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia; and St. Pauls Hospital, Vancouver, British Columbia. The study was approved by the ethics review committees at each of the institutions. Consecutive patients presenting to the emergency departments of the participating centers were eligible if they had suspicion of pulmonary embolism with symptoms for less than 30 days and were experiencing acute onset of new or worsening shortness of breath or chest pain. Exclusion criteria were 1) suspected deep venous thrombosis of the upper extremity as a likely source of pulmonary embolism, 2) no symptoms of pulmonary embolism within 3 days of presentation, 3) anticoagulant therapy for more than 24 hours, 4) expected survival time less than 3 months, 5) contraindication to contrast media, 6) pregnancy, 7) geographic inaccessibility precluding follow-up, or 8) age younger than 18 years. Interventions After giving informed consent, patients were evaluated by 1 of 43 emergency department physicians, who used a simple clinical model to determine the clinical probability of pulmonary embolism (5). The physician assigned points for the following: clinical signs and symptoms of deep venous thrombosis (objectively measured leg swelling and pain with palpation in the deep-vein region), 3.0 points; heart rate higher than 100 beats/min, 1.5 points; immobilization (bedrest, except to access the bathroom, for 3 consecutive days) or surgery in the previous 4 weeks, 1.5 points; previous objectively diagnosed deep venous thrombosis or pulmonary embolism, 1.5 points; hemoptysis, 1.0 point; malignancy (patients with cancer who were receiving treatment, those in whom treatment had been stopped within the past 6 months, or those who were receiving palliative care), 1.0 point; and pulmonary embolism as likely as or more likely than an alternative diagnosis, 3.0 points (5). For the final variable, which was not strictly defined, physicians were told to use the clinical information (obtained by history and physical examination), along with results on chest radiography, electrocardiography, and whatever blood tests were considered necessary to diagnose pulmonary embolism. The pretest probability of pulmonary embolism was considered low in patients whose score was less than 2.0, moderate in patients whose score was at least 2.0 but no higher than 6.0, and high in patients whose score was greater than 6.0. The SimpliRED whole-blood agglutination d-dimer test (AGEN Biomedical, Ltd., Brisbane, Australia) was performed on citrated blood samples in a local coagulation laboratory. In all patients, the d-dimer test was performed only after the clinical model had been applied and the resultant probability had been recorded. Patients were to be managed as outlined in Figure 1. Pulmonary embolism was considered excluded if the patient had been assigned a low clinical pertest probability and had a negative result on d-dimer testing; no imaging procedures were performed in these patients. All other patients had ventilation-perfusion lung scanning. For patients who presented outside normal working hours (between 3:30 p.m. and 7:00 a.m.), a therapeutic dose (200 U/kg of body weight) of the low-molecular-weight heparin Dalteparin (Pharmacia-Upjohn, Mississauga, Ontario, Canada) was given subcutaneously, and diagnostic testing was done in the next 18 hours (6). Dalteparin was given to these patients only after the clinical model was applied and d-dimer testing was done. Figure 1. Diagnostic algorithm for initial evaluation of patients with suspected pulmonary embolism. Ventilation-perfusion scans were interpreted by nuclear medicine physicians who had no knowledge of the clinical model outcome or d-dimer result. The scan interpretations were used to determine patient management. Ventilation-perfusion scans were interpreted as 1) normal, if no perfusion defects were found, 2) high probability, if at least one segmental (or larger) perfusion defect with normal ventilation or at least two large subsegmental perfusion defects [>75% of a segment] with normal ventilation were found, or 3) nondiagnostic, if ventilation-perfusion defects were detected but did not meet the criteria for high probability (7). A lung-segment reference chart was used to interpret ventilation-perfusion scans (8). Compression ultrasonography, when indicated, was performed on both lower extremities from the common femoral vein to the trifurcation of the calf veins, but the calf veins were not examined. Lack of vein compressibility was diagnostic of deep venous thrombosis [9]. In patients with a history of deep venous thrombosis, diagnosis of recurrent thrombus required 1) the noncompressibility on ultrasonography to be in the previously uninvolved extremity or in an area previously unaffected by thrombus or 2) the clot diameter to be more than 4 mm greater than on previous measurement (10). In patients with previous pulmonary embolism, only new defects were considered. Patients were considered to have pulmonary embolism if they had abnormal results on ultrasonography or angiography, a high-probability result on ventilation-perfusion scan, or a venous thromboembolic event during the 3-month follow-up. In all other patients, a diagnosis of pulmonary embolism was considered excluded. Treatment and Follow-up Anticoagulant therapy was withheld in patients in whom a diagnosis of pulmonary embolism was excluded. These patients were given instruction cards and were directed to return at once if they developed new or worsening symptoms or signs suggesting pulmonary embolism or deep venous thrombosis. If at any time venous thromboembolism (deep venous thrombosis or pulmonary embolism) was suspected, patients were studied by using a standardized approach (3). Diagnoses of deep venous thrombosis and pulmonary embolism were excluded if results on ultrasonography and ventilation-perfusion scanning, respectively, were normal. Pulmonary embolism was diagnosed if a new ventilation-perfusion scan showed high probability, and deep venous thrombosis was diagnosed if results on ultrasonography were abnormal. Patients with nondiagnostic scans and equivocal ultrasonography results had gold-standard testing-pulmonary angiography and venography, respectively; the results were evaluated according to previously defined criteria (3). After 3 months, patients were followed up for development of thromboembolic events at a return appointment or by telephone contact. A committee blinded to all patient variables adjudicated suspected outcome events during follow-up. Statistical Analysis Our primary outcome was the proportion of patients who had a venous thromboembolic event during 3-month follow-up among patients in whom the diagnosis of pulmonary embolism had been excluded before follow-up (Figure 1). We and other authors have used this type of outcome in previous studies (3, 11, 12). Our primary analysis was an intention-to-treat analysis of all enrolled patients. We also planned a secondary analysis to evaluate the safety of our strategy in patients in whom the diagnostic algorithm was followed correctly. Because the SimpliRED test can rule out thromboembolism by yielding a negative result, we could also determine the negative predictive values of the d-dimer results in the three pretest-probability groups by determining thromboembolic event rates during the entire study period in those with negative d-dimer results. Before calculating the negative predictive values, we computed the total number of venous thromboembolic events diagnosed during the initial study period (the study period from presentation to follow-up) or follow-up to determine the overall event rates. Then, we determined the negative predictive value by dividing the number of patie

A Comparison of Aprotinin and Lysine Analogues in High-Risk Cardiac Surgery

BACKGROUND Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding and to reduce exposure to blood products. We sought to determine whether aprotinin was superior to either tranexamic acid or aminocaproic acid in decreasing massive postoperative bleeding and other clinically important consequences. METHODS In this multicenter, blinded trial, we randomly assigned 2331 high-risk cardiac surgical patients to one of three groups: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid. The primary outcome was massive postoperative bleeding. Secondary outcomes included death from any cause at 30 days. RESULTS The trial was terminated early because of a higher rate of death in patients receiving aprotinin. A total of 74 patients (9.5%) in the aprotinin group had massive bleeding, as compared with 93 (12.1%) in the tranexamic acid group and 94 (12.1%) in the aminocaproic acid group (relative risk in the aprotinin group for both comparisons, 0.79; 95% confidence interval [CI], 0.59 to 1.05). At 30 days, the rate of death from any cause was 6.0% in the aprotinin group, as compared with 3.9% in the tranexamic acid group (relative risk, 1.55; 95% CI, 0.99 to 2.42) and 4.0% in the aminocaproic acid group (relative risk, 1.52; 95% CI, 0.98 to 2.36). The relative risk of death in the aprotinin group, as compared with that in both groups receiving lysine analogues, was 1.53 (95% CI, 1.06 to 2.22). CONCLUSIONS Despite the possibility of a modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend associated with aprotinin, as compared with the lysine analogues, precludes its use in high-risk cardiac surgery. (Current Controlled Trials number, ISRCTN15166455 [controlled-trials.com].).

Computed Tomographic Pulmonary Angiography vs Ventilation-Perfusion Lung Scanning in Patients With Suspected Pulmonary Embolism: A Randomized Controlled Trial

CONTEXT Ventilation-perfusion (V(dot)Q(dot) lung scanning and computed tomographic pulmonary angiography (CTPA) are widely used imaging procedures for the evaluation of patients with suspected pulmonary embolism. Ventilation-perfusion scanning has been largely replaced by CTPA in many centers despite limited comparative formal evaluations and concerns about CTPAs low sensitivity (ie, chance of missing clinically important pulmonary embuli). OBJECTIVES To determine whether CTPA may be relied upon as a safe alternative to V(dot)Q(dot scanning as the initial pulmonary imaging procedure for excluding the diagnosis of pulmonary embolism in acutely symptomatic patients. DESIGN, SETTING, AND PARTICIPANTS Randomized, single-blinded noninferiority clinical trial performed at 4 Canadian and 1 US tertiary care centers between May 2001 and April 2005 and involving 1417 patients considered likely to have acute pulmonary embolism based on a Wells clinical model score of 4.5 or greater or a positive D-dimer assay result. INTERVENTION Patients were randomized to undergo either V(dot)Q(dot scanning or CTPA. Patients in whom pulmonary embolism was considered excluded did not receive antithrombotic therapy and were followed up for a 3-month period. MAIN OUTCOME MEASURE The primary outcome was the subsequent development of symptomatic pulmonary embolism or proximal deep vein thrombosis in patients in whom pulmonary embolism had initially been excluded. RESULTS Seven hundred one patients were randomized to CTPA and 716 to V(dot)Q(dot scanning. Of these, 133 patients (19.2%) in the CTPA group vs 101 (14.2%) in the V(dot)Q(dot scan group were diagnosed as having pulmonary embolism in the initial evaluation period (difference, 5.0%; 95% confidence interval [CI], 1.1% to 8.9%) and were treated with anticoagulant therapy. Of those in whom pulmonary embolism was considered excluded, 2 of 561 patients (0.4%) randomized to CTPA vs 6 of 611 patients (1.0%) undergoing V(dot)Q(dot scanning developed venous thromboembolism in follow-up (difference, -0.6%; 95% CI, -1.6% to 0.3%) including one patient with fatal pulmonary embolism in the V(dot)Q(dot group. CONCLUSIONS In this study, CTPA was not inferior to V(dot)Q(dot scanning in ruling out pulmonary embolism. However, significantly more patients were diagnosed with pulmonary embolism using the CTPA approach. Further research is required to determine whether all pulmonary emboli detected by CTPA should be managed with anticoagulant therapy. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN65486961.

Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy

Background: Whether to continue oral anticoagulant therapy beyond 6 months after an “unprovoked” venous thromboembolism is controversial. We sought to determine clinical predictors to identify patients who are at low risk of recurrent venous thromboembolism who could safely discontinue oral anticoagulants. Methods: In a multicentre prospective cohort study, 646 participants with a first, unprovoked major venous thromboembolism were enrolled over a 4-year period. Of these, 600 participants completed a mean 18-month follow-up in September 2006. We collected data for 69 potential predictors of recurrent venous thromboembolism while patients were taking oral anticoagulation therapy (5–7 months after initiation). During follow-up after discontinuing oral anticoagulation therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated. We performed a multivariable analysis of predictor variables (p < 0.10) with high interobserver reliability to derive a clinical decision rule. Results: We identified 91 confirmed episodes of recurrent venous thromboembolism during follow-up after discontinuing oral anticoagulation therapy (annual risk 9.3%, 95% CI 7.7%–11.3%). Men had a 13.7% (95% CI 10.8%–17.0%) annual risk. There was no combination of clinical predictors that satisfied our criteria for identifying a low-risk subgroup of men. Fifty-two percent of women had 0 or 1 of the following characteristics: hyperpigmentation, edema or redness of either leg; D-dimer ≥ 250 μg/L while taking warfarin; body mass index ≥ 30 kg/m2; or age ≥ 65 years. These women had an annual risk of 1.6% (95% CI 0.3%–4.6%). Women who had 2 or more of these findings had an annual risk of 14.1% (95% CI 10.9%–17.3%). Interpretation: Women with 0 or 1 risk factor may safely discontinue oral anticoagulant therapy after 6 months of therapy following a first unprovoked venous thromboembolism. This criterion does not apply to men. (http://Clinicaltrials.gov trial register number NCT00261014)

Single-Arm Study of Bridging Therapy With Low-Molecular-Weight Heparin for Patients at Risk of Arterial Embolism Who Require Temporary Interruption of Warfarin

Background—When warfarin is interrupted for surgery, low-molecular-weight heparin is often used as bridging therapy. However, this practice has never been evaluated in a large prospective study. This study was designed to assess the efficacy and safety of bridging therapy with low-molecular-weight heparin initiated out of hospital. Methods and Results—This was a prospective, multicenter, single-arm cohort study of patients at high risk of arterial embolism (prosthetic valves and atrial fibrillation with a major risk factor). Warfarin was held for 5 days preoperatively. Low-molecular-weight heparin was given 3 days preoperatively and at least 4 days postoperatively. Patients were followed up for 3 months for thromboembolism and bleeding. Eleven Canadian tertiary care academic centers participated; 224 patients were enrolled. Eight patients (3.6%; 95% CI, 1.8 to 6.9) had an episode of thromboembolism, of which 2 (0.9%; 95% CI, 0.2 to 3.2) were judged to be due to cardioembolism. Of these 8 episodes of thromboembolism, 6 occurred in patients who had warfarin deferred or withdrawn because of bleeding. There were 15 episodes of major bleeding (6.7%; 95% CI, 4.1 to 10.8): 8 occurred intraoperatively or early postoperatively before low-molecular-weight heparin was restarted, 5 occurred in the first postoperative week after low-molecular-weight heparin was restarted, and 2 occurred well after low-molecular-weight heparin was stopped. There were no deaths. Conclusions—Bridging therapy with subcutaneous low-molecular-weight heparin is feasible; however, the optimal approach for the management of patients who require temporary interruption of warfarin to have invasive procedures is uncertain.

Systematic Review: Case-Fatality Rates of Recurrent Venous Thromboembolism and Major Bleeding Events Among Patients Treated for Venous Thromboembolism

BACKGROUND Case-fatality rates are important for assessing the risks and benefits of anticoagulation in patients with venous thromboembolism (VTE). PURPOSE To summarize case-fatality rates of recurrent VTE and major bleeding events during anticoagulation and recurrent VTE after anticoagulation. DATA SOURCES MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and all evidence-based medicine reviews in the Ovid interface through the second quarter of 2008. STUDY SELECTION 69 articles (13 prospective cohort studies and 56 randomized, controlled trials) that reported on patients with symptomatic VTE who received anticoagulation therapy for at least 3 months and on the rate of fatal recurrent VTE and fatal major bleeding. DATA EXTRACTION Two reviewers independently extracted data onto standardized forms. DATA SYNTHESIS During the initial 3 months of anticoagulation, the rate of recurrent fatal VTE was 0.4% (95% CI, 0.3% to 0.6%), with a case-fatality rate of 11.3% (CI, 8.0% to 15.2%). The rate of fatal major bleeding events was 0.2% (CI, 0.1% to 0.3%), with a case-fatality rate of 11.3% (CI, 7.5% to 15.9%). After anticoagulation, the rate of fatal recurrent VTE was 0.3 per 100 patient-years (CI, 0.1% to 0.4%), with a case-fatality rate of 3.6% (CI, 1.9% to 5.7%). LIMITATIONS Estimates come from heterogeneous trial and cohort populations and are not derived from patient-level longitudinal data. Differences in case-fatality rates during and after anticoagulation may be attributable to unmeasured patient characteristics. CONCLUSION The case-fatality rates of recurrent VTE and major bleeding events are similar during the initial period of VTE treatment. The case-fatality rate of recurrent VTE decreases after completion of the initial period of anticoagulation. When combined with absolute rates of recurrent VTE and major bleeding events, case-fatality rates provide clinicians with a surrogate measure of mortality to balance the risks and benefits of anticoagulant therapy in patients with VTE. PRIMARY FUNDING SOURCE Canadian Institute for Health Research and Heart and Stroke Foundation of Ontario.

Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies

Summary.  Background: Multiple‐detectors computed tomographic pulmonary angiography (CTPA) has a higher sensitivity for pulmonary embolism (PE) within the subsegmental pulmonary arteries as compared with single‐detector CTPA. Multiple‐detectors CTPA might increase the rate of subsegmental PE diagnosis. The clinical significance of subsegmental PE is unknown. We sought to summarize the proportion of subsegmental PE diagnosed with single‐ and multiple‐detectors CTPA and assess the safety of diagnostic strategies based on single‐ or multiple‐detectors CTPA to exclude PE. Patients and methods: A systematic literature search strategy was conducted using MEDLINE, EMBASE and the Cochrane Register of Controlled Trials. We selected 22 articles (20 prospective cohort studies and two randomized controlled trials) that included patients with suspected PE who underwent a CTPA and reported the rate of subsegmental PE. Two reviewers independently extracted data onto standardized forms. Results: The rate of subsegmental PE diagnosis was 4.7% [95% confidence interval (CI): 2.5–7.6] and 9.4 (95% CI: 5.5–14.2) in patients that underwent a single‐ and multiple‐detectors CTPA, respectively. The 3‐month thromboembolic risks in patients with suspected PE and who were left untreated based on a diagnostic algorithm including a negative CTPA was 0.9% (95% CI: 0.4–1.4) and 1.1% (95% CI: 0.7–1.4) for single‐ and multiple‐detectors CTPA, respectively. Conclusion: Multiple‐detectors CTPA seems to increase the proportion of patients diagnosed with subsegmental PE without lowering the 3‐month risk of thromboembolism suggesting that subsegmental PE may not be clinically relevant.

Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial.

BACKGROUND Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. METHODS We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsbergs criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. FINDINGS From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. INTERPRETATION ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. FUNDING Canadian Institutes of Health Research.

Comparison of 10-mg and 5-mg Warfarin Initiation Nomograms Together with Low-Molecular-Weight Heparin for Outpatient Treatment of Acute Venous Thromboembolism: A Randomized, Double-Blind, Controlled Trial

Context The optimal methods for achieving therapeutic levels of anticoagulation with warfarin remain uncertain. Contribution In this randomized trial of two warfarin dosing nomograms, a 10-mg initiation dose led to a therapeutic international normalized ratio (INR) 1.4 days sooner than a 5-mg initiation dose. The two nomograms had the same rate of adverse events and the same proportion of INR values greater than 5.0. Clinical Implications Physicians can more quickly get their patients to a therapeutic INR with warfarin by using a dosing nomogram that starts with a 10-mg dose rather than a 5-mg initiation dose. The Editors The management of venous thromboembolism has improved substantially in the past 10 years. Conventional therapy consists of unfractionated or low-molecular-weight heparin for 5 to 7 days, together with oral anticoagulation with warfarin given for a minimum of 3 months (1, 2). Low-molecular-weight heparin facilitates outpatient treatment, and warfarin is usually initiated within 24 hours. Clinical trials have demonstrated that low-molecular-weight heparin may be safely discontinued after 5 days once the international normalized ratio (INR) has remained greater than 1.9 for 24 hours (2, 3). Nurses or pharmacists often coordinate outpatient management of venous thromboembolism with appropriate physician support (4). For outpatient therapy, minimizing the time to a therapeutic INR is advantageous because it potentially decreases the cost and inconvenience of low-molecular-weight heparin therapy. The initiation of warfarin treatment is problematic, however, because of variations in dose response. A dosing nomogram to facilitate safe, timely warfarin initiation to achieve therapeutic INRs would be useful. We previously developed and tested a nomogram for the initiation of warfarin therapy using a 10-mg loading dose and found that it was superior to standard physician practice because it resulted in shorter time to a therapeutic INR (5). This nomogram, however, required daily INR testing and was therefore not ideal for outpatient management. We subsequently revised the nomogram so that it requires INR assessments only on days 3 and 5 during the first 8 days of therapy. We found that the revised nomogram was successful: Almost 90% of patients had a therapeutic INR by the 5th day of treatment (6). The objective of our current study was to perform a randomized, controlled trial comparing the effectiveness and feasibility of a warfarin nomogram using a 10-mg loading dose with those of a nomogram using a 5-mg loading dose for the management of outpatients with acute venous thromboembolism. Methods Patients Consecutive outpatients with a diagnosis of objectively confirmed acute venous thromboembolism (deep venous thrombosis or pulmonary embolism) who presented to the thrombosis clinics of four Canadian academic centers were candidates for study inclusion. Patients were not admitted to the study if they had a baseline INR greater than 1.4, had thrombocytopenia (platelet count < 50 109 cells/mL), were younger than 18 years of age, required hospitalization, had received oral anticoagulant therapy within the previous 2 weeks, or were at high risk for major bleeding (as judged by the attending physician). Design This study was a randomized, double-blind (physicianpatient), controlled trial. Randomization was stratified by study center and presence of active malignant disease. The randomization sequence was computer generated by the trial statistician. The details of the randomization sequence, which were not known to the investigators or to the study coordinator, were contained in sets of sequentially numbered, opaque, sealed envelopes. The outside of each envelope was marked only with the name of the hospital, whether the patient had a malignant condition, and a patient number. Patients were assigned to 5-mg or 10-mg warfarin induction by using previously validated nomograms (Table 1 and Figure 1) (6, 7). The 5-mg nomogram, as published, specifies a dose range on each day after the first day of treatment with no indication of how to choose the dose (7). For the current study, we chose the higher dose whenever a range was indicated. The research ethics boards at each of the participating institutions approved the study, and informed consent was obtained from all participants. Table 1. 5-mg Warfarin Initiation Nomogram Figure 1. 10-mg warfarin initiation nomogram. Interventions Study participants were randomly allocated to warfarin induction with a 10-mg or 5-mg warfarin nomogram (Table 1 and Figure 1) (6, 7). Baseline data collected included demographic characteristics (age, sex), diagnosis, weight, presence of active malignant disease, complete blood count, and INR. International normalized ratios were measured in local licensed clinical laboratories. Treatment was initiated on the first day (day 1) with subcutaneous low-molecular-weight heparin (dalteparin [200 U/kg of body weight] or tinzaparin [175 U/kg]). Low-molecular-weight heparin was continued for a minimum of five daily injections until the INR was therapeutic (>1.9). The initial warfarin dose was determined by using treatment allocation. All warfarin doses were administered in the evening, and blood samples for INR assessments were drawn before 10:00 a.m. Patients in the 10-mg group received 10 mg of warfarin on each of the first 2 days, whereas patients in the 5-mg group were given 5 mg on each of the first 2 days. Subsequent dose adjustments after day 3 were made by using the respective nomograms. International normalized ratios were measured in all patients on the mornings of days 3, 4, and 5. The 10-mg nomogram, unlike the 5-mg nomogram, did not require an INR measurement on day 4 for dosing; however, a measurement was performed for study end point purposes only. If a patient did not have a therapeutic INR by day 5, the INR was measured daily until it was therapeutic. Local attending physicians directed management of warfarin monitoring from day 8 to day 90. End Points The primary end point of the study was time in days to a therapeutic INR (>1.9). The secondary end points included the proportion of patients whose INRs were within the therapeutic range (2.0 to 3.0) on the 5th day, incidence of recurrent venous thromboembolism within 90 days of diagnosis (as defined by previously published criteria [2, 3]), incidence of major bleeding within 28 days of diagnosis (as defined by previously published criteria [2, 3]), number of INR measurements greater than 5, absolute number of INR assessments in the first 28 days, and 90-day survival. An adjudication committee consisting of three study investigators evaluated all clinical events in a blinded fashion, and end points were determined by consensus. Hypothesis We tested the hypothesis that patients managed with a 10-mg warfarin induction nomogram would achieve therapeutic INRs more rapidly than patients managed with a 5-mg warfarin nomogram. We believed these improvements would occur without increased risk for bleeding. Sample Size Using data from our pilot nomogram to estimate standard deviation (1 day), we calculated that 92 patients per group would be required to show a 0.5-day difference in time to a therapeutic INR (90% power; two-sided = 0.05). We considered a 0.5-day difference to be the minimal clinically important difference because it would yield a significant proportion of patients who would not require low-molecular-weight heparin therapy beyond 5 days. Statistical Analysis All statistical analyses were performed according to a pre-established analysis plan and by intention to treat. We used SPSS software for all analyses (SPSS, Inc., Chicago, Illinois). Baseline characteristics were described by using descriptive statistics. Mean time to therapeutic INR was compared between the groups by using the unpaired Student t-test. Proportions (including the proportion in each group with a therapeutic INR on day 5) were compared by using the unadjusted chi-square test. No interim analyses were conducted. Two-sided significance tests were used throughout, and a P value less than 0.05 was considered statistically significant. Multiple linear regression was performed to explore determinants of time to therapeutic INR (after appropriate testing was done to prove the suitability of this analysis). Biologically plausible predictors (age, sex, weight, presence of cancer, and treatment assignment) were included in the original model. Backward stepwise regression was performed, and a P value greater than 0.20 was used for variable removal. Results Between August 1999 and June 2000, 210 patients were approached for participation in the study. Two patients were excluded because they had a baseline INR greater than 1.4, 2 were excluded because they required hospitalization, and 5 were excluded because they had received warfarin in the previous 2 weeks. The last patient completed follow-up in September 2000. A total of 201 eligible, consenting patients were enrolled and randomly assigned to treatment (Table 2). One hundred four patients were assigned to the 10-mg group, and 97 were assigned to the 5-mg group. The baseline characteristics of both groups were similar, although the 10-mg group included more men. The overall age range was 18 to 98 years, and 32 patients (16%) were older than 75 years of age. All patients were followed for 90 days. Table 2. Comparison of the 10-mg and 5-mg Nomogram Groups Patients in the 10-mg group achieved a therapeutic INR 1.4 days earlier than patients in the 5-mg group (P < 0.001). In addition, many more patients in the 10-mg group than in the 5-mg group achieved a therapeutic INR by day 5 (83% vs. 46%; P < 0.001) (Figure 2). The 5-mg group also required more INR assessments in the first 28 days (9.1 vs. 8.1; P = 0.04). Only two episodes of major bleeding were observed, one in each group, and rates of recurrence of venous thromboembolism did not differ significantly between the

The Association of Factor V Leiden and Prothrombin Gene Mutation and Placenta-Mediated Pregnancy Complications: A Systematic Review and Meta-analysis of Prospective Cohort Studies

Marc Rodger and colleagues report the results of their systematic review and meta-analysis of prospective cohort studies that estimated the association of maternal factor V Leiden and prothrombin gene mutation carrier status and placenta-mediated pregnancy complications.