Michael J. Kovacs

A COMPARISON OF LOW-MOLECULAR-WEIGHT HEPARIN ADMINISTERED PRIMARILY AT HOME WITH UNFRACTIONATED HEPARIN ADMINISTERED IN THE HOSPITAL FOR PROXIMAL DEEP-VEIN THROMBOSIS

BACKGROUND Patients with acute proximal deep-vein thrombosis are usually treated first in the hospital with intravenous standard (unfractionated) heparin. However, the longer plasma half-life, better bioavailability after subcutaneous administration, and more predictable anticoagulant response of low-molecular-weight heparins make them attractive for possible home use. We compared these two approaches. METHODS Patients with acute proximal deep-vein thrombosis were randomly assigned to receive either intravenous standard heparin in the hospital (253 patients) or low-molecular-weight heparin (1 mg of enoxaparin per kilogram of body weight subcutaneously twice daily) administered primarily at home (247 patients). The study design allowed outpatients taking low-molecular-weight heparin to go home immediately and hospitalized patients taking low-molecular-weight heparin to be discharged early. All the patients received warfarin starting on the second day. RESULTS Thirteen of the 247 patients receiving low-molecular-weight heparin (5.3 percent) had recurrent thromboembolism, as compared with 17 of the 253 patients receiving standard heparin (6.7 percent; P=0.57; absolute difference, 1.4 percentage points; 95 percent confidence interval, -3.0 to 5.7). Five patients receiving low-molecular-weight heparin had major bleeding, as compared with three patients receiving standard heparin. After randomization, the patients who received low-molecular-weight heparin spent a mean of 1.1 days in the hospital, as compared with 6.5 days for the standard-heparin group; 120 patients in the low-molecular-weight- heparin group did not need to be hospitalized at all. CONCLUSIONS Low-molecular-weight heparin can be used safely and effectively to treat patients with proximal deep-vein thrombosis at home.

A COMPARISON OF THREE MONTHS OF ANTICOAGULATION WITH EXTENDED ANTICOAGULATION FOR A FIRST EPISODE OF IDIOPATHIC VENOUS THROMBOEMBOLISM

BACKGROUND Patients who have a first episode of venous thromboembolism in the absence of known risk factors for thrombosis (idiopathic thrombosis) are often treated with anticoagulant therapy for three months. Such patients may benefit from longer treatment, however, because they appear to have an increased risk of recurrence after anticoagulant therapy is stopped. METHODS In this double-blind study, we randomly assigned patients who had completed 3 months of anticoagulant therapy for a first episode of idiopathic venous thromboembolism to continue receiving warfarin, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0, or to receive placebo for a further 24 months. Our goal was to determine the effects of extended anticoagulant therapy on rates of recurrent symptomatic venous thromboembolism and bleeding. RESULTS A prespecified interim analysis of efficacy led to the early termination of the trial after 162 patients had been enrolled and followed for an average of 10 months. Of 83 patients assigned to continue to receive placebo, 17 had a recurrent episode of venous thromboembolism (27.4 percent per patient-year), as compared with 1 of 79 patients assigned to receive warfarin (1.3 percent per patient-year, P<0.001). Warfarin resulted in a 95 percent reduction in the risk of recurrent venous thromboembolism (95 percent confidence interval, 63 to 99 percent). Three patients assigned to the warfarin group had nonfatal major bleeding (two had gastrointestinal bleeding and one genitourinary bleeding), as compared with none of those assigned to the placebo group (3.8 vs. 0 percent per patient-year, P=0.09). CONCLUSIONS Patients with a first episode of idiopathic venous thromboembolism should be treated with anticoagulant agents for longer than three months.

Efficacy of Pamidronate in Reducing Skeletal Events in Patients with Advanced Multiple Myeloma

BACKGROUND Skeletal complications are a major clinical manifestation of multiple myeloma. These complications are caused by soluble factors that stimulate osteoclasts to resorb bone. Bisphosphonates such as pamidronate inhibit osteoclastic activity and reduce bone resorption. METHODS Patients with stage III multiple myeloma and at least one lytic lesion received either placebo or pamidronate (90 mg) as a four-hour intravenous infusion given every four weeks for nine cycles in addition to antimyeloma therapy. The patients were stratified according to whether they were receiving first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy at entry into the study. Skeletal events (pathologic fracture, irradiation of or surgery on bone, and spinal cord compression), hypercalcemia (symptoms or a serum calcium concentration > or = 12 mg per deciliter [3.0 mmol per liter]), bone pain, analgesic-drug use, performance status, and quality of life were assessed monthly. RESULTS Among 392 treated patients, the efficacy of treatment could be evaluated in 196 who received pamidronate and 181 who received placebo. The proportion of patients who had any skeletal events was significantly lower in the pamidronate group (24 percent) than in the placebo group (41 percent, P < 0.001), and the reduction was evident in both stratum 1 (P = 0.04) and stratum 2 (P = 0.004). The patients who received pamidronate had significant decreases in bone pain and no deterioration in performance status and quality of life. Pamidronate was tolerated well. CONCLUSIONS Monthly infusions of pamidronate provide significant protection against skeletal complications and improve the quality of life of patients with stage III multiple myeloma.

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

Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group.

PURPOSE To determine the efficacy and safety of 21 monthly cycles of pamidronate therapy in patients with advanced multiple myeloma. PATIENTS AND METHODS Patients with stage III myeloma and at least one lytic lesion received either placebo or pamidronate 90 mg intravenously administered as a 4-hour infusion monthly for 21 cycles. At study entry, the patients were stratified according to whether they were to receive first-line (stratum 1) or second-line (stratum 2) antimyeloma chemotherapy. Skeletal events (pathologic fracture, radiation or surgery to bone, and spinal cord compression) and hypercalcemia were assessed monthly. RESULTS The results of the first nine previously reported cycles are extended to 21 cycles. Of the 392 randomized patients, efficacy could be evaluated in 198 who received pamidronate and 179 who received placebo. After 21 cycles, the proportion of patients who developed any skeletal event was lower in the pamidronate-group (P = .015). The mean number of skeletal events per year was less in the pamidronate-group (1.3) than in placebo-treated patients (2.2; P = .008). Although survival was not different between the pamidronate-treated group and placebo patients overall, stratum 2 patients who received pamidronate lived longer than those who received placebo (14 v 21 months, P = .041). Pamidronate was safe and well tolerated during the 21 cycles of therapy. CONCLUSION Long-term monthly infusions of pamidronate as an adjunct to chemotherapy are superior to chemotherapy alone in reducing skeletal events in stage III multiple myeloma patients, and may improve the survival of patients on salvage therapy.

Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices. METHODS The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education. CONCLUSIONS We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.

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)

Safety of Withholding Heparin in Pregnant Women with a History of Venous Thromboembolism

BACKGROUND Women with a history of venous thromboembolism may be at increased risk for venous thromboembolic events during pregnancy. In these women, the decision to give or withhold heparin in the antepartum period is controversial, because accurate estimates of the frequency of recurrent thromboembolic events if antepartum heparin is withheld are not available. METHODS We prospectively studied 125 pregnant women with a single previous episode of venous thromboembolism. Antepartum heparin was withheld, but anticoagulant therapy was given for four to six weeks post partum. Our primary objective was to determine the rate of antepartum recurrence of venous thromboembolism. Laboratory studies were performed to identify thrombophilia in 95 women. RESULTS Three of the 125 women (2.4 percent) had an antepartum recurrence of venous thromboembolism (95 percent confidence interval, 0.2 to 6.9 percent). There were no recurrences in the 44 women who had no evidence of thrombophilia and who also had a previous episode of thrombosis that was associated with a temporary risk factor. Among the 51 women with abnormal laboratory results or a previous episode of idiopathic thrombosis, or both, 3 (5.9 percent) had an antepartum recurrence of venous thromboembolism (95 percent confidence interval, 1.2 to 16.2 percent). CONCLUSIONS The risk of recurrent antepartum venous thromboembolism in women with a history of venous thromboembolism is low, and therefore routine antepartum prophylaxis with heparin is not warranted.

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.