Sergio Siragusa

Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: Results of a meta-analysis

PURPOSE To obtain reliable estimates of the relative efficacy and safety of low-molecular-weight heparins (LMWHs) and unfractionated heparin (UFH) in the treatment of patients with venous thromboembolism. METHODS A literature search of randomized trials evaluating LMWH and UFH for the period from 1980 to 1994 was conducted to obtain data for a meta-analysis. Studies were classified as level 1 if they were double-blind or if there was blinded assessment of outcome measures, and level 2 if they did not provide assurance of blinded outcome assessment. RESULTS In level 1 studies, the relative risk (RR) of recurrent venous thromboembolism during the first 15 days and over the entire period of anticoagulant therapy was 0.24 (95% confidence intervals [CI] 0.06 to 0.80, P = 0.02) and 0.39 (95% CI 0.30 to 0.80, P = 0.006), respectively, in favor of LMWH treatment. The RR for major bleeding was 0.42 (95% CI 0.2 to 0.9, P = 0.01), in favor of LMWH. In level 2 studies, no significant differences in the rates of recurrent venous thromboembolism or major bleeding were observed. Pooling level 1 and level 2 studies, the RR for overall mortality and mortality in cancer patients was 0.51 (95% CI 0.2 to 0.9, P = 0.01), and 0.33 (95% CI 0.1 to 0.8, P = 0.01), respectively in favor of LMWH. CONCLUSIONS LMWH are likely to be more effective than UFH in preventing recurrent venous thromboembolism, to produce less major bleeding, and to be associated with a lower mortality rate, particularly in the subgroup of patients with cancer.

Cardiovascular Events and Intensity of Treatment in Polycythemia Vera

BACKGROUND Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical trial. METHODS We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed. RESULTS After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events. CONCLUSIONS In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007-006694-91.).

Risk of Recurrence After a First Episode of Symptomatic Venous Thromboembolism Provoked by a Transient Risk Factor: A Systematic Review

BACKGROUND We aimed to determine the risk of recurrence for symptomatic venous thromboembolism (VTE) provoked by different transient risk factors. DATA SOURCES MEDLINE, EMBASE, and Cochrane Collaboration Registry of Randomized Trials databases were searched. STUDY SELECTION Prospective cohort studies and randomized trials of patients with a first episode of symptomatic VTE provoked by a transient risk factor and treated for at least 3 months were identified. DATA EXTRACTION Number of patients and recurrent VTE during the 0- to 12-month and 0- to 24-month intervals after stopping therapy, study design, and provoking risk factor characteristics were extracted. DATA SYNTHESIS Annualized recurrence rates were calculated and pooled across studies. At 24 months, the rate of recurrence was 3.3% per patient-year (11 studies, 2268 patients) for all patients with a transient risk factor, 0.7% per patient-year (3 studies, 248 patients) in the subgroup with a surgical factor, and 4.2% per patient-year (3 studies, 509 patients) in the subgroup with a nonsurgical factor. In the same studies, the rate of recurrence after unprovoked VTE was 7.4% per patient-year. The rate ratio for a nonsurgical compared with a surgical factor was 3.0 and for unprovoked thrombosis compared with a nonsurgical factor was 1.8 at 24 months. CONCLUSIONS The risk of recurrence is low if VTE is provoked by surgery, intermediate if provoked by a nonsurgical risk factor, and high if unprovoked. These risks affect whether patients with VTE should undergo short-term vs indefinite treatment.

Serial 2-Point Ultrasonography Plus D-Dimer vs Whole-Leg Color-Coded Doppler Ultrasonography for Diagnosing Suspected Symptomatic Deep Vein Thrombosis: A Randomized Controlled Trial

CONTEXT Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies. OBJECTIVE To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities. DESIGN, SETTING, AND PATIENTS A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n = 2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007. MAIN OUTCOME MEASURE Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup. RESULTS Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n = 1045) or whole-leg (n = 1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%;95% CI, -1.4% to 0.8%). CONCLUSION The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00353093.

Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis : the Duration of Anticoagulation based on Compression UltraSonography (DACUS) study

Residual vein thrombosis (RVT) indicates a prothrombotic state and is useful for evaluating the optimal duration of oral anticoagulant treatment (OAT). Patients with a first episode of deep vein thrombosis, treated with OAT for 3 months, were managed according to RVT findings. Those with RVT were randomized to either stop or continue anticoagulants for 9 additional months, whereas in those without RVT, OAT was stopped. Outcomes were recurrent venous thromboembolism and/or major bleeding. Residual thrombosis was detected in 180 (69.8%) of 258 patients; recurrent events occurred in 27.2% of those who discontinued (25/92; 15.2% person-years) and 19.3% of those who continued OAT (17/88; 10.1% person-years). The relative adjusted hazard ratio (HR) was 1.58 (95% confidence interval [CI], 0.85-2.93; P = .145). Of the 78 (30.2%) patients without RVT, only 1 (1.3%; 0.63% person-years) had a recurrence. The adjusted HR of patients with RVT versus those without was 24.9 (95% CI, 3.4-183.6; P = .002). One major bleeding event (1.1%; 0.53% person-years) occurred in patients who stopped and 2 occurred (2.3%; 1.1% person-years) in those who continued OAT. Absence of RVT identifies a group of patients at very low risk for recurrent thrombosis who can safely stop OAT. This trial was registered at http://www.ClinicalTrials.gov as no. NCT00438230.

Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial.

Context Vitamin K decreases the international normalized ratio (INR) in overanticoagulated patients who receive warfarin therapy, but its effect on clinical outcomes is less clear. Contribution Trial investigators detected no differences in the frequency of bleeding, thromboembolism, or death among overanticoagulated patients who received warfarin therapy and were randomly assigned to receive low-dose vitamin K or placebo. Caution The study was underpowered to detect differences in major bleeding. Implication Low-dose vitamin K corrects the INR in overanticoagulated patients who received warfarin therapy, but it has little effect on clinical outcomes. Withdrawal of warfarin may be all that is necessary to manage elevated INRs. The Editors Warfarin is a remarkably effective drug for primary and secondary prevention of arterial and venous thromboembolism. Among commonly used medications, warfarin is unique because its doseresponse characteristics are highly unpredictable, varying both among and within individuals over time. As a result, warfarin therapy requires ongoing monitoring using the international normalized ratio (INR), a value that reflects the degree to which warfarin has reduced coagulation factor levels and the coagulant potential of blood (1). For most indications, an INR range of 2.0 to 3.0 is targeted; INR values less than 2.0 are associated with an increased risk for thromboembolism, and INR values greater than 4.0 are associated with an increase in bleeding complications. The risk for bleeding, particularly intracranial bleeding, increases markedly as the INR exceeds 4.5 (13). Even in clinics dedicated to warfarin management, INRs are outside the therapeutic range one third to one half the time (4). When managing a patient with an INR greater than 4.5 who is not bleeding, clinicians generally either withhold warfarin treatment and allow the INR to decrease to the desired value or administer vitamin K (orally or intravenously) to more rapidly reduce the INR (1, 510). Small randomized trials have shown that a single dose of low-dose oral vitamin K (for example, 1 to 2.5 mg) effectively reduces the INR in otherwise-stable overanticoagulated patients within 24 hours of its administration; however, these studies were not large enough to determine whether low-dose vitamin K reduces bleeding without increasing the risk for thromboembolism (1115). A recent systematic review (16) supported this observation. To determine whether oral vitamin K is indicated in overanticoagulated patients who are not bleeding, we did a randomized trial in which we allocated oral vitamin K or placebo, 1.25 mg, to patients who presented with an INR of 4.5 to 10.0. The primary outcome measure was the frequency of all forms of bleeding events during the first 90 days. Our hypothesis that bleeding events would be reduced was based on our previously published, smaller studies of low-dose oral vitamin K administered to various patient groups. In these studies, we found a consistent and rapid decrease in the INR after low-dose vitamin K was administered (13, 15, 1722). Methods Study Patients We identified patients with INRs of 4.5 to 10.0 in participating outpatient anticoagulant therapy clinics. We screened patients as they presented for routine INR assessment and considered them for eligibility if they were receiving warfarin therapy with a target INR of 2.0 to 3.5, their most recent INR was between 4.5 and 10.0 in the past 24 hours, and they were not bleeding. We excluded patients if discontinuation of warfarin therapy was scheduled and if they were younger than 18 years, had a life expectancy less than 10 days, had an indication for acute normalization of their INR (such as imminent surgery), had a known severe liver disease, had a history of a major bleeding event within 1 month, had a known bleeding disorder, had received thrombolytic therapy within 48 hours, had a platelet count less than 50109 cells/L, could not take oral medications, had a known allergy to vitamin K, or could not return for laboratory or clinical monitoring. Study staff at each participating anticoagulant therapy clinic approached patients who met inclusion criteria for consent to participate. This study ran in parallel with a cohort study in which patients with INRs greater than 10.0 received oral vitamin K, 2.5 mg. Patients were otherwise identical to those enrolled in this study, and we followed them for similar outcome events. The results of the concurrent cohort study will be presented in a subsequent paper. Randomization and Treatment We instructed all eligible, consenting patients to withhold warfarin for 1 day and randomly assigned them to receive a capsule containing either vitamin K, 1.25 mg, or placebo. Randomization was done by using a computer-generated random-number table at the coordinating and methods center and was stratified by clinical center. Vitamin K capsules were compounded from 5-mg vitamin K tablets (Merck & Co., Whitehouse Station, New Jersey) by a commercial pharmacy with Health Canada approval (Clinical Trials Application control number 092635). Placebo capsules contained inert filler and were indistinguishable from the capsules that contained vitamin K. Random allocation of patients was accomplished when site-specific study personnel dispensed the next numbered study drug container at each clinical center; thus, patients, treating clinicians, and research coordinators were unaware of treatment allocation. In 2 centers, we monitored the INR of outpatients in clinics or laboratories outside the clinical center. In such centers, we obtained consent for the study by telephone, and the study drug was shipped within hours to the patients home by using a courier service. In all cases, we confirmed receipt and consumption of the study drug on the day of randomization by telephone. In the remaining centers, in which patients were seen in person, consent and study drug administration occurred at the same time that the elevated INR was detected. Follow-up and Outcome Measures At enrollment, we advised patients to promptly seek medical evaluation if they developed signs or symptoms of bleeding or thromboembolism. At minimum, we assessed patients by telephone or in person on days 1, 3, 7, 14, 28, and 90 after randomization. Additional contact and INR sampling necessary to manage the patients anticoagulant therapy were done at the discretion of the patients physician. At each follow-up, we sought signs and symptoms of bleeding and thromboembolism and collected details about all such events. We asked patients a focused series of questions to help them recall these events. We reviewed and abstracted medical records of all suspected bleeding episodes, thromboembolism, and deaths. Our primary outcome measure was the frequency of bleeding events during the 90 days after randomization. We defined major bleeding as fatal bleeding, bleeding requiring transfusion of 2 or more units of packed red blood cells, bleeding resulting in a therapeutic intervention (such as endoscopy), or objectively confirmed bleeding into an enclosed space. We defined minor bleeding as bleeding resulting in a medical assessment that did not meet criteria as a major bleeding event. We defined trivial bleeding as all patient-reported bleeding events that did not result in a medical assessment. We combined all reported bleeding events (major, minor, and trivial) for this analysis. We chose to combine these events because our clinical experience suggested that reducing medically unimportant but bothersome bleeding, such as epistaxis, bruising, and menorrhagia, was a clinically important goal for our patients; patients with a minor or trivial bleeding event may be at greater risk for subsequent major bleeding; and the frequency of major bleeding was likely to be very low, calling into question the feasibility of a study powered to detect differences in major bleeding events. Secondary outcome measures included the frequency of major bleeding events, objectively confirmed venous or arterial thromboembolism, and death during the 90 days after randomization. We chose the 90-day period on the basis of our previous studies wherein we found a significant reduction in bleeding events (90 days) after the administration of similar doses of oral vitamin K (13). We hypothesized that low-dose oral vitamin K might influence a bleeding event during this extended period, because even small doses of this highly lipophilic drug might have an extended influence on INR control (and thus the risk for bleeding and thrombosis). In post hoc analyses, we examined the frequency of all bleeding and major bleeding events in the first 7 days and the number of clinical events in patients who were older than 70 years at enrollment. An independent adjudication committee, blinded to treatment allocation and not otherwise involved in the study, reviewed all bleeding events, thromboembolism, and deaths. Confirmation of venous thromboembolism required a nononcompressible venous segment on ultrasonography, an intraluminal filling defect on venography or computed tomographic pulmonary angiography, or a segmental (or larger) mismatch defect on ventilationperfusion lung scan. Arterial thromboembolism required either direct surgical visualization of thrombus; an intraluminal filling defect on angiography; or clear evidence of a new ischemic event on an objective test, such as electrocardiography, computed tomography, or magnetic resonance imaging. We advised clinics to reinstitute warfarin therapy once the INR was within the therapeutic reference interval after administration of the study drug. The clinicians who cared for the patients determined the warfarin dose when the drug was readministered. Target INR ranges for individual patients did not change as a result of the elevated INR that led to enrollment. Statistical Analysis Our primary analysis was an intention-to-treat comparison of the proportions of patien

Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: a single center study of 433 patients

We have previously identified sole +9, 13q- or 20q-, as ‘favorable’ and sole +8 or complex karyotype as ‘unfavorable’ cytogenetic abnormalities in primary myelofibrosis (PMF). In this study of 433 PMF patients, we describe additional sole abnormalities with favorable (chromosome 1 translocations/duplications) or unfavorable (−7/7q-) prognosis and also show that other sole or two abnormalities that do not include i(17q), −5/5q-, 12p-, inv(3) or 11q23 rearrangement are prognostically aligned with normal karyotype, which is prognostically favorable. These findings were incorporated into a refined two-tired cytogenetic-risk stratification: unfavorable and favorable karyotype. The respective 5-year survival rates were 8 and 51% (hazard ratio (HR): 3.1, 95% confidence interval (CI): 2.2–4.3; P<0.0001). Multivariable analysis confirmed the International Prognostic Scoring System (IPSS)-independent prognostic value of cytogenetic-risk categorization and also identified thrombocytopenia (platelets <100 × 109/l) as another independent predictor of inferior survival (P<0.0001). A similar multivariable analysis showed that karyotype (P=0.001) and platelet count (P=0.04), but not IPSS (P=0.27), predicted leukemia-free survival; the 5-year leukemic transformation rates for unfavorable versus favorable karyotype were 46 and 7% (HR: 5.5, 95% CI: 2.5–12.0; P<0.0001). This study provides the rationale and necessary details for incorporating cytogenetic findings and platelet count in future prognostic models for PMF.

Clinical experience with retrievable vena cava filters: results of a prospective observational multicenter study.

Summary.  Background: Retrievable inferior vena cava (IVC) filters offer the attractive possibility to be definitive or to be removed when they become unnecessary. Objective: The purpose of this study was to evaluate the efficacy and the likelihood to remove the retrievable IVC filter ALN. Methods: A total of 30 patients (13 males and 17 females, mean age 57 ± 15 years) underwent placement of ALN filters. Indications for implantation were acute venous thromboembolism (VTE) with a contraindication to anticoagulation in 26 cases (86%), primary prophylaxis after major trauma in two cases (7%) or before surgery in two patients with very high thromboembolic risk (7%). Results: The filter was successfully placed in all patients. After a median follow‐up of 18.2 months, there were three cases (10%) of trapped emboli within the filter, one case (3%) of asymptomatic migration of the filter toward the heart and two patients (7%) had deep vein thrombosis (DVT) recurrences. ALN retrieval was attempted through transjugular approach in 18 patients (60%) and the maneuver was successful in 14 of them (78%); when the decision of removal was taken more than 3 months after the implantation, the retrieval was possible only in four of eight patients (50%). The median implantation period was 123 days (range: 30–345). Conclusions: The present study shows the efficacy of ALN filter; it also demonstrates the feasibility and safety of retrieval after a medium‐term period of placement. Removal after 3 months after implantation can be unsuccessful and maximum implantation time requires further studies.

Transfusion-dependency at presentation and its acquisition in the first year of diagnosis are both equally detrimental for survival in primary myelofibrosis—prognostic relevance is independent of IPSS or karyotype†

The International Prognostic Scoring System (IPSS) and karyotype are useful tools for risk stratification in primary myelofibrosis (PMF). We examined the additional prognostic impact of red blood cell transfusion need among 254 consecutive patients (median age, 59 years). Sixty‐two patients (∼24%) required transfusions at diagnosis whereas 22 (∼9%) became transfusion‐dependent and 170 remained transfusion‐independent during the first year postdiagnosis; after a median follow‐up of 55 months, the respective median survivals were 35, 25, and 117 months (P < 0.01). Multivariable analysis confirmed the IPSS‐ and karyotype‐independent prognostic weight of transfusion status. Among IPSS intermediate‐1 risk patients, overall median survival of 82 months was modified to 60 or 118 months, based on presence or absence of transfusion need, respectively (P < 0.01). The corresponding figures for intermediate‐2/high risk patients were 30 and 64 months (P < 0.01). Documented causes of death did not include iron overload. We conclude that transfusion status in PMF downgrades or upgrades prognosis within specific IPSS categories; transfusion need is a marker of aggressive disease biology in PMF, as it is in myelodysplastic syndromes. Am. J. Hematol., 2010.

Long-term outcomes of patients with cerebral vein thrombosis: a multicenter study

Summary.  Background:  Little information is available on the long‐term clinical outcome of cerebral vein thrombosis (CVT).