Significant Bleeding Events Research Articles

Bendamustine plus alemtuzumab is safe and feasible treatment for fludarabine refractory chronic lymphocytic leukaemia (CLL)

Bendamustine plus alemtuzumab is safe and feasible treatment for fludarabine refractory chronic lymphocytic leukaemia (<scp>CLL</scp>)

Effective Anticoagulation for a Percutaneous Ventricular Assist Device Using a Heparin-Based Purge Solution

To report on a series of patients who were successfully anticoagulated with a novel protocol including a heparin-based purge solution. Four patients were supported for a total of 300 hours on the new Impella anticoagulation protocol, which was based on our current nurse-driven cardiology heparin protocol. Three patients were in cardiogenic shock after acute myocardial infarction, and 1 patient was in shock from severe aortic valvular disease. Despite prolonged cardiogenic shock, none of the patients developed significant renal or liver dysfunction while on device support. All 4 patients survived to hospital discharge, and there were no significant bleeding or thromboembolic events. Furthermore, there were no device malfunctions or clotting events within with pump motors. Despite frequent changes to the purge solution flow rate by the Automated Impella Controller, the patients in our cohort had relatively stable activated partial thromboplastin time values. Our novel anticoagulation protocol, which incorporates the heparin included in the purge solution into the total hourly heparin dosage, was successful in the first cohort of patients receiving extended Impella support for cardiogenic shock. Our case series also highlights that the Automated Impella Controller makes frequent adjustments to the purge solution, which depending on the heparin concentration, can result in significant fluctuations in the patient's total hourly heparin dosage. Furthermore, balancing the heparin in the purge solution with the intravenous heparin is important to ensuring adequate anticoagulation in patients supported by the Impella devices in the intensive care unit. Development of a standardized anticoagulation protocol for the Impella device that factors the heparin-based purge into the total heparin dosage and makes appropriate adjustments based on the fluctuating rate of the purge solution can provide effective anticoagulation to patients receiving extended circulatory support from this device.

Aortic valve repair in patients with aortic regurgitation: Experience with the first 100 cases

IntroductionThe aim of this study was to analyze short- and mid-term results of aortic valve repair. Material and methodsOne hundred consecutive patients (24 females; mean age 50.3 years, range 23–77 years) with aortic regurgitation underwent aortic valve repair between November 2007 and October 2012. Sixty patients had bicuspid aortic valve, and 82 patients demonstrated aortic regurgitation greater than mild (> grade 2). The ascending aorta/aortic root was replaced in 67 patients. Aortic cusp repair was necessary in 74 patients and additional aortic annulus stabilization was required in 48 cases. Follow-up ranged from 1 to 59 months (cumulative of 220 patient-years, median 25 months) and was complete in 100%. ResultsThere was no 30-day mortality and two patients died in the follow-up. The overall 4-year survival was 98% and freedom from cardiac death was 99% at 4 years. During the follow-up eight patients underwent aortic valve-related reoperation due to progression of aortic regurgitation and another six patients showed aortic regurgitation more than mild (> grade 2). In both aspects there was no statistically significant difference between patients without and with aortic root replacement (p=0.402 and p=0.650). There were no significant bleeding or thromboembolic events during the follow-up. ConclusionsShort- and mid-term data analysis revealed an excellent survival and acceptable results of aortic repair, comparable with other larger published studies. We think, therefore, aortic valve repair should be a part of contemporary cardio-surgical armamentarium, especially in younger patients with an appropriate indication.

Percutaneous Placement of an Intra-Aortic Balloon Pump in the Left Axillary/Subclavian Position Provides Safe, Ambulatory Long-Term Support as Bridge to Heart Transplantation

This study evaluated the feasibility, tolerability, and efficacy of a strategy for percutaneous intra-aortic balloon pump (IABP) placement through the left axillary-subclavian artery to provide mechanical circulatory support in patients with end-stage heart failure as a bridge to heart transplantation. The transfemoral approach to IABP placement is associated with major disadvantages, including the risk for infection and limitation of patient mobility in those requiring extended support. We developed a percutaneous technique for placing IABPs in the left axillary artery that permits upright sitting and ambulation. We performed a retrospective review of data from patients who had undergone left axillary IABP implantation between 2007 and 2012. Fifty patients who received a left axillary IABP as a bridge to transplantation were identified, of whom 42 (84%) underwent heart or heart-multiorgan transplantation. Cumulative survival on IABP support was 92%, and post-transplant 90-day survival was 90%. Median duration of support was 18 days. Four of 50 patients (8%) died while on IABP support, and 3 (6%) received greater mechanical circulatory support. Four patients (8%) had clinically significant thromboembolic or bleeding events without long-term sequelae. The most common minor adverse event was IABP malposition, in 22 patients (44%). Prolonged IABP support in the heart-transplantation cohort was associated with significant improvements in mean pulmonary artery pressure and in creatinine and total bilirubin concentrations. Percutaneous insertion of an IABP through the left axillary artery is a feasible and relatively well-tolerated strategy to bridge patients with end-stage heart failure to heart transplantation. This form of mechanical-device treatment permits upright sitting and ambulation in those requiring extended support.

Bleed-myocardial infarction score: predicting mid-term post-discharge bleeding events

Purpose: Prediction of hemorrhagic events in the acute/sub-acute phases of a Myocardial Infarction (MI) has already been addressed before. However, prediction of mid- to long-term bleeding has received scarce attention. We aim at deriving and validating a score for the prediction of mid-term bleeding events following discharge for MI. Methods: 917 patients admitted for MI and followed for 19.9±6.7 months were assigned to a derivation cohort. A new risk model, called BLEED-MI, was developed for predicting clinically significant bleeding events during follow-up (primary endpoint) and a composite endpoint of significant hemorrhage plus all-cause mortality (secondary endpoint), incorporating the following variables: Age, Diabetes Mellitus, arterial hypertension, smoking habits, urea, creatinine clearance and hemoglobin at admission, history of stroke, bleeding during hospitalization or previous major bleeding and heart failure during hospitalization. The BLEED-MI model was tested for calibration, accuracy and discrimination in the derivation sample and in a new, independent, validation cohort comprising 798 patients admitted at a later date. Results: The BLEED-MI score showed good calibration in both derivation and validation samples (Hosmer-Lemeshow test p-value 0.350 and 0.514, respectively) and high accuracy within each individual patient (Brier score 0.060 and 0.066, respectively). Its discriminative performance in predicting the primary outcome was relatively high (c-statistic of 0.751±0.031 in the derivation cohort and 0.720±0.036 in the validation sample). Incidence of primary/secondary endpoints increased progressively with increasing BLEED-MI scores. In the validation sample, a BLEED-MI score below 2 had a negative predictive value of 98.7% (152/154) for the occurrence of a clinically significant hemorrhagic episode during follow-up and for the composite endpoint of post-discharge hemorrhage plus all-cause mortality. Conclusions: A new bedside prediction-scoring model for post-discharge mid-term bleeding has been derived and preliminarily validated. This is the first score designed to predict mid- term hemorrhagic risk in patients discharged following admission for acute MI. This model should be externally validated in larger cohorts of patients before its potential clinical implementation.

Aspirin Versus Low-Molecular-Weight Heparin for Extended Venous Thromboembolism Prophylaxis After Total Hip Arthroplasty

The role of aspirin in thromboprophylaxis after total hip arthroplasty (THA) is controversial. To compare extended prophylaxis with aspirin and dalteparin for prevention of symptomatic venous thromboembolism (VTE) after THA. Multicenter randomized, controlled trial with a noninferiority design based on a minimal clinically important difference of 2.0%. Randomization was electronically generated; patients were assigned to a treatment group through a Web-based program. Patients, physicians, study coordinators, health care team members, outcome adjudicators, and data analysts were blinded to interventions. (Current Controlled Trials: ISRCTN11902170). 12 tertiary care orthopedic referral centers in Canada. 778 patients who had elective unilateral THA between 2007 and 2010. After an initial 10 days of dalteparin prophylaxis after elective THA, patients were randomly assigned to 28 days of dalteparin (n = 400) or aspirin (n = 386). Symptomatic VTE confirmed by objective testing (primary efficacy outcome) and bleeding. Five of 398 patients (1.3%) randomly assigned to dalteparin and 1 of 380 (0.3%) randomly assigned to aspirin had VTE (absolute difference, 1.0 percentage point [95% CI, -0.5 to 2.5 percentage points]). Aspirin was noninferior (P < 0.001) but not superior (P = 0.22) to dalteparin. Clinically significant bleeding occurred in 5 patients (1.3%) receiving dalteparin and 2 (0.5%) receiving aspirin. The absolute between-group difference in a composite of all VTE and clinically significant bleeding events was 1.7 percentage points (CI, -0.3 to 3.8 percentage points; P = 0.091) in favor of aspirin. The study was halted prematurely because of difficulty with patient recruitment. Extended prophylaxis for 28 days with aspirin was noninferior to and as safe as dalteparin for the prevention of VTE after THA in patients who initially received dalteparin for 10 days. Given its low cost and greater convenience, aspirin may be considered a reasonable alternative for extended thromboprophylaxis after THA. Canadian Institutes of Health Research.

Dose adjusting enoxaparin is necessary to achieve adequate venous thromboembolism prophylaxis in trauma patients

Standard venous thromboembolism (VTE) prophylaxis with enoxaparin results in inadequate protection in certain patients, with subtherapeutic plasma anti-Xa levels associated with elevated VTE rates. We hypothesized that many trauma patients would be subtherapeutic on the standard prophylactic dose of enoxaparin. Our goal was to adjust the enoxaparin dose to achieve target anti-Xa levels to take advantage of the drug based on its pharmacologic properties. Patients admitted to the trauma service were included if they received at least three doses of prophylactic enoxaparin and underwent at least two screening venous duplex. Peak plasma anti-Xa levels of 0.2 IU/mL or less were considered low, and the dose was increased by 10 mg twice daily until adequate anti-Xa levels were obtained. A strict screening venous duplex protocol was followed. Patients were excluded if they were diagnosed with a deep venous thrombosis before beginning enoxaparin or did not have correctly timed anti-Xa levels. Sixty-one trauma patients met inclusion criteria. There were three patients diagnosed with VTE (4.9%). Patients had a mean age of 45.9 years and were predominantly male (70.5%). Of the 61 patients, 18 (29.5%) had therapeutic anti-Xa levels on standard enoxaparin 30 mg twice daily. Compared with patients who had therapeutic anti-Xa levels on enoxaparin 30 mg twice daily, the 43 patients (70.5%) who were subtherapeutic were more likely to be male, have greater body weight, and larger body surface area. There were no significant bleeding events in the group that received an enoxaparin dose adjustment. Most patients had subtherapeutic anti-Xa levels while on enoxaparin 30 mg twice daily, suggesting inadequate VTE prophylaxis. The need for routine use of a higher dose of prophylactic enoxaparin in trauma patients and the effects of routinely dose adjusting enoxaparin on VTE rates should be the study of future prospective, randomized trials. Therapeutic study, level IV.

BLEED-Myocardial Infarction Score: Predicting mid-term post-discharge bleeding events

To derive and validate a score for the prediction of mid-term bleeding events following discharge for myocardial infarction (MI). One thousand and fifty patients admitted for MI and followed for 19.9 ± 6.7 mo were assigned to a derivation cohort. A new risk model, called BLEED-MI, was developed for predicting clinically significant bleeding events during follow-up (primary endpoint) and a composite endpoint of significant hemorrhage plus all-cause mortality (secondary endpoint), incorporating the following variables: age, diabetes mellitus, arterial hypertension, smoking habits, blood urea nitrogen, glomerular filtration rate and hemoglobin at admission, history of stroke, bleeding during hospitalization or previous major bleeding, heart failure during hospitalization and anti-thrombotic therapies prescribed at discharge. The BLEED-MI model was tested for calibration, accuracy and discrimination in the derivation sample and in a new, independent, validation cohort comprising 852 patients admitted at a later date. The BLEED-MI score showed good calibration in both derivation and validation samples (Hosmer-Lemeshow test P value 0.371 and 0.444, respectively) and high accuracy within each individual patient (Brier score 0.061 and 0.067, respectively). Its discriminative performance in predicting the primary outcome was relatively high (c-statistic of 0.753 ± 0.032 in the derivation cohort and 0.718 ± 0.033 in the validation sample). Incidence of primary/secondary endpoints increased progressively with increasing BLEED-MI scores. In the validation sample, a BLEED-MI score below 2 had a negative predictive value of 98.7% (152/154) for the occurrence of a clinically significant hemorrhagic episode during follow-up and for the composite endpoint of post-discharge hemorrhage plus all-cause mortality. An accurate prediction of bleeding events was shown independently of mortality, as BLEED-MI predicted bleeding with similar efficacy in patients who did not die during follow-up: Area Under the Curve 0.703, Hosmer-Lemeshow test P value 0.547, Brier score 0.060; low-risk (BLEED-MI score 0-3) event rate: 1.2%; intermediate risk (score 4-6) event rate: 5.6%; high risk (score ≥ 7) event rate: 12.5%. A new bedside prediction-scoring model for post-discharge mid-term bleeding has been derived and preliminarily validated. This is the first score designed to predict mid- term hemorrhagic risk in patients discharged following admission for acute MI. This model should be externally validated in larger cohorts of patients before its potential implementation.

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Introduction: Thrombus formation has been linked to adverse outcomes following the Fontan operation. No data exist to describe the effect of warfarin on INR values when the drug is initiated during the early post-operative (PO) period. Hypothesis: Patients will be more likely to achieve a supratherapeutic (ST) INR if their baseline INR was > 1.3 or if warfarin was started early in the PO period. Methods: This retrospective study describes the incidence of ST (> 2.5) INR values after the Fontan procedure at our institution between April, 2009 and January, 2012. Patients met inclusion criteria if the surgical procedure involved the initial conversion to a Fontan circuit and were initiated on warfarin during the immediate PO hospital stay. Excluded patients were those without a documented INR within 24 hours before warfarin initiation or those with < 2 INR values after initiating therapy. Data were analyzed with the Fisher’s exact test, Student’s t-test or Mann-Whitney Rank Sum test, as appropriate. Statistical significance was taken at p < 0.05. Results: A total of 32 patients met inclusion criteria: female (59.4%), systemic right ventricle (61.3%), under 3 y of age (81.3%), lateral caval tunnel Fontan (96.9%), with fenestration (93.8%). The median length of stay was 10 days. ST INR values after warfarin initiation occurred in 12.5 % of patients with an additional 6.3 % requiring dose adjustments due to a rapidly increasing INR. Patients with a ST INR were started on warfarin earlier compared to those in the non-ST group (POD 5 vs POD 2, p=0.037, respectively). Baseline INR values or initial warfarin doses were not significantly different between the groups. There were no reported thrombi or thromboembolic events and the only clinically significant bleeding event occurred while the INR value was subtherapeutic. Conclusions: Patients undergoing the Fontan procedure may require lower doses to achieve similar target INR values when warfarin is initiated closer to the surgical procedure date. Despite this observation, warfarin appears to be a safe agent in the early Fontan PO period when INR is monitored closely. One should use caution and consider dose reduction when initiating warfarin before PO day 3 after a Fontan operation.

Syndrome myéloprolifératif chez un patient traité pour un myélome multiple en rechute par lénalidomide

Tumor vasculature and tumor-associated neo-angiogenesis have recently become major targets of antineoplastic therapy. Beside the agents which have already obtained US Food and Drug Administration (FDA) approval for clinical use (thalidomide, lenalidomide, bevacizumab, sunitinib, sorafenib), many others are being tested in clinical trials. Angiogenesis inhibitors, in particular inhibitors of the vascular endothelial growth factor (VEGF) pathway, have shown significant vascular complications, including both thromboembolic and bleeding events. The definition of the clinical impact of bleeding complications (increase in the rate of hemorrhages in comparison with the control group) and the knowledge of the pathogenesis of this toxicity are very important in order to evaluate the results of many studies using antiangiogenic agents in the treatment of cancer patients.

Treatment with the Thrombopoietin (TPO)-Receptor Agonist Romiplostim in Thrombocytopenic Patients (Pts) with Low or Intermediate-1 (int-1) Risk Myelodysplastic Syndrome (MDS): Follow-up AML and Survival Results of a Randomized, Double-Blind, Placebo (PBO)-Controlled Study

Treatment with the Thrombopoietin (TPO)-Receptor Agonist Romiplostim in Thrombocytopenic Patients (Pts) with Low or Intermediate-1 (int-1) Risk Myelodysplastic Syndrome (MDS): Follow-up AML and Survival Results of a Randomized, Double-Blind, Placebo (PBO)-Controlled Study

Circuit lifespan during continuous renal replacement therapy for combined liver and kidney failure

PurposeTo evaluate circuit lifespan (CL) and bleeding risk during continuous renal replacement therapy (CRRT), in combined liver and renal failure. MethodsSingle-center retrospective analysis of adults with acute liver failure or decompensated cirrhosis who received CRRT, without anticoagulation or with heparinization in intensive care unit. ResultsSeventy-one patients with 539 CRRT circuits were evaluated. Median overall CL was 9 (6–16) hours. CL was 12 (7-24) hours in 51 patients never anticoagulated for CRRT. In 20 patients who subsequently received heparinization, CL was 7 (5-11) hours without anticoagulation, which did not improve with systemic or regional heparinization (P = .231), despite higher peri-circuit activated partial thromboplastin time (APTT) and heparin dose. Using multivariate linear regression, patients with higher baseline APTT or serum bilirubin, or who were not mechanically ventilated, had longer CL (P < .05). Additionally, peri-circuit thrombocytopenia (P < .0001) or higher international normalized ratio (P < .05) predicted longer CL. Of 71 patients, 33 had significant bleeding events. Using multivariate logistic regression, patients with higher baseline APTT, vasoactive drug use >24 hours, or thrombocytopenia, had more bleeding complications (P < .05). Decreasing platelet counts (especially <50 × 109/mm3) had an incremental effect on CL (P < .0001). ConclusionCRRT CL is short in patients with liver failure despite apparent coagulopathy. Thrombocytopenia predicts longer CL and bleeding complications.

Drug Interactions with Rivaroxaban following Total Joint Replacement Surgery

To evaluate potential drug-drug interactions with rivaroxaban in patients undergoing total hip replacement (THR) and total knee replacement (TKR) surgeries. PubMed; January 2009-April 2012 abstract databases of major congresses for hematology and cardiovascular medicine. Searches were performed using the key words rivaroxaban and drug interaction. Studies were included if they evaluated interactions with drugs that are commonly used in patients undergoing THR or TKR, based on our clinical experience. A Phase 1 study found that coadministration of rivaroxaban and the nonsteroidal antiinflammatory drug (NSAID) naproxen significantly increased bleeding time. However, in a retrospective analysis of 4 large trials evaluating rivaroxaban in patients undergoing THR or TKR, the difference between major and clinically relevant nonmajor bleeding was not significantly different between NSAID users and nonusers. In addition, proton pump inhibitors, which are frequently coadministered with NSAIDs to prevent gastrointestinal toxicity, have not been demonstrated to cause any appreciable changes in rivaroxaban pharmacokinetics or pharmacodynamics. A Phase 2 study that evaluated several doses and administration intervals of rivaroxaban in combination with aspirin or both aspirin and clopidogrel in patients with acute coronary syndrome found that clinically significant bleeding events occurred in patients receiving rivaroxaban 10 mg daily (the dose approved for the orthopedic indication). However, this risk was not great enough to end the trial early. Phase 1 drug-drug interaction studies in healthy humans provided little insight into the pharmacodynamic drug interactions between rivaroxaban and NSAIDs or antiplatelet agents. A pooled analysis of the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism) trials and data from other large trials provides clinical evidence that these agents can be coadministered with rivaroxaban, as long as proper monitoring is instituted.

Lack of clinically significant pharmacological interactions between ticagrelor and enoxaparin or unfractionated heparin in healthy subjects

Patients with acute coronary syndromes (ACS) receive several pharmacological therapies concomitantly, including antiplatelet and anticoagulant agents. As unfractionated heparin (UFH) activates platelets in vitro and in vivo, co-administration with an antiplatelet agent may lead to decreased clinical effectiveness of the latter. The aim was therefore to determine any potential drug-drug interactions between the new oral antiplatelet agent ticagrelor, and UFH or enoxaparin. In two open-label, three-period, crossover trials, healthy subjects were randomized to receive ticagrelor alone or with enoxaparin (study 1) or UFH (study 2), or enoxaparin or UFH alone. Ticagrelor plasma concentrations, inhibition of platelet aggregation (IPA), anti-factor Xa levels, activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) were measured. Thirty and 28 subjects completed studies 1 and 2, respectively. Study drugs were generally well tolerated, with no significant bleeding or serious adverse events. Co-administration with enoxaparin or UFH had no significant effect on ticagrelor pharmacokinetics. The effect of ticagrelor on IPA was unimpaired by co-administration of enoxaparin, except for a marginal (-2.9%; 908.7%.h, 881.9%.h) reduction in final extent area under the effect curve (AUEC)(2-12) (95% CI: -51.6%.h, -2.0%.h). Co-administering UFH with ticagrelor caused small decreases in IPA(max) (-3.8%; 94.6%, 91.0%) and AUEC(2-12) (-6.8%; 888.6%.h, 828.3%.h) vs. ticagrelor alone (95% CI: final extent IPA(max) -5.7%, -1.6%; AUEC(2-12) -109.8%.h, -10.8%.h). Ticagrelor had no clinically significant effects on enoxaparin as assessed by anti-factor Xa (study 1), or UFH as assessed by aPTT or ACT (study 2). Enoxaparin and UFH had no effect on the pharmacokinetics and no clinically significant effect on the pharmacodynamics of ticagrelor. Ticagrelor had no clinically significant effects on the pharmacodynamics of enoxaparin or UFH.

Duration and morbidity of chronic immune thrombocytopenic purpura in children: five‐year follow‐up of a Nordic cohort

To describe the clinical course, morbidity and platelet recovery in an unselected Nordic cohort of children with chronic Immune Thrombocytopenic Purpura (ITP). Prospective 5-year follow-up of 96 children with ITP lasting more than 6 months, with reporting of hospital admissions, severity of bleeding episodes and stabilization of platelet counts above 20, 50 and 150 × 10(9) /L. The estimated 5-year recovery rate was 52%; exclusion of 12 splenectomized children did not change the estimate. Events eliciting admission to hospital occurred in 39 (41%). Major haemorrhages occurred in eight children (8%), including a nonfatal intracranial haemorrhage in one child (1%). The overall admission rate was 0.4/year of thrombocytopenia, decreasing during follow-up as thrombocytopenia converted to milder degrees. Early recovery within 2 years of diagnosis occurred in 35%, was associated with low morbidity and was more likely in young children with abrupt onset of symptoms. In a Nordic cohort of children with chronic ITP, one half had recovered 5 years after diagnosis, more than half never required hospitalization and <10% experienced serious bleeding episodes, always with a platelet count <20 × 10(9) /L. Aggressive management can be restricted to the minority of children with continuing severe thrombocytopenia and frequent, clinically significant bleeding events.

Frequency and impact of bleeding in elective coronary stent clinical trials—Utility of three commonly used definitions

Bleeding events are common after percutaneous coronary intervention (PCI) and have been shown to increase mortality in studies of acute coronary syndrome (ACS) and anti-thrombotic therapy. Despite this evidence, bleeding has not been included as a traditional major endpoint in clinical trials of low-risk populations enrolled in PCI clinical trials. Thus, the impact of specific bleeding definitions has not been evaluated fully among these patients. Using patient-level pooled data from sirolimus and zotarolimus drug-eluting stent clinical trials, we identified bleeding events using three common definitions of bleeding, ACUITY, TIMI, and GUSTO, and assessed the impact on mortality and MI at 12 months after PCI. The GUSTO, ACUITY, and TIMI classifications identified bleeding rates of 2.3%, 1.9%, and 2.1%, respectively. The GUSTO criteria classified all 118 suspected bleeding events. There were 22 (18.6%) and 8 (6.8%) suspected bleeding events that did not meet ACUITY and TIMI criteria, respectively. The combined endpoint of all-cause death or myocardial infarction (MI) at 12 months was significantly higher for patients with a bleeding event compared with those who did not bleed [hazard ratio 1.95 (95% CI 1.06-3.60)]. There is a substantial variability in the utility and inclusiveness of three widely used bleeding definitions in identifying clinically significant bleeding events in clinical trials of low risk patients undergoing PCI with DES. Patients with bleeding after elective PCI have an increased one-year risk of death or MI compared to those patients who do not bleed.

Clopidogrel for Atherothrombotic Event Management in Patients with Peripheral Arterial Disease (COOPER) Study: Safety and Efficacy of Clopidogrel versus Ticlopidine in Japanese Patients.

Peripheral arterial disease (PAD) has been recognized as an independent risk factor for vascular events and contributes to an adverse prognosis. Long-term administration of clopidogrel is recommended to prevent atherothrombotic events for patients with established PAD. We investigated the benefits of clopidogrel treatment in Japanese patients with PAD. COOPER (Clopidogrel for atherOthrombOtic event management in patients with PERipheral arterial disease) was a multicenter, randomized, double-blind study to evaluate the safety and efficacy of clopidogrel (75 mg/day) compared to ticlopidine (200 mg/day) in Japanese patients with PAD. The primary endpoint was the cumulative incidence of "safety events of interest" comprising clinically significant bleeding, blood disorders, hepatic dysfunction and other serious adverse events up to 12 weeks. The other safety events and vascular events were also assessed. Patients were followed up to 52 weeks. A total of 431 patients with PAD were randomly assigned to receive either clopidogrel or ticlopidine. The cumulative incidences of "safety events of interest" at 12 weeks were 2.4% and 13.6% of patients who received clopidogrel and ticlopidine, respectively (adjusted hazard ratio, 0.161; 95% confidence interval, 0.062 to 0.416; p <0.0001). Bleeding and vascular events were similar in both groups. Clopidogrel demonstrated a favorable benefit/risk profile than ticlopidine in Japanese patients with PAD. ( ClinicalTrials.gov, Identifier: NCT00862420).

Update of An Open-Label Extension Study Evaluating the Long-Term Safety and Efficacy of Romiplostim in Thrombocytopenic Patients with Myelodysplastic Syndromes (MDS)

Abstract 2772 Background:Thrombocytopenia, found in 40–65% of MDS patients, is an independent risk factor for survival. Romiplostim increases platelet production, with 46% of MDS patients in a phase 1/2 study having a durable platelet response [Kantarjian JCO 2010, 28:437–444]. MDS patients who completed a romiplostim clinical study could enroll in this open-label extension study. Interim results are reported to provide an update on continued, long-term romiplostim treatment in MDS patients. Methods:MDS patients who completed a prior romiplostim study with platelets ≤50×109/L and no evidence of disease progression were eligible to enroll. Prior studies were as follows: (1) romiplostim only for up to 52 weeks [Kantarjian JCO 2010, 28:437–444], (2) romiplostim or placebo plus decitabine for ≥4 cycles [Greenberg ASH 2009], (3) romiplostim or placebo plus lenalidomide for ≥4 cycles [Lyons ASH 2009], or (4) 58-week placebo-controlled study. The primary endpoint was adverse event incidence; secondary endpoints were bleeding event incidence, platelet transfusions, and platelet response duration. Based on previous dosing, patients received romiplostim at 250, 500, 750, 1000, or 1500 mcg weekly or biweekly, adjusting for platelet counts. If no response was observed after 4 weeks at 1000 mcg/week, treatment was discontinued. Results:As of May 31, 2011, 72 patients had enrolled; previous treatments were romiplostim or placebo (60), romiplostim with decitabine (7), or with lenalidomide (5). Patients (56% male) had median age 71.0 (Q1-Q3: 65.0–76.5) years, median baseline platelet count of 27×109/L (Q1-Q3:14–42×109/L), MDS subtypes: RA (22 patients), RARS (1), RAEB-1 (6), RAEB-2 (1), RCMD (25), RCMD-RS (2), and MDS-U (15), and IPSS status at prior study baseline: low (22), int-1 (44), int-2 (4), and unknown (2). Median duration of MDS (until last contact or AML progression) was 3.1 years (Q1-Q3:1.7–5.2 years). Median treatment duration during this extension study was 28 weeks (range: 2–181 weeks); for those patients who received romiplostim in prior studies, there was additional exposure for a median of 52 weeks (range: 7–74 weeks). The median average weekly dose was 750 mcg (Q1-Q3: 669–923 mcg). Romiplostim was well tolerated; the most common adverse events were epistaxis (32%), cough (25%), and fatigue (24%). No neutralizing antibodies to romiplostim or thrombopoietin were detected. Five cases of AML progression occurred (Table). There were a total of 11 deaths, 4 on-study and 7 post-study. The on-study deaths included cardiac arrest and intestinal obstruction after 83 weeks, congestive heart failure after 17 weeks, progressive muscle dystrophy after 153 weeks, and pulmonary fibrosis in a patient with a history of chronic obstructive pulmonary disease and congestive heart failure after 35 weeks. This last death was considered to be related to romiplostim by the investigator. The post-study deaths included four due to AML, one due to respiratory causes, one due to cerebral hemorrhage, and one due to unknown causes. The annual rate of AML or death was 14.3% (95% CI: 8.1%-25.2%). Fifty-two (72.2%) patients reported ≥1 bleeding event(s); the incidence rate was 23.3/100 patient-weeks; 23 patients (32%) reported ≥1 clinically significant bleeding event(s). The proportion of patients with significant bleeding events decreased over time. Platelet transfusions occurred in 32 (44%) patients, with none after 48 weeks of romiplostim. From Week 3 onwards, the median platelet count was ≥50×109/L; 60 patients (83%) had a platelet response (per IWG 2006). The median time to first platelet response was 2.1 weeks (Q1-Q3: 1.1–3.7 weeks) and the median platelet response duration was 20 weeks (Q1-Q3: 6.5–72 weeks). Shortly after this data cutoff, all patients were discontinued from romiplostim treatment and moved into the long-term observation portion of the study.Table:AML CasesWHOIPSSMDS duration at time of AML progression (years)Total romiplostim exposure (weeks)*RCMDInt-11.942RCMDInt-11.522RAEB-1Int-22.027RAEB-1Int-19.299RAEB-2Low1.780*Prior study and open-label extension combined Conclusion:In this study, long-term treatment of MDS patients with romiplostim for up to 3.5 years (5 years with prior studies) was well tolerated and resulted in platelet responses in 83% of patients. Among patients in this extension study, AML progression occurred at expected rates. [Display omitted] Disclosures:Fenaux:Merck: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Off Label Use: Use of romiplostim, which is indicated for ITP, will be discussed in patients with MDS. Kantarjian:Amgen: Research Funding. Muus:Amgen: Membership on an entity's Board of Directors or advisory committees. Lyons:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Larson:Amgen: Research Funding. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau. Becker:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jia:Amgen: Employment, Equity Ownership. Yang:Amgen: Employment, Equity Ownership.

Health Care Utilization, Risk of Infection and Bleeding Among MDS Patients During Periods of Transfusion Dependency or Independency with or without Active Therapy

Abstract 3149 Introduction:Clinical manifestations of MDS include recurrent infections from neutropenia and bleeding from thrombocytopenia. These events often result in increased healthcare resource utilization (ER visits and hospitalizations) and are associated with disease-related deaths. Understanding the interplay between disease activity, transfusion needs, and medical interventions that can initially worsen baseline cytopenias, may help to improve treatment approaches for MDS patients.This retrospective claims review analyzed the occurrence of infection and significant bleeding (defined as GI, intracranial, and hospitalized bleeds as well as bleeding deaths) related to pre-defined follow-up periods which captured the clinical activity of MDS based on transfusion dependency vs. independency and active therapy Rx (defined as use of lenalidomide, 5-azacitidine, or decitabine). Methods:Claims data from a US national commercial health insurer were retrospectively reviewed to assess the impact of RBC transfusion dependency (TD) on bleeding and infection events. Pts ≥ 18 yrs with ≥ 1 claim for MDS (ICD-9-CM codes 238.72–238.75) between 01 Jan 07 and 31 Dec 09 were assessed using the 1st MDS date as the index date. Continuous enrollment in a commercial or Medicare Advantage plan with a medical and pharmacy benefit for 6 mos before the index date (baseline period) and for a variable period after the index date was required. Pt follow-up was divided according to 4 unique treatment periods: transfusion independent (TI) periods without active therapy termed “watch and wait” (A), TI periods on active therapy (B), (TD) periods on no active therapy (C), TD on active therapy (D). Health care utilization focused on infectious complications and significant bleeding events and was captured within each follow-up period. TD was defined as ≥ to 2 RBC transfusions in 8 weeks and TI as < 2 transfusions in 8 weeks. The number (%) of periods with events is reported. Health care utilization was also calculated as “incidence per person-year” to account for the variable length of the pre-defined periods and to compare results across the follow-up period cohorts. Results:A total of 3, 886 pts with MDS with a mean age of 67.1 years (SD=14.9) represented 4, 007 total follow-up periods. Each patient could account for multiple periods. The follow-up periods (A, B, C, D) appear to predict expected disease activity based on the results of incidence per person-year in each period. For example – the TI periods (A and B) had lower incidence per person-year compared to the TD periods (C and D). Furthermore, within the TI periods, those requiring medical treatment (B) had more events compared to the watch and wait periods (A). Interestingly, the TD periods were not differentiated based on medical intervention and the TI periods with therapy (B) had lower events than either TD periods. Conclusion:This retrospective analysis helps to define the health care utilization patterns of MDS pts based on transfusion requirements and treatment interventions. Periods of TD are associated with higher numbers of medical events compared to TI periods. These data also suggest that periods of TI on therapy had fewer events compared to either TD period and may allay concerns that active therapy could worsen baseline cytopenias. In fact, active therapy plays a role in lowering supportive care requirements and resources utilization for many pts and may also reduce the incidence of MDS-related medical events. Results demonstrate that active therapy should be considered in all eligible TD MDS pts.Periods of Transfusion IndependencePeriods of Transfusion DependenceNo Transfusions & No Rx ‘Watch & Wait' A N=3,028 (%)On Rx B* N=598 (%)No Rx C N=404 (%)On Rx D* N=199 (%)Mean Duration (days)516153416136Infection1561 (52)209 (35)317 (78)94 (47)Significant bleeding775 (26)77 (13)202 (50)54 (27)Inpt hospitalization1120 (37)187 (31)339 (84)107 (54)ER visit1398 (46)195 (33)313 (78)109 (55)Incidence Per Person-years (95% CI Intervals)1.77 (1.45,2.17)Infection0.59 (0.56,0.62)1.05 (0.91,1.20)1.71 (1.53,1.91)Significant bleeding0.22 (0.20,0.24)0.33 (0.27,0.42)0.7 (0.61,0.81)0.85 (0.65,1.11)Inpt hospitalization0.35 (0.33,0.37)0.88 (0.77,1.02)1.96 (1.76,2.18)2.15 (1.78,2.59)ER visit0.47 (0.47,0.52)0.87 (0.87,1.16)1.47 (1.47,1.83)1.77 (1.77,2.58)*ESA utilization was permitted across these time periods. Disclosures:Smith:Celgene: Consultancy; Genzyme: Consultancy; Incyte: Consultancy; Infinity: Consultancy; Merck-Serono: Research Funding; Synta: Research Funding; Celator: Research Funding; Calistoga: Research Funding; BMS: Research Funding; Novartis: Research Funding. Mahmoud:Celgene: Employment. Khan:Celgene: Employment.

Treatment with the Thrombopoietin (TPO)-Receptor Agonist Romiplostim in Thrombocytopenic Patients (Pts) with Low or Intermediate-1 (Int-1) Risk Myelodysplastic Syndrome (MDS): Results of a Randomized, Double-Blind, Placebo(PBO)-Controlled Study

Abstract 117 Background:There are few therapies for thrombocytopenia in MDS, which is found in ∼50% of pts with low/int-1 MDS and is associated with shortened survival. Methods:IPSS low/int-1 MDS pts receiving supportive care, with platelets 1) ≤20×109/L or 2) ≤ 50×109/L with a history of bleeding, were randomized 2:1 to 750 μg romiplostim:PBO for 26 wk with MDS supportive care, and a 4-wk washout followed by bone marrow (BM) biopsy. Pts continued as randomized, with any MDS therapy, for 24 wk with another 4-wk washout followed by a BM biopsy. The 1° endpoint was the number of clinically significant bleeding events (CSBE, grade ≥2 per modified WHO scale); other endpoints included protocol-defined platelet transfusion events (PTE), platelet response per IWG 2006 (HI-P), survival, and safety, including progression to AML, defined conservatively as: 1) ≥20% blasts in the BM or peripheral blood after 4 wk off romiplostim, or 2) pathology consistent with leukemia (eg, chloroma or leukemia cutis), or 3) anti-leukemic treatment initiation. Results:Of 250 pts enrolled (romiplostim 167, PBO 83): 59% were male, median (Q1, Q3) age was 70 (61, 77) year, WHO classes RCMD (68%), RAEB-1 (13%), MDS-U (11%), RA (4.4%), RCMD-RS (2.4%), RARS (0.8%), RAEB-2 (1%), IPSS status low (25%), int-1 (71%), int-2 (0.4%), and IPSS cytogenetics good (78%), intermediate (18%), poor (1.6%). There were more pts who were RAEB-1 (14% vs 11%) and RAEB-2 (1% vs 0%) and fewer who were MDS-U (10% vs 15%) with romiplostim (all NS). Due to DMC concerns regarding the potential for transient increases in blast cell counts and the risk for progression to or treatment for AML, study drug was discontinued in Feb 2011, affecting 28% of pts. Also leading to withdrawal were consent withdrawn (romiplostim 13%, PBO 15%), adverse events (AE) (12%, 5%), and alternative therapy (7%, 11%). The mean number of CSBE/pt was romiplostim 1.47, PBO 1.94 (HR 0.83, 95% CI: 0.66, 1.05, p = 0.13); rates were romiplostim 18.6%, PBO 26.5%. The overall number of bleeding events was reduced with romiplostim (RR 0.92, 95% CI: 0.86, 0.99, p = 0.026). PTE rates/100 pt-year were romiplostim 748.9, PBO 1013.5 (RR 0.77, 95% CI: 0.66, 0.88, p<0.001). HI-P rates were romiplostim 36.5% (61 pts), PBO 3.6% (3 pts) (OR 15.6, 95% CI: 4.7, 51.8, p<0.001). From wk 4 on, median platelets with romiplostim were consistently higher than with PBO (p<0.001). The overall 1-year K-M survival was romiplostim 80%, PBO 78% (HR 1.03, 95% CI: 0.54, 1.95) (Figure 1), with 28 deaths (17%), none (0%) hemorrhagic and 5 (3%) from AML and MDS disease progression, with romiplostim and 14 deaths (17%), including 4 (4.8%) hemorrhagic and 3 (3.6%) from AML and MDS disease progression, with PBO.Median time on romiplostim was 21.5 wk (range: 1, 50). SAE rates were romiplostim 40%, PBO 27%; those frequent (≥5%) SAE occurring ≥2x more with romiplostim were pneumonia, pyrexia, thrombocytopenia, and atrial fibrillation; those occurring ≥2x more with PBO were diarrhea, dyspnea, and cerebral hemorrhage. Peripheral blast increases are described below (Table).TableOn treatmentEnd of studyPeripheral blasts >10%Blasts ↓to ≤10%Persistently elevated blasts confirmedNo follow-up availableRomiplostim25 (15%)14 (8.4%)2 (1.2%)9 (5.4%)PBO3 (3.6%)2 (2.4%)0 (0%)1 (1.2%)AML rates through 58 wk were romiplostim 6.0%, PBO 2.4% (HR 2.51, 95% CI: 0.55, 11.47). Of the 13 AML cases, 9 (69%) were in pts who were initially RAEB-1 and 4 (31%) were diagnosed by anti-leukemic therapy initiation, which could include hypomethylating agents. Of pts who were RAEB-1 at baseline, 2/9 (22%) PBO pts developed AML vs 7/24 (29%) of romiplostim pts. AML-free survival rates were similar (HR 1.13, 95% CI: 0.60, 2.13). Conclusion:Romiplostim treatment in low/int-1 MDS pts resulted in a 15-fold increase in achieving HI-P. Although there were more platelet transfusions with PBO (p <0.001), there still was a trend for more clinically significant bleeding events with PBO (p = 0.13) than romiplostim. The AE profile of romiplostim was generally comparable with PBO, with no hemorrhagic deaths with romiplostim. Increases in peripheral blasts >10% occurred more frequently with romiplostim but generally resolved after romiplostim discontinuation. AML was defined conservatively; cases are pending central pathology review. AML occurred primarily in pts who were initially RAEB-1 and in more pts with romiplostim. Overall and AML-free survival rates were similar. [Display omitted] Disclosures:Giagounidis:Amgen: Consultancy; GlaxoSmithKline: Consultancy. Off Label Use: This trial examined the use of romiplostim, which is indicated for use in ITP, in MDS. Mufti:Celgene: Consultancy, Research Funding. Kantarjian:Amgen: Research Funding. Fenaux:Celgene: Honoraria, Research Funding; Amgen: Honoraria; Roche: Research Funding; Janssen Cilag: Research Funding. Sekeres:Celgene Corp: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kuendgen:Celgene: Honoraria. Platzbecker:Amgen: Honoraria; GSK: Honoraria. Gaidano:Amgen: Honoraria. Jedrzejczak:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hu:Amgen: Employment, Equity Ownership. Yang:Amgen: Employment, Equity Ownership. Jun:Amgen: Employment, Equity Ownership.