Bivalirudin Therapy Research Articles

ROTEM and Bivalirudin: The Confounding Challenges Ahead

Direct thrombin inhibitors directly bind to active sites on thrombin and exert their anticoagulant effect. Bivalirudin is used an alternative in cases of heparin-induced thrombocytopenia, heparin resistance, anaphylactic reaction to UFH, or anti-thrombin III deficiency. Here, we report a case of a 31-year-old female patient, diagnosed with recurrent chronic thromboembolic pulmonary hypertension posted for redo pulmonary thromboendarterectomy. Monitoring anticoagulation during bivalirudin therapy is sometimes confounding and challenging. Prolongation of CT on INTEM and HEPTEM has shown moderate to strong correlation with traditional laboratory tests like aPTT and HPTT (aPTT with Hepzyme). ROTEM can be a way forward for monitoring bivalirudin therapy.

Evaluation of anticoagulation with bivalirudin for heparin-induced thrombocytopenia during extracorporeal membrane oxygenation.

Unfractionated heparin is the most commonly utilized anticoagulant in extracorporeal membrane oxygenation (ECMO) due to clinician familiarity, ease of reversal, and low cost compared to alternative agents. However, heparin's anticoagulant effect can be unpredictable and its use accompanies a risk of heparin induced thrombocytopenia (HIT). Successful use of bivalirudin as an alternative to heparin in non-HIT ECMO patients has previously been described. However, there is a paucity of data regarding its utilization in patients with confirmed HIT on ECMO. This single-center retrospective chart review at Cleveland Clinic Main Campus included 12 ECMO patients who were managed with bivalirudin for a new diagnosis of HIT. Descriptive statistical analyses were performed utilizing median with interquartile range and number with percent as appropriate. Of the 12 patients included, median ECMO duration was 328.5 (218.8-502.1) h and venoarterial ECMO was the most common configuration. No patients experienced the primary outcome of in-circuit thrombosis while on bivalirudin. One patient developed a deep vein thrombosis 22.5 h after switching from heparin to bivalirudin. Major bleeding occurred during bivalirudin therapy in 8 (66.7%) patients. Overall, our study results suggest that bivalirudin is effective for the management of HIT and did not show evidence of in-circuit thrombosis. A high incidence of major bleeding was observed with bivalirudin use within this study. Clinicians should view bivalirudin as an acceptable agent for the treatment of HIT in the ECMO population, but must consider bleeding risk given the lack of effective reversal agents.

Serious Gastrointestinal Complications After Cardiac Surgery and Associated Mortality

Severe gastrointestinal (GI) complications (GICs) after cardiac surgery are associated with poor outcomes. Herein, we characterize the severe forms of GICs and associated risk factors of mortality. We retrospectively analyzed the clinically significant postoperative GICs after cardiac surgical procedures performed at our institution from January 2010 to April 2017. Multivariable analysis was used to identify predictors for in-hospital mortality. Of 29,909 cardiac surgical procedures, GICs occurred in 1037 patients (3.5% incidence), with overall in-hospital mortality of 14% compared with 1.6% in those without GICs. GICs were encountered in older patients with multiple comorbidities who underwent complex prolonged procedures. The most lethal GICs were mesenteric ischemia (n= 104), hepatopancreatobiliary (HPB) dysfunction (n= 139), and GI bleeding (n= 259), with mortality rates of 45%, 27%, and 17%, respectively. In the mesenteric ischemia subset, coronary artery disease (odds ratio [OR], 4.57; P= .002], coronary bypass grafting (OR, 6.50; P= .005), reoperation for bleeding/tamponade (OR, 12.07; P= .01), and vasopressin use (OR, 11.27; P < .001) were predictors of in-hospital mortality. In the HPB complications subset, hepatic complications occurred in 101 patients (73%), pancreatitis in 38 (27%), and biliary disease in 31 (22%). GI bleeding occurred in 20 patients (31%) with HPB dysfunction. In the GI bleeding subset, HPB disease (OR, 10.99; P < .001) and bivalirudin therapy (OR, 12.84; P= .01) were predictors for in-hospital mortality. Although relatively uncommon, severe forms of GICs are associated with high mortality. Early recognition and aggressive treatment are mandatory to improve outcomes.

Use of Bivalirudin in Treatment of Acute Left Ventricular Assist Device Thrombosis: Case Series

Bivalirudin has been used in treatment of left ventricular assist device thrombosis (LVAD) however, outcomes remain unclear. We retrospectively examined 10 patients (21 admissions) admitted for suspected left ventricular assist device (LVAD) thrombosis and were treated with bivalirudin. Diagnosis and treatment response were based on hemolysis markers and LVAD parameters. Overall patients were younger (mean age 48years, 90% males) and heavier (mean BMI 35.2 kg/m2). 9/10 patients had Heartmate II and 1 had HeartWare device. 6 patients had LVAD implant as a bridge to transplant. All patients were on warfarin with mean INR of 2.8±0.8 on presentation. Over the course of hospitalization, in general LDH levels showed a biphasic response peaking between day 3-7 and day 21-25 (Figure). With bivalirudin therapy (median duration 28days), 4 patients were successfully discharged from hospital, 2 died and 4 underwent LVAD exchange. Patients who underwent LVAD exchange had recurrent thrombosis requiring urgent transplant (n=2), repeat LVAD exchange (n=1) or died (n=1). Out of the 4 patients who were discharged initially, 1 required urgent transplant, 1 had LVAD exchange with HM III, 1 died and 1 had repeated thrombosis episodes treated conservatively with bivalirudin. 10/21 (47.6%) hospitalizations were treated successfully with bivalirudin. Recurrent thrombotic episodes generally happened after 3 months (mean 100.54 days). Although bivalirudin therapy was partially successful in treatment of LVAD thrombosis, long term outcomes of these patients without transplantation were poor.

Cost Comparison of Bivalirudin versus Unfractionated Heparin for Children on Left Ventricular Assist Devices

Intravenous unfractionated heparin (UFH) has been the traditional immediate post-operative anticoagulant for pediatric ventricular assist device (VAD) recipients. In recent years, bivalirudin has been increasingly used as an alternative agent and may confer advantages over UFH. However, bivalirudin may be cost-prohibitive, due to the price of the drug. The aim of this study was to compare early post-operative costs for patient cohorts receiving UFH versus bivalirudin. Patients supported on the Berlin EXCOR® at Primary Children's Hospital (PCH) and Lucile Packard Children's Hospital (LPCH) from 01/2016 and 12/2018 were included. Patients treated with bivalirudin were matched by underlying diagnosis and implant weight to patients treated with UFH. The cost of heparin therapy included the cost of Heparin Activity Levels (HAL, Anti-Xas), antithrombin activity levels, and antithrombin drug cost. The cost of bivalirudin therapy included drug cost and cost of activated partial thromboplastin times (aPTTs). Drug pricing was based on average wholesale price. Laboratory costs were based on PCH cost. Cost analysis was based on post-operative day 0 - 14, the time frame of greatest anticoagulant lability. Twelve matched patients were included; 5 cardiomyopathy and 1 congenital heart disease per cohort with similar median implant weights (9 kg UFH vs 12 kg bivalirudin, p = 0.58). For the UFH cohort, median cost per patient day of support was $1,025.07/day; labs comprised 69% of total costs, and drug 31%. Bivalirudin median cost per patient day of support was $740.49/day, with 97% drug cost and 3% lab cost. Cost per patient day of support was not significantly different between the groups (p = 0.38). HALs were obtained a median of 2.1 times per patient day for the UFH cohort, while aPTTs were obtained a median of 4.4 times per patient day in the bivalirudin cohort (p=0.006). Bivalirudin and UFH have similar costs during the first 14 days after Berlin EXCOR® implant, when therapeutic drug monitoring is included, thus illustrating noninferiority of bivalirudin from a cost perspective.

Monitoring bivalirudin therapy in children on extracorporeal circulatory support devices: Thromboelastometry versus routine coagulation testing

IntroductionBivalirudin is an alternative to heparin anticoagulation in infants and children in the setting of extracorporeal life support (ECLS). While activated partial thromboplastin time (aPTT) is widely accepted as the standard test to monitor bivalirudin therapy, the usefulness of thromboelastometry (ROTEM) to monitor bivalirudin infusion in the setting of ECLS is unknown. ObjectiveWe aimed to assess the utility of ROTEM in monitoring hemostasis and bivalirudin effect in children on either extracorporeal membrane oxygenation (ECMO) or ventricular assist devices (VAD) compared to standard plasma based coagulation assays. MethodsA retrospective study of children undergoing bivalirudin infusion for ECMO/VAD support from a tertiary care pediatric hospital (January 2017–June 2018) was performed. ROTEM assays for extrinsic (EXTEM) and intrinsic (INTEM) coagulation pathways, INTEM with heparinase (HEPTEM), fibrin formation (FIBTEM) with measurement of the clotting time (CT) and maximum clot firmness (MCF) were compared to routine hemostasis testing including: aPTT, aPTT Hepzyme (HPTT), prothrombin time (PT), fibrinogen and platelet count. ResultsOne hundred and six blood samples from 18 children were tested. There was a strong positive correlation between HPTT and HEPTEM CT, and moderate correlation between aPTT and INTEM CT. The bivalirudin dose did not correlate with any test, but displayed strong age-dependence, with infants requiring higher doses of bivalirudin to maintain therapeutic targets. Excellent correlation was found between FIBTEM MCF values and fibrinogen, but FIBTEM overestimated fibrinogen level when platelet count was >300 × 109/L. Heparin-like effect was identified in 39% of specimens, and an improved correlation between aPTT and INTEM CT was observed in specimens without heparinoids. ConclusionsIn the setting of bivalirudin therapy, prolongation of CT on INTEM and HEPTEM showed moderate to strong correlation with aPTT and HPTT, and therefore, may provide a good alternative to these assays. In addition, HPTT and HEPTEM CT might be preferable for monitoring bivalirudin in the setting of ECLS due to frequent detection of heparin-like effect.

Bivalirudin Experience in a Heterogeneous Ventricular Assist Device Population

Ventricular assist devices (VADs) are an increasingly common therapy for end-stage heart failure across all ages as a bridge to recovery or transplant and more recently as destination therapy. With increasing experience and difficulties with establishing therapeutic heparin levels, we have begun to explore the effectiveness of direct thrombin inhibitors in this patient population. This is a retrospective review of all long-term VAD patients, both adult and pediatric, who were anticoagulated with bivalirudin between January 2009 and January 2016. The starting dose was 0.3 mg/kg/hr, and dose was titrated for a goal partial thromboplastin time (PTT) of 70-100. There were 14 patients (13 males, 5 ≤18 years) with 17 episodes of bivalirudin therapy. The median age on initiation was 45 years (range, 15 days-67 years) with 10 episodes associated with a HeartWare HVAD, five a HeartMate II, and two with a Berlin Heart EXCOR. The predominant indication of bivalirudin therapy was suspected pump thrombosis (13/17). The median time from VAD insertion to initiation of bivalirudin was 116 days (range, 3-1,870) with the median duration of therapy being 21 days (range, 3-113). In patients with pump thrombosis, the mean baseline lactate dehydrogenase (LDH) was 229 ± 64 U/L, peak 690 ± 380 U/L, and decreased to 330 ± 243 U/L when bivalirudin was stopped. The outcomes following suspected pump thrombosis included: transitioned to warfarin (n = 7), death in two destination therapy patients who did not undergo pump exchange, transplantation (n = 2), and pump exchange (n = 2). A major bleeding complication occurred in only one patient. Our experience highlights the potential use of bivalirudin in a heterogenous VAD population. Although these initial results suggest some potential role for direct thrombin inhibitors for use in long-term VADs, larger prospective studies are required to support these preliminary observations and to determine who may benefit from direct thrombin inhibitors (DTIs) and the side effect profile in this patient population.

Enhanced potency of prasugrel on protease-activated receptors following bivalirudin treatment for PCI as compared to clopidogrel

ACS patients undergoing percutaneous coronary intervention (PCI) when treated with bivalirudin and clopidogrel had increased frequency of early stent thrombosis. 24 patients referred for intervention with planned bivalirudin therapy, not previously treated with a P2Y12 inhibitor and not receiving heparins or αIIbβ3 inhibitors were randomized to treatment with either clopidogrel (600 mg) or prasugrel (60 mg). Platelet aggregation (PA) was measured by light transmission aggregometry (LTA) of platelet-rich plasma in response to ADP, PAR1/PAR4 thrombin receptor agonists and collagen at baseline and at 1, 2, 4 and 16 h following the cessation of bivalirudin infusion. Prasugrel-mediated inhibition of PA was significantly greater than that of clopidogrel at all time points for ADP as well as PAR1. There was an unanticipated, significantly greater protection of PAR4-mediated platelet aggregation only detected with prasugrel and not observed with clopidogrel. We further examined the effect of the hyperreactive PAR4 Thr120 variant in the protease-activated receptor 4 (PAR4), single nucleotide polymorphism (SNP) rs773902 on aggregation protection. The PAR4 protective effect with prasugrel was lost in individuals carrying the PAR4 Thr120 variant, and not in Ala120 homozygote. PAR1, ADP and collagen inhibition was not significantly affected in the hyperreactive PAR4 Thr120 variant. We documented that the P2Y12 ADP receptor-mediated regulation of the strength of the high-affinity conformation of αIIbβ3 as detected by PAC-1 ab, and in control of platelet adhesiveness through Rap1 GTPase protein activation. Importantly, the PAR4 Thr120 variant resulted in the increased rate and magnitude of Rap1 activation. Human platelet PAR4 mediated-activation of αIIbβ3 was phospholipase C beta (PLCβ)-dependent and unlike mouse platelet PI3K-independent. These data identify a PAR4-dependent inhibitory mechanism for the prasugrel-mediated platelet inhibition, not seen with clopidogrel that could explain the reduction in stent thrombosis documented in clinical trials with prasugrel.

Meta-analysis of risk and protective factors for gastrointestinal bleeding after percutaneous coronary intervention.

To quantitatively analyse factors related to gastrointestinal bleeding after percutaneous coronary intervention and provide evidence for the prevention of gastrointestinal bleeding. Cochrane Library, Pubmed, Embase, and Ovid databases were searched from inception to 31 May 2018; case-control and cohort studies published in English were included. The methodological quality of each study was assessed by two independent reviewers using the Newcastle-Ottawa Scale. Meta-analysis was performed using Revman version 5.3. A total of 16 publications yielded data about risk factors. It was found that age older than 70years, age (per 10-year increase), female sex, baseline anaemia, history of smoking, history of using alcohol, history of peptic ulcer disease, chronic renal failure, previous bleeding, shock, congestive heart failure, acute myocardial infarction, prior use of inotropic medications, and prior use of antithrombotic medications were positively associated with gastrointestinal bleeding. Four articles yielded data about protective factors. It was found that proton-pump inhibitor and bivalirudin therapy were negatively associated with gastrointestinal bleeding after percutaneous coronary intervention. This research found risk and protective factors which can assist in effective management of this potentially fatal complication.

Bivalirudin and ECLS

Bivalirudin and ECLS

Bivalirudin for left ventricular assist device thrombosis

Pump thrombosis remains a serious complication of implantable ventricular assist device therapy and is associated with increased risk of morbidity and mortality. Optimal management strategies remain controversial and are guided largely by limited literature and expert opinion. Medical management of pump thrombosis, including the use of direct thrombin inhibitors, has been associated with mixed results. The purpose of this study is to report the outcomes associated with bivalirudin therapy in LVAD patients with suspected pump thrombosis. A single-center, retrospective observational study of 15 patients with suspected pump thrombosis that were all treated with bivalirudin therapy was conducted. The majority of subjects' initial treatment courses were unsuccessful [9/15 (60%)]; however, 6/15 (40%) achieved an initial improvement in serum lactate dehydrogenase (LDH) levels and were stabilized to be successfully discharged from the hospital. Of the subjects discharged, there was a high rate of recurrence of pump thrombosis within 6months [5/6 (83.3%)]. Bivalirudin therapy was not associated with a consistent reduction in LDH among all subjects studied, and clinical responses to therapy appear to be associated with high rates of thrombosis recurrence. This study analyzes the largest cohort to date of LVAD patients with pump thrombosis treated with bivalirudin therapy, and suggests that alternative therapies should be considered in management.

Bivalirudin Medication Use Evaluation and Cost Savings Initiative.

Bivalirudin is a parenteral anticoagulant that elicits its effect through inhibition of both free and clot bound-thrombin. Inhibition of thrombin serves as a unique mechanism for anticoagulation when compared to heparin as thrombin serves as the final common pathway for the intrinsic and extrinsic coagulation cascades. Due to unclear benefit over heparin, concerns regarding reversibility, and most importantly cost its use as a parenteral anticoagulant varies by institution. A recent drug expenditure review within our institution noted a significant increase in the contribution bivalirudin had on the overall drug budget. In an effort to establish the rationale for the cost increase, a medication use evaluation was performed. While it was discovered that 625 out of 1364 days of bivalirudin therapy were potentially avoidable, an equally important discovery was the amount of waste that was associated with bivalirudin therapy. Calculating daily requirements for bivalirudin indicated that 60% of patients required less than 100 mg per day. Within this article, we describe a cost-savings initiative to reduce bivalirudin waste and the resulting cost-avoidance following implementation.

Impact of Bleeding and Bivalirudin Therapy on Mortality Risk in Women Undergoing Percutaneous Coronary Intervention (from the REPLACE-2, ACUITY, and HORIZONS-AMI Trials)

Women have higher bleeding complication and mortality rates after percutaneous coronary interventions (PCI). The contribution of female gender to bleeding and mortality is poorly understood. We evaluated the effect of gender and bleeding on outcomes of patients treated with bivalirudin during PCI by performing a patient-level pooled analysis of 3 randomized controlled trials (the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events, Acute Catheterization and Urgent Intervention Triage strategY, and Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) comparing bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitor (GPI) treatment in patients undergoing PCI. Of 14,784 patients, 7,413 patients received bivalirudin (1,870 women) and 7,371 patients received heparin + GPI (1,910 women). Women had significantly higher 30-day non-coronary artery bypass grafting (CABG)-related major bleeding rates (7.6% vs 3.8%, p <0.0001). After multivariate adjustment, female gender increased the hazard of major bleeding by 80% (hazard ratio 1.80, 95% confidence interval 1.52 to 2.11, p <0.001). Furthermore, women had a higher 1-year mortality rate (3.7% vs 2.7%, p = 0.002) than men; 30-day major bleeding was the strongest independent predictor of 1-year mortality in women (hazard ratio 2.48, 95% confidence interval 1.57 to 3.91, p = 0.001). Bivalirudin therapy in women reduced 30-day non-CABG-related major bleeding (5.6% vs 9.7%, p <0.0001) and 1-year mortality (2.9% vs 4.4%, p = 0.02) compared to standard therapy. In conclusion, in this cohort of patients treated for acute coronary syndrome and ST-segment elevation myocardial infarction, women have a near 2-fold increase in bleeding complications compared to men after PCI. Bleeding complications rather than gender is the strongest independent predictor of 1-year mortality in patients undergoing PCI. Furthermore, we observed a more pronounced clinical benefit in women treated with bivalirudin including a 44% reduction in major bleeding and a significant reduction in mortality rates at 1 year.

Prediction of 1-year mortality and impact of bivalirudin therapy according to level of baseline risk: A patient-level pooled analysis from three randomized trials.

We aimed to construct a predictive model for one-year mortality in patients undergoing invasive coronary evaluation and to examine the impact of bivalirudin on survival according to the level of baseline risk. Compared to heparin plus GP IIb/IIIa inhibitors (HEP/GPI), bivalirudin decreases bleeding complications in a range of clinical presentations. The impact of preprocedural risk assessment on survival and whether this is modified by bivalirudin, has not been investigated in detail. We examined patient-level data from the REPLACE-2, ACUITY, and HORIZONS-AMI trials (n = 18,819) to construct a risk-adjusted mortality model using baseline clinical variables. One-year mortality occurred in 287 patients (3.1%) assigned to bivalirudin and 336 patients (3.6%) assigned to HEP/GPI (HR 0.85; 95% CI, 0.73-1.00; P = 0.048). Using 11 highly significant predictors of mortality, we developed an integer-risk score to classify patients into risk tertiles. High-risk patients had a rate of 1-year mortality over 9-fold greater than low-risk patients. Consequently, the absolute mortality reduction attributed to bivalirudin was more marked in high-risk patients: 3.1% (-0.8% to 7.0%) in the overall cohort, 4.8% (0.5% to 9.2%) in the PCI cohort (P-interaction versus intermediate and low risk categories, 0.09 and P = 0.02, respectively). In patients undergoing invasive coronary evaluation, 1-year mortality can be predicted using baseline variables. Bivalirudin treatment (versus HEP/GPI) conferred a survival benefit.

A systematic review on the role of bivalirudin in patients undergoing percutaneous coronary interventions: primus inter pares or a falling star?

Intracoronary thrombosis triggered by ruptured or eroded atherosclerotic plaques constitutes the predominant underlying cause of acute coronary syndromes (ACS). Thrombin is considered a central enzyme in hemostasis and thrombosis, and a well-established target for anticoagulant therapies. Bivalirudin was introduced in the clinical practice as a promising, reversible, direct thrombin inhibitor with a predictable anticoagulant effect. Initial randomized clinical trials demonstrated that bivalirudin compared with heparin on top of a glycoprotein IIb/IIIa inhibitor was associated with a significant reduction of major bleeding and favorable net clinical outcomes in patients undergoing percutaneous coronary interventions (PCI). The HORIZON-AMI trial even indicated mortality benefit in bivalirudin-treated patients. Thereby, the 2011 and 2012 European Society of Cardiology Guidelines on the management of non-ST-segment elevation ACS and ST-segment elevation myocardial infarction positioned bivalirudin as the anticoagulant of choice in the PCI setting. Further randomized studies, better reflecting routine clinical practice, revealed significantly increased rates of stent thrombosis and myocardial infarction in the bivalirudin arm. Additionally, these findings were corroborated in the subsequent meta-analyses. Speculations that excessive occurrence of stent thrombosis and myocardial infarction may be caused by too short duration of post PCI bivalirudin infusion did not find confirmation in the latest MATRIX trial. In this systematic review, we aim to assess the efficacy and safety of bivalirudin therapy in patients undergoing PCI and to formulate recommendations on the bivalirudin use for clinicians. In our opinion, the research evidence and pharmacoeconomic considerations strongly support the use of bivalirudin in PCI patients at high risk of bleeding complications, while in other situations old and inexpensive UFH or enoxaparin remain the first line antithrombotic drugs.

What is the best anticoagulant therapy during primary percutaneous coronary intervention for acute myocardial infarction?

Both ST-segment elevation myocardial infarction and percutaneous coronary intervention (PCI) are associated with a highly prothrombotic state, and thrombin plays a critical role during occlusive clot generation and subsequent occurrence of an ischemic event. Therefore, a strategy of anticoagulation plus dual antiplatelet therapy has been regarded as de facto standard therapy during primary PCI (pPCI). Recently, there has been great controversy surrounding the role of bivalirudin versus unfractionated heparin in pPCI. Earlier, the results of the HORIZONS-AMI trial, particularly those regarding the long-lasting mortality benefit, provided a strong rationale for recommending bivalirudin therapy in pPCI. However, the mortality benefit of bivalirudin observed in HORIZONS-AMI has not been repeated in more contemporary studies or demonstrated in recent meta-analyses. The current report will provide a concise review of the controversy surrounding the optimal anticoagulant therapy for pPCI. Recent evidence suggests that unfractionated heparin deserves strong reconsideration despite the reports of pharmacologic weaknesses, particularly when used with a strategy of selective glycoprotein IIb/IIIa therapy, and it appears that a strategy of bivalirudin therapy in pPCI should be reserved for patients at high bleeding risk.

Bivalirudin Use in the Elderly for Acute Coronary Syndrome

ABSTRACT Introduction: Bivalirudin has been approved for use in acute coronary syndromes as part of the anticoagulation regimen. Elderly patients are at a higher risk for bleeding because of their co morbidities, decreased body mass and their age. Hence, this article reviews the landmark published papers on bivalirudin therapy in this patient population with the goal of understanding the particular benefits and risks. Discussion: Several review articles suggest that the use of bivalirudin alone is associated with lower rates of major bleeding when compared with unfractionated heparin plus glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndrome with invasive strategy planned. These beneficial effects span through the age ranges. Therefore, it is a good option for elderly patients. Decreased bleeding complications lead to better clinical outcomes in the elderly after percutaneous coronary intervention. It also leads to decreased length of stay in the hospital. Keywords: Anticoagulants; elderly; acute coronary syndrome; ST elevation myocardial infarction.

Clot-targeted micellar formulation improves anticoagulation efficacy of bivalirudin.

Application of anticoagulants remains the primary strategy for prevention and treatment of thrombosis. However, high rate of bleeding complications limits their use. The peptide anticoagulant bivalirudin has been reported to exhibit a lower rate of bleeding complications than heparin, and it also has the advantage of not causing thrombocytopenia, which is a problem with heparin. Nonetheless, hemorrhage is the most common complication of bivalirudin therapy, and there is no effective antidote. Here we use a thrombus-binding peptide, CR(NMe)EKA, to accomplish selective delivery of the bivalirudin-carrying micellar nanocarrier to sites of thrombosis. Bivalirudin and CR(NMe)EKA, each with a PEG-lipid tail, spontaneously assembled into 30 nm micelles, which almost completely retained the anticoagulant activity of bivalirudin. The micellar formulations exhibited high stability both in vitro and in vivo. In a thromboplastin-induced mouse thrombosis model, the targeted micelles accumulated in lung thrombi 10-fold more than nontargeted micelles. Moreover, the micellar formulation significantly prolonged the half-life and thereby increased the bioavailability of bivalirudin. The micellar bivalirudin had significantly higher anticoagulant activity than free bivalirudin in both the lung thrombosis model and a ferric chloride-induced carotid artery thrombosis model. The specific targeting of thrombi demonstrated here makes it possible to increase the efficacy of bivalirudin as an anticoagulant. Alternatively, the dose could be reduced without loss of efficacy to lower the systemic exposure and improve safety.

Impact of Major Bleeding on Long-Term Mortality in Anemic Versus Nonanemic Patients Undergoing Percutaneous Coronary Intervention Using Bivalirudin

Bleeding complications after percutaneous coronary intervention (PCI) have been associated with higher short and long-term mortality. Bivalirudin has been shown to reduce bleeding complications in patients who underwent PCI; however, the impact of anemia on bleeding complications and long-term mortality has not been studied. A total of 11,991 patients who underwent PCI over a period of 8years with bivalirudin as the primary antithrombotic agent were included. Anemia was defined according to the World Health Organization definition. Bleeding complications were prospectively collected. Survival analysis was performed using multivariable Cox proportional hazards models. Of the 11,991 patients, 4,815 patients (40%) had baseline anemia. Major bleeding occurred in 3.3% of patients with anemia compared with 0.7% of patients without anemia (p <0.001) driven largely by transfusion events. In the overall study population, major bleeding was a significant predictor of mortality (hazard ratio [HR] 1.4, 95% confidence interval [CI] 1.04 to 1.8, p= 0.027) at a mean follow-up of 2.6years (interquartile range 1.4 to 3.5). In patients with anemia, major bleeding remained an independent predictor of mortality (HR 1.5, 95% CI 1.1 to 2.0, p= 0.008); however, in patients without anemia, it did not (HR 1.25, 95% CI 0.52 to 3.03, p= 0.62). In patients who underwent PCI with bivalirudin therapy, major bleeding is associated with early and long-term mortality, which is more pronounced in patients with baseline anemia.

Bivalirudin or heparin in primary angioplasty performed through the transradial approach: results from a multicentre registry

Data on the effect of bivalirudin therapy in primary percutaneous coronary interventions (PCI) performed through the transradial approach are limited. The aim of our study was to evaluate bleeding complications and clinical outcomes in primary PCI performed through the transradial approach with bivalirudin therapy. We retrospectively evaluated primary PCI performed through the transradial approach from January 2008 to June 2013. Patients were divided in two groups according to the use (group 1) or not (group 2) of bivalirudin. The primary end points were major bleedings and major adverse cardiac events (MACE) within 30 days. During the 5 years analysed, 1009 patients underwent primary PCI through the transradial approach: 154 patients were treated with bivalirudin (males 79%, age 65 ± 14 years) and 855 with heparin (males 82%, 63 ± 12 years). In group 1, the use of glycoprotein IIb/IIIa inhibitors was only 4%, compared to 55% (p<0.001) in group 2. There were no significant differences between the two groups for major bleedings (0.65% in group 1 and 1.17% in group 2, p=0.88) nor for minor bleedings (1.3% in group 1 and 1.5% in group 2, p=0.83). There were also no significant differences in MACE (7.1% in group 1 and 10.4% in group 2, p=0.27). The 30-day mortality rate was 3.9% in group 1 and 5.4% in group 2 (p=0.56). In this registry of primary PCI performed through the transradial approach, bivalirudin was not associated with a significant reduction in major bleeding or MACE compared to heparin and provisional glycoprotein IIb/IIIa inhibitors.