SSRI/SNRI Therapy is Associated With a Higher Risk of Gastrointestinal Bleeding in LVAD Patients.

BACKGROUND: Gastrointestinal bleeding (GIB) is common in left ventricular assist device (LVAD) patients. Serotonin release from platelets promotes platelet aggregation, and selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) therapy inhibits the transporter responsible for re-uptake. METHODS: We reviewed the records of LVAD (HeartMateII™, Abbott Medical, Lake Bluff, IL, USA and Heartware™, Medtronic, Minneapolis, MN, USA) patients at the Medical University of South Carolina and Johns Hopkins Hospital between January 2009 and January 2016. After exclusions, 248 patients were included for analysis. After univariate analysis, logistic regression multivariate analysis was performed to adjust for any demographic, cardiovascular, and laboratory data variables found to be associated with GI bleeding post-LVAD. RESULTS: Gastrointestinal bleeding occurred in 85 patients (35%) with 55% of GIBs due to arteriovenous malformations (AVMs). Of the total cohort, 105 patients received an SSRI or SNRI during LVAD support. Forty-four (44) SSRI/SNRI (41.9%) and 41 non-SSRI/SNRI (28.7%) patients had a GIB (RR 1.46, p = 0.03). Twenty-six (26) (24.8%) of the SSRI/SNRI patients had a GIB due to AVMs versus 21 (14.7%) of the non-SSRI/SNRI patients (RR 1.69, p = 0.05). In fully-adjusted multivariate regression analysis, SSRI/SNRI therapy was independently associated with GIB (OR 1.78, p = 0.045). For GIB, the number needed to harm (NNH) was 7.6. CONCLUSION: In conclusion, SSRI/SNRI therapy is independently associated with an increased risk of GIB in LVAD patients.

Evaluation of anticoagulation and nonsurgical major bleeding in recipients of continuous-flow left ventricular assist devices.

Continuous-flow left ventricular assist device (LVAD) placement has become a standard of care in advanced heart failure treatment. Bleeding is the most frequently reported adverse event after LVAD implantation and may be increased by antithrombotic agents used for prevention of pump thrombosis. This retrospective cohort included 85 adult patients implanted with a Heartmate II LVAD. Major bleeding was defined as occurring >7 days after implant and included intracranial hemorrhage, events requiring 2 units of packed red blood cells within a 24-h period, and death from bleeding. Primary outcome was intensity of anticoagulation between patients with or without at least one incidence of nonsurgical major bleeding. Major bleeding occurred in 35 (41%) patients with 0.48 events per patient year and a median (IQR) time to first bleed of 134.5 (39.3, 368.5) days. The median (IQR) INR at time of bleed was 1.7 (1.4, 2.5). Median INR during follow-up did not differ between groups and patients with major bleeding were not more likely to have a supra-therapeutic INR. Patients who bled were more likely to have received LVAD for destination therapy, to have lower weight, worse renal function, and lower hemoglobin at baseline. Duration of LVAD support and survival were similar between groups with no difference in occurrence of thrombosis. Incidence of nonsurgical major bleeding was not significantly associated with degree of anticoagulation. Certain baseline characteristics may be more important than anticoagulation intensity to identify patients at risk for bleeding after LVAD implant. Modification of anticoagulation alone is not a sufficient management strategy and early intervention may be required to mitigate bleeding impact.

The effect of ultrafiltration with cardiopulmonary bypass on the removal of dabigatran from the circulation of adult pigs.

OBJECTIVE: Dabigatran etexilate is a direct thrombin inhibitor approved for use in patients with non-valvular atrial fibrillation. There is no currently available pharmacological therapy to reverse this renally cleared anticoagulant. Dabigatran has a low level of plasma protein binding and has been considered dialyzable. We used a pig model with renal artery ligation to exclude intrinsic drug excretion to examine the efficacy of ultrafiltration (UF) during cardiopulmonary bypass (CPB) for dabigatran removal. METHOD: Dabigatran was intravenously infused (20 mg) in Yorkshire pigs (male, n=7, 70±1 kg) following renal artery ligation. CPB with UF was initiated after heparinization and continued until a total volume of 6 liters of UF effluent was removed. Serial labs, including dabigatran concentration, activated coagulation times (ACT), hematocrit and creatinine were drawn at intervals before the start of CPB and then incrementally during UF (0, 2, 4 and 6 L removed). Hemodialysis (HD) was performed on one animal following UF. RESULTS: Dabigatran concentration (ng/mL) rose from undetectable levels at baseline to 296±70 (p<0.05) at the conclusion of infusion, but dropped significantly upon administration of heparin (178±40, p<0.05). A further decrement in dabigatran concentration was observed from the administration of heparin to the start of CPB (to 135±28, p<0.05). Once on CPB, dabigatran remained stable, with the end UF (eUF) dabigatran concentration being 133±34. Dabigatran concentration in the UF effluent was measured in one animal and was 98.8, with 6 L of effluent having been removed. The total recovery of dabigatran was calculated to be less than 5%. Dabigatran concentrations also did not decrease appreciably with HD on CPB following UF. CONCLUSIONS: UF in conjunction with CPB was ineffective at removing dabigatran. Heparin demonstrated a dabigatran-lowering effect, suggesting a possible drug interaction or assay impairment. Based on these findings, emergent cardiac surgery with UF on cardiopulmonary bypass to remove dabigatran is not advisable. Alternative forms of drug removal or reversal must be identified.

Early postoperative outcomes and blood product utilization in adult cardiac surgery: the post-aprotinin era.

BACKGROUND: Aprotinin was a commonly used pharmacological agent for homeostasis in cardiac surgery but was discontinued, resulting in the extensive use of lysine analogues. This study tested the hypothesis that early postoperative adverse events and blood product utilization would affected in this post-aprotinin era. METHODS AND RESULTS: Adult patients (n=781) undergoing coronary artery bypass, valve replacement, or both from November 1, 2005, to October 31, 2008, at a single institution were included. Multiple logistic regression modeling and propensity scoring were performed on 29 preoperative and intraoperative variables in patients receiving aprotinin (n=325) or lysine analogues (n=456). The propensity-adjusted relative risk (RR) for the intraoperative use of packed red blood cells (RR, 0.75; 95% confidence interval [CI], 0.57 to 0.99), fresh frozen plasma (RR, 0.37; 95% CI, 0.21 to 0.64), and cryoprecipitate (RR:0.06; 95% CI, 0.02 to 0.22) were lower in the aprotinin versus lysine analog group (all P<0.05). The risk for mortality (RR, 0.53; 95% CI, 0.16 to 1.79) and neurological events (RR, 0.87; 95% CI, 0.35 to 2.18) remained similar between groups, whereas a trend for reduced risk for renal dysfunction was observed in the aprotinin group. CONCLUSIONS: In the post-aprotinin era, with the exclusive use of lysine analogues, the relative risk of early postoperative outcomes such as mortality and renal dysfunction have not improved, but the risk for the intraoperative use of blood products has increased. Thus, improvements in early postoperative outcomes have not been realized with the discontinued use of aprotinin, but rather increased blood product use has occurred with the attendant costs and risks inherent with this strategy.

Unfractionated and Low-Molecular-Weight Heparin for Bridging Patients with Left Ventricular Assist Device: An Event-Based Analysis.

The relative efficacy of bridging with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) in left ventricular assist device (LVAD) patients has not been established. We performed a retrospective, longitudinal cohort study to evaluate safety and efficacy of bridging strategies including all adult LVAD patients implanted at the Medical University of South Carolina from August 2014 to July 2017. In addition to LMWH and UFH exposure, we recorded any time period a patient did not receive a bridging agent for a subtherapeutic international normalized ratio (INR) value as a control group; these events were defined as nonbridging (NB) events. Multivariable Cox regression survival models were utilized for analysis. There were 563 episodes evaluated in 50 patients. Compared with NB events, UFH (adjusted hazard ratio [aHR], 3.75; 95% CI, 1.45-9.73; p = 0.007) and LMWH (aHR, 2.25; 95% CI, 1.03-4.94; p = 0.043) were both associated with an increased risk of bleeding. Compared with NB events, LMWH was not associated with a decreased risk of clotting events (aHR, 1.56; 95% CI, 0.28-8.73; p = 0.616). In the 381 NB events, a nonsignificant signal was noted toward increased risk of thrombotic events in those with an INR ≤ 1.5 (aHR, 2.99; 95% CI, 0.57-15.8; p = 0.2). Among all 563 episodes, those with a baseline INR ≥ 2.0 demonstrated an increased risk of bleeding events (aHR, 2.35; 95% CI, 1.18-5.69; p = 0.016). Our data suggest that the efficacy of LMWH bridging in LVAD patients warrants further investigation.

Effect of Angiotensin II Inhibitors on Gastrointestinal Bleeding in Patients With Left Ventricular Assist Devices.

BACKGROUND: Angiotensin II receptor activation may result in angiogenesis, and ultimately arteriovenous malformations (AVM), through transforming growth factor (TGF)-ß and angiopoietin-2 pathway activation. OBJECTIVES: The goal of this study was to determine whether angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) were associated with lower risk of major gastrointestinal bleeds (GIB) and AVM-related GIBs in continuous-flow left ventricular assist device (CF-LVAD) patients. METHODS: The authors reviewed HeartMate II CF-LVAD recipients between January 2009 and July 2016. Major GIBs were endoscopically confirmed requiring ≥2 U of packed red blood cells or resulting in death. ACE inhibitor/ARB dose was abstracted from medical records. ACE inhibitor/ARB exposure status was landmarked at 30 days post-operatively to avoid immortal time bias. Fine and Gray hazard models assessed the impact of ACE inhibitor/ARB therapy on major GIB and AVM-related GIB, whereas standard Cox regression assessed the impact on mortality, adjusting for baseline variables. RESULTS: One-hundred and eleven patients were included with a mean 2.1 ± 1.4 years follow-up. Patients who received an ACE inhibitor/ARB within 30 days post-operatively had a 57% reduction in the risk of major GIB (adjusted hazard ratio [aHR]: 0.43; 95% confidence interval [CI]: 0.19 to 0.97; p = 0.042) and a 63% reduction in the risk of AVM-related GIB (aHR: 0.37; 95% CI: 0.16 to 0.84; p = 0.017). When the mean daily post-operative lisinopril-equivalent ACE inhibitor/ARB dose was >5 mg, the risk of major GIB decreased in a dose-threshold manner (aHR: 0.28; 95% CI: 0.09 to 0.85; p = 0.025). CONCLUSIONS: ACE inhibitor/ARB therapy is associated with a protective effect of developing GIBs in CF-LVAD patients, with a dose threshold of >5 mg of daily lisinopril equivalence, possibly due to prevention of AVM formation.

Assessment of Bleeding and Thrombosis Based on Aspirin Responsiveness after Continuous-Flow Left Ventricular Assist Device Placement.

Pump thrombosis (PT) is a severe complication of left ventricular assist device (LVAD) support. This study evaluated PT and bleeding after LVAD placement in patients responsive to a standard aspirin dose of 81 mg using platelet inhibition monitoring compared with initial nonresponders who were then titrated upward to achieve therapeutic response. Patients ≥ 18 years of age with initial placement of HeartMate II LVAD at our institution and at least one VerifyNow Aspirin test performed during initial hospitalization were included. The primary endpoints were bleeding and PT compared between initial aspirin responders and nonresponders. Of 85 patients, 19 (22%) were nonresponsive to initial aspirin therapy. Responders and nonresponders showed similar survival (p = 0.082), freedom from suspected/confirmed PT (p = 0.941), confirmed PT (p = 0.273), bleeding (p = 0.401), and incidence rates in PT and bleeding. Among the initial responders (<500 vs. 500-549 aspirin reaction units), there were no significant differences in survival (p = 0.177), freedom from suspected/confirmed PT (p = 0.542), confirmed PT (p = 0.159), bleeding (p = 0.879), and incidence of PT and bleeding. Platelet function testing may detect resistance to standard aspirin regimens used in LVAD patients. Dose escalation in initially nonresponsive patients to achieve responsiveness may confer a similar PT risk to patients initially responsive to standard aspirin dosing without increased bleeding risk.

Is platelet function as measured by Thrombelastograph monitoring in whole blood affected by platelet inhibitors?

Platelet inhibitors, especially the glycoprotein (GP) IIb/IIIa receptor antagonists, have demonstrated their effectiveness in reducing the acute ischemic complications of percutaneous coronary intervention (PCI) and in improving clinical outcomes in patients with acute coronary crisis. Three common platelet inhibitors observed in emergent cardiopulmonary bypass (CPB) for failed PCI are abciximab, eptifibatide, and tirofiban. An in vitro model was constructed in two parts to determine whether platelet aggregation inhibition induced by platelet inhibitors would be demonstrated by the Thrombelastograph (TEG) monitor when compared with baseline samples with no platelet inhibitor. In part A, 20 mL of fresh whole blood was divided into four groups: group I = baseline, group A = abcix-imab microg/mL, group E = eptifibatide ng/mL, and group T = tirofiban ng/mL. Platelet inhibitor concentrations in whole blood were derived starting with reported serum concentrations with escalation to achieve 80% platelet inhibition using the Medtronic hemoSTATUS and/or Lumi-aggregometer. A concentration range determined by our in vitro tests were chosen for each drug using concentrations achieving less than, equal to, or greater than 80% platelet inhibition. In part B, TEG analysis was then performed using baseline and concentrations for each drug derived in part A. Parameters measured were clot formation reaction time (R), coagulation time (K), maximum amplitude (MA) and alpha angle (A). Groups E1000 and E2000 extended R over control by 37% and 23%, respectively (p = 0.01 and 0.03). Groups E1000 and E2000 increased K times by 45% and 58% (p = .02 and .04). T160 samples prolonged K by 20% (p = 0.01). The angle or clot strength (A) was decreased in groups T160 and E1000 by 23% (+ 7.06 SD) and 18% (+ 11.23 SD), respectively (p = 0.001 and 0.01). The MA decrease was statistically significant in the T160, E1000 and E2000 by 9%, 6% and 13% respectively (p = 0.01). Samples treated with abciximab were comparable to control values for all parameters measured. Although statistical significance could be demonstrated with some parameters, sensitivity was only observed at increased doses and was not seen with all agents tested. In our in vitro model, the TEG monitor was unable to demonstrate clinically significant differences in platelet function and may not be reflective of platelet function in samples which have been treated with these GP IIb/IIIa inhibitors.

Developing an Anti-Xa-Based Anticoagulation Protocol for Patients with Percutaneous Ventricular Assist Devices.

Because of the complexities associated with anticoagulation in temporary percutaneous ventricular assist device (pVAD) recipients, a lack of standardization exists in their management. This retrospective analysis evaluates current anticoagulation practices at a single center with the aim of identifying an optimal anticoagulation strategy and protocol. Patients were divided into two cohorts based on pVAD implanted (CentriMag (Thoratec; Pleasanton, CA) / TandemHeart (CardiacAssist; Pittsburgh, PA) or Impella (Abiomed, Danvers, MA)), with each group individually analyzed for bleeding and thrombotic complications. Patients in the CentriMag/TandemHeart cohort were subdivided based on the anticoagulation monitoring strategy (activated partial thromboplastin time (aPTT) or antifactor Xa unfractionated heparin (anti-Xa) values). In the CentriMag/TandemHeart cohort, there were five patients with anticoagulation titrated based on anti-Xa values; one patient developed a device thrombosis and a major bleed, whereas another patient experienced major bleeding. Eight patients received an Impella pVAD. Seven total major bleeds in three patients and no thrombotic events were detected. Based on distinct differences between the devices, anti-Xa values, and outcomes, two protocols were created to guide anticoagulation adjustments. However, anticoagulation in patients who require pVAD support is complex with constantly evolving anticoagulation goals. The ideal level of anticoagulation should be individually determined using several coagulation laboratory parameters in concert with hemodynamic changes in the patient's clinical status, the device, and the device cannulation.

Systemic-to-pulmonary artery shunt thrombosis in a neonate with factor V Leiden mutation.

We present the case of a newborn male with D-transposition of the great arteries, ventricular septal defect, and subpulmonary stenosis who experienced two episodes of systemic-to-pulmonary artery shunt thrombosis. Hematologic evaluation revealed heterozygous factor V Leiden mutation. This report emphasizes the importance of evaluation for inherited coagulation disorders in pediatric patients with unexpected thrombotic complications.

Tackling the devastating effects of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia with associated thrombosis is a potentially catastrophic complication of heparin therapy. Heart failure patients often require heparin therapy in the setting of multiple comorbidities, particularly renal insufficiency. The authors report a case of heparin-induced thrombocytopenia with associated thrombosis in a patient with multisystem organ failure and discuss dosing regimens using lepirudin for the treatment of this disorder. The potential risk for excessive anticoagulation is highlighted and a conservative dosing strategy with frequent monitoring of this agent in the presence of renal failure is emphasized.

Safety and effectiveness outcomes of an inpatient collaborative drug therapy management service for direct thrombin inhibitors.

PURPOSE: The impact of a collaborative drug therapy management (CDTM) agreement enabling pharmacist-managed direct thrombin inhibitor (DTI) therapy was evaluated. METHODS: A retrospective chart review was conducted to compare selected outcome measures between cohorts of adults who received argatroban or bivalirudin therapy for suspected heparin-induced thrombocytopenia (HIT) before (n = 25) and after (n = 25) the implementation of an institutional DTI protocol under which properly trained and credentialed pharmacists have a primary role in dosing and monitoring DTI infusions. The primary endpoints were the mean time to attainment of activated partial thromboplastin time (aPTT) values in a specified therapeutic range and the proportion of total inpatient treatment time during which aPTT values were in that range. Secondary endpoints included the incidence of major and minor bleeding and the incidence of medication errors. RESULTS: After implementation of the DTI protocol, therapeutic aPTT values were achieved more rapidly (a mean of 3.4 hours in the postimplementation cohort versus a mean of 7.7 hours in the preimplementation cohort, p = 0.009) and maintained more consistently. Rates of bleeding and overall mortality were similar in the two groups; the frequencies of documented medication errors were 12% and 40% in the postimplementation and preimplementation cohorts, respectively (p = 0.05). CONCLUSION: A pharmacist-driven DTI program resulted in improved effectiveness and safety outcomes, as demonstrated by improved attainment of target aPTT values and a decreased frequency of medication errors.

Differential effects of aprotinin and tranexamic acid on outcomes and cytokine profiles in neonates undergoing cardiac surgery.

OBJECTIVE: Factors contributing to postoperative complications include blood loss and a heightened inflammatory response. The objective of this study was to test the hypothesis that aprotinin would decrease perioperative blood product use, reduce biomarkers of inflammation, and result in improved clinical outcome parameters in neonates undergoing cardiac operations. METHODS: This was a secondary retrospective analysis of a clinical trial whereby neonates undergoing cardiac surgery received either aprotinin (n = 34; before May 2008) or tranexamic acid (n = 42; after May 2008). Perioperative blood product use, clinical course, and measurements of cytokines were compared. RESULTS: Use of perioperative red blood cells, cryoprecipitate, and platelets was reduced in neonates receiving aprotinin compared with tranexamic acid (P < .05). Recombinant activated factor VII use (2/34 [6%] vs 18/42 [43%]; P < .001), delayed sternal closure (12/34 [35%] vs 26/42 [62%]; P = .02), and inotropic requirements at 24 and 36 hours (P < .05) were also reduced in the aprotinin group. Median duration of mechanical ventilation was reduced compared with tranexamic acid: 2.9 days (interquartile range: 1.7-5.1 days) versus 4.2 days (2.9-5.2 days), P = .04. Production of tumor necrosis factor and interleukin-2 activation were attenuated in the aprotinin group at 24 hours postoperatively. No differential effects on renal function were seen between agents. CONCLUSIONS: Aprotinin, compared with tranexamic acid, was associated with reduced perioperative blood product use, improved early indices of postoperative recovery, and attenuated indices of cytokine activation, without early adverse effects. These findings suggest that aprotinin may have unique effects in the context of neonatal cardiac surgery and challenge contentions that antifibrinolytics are equivalent with respect to early postoperative outcomes.

Administration of recombinant activated factor VII in the intensive care unit after complex cardiovascular surgery: clinical and economic outcomes.

OBJECTIVE: Refractory bleeding after complex cardiovascular surgery often leads to increased length of stay, cost, morbidity, and mortality. Recombinant activated factor VII administered in the intensive care unit can reduce bleeding, transfusion, and surgical re-exploration. We retrospectively compared factor VII administration in the intensive care unit with reoperation for refractory bleeding after complex cardiovascular surgery. METHODS: From 1501 patients who underwent cardiovascular procedures between December 2003 and September 2007, 415 high-risk patients were identified. From this cohort, 24 patients were divided into 2 groups based on whether they either received factor VII in the intensive care unit (n = 12) or underwent reoperation (n = 12) for refractory bleeding. Preoperative and postoperative data were collected to compare efficacy, safety, and economic outcomes. RESULTS: In-hospital survival for both groups was 100%. Factor VII was comparable with reoperation in achieving hemostasis, with both groups demonstrating decreases in chest tube output and need for blood products. Freedom from reoperation was achieved in 75% of patients receiving factor VII, whereas reoperation was effective in achieving hemostasis alone in 83.3% of patients. Prothrombin time, international normalized ratio, and median operating room time were significantly less (P < .05) in patients who received factor VII. Both groups had no statistically significant differences in other efficacy, safety, or economic outcomes. CONCLUSIONS: Factor VII administration in the intensive care unit appears comparable with reoperation for refractory bleeding after complex cardiovascular surgical procedures and might represent an alternative to reoperation in selected patients. Future prospective, randomized controlled trials might further define its role.

Use of bivalirudin to prevent thrombosis following orthotopic liver transplantation in a patient with Budd-Chiari syndrome and a history of heparin-induced thrombocytopenia.

Type II heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome that may arise in a time-dependent manner following heparin therapy, placing patients at significant risk for thromboembolic events. Therapy includes anticoagulation with a direct thrombin inhibitor and avoidance of heparin. We report a patient with Budd-Chiari syndrome and a history of heparin-induced thrombocytopenia who presented for orthotopic liver transplant and required postoperative anticoagulation with bivalirudin. During the post-transplant graft function improvement, we observed a significant dose-effect alteration manifested by an increased bivalirudin dose requirement as factor V activity increased. This observation is an important consideration in the attempt to maintain an optimal balance between effective anticoagulation and a reduced risk of postoperative bleeding.

Use of recombinant activated factor VII concentrate to control postoperative hemorrhage in complex cardiovascular surgery.

BACKGROUND: Complex cardiovascular surgery often results in postoperative hemorrhage. Excessive blood product use may cause systemic thrombosis, end-organ dysfunction, and edema preventing chest closure. Recombinant activated factor VII (rFVIIa) concentrate may decrease hemorrhage where other treatment measures failed. We reviewed our experience with rFVIIa after complex cardiovascular surgery. METHODS: A retrospective review evaluating 846 complex cardiovascular surgery patients of whom 36 received rFVIIa between January 1, 2001, and December 31, 2006, was performed. Efficacy and safety data were collected for the entire cohort in addition to delayed sternal closure requirements, reoperation, and operative mortality in the patient cohort temporally separated into two groups (pre-rFVIIa era, 2001 to 2003, 1 patient received rFVIIa; rFVIIa era, 2004 to 2006, 35 patients received rFVIIa). RESULTS: A total of 36 patients received 41 rFVIIa doses with an in-hospital survival of 91.7%. Hemorrhage was controlled in 83.3% of patients, with 1 dose sufficient in 75.0%. There was a significant decrease (p < 0.005) in all blood product requirements post-rFVIIa compared with pre-rFVIIa administration. In the intensive care unit (n = 6), rFVIIa significantly reduced chest tube output (p = 0.028) and prevented reexploration for bleeding in 5 patients. The requirement for delayed sternal closure was significantly higher in the pre-rFVIIa era versus the rFVIIa era (p = 0.011). The incidence of thrombosis in all patients receiving rFVIIa was 11.1%. In the rFVIIa era, a higher incidence of postoperative renal failure (p = 0.005) and pneumonia (p < 0.002) was detected in patients receiving rFVIIa. CONCLUSIONS: Recombinant activated factor VII appears to be effective in patients with refractory coagulopathy undergoing high-risk cardiovascular surgery.