Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage: A Systematic Review and Meta-analysis.

Importance: Direct oral anticoagulant (DOAC)-associated intracranial hemorrhage (ICH) has high morbidity and mortality. The safety and outcome data of DOAC reversal agents in ICH are limited. Objective: To evaluate the safety and outcomes of DOAC reversal agents among patients with ICH. Data Sources: PubMed, MEDLINE, The Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL databases were searched from inception through April 29, 2022. Study Selection: The eligibility criteria were (1) adult patients (age ≥18 years) with ICH receiving treatment with a DOAC, (2) reversal of DOAC, and (3) reported safety and anticoagulation reversal outcomes. All nonhuman studies and case reports, studies evaluating patients with ischemic stroke requiring anticoagulation reversal or different dosing regimens of DOAC reversal agents, and mixed study groups with DOAC and warfarin were excluded. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for abstracting data and assessing data quality and validity. Two reviewers independently selected the studies and abstracted data. Data were pooled using the random-effects model. Main Outcomes and Measures: The primary outcome was proportion with anticoagulation reversed. The primary safety end points were all-cause mortality and thromboembolic events after the reversal agent. Results: A total of 36 studies met criteria for inclusion, with a total of 1832 patients (967 receiving 4-factor prothrombin complex concentrate [4F-PCC]; 525, andexanet alfa [AA]; 340, idarucizumab). The mean age was 76 (range, 68-83) years, and 57% were men. For 4F-PCC, anticoagulation reversal was 77% (95% CI, 72%-82%; I2 = 55%); all-cause mortality, 26% (95% CI, 20%-32%; I2 = 68%), and thromboembolic events, 8% (95% CI, 5%-12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI, 67%-81%; I2 = 48%); all-cause mortality, 24% (95% CI, 16%-34%; I2 = 73%), and thromboembolic events, 14% (95% CI, 10%-19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI, 55%-95%; I2 = 41%), all-cause mortality, 11% (95% CI, 8%-15%, I2 = 0%), and thromboembolic events, 5% (95% CI, 3%-8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events. Conclusions and Relevance: In the absence of randomized clinical comparison trials, the overall anticoagulation reversal, mortality, and thromboembolic event rates in this systematic review and meta-analysis appeared similar among available DOAC reversal agents for managing ICH. Cost, institutional formulary status, and availability may restrict reversal agent choice, particularly in small community hospitals.

Outcomes of Direct Oral Anticoagulants Co-Prescribed with Common Interacting Medications.

Direct oral anticoagulants (DOACs) can potentially interact with multiple prescription medications. We examined the prevalence of co-prescription of DOACs with interacting medications and its impact on outcomes in patients with atrial fibrillation (AF). Patients with AF treated with a DOAC from 2010 to 2017 at the Mayo Clinic and co-prescribed medications that are inhibitors or inducers of the P-glycoprotein and/or Cytochrome P450 3A4 pathways were identified. The outcomes of stroke, transient ischemic attack, or systemic embolism, major bleeding, and minor bleeds were compared between patients with and without an enzyme inducer. Cox proportional hazards model was used to assess the association between interacting medications and outcomes. Of 8,576 patients with AF (mean age 70 ± 12 years, 35% female) prescribed a DOAC (38.6% apixaban, 35.8% rivaroxaban, 25.6% dabigatran), 2,610 (30.4%) were on at least 1 interacting agent: the majority were on an enzyme inhibitor (n = 2,592). Prescribed medications included non-dihydropyridine calcium channel blocker (n = 1,412; 16.5%), antiarrhythmic medication (n = 790; 9.2%), antidepressant (n = 659; 7.7%), antibiotic/antifungal (n = 77; 0.90%), antiepileptics (n = 17; 0.2%) and immunosuppressant medications (n = 19; 0.2%). Patients on an interacting medication were more likely to receive a lower dose of DOAC than indicated by the manufacturer's labeling (15.0% vs 11.4%, p <0.0001). In multivariable analysis, co-prescription of an enzyme inhibitor was not associated with risk of any bleeding (hazard ratio 0.87 [0.71 to 1.05], p = 0.15) or stroke, transient ischemic attack, or systemic embolism (hazard ratio 0.82 [0.51 to 1.31], p = 0.39). In conclusion, DOACs are co-prescribed with medications with potential interactions in 30.4% of patients with AF. Co-prescription of DOACs and these drugs are not associated with increased risk of adverse embolic or bleeding outcomes in our cohort.

Pain Associated With Continuous Intravenous Infusion of Bumetanide: A Case Series.

INTRODUCTION: Bumetanide can induce generalized musculoskeletal pain when administered as a continuous infusion, an effect that may be underrecognized. The purpose of this case series is to educate health care providers about the incidence and presentation of pain associated with bumetanide infusions, adding to the existing literature describing this adverse event. CLINICAL FINDINGS: Of 40 critically ill patients, 15 (38%) had increased pain scores after initiation of a continuous infusion of bumetanide, with symptoms commonly occurring 12 to 24 hours after initiation of the infusion. Reported descriptions of the pain included generalized aching, soreness, burning, allodynia, headaches, and exacerbation of underlying pain in localized areas. Increases in patient-reported pain correlated directly with initiation of the continuous infusion of bumetanide. DIAGNOSIS: Four of the 15 bumetanide-associated pain events (27%) were recognized as such by the health care team. INTERVENTIONS: Bumetanide was promptly discontinued in the 4 identified cases. The 11 patients (73%) whose pain was not recognized as related to bumetanide remained on a continuous infusion of bumetanide and received pain medications including opioids. Infusions were stopped when patients transitioned to dialysis (n = 8 [53%]), began receiving comfort care (n = 5 [33%]), or completed diuresis therapy (n = 2 [13%]). OUTCOMES: For all patients, pain symptoms resolved within 24 to 48 hours after discontinuation of bumetanide infusion with no significant electrolyte abnormalities. CONCLUSION: Bumetanide-induced pain is more common than previously described. Early recognition of this adverse event can prevent patient discomfort and escalation of treatment.

Anticoagulation in COVID-19: A Systematic Review, Meta-analysis, and Rapid Guidance From Mayo Clinic.

A higher risk of thrombosis has been described as a prominent feature of coronavirus disease 2019 (COVID-19). This systematic review synthesizes current data on thrombosis risk, prognostic implications, and anticoagulation effects in COVID-19. We included 37 studies from 4070 unique citations. Meta-analysis was performed when feasible. Coagulopathy and thrombotic events were frequent among patients with COVID-19 and further increased in those with more severe forms of the disease. We also present guidance on the prevention and management of thrombosis from a multidisciplinary panel of specialists from Mayo Clinic. The current certainty of evidence is generally very low and continues to evolve.

Towards appropriate polypharmacy in older cardiovascular patients: How many medications do I have to take?

BACKGROUND: Polypharmacy in older adults leads to increased risks of side effects and drug-drug interactions, affecting their health outcomes and quality of life. Deprescribing, the act of simplifying medication regimens, is challenging due to the lack of consensus guidelines. HYPOTHESIS: To offer some guidance on managing medication regimens for older cardiovascular patients. METHODS: We reviewed the most recent pertinent guidelines and literature. RESULTS: This review provides practical considerations for appropriate prescribing in the older population with cardiovascular disease in order to strike a balance between unnecessary or harmful medications and therapies with proven long-term benefits. CONCLUSION: On-going dialogue between healthcare providers and patients allows close monitoring of medication effectiveness and prevention of side effects. Medication regimens require individualization, as patients' goals of care change with advancing age.

Unfractionated heparin infusion for treatment of venous thromboembolism based on actual body weight without dose capping.

Controversy exists regarding the use of dose capping of weight-based unfractionated heparin (UFH) infusions in obese and morbidly obese patients. The primary objective of this study was to compare time to first therapeutic activated partial thromboplastin time (aPTT) in hospitalized patients receiving UFH for acute venous thromboembolism (VTE) among three body mass index (BMI) cohorts: non-obese (< 30 kg/m2), obese (30-39.9 kg/m2), and morbidly obese (⩾ 40 kg/m2). In this single-center, retrospective cohort study, patients were included if they ⩾ 18 years of age, had a documented VTE, and were on an infusion of UFH for at least 24 hours. Weight-based UFH doses were calculated using actual body weight. A total of 423 patients met the inclusion criteria, with 230 (54.4%), 146 (34.5%), and 47 (11.1%) patients in the non-obese, obese, and morbidly obese cohorts, respectively. Median times to therapeutic aPTT were 16.4, 16.6, and 17.1 hours in each cohort. Within 24 hours, the cumulative incidence rates for therapeutic aPTT were 70.7% for the non-obese group, 69.9% for the obese group, and 61.7% for the morbidly obese group (obese vs non-obese: HR = 1.02, 95% CI: 0.82-1.26, p = 0.88; morbidly obese vs non-obese: HR = 0.87, 95% CI: 0.62-1.21, p = 0.41). There was no significant difference in major bleeding events between BMI groups (obese vs non-obese, p = 0.91; morbidly obese vs non-obese, p = 0.98). Based on our study, heparin dosing based on actual body weight without a dose cap is safe and effective.

Development of best practice recommendations for the safe use of pulmonary hypertension pharmacotherapies using a modified Delphi method.

PURPOSE: The Delphi method was used to develop best practice recommendations (BPR) for safe use of pulmonary hypertension (PH) pharmacotherapies and to describe the pharmacist's role in provision of care. METHODS: A core group reviewed PH medication-safety literature and developed initial BPR. Pharmacists practicing at PH-accredited Centers of Comprehensive Care who met defined PH expert criteria were invited to participate on an expert panel. In round 1 of a 4-round Delphi process, expert input was provided on the BPR. Feedback was incorporated into BPR for the next round. Round 2 proceeded in identical fashion to round 1. In round 3, BPR were deliberated in a teleconference and underwent voting at the cessation of the round using a 5-point Likert scale. Median scores of < 2.5, 2.5-3.75, and > 3.75 resulted in a best practice statement being rejected, reviewed in round 4, or accepted in the final BPR, respectively. In round 4, the remaining BPR were discussed and underwent voting. BPR were assigned a level of evidence and strength of recommendation based on voting results. RESULTS: Eleven PH experts agreed to participate and met expert inclusion criteria, along with 2 pharmacists from the core group, bringing the total number of expert panel members to 13. To guide safe use of PH pharmacotherapies, 26 BPR were developed, categorized into 5 practice domains, comprising the PH Care Center accreditation process, inpatient practice, formulary management, diagnostics, and ambulatory care. BPR included provisions for safe use of parenteral prostacyclin agents and healthcare practitioner education. CONCLUSION: The Delphi method was used to develop BPR to guide safe use of PH pharmacotherapies.

Comparison of In-Hospital Bleeding and Cardiovascular Events with High-Dose Bolus Tirofiban and Shortened Infusion to Short-Duration Eptifibatide as Adjunctive Therapy for Percutaneous Coronary Intervention.

Potent platelet inhibition is one of the most important medical interventions to prevent ischemic complications during and after percutaneous coronary intervention (PCI). Practice has evolved with the introduction of potent oral P2Y12 inhibitors that provide quick, effective platelet inhibition, and the need for routine glycoprotein IIb/IIIa inhibitors (GPIs) has decreased. Additionally, a shorter duration of GPI infusion has been shown to be safe with adequate oral antiplatelet loading, but clinical outcome data are limited to eptifibatide. This single-center, retrospective cohort study analyzed in-hospital outcomes for patients who received adjunctive GPI therapy for PCI before and after an institution-wide switch to high-dose bolus tirofiban with shortened infusion from short-duration eptifibatide. The primary end point was a composite in-hospital outcome of major and minor bleeding and cardiovascular events (death, myocardial infarction, coronary artery bypass grafting, ischemic stroke, and target vessel revascularization). Secondary end points included bleeding and cardiovascular event types. A total of 357 and 446 patients received eptifibatide and tirofiban, respectively, from February 1, 2014 through September 30, 2017. Thirty five eptifibatide and 46 tirofiban patients experienced an in-hospital composite event (9.8% vs 10.3%, p = 0.81). There was no difference found between in-hospital bleeding (6.4% vs 5.4%, p = 0.52) or cardiovascular events (5.6% vs 6.5%, p = 0.60) with the use of eptifibatide or tirofiban, respectively. Multivariable analysis showed that patients with transradial access or an indication of unstable angina were less likely to experience an in-hospital composite event (OR 0.30 and 0.19, respectively, p <0.001 for both). In conclusion, the use of high-dose bolus tirofiban with shortened infusion versus short-duration eptifibatide was not associated with an increase of in-hospital bleeding or cardiovascular events.

Improving inpatient warfarin therapy safety using a pharmacist-managed protocol.

INTRODUCTION: Safe management of warfarin in the inpatient setting can be challenging. At the Mayo Clinic hospitals in Rochester, Minnesota, we set out to improve the safety of warfarin management among surgical and non-surgical inpatients. METHODS: A multidisciplinary team designed a pharmacist-managed warfarin protocol (PMWP) which designated warfarin dosing to inpatient pharmacists with guidance from computerised dosing algorithms. Ordering this protocol was ultimately designed as an 'opt out' practice. The primary improvement measure was frequency of international normalised ratio (INR) greater than 5; secondary measures included adoption rate of the protocol, a counterbalance INR metric (INR <1.7 three days after first inpatient warfarin dose), and complication rates, including bleeding and thrombosis events. An interrupted time series analysis was conducted to compare outcomes. RESULTS: Among over 50 000 inpatient warfarin recipients, the PMWP was adopted for the majority of both surgical and non-surgical inpatients during the study period (1 January 2005 to 31 December 2011). The primary improvement measure decreased from 5.6% to 3.4% for medical patients and from 5.2% to 2.4% for surgical patients during the preimplementation and postimplementation periods, respectively. The INR counterbalance measure did not change. Postoperative bleeding decreased from 13.5% to 11.1% among surgical patients, but bleeding was unchanged among medical patients. CONCLUSION: Our PMWP led to achievement of improved INR control for inpatient warfarin recipients and to less near-term bleeding among higher risk, surgical patients.

Comparison of Warfarin Requirements in Post-cardiac Surgery Patients: Valve Replacement Versus Non-valve Replacement.

INTRODUCTION: Anticoagulation with warfarin affects approximately 140,000 post-cardiac surgery patients every year, yet there remains limited published data in this patient population. Dosing remains highly variable due to intrinsic risk factors that plague cardiac surgery candidates and a lack of diverse literature that can be applied to those who have undergone a cardiac surgery alternative to heart valve replacement (HVR). In the present study, our aim was to compare the warfarin requirements between HVR and non-HVR patients. METHODS: This was a single-center, retrospective study of post-cardiac surgery patients initiated on warfarin at Mayo Clinic Hospital, Rochester, from January 1st, 2013 to October 31st, 2016. The primary outcome was the maintenance warfarin dose at the earliest of discharge or warfarin day 10 between patients with HVR and non-HVR cardiac surgeries. RESULTS: A total of 683 patients were assessed during the study period: 408 in the HVR group and 275 in the non-HVR group. The mean warfarin maintenance doses in the HVR and non-HVR groups were 2.55 mg [standard deviation (SD) 1.52] and 2.43 mg (SD 1.21), respectively (adjusted p = 0.65). A multivariable analysis was performed to adjust for gender, age, body mass index and drug interactions. CONCLUSIONS: This was the largest study to evaluate warfarin dose requirements in post-cardiac surgery patients and is the first to compare warfarin requirements between HVR and non-HVR patients during the immediate post-operative period. Both groups had similar warfarin requirements, which supports expanding the initial warfarin dosing recommendations of the 9th edition Chest guideline to include non-HVR patients as well as HVR patients.

Going Beyond Administrative Data: Retrospective Evaluation of an Algorithm Using the Electronic Health Record to Help Identify Bleeding Events Among Hospitalized Medical Patients on Warfarin.

To reliably assess quality, a standardized electronic approach is needed to identify bleeding events. The study aims were the following: (1) clinically validate an electronic health record-based algorithm for bleeding and (2) assess interrater results to determine validity and reliability. Data were analyzed before and after implementation of a pharmacist-managed warfarin protocol. Bleeding was based on ≥2 of 3 criteria: (1) diagnosis indicating bleeding, (2) lab value decrease suggesting bleeding, and (3) blood product use. All suspected bleeds (234) and a sample (58) not meeting criteria were compared with clinical review. There were 234 bleeding cases identified electronically. Reviewer agreement was 78.2% (κ = 0.565). Algorithm sensitivity was 93.9% and positive predictive value 46.2%. Algorithm identification was least accurate for those with only 2 criteria but good for those with all criteria. This study supports using multiple electronic criteria to identify bleeding events. However, cases having exactly 2 criteria may require manual review for validation.

Heparin dose adjustment required to maintain goal-activated partial thromboplastin time during therapeutic hypothermia.

PURPOSE: The impact of therapeutic hypothermia (TH) on unfractionated heparin (UFH) management is essentially unknown. The aim of this study was to evaluate the effect of TH on UFH dosing and activated partial thromboplastin (aPTT) response. MATERIALS AND METHODS: Consecutive patients treated from 2005 to 2011 who received intravenous UFH via a dosing nomogram during TH were included. First, heparin doses and aPTT responses were compared between 2 core temperature groups, less than or equal to 33°C and greater than 35°C. Next, the first aPTT, drawn at 6 hours for temperature less than or equal to 33°C, was assessed. Lastly, a linear model was developed to predict the mean aPTT, based on temperatures and heparin doses. RESULTS: Of the 156 TH patients, 68 were included. At temperatures less than or equal to 33°C, 76.3% of all aPTT levels and 81.0% of the first aPTTs were above goal range, respectively. Using a linear model, an UFH dose of 12 U/kg per hour predicts an aPTT of 134 seconds at less than or equal to 33°C. CONCLUSIONS: Using guideline-recommended heparin dosing without dose adjustment for temperature changes produced excessive aPTT during the cooling phase for TH patients. Reduction in the UFH dose of 43% to 54% may be required during TH. We recommend frequent aPTT monitoring during the cooling and rewarming phases to attain a desired aPTT range.

Effect of a shortened-duration Eptifibatide infusion (75 mg) as adjunctive therapy for percutaneous coronary intervention on in-hospital cardiovascular outcomes and bleeding.

A retrospective cohort analysis was conducted on patients who underwent percutaneous coronary intervention (PCI) before and after a practice change which reduced the infusion duration of eptifibatide from 18 hours to the time required for completion of a single vial of 75 mg initiated during PCI. Primary end points were inhospital cardiovascular events, target vessel revascularization, and major or minor bleeding. The secondary end point was drug cost. A total of 1,647 patients received the standard-duration infusion (18 hours), and 1,237 received the short-duration infusion. The median infusion times were 18.1 hours (interquartile range 17.7 to 18.7) and 6.6 hours (interquartile range 5.6 to 11.3) in the standard- and short-duration groups, respectively. No differences were found for the rate of inhospital cardiovascular events (2.0% vs 1.9%, respectively; p = 0.78) or inhospital revascularization (0.2% vs 0.3%, respectively; p = 0.68). Also, no statistically significant difference was observed in major bleeding (standard 4.3% vs short 4.4%; p = 0.94) or minor bleeding (standard 3.3% vs short 2.3%; p = 0.09). In conclusion, using a shortened infusion reduced eptifibatide use by an average of 1.6 vials at cost savings of $823 per patient and resulted in no difference in inhospital cardiovascular events, revascularization, or bleeding.

Risk factors for excessive anticoagulation among hospitalized adults receiving warfarin therapy using a pharmacist-managed dosing protocol.

STUDY OBJECTIVE: To identify specific risk factors for excessive anticoagulation, defined as an international normalized ratio (INR) higher than 5, in hospitalized adults receiving warfarin therapy using a pharmacist-managed dosing protocol. DESIGN: Retrospective nested case-control study. SETTING: Large academic tertiary care medical center. PATIENTS: Hospitalized nonsurgical patients 18 years or older who received at least one dose of warfarin according to the pharmacist-managed protocol from January 1, 2009, to January 31, 2012, were included. Patients who experienced an INR higher than 5 were designated as case patients; those who received warfarin for at least as many days as the case patients but who did not experience an INR more than 5 were deemed control patients. Controls were matched to cases in a 2:1 ratio by age, sex, INR goal, and type of warfarin therapy (new start or continuation). MEASUREMENTS AND MAIN RESULTS: A total of 87 case patients were matched to 174 controls. Ten different hypothesized risk factors were examined. Two variables, severity of illness score (odds ratio [OR] 4.89, p<0.001) and poor nutritional status (OR 4.27, p<0.001), demonstrated strong independent associations with risk of excessive anticoagulation. Administration of interacting drugs that highly potentiate warfarin's effect (OR 2.26, p=0.011) and concurrent diarrheal illness (OR 4.75, p<0.001) also displayed a statistically significant risk for excessive anticoagulation. CONCLUSION: Even in a highly standardized system for warfarin dosing by a pharmacist-managed protocol, higher disease severity and poor nutritional status placed hospitalized patients at greater risk of experiencing excessive anticoagulation. In addition, administration of interacting drugs that highly potentiate warfarin's effect or the occurrence of diarrheal illness may predict increased risk.

Development and evaluation of a pharmacogenomics educational program for pharmacists.

Objectives. To evaluate hospital and outpatient pharmacists' pharmacogenomics knowledge before and 2 months after participating in a targeted, case-based pharmacogenomics continuing education program.Design. As part of a continuing education program accredited by the Accreditation Council for Pharmacy Education (ACPE), pharmacists were provided with a fundamental pharmacogenomics education program.Evaluation. An 11-question, multiple-choice, electronic survey instrument was distributed to 272 eligible pharmacists at a single campus of a large, academic healthcare system. Pharmacists improved their pharmacogenomics test scores by 0.7 questions (pretest average 46%; posttest average 53%, p=0.0003).Conclusions. Although pharmacists demonstrated improvement, overall retention of educational goals and objectives was marginal. These results suggest that the complex topic of pharmacogenomics requires a large educational effort in order to increase pharmacists' knowledge and comfort level with this emerging therapeutic opportunity.