Treating patients with obesity with anticoagulants can present difficulties that have been known and discussed for many years.

best practices for use of direct oral anticoagulants in obesity

, leaders in the field provided an overview of drug classes in the direct oral anticoagulant (DOAC) class and discussed how to define obesity to effectively treat patients with anticoagulants.

The discussion was led by Jessica Kerr, PharmD, CDE, associate dean of Professional and Student Affairs and professor in the Department of Pharmacy Practice at Southern Illinois University Edwardsville School of Pharmacy, with participation from Paul Dobesh, PharmD, FCCP, BCPS, professor of pharmacy practice and science in the College of Pharmacy at University of Nebraska Medical Center in Omaha, and Matthew Johnson, MD, a cardiologist at Bryan Health in Lincoln, Nebraska.

The DOAC mechanism of action is broken down into direct factor Xa inhibitors and direct thrombin inhibitors, Johnson said.

The mechanism of action is pinpointed at a single molecule, as opposed to warfarin (Coumadin), which may affect multiple factors. The DOAC mechanism of action will be directed to factor Xa, except for dabigatran (Pradaxa), which is a direct thrombin inhibitor or a factor IIa inhibitor.

Kerr said the DOAC class has grown tremendously because of the research conducted over the past decade. Many of the agents have the same indications, but some have fewer or more indications than others.

The indications that these agents have tell whether they have been studied and are successful, Dobesh said, adding that 1 drug will not work for all patients—making the number of drugs available an important aspect of successful treatment.

For example, betrixaban (Bevyxxa), the newest of the DOACs, has an indication for extended prophylaxis in medically ill patients. However, it is not indicated for preventing atrial fibrillation and stroke. It is also not indicated for orthopedic surgery or venous thromboembolism (VTE), demonstrating that it has just 1 indication.

On the other hand, apixaban (Eliquis), edoxaban (Savaysa), and rivaroxaban (Xarelto) are all indicated for reducing the risk of non—valve-related defibrillation and stroke, Dobesh said. All 3 are also indicated for the treatment of VTE, both deep vein thrombosis and pulmonary embolism.

All 4 drugs have a half-life of about 12 hours. This can make dosage difficult because for 90% to 95% of the drugs used in clinical practice, the pharmacokinetics dictate the pharmacodynamics, Dobesh said.

However, for some anticoagulants, the effect of the drug is longer than the pharmacokinetic effect. For apixaban and dabigatran, each has a 12-hour half-life and provides 12 hours of anticoagulation, meaning that their pharmacodynamics and pharmacokinetics align. But edoxaban and rivaroxaban are both once-daily drugs, as their 12-hour half-life clearly provides 24 hours of anticoagulant effect. Additionally, the difference between a onceand a twice-daily drug is important to consider in terms of adherence.

In relation to defining obesity, Kerr noted that the Centers for Disease Control and Prevention and World Health Organization have published guidelines for definitions.

The best method of assessment has been body mass index (BMI), which takes the weight in kilograms over the height in meters squared, Johnson said.

In its assessment, the CDC breaks down BMI into different categories. A BMI of 25 to less than 30 falls within the overweight range. The CDC often subdivides obesity into 3 categories: Class 1 is a BMI of 30 to less than 35, class 2 is a BMI of 35 to less than 40, and class 3, “extreme” or “severe” obesity, is a BMI of 40 or higher.

A lot of simplification goes into categorizing BMI, Johnson said.

During scientific reviews of DOAC, whether post hoc analysis or randomized trials, the data often separate into those categories. The categories are generally broken down similarly, with obesity being a BMI of more than 30 and severe obesity being more than 40.

Additionally, some reviews of DOAC have been conducted to assess that 30-to-40 range, but very little data are available to review DOAC dosage and efficacy in the severe obesity range with a BMI of 40 or higher, Johnson said.

When assessing many acute and chronic disease states, it’s important to remember that patients with obesity may be at higher risk for negative outcomes associated with the specific disease state, Kerr said, noting that this is specifically the case for the risk of thrombosis in patients with obesity—as obesity is, in and of itself, a risk factor for venous thromboembolic disease. The management of thrombosis risk among patients with obesity versus other comorbidities is multifaceted.

Patients with obesity have an increased risk of developing atrial fibrillation, Dobesh said. Additionally, obesity is directly correlated to the development of diabetes from hyperinsulinemia and is directly related to hypertension.

The International Society on Thrombosis and Haemostasis (ISTH) recently released recommendations that support the use of DOACs over warfarin, except for patients with BMIs higher than 40 because of a lack of data for that population, Dobesh said.

However, noted Dobesh, despite there not being a wealth of data on the use of antibiotics in patients with BMIs higher than 40, these patients are still prescribed them.

For this reason, the decision to restrict DOAC use in these patients seems odd, Dobesh said.

The ISTH made this decision because warfarin performs better due to its ability to titrate the international normalized ratio (INR). Once an INR is achieved, the patient can be considered successfully anticoagulated. Because DOACs are not monitored, this cannot be determined.

Dobesh said that although he is aware of this recommendation from the ISTH, he no longer follows it because of evolving data over the last 4 years.

Johnson agreed with Dobesh, noting that he has also adjusted his adherence to the ISTH guidance, as new data have made clear the efficacy and safety of DOACs in patients with BMI higher than 40.

Kerr J, Johnson M, Dobesh P. Best practices for the use of direct oral anticoagulants in obesity. Pharmacy Times®. July 15, 2020. Accessed July 29, 2020. https://www.pharmacytimes.com/practice-pearls/ best-practices-for-the-use-of-direct-oral-anticoagulants-in-obesity/ introduction-and-overview-of-direct-oral-anticoagulants

Articles

Health-System Edition

Leaders in the field provide an overview of the DOAC drug class and how best to use the growing number of options.

Using Anticoagulants to Treat Patients With Obesity Presents Challenges

Bloodstream infections (BSI) are a significant source of morbidity and mortality.

Rapid identification of infectious pathogens is paramount in assuring therapy initiation is both appropriate and timely. Traditional blood culture methods may take up to 96 hours for organism identification (ID) and susceptibility, and delays in initiation of optimal therapy have been associated with increases in mortality.

 As such, rapid diagnostic testing (RDT) has become an attractive tool in the diagnosis and management of BSI and has been associated with improvements in time to initiation of appropriate antibiotic therapy, mortality, length of stay, hospital costs, and decreased time to de-escalation.

 The ability to de-escalate therapy more quickly may reduce unintended consequences of antibiotic therapy.

 Several platforms are available to institutions seeking to implement RDT for BSI. What follows is a brief overview of the available technologies.

Polymerase chain reaction (PCR) platforms vary in the number of gene targets per organism and/or number of organisms per panel. PCR can be run directly from a positive blood culture prior to growth on standard culture media. The GeneOhm StaphSR (BD Diagnostics) assay and Xpert MRSA/SA BC (Cepheid) assay (Cepheid) are single-organism/ multitarget panels with a turnaround time of 1 to 2 hours.

 with 1 target and methicillin resistance using a second target.

 Multiorganism/multitarget panels can concurrently detect gram-negative and gram-positive bacteria, yeast, and genotypic resistance markers (carbapenem, methicillin, or vancomycin resistance). FilmArray BCID (bioMérieux/BioFire) and Verigene BC-GP/-GN (Luminex) are multiorganism/ multitarget panels with turnaround times of 1.2 hours and 2 to 2.5 hours, respectively.

Implementation of PCR within antimicrobial stewardship programs (ASPs) has been shown to improve outcomes. For example, Banerjee and colleagues investigated outcomes of traditional ID versus rapid multiplex PCR (rmPCR) with and without real-time antimicrobial stewardship (AS) intervention in 617 patients with BSI.

 Their study demonstrated reduced vancomycin use for organisms not necessitating vancomycin, increased use of narrow spectrum agents, and increased de-escalation. By comparison, a study by Tseng et al evaluated the implementation of rmPCR without the provider being notified or AS recommendations. They observed a decrease in time to organism ID in the rmPCR group (gram negative, 2.6 hours vs 25.8 hours; P < .001; gram positive, 17.4 hours vs 28.8 hours; P = .0002), but did not identify significant changes in antimicrobial therapy.

 The differences between these 2 studies highlight a larger trend in the RDT implementation literature that indicates the benefits of PCR are best realized when combined with intervention from an ASP.

Matrix-Assisted Laser Desorption/ Ionization Time of Flight 

Mass spectrometry cross-references bacterial protein signatures to reference libraries to produce organism ID in 20 to 60 minutes. One of the first studies that evaluated this demonstrated that implementation of matrix-assisted laser desorption/ionization time of flight with AS with prospective audit and feedback improved time to effective antibiotic therapy (30.1 vs 20.4 hours; P = .021) and improved time to optimal therapy (90.3 vs 47.3 hours; P < .001). Similar findings have been confirmed in multiple other observational studies.

 Interestingly, a recent randomized controlled trial without prospective audit and feedback demonstrated a similar proportion of patients on optimal antibiotics at 24 or 48 hours.

Peptide Nucleic Acid Fluorescence in Situ Hybridization 

Peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) uses a DNA probe to target pathogen ribosomal RNA from positive blood cultures.

 PNA-FISH and QuickFISH (AdvanDx) provide organism identification in 1.5 hours and 20 minutes, respectively. Commercially available assays can detect 

Staphylococcus aureus, coagulase-negative Staphylococcus

 (CoNS), numerous gram-negative rods (including 

Serratia marcescens, Pseudomonas aeruginosa,

 BSI were evaluated by standard blood culture processes or standard processes plus PNA-FISH. After PNA-FISH results became available, the microbiology department reported the results to the provider, along with standard comments regarding empiric therapy depending on the organism identified.

 There was no AS intervention in either arm and no difference in time to effective therapy, time to optimal therapy, length of stay, or in-hospital mortality implementation. In a separate study, the addition of AS guidance to PNA-FISH was associated with decreased hospital length of stay in patients with CoNS BSI, reduced time to effective therapy, and decreased 30-day mortality in patients with 

BSI when compared with rapid diagnostics alone.

Accelerate PhenoTest BC Kit (Accelerate Diagnostics) combines PNA-FISH with morphokinetic cellular analysis (MCA) to provide rapid ID and susceptibility directly from a blood culture sample. MCA tracks phenotypic features including the size, shape, and division rate of individual live cells growing into microcolonies while being challenged by antibiotics to rapidly determine antimicrobial susceptibilities. This unique technology allows for antibiotic susceptibilities in 7 hours, enabling the rapid transition to definitive therapy. A single-center retrospective study investigated laboratory and clinical outcomes after the implementation of the Accelerate PhenoTest BC kit. Compared with conventional identification and antimicrobial susceptibility testing, implementation was associated with reduced length of stay (12.1 days vs 9.1 days; P = .03), time to optimal therapy (73.5 hours vs 37.5 hours; P < .001), and total antimicrobial days of therapy (9 vs 7; P = .05).

 Future studies are needed to determine the full potential of this technology in gram-negative BSI.

The T2Dx Instrument (T2 Biosystems) combines PCR and magnetic resonance technology to detect organisms in 3 to 5 hours from whole blood specimens without incubation.

 This technology is unique because it is the only platform reviewed that provides bacterial identification prior to positive blood cultures. The available panels include T2Candida and T2Bacteria. Limited patient outcomes data are available. However, the theoretical advantage of using the T2Dx is the potential for antimicrobial escalation within 5 hours of initial therapy. Further research is needed to fully identify the optimal way to implement this assay with an ASP.

Many platforms are available for rapid detection (see table) with or without antimicrobial susceptibilities in BSI. Institutions looking to implement an RDT for BSI should consider their optimal targets, testing volumes, and notification and reporting practices. The impact of these tests on both institutional and patient outcomes may vary depending on the institutional practices and platform implemented. ASPs should play a key role in decisions regarding the selection, implementation, and reporting of RDT for BSI, given their proven impact on patient outcomes, inappropriate antimicrobial use, and costs with real-time review and intervention.

, is a clinical specialist for infectious diseases at Olathe Health in Kansas City, Missouri.

, is an antimicrobial stewardship/outpatient antimicrobial therapy pharmacist at the Mayo Clinic in Rochester, Minnesota.

, is an associate professor of infectious disease at Albany College of Pharmacy and Health Sciences in New York. 

Vergis EN, Hayden MK, Chow JW, et al. Determinants of vancomycin resistance and mortality rates in enterococcal bacteremia. a prospective multicenter study. 

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Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. 

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Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. 

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Banerjee R, Teng CB, Cunningam SA, et al. Randomized trial of rapid multiplex polymerase chain reaction-based blood culture identification and susceptibility testing. 

. 2015;61(7):1071-1080. doi:10.1093/cid/civ447

Rubach MP, Hanson KE. ID Learning unit-diagnostics update: current laboratory methods for rapid pathogen identification in patients with bloodstream infections. 

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McHugh MP, Parcell BJ, MacKenzie FM, Templeton, KE; Scottish Microbiology And Virology Network Smvn Molecular Diagnostics Evaluation Group. Rapid molecular testing for Staphylococcus aureus bacteraemia improves clinical management.

. 2020;69(4):552-557. doi:10.1099/jmm.0.001171

Tseng AS, Kasule SN, Rice F, et al. Is it actionable? an evaluation of the rapid PCR-based blood culture identification panel on the management of gram-positive and gram-negative blood stream infections. 

. 2018;5(12):ofy308. doi:10.1093/ofid/ofy308

Bauer KA, West JE, Balada-Llasat JM, Pancholi P, Stevenson KB, Goff DA. An antimicrobial stewardship program’s impact. 

. 2010;51(9):1074-1080. doi:10.1086/656623

Wong JR, Bauer KA, Mangino JE, Goff DA. Antimicrobial stewardship pharmacist interventions for coagulase-negative staphylococci positive blood cultures using rapid polymerase chain reaction. 

. 2012;46(11):1484-1490. doi:10.1345/aph.1R439

Nagel JL, Huang AM, Kunapuli A, et al. Impact of antimicrobial stewardship intervention on coagulase-negative staphylococcus blood cultures in conjunction with rapid diagnostic testing. 

. 2014;52(8):2849-2854. doi:10.1128/ JCM.00682-14

Nadjm B, Dat VQ, Campbell JI, et al. A randomized controlled trial of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDITOF-MS) versus conventional microbiological methods for identifying pathogens: impact on optimal antimicrobial therapy of invasive bacterial and fungal infections in Vietnam.

 2019;78(6):454- 460. doi:10.1016/j.jinf.2019.03.010

Cosgrove SE, Li DX, Tamma PD, et al. Use of PNA FISH for blood cultures growing gram-positive cocci in chains without a concomitant antibiotic stewardship intervention does not improve time to appropriate antibiotic therapy. 

. 2016;86(1):86-92. doi:10.1016/j. diagmicrobio.2016.06.016

Forrest GN, Mehta S, Weekes E, et al. Impact of rapid in situ hybridization testing on coagulase-negative staphylococci positive blood cultures. 

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Dare RK, Lusardi K, Pearson C, et al. Clinical impact of accelerate pheno rapid blood culture detection system on laboratory and clinical outcomes in bacteremic patients. 

Huang AM, Newton D, Kunapuli A, et al. Impact of rapid organism identification via matrix-assisted laser desorption/ ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. 

. 2013;57(9):1237-1245. doi:10.1093/cid/cit498

The Society of Infectious Diseases Pharmacists (SIDP) is an association of pharmacists and other allied healthcare professionals who are committed to promoting the appropriate use of antimicrobial agents and supporting practice, teaching, and research in infectious diseases. We aim to advance infectious diseases pharmacy and lead antimicrobial stewardship in order to optimize the care of patients. To learn more about SIDP, visit

Institutions should consider optimal targets, testing volumes, and notification and reporting practices when making their choice.

Many Platforms Offer Rapid Detection in Bloodstream Infections

The National Institutes of Health estimates that gastric cancer will account for 1.8% of all cancer deaths in the United States in 2020.

The most recent global statistics from 2018 show that the disease ranked fifth in cancer incidence rates (Figure 1), representing more than 1 million new cases diagnosed in 2018.

Gastric cancer occurs when cells in the lining of the stomach proliferate and grow abnormally, causing tumor formation. Over time, the tumor can invade surrounding tissues, leading to metastases in other organs of the body. The most common form of gastric cancer is adenocarcinoma.

 Risk factors and statistics are shown in Figure 2.

 Trends in mortality rates associated with gastric cancer are declining by 32%, leading to an overall 5-year relative survival and a 69% 5-year relative survival for localized gastric cancer.

Upper endoscopy is typically used for the primary diagnosis of gastric cancer along with other modalities to determine staging, such as computed tomography, hematologic testing, laparoscopic surgery, positron emission tomography, tumor biopsy, and ultrasound.

 Staging is based on the tumor, nodes, and metastasis systems. Additional testing for human epithelial growth factor receptor- 2 (

) expression and programmed death-ligand 1 (PD-L1) expression, as well as microsatellite instability or mismatch repair genomic testing, can help determine eligibility for targeted therapy or immunotherapy. The National Comprehensive Cancer Network (NCCN) does not offer screening recommendations for patients not diagnosed with gastric cancer.

Surgery remains the only known curative treatment for gastric cancer.

 In patients who are considered medically fit with a resectable tumor, surgery is the first-line treatment with optional subsequent chemoradiation. For patients with resectable gastric cancer, the NCCN recommends a fluoropyrimidine-based doublet with either cisplatin or oxaliplatin, with the latter generally expressing less toxicity. For patients with metastatic, recurrent, or unresectable gastric cancer, chemotherapy is the primary treatment option, with the same recommended chemotherapy regimens as resectable gastric cancer.

Significant attention has been focused on the newer targeted immunotherapies for gastric cancer: ramucirumab, pembrolizumab, and trastuzumab. Pharmacologic options for patients whose cancer expresses certain traits, such as overexpression of 

, include trastuzumab, whereas microsatellite instability-high or deficient mismatch repair solid tumors can be targeted by pembrolizumab. Ramucirumab is a vascular endothelial growth factor receptor-2 antibody that targets angiogenesis and is a potential adjunct to the preferred chemotherapy regimens, but efficacy data are lacking.

 The RAINFALL study (NCT02314117) was conducted to determine the benefit of adding ramucirumab to firstline chemotherapy regimens in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. The results of this trial were not as promising as investigators had hoped, showing no change in overall survival compared with first-line chemotherapy regimens alone.

 The results of a retrospective observational study conducted in Japan suggest that ramucirumab is more of a third-line option or “salvage therapy.”

 Ongoing clinical trials are trying to further assess the place in therapy of ramucirumab, such as the RAMSES study in Germany that is comparing the effects of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) alone and in combination with ramucirumab in patients who are 

 negative with locally advanced esophagogastric adenocarcinoma.

The results of a recent study offered promise with the use of dasatinib, a tyrosine kinase inhibitor, as a possible treatment option for gastric cancer. This study identified several kinases that are prominent in patients with gastric cancer, specifically ones that dasatinib is known to inhibit, warranting further studies assessing the drug’s efficacy in vivo.

The EPOC 1706 phase 2 study (NCT03609359) looked at lenvatinib plus pembrolizumab in patients with recurrent or metastatic adenocarcinoma. In this study, 20 of 29 patients showed an objective response with no serious or grade 4 adverse events.

 These results show potential for future research.

Many ongoing clinical trials for the treatment of gastric cancer are focusing on newer immunotherapy options, such as JAVELIN Gastric 100 (NCT02625610) in Germany and the DANTE study (NCT03421288) in Germany and Switzerland. JAVELIN Gastric 100 intended to determine the superiority of avelumab, a PD-L1 antibody, against the first-line treatment of a fluoropyrimidine-based doublet with oxaliplatin, in patients with unresectable, locally advanced, or metastatic adenocarcinoma.

DANTE is comparing FLOT in combination with atezolizumab to FLOT alone in the same setting.

There is an abundance of ongoing clinical trials exploring a variety of pharmacologic agents for treating gastric cancer. Pharmacists play an integral role in collaborating with physicians to manage gastric cancer therapy. Through this multidisciplinary alliance, pharmacists enhance the prospects for favorable outcomes while reducing toxicities for patients.

Glenn Schulman, PharmD, MS, BCPS, BCACP, BCGP, BCIDP

, are clinical pharmacists in Pensacola, Florida.

 is a PharmD candidate at the University of Florida College of Pharmacy in Gainesville. 

Cancer stat facts: stomach cancer. National Cancer Institute. Accessed June 28, 2020. https://seer.cancer.gov/statfacts/html/stomach.html

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Stomach cancer: risk factors. Cancer.Net. January 2019. Accessed July 2, 2020. https://www.cancer.net/cancer-types/stomach-cancer/risk-factors

All about gastric cancer. OncoLink. Updated April 26, 2019. Accessed June 28, 2020. https://www.oncolink.org/cancers/gastrointestinal/gastric-cancer/all-about-gastric-cancer

Ajani JA, D’Amico TA, Almhanna K, et al. Gastric cancer, version 3.2016, NCCN Clinical Practice Guidelines in Oncology. 

 2016;14(10):1286-1312. doi:10.6004/jnccn.2016.0137

Fuchs CS, Shitara K, Di Bartolomeo M, et al; RAINFALL Study Group. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. 

 2019;20(3):420-435. doi:10.1016/S1470-2045(18)30791-5

Kawai S, Fukuda N, Yamamoto S, et al. Retrospective observational study of salvage line ramucirumab monotherapy for patients with advanced gastric cancer. 

 2020;20(1):338. doi:10.1186/s12885-020-06865-7

FLOT vs FLOT/ramucirumab for perioperative therapy of gastric or GEJ cancer (RAMSES) (RAMSES/FLOT7). ClinicalTrials.gov. Updated April 22, 2020. Accessed July 2, 2020. 

https://clinicaltrials.gov/ct2/show/NCT02661971

Montenegro RC, Howarth A, Ceroni A, et al. Identification of molecular targets for the targeted treatment of gastric cancer using dasatinib. 

. 2020;11(5):535-549. doi:10.18632/oncotarget.27462

Kawazoe A, Fukuoka S, Nakamura Y, et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. 

 2020;21(8):1507-1065. doi:10.1016/S1470-2045(20)30271-0

Avelumab in first-line maintenance gastric cancer (JAVELIN Gastric 100). ClinicalTrials.gov. Updated May 7, 2020. Accessed July 2, 2020. https://clinicaltrials.gov/ct2/show/study/NCT02625610

Phase II study of atezolizumab + FLOT vs FLOT alone in patients with gastric cancer and GEJ (DANTE). ClinicalTrials.gov. Updated March 24, 2020. Accessed July 2, 2020. https://clinicaltrials.gov/ct2/show/study/NCT03421288

Pharmacists can play an integral role in collaborating with physicians to manage patient therapy.

Plethora of Clinical Trials Explore Gastric Cancer Treatments

The number of individuals with HIV aged 13 or older living in the United States was estimated to be more than 1.1 million at the end of 2015.

 Of that number, 162,500 (15%) had not received a diagnosis.

The incidence of HIV has remained stable, with 50,000 new cases of HIV diagnosed each year, leading to a decreased mortality rate. The disease was responsible for 3 deaths per 100,000 individuals in 2013 compared with 17 deaths per 100,000 between 1994 and 1995.

Significant morbidity and mortality are associated with an aging population because of cardiovascular disease, which is very common in individuals with HIV. Atrial fibrillation (AF), the most common type of cardiac arrhythmia, increases with the severity of HIV disease, with a 40% increase with a CD4 cell count of less than 200 cells per mm

 and a 70% increase with an HIV viral load greater than 100,000.

 Overall, the rate of AF in individuals with HIV per year is about 3.6.

An estimated 2.7 to 6.1 million people in the United States had AF in 2010, and that number is expected to rise to between 5.6 and 12 million by 2050.

 More than 750,000 hospitalizations occur each year, causing an annual increase of about $6 billion in medical costs. Per-person medical costs for individuals with AF were $8705 higher than for those who did not have the condition.

There are numerous risk factors associated with AF, including advanced age, chronic kidney disease, diabetes, European ancestry, heart failure, hypertension, hyperthyroidism, and obesity.

 Moreover, the increased risk of stroke associated with AF is 5 times more severe and causes 15% to 20% of all ischemic strokes.

Randomized trials tested the long-term use of antithrombotic agents in patients with nonvalvular AF from 1966 to 2007.

 Compared with a placebo, adjusted-dose warfarin reduced the risk of a stroke by 64%.

With a long track record, a low cost, and rapid-turnaround genetic testing, warfarin has shown significant efficacy. Nonetheless, challenges exist, such as an increased risk of major and minor bleeds, multiple drugdrug and drug-food interactions, narrow therapeutic index, ongoing dose adjustment and laboratory testing, and unpredictable pharmacology.

Gradually, the era of direct oral anticoagulants (DOACs), such as apixaban (Eliquis), dabigatran (Pradaxa), edoxaban (Savaysa), and rivaroxaban (Xarelto), has taken the market by storm. DOACs are becoming more favored by patients and physicians.

Countless AF studies have been conducted to assess the efficacy and safety of DOACs in patients with nonvalvular AF. The open-label, randomized RE-LY trial (NCT00262600) comparing dabigatran and warfarin has shown an annual rate of stroke and systemic embolism of 1.1% and 1.7%, respectively.

 The annual rate of stroke and systemic embolism was 2.1% with rivaroxaban and 2.4% with warfarin in the ROCKET- AF trial (NCT00403767).

 ARISTOTLE (NCT00412984), comparing apixaban and warfarin, has shown an annual stroke and systemic embolism rate of 1.3% and 1.6%, respectively.

 Additionally, in the EngageAFTIMI48 trial (NCT00781391), the annual rate of the conditions was 1.6% with edoxaban and 1.8% with warfarin.

 There is major concern about the lack of ability to monitor the level of anticoagulation with the newer agents.

Patients and physicians tend to overestimate the risk of bleeding and, thus, anticoagulation in eligible patients is often withheld. According to an analysis of stroke prevention studies, approximately 25% to 30% of patients with a CHA2DS2-VASc score of 2 or higher are not on anticoagulants.

 Stroke prevention is vital in patients with HIV.

There are potential drug-drug interactions between anticoagulants and antiretrovirals (ARVs). Certain ARVs, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs), the PK booster cobicistat (COBI), and protease inhibitors (PIs), have significant drug interactions with other medications. These interactions may be complex and difficult to predict.

The coadministration of some ARVs with non-ARV medications may be contraindicated or require dosage adjustment. All NNRTIs and PIs are metabolized by the hepatic CYP 450 system, particularly CYP3A4.

All PIs are CYP3A4 substrates. They are either inducers or inhibitors of other CYP isoenzymes or P-glycoprotein (P-gp). NNRTIs are substrates of CYP3A4, and can act as inducers, inhibitors, or mixed inducers.

Warfarin is metabolized in the liver by the CYP 450 enzymes, with the R enantiomer metabolized by CYP3A4, CYP1A2, and CYP2C19 and the S enantiomer by CYP2C9.

 PIs, such as atazanavir, darunavir, ritonavir, saquinavir, and tipranavir combined with ritonavir, have been shown to inhibit CYP 2C9 or 3A4. Hence, a 20% reduction in warfarin dose may be required.

Other PIs, such as lopinavir/ritonavir, nelfinavir, and ritonavir, can induce CYP 2C9 or 3A4 and, therefore, a 50% increase in a warfarin dose may be required.

 NNRTIs, such as delavirdine, efavirenz (2C9), and etravirine (2C9), can inhibit CYP 2C9 or 3A4. Thus, patients on these NNRTIs need a 50% reduction in warfarin dose.

Other NNRTIs, such as efavirenz (3a4), etravirine (3a4), nevirapine, and rilpivirine, can induce 2C9 or 3A4, causing an increase in the warfarin dose that is required to maintain the therapeutic international normalization ratio range of 100% to 140%.

 Hence, the challenge to treat patients with HIV who are anticoagulated with warfarin for stroke prevention is convoluted.

There are interaction possibilities at the level of absorption or first transformation and at the level of metabolism and excretion. The PI ritonavir, which is a strong 3A4 inhibitor, is more likely to precipitate a clinical effect when used with certain DOACs, such as Eliquis and Xarelto, concomitantly.

The area under the curve of dabigatran may rise as a result of the administration of P-gp. However, it may be clinically irrelevant if the administration is separated by 2 hours.

 There are no expected clinical drug interactions between dabigatran and the NNRTIs/integrase inhibitors.

Dabigatran appears to be favorable for patients who have HIV with AF. The Department of Health & Human Services’ Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV recommend specific adjustments if the administration of an ARV and DOAC is necessary.

A 50% Eliquis dose reduction and toxicity monitoring are required when the drug is combined with Elvitegravir/Cobicistat (EVG/c).

 The coadministration of betrixaban, dabigatran, edoxaban, and rivaroxaban and EVG/c is not recommended.

Selecting the ARV and DOAC with a lower potential of drug interactions is the key to drug interaction management.

Individuals with HIV have an increased risk of AF and stroke. DOACs provide the promise of more convenient and safer anticoagulation. However, concerns arise about the lack of an antidote for some of these agents. In addition, periprocedural management remains questionable. Although guidelines recommend DOACs as alternatives to warfarin, because of increased efficacy and safety, it is important to conduct a proper review and evaluation of ARV and DOAC pharmacokinetics and metabolism prior to recommending treatment in individuals with HIV to prevent stroke in AF.

, is an advanced practice clinical pharmacist at Brigham and Women’s Hospital in Boston, Massachusetts. 

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