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An 80-year-old male arrived at the Emergency Department (ED) in a serious condition: he was coughing up blood. Although he coughed up about three tablespoons (50cc/hr), he was hemodynamically stable. A physician approached me with an unfamiliar question: “Could we give him nebulized TXA?” I looked at him for a moment, nonplussed. “What?!” I exclaimed, “Hold on—let me look it up and get back to you.” Questions flooded my mind: Is it effective? Is it safe? If so, what is the appropriate dosage? 

Hemoptysis, defined as the expectoration of blood, alone or mixed with mucus, is a common symptom encountered in the ED.[ 1] In most cases, hemoptysis is a self-limiting condition. In others, it may become a life-threatening condition that warrants urgent investigation and treatment. [2] Although the choice of a cutoff value is controversial, the method of distinguishing between “massive” and “non-massive” hemoptysis involves measuring the volume of blood expectorated over a period of 24 hours; some sources cite the amount that has to be coughed up for the hemoptysis to count as “massive” to be in the 100 mL to 1000 mL range. However, no specific volume has been accepted universally. It is worth noting that the volume of blood is not solely indicative of massive hemoptysis; rather, it is the continuous bleeding which causes life-threatening conditions such as abnormal gas exchange or hemodynamic instability.[3] 

An invasive procedure may be required to control hemoptysis; this generally lies outside the scope of emergency medicine.[1] Thus, management of hemoptysis in the ED primarily focuses on airway protection, reversal of coagulopathies, supportive care, and investigation of the bleeding site, after which one may guide the patient toward other definitive treatment measures. Tranexamic acid (TXA) is a synthetic derivative of lysine.[4] It acts as an inhibitor of fibrinolysis by blocking the lysine-binding site of plasminogen to fibrin. The drug has been widely used to promote hemostasis during surgery or in cases of inner organ bleeding. Its use has been steadily increasing and multiple studies have shown it to be effective in treating non-massive hemoptysis, whether given orally or intravenously. However, few studies have described the potential benefits of using TXA as a nebulizer to control hemoptysis save for a randomized controlled trial that was published in October of this year. 

A number of case reports have demonstrated nebulized TXA to be both safe and effective.[5, 6] Each of the two cases detailed a scenario of patients presented to the ED suffering from massive hemoptysis and mild respiratory distress. 1000 mg of nebulized TXA was diluted with 0.9% normal saline to form either a 10 mg/mL or 50 mg/mL solution. The bleeding ceased within 10 to 15 minutes of administration with no recurring episodes of hemoptysis. Moreover, a total of three case series examining the effects of inhaled TXA as a nebulizer to control hemoptysis have been published.[7, 8, 9] In the first series, four patients were presented to the ED with hemoptysis: one of them suffered from a massive hemoptysis of 500 mL while no volume was reported for the other three patients.[7] Their conditions were managed with aerosolized TXA (500mg administered four times daily). TXA caused a rapid cessation of bleeding. In a second series, four patients with moderate hemoptysis (mean blood volume of 100 mL/ day) were treated with 250 to 500mg doses every 8 hours of TXA via nebulizer with a flow rate of 5 L of oxygen per minute.[8] The treatment resulted in successful bleeding cessation in all cases. There was a caveat, however: researchers noted that one patient experienced a bronchospasm after three doses of TXA. In the third case series, it was reported that a series of two patients with acute massive hemoptysis were treated with nebulized TXA in doses of 500 mg every 8 hours.[9] Both patients experienced a complete cessation of bleeding within a 48 to 72-hour period. 

In 2010, a group of investigators from Spain published a two-year prospective observational trial that tested endobronchial TXA as a treatment for moderate hemoptysis in patients who failed to respond to either topical adrenaline or ice-cold saline lavage.[10] The study included patients whose bleeding rates ranged from 50-100 mL/hr for patients with normal lung function or from 25-50 mL/hr for patients with chronic lung failure. 

The bleeding was categorized into two groups: the iatrogenic group, composed of patients whose bleeding was a result of bronchoscopy (regardless of the amount of blood), and the non-iatrogenic group, made up of those patients suffering from spontaneous bronchial bleeding (> 200 mL within a 24-hour period).[10] TXA was administered via endobronchial instillation in doses of 500 mg; it was diluted with 15mL normal saline. A total of 48 patients were treated with TXA; 20 were in the iatrogenic group and 28 in the non-iatrogenic group. All 20 patients in the iatrogenic group successfully responded to TXA and 11 out of 28 patients in the non-iatrogenic group responded to the treatment (39.2%). In terms of safety, none of the subjects in either patient group suffered from thrombosis or otherwise adverse events related to TXA. 

A recent prospective, double-blind, placebo-controlled, randomized controlled trial (RCT) was conducted to evaluate the efficacy of TXA as nebulizer for hemoptysis.[11] Patients were excluded if they presented with more than 200 mL of expectorated blood over 24 hours, hemodynamic instability, renal failure, or hepatic failure. Antiplatelet and anticoagulant agents were held until the hemoptysis was resolved. Patients received either 500 mg of nebulized TXA or a placebo (5 mL of 0.9% normal saline) three times daily for up to 5 days from date of admission. A total of 47 patients were randomly assigned to receive either TXA (25 patients) or a placebo (22 patients). The study showed that nebulized TXA resulted in complete resolution of hemoptysis within 5 days in 96% of patients in the TXA group versus 50% in the placebo group. From the second day of admission, those who were administered nebulized TXA experienced a marked reduction in bleeding levels compared to those patients in the placebo group. Notably, the length of stay was also shorter for those in the TXA group vs. placebo group by an average of 2.1 days. In terms of safety, no adverse effects were reported from either group. 

TXA has a number of minor side effects including nausea, headache, and musculoskeletal pain.[4] Another potential concern is the theoretical risk of arterial and venous thrombosis based on its mechanism of action. Although multiple trials have showed no increase in the risk for thrombosis with systemic administration of TXA, seizure did occur in one case. Apart from seizure (<1%), no other major side effects have been reported.  Based on published RCTs, observational trial, case series, and case reports, only one instance of bronchospasm was reported. 

We can safely conclude that nebulized TXA administration via inhalation is a successful treatment with few to nil adverse effects.[4] It can rapidly control hemoptysis and serves as a palliative option in treating chronic hemoptysis.  It also serves as a viable form of bridging therapy for hemodynamically stable patients to avoid endotracheal intubation until other definitive therapies can be arranged. The dosage for nebulizer use ranges from 250-500 mg every 6 to 8 hours or 1000 mg as a single dose.[4,6]  
 
Raniah Aljadeed, PharmD
PGY2 Emergency Medicine Pharmacy Resident
University of Arizona College of Pharmacy 
Northwest Medical Center

Peer reviewed by Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)


References: 

  1. Ittrich H, Bockhorn M, Klose H, et al. The Diagnosis and Treatment of Hemoptysis. Dtsch Arztebl Int. 2017 Jun; 114(21): 371–381. 
  2.  Larici AR, Franchi P, Occhipinti M, et al. Diagnosis and management of hemoptysis. Diagn Interv Radiol. 2014 Jul-Aug; 20(4): 299–309. 
  3. WH Ibrahim. Massive haemoptysis: the definition should be revised. Eur Respir J. 2008 Oct; 32(4):1131-2.  
  4. Gadre A, Stoller JK. Tranexamic acid for hemoptysis: a review. Clin Pulm Med. 2017; 24(2):69-74. 
  5. Hankerson MJ, Raffetto B, Mallon WK, et al. Nebulized Tranexamic Acid as a Noninvasive Therapy for Cancer-Related Hemoptysis. J Palliat Med. 2015 Dec; 18(12):1060-2. 
  6. Komura S, Rodriguez RM, Peabody CR. Hemoptysis? Try Inhaled Tranexamic Acid. J Emerg Med. 2018 May; 54(5):e97-e99.  
  7. Solomonov A, Fruchter O, Zuckerman T, et al. Pulmonary hemorrhage: A novel mode of therapy. Respir Med. 2009 Aug; 103(8):1196-200. 
  8. Segrelles Calvo G, De Granda-Orive I, Lopez Padilla D. Inhaled tranexamic acid as an alternative for hemoptysis treatment. Chest. 2016; 149:604. 
  9.  Patel M, Abbas F, Sheppard T. 1887: hemoptysis controlled with the use of inhaled tranexamic acid: a case series. Crit Care Med. 2016; 44(suppl 1):547. 
  10. Márquez-Martín E, Vergara DG, Martín-Juan J, et al. Endobronchial administration of tranexamic Acid for controlling pulmonary bleeding: a pilot study. J Bronchology Interv Pulmonol. 2010 Apr; 17(2):122-5. 
  11. Wand O, Guber E, Guber A, et al. Inhaled Tranexamic Acid for Hemoptysis Treatment: A Randomized Controlled Trial.  Chest. 2018 Oct 12.
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Nausea and vomiting is a common chief complaint in the ED, one I never really paid much attention to unless prompted (appropriate agent to use in pregnancy, which medication to use for a patient with a prolonged QTc, etc.) - at least, that was my practice before I began practicing in Miami.

 In one of the many unforgettable cases I have had in the ED, there was a young patient who presented with nausea and vomiting. The interesting part of this case was the medication request – mannitol. I for sure thought the team had come back from CT where they discovered a huge intracranial hemorrhage with midline shift. I ran to the ED with the medication fully expecting the team to be mid-intubation. Catching my breath, I asked what the mannitol was for? The resident responded with, “Ciguatera poisoning!”

Ciguatera was something I never heard in my practice prior to moving to Miami (admittedly, I never used mannitol other than for managing increased ICPs). Ciguatera fish poisoning (CFP) is the most common worldwide fish poisoning. Annually, anywhere from 10,000 to 500,000 cases are reported; however, the true incidence is difficult to determine due to underreporting (1-3). It is the most common fish-related foodborne illness reported in the United States. CFP arises from ingesting fish containing ciguatoxin (CTX) and is not prevented by any storage, handling, or cooking method.

Microscopic algae, known as dinoflagellates from the Gambierdiscus spp., produce ciguatoxins (CTX), a class of tasteless, heat-stable, polycyclic toxins. These dinoflagellates grow on seaweed, living and dead coral, and other substrates in shallow tropical and subtropical waters (3). They are ingested by herbivorous reef fish, which in turn are consumed by larger carnivorous fish, with the latter serving as the primary source of human illness. CTXs are lipid-soluble and bioaccumulate through the food chain, having larger concentrations in larger carnivorous fish in tropical, pelagic (open) waters (these fish are more likely to cause toxicity in humans; however, ingestion of any reef fish may cause harm). There are case reports of passage of CFP as a result of human-to-human transmission through sexual intercourse and from nursing mother to infant and pregnant mother to fetus.

Examples of Fish Containing Ciguatoxin
Barracuda
Grouper
Wrasses
Amberjack
Moray
Eel Snapper
Parrot Fish

Greater than 500 species of fish are associated with CFP. Examples of fish implicated in causing CFP are listed above. This poisoning is endemic in tropical and subtropical areas, particularly in the Caribbean and Indo-Pacific regions; however, due to international seafood trade, travel, and climate change, CFP is increasingly encountered in non-endemic regions (2, 3, 5, 6).

 
Photo credit: Kloss and Bruce. Video Flashcard: Ciguatoxin

CTX is tasteless, colorless, and odorless. It is not affected by any food storage or preparation techniques as it is heat and acid stable, and is stable for at least 6 months at commercial freezing temperatures (3-4). Interfering with neuronal voltage-gated sodium channels, CTXs render sodium channels open at resting membrane potential, causing an influx of sodium, which results in uncontrolled membrane depolarization and repetitive action potentials. Neuronal potassium channels may also be inhibited. The sodium influx draws water into the neurons and as animal evidence illustrates, results in axonal edema at the nodes of Ranvier. This swelling impairs saltatory conduction along the axon, slowing sensorimotor conduction velocities. Edema may also occur in Schwann cells and myelin fibers, affecting nerve conduction. Intracellular calcium also increases, disrupting cell-ion exchange mechanisms, producing fluid secretion and diarrhea (3, 5, 6)

Gastrointestinal (GI), neurological, and cardiovascular symptoms may occur and could begin as early as 6 hours post-ingestion. GI symptoms usually begin within 6 to 12 hours and may resolve spontaneously within 1 to 4 days. The most commonly reported GI symptom is diarrhea. Other symptoms include abdominal pain, nausea, and vomiting. Neurological symptoms present within the first 2 days of illness, often becoming more prominent after GI symptoms. These symptoms begin appearing within 24 hours post ingestion, but may be delayed up to 72 hours. Symptoms include paresthesias in the limb extremities and circumoral regions, metallic taste, pruritus, myalgias, and arthralgias. Sensation of loose teeth, headache, and dizziness may also occur. One of the coolest symptoms (no pun intended) is cold allodynia, which is pathognomonic for ciguatera toxicity. This distinctive neurologic symptom causes a reversal of temperature sensation: cold feels hot and hot feels cold. In essence, when a patient touches something cold it causes a burning sensation or dysesthesia, an unpleasant, abnormal sensation. Coma and hallucinations have also been reported. Neurological symptoms may persist for months and up to years. Cardiovascular symptoms generally manifest in the early stage of the illness and present as bradycardia and hypotension (2-7).

Diagnosis of CFP consists of presenting symptoms, time course, history of eating reef fish, and the exclusion of other diagnoses (particularly other marine ingestion toxicities such as paralytic and neurotoxic shellfish poisonings, scombroid, and tetrodotoxin). Scombroid, another common fish poisoning, is associated with oceanic fish, with symptoms largely attributed to histamine reaction (swelling, flushing, hives, etc.). Other items on the differential include botulism, enterovirus, bacteremia, and organophosphate poisoning. CFP also shares clinical features with polyneuropathies such as multiple sclerosis. Currently, the gold standard for the confirmation of CFP is the detection of CTX in the flesh of the consumed fish. CTX may be detected in fish flesh through a number of assays; however, these tests are rarely available to the treating physician and are not completed in a timely fashion that would impact acute clinical management (2-6).

Management of CFP is largely supportive, treating hypovolemia with intravenous fluids, correcting electrolyte abnormalities, and using atropine in instances of bradycardia. Mannitol may also be used in the treatment of CFP. The use of mannitol is two-fold: (1) to reduce symptoms in the acute phase of illness (primarily neurologic symptoms); and (2) shorten the duration of symptoms beyond the acute phase. The beneficial effects of mannitol is thought to be attributed to the osmotic reduction of neuronal edema. Mannitol may also act as a scavenger of free radicals produced by CTX, may reduce the action of CTX at sodium and/or potassium channels, and may increase dissociation of CTX from its binding site. Mannitol is an osmotic diuretic, therefore, patients must be adequately resuscitated prior to initiating therapy. Mannitol is dosed at 0.5 - 1 g/kg (commonly 1 g/kg), is administered over 30 - 45 minutes, and should be given within 48 - 72 hours of toxic fish ingestion, although benefits have been observed weeks after ingestion (2-5).

The use of mannitol began in the 1980s, when 2 patients were treated with mannitol for presumed cerebral edema due to ciguatera poisoning. The ciguatera symptoms quickly and unexpectedly improved. This serendipitous discovery led to the use of mannitol in 22 additional patients with presumed CTX exposure. Mannitol was administered as 1 g/kg in this case series. This total group of patients consisted of 9 women and 15 men, ranging in age from 6 to 66 years of age. Mannitol was administered if the following criteria were met: paresis, vomiting severe enough to require fluid replacement, diarrhea at a frequency greater than one time per one and a half hours, muscle pain restricting ambulation, and hypotension requiring therapy (8).

After receiving mannitol, 18 out of 24 patients were released from the ED or hospital within 24 hours, 4 hospitalized for 48 hours, and 2 patients were hospitalized for 7 days. The mean time of symptom onset to mannitol administration was 10 hours in 21 patients. In 17 of 23 patients, all neurologic and neurosensory symptoms responded to mannitol within 10 minutes, and were completely resolved within 48 hours. The mean time to complete resolution of neurological symptoms of all cases was 10 hours. The authors concluded that mannitol should be considered in patients with signs and symptoms consistent with CFP (8).

When reviewing the evidence beyond the case series by Palafox et. al., much of the literature is anecdotal and reported in case reports and case series. There are two randomized trials comparing mannitol to other therapies. One trial by Bagnis et. al. compared mannitol to a combined infusion of glucose, calcium gluconate, pyridoxine, and ascorbic acid. In this study, patients who received mannitol had greater improvement in symptoms compared to the combination therapy (2, 6).

The other trial was a single center, randomized, double-blind trial by Schnorf et. al., that compared mannitol to normal saline for patients presenting with suspected CFP. This study found similar rates of the resolution of symptoms between mannitol and normal saline groups; however, there were limitations to this trial. Patients were treated all the way up to 672 hours post exposure (for maximal benefit, it is recommended to treat within the initial 48 to 72 hours), only observed for 24 hours (benefits may be seen 48 to 72 hours after the administration of mannitol), and was not known if this was the initial episode of CFP, as subsequent episodes could be more severe (2, 6, 9)

As a result, through case studies, case series, and anecdotal reports, mannitol should be considered for patients presenting with CFP that present within 48 to 72 hours of exposure. Patients presenting beyond 72 hours should be evaluated on a case by case basis prior to administering mannitol. Always consult your poison center for poisonings and overdoses at 1-800-222-1222.

When patients present with nausea and vomiting in the ED, don’t just brush off the symptoms as typical - always inquire if they have had any seafood, and what type - it could be ciguatera.

Ruben Santiago, PharmD, BCPS, BCCCP
Associate Residency Program Director, Emergency Medicine
Jackson Memorial Hospital
Miami, FL Twitter: @thepeoplesruben 
Instagram: @TheEDTraumacist 

Reviewed and edited by: Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)

References:


1. Traylor J, Gossman W. Toxicity, Ciguatera. StatPearls. Treasure Island (FL): StatPearls Publishing. 2018. https://www.ncbi.nlm.nih.gov/books/NBK482511/


2. Friedman M, Fleming L, Fernandez M, et. al. Ciguatera fish poisoning: treatment, prevention and management. Mar Drugs. 2008; 6: 456-479.


3. Friedman M, Fernandez M, Backer L, et. al. An updated review of ciguatera fish poisoning: clinical, epidemiological, environmental, and public health management. Mar Drugs. 2017; 15(72): 1-43.


4. Copeland N, Palmer W, Bienfang P. Ciguatera fish poisoning in Hawai’i and the Pacific. Hawai’i Journal of Medicine and Public Health. 2014; 73(11): 24-27.


5. Greene S. Ciguatera. In: Critical Care Toxicology. Springer International Publishing AG 2017.


6. Mullins M, Hoffman R. Is mannitol the treatment of choice for patients with ciguatera fish poisoning? Clinical Toxicology. 2017; 55(9): 947-955.


7. Ting J, Brown A. Ciguatera poisoning: a global issue with common management problems. European Journal of Emergency Medicine. 2001; 8: 295-300.  


8. Palafox N, Jain L, Pinano A, et. al. Successful treatment of ciguatera fish poisoning with intravenous mannitol. JAMA. 1988; 259: 2740-2724.


9. Schnorf H, Taurarii M, Cundy T. Ciguatera fish poisoning: a double-blind randomized trial of mannitol therapy. Neurology: 2002; 58: 873-880.


10. Schwarz E, Mullins M, Brooks C. Ciguatera poisoning successfully treated with delayed mannitol. Annals of Emergency Medicine. 2008; 52(4): 476-477.  

11. Suguitan M, Rao R. Scombroid. In: Critical Care Toxicology. Springer International Publishing AG 2017.
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Emergency Medicine PharmD by Mark Mixon - 11M ago

Fosfomycin: The Forgotten Treasure


We have all been there, a patient with so many complicating factors that it’s difficult to choose the least worst option to treat a urinary tract infection. For example: a patient with a CrCl ~22 ml/min, a prolonged QTc, sulfa allergy (described as immediate death), and amoxicillin allergy (also somehow described as immediate death) who absolutely refuses to try a cephalosporin. How is it this difficult to treat a simple urinary tract infection?!?!?!

There is one antibiotic that has your back, fosfomycin (Monurol®). (And to get this out of the way, I fully endorse challenging penicillin allergies with appropriate agents, as long as the provider, the care team, and the patient are on board with the plan.)

What is Fosfomycin1,2
Fosfomycin is a bactericidal phosphoric acid derivative antibiotic that disrupts cell wall synthesis by inhibiting pyruvyl transferase. Fosfomycin is only available as a 3g oral sachet in the United States, though it is available as an intravenous product elsewhere.

Spectrum of Activity
Fosfomycin has activity against a broad range of gram-positive and gram-negative aerobic microorganisms commonly associated urinary tract infections. These include E.coli, Klebsiella spp. Enterococcus spp.(including vancomycin resistant Enterococcus spp [VRE]), Enterobacter spp., Citrobacter spp. Pseudomonas spp., and Serratia spp. Additionally, and discussed in more detail below, fosfomycin commonly retains activity against extended spectrum beta-lactamase (ESBL) producing organisms and  carbapenem-resistant enterobacteriaceae (CRE).

Notable PK1,2
●     Absorption- Fosfomycin’s oral bioavailability is approximately 30-37%. Due to the limited systemic absorption, use in pyelonephritis, peri-nephric abscess, or any systemic infection is contraindicated.
●     Distribution- Due to limited systemic absorption, it is expected that oral fosfomycin has minimal tissue distribution.

Adverse Effects of Significance 2
Fosfomycin is generally very well tolerated. The most common adverse effects include diarrhea, nausea, and headache, which happen to be common adverse effects of most drugs.

Fosfomycin in Pregnancy 1
Adverse events have not been observed in animal reproduction studies. Several studies have used a single dose of fosfomycin for the treatment of asymptomatic bacteriuria in pregnant women with no adverse fetal effects reported. Fosfomycin is classified as a pregnancy category B drug.

Preparation and Administration 1,2
The contents of each 3g sachet should be poured into 3-4 ounces (½ cup) of cold water and stirred until completely dissolved. Hot water should not be used. The solution should be administered by mouth immediately after it is prepared.

Potential Roles of Fosfomycin
Fosfomycin is a first line option for uncomplicated cystitis per the current IDSA guidelines for the treatment of uncomplicated cystitis. However, we have no shortage of agents for uncomplicated cystitis, many of which are less expensive, narrower in spectrum, and more readily available at a typical community pharmacy than fosfomycin. Where fosfomycin really presents a unique option is in the following situations:


Potential Role
Fosfomycin In-vitro susceptibility
Clinical Cure Rate
ESBL cystitis3,4,5,10,16  
95.1-100%
93%
VRE cystitis*† 6,7,8,9,10,16
86-98.7%
82%
CRE cysitis† 10,11,16
73.5-93%
-
Pseudomonal cystitis† 10,14
75-85%
-
Patients with multiple severe allergies or predisposing factors that limit other options13,14,15,17,18


E.coli: 94-100%
(non-ESBL/CRE)


91.1-96%
Patients at high risk for noncompliance 13,14,15,17,18
*One study showed 77% in-vitro susceptibility with an additional 21% intermediate          †Due to the lack of acknowledged fosfomycin breakpoints for bacteria other than E. coli and E. faecalis, results were interpreted according to criteria for E.coli and E. faecalis (i.e. susceptible at a MIC ≤64 g/ml)

Despite promising in-vitro data for the treatment of CRE and Pseudmonal cysitits there is limited clinical data for use against these pathogens. Patients should be carefully selected when using fosfomycin in these situations.

Drug-Drug Interactions
Medications used to increase gastrointestinal motility (e.g. metoclopramide) may decrease oral absorption of fosfomycin, thus reducing its efficacy.

Help with Adding to Formulary

Susceptibility Testing
Most microbiology laboratories do not routinely perform susceptibility testing for fosfomycin. Send outs usually take some time, and in my experience I rarely receive the results before the patient has finished their course of fosfomycin. Meaning the results weren’t useful in that we already clinically knew if the treatment had worked or not. For this reason I generally don’t recommend send out fosfomycin susceptibilities, even when using fosfomycin for a pathogen for which it has variable activity.

Other Tips
●     Team up with your inpatient colleagues- They have just as much incentive to want fosfomycin available. Fosfomycin can prevent admissions solely for IV antibiotic therapy to treat MDR-pathogens for which no other oral options are available, this is important to us from an ED perspective. From an inpatient perspective fosfomycin may help facilitate the discharge of a patient receiving IV antibiotics for MDR-pathogens. It’s a great way to build relationships and having multiple areas of the institution pushing for fosfomycin make it difficult to say no.
●     Reach out to local pharmacies-  Ask them to stock fosfomycin so you have a go to place for patients to get it. Preferably something close to the ED.
●     Work with case management- Many insurances require a prior authorization to cover fosfomycin. Pharmacies in my area charge about $90 per dose without insurance making it cost prohibitive for many patients. I’ve found case management to be extremely helpful in these instances.

Dosing Considerations1,2,10,12


Indication
Dose*
Uncomplicated UTI
3g PO x 1 dose
Complicated UTI
3g PO q48-72h x 3 doses
Prostatitis
3g q48-72h x 21 days
*There are no renal or hepatic doses adjustments for oral fosfomycin.




One Punch Knockout Too Good To Be True?
Huttner et al. recently published a study comparing clinical and microbiologic efficacy of nitrofurantoin 100mg po three times daily and fosfomycin 3g as a single dose in women with uncomplicated cystitis.19 They found clinical resolution through day 28 was achieved in 70% of patients receiving nitrofurantoin vs 58% receiving fosfomycin ([95% CI, 4%-21%]; P = 0.004). This calls into question if a single 3g dose of fosfomycin is adequate for the treatment of uncomplicated cystitis. Until there is a study to specifically answer this question, we will have to practice in a grey area. Here are some things to consider:

●     MacroTID???- nitrofurantoin 100mg po twice daily is endorsed by the IDSA rather then the three times daily used in this study. Since the pharmacokinetic/pharmacodynamic index that best correlated to the antibacterial activity of nitrofurantoin against E.coliwas T>MIC, increasing the frequency of nitrofurantoin dosing may make it an unfair comparison.20
●     Most patients with MDR pathogens have complicated cystitis- in reserving fosfomycin primarily for MDR pathogens we will therefore primarily be using 3 dose regimens
●     One dose of fosfomycin > zero doses of anything else- for non-compliant patients giving a single dose in the ED may be the only reasonable option


If you read nothing else:
●     Fosfomycin is an often forgotten oral antibiotic available for the treatment of lower urinary tract infections.
●     Fosfomycin retains activity against many MDR-pathogens such as ESBL, VRE, CRE, and Pseudomonas spp. making it an attractive oral option for cystitis caused by these pathogens.
●     Despite being a first line recommendation for uncomplicated cystitis per IDSA guidelines, fosfomycin may not be ideal for the majority of these situations. It is more broad in spectrum of activity,  is more expensive, and is less commonly stocked in retail pharmacies then many other options for uncomplicated cystitis.
●     Consider fosfomycin in patients with current or recent  history of MDR lower urinary tract infections, in patients with multiple drug allergies/predisposing factors that make other options not feasible, and/or in patients at high risk for noncompliance.
●     Fosfomycin can prevent admissions solely for IV antibiotic therapy to treat MDR-pathogens for which no other oral options are available.
●     Dosing of fosfomycin is unique in that uncomplicated UTIs may be treated with a single dose, though recent data has called this into question. Complicated UTIs should be treated with 3 doses.



Tony Mixon, PharmD, BCPS
Emergency Medicine/Infectious Disease Clinical Pharmacist




Peer reviewed by Craig Cocchio, PharmD, BCPS (@iEMPharmD), Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD), and Scott Dietrich, PharmD (@PCC_PharmD)


References
1.)   Product Information: MONUROL(R) sachet oral solution, fosfomycin tromethamine oral solution. Zambon Switzerland Ltd, Cadempino, Switzerland, 2007
2.)   Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc.; February 1, 2018.
3.)   Pullukcu H, Tasbakan M, Sipahi OR, et al. Fosfomycin in the treatment of extended spectrum beta-lactamase-producing Escherichia coli-related lower urinary tract infections. Int J Antimicrob Agents 2007; 29: 62-5.
4.)   Rodriguez-Bano J, Alcala JC, Cisneros JM, et al. Community infections caused by extended-spectrum beta-lactamase-producing Escherichia coli. Arch Intern Med 2008; 168: 1897-902.
5.)   Auer S, Wojna A, Hell M. Oral treatment options for ambulatory patients with urinary tract infections caused by extended-spectrum-beta-lactamase-producing Escherichia coli. Antimicrob Agents Chemother 2010; 54: 4006-8
6.)   Varughese C, Tichy E, Topal J. Oral fosfomycin in the treatment of vancomycin-resistant enterococcal urinary tract infections. Abstract #215. IDSA Annual Meeting; October 21, 2011 Boston, MA.
7.)   Shrestha NK, Chua JD, Tuohy MJ, et al. Antimicrobial susceptibility of vancomycin-resistant Enterococcus faecium: potential utility of fosfomycin. Scand J Infect Dis. 2003; 35: 12-4.
8.)   Allerberger F, Klare I. In-vitro activity of fosfomycin against vancomycin-resistant enterococci. J Antimicrob Chemother 1999; 43: 211-7.
9.)   Perri MB, Hershberger E, Ionescu M, et al. In vitro susceptibility of vancomycin-resistant enterococci (VRE) to fosfomycin. Diagn Microbiol Infect Dis 2002; 42: 269-71.
10.) Neuner EA, Sekeres J, Hall GS, van Duin D. Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms. Antimicrob Agents Chemother 2012 ;56:5744-8.
11.) Endimiani A, Patel G, Hujer KM, et al. In vitro activity of fosfomycin against blaKPC-containing Klebsiella pneumoniae isolates, including those nonsusceptible to tigecycline and/or colistin. Antimicrob Agents Chemother 2010; 54: 526–9.
12.) Los-Arcos I,  Pigrau C, Rodríguez-Pardo D, et al.  Long-term fosfomycin-tromethamine oral therapy for difficult-to-treat chronic bacterial prostatitis. Antimicrob Agents Chemother 2016 ; 60: 1854–58.
13.) Swiatlo E, Sells N, Chasta D et al. In Vitro Susceptibility of Common Urinary Tract Pathogens to Fosfomycin. Open Forum Infectious Diseases, Volume 1, Issue suppl_1, 1 December 2014, Pages S36
14.) Maraki S, Samonis G, Rafailidis P et al. Susceptibility of urinary tract bacteria to fosfomycin. Antimicrob Agents Chemother. 2009 Oct;53(10):4508-10
15.) Karlowsky JA, Denisuik AJ, Lagacé-Wiens PR et al. In Vitro activity of fosfomycin against Escherichia coli isolated from patients with urinary tract infections in Canada as part of the CANWARD surveillance study. Antimicrob Agents Chemother. 2014;58(2):1252-6
16.) Vardakas KZ, Legakis NJ, Triarides N, Falagas ME. Susceptibility of contemporary isolates to fosfomycin: a systematic review of the literature. Int J Antimicrob Agents. 2016 Apr;47(4):269-85.
17.) Stein GE. Comparison of single-dose fosfomycin and a 7-day course of nitrofurantoin in female patients with uncomplicated urinary tract
infection. Clin Ther. 1999; 21: 1864-72
18.) Bozkurt O, Kara C, Akarsu S et al. Comparison efficacy of single dose fosfomycin with ciprofloxacin in the treatment of urinary tract infection in symptomatic women. Turk Uroloji Dergisi 2008; 34: 360–2.
19.) Huttner A, Kowalczyk A, Turjeman A et al. Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial. JAMA. 2018 May 1;319(17):1781-1789
20.) Komp Lindgren P, Klockars O, Malmberg C et al. Pharmacodynamic studies of nitrofurantoin against common uropathogens.J Antimicrob Chemother. 2015 Apr;70(4):1076-82


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In two previous post, I outlined my impressions of High-Yield Med Reviews based on my experience going through the modules and webinar. While I still stand behind my evaluation of HYMR, my assessment was somewhat limited because it was all before the exam. Now that I have my scores, I feel I can give a more complete assessment of HYMR. In a nutshell: I passed, and highly recommend HYMR. 

In the final days before the exam, I was actually contemplating sitting for the full 200 question exam rather than the abridged recertification. My rationale was simply that I’d rather have more questions to attempt given the VAST amount of material that encompasses the pharmacotherapy exam. While I am glad I still went with the shorter version based on my result, my exam preparation had to consider that I couldn’t possibly cover all subjects of pharmacotherapy. Rather I took a more measured, calculated approach. With that in mind, I have a few tips to get the most out of studying with HYMR.

1) Get started early (3 months before) and do a little every day. It could be as little as 20 minutes, but getting in a regular habit of studying can have that initial 20 minutes stretch to an hour or two after a few weeks. With the format of the lecture modules from Dr. Busti, it’s easy to fit in at least one lecture during my morning run. For subjects like hypertension or asthma that I knew pretty well, I played them at 1.5x or 2x speed to review and slow down or rewind for elements I needed to hear again (ie, newish drugs, guideline updates, etc.)

2) Do as many practice questions as you can. Practice questions are the easiest way to identify weak areas, and brush up on your test taking skills. Similarly to the lectures, when you only have 5-10 minutes when your 10 month old is napping, you can bang out 5 questions and review the rationale, core concept and fast facts. Closer to the exam date, I set up ‘practice’ exams by selecting 200 randomized questions.

3) Don’t ignore practice management and regulatory issues. These are always the questions test takers talk about among each other after the exam. They aren’t difficult questions and there isn’t that much material. The succinct practice management modules are certainly a high-yield study tool.

4) It’s no secret that if you know stats inside out, you have a good chance of passing the exam. Spend time studying stats, participate in the webinars conducted with Dr. Busti, and read primary literature on a regular basis. These steps will ensure you’re able to answer any question.

5) Don’t forget, the reason you’re putting in all this effort is to become a better pharmacist! So constantly think of ways to implement your new knowledge (or reinforced knowledge) in practice through either direct patient care, clinical activities, or research.

Incorporating these five simple tips into your studying efforts with HYMR will ensure that you’re a) getting the most out of your investment, b) practicing efficient studying habits, and c) becoming a better clinician.

Disclosure:

I have a continuing partnerships with HYMR. I believe in Dr. Busti, and I am actively contributing to HYMR.
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Patient Case:
A 62-year-old female presents to the ED with left lower extremity pain and swelling and is diagnosed with a LLE deep vein thrombosis (DVT) on ultrasound. The patient’s past medical history is significant for hypertension and she takes amlodipine at home. Laboratory values, pulse oximetry, and vital signs are within normal limits. The ED physician approaches you about discharge anticoagulation options and asks for a recommendation. Which agent would you recommend for outpatient management of this patient’s DVT?

Background:
EM pharmacists are frequently involved in the drug selection, ordering, dose verification, and patient education regarding anticoagulants in the ED for admitted and discharge patients. We are in a unique situation in which we work closely with providers everyday to make our recommendation on the the best option for individual patients based on patient-specific factors, cost, potential drug interactions, and balancing safety with efficacy.

Since FDA approval of dabigatran in 2010, the NOAC class of anticoagulants has rapidly gained popularity. Zhu et al.1 recently published data concerning NOAC use among atrial fibrillation (AF) patients between 2010 and 2017. In 2017, they identified more than 7500 new patients started on an oral anticoagulant and 79% received a NOAC compared to 21% with warfarin. Of those NOACs, apixaban was the most common agent at 50.1%, followed by rivaroxaban at 25%, and dabigatran at 3.8%. With so many options available, how do you choose which agent to send your patient home on?

Efficacy and Safety Data
Based on the results of the industry sponsored trials, we know apixaban and rivaroxaban are non-inferior to warfarin,2-5 but what about compared to each other?

Lopez-Lopez et al. completed a systematic review and meta-analysis of all available Phase II and Phase III superiority and non-inferiority trials of NOACs and VKAs for stroke prevention in patients with AF.6 The best part about this study (aside from being open-access) was they actually compared each agent against each other. In terms of efficacy, rivaroxaban 20 mg daily was shown to be no different than apixaban 5 mg twice-daily in terms of stroke and systemic embolism, ischemic stroke, myocardial infarction, or all-cause mortality (see Table 1). When looking at safety outcomes, rivaroxaban was shown to increase the risk for major bleeding, GI hemorrhage, and clinically relevant bleeding compared to apixaban with no difference in intracranial hemorrhage (see Table 2).

Table 1: Indirect efficacy comparison of rivaroxaban and apixaban

Stroke or systemic embolism
Ischemic stroke
Myocardial infarction
All-cause mortality
Rivaroxaban 20 mg daily vs apixaban 5 mg BID,
OR (95% CI)
 1.11
(0.87-1.41)
1.01
(0.74-1.38)
0.92
(0.63-1.34)
0.94
(0.76-1.17)

Table 2: Indirect safety comparison of rivaroxaban and apixaban

Major Bleeding
Intracranial hemorrhage
Gastrointestinal hemorrhage
Clinically relevant bleeding
Rivaroxaban 20 mg daily vs
apixaban 5 mg BID,
OR (95% CI)
1.45 
(1.19-1.78)
1.55
(0.97-2.49)
1.66
(1.19-2.33)
1.53
(1.33-1.75)

What about real-world data? We know that Phase II and Phase III clinical trial results don't always translate equally to the general public, so how might these numbers change? Larsen et al. completed a large, retrospective, Danish study which extracted prescription data from three nationwide databases.7 Patients with AF were identified by first time purchases of NOACs or warfarin between 2011 and 2015. More than 122,000 patients were identified, and after exclusions approximately 62,000 patients were analyzed. Patients were mostly males aged 68 to 72 years with a CHADS2-VASC Score of 2.2-2.8. When compared to warfarin, there was no difference in hazard ratios (HR) for ischemic stroke or ischemic stroke + systemic embolism for apixaban compared to warfarin. Rivaroxaban showed a reduced HR compared to warfarin with the composite endpoint of ischemic stroke + systemic embolism (with the 95% CI upper limit at 0.99); but no difference in ischemic stroke alone. The composite endpoint of ischemic stroke + systemic embolism + death favored apixaban and rivaroxaban compared to warfarin (see Table 3).

In terms of safety outcomes including death, any bleeding event, and major bleeding events, HRs were lower with apixaban compared to warfarin, but not with rivaroxaban compared to warfarin (see Table 3). These trends favoring apixaban also continued when patients were stratified based on age of <65 or >65 years. Interestingly, intracranial hemorrhages with apixaban were no different compared to warfarin, but actually lower with rivaroxaban compared to warfarin in this cohort (see Table 3).

However, the original AMPLIFY2 and ARISTOLE4 trials both showed lower intracranial hemorrhage risk with apixaban compared to warfarin. Additionally, this systematic review and meta-analysis showed a lower ICH risk with apixaban vs warfarin and no difference between rivaroxaban vs warfarin.8 Taken together, I give the slight advantage to the RCT data over the Danish registry data given multiple trials with the same results and trust that apixaban is safer than warfarin.

Table 3: Real-world comparison of NOACs to warfarin
Apixaban vs Warfarin
HR (95% CI)
Rivaroxaban vs Warfarin
HR (95% CI)
Ischemic stroke + systemic embolism
1.08 (0.91-1.27)
0.83 (0.69-0.99)
Ischemic stroke
1.11 (0.904-1.3)
0.86 (0.72-1.04)
Ischemic stroke +
systemic embolism + death
0.79 (0.7-0.88)
0.87 (0.79-0.96)
Death
0.62 (0.56-0.75)
0.9 (0.82-1.03)
Any bleeding event
 0.63 (0.53-0.76)
0.99 (0.86-1.14)
Major bleeding
0.61 (0.49-0.75)
1.06 (0.91-1.23)
Intracranial hemorrhage
0.72 (0.42-1.24)
 0.56 (0.34-0.9)

Granted these data do not represent a direct, head-to head comparison between apixaban and rivaroxaban (and neither did the previous study as that data was generated via an indirect method). However, when the real world data closely mirrors clinical trial data with such large study populations, I feel fairly confident generalizing these overall trends when comparing apixaban and rivaroxaban against each other in terms of efficacy and safety.

Renal dosing concerns:
Both apixaban and rivaroxaban require renal dose adjustments. It is very important to note the dose cutoffs for each agent vary depending on the indication (AF vs VTE). Rivaroxaban can be utilized for AF patients with a CrCl > 15 ml/min but for VTE patients the cutoff is increased to a CrCl > 30 ml/min. Apixaban’s adjustments are based on serum creatinine and not necessarily a specific CrCl cutoff. Additionally, there is some data with reduced-dose apixaban showing similar AUCs in patients on hemodialysis as standard doses in patients with normal renal function.9 As only 4% of the drug was removed during a 4-hour HD session, it is unclear if the same dosing scheme of 2.5 mg BID could be applied to non-dialysis patients with significant chronic renal impairment.

Overall, check your drug references to ensure proper dosing given the varying cutoffs in CrCl, Scr, age, and indication used. If you have a patient in your ED with renal disease and for some reason they cannot (or refuse to) be treated with warfarin, choosing an alternative oral agent may be difficult. Among AF patients, rivaroxban’s lower CrCl cutoff of 15 ml/min should encompass a large number of potential patients. Alternatively, given the PK data of apixaban in HD patients, you could consider having a conversation with the provider and patient to decide if apixaban would be worth a try.

Drug interaction considerations:
Compared to warfarin, both apixaban and rivaroxaban have less concerns for drug-drug interactions. However, significant interactions do remain and the ED pharmacist should be vigilant to identify and correct such interactions. Both agents are substrates of CYP3A4 and P-glycoprotein (see Table 4 and Table 5). The most concerning interaction for either agent is with diltiazem and apixaban as is not uncommon for patients with atrial fibrillation to be maintained on diltiazem for rate control and therefore need long term anticoagulation. It’s unknown if the approximate 40% increase in apixaban AUC has any clinical significance, but for elderly patients, or those with a high bleeding risk, this combination should likely be avoided.

Table 4: Drug interactions with apixaban10,11
Drug
Dose
Change in apixaban AUC
Diltiazem
360 mg x10 days
↑ 40%
Ketoconazole
400 mg x6 days
↑ 100%
Naproxen
500 mg, single dose
↑ 50%
Rifampin
600 mg x11 days
↓ 54%


Table 5: Drug interactions with rivaroxaban12
Drug
Dose
Change in rivaroxaban AUC
Clarithromycin
500 mg BID x5 days
↑ 54%
Erythromycin
500 mg TID x5 days
↑ 34%
Ketoconazole
200 mg x3 days
↑ 53%
Ketoconazole
400 mg x5 days
↑ 2.6-fold
Rifampin
150 mg, 300 mg, 450 mg, then 600 mg x4 days
↓ 49%
Ritonavir
600 mg BID x6 days
↑ 2.5-fold


Cost considerations:
Given the relative “newness” of the NOACs, generic equivalents are not yet available. Therefore, as can be expected, these medications can be expensive. However, as they are no longer brand new, a larger percentage of private insurance and some state’s Medicaid Formularies will cover at least one NOAC. Additionally, cost-effectiveness analyses have shown favorable results with NOACs compared to warfarin, with apixaban conferring the greatest cost savings.13,14

In my home state of Colorado, the Medicaid Preferred Drug List still has warfarin as its first line option. However, rivaroxaban is a “preferred” agent, albeit second-line. Patients must meet some eligibility criteria to receive coverage, but we have not encountered any problems so far when properly selecting patients for discharge on rivaroxaban.

Most private insurance companies will cover at least one NOAC, likely more. According to Eliquis’s website, almost 95% of patients nationwide “have access to Eliquis.” They even have a tool for people to enter their state or ZIP code to find common prescription insurance plans in those areas to see if coverage is an option.

Luckily, our outpatient pharmacies associated with the hospitals have the ability to offer the first 30-days of therapy for either apixaban or rivaroxaban at no cost to the patient through manufacturer-sponsored programs. Although this is classic “drug dealing behavior,” we take advantage as frequently as possible. This one month of free therapy likely increases compliance which in turn would hopefully decrease the risk for return visits related to thromboembolic events. Additionally, the free month allows the patient to work with their insurance company to verify long term prescription coverage. If a different agent is required, it allows the patient time to meet with their PCP and set up the plan for change. Overall, these free “starter packs” are a great resource. Patients love being able to leave the ED with a 30-day supply of free medication and I’ll take any opportunity for the drug companies to give out free medication. It is unclear if this is available everywhere, but it may not hurt to contact a drug rep in your area to inquire about it if it is not something already available.

Which Agent to Choose?
Several points must be considered when choosing between rivaroxaban and apixaban. Both agents appear to be equally efficacious, but from a safety standpoint, apixaban is the winner in my book. Renal disease may preclude NOAC use, but for some patients rivaroxaban has a lower CrCl cutoff when used for AF than apixaban, so potentially slight advantage there. Cost considerations are very patient- and location-specific. Not mentioned thus far, but worth considering is the BID dosing of apixaban vs daily dosing with rivaroxaban. If patient compliance is a major concern, rivaroxaban will likely be preferred.

Consideration
Winning Medication
Efficacy
Apixaban = Rivaroxaban
Safety
Apixaban
Renal Dosing
Maybe rivaroxaban, varies by indication
Drug Interactions
Patient specific, unless on diltiazem then maybe favor rivaroxaban
Cost
Variable
Compliance
Rivaroxaban

Taken all together, there is a preferred agent in my book. Given similar efficacy, interaction potential, and medication costs, the major deciding factor is safety. Given the fact we don’t have a reliable reversal agent for Xa inhibitors at this point, and knowing the morbidity and mortality associated with major bleeding events, minimizing bleeding risk is of the utmost importance. Apixaban is a clear winner in this regard and is the reason I routinely recommend apixaban over rivaroxaban when both agents are options. In my experience so far, after having a discussion with the patient regarding the improved safety profile weighed against taking the medication twice daily, the vast majority of patients want the safer medication (and I would too). Even if the patient is only on once daily medications at home, you shouldn't rule out apixaban as they may want the safer option and just because a patient isn’t on a BID therapy doesn’t mean they can’t start now. Have a conversation, discuss the pros and cons, and give your patient all of the information to allow them to make the best decision.

Apixaban is likely the safest oral anticoagulant available, it is equally effective as other NOACs, and with more and more patients eligible for prescription coverage, it is my preferred oral anticoagulant.

Scott Dietrich, PharmD, BCCCP
Emergency Medicine Pharmacist
University of Colorado Health – North Region


*** Dabigatran Disclaimer ***
This post only mentions two oral anticoagulants. There are several more Xa inhibitors now available, but they are cost-prohibitive at this point. The other alternative NOAC is dabigatran. As mentioned above, in 2017, < 4% of new NOAC prescriptions were for dabigatran.1 Why? According to a series of 2014 BMJ articles,15,16 the manufacturer of dabigatran, Boehringer  Ingelheim, withheld information regarding the potential utility of serum drug monitoring. The confidential internal documents were only made available during the litigation process in the US. Though not published within the initial RE-LY trial, there was a large sub-study within RE-LY that measured serum drug levels.17 While only analyzing patients receiving the 150 mg BID dose of dabigatran, researchers found a extraordinarily wide variability in measured plasma concentrations. After 30 days of therapy, plasma levels ranged from 2.3 ng/ml to a max of 1000 ng/ml. After some adjustments, the researchers determined there was a 5.5-fold variability amongst the population. While there was a negligible decrease in event rates with higher plasma levels, there was a clear linear relationship with increasing bleeding event rates (see figure below).14 Despite this, the drug company did not recommend routine drug level monitoring to ensure safety even though the company determined that measuring and appropriately dosing dabigatran could reduce major bleeding by 30-40%.16 Overall, this medication is not as safe as apixaban6 and given the unethical behavior of the manufacturer and likely requirement for drug level monitoring to ensure safety, I am not recommending dabigatran in anyone at this time.





































References:
  1. Zhu J, Alexander GC, Nazarian S, Segal JB, Wu AW. Trends and variations in oral anticoagulant choice in patients with atrial fibrillation, 2010-2017. Pharmacotherapy. 2018, June [epub ahead of print]
  2. Agnelli G, Buller HR, Cohen et al. Oral apixaban for the treatment of acute venous thromboembolism (AMPLIFY). NEJM. 2013;29;369(9):789-808
  3. Prins MH, Lensing AW, Brighton TA, et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematology. 2014;1(1):e37-46
  4. Avezum A, Lopes RD, Schulte PJ, et al. Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Circulation. 2015;132(8):624-632
  5. Bansilal S, Bloomgarden Z, Halperin JL, et al. Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial). American Heart Journal. 2015;170(4):675-682
  6. Lopez-Lopez JA, Sterne JA, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ. 2017;359:j5058
  7. Larsen TB, Skoth F, Nielsen PB, Kjaeldgaard JN, Lip GYH. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation:propensity weighted nationwide cohort study. BMJ. 2016;353:i3189
  8. Almutairi AR, Zhou L, Gellad WF, Lee JK, Slack MK, Martin JR, Lo-Ciganic WH. Effectiveness and Safety of Non-vitamin K Antagonist Oral Anticoagulants for Atrial Fibrillationand Venous Thromboembolism: A Systematic Review and Meta-analyses. Clinical Therapeutics. 2017;39(7):1456-1478
  9. Mavrakanas TA, Samer CF, Nessim SJ, Frisch G, Lipman ML. Apixaban pharmacokinetics at steady state in hemodialysis patients. J Am Soc Nephrology. ..
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