• 24 Jan 2019 10:04 AM | MSHP Office (Administrator)

    Authors:  Emily Shor, PharmD; Alex Meyr, PharmD
    PGY-1 Pharmacy Practice Residents
    Mentor:  Davina Dell-Steinbeck, PharmD, BCPS
    SSM Health St. Mary’s Hospital – St. Louis

    Program Number:
    Approval Dates:
    Approved Contact Hours: One (1) CE(s) per LIVE session.

    Learning Objectives:

    1. Identify key differences between indications and dosing requirements for oral anticoagulants.
    2. List risk factors for bleeding complications caused by oral anticoagulation.
    3. Describe current and developing oral anticoagulant reversal strategies in patients with life-threatening bleeding.
    4. Explain the mechanism of action of each anticoagulant reversal agent.
    5. Evaluate current literature pertaining to reversal strategies in patients taking oral anticoagulants.

    Background
    Warfarin, a vitamin K antagonist (VKA) discovered in the 1920s, has been commonly used for prophylaxis and treatment of venous thromboembolism (VTE).1 The Food and Drug Administration (FDA) approved the first direct oral anticoagulant (DOAC), dabigatran, in 2010. This was followed by rivaroxaban in 2011, apixaban in 2012, and edoxaban in 2015.2-5 While warfarin is dosed to achieve target International Normalized Ratio (INR), the doses for DOACs for VTE treatment, VTE prophylaxis, and stroke/systemic embolism prophylaxis in nonvalvular atrial fibrillation (NVAF) are shown in Table 1.1-5


    The pharmacokinetic and pharmacodynamic profiles of each oral anticoagulant differ and should be considered when selecting an oral anticoagulant (Table 2). To varying extents, all DOACs are excreted renally. Dabigatran has the lowest protein binding and is the only dialyzable DOAC. As renal function decreases, each DOAC’s half-life and anticoagulant effects increase, resulting in increased risk for bleeding.2-5


    A patient’s risk for bleeding while receiving an oral anticoagulant can be assessed using the HEMORR2HAGES or HAS-BLED scores.7 Patients’ bleeding risk can vary based on the type of surgery; major orthopedic, cardiac, vascular, neurosurgical, cancer, and urologic surgeries are associated with an increased bleeding risk whereas minor surgeries are associated with low bleeding risk. Therefore, depending on the procedure, patients may need to hold their oral anticoagulant to avoid an increased risk of bleeding. Other key factors that are associated with increased risk of bleeding with concurrent oral anticoagulants include history of stroke/bleeding, trauma, nonadherence, concurrent use of antiplatelet or nonsteroidal anti-inflammatory drugs, advanced age, impaired renal or liver function, alcohol abuse, malignancy, and rheumatic heart disease.8

    Warfarin is routinely monitored with INR levels; however, DOAC therapy does not require routine drug monitoring. Routine coagulation assays, such as prothrombin time (PT), activated partial thromboplastin time (aPTT), or anti-Xa levels, have not been used for therapeutic monitoring of DOACs because results of these tests have not been reliably correlated to therapeutic outcomes. However, some studies show that PT, aPTT, and INR can be used to determine excessive DOAC plasma concentrations. Because the results of these tests are not sensitive, in patients with elevated levels, other etiologies should be assessed alongside the patient’s anticoagulation history.9 

    In patients with high risk of bleeding, reversal of anticoagulation may be necessary. Some approaches to managing acute bleeding may include mechanical intervention or administration of antidotes. This review will assess the role of possible antidotes for oral anticoagulants, including warfarin, dabigatran, and Factor Xa inhibitors.

    Warfarin Reversal
    The risk of bleeding with warfarin administration increases significantly when the INR exceeds 4.5. Currently there are three options for the urgent reversal of vitamin K antagonists, including vitamin K, four-factor prothrombin complex concentrate (PCC), and fresh frozen plasma (FFP). For patients with VKA-associated major bleeding, ACCP/CHEST guidelines recommend rapid reversal of anticoagulation with PCC rather than FFP (Grade 2C). Vitamin K 5 to 10 mg may also be administered by slow IV injection rather than reversal with coagulation factors alone (Grade 2C).10 ACCP/CHEST guidelines provide the following recommendations for warfarin reversal based on INR and evidence of bleeding:


    The time to effect of oral and intravenous vitamin K, respectively, is 24 hours and 8-12 hours. Both formulations’ effects can last for several days. In contrast, FFP and PCC have an immediate effect, which typically lasts 12 to 24 hours. The risk of thrombosis with vitamin K or FFP is insignificant; however, the use of PCC is associated with an increased risk of thrombosis.1,11

    While vitamin K has historically been used as warfarin’s primary reversal agent, in 2013, the FDA approved PCC (KCentra®) for the urgent reversal of VKA-associated acute major bleeding or need for urgent surgery or invasive procedure. PCC increases the levels of vitamin K-dependent coagulation factors (II, VII, IX, and X) and proteins C and S. PCC is contraindicated in patients with disseminated intravascular coagulation or known heparin-induced thrombocytopenia. Additionally, PCC has boxed warnings for arterial and venous thromboembolic complications. Both fatal and on-fatal arterial and venous thromboembolic complications have been reported with PCC in clinical trials and post-marketing surveillance.11

    PCC’s package insert provides the following recommendations for dosing based on the patient’s pre-treatment INR:11


    While PCC’s package insert recommends variable dosing, literature has supported the use of fixed-dose PCC as well.11 A randomized, plasma-controlled, phase IIIb study evaluated the safety and efficacy of 4FPCC for urgent VKA reversal. Adult patients (n=98) with an INR of at least 2.0 within three hours prior to study treatment and presenting with an active major bleed (life-threatening or potentially life threatening, acute bleed with a decrease in hemoglobin of at least 2 g/dL, or bleeding requiring transfusion of a blood product) were included. These patients received PCC, which was dosed based on the package insert’s recommended dosing strategy. 44.9%, 27.6%, and 72.5% of patients were reported to have a primary rating of excellent, good, and effective response, respectively. Overall, 62% of patients achieved an INR of less than or equal to 1.3 within 30 minutes post infusion with a median dose of 2475 IU. Four of the eight thromboembolic events reported were determined to be related to PCC.12

    An observational cohort pilot study assessed the safety and efficacy of PCC (Cofact®) for the reversal of VKA treatment in the setting of major or clinically relevant non-cranial bleeding or an emergency invasive procedure. In this study, the indication for PCC use and target INR was defined by the provider. Patients either received fixed dose PCC (1040 IU for major bleeding, 530 IU for emergency invasive procedure) or doses based on presenting INR, target INR, and body weight (pre-specified by study protocol). Ultimately, the study did not find any statistically significant differences in outcomes. Target INR was achieved in 70% and 81% of patients receiving fixed dose (n=35) or variable dose (n=32), respectively. The median dose utilized in the fixed dose group was 1040 IU and 1560 IU in the variable dose group (p=0.001). 28.8% of patients in the fixed dose group received 530 IU for an emergency invasive procedure and 62.8% received 1040 IU for major bleeding. One patient in the fixed dose group experienced a thromboembolic event compared to two patients in the variable dose group. This study suggests that a fixed dose of 1040 IU of PCC may be efficacious in rapidly reversing VKA therapy. If fixed dose PCC is shown to be as efficacious and safe as variable dosing, then this may result in significant cost savings. However, many studies reporting fixed dose PCC results have varying study methodologies, making it challenging to extrapolate this data.13

    For example, a retrospective cohort study assessed the safety, efficacy, and cost of a fixed dose PCC (Kcentra®) protocol. This study included adult patients receiving 1500 IU of PCC per the hospital’s protocol for any clinical indication for emergent VKA reversal and who were on chronic VKA therapy (mean presenting INR 3.3). Of the 39 included patients, 71.8% received PCC for an intracranial bleed. Their mean age and weight were 70 years and 79.5 kg respectively. With a single dose of 1500 IU PCC, 92.3% of patients’ INRs decreased to less than 2.0, and 71.8% of patients’ INRs successfully decreased to less than or equal to 1.5. One patient required a second dose of PCC, and no patients experienced a thromboembolic event within seven days. This study concluded that 1500 IU PCC was safe and efficacious for emergent warfarin reversal. While this study identified cost-savings, they did not directly compare these results to a variable dosing strategy. Additionally, patients with a presenting INR of less than 2.0 (n=4) and patients receiving FFP (n=11) were included, which may confound results.14 Because the mean presenting INR in this study was 3.3, it is also difficult to assess PCC’s efficacy and safety in patients with significantly higher INRs at baseline.

    Few studies have evaluated the safety and efficacy of fixed-dose PCC in comparison to variable dose PCC. However, reported studies show promising utility. The reported fixed-dose PCC studies have shown to be effective and offer similar outcomes as the landmark trials approving variable dose PCC. However, studies assessing fixed dose PCC included varying populations, making extrapolation of results challenging. For example, studies have not assessed the use of fixed dosing in the extremes of weight where the fixed dose may vary significantly when compared to variable dosing strategies. Because fixed dose PCC for the reversal of major bleeding has not been FDA approved, this may pose as an ethical dilemma if the fixed dose chosen is significantly higher or lower compared to a patient’s ultimate variable dose. Additionally, studies assessing the safety and efficacy of PCC for intracranial hemorrhages utilize varying fixed doses, so this niche population needs further study.

    Direct Thrombin Inhibitor Reversal

    Idarucizumab

    Idarucizumab (Praxbind®) is a humanized monoclonal antibody approved in 2015 for the reversal of dabigatran in patients undergoing emergency surgery or urgent procedure, as well as for life-threatening or uncontrolled bleeding.15 Idarucizumab binds to dabigatran and its metabolites with greater affinity than dabigatran binds to thrombin. Specifically, in vitro studies have shown that its affinity toward dabigatran is approximately 350 times stronger than dabigatran’s affinity for thrombin. It has also been demonstrated that idarucizumab does not bind to thrombin substrates, nor does it impact platelet aggregation.16

    In terms of safety, idarucizumab was studied by Glund and colleagues in a trial that included 110 healthy male volunteers, in a 3:1 ratio (idarucizumab to placebo) to receive doses of idarucizumab ranging from 20 mg to 8 g, given either as 1-hour infusions or 5-minute infusions.17 Drug-related adverse events seen in this study were infrequent and of mild intensity. Additionally, this study demonstrated that idarucizumab had no effect on thrombin or other coagulation factors when given to patients not taking dabigatran.17

    In another study by Glund and colleagues, both the safety and efficacy of idarucizumab was assessed in a phase 1, randomized, placebo-controlled trial in Belgium. This study included healthy male volunteers from the age of 18 to 45 who were given dabigatran 220 mg twice daily for three days and once on day four and then randomly assigned them to four different idarucizumab dose groups (1 g, 2 g, 4 g, or 5 g plus 2.5 g).18 Twelve patients were included in each of the first three groups, and 11 patients were included in the last group. Within each group, patients were assigned in a 3:1 ratio of idarucizumab to placebo. Overall, this study found idarucizumab to be well-tolerated as all drug-related adverse events reported (~15% of patients) were of mild intensity, ranging from infusion site erythema to epistaxis and hematuria. Regarding efficacy, idarucizumab’s ability to reverse dabigatran was rapid, complete, and dose-dependent (reduction in diluted thrombin time for each of the four dosing strategies mentioned above was 74%, 94%, 98%, and 99%, respectively).18

    Given the demonstrated safety and efficacy of idarucizumab in healthy individuals, Pollack and colleagues subsequently published a prospective cohort study that aimed to assess the effects of idarucizumab in patients on dabigatran who either had serious bleeding (group A) or required an urgent procedure (group B).19 In the interim analysis of this trial (RE-VERSE AD trial), 90 patients received 5 g of idarucizumab given as two, 2.5 g bolus infusions no more than 15 minutes apart. The primary efficacy endpoint of this study was the maximum reversal effect of dabigatran from the end of the first idarucizumab infusion to four hours after the second infusion. The maximum reversal effect was determined by dilute thrombin time or ecarin clotting time (ECT) and was calculated as a percentage. Extent and severity of bleeding, hemodynamic stability, and adverse events made up most of the secondary endpoints.19

    Over 90% of patients included in the RE-VERSE AD trial had atrial fibrillation and were on dabigatran for stroke prevention. The average age of this group of patients was 76.5 years, the median creatinine clearance was 58 mL/min, and the median time since last dabigatran dose was 15.4 hours.19 The primary efficacy outcome (reversal effect of idarucizumab) was assessed in 68 of the 90 included patients because the other 22 patients had dilute thrombin times that were within normal limits at study entry. The primary outcome was also assessed based on the ECT test in 81 of the 90 patients. Overall, idarucizumab was efficacious for patients in both groups (serious bleeding and urgent procedure), as the median maximum percent reversal was calculated to be 100% (95% CI: 100 to 100).19 Additionally, the dilute thrombin time was normalized in 98% and 93% of patients in group A and B respectively, while the ECT was normalized in 89% and 88% of patients, respectively. The median time to cessation of bleeding was estimated to be approximately 11.4 hours in a subset of patients in group A. In terms of pharmacokinetics, this study found that concentrations of unbound dabigatran were less than 20 ng/mL, which  indicated minimal or no anticoagulant activity in 93% of patients after 12 hours and 79% of patients after 24 hours of idarucizumab administration.19 With regard to safety outcomes, there were 21 serious adverse events, including 18 deaths, five thrombotic events, and two cases of gastrointestinal hemorrhage; however, few were directly related to the use of idarucizumab (one thrombotic event occurred within 72 hours of its use).19

    An update to this study was published about a year after the interim analysis of RE-VERSE AD and included an additional 43 patients. Thus, a total of 123 patients (66 in group A and 57 in group B) were included in the analysis.20 Baseline characteristics remained about the same as in the interim analysis, and 95% of patients received dabigatran for the indication of stroke/systemic embolism prophylaxis in NVAF. With regard to the primary outcome, Pollack and colleagues found that complete reversal of dabigatran occurred in over 89% of patients, and the median time to cessation of bleeding in 48 of the group A patients was 9.8 hours.20 Additionally, mean time to surgery in group B patients was approximately 1.7 hours after infusion of idarucizumab with no major bleeding occurring post-surgery. Thrombotic events occurred in five patients over a 24-day post-infusion period; however, none of those patients were anticoagulated during that time. Death occurred in 21% of patients, but these were not found to be directly related to use of idarucizumab.20 Overall, this study continued to show that idarucizumab can rapidly and completely reverse dabigatran, reduce time to surgery or an urgent procedure, and achieve hemostasis within approximately ten hours.

    Factor Xa-Inhibitor Reversal

    Andexanet Alfa

    Unlike idarucizumab, which is a monoclonal antibody with high affinity toward dabigatran, andexanet alfa (Andexxa®) is a recombinant modified human Factor Xa (FXa) protein that exhibits a procoagulant effect through binding and sequestering FXa inhibitors.21 Additionally, andexanet alfa has demonstrated an ability to inhibit Tissue Factor Pathway Inhibitor (TFPI), which can lead to increased thrombin generation.21

    The safety and efficacy of andexanet alfa was assessed in two trials, where healthy volunteers were given either apixaban 5 mg twice daily (ANNEXA-A trial) or rivaroxaban 20 mg daily (ANNEXA-R trial), followed by various regimens of andexanet alfa.22 Specifically, part 1 of each trial assessed the effects of an andexanet alfa bolus, while part 2 of each trial studied the effects of an andexanet alfa bolus followed by a 2-hour continuous infusion. The primary outcome of these studies was the average percent change in anti-factor Xa activity. Between the two studies, 101 participants were included (48 in ANNEXA-A and 53 in ANNEXA-R).22 In part 1 of each trial, Siegal and colleagues found anti-factor Xa activity to be rapidly reversed (within 5 minutes) significantly more with a bolus administration of andexanet alfa compared to placebo (ANNEXA-A: mean reduction, 94±2% vs. 21±9%; p<0.001; and ANNEXA-R: 92±11% vs. 18±15%, p<0.001).22 However, given the short half-life of andexanet alpha (approximately 1 hour), its anti-factor Xa activity only lasted for about two hours and then slowly returned to levels seen in the placebo arms. Similarly, in part 2 of these trials (bolus plus infusion), use of andexanet alfa continued to provide a significantly greater reduction of anti-factor Xa activity compared to placebo, and this activity was retained for about one to two hours after the infusion ended. Furthermore, both studies showed that patients who received andexanet alfa had significantly greater restoration of thrombin generation compared to patients who received placebo. Additionally, no serious adverse events (including thrombotic events) were reported, and antibodies to FXa did not develop in any participant.22

    Given the promising results of the ANNEXA-A and ANNEXA-R trials, a subsequent study is being conducted by Connolly and colleagues (ANNEXA-4) to assess the safety and efficacy of andexanet alfa in patients who had acute bleeding within 18 hours of receiving a FXa inhibitor.23 In the interim analysis, 67 included patients received a bolus of andexanet alfa followed by a 2-hour infusion. The average age of the patients included was 77 years, and most patients had either gastrointestinal or intracranial bleeding. Additionally, the majority of patients were receiving either rivaroxaban or apixaban (less than 6% received enoxaparin prior to the study, and none were taking edoxaban).23 This study had several exclusion criteria, including (but not limited to): surgery scheduled within 12 hours of presentation; intracranial hemorrhage and Glasgow Coma Scale score of less than 7 or intracerebral hematoma volume of greater than 60 ml; survival expected to be less than 1 month; major thrombotic event in the past 2 weeks; receipt of warfarin, dabigatran, prothrombin complex concentrate, or whole blood or plasma within the past week. Additionally, while each patient was given a bolus dose of andexanet alfa followed by a continuous infusion, the actual amount given varied depending on the FXa inhibitor and the timing of its last administration (Table 5).23


    In terms of the primary outcome, only 47 of the 67 patients were analyzed because 20 patients had baseline anti-factor Xa levels that were too low or missing. Overall, patients who were taking either rivaroxaban or apixaban before receiving andexanet alfa experienced a decrease in anti-factor Xa activity of 89% and 93% (respectively).23 However, four hours after the end of the infusion, this decrease was only 39% in the rivaroxaban arm and 30% in the apixaban arm. Clinical hemostasis was considered “excellent” or “good” (assessed by an adjudicator) in 79% of the patients in the efficacy subgroup (n=47) 12 hours after the infusion. Furthermore, in terms of the safety population (n=67), 12 patients (18%) experienced thrombotic events during the 30-day follow-up, and 10 patients died (15%).23 Although the results of this study make andexanet alfa an interesting option for reversal of FXa inhibitors, a major limitation is the exclusion of many surgical patients. Most patients were determined to achieve hemostasis 12 hours after the infusion, but given its short half-life, it is unclear if surgical patients will have adequate anticoagulant reversal prior to a procedure. This study is ongoing, and more studies are necessary to determine the most appropriate indications for andexanet alfa.

    Andexanet alfa’s package insert defines low and high doses of andexanet alfa consistently with the dosing strategy utilized in the ANNEXA-4 trial (Table 5).21,23 The average wholesale price for 100 mg of andexanet alfa is $3,300. The cost of the low dose regimen would be approximately $29,040, which would include patients receiving less than or equal to 10 mg doses of rivaroxaban or less than or equal to 5 mg doses of apixaban. The cost of the high dose regimen would be approximately $58,080, which would include patients receiving greater than 10 mg doses of rivaroxaban, greater than 5 mg doses of apixaban, or if the previously administered dose of rivaroxaban/apixaban is unknown.21

    Because there is limited data supporting the use of andexanet alfa in patients who require surgical intervention, along with the high cost associated with its use, many institutions may be reluctant to include it on their formulary. However, guidelines by the European Heart Rhythm Association and the American Heart Association/American Stroke Association state that in the event of a life-threatening bleed caused by a FXa inhibitor, PCC can be used even though it is not currently FDA approved for this indication.24-25

    Ciraparantag
    Ciraparantag (PER977) is a new, investigational drug that is being developed for use as a potential reversal agent for both FXa inhibitors and factor IIa inhibitors.26 The exact mechanism of ciraparantag is unknown but in vitro studies have shown that it binds to anticoagulants via noncovalent hydrogen bonds. A study by Ansell and colleagues assessed the safety and efficacy of this agent when given as monotherapy and after a 60 mg dose of edoxaban in 80 healthy volunteers.26 In this study, whole-blood clotting time was used as means to determine the anticoagulant effect of edoxaban as well as assess the efficacy of ciraparantag. The patients were given a dose of edoxaban followed by a single intravenous dose of ciraparantag (ranging from 25 mg to 300 mg) or placebo three hours later. Patients who received ciraparantag 100 mg or 300 mg demonstrated a statistically significant decrease in whole-blood clotting time to within 10% of the baseline value, which occurred within 10 minutes. Conversely, it took patients in the placebo arm roughly 12 to 15 hours to reach a similar decrease in whole-blood clotting time.26 Furthermore, patients maintained the reduction in whole-blood clotting time for 24 hours after the administration of one dose of ciraparantag. Procoagulant activity of ciraparantag was not evident based on D-dimer levels, TFPI levels, and whole-blood clotting time. Overall adverse events were transient, mild, and/or not related to ciraparantag.26 There are more studies to come involving this new agent, which will determine if its reversal ability is similar with the other direct oral anticoagulants.

    Conclusions
    Lots of patients require anticoagulation for a variety of indications which puts these patients at an increased risk of bleeding. Educating patients on the appropriate use of their anticoagulant therapy, as well as encouraging adherence, is key in order to help improve safety and efficacy. Specifically, providers need to be aware of other concomitant bleeding risk factors that their patients may have so that modifiable risk factors can be mitigated, and the most appropriate anticoagulant regimen is selected. Warfarin has therapeutic monitoring, which can help identify patients who are at a high risk of bleeding. Additionally, there are well-studied reversal strategies, including vitamin K and PCC. However, warfarin reversal strategies are continuing to be evaluated regarding fixed versus variable dosing of PCC. Unlike warfarin, DOACs do not require therapeutic monitoring, so their use continues to increase; however, because of the lack of sensitive therapeutic monitoring, correlating a patient’s bleed to the use of a DOAC can be more challenging. Thus, appropriate supportive care and treatment options need to be available for patients in the event of bleeding directly related to a DOAC. The current FDA-approved reversal agents for DOACs include idarucizumab and andexanet alfa. Idarucizumab is only indicated for the reversal of dabigatran, and it has been shown to be safe and efficacious in various patient populations, including those who require urgent surgical intervention. Conversely, andexanet alfa is indicated for the reversal of rivaroxaban and apixaban, and studies have shown that it can quickly reverse levels of these FXa inhibitors; however, because of its short half-life, it has not been well studied in patients requiring acute surgical intervention. Given that the aforementioned reversal agents are relatively new to the market, more data is needed in order to determine their optimal use. Currently, more patients are being enrolled in studies assessing the use of these agents, and newer agents are being developed (i.e. ciraparantag) which may potentially provide even more options available for providers to use in the setting of acute bleeding caused by DOACs.

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    References:

    1. Coumadin (warfarin) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; October 2011.
    2. Pradaxa (dabigatran) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim; November 2015.
    3. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; August 2016. 
    4. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; July 2016.
    5. Savaysa (edoxaban) [prescribing information]. Parsippany, NJ: Daiichi Sankyo, Inc.; September 2016.
    6. Shoeb M, Fang MC. Assessing bleeding risk in patients taking anticoagulants. J Thromb Thrombolysis. 2013;35(3):312-9.
    7. Apostolakis S, Lane DA, Guo Y, et al. Performance of the HEMORR(2)HAGES, ATRIA, and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation: the AMADEUS study. J Am Coll Cardiol. 2012;60(9):861-7.
    8. Nutescu EA. Oral anticoagulant therapies: balancing the risks. Am J Health Syst Pharm. 2013;70(10 Suppl 1):S3-11.
    9. Cuker A, Siegal DM, Crowther MA, Garcia DA. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64(11):1128-39.
    10. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e152S-84S.
    11. Kcentra (prothrombin complex concentrate). Kankakee, IL: CSL Behrine GmbH; 2013.
    12. Sarode R, Milling TJ, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128(11):1234-43.
    13. Khorsand N, Veeger NJ, Muller M, et al. Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy. Transfus Med. 2011;21(2):116-23
    14. Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal. Am J Emerg Med. 2015;33(9):1213-8.
    15. Praxbind (idarucizumab) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2015.
    16. Schiele F, van Ryn J, Canada K et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013; 121:3554-62.
    17. Glund S, Moschetti V, Norris S et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost. 2015; 113:943-51.
    18. Glund S, Stangier J, Schmohl M et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet. 2015; 386:680-90.
    19. Pollack CV Jr, Reilly PA, Eikelboom J et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015; 373:511-20.
    20. Pollack CV, Reilly P, Eikelboom J et al. Idarucizumab for reversal of the anticoagulant effects of dabigatran in patients in an emergency setting of major bleeding, urgent surgery, or interventions. J Am Coll Cardiol. 2016; 67(13 Suppl):664.
    21. Andexxa (andexanet alfa) [package insert]. San Francisco, CA: Portola Pharmaceuticals, Inc; 2017.
    22. Siegal DM et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413-24.
    23. Connolly SJ et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131-41.
    24. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39(16):1330-1393.
    25. Hemphil JC, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46:2032-2060.
    26. Ansell JE, Bakhru SH, Laulicht BE et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med.2014; 371:2141-2.


  • 24 Jan 2019 9:41 AM | MSHP Office (Administrator)

    Author:  Emily Henningsen, PharmD, PGY1 Pharmacy Resident
    St. Louis College of Pharmacy/Mercy Hospital St. Louis

    Introduction
    Osteoporosis is a disease characterized by loss of bone mass and increased bone turnover. Approximately 10 million Americans have osteoporosis and 44 million have low bone mineral density, meaning half of all adults 50 years of age and older are at an increased risk of fractures.1 Fractures caused by osteoporosis can lead to mortality and negative impacts on quality of life. Osteoporosis related fractures are also costly, and it is estimated that by 2025, $23.5 billion will be spent annually on fracture-related costs.1

    Bisphosphonates are the most widely used treatment for osteoporosis and are considered first line therapy.2 Bisphosphonates work by inhibiting osteoclast activity, leading to increased bone resorption, decreased bone remodeling and decreased risk of fractures. Alendronate, risedronate, and zoledronic acid have been shown to reduce the risk of vertebral fractures by 47-70%, non-vertebral fracture by 19-38%, and hip fractures by 28-50%.4

    Optimal duration of therapy
    Much controversy exists regarding the optimal duration of bisphosphonate therapy. In 2011, the FDA reviewed available literature regarding the safety and efficacy of bisphosphonates, in which they concluded that efficacy was questionable beyond 5 years of therapy. This led to labeling changes that state: ‘The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.’ The FLEX and HORIZON-PFT trials aimed to examine the effects of extended duration-bisphosphonate therapy.

    Fracture Intervention Trial Long-Term Extension (FLEX)5
    In the FLEX trial, 1099 postmenopausal women with a T score < -2.0 who previously received alendronate for 5 years were randomized to continue or discontinue alendronate therapy for an additional five years. Total hip bone mineral density decreased in both groups but remained at the same or at higher levels compared to those at initial study enrollment 10 years prior. There was no difference between groups in the rate of nonvertebral or morphometric vertebral fractures, but there was a significantly higher risk of clinical vertebral fractures seen in patients taking placebo compared to those continuing alendronate (5.3% vs 2.4%; RR 0.45; 95% CI 0.24-0.85). The authors concluded that discontinuation of alendronate after five years does not significantly increase fracture risk. However, women at higher risk of clinical vertebral fractures due to factors such as previous vertebral fracture or low bone mineral density should consider treatment beyond five years.

    HORIZON-PFT6
    In the HORIZON-PFT trial, 1233 postmenopausal women with a diagnosis of osteoporosis who previously received zoledronic acid for 3 years were randomized to continue or discontinue zoledronic acid therapy for an additional three years. Patients receiving zoledronic acid saw a constant femoral neck bone mineral density, while those randomized to placebo experienced a slight drop in BMD. Treatment with zoledronic acid resulted in a statistically significant decrease in morphometric vertebral fracture (14 vs 30, OR 0.51; p = 0.035), but there was no difference between groups in regards to non-vertebral and hip fractures.  The authors concluded that patients receiving zoledronic acid for three years may discontinue therapy for up to three years. However, those with high risk of fracture, especially those that are vertebral in nature, could benefit from continued treatment.

    Why consider a drug holiday?
    A drug holiday is a disruption of therapy with plans for reinitiation at a later time. Drug holidays are considered for medications that continue to exert an effect after they are stopped. Providers may desire to pause treatment to see how patients respond without therapy or due to the risk of adverse effects from long term use. The concept of a bisphosphonate drug holiday has developed based on available efficacy and safety data. Bisphosphonates accumulate in the bone, which provides continued osteoclast inhibition even after therapy is discontinued. Zoledronic acid has the highest binding affinity for bone, followed by alendronate and risedronate.3 As shown in the FLEX and HORIZON-PFT trial, bone mineral density remains elevated from baseline even after discontinuation of therapy, which suggests continued benefit from bisphosphonate therapy after cessation of treatment.

    Rare but serious side effects have been reported by patients receiving bisphosphonate therapy. Postmarketing reports have linked the use of bisphosphonates to osteonecrosis of the jaw and atypical femur fractures. Osteonecrosis of the jaw (ONJ) is defined by the American and Canadian Associations of Oral and Maxillofacial Surgeons as exposed bone in the maxillofacial region that has persisted beyond eight weeks in a patient currently or previously treated with a bisphosphonate and no history of radiotherapy to the jaw.7  The overall incidence is 1 in 100,000 patient/years.8 Risk factors like poor oral hygiene, chemotherapy, and glucocorticoid therapy may increase the risk of development of ONJ. Atypical femur fractures are fractures located in the subtrochanteric region and femoral shaft that occur spontaneously or after minimal trauma. A retrospective analysis of femur fractures in American patients found an increased risk of atypical femur fractures in patients treated with bisphosphonate therapy for two years (1.78 per 100,000 patient/years) compared to eight to ten years (113.1 per 100,000 patient/years).9 Although these side effects are rare, they can lead to significant morbidity. By utilizing the long lasting effects of bisphosphonates, duration of treatment can be shortened to decrease the risk of these adverse reactions.

    Drug holiday duration
    A report published by the American Society for Bone and Mineral Research in 2015 provided an approach to the management of postmenopausal women on long-term bisphosphonate therapy, which is summarized in the table below.10 Initial treatment duration should be based on the patient’s clinical factors, fracture history and risk for future fracture include age, low body weight, fall risk and fall history. There is no data providing information regarding how long a bisphosphonate holiday should last.  In patients at low risk of fracture, it is reasonable to withdraw therapy and consider reinitiation at a later time. Although evidence is lacking, it is thought that monitoring bone mineral density and bone turnover markers could assist in guiding bisphosphonate reinitiation. In patients with a history of fracture, drug holidays should be short as the benefit of treatment likely outweighs the risk of rare adverse effects. Non-bisphosphonate drugs like denosumab or teriparatide could be considered during the holiday.

    Conclusion
    Bisphosphonates are first line therapy in the treatment of osteoporosis. Given the longstanding positive effect of bisphosphonates on bone and risk of rare but serious adverse effects, a drug holiday can be considered. Limited data exists regarding the duration of therapy or when to reinitiate therapy after a drug holiday. Decisions regarding initiation and termination of drug holidays should be individualized based on the patient’s history of fracture and risk of future fracture.

    References:

    1. Osteoporosis Fast Facts. National Osteoporosis Foundation website https://cdn.nof.org/wp-content/uploads/2015/12/Osteoporosis-Fast-Facts.pdf . Updated 2015. Accessed December 29, 2018.
    2. Wysowski DK, Greene P. Trends in osteoporosis treatment with oral and intravenous bisphosphonates in the United States, 2002-2012. Bone. 2013; 57(2):423-428.
    3. Camancho PM, Petak SM, Binkley N, et al. AACE/ACE practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis – 2016. Endocr Pract. 2016;22(14):1-42.
    4. Villa JC, Gianakos A, Lane JM. Bisphosphonate treatment in osteoporosis: optimal duration of therapy and the incorporation of a drug holiday. HSS J. 2016;12(1):66-73.
    5. Black DM, Schwartz AV, Ensrud KE, et al. FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296(24):2927–38.
    6. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012;7(2):243–54.
    7. ARuggiero SL, Dodson TB, Assael LA, Landesberg R, Marx RE, Mehrotra B. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws—2009 update. J Oral Maxillofac Surg. 2009;67(5 suppl):2–12.
    8. Khosla S et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the american society for bone and mineral research. J Bone and Min Research 2007;22(10)1479-1491.
    9. Dell RM, Adams AL, Greene DF, et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res. 2012;27(12):2544-2550.
    10. Adler RA, El-Hajj Fuleihan G, Bauer DC, et al. Managing Osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2016;31(16).
  • 24 Jan 2019 9:29 AM | MSHP Office (Administrator)

    Authors:  Ayah Sumren, PharmD Candidate 2019
    Scott Coon PharmD, BCPS, BCACP
    St. Louis College of Pharmacy

    Introduction
    We are entering a period in which Americans are living longer with type 2 diabetes mellitus (T2DM) and patient-centered care is paramount.1 Consequently, quality of life, medication adherence, and cost become particularly important considerations. Unfortunately, drug costs continue to rise for mainstay T2DM therapies (or not drop quickly enough, despite an approved biosimilars for glargine U-100), and patients feel the crunch. This has prompted reflection on policies that prioritize use long-acting, basal insulin analogs in our patients at the St. Louis County Department of Public Health. With similar efficacy between NPH and basal analogs, the reduced risk for hypoglycemia, more predictable insulin release, and reduced injection burden have made basal analogs an easy go-to, so long as “insurance is going to pay for it.” Arguably, this mindset has led to basal analogs dominating the global insulin market.2 However, is the cost of these expensive insulins truly gone just because the patient isn’t responsible for a significant portion of the bill? This argument can only really be made for uninsured persons who qualify for patient assistance programs, where medications are sent directly from drug manufacturers at no cost to the patient. For the majority of patients, we have to think big picture – whole health-system big – on an issue like this. The current review will examine the “hows” related to choice in basal insulin: how do these products really compare, and how do we proceed?

    Insulin Therapy in Type 2 Diabetes
    Pharmacologic management of T2DM is guided by many factors, such as hemoglobin-A1c (A1c), presence of cardiovascular or renal disease, and drug safety, efficacy, route, and cost. In outpatient treatment settings, insulin is typically reserved for persons unable achieve their A1c goal using oral or non-insulin injectable agents alone – and is generally added to versus replacing therapies – or for persons who present with markedly elevated blood sugars and symptoms of hyperglycemia. The main benefit of insulin in T2DM is that it has no therapeutic ceiling, while other agents are limited to an average A1c lowering potential of 0.5-2%. For some patients, insulin is the only agent able to control their blood glucose and is a vital part of their therapy. Basal insulin is often the patient’s first introduction to insulin, due to its relative ease of use and dosing titration.

    Basal insulin can be broken into two types: human insulin and insulin analogs. The most widely used human insulin is Neutral Protamine Hagedorn (NPH) insulin, which is intermediate-acting. NPH is human insulin made using recombinant DNA technology and formulated in an isophane suspension.3 Its onset of action ranges 1-2 hours with a peak at 4-12 hours, and a duration of action ranging 12-24 hours. Basal insulin analogs are structurally altered to prevent metabolism and provide a flatter time-action profile, or a “peak-less” insulin release. Examples of basal analogs include: insulin glargine (U-100, U-300), detemir and degludec. The onset of action for analogs is 3-4 hours (longer for glargine U-300). However, insulins glargine & degludec have a peak-less profile, while detemir has a minor peak at 3-9 hours. Furthermore, the duration of action for insulin glargine is 22-24 hours (U-300 is >24 hours), while detemir is dose-dependent between 6-23 hours (duration increased with unit/kg ratio).

    Current Guideline Recommendations
    Clinical practice guidelines indicate different preferences when it comes to using basal insulin. The 2019 ADA Standards of Medical Care states basal insulin is a convenient initial insulin regimen and doesn’t give strong preference towards any particular product.4 They mention that analogs have shown reduced symptomatic and nocturnal hypoglycemia compared to NPH in clinical trials, but that development of hypoglycemia is similar between agents in practice. The 2018 ADA/EASD Consensus Statement also does not indicate a preference for basal insulin.5 However, 2018 AACE/ACE Consensus Statement states insulin analogs are preferred over NPH insulin due to the “flat serum insulin concentration for 24 hours or longer”.6 In contrast, large health plans like Kaiser Permanente explicitly prefer NPH over analogs in their treatment guidelines.7 To reconcile differences between treatment guidelines, a review of randomized control trials and real-world data is needed.

    Efficacy-Glycemic Control
    To evaluate whether or not the two types of basal insulins are similar in efficacy is crucial when weighing basal insulin options for your patients. A Cochrane systematic review and meta-analysis compared NPH to insulin glargine (n=6) & detemir (n=2) using data from eight randomized control trials (RCT).8 They measured efficacy by comparing mean changes in A1c from baseline to end of trial, pooling results using a random-effects model. Results showed there was no statistical difference in efficacy outcomes between the two types of basal insulin. Unfortunately, most of the trials had a short duration (6 months). More recently, Rosenstock et al. conducted an analysis of data from an open-label five year RCT comparing once daily insulin glargine to twice daily NPH insulin.9,10 The trial was originally designed to better understand the long-term differences in retinopathy progression, but measured other outcomes including glycemic control and hypoglycemia. The difference in change from baseline HbA1c was found to be significantly lower in the NPH group -0.19 (p=0.012).9 Although statistically significant, a difference of only 0.19 is not considered clinically significant. Progression of diabetic retinopathy was similar.10 Unfortunately, results from RCTs often have limited generalizability to practice in real-world settings, particularly when it comes to adherence. Lipska et al. conducted large cohort study utilizing data from the Kaiser Permanente North Carolina Diabetes Registry (n=25,489) over a mean follow-up of 1.7 years.11 Results again showed a statistically significant difference in glycemic efficacy favoring NPH insulin with a mean difference in A1c -0.22 [95% CI -0.09, -0.37]. Adherence was similar between groups. From a glycemic efficacy standpoint, there is no reason to anticipate better results with basal analogs over NPH. However, data are still limited for macro- and microvascular outcome differences between NPH and basal analogs, due to the long follow-up period needed to observe these outcomes.

    Safety: Severe Hypoglycemia
    For patients susceptible to symptomatic hypoglycemia, choice of basal insulin therapy needs to be made carefully, particularly in persons with established cardiovascular disease. Severe hypoglycemia (hypoglycemia requiring third party assistance) was evaluated in six of the eight trials included in the Cochrane review.8 Results showed no significant difference between glargine and NPH, with an OR 0.70 [95% CI 0.4, 1.23], or between detemir to NPH OR 0.50 [95% CI 0.18, 1.38]. It’s important to note that none of the trials were adequately powered to evaluate severe hypoglycemia – which had an overall low incidence – and that the subjective definitions used for severe hypoglycemia and lack of adequate blinding introduce bias. Results are confirmed in other analyses, even in persons more vulnerable to the deleterious effects of hypoglycemia, such as older adults > 65 years.12 Results from the long-term RCT by Rosenstock et al. showed increased risk for severe hypoglycemia (hypoglycemia requiring assistance and BG < 56 mg/dL or prompt recovery after reversal using oral/IV glucose or glucagon) over 5 years with a RR 0.62 [95% CI 0.41, 0.95].9 However, the large cohort study by Lipska et al., for which the primary endpoint was the incidence of hypoglycemia-related emergency department visits (ICD-9 coding), there was no significant difference in severe hypoglycemia between NPH and analogs (glargine or detemir) HR 1.16 [95% CI 0.71, 1.78].11 In conclusion, results for severe hypoglycemia are mixed and tend to favor analogs (glargine), particularly in long-term study settings. However, the majority of data indicate similar incidence of severe hypoglycemia in both RCT and real-world settings.

    Safety: Symptomatic and Nocturnal Hypoglycemia
    Although the Cochrane review found no significant differences in severe hypoglycemia, authors did see a significant increase in risk for symptomatic hypoglycemia (16-18%) and nocturnal hypoglycemia (34-37%) with NPH compared to basal analogs (glargine and detemir).8 Other meta-analyses have confirmed similar results.13,14 Symptomatic hypoglycemia was variably defined in the Cochrane review, including: symptoms of hypoglycemia, BG measurements, or both meaning bias is possible in these studies as well. In the long-term RCT by Rosenstock et al., rates of symptomatic hypoglycemia confirmed by a blood glucose readings favored glargine over NPH for mild, symptomatic hypoglycemia (BGs < 70 mg/dL) (HR 0.70 [95% CI 0.56, 0.87]) and nocturnal hypoglycemia (HR 0.75 [95% CI 0.58, 0.97]).9 Authors report a corresponding number needed to harm (NNH) of 19 [95% CI 10, 1213] for symptomatic hypoglycemia (BG < 70mg), which is considered clinically relevant.

    Take Away
    Based on available data, basal analogs and NPH are similar in efficacy and incidence of severe hypoglycemia, although incidence of severe hypoglycemia appears may be higher when used long-term (e.g. > 5 years). The most palpable difference between agents is the increased risk for for mild, symptomatic hypoglycemia (BG < 70 mg/dL) and nocturnal hypoglycemia with NPH. Aside from glycemic control and hypoglycemia, clinicians must also consider injection burden, formulations (pen vs. vial, both of which will heavily influence adherence), cardiovascular outcomes, cost, and other variables. NPH insulin is often dosed twice daily based drug- and patient-specific factors, which may be a big disadvantage over once-daily analogs. However, the major difference in cost between NPH and analogs should give clinicians some pause, regardless of whether the patient has “good or bad coverage.” Average wholesale prices for basal analogs range from $26.11/mL to $77.55/mL, compared to ReliON NPH, which is $2.50/mL.3 Are basal analogs truly worth a price point that is ten times the cost of NPH? Analyses of cost-effectiveness comparing NPH to basal analogs are inconsistent, but rarely favor analogs.15 In conclusion, some general considerations for use of basal insulin:

    • NPH insulin is an acceptable basal insulin in T2DM, generally given once or twice daily and in addition to first-line oral agents (e.g. metformin).
    • NPH insulin has similar efficacy and safety to basal analogs, though symptomatic hypoglycemia and nocturnal hypoglycemia risk is consistently higher. Long-term studies also indicate higher risk for severe hypoglycemia after years of use.
    • NPH should be first-line for persons indicated for basal insulin, unless patients have high-risk for hypoglycemia or comorbidities particularly susceptible to hypoglycemia, such as cardiovascular disease. The decision should be individualized.
    • Clinicians should comfortable initiating NPH and/or changing between NPH and basal analogs. Kaiser Permanente’s NPH initiation and titration guidelines are summarized in Table 1.
    • If symptomatic hypoglycemia occurs in patients on any basal insulin, clinicians should consider switching patients to a basal analog.

    References:

    1. The US Burden of Disease Collaborators. The state of US health. 1990-2016: burden of diseases, injuries, and risk factors among US states. JAMA. 2018;319(14):1444–1472.
    2. Beran D, Ewen M, Lepeska M, et al. Access to Insulin: Addressing the Challenges and Constraints. Health Action International. http://haiweb.org/wp-content/uploads/2017/03/Issues_Paper_2017.pdf. Accessed: January 2019.
    3. Wolters Kluwer Clinical Drug Information, Inc. (Lexi-Drugs). Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com/lco/action/home. Accessed: January 2019.
    4. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019;42(Supplement 1):S90-S102. doi:10.2337/dc19-S009.
    5. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-2701. doi:10.2337/dci18-0033.
    6. Garber AJ, Abrahamson MJ, Barzilay JI, et al. CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM – 2018 EXECUTIVE SUMMARY. Endocrine Practice. 2018;24(1):91-120. doi:10.4158/CS-2017-0153
    7. Kaiser Permanente Washington Team. Type 2 Diabetes Screening and Treatment Guideline. KPWA. https://wa.kaiserpermanente.org/static/pdf/public/guidelines/diabetes2.pdf. 2017: 1-19.
    8. Horvath K, Jeitler K, Berghold A, et al. Long acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007;2:CD005613
    9. Rosenstock J, Fonseca V, Schinzel S, Dain M-P, Mullins P, Riddle M. Reduced risk of hypoglycemia with once-daily glargine versus twice-daily NPH and number needed to harm with NPH to demonstrate the risk of one additional hypoglycemic event in type 2 diabetes: Evidence from a long-term controlled trial. J Diabetes Complications. 2014;28(5):742-749
    10. Rosenstock J, Fonseca V, McGill JB, et al. Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study. Diabetologia. 2009;52(9):1778-1788. doi:10.1007/s00125-009-1415-7
    11. Lipska KJ, Parker MM, Moffet HH, et.al. Association of initiation of basal insulin analogs vs neutral protamine Hagedorn insulin with hypoglycemia-related emergency department visits or hospital admissions and with glycemic control in patients with type 2 diabetes. JAMA. 2018;320(1):53–62.
    12. Lee PChang ABlaum CVlajnic AGao LHalter J. Comparison of safety and efficacy of insulin glargine and neutral protamine hagedorn insulin in older adults with type 2 diabetes mellitus: results from a pooled analysis. J Am Geriatr Soc. 2012 Jan;60(1):51-9
    13. Bazzano LA, Lee LJ, Shi L, Reynolds K, Jackson JA, Fonseca V. Safety and efficacy of glargine compared with NPH insulin for the treatment of Type 2 diabetes: a meta-analysis of randomized controlled trials. Diabet Med. 2008 Aug;25(8):924-32.
    14. Owens DR, Traylor L, Mullins P, Landgraf W. Patient-level meta-analysis of efficacy and hypoglycaemia in people with type 2 diabetes initiating insulin glargine 100 U/mL or neutral protamine Hagedorn insulin analysed according to concomitant oral antidiabetes therapy. Diabetes Res Clin Pract. 2017 Feb;124:57-65.
    15. Tricco AC, Ashoor HM, Antony J, et al. Safety, effectiveness, and cost effectiveness of long acting versus intermediate acting insulin for patients with type 1 diabetes: systematic review and network meta-analysis. BMJ. 2014;349:g5459. doi:10.1136/bmj.g5459.
  • 24 Jan 2019 9:23 AM | MSHP Office (Administrator)

    Author:  Anne M. Schwartz, PharmD, PGY1 Ambulatory Care Resident, University of Minnesota College of Pharmacy at Avera Marshall Regional Medical Center

    Whether you are chasing your dreams of completing a pharmacy residency or serving as a mentor for an aspiring student, navigating through Phase II of ASHP’s Pharmacy Residency Match can be challenging. The process is quick, and if you are unprepared you may find yourself scrambling at the last minute. Here are some tips I learned along the way that helped me successfully tackle Phase II of the Match.

    Request Off.  If you are on rotations Match Day, talk with your preceptor well in advance regarding the possibility of having the day off. I was given advice that “whether you match or not, your head will not be in the right place – and that is not fair to your patients.” If you do not match in Phase I, having the day off will allow you the time to process the disappointment, and quickly rally to start preparing for Phase II. 

    Communication. Make sure to lean on your network throughout the entire process. While you may be embarrassed or devastated, it is crucial to reach out to the pharmacy mentors in your life. Informing them that you did not match in Phase I may lead to other connections with residency sites you had not yet considered that also have an open position after Phase I. This conversation could also spark your interest elsewhere and lead you down a completely different path.

    Regroup and Stay Focused. The turnaround time for Phase II is very quick. The 2018 Phase I Match results were released around 7am central time with the list of programs going through Phase II made available roughly 4 hours later. This gives you time to begin processing from the news and reach out to your pharmacy mentors as previously discussed. Start looking through the list of Phase II programs as soon as you can to find programs that are of interest. Keep in mind that this document is continuously updated, and programs are constantly being added and removed. It will be important to pay attention to the edited date at the bottom of the list, as this will let you know when it was last updated. I recommend creating an Excel spreadsheet to keep the programs you are considering organized and track any changes.

    Letters of Recommendation. I encourage you to have one general letter of recommendation from your reference writers. While not mandatory, having this comes in handy in the event you find yourself navigating Phase II of the Match. If you do not have a general letter, make sure to contact your letter writers as soon as possible to request one. If you are reading this before Phase I results are released and you do not have a general letter of recommendation from your writers, do not hesitate to reach out to them now to give them more time to prepare a letter if you find yourself in Phase II.

    Letters of Intent. Within the first couple days following Phase I results, you should have letters of intent written for programs that interest you the most. Do not sacrifice quality, but the sooner you can complete your letters of intent, the better. The reason behind this will become more evident in my subsequent tips.

    Contact Programs. Before applications are due, consider emailing the sites you are most interested in. Make sure to attach a copy of your updated CV, letter of intent, and any other supplemental requirements. 

    Application Submission. It is in your best interest to submit your application as soon as PhORCAS allows, as most Phase II programs stop accepting applications after a certain number are submitted. Keep in mind that a large number of people will be submitting their applications at the same time. This can potentially cause technology challenges for the website, so pack your patience, expect delays, and stay calm. Last year, due to application volume, there was a delay from the time applications were submitted to PhORCAS and when the respective sites received the applications.  A PhORCAS representative informed me it could be 2-3 days before the programs were able to view my information. This is another reason I would advise reaching out to programs with your information beforehand. This gives them the chance to review your material and know to be looking for your application.

    Interviews. Depending on your location and which programs you apply to, most Phase II interviews are conducted via telephone or through a webcam-based application. To prepare for a webcam-based interview, make sure you have a professional email and a clean, quiet, and non-distracting background. In addition, many universities have recording systems available to help prepare for these interview types. Don’t forget to reach out to your mentors for other advice to ensure you are fully prepared.

    Mentors. If you find yourself navigating through Phase II of the Match with a student, remember the best service you can provide in this moment is encouragement. Remind your student of their successes and that this moment of disappointment does not define their future pharmacy career. Encourage your student to take a moment to process the discontent, and then buckle up for Phase II. This is an exciting journey that might open their eyes to new opportunities.

    Phase II can seem extremely stressful and overwhelming. Taking steps now to ensure you are prepared can help reduce your stress and keep you organized. I hope these tips can help you or someone you know tackle Phase II with confidence and perseverance. Do not forget to stay composed and to trust the process. There is growth in this part of the journey, and just remember that everything works out the way it should in the end.


  • 24 Jan 2019 9:20 AM | MSHP Office (Administrator)

    Authors:
    Jordyn Williams, UMKC SSHP Colombia President
    Anna Parker, UMKC SSHP Kansas City President
    Amelia Godfrey, UMKC SSHP Springfield Liaison

    At the beginning of the Fall semester, UMKC's SSHP chapter held a membership drive from August to September 21st.  Members of the executive team attended the Class of 2022 Orientation Day in Kansas City on August 15th where they participated in the Student Organization Fair.   Executive members were able to tell incoming students about SSHP, get a list of interested students, and hand out flyers with upcoming events and contact information.  This year, SSHP moved membership registration online by working in combination with MSHP to make it easier for students to join both organizations. SSHP held its first general meeting on August 27th where our guest speaker, Dr. Kat Burnett, talked about her experience with SSHP and GKC and why students should get involved.  The Columbia campus also held a joint membership drive for MMSHP and SSHP through a Trivia Night on August 30th where they presented information about the benefits of joining both organizations while providing an opportunity for students to network with pharmacists in the area.  At the end of our membership drive, we had a total of 119 members join from the Kansas City, Columbia, and Springfield campuses. A special thank you to MSHP for letting us create the joint membership and helping us set up the online registration!

    Throughout the Fall semester, we held monthly general meetings where guest speakers talked about their current employment and their journey to where they are now. Students were able to come and listen to these three speakers over the lunch hour to learn more about clinical pharmacy career options.  In September, we had the pleasure to have Dr. Jordan Anderson, a Pediatric Clinical Specialist and PGY1 Residency Director at the University of Missouri Women’s and Children’s Hospital, visit us to discuss her various roles and how SSHP and MSHP helped set her up for success.  At the October meeting, Dr. Karrie Derenski discussed her duties as a Pharmacy and Metabolic Support Supervisor and PGY2 Director at Cox Medical Center.  For our last meeting in November, Dr. Andrew Smith and Dr. Lauren Andrew discussed the importance of a letter of intent and gave a presentation on what to include when writing one.  All of these meetings targeted different aspects of pharmacy and helped SSHP members gain a broader knowledge of career paths. 

    Across all three campuses, we hosted two major events this semester.  On September 28th, we held our annual Residency Roundtable event where pharmacists, residency directors, and residents from surrounding areas came to discuss their programs and what they look for in residency candidates.  Dr. Tony Huke gave a presentation on the residency process to start the event and then there was a panel discussion where students could ask questions.  We ended the event with a presentation about PhORCAS that was provided by Dr. Ryan Buckman, a PGY1 Resident at Truman Medical Center.  On October 8th, SSHP held a Clinical Skills Competition where students competed in a team-based analysis of a clinical scenario.  This gave students the chance to practice skills in collaboration with other team members. The first round was a case work-up and the second round had the top teams present their cases to the judges. The winning team, consisting of Kaily Kurzweil and Michelle Sproat, was then given the chance to compete at Mid-Year's national competition in Anaheim. They represented our chapter so well with their professionalism and clinical knowledge and we are very proud of them!

    Our SSHP chapter is unique in that it is spread across three campuses which enables our chapter to reach out to multiple local communities very easily. This past semester, the Columbia campus held a drive during October to collect candy and other items to be donated to the University of Missouri Women’s and Children’s Hospital so the pediatric patients could go trick-or-treating through the hospital. In Kansas City, our project chair hosted an event partnered with Vial of Life at a health fair for students to hand out vials with materials for community members to fill out a medication list and important health information in case of an emergency. Springfield utilized Vial of Life kits at a health fair for older adults in conjunction with other campus organizations. Overall, over 60 seniors received kits and many more received education about how to get a kit of their own. This event also provided a chance to present the Vial of Life program to local businesses and organizations, such as assisted living facilities and emergency medical personnel, in hopes that the program will be fully utilized in additional homes across the region.

    For the Spring semester, we are looking forward to our monthly general meetings and our upcoming events.  On January 24th we will be partnering with KU School of Pharmacy for a new Pharmacy Forecast Workshop.  We are excited to participate in this event and hope that we can continue it in the future. A special thank you to the KU SSHP chapter, KSHP, and MSHP for helping us start this new event!


  • 24 Jan 2019 9:17 AM | MSHP Office (Administrator)

    Authors:
    Hubert Kusdono, STLCOP SSHP Chapter President
    Lauren Busch, STLCOP SSHP President-Elect

    Throughout the Fall Semester of the 2018-2019 academic year, the STLCOP SSHP chapter aimed to build upon its current initiatives and create new goals with regards to community outreach and health-system service, professional development, and networking opportunities for its student members.

    With regards to our community outreach and health-system service initiatives, our SSHP chapter held three events throughout the semester. The first event was a health fair held at Midtown Community Services, where 10 students (ranging from P1’s through P3’s) volunteered to hold blood pressure and blood glucose screenings and interact with patients in the community. Another health-system service project we did was Blankets for Cancer Patients, during which students volunteered to weave together blankets to be donated to patients at Siteman Cancer Center and St. Mary’s Hospital. A total of 30 blankets were made and donated during the months of November and December, and are planned to be donated throughout the colder months of early 2019. The last service project that our SSHP chapter held was Cancer Care Packages for patients at Siteman Cancer Center – an event that our chapter continues to organize every year. For this project, students put together small care packages consisting of socks, gloves, coloring books, and other small items to be enjoyed during the Christmas season. These care packages were donated to patients at Siteman Cancer Center, and students were also given the opportunity to take a tour of the infusion clinic and outpatient pharmacy.

    To continue creating new events for our professional development initiative, our SSHP chapter held a number of seminars and Lunch ‘N Learns to provide students with learning opportunities with regards to residency preparation, as well as other important and interesting topics in healthcare. Our SSHP chapter held two Lunch ‘N Learns called Introduction to Residency and Interviewing 101. The Introduction to Residency seminar focused on the basics of pharmacy residencies, what residency programs are looking for in their candidates, and what personal factors students can emphasize to stand out during the application process. The Interviewing 101 seminar provided students with general information regarding the residency interviewing process, as well as tips that students can keep in mind to make a good impression during interviews. Both of these presentations were given by Dr. Burke, and they will serve as a transition to the next portion of our Residency Preparation Series, including mock interview and CV review workshops, which we will host during the spring semester. Our SSHP chapter also held a Lunch ‘N Learn called Keeping up with Cannabinoids, where a presentation was given regarding the increasing utilization of cannabinoids in the pharmaceutical industry.

    One of the main events our SSHP chapter held towards the end of the fall semester was our annual Residency Roundtable with Residency Program Directors. The objective of this networking event was to give students the opportunity to sit down with residency program directors to ask questions and acquire more information about their respective residency programs. Students were also able to ask these program directors for their personal insight regarding how to best prepare themselves for the residency process and what these programs look for in their ideal candidates. During this roundtable-style networking event, eight residency program directors around the local St. Louis area attended the event and were able to network with approximately 70 of our students over dinner. Both PGY1 and PGY2 residency program directors representing a variety of different practice sites and specialties were in attendance, such as community, infectious disease, pediatrics, ambulatory care, and health-system administration. This was a unique opportunity for our students to speak with program directors in a low-stress environment, while also allowing them to network and build their connections in the profession. A variety of students attended the event, ranging from first to fourth year professional pharmacy students, with some undergraduate students in attendance. Participating in this event gave students a unique, inside perspective on residency programs and the overall residency process from the program directors themselves.

    A new program that our SSHP chapter initiated this semester was the SSHP Residency Mentor/Mentee Program, which was led by our Innovation and Development committee. This residency mentoring program focuses particularly on pairing students who are earlier in the pharmacy curriculum, who may not have as much background regarding the residency process, with students who intend to pursue a pharmacy residency post-graduation. Thus, the program aims to have mentors guide their undergraduate or P1 mentees through the transition into the professional program, as well as the decision-making process in choosing the residency route as they progress through pharmacy school. We currently have 20 students participating in this mentoring program and have hosted a few social events so far throughout the semester so that mentors and mentees could continue to get to know each other. We hope to continue expanding this program throughout the spring semester and add more students who are interested in pursuing a residency after graduation.

    Overall, throughout the fall semester, the STLCOP SSHP chapter was successful in introducing new events and expanding upon previously successful ones in light of its initiatives for community outreach and health-system service, professional development, and networking. Our chapter hopes to build upon our goal to prepare student pharmacists for the residency preparation process that lies ahead. We hope that our SSHP chapter can continue to serve as a resource for students who seek to develop their knowledge and skills as aspiring pharmacists.


  • 24 Jan 2019 9:09 AM | MSHP Office (Administrator)

    Author:  Sarah Cox, PharmD, MS
    MSHP Public Policy Chair/Assistant Professor, UMKC School of Pharmacy at MU

    Introduction
    The Environmental Protection Agency (EPA) governs the Resource Conservation and Recovery Act (RCRA), which defines hazardous versus non-hazardous waste and describes how each must be disposed of. Pharmaceutical waste was added to the hazardous wastes managed by the EPA in 2008. These regulations apply to any entity that generates “hazardous pharmaceutical waste”.1,2 

    What is pharmaceutical waste versus hazardous waste?
    The rule defines the term pharmaceutical as “any drug or dietary supplement for use by humans or other animals; any electronic nicotine delivery systems”3,4. This is differentiated from “pharmaceutical universal waste” which indicates that the waste is hazardous and must be disposed of according to the RCRA. The RCRA contains a list of hazardous materials, which includes pharmaceuticals , that are given either a P-listing or a U-listing (see figure 1).2

    Figure 1: List of pharmaceutical waste designated either as P-listed or U-listed2

    P-listed Pharmaceutical Waste

    U-listed Pharmaceutical Waste

    Arsenic trioxide

    Chloral hydrate

    Phentermine

    Paraldehyde

    Epinephrine

    Chlorambucil

    Physostigmine

    Phenol

    Nicotine

    Cyclophosphamide

    Physostigmine salicylate

    Reserpine

    Nitroglycerin

    Daunomycin

    Warfarin (>0.3%)

    Resorcinol

    Dichlorodifluoromethane

    Diethylstilbestrol

    Selenium sulfide

    Hexachlorophene

    Streptozotocin

    Lindane

    Trichloromonofluoromethane

    Melphalan

    Uracil mustard

    Mercury

    Warfarin (0.3%)

    Mitomycin

    Examples of how pharmaceutical waste is generated includes: spills, expired medications, or left-over products from compounding.2

    Updates to EPA Rules
    The EPA released a statement that they would be removing over the counter (OTC) nicotine from the P075 designation that other nicotine products currently have. The agency states that “FDA-approved [OTC] nicotine replacement therapies (i.e. patches, gum, and lozenges)…may [be discarded] as non-hazardous waste.” Additional updates to the rule will allow healthcare facilities that generate more than 1kg of pharmaceutical waste per month to manage waste as a “standard RCRA generator” rather than a “large quantity generator” as was required in the previous rule. Healthcare facilities will also no longer be required to follow the “satellite accumulation area regulations”.3,4

    Bottom Line for Pharmacy
    OTC nicotine replacement therapy including patches, gum, and lozenges no longer must be discarded as hazardous pharmaceutical waste. However, healthcare facilities should not change their waste protocols yet because the rule does not go into effect until 6 months after it is published on the Federal Register, which has yet to occur. The Public Policy Committee will bring you additional updates on this rule as it is published and let you know when you can update your disposal practices.3,4

    References:

    1. Resource Conservation and Recovery Act (RCRA) Orientation Manual. Environmental Protection Agency. 2014. Accessed January 13, 2019.  https://www.epa.gov/sites/production/files/2015-07/documents/rom.pdf
    2. 40 CFR Part 260, 261, 264, et al. Amendment to the Universal Waste Rule: Addition of Pharmaceuticals; Proposed Rule. Federal Register. 2008;73(232):73520-44.
    3. Frequent Questions about the Management Standards for Hazardous Waste Pharmaceuticals and Amendment to the P075 Listing for Nicotine Final Rule. Environmental Protection Agency. Accessed January 13, 2019. https://www.epa.gov/hwgenerators/frequent-questions-about-management-standards-hazardous-waste-pharmaceuticals-and
    4. 40 CFR Parts 261, 262, 264, 265, 266, 268, 270, and 273. Management Standards for Hazourdous Waste Pharmaceuticals and Amendment to the P075 Listing for Nicotine (Pre-Publication Copy). Environmental Protection Agency. Docet ID No. EPA-HQ-RCRA-2007-0932. Accessed January 13, 2019. https://www.epa.gov/sites/production/files/2018-12/documents/pharmaceuticals_final.pdf
  • 27 Nov 2018 1:33 PM | MSHP Office (Administrator)

    Current Recommendations for the Use of Antiplatelet Therapy in Secondary Prevention of Non-Cardioembolic Ischemic Stroke

    Author: Sarah Tortora, PharmD, PGY1 Pharmacy Practice Resident
    Preceptor: Jackie Harris, PharmD, BCPS, PGY1 Pharmacy Practice Residency Director, Christian Hospital Northeast – St Louis, MO

    Program Number: 2018-11-04
    Approval Dates: December 1, 2018 - June 1, 2019
    Approved Contact Hours: One (1) CE(s) per LIVE session.

    Learning Objectives

    1. Identify modifiable and non-modifiable risk factors of recurrent atherosclerotic cardiovascular events.
    2. Evaluate guidelines with regard to the use of antiplatelet therapy for prevention of recurrent ischemic stroke.
    3. Interpret recent literature regarding dual antiplatelet therapy in secondary prevention of non-cardioembolic ischemic stroke to identify when and in whom this strategy is appropriate.
    4. Identify and utilize tools available to clinicians to assist with decision-making for patients at risk for ischemic stroke.

    Introduction
    Cardiovascular disease (CVD) is a major source of morbidity and the leading cause of mortality in the United States. The American Heart Association (AHA) has found that 11.5% of the adult population (27.6 million) has a diagnosis of cardiovascular disease (including coronary heart disease (CHD), hypertension, heart failure, and stroke)1. Stroke can be particularly devastating, and is the fourth most common cause of death in the United States. There are approximately 795,000 new or recurrent cases of stroke each year in the United States, and as of 2015, there were 6.6 million American stroke survivors2. Having a history of stroke is, in itself, a risk factor for having another one; one meta-analysis showed that there was a recurrence risk of 3.1% at 30 days, 11.1% at one year, 26.4% at five years, and 39.2% at 10 years3. In fact, nearly 25% of strokes annually in the United States are not first-time events, and these recurrent events are more likely to result in death than first-time strokes4,5.

    The financial cost of stroke is staggering as well: an estimated $40.1 billion was spent on direct and indirect costs associated with stroke in 20131. Over 40% of that cost was due to loss of productivity and mortality. The AHA expects that, by 2035, 45.1% of American adults will have CVD in some capacity, and costs may exceed $1.1 trillion annually. Clearly, CVD is an extremely common aspect of American life, and one that will continue to have huge human and financial costs going forward. Primary prevention is and will be extremely important, but as the incidence of CVD, and thus, ischemic stroke increases, efficacious and efficient secondary prevention will be key to controlling excess morbidity and mortality. As the number of patients living with a history of stroke increases, pharmacists should be prepared to play a role in taking care of this vulnerable patient population.

    The most common manifestation of CVD is CHD, with stroke not far behind; together, these plus peripheral vascular disease constitute atherosclerotic cardiovascular disease (ASCVD)1. ASCVD is characterized by a narrowing of the blood vessels, limiting blood flow to tissues downstream and putting tissues at risk of ischemic damage. In ischemic stroke, this narrowing can either be due to atherosclerosis or thromboembolism, and the damage can be especially catastrophic and potentially fatal, depending on where in the brain this ischemia occurs. While there are a number of proven strategies to mitigate the risks of having a devastating event associated with ASCVD, arguably the mainstay is antiplatelet therapy. For many years, this simply meant aspirin. But as new drugs have come to the market in the last 20 years and new data has come out, there are many more options for treating patients with a history ASCVD, including stroke. Recommendations about which agents to use and for how long vary based on the clinical scenario, time since the event, and patient characteristics. This article will review those agents, summarize current guideline recommendations, and address gray areas and current data where guidelines have not with respect to the use of antiplatelet therapy in non-cardioembolic ischemic stroke.

    Risk Factors
    As with many disease states, risk factors for non-cardioembolic ischemic stroke can be modifiable or non-modifiable in nature. Well-documented non-modifiable risk factors include increased age, race, sex, low birth weight (less than 5.5 pounds), and genetic factors6. As patients age, their risk of stroke doubles with each decade they are older than 55, on average2. African Americans, Asian-Pacific Islanders, Native Americans, and Latinos experience worse outcomes for a number of metrics than whites in the United States. Among these, incidence and mortality rates are higher, age at the time of first-ever stroke tends to be lower, and as incidence of ischemic stroke has been shown to be decreasing overall and for whites in the United States since the 1990s, a similar decrease has not been noted in African Americans or Latinos2. Women represent a disproportionately high share of annual strokes in the United States, and have a one in five lifetime risk, compared to men’s one in six. However, men are more likely than women to have a stroke at a younger age2. The exact effect genetics has on one’s stroke risk is not yet fully understood, but one meta-analysis found that a “positive family history” of stroke increases one’s risk by about 30%7. In addition, having a parent with a history of stroke younger than age 65 is associated with a three-fold increase in stroke risk in their children.

    There are a number of modifiable risk factors that have been shown to increase one’s risk of stroke. They include cigarette smoking, hypertension, diabetes, carotid stenosis, dyslipidemia, poor diet, obesity, physical inactivity, and other cardiovascular diseases, such as coronary artery disease, heart failure, and peripheral artery disease6. Many of these risk factors are addressed in various guidelines related to treating stroke and have high quality evidence for modifying them in order to reduce the risk of an ischemic event. For example, for those with a history of stroke (not in the first 72 hours after an acute event) should have antihypertensive therapy initiated when their blood pressure is >140/90 mmHg, with a goal of <130/80 mmHg according to the 2017 AHA/ACC guidelines8. Great care should be taken in treating patients with a history of stroke and these concomitant risk factors, as this population is already at a higher risk of having a recurrent stroke than those who haven’t had such an event.

    Current Guidelines and Literature
    There are several different guidelines that make recommendations for the use of antiplatelet therapy in the setting of secondary prevention of stroke. While their overall recommendations are quite similar, they do vary slightly. Relevant guidelines are summarized in Appendix 1. Landmark studies referenced will be summarized in Appendix 2.

    As previously stated, prevention of recurrent strokes is of the utmost importance. Central to this treatment plan is the use of antiplatelet therapy. Anticoagulation in the form of vitamin K antagonists or the newer direct acting anticoagulants has been shown to be beneficial for the treatment of cardioembolic ischemic events, especially those as a result of atrial fibrillation. The majority of strokes, however, are due to progressive atherosclerosis and are better treated by antiplatelet agents9,10.

    In 2018, the American Heart Association and American Stroke Association released a guideline for the early management of patients with acute ischemic stroke11. This new guideline make new and revised recommendations for the use of antiplatelet therapy in the early secondary prevention period, in which patients are particularly vulnerable to recurrence. Firstly, aspirin should be initiated within 24-48 hours of the onset of stroke symptoms. They do not make a specific dosing recommendation, and an optimal aspirin dose has yet to be determined, but numerous studies have shown that doses between 50-325 mg daily are appropriate, and higher doses within this range offer no benefit over lower doses12-16. This is similar to the corresponding recommendation made by the 2012 American College of Chest Physicians Guideline on Antithrombotic and Thrombolytic Therapy in Ischemic Stroke; they recommend 160-326 mg of aspirin daily, and then 75-100 mg daily starting one week after acute stroke treatment17.

    The International Stroke Trial (IST) and Chinese Acute Stroke Trial (CAST) demonstrated the benefits of aspirin vs. placebo; 9 fewer deaths, 7 more good functional outcomes, and just 4 more occurrences of nonfatal major bleeding occurred per 1000 patients18. Another 2009 meta-analysis showed this benefit is even more pronounced when follow-up time was extended to two years19. Aspirin is considered the mainstay of secondary prevention of non-cardioembolic ischemic stroke as it is the most well studied, is relatively safe and effective, and is extremely cheap.

    Until just two decades ago, this would have been the end of the discussion about antiplatelet therapy. However, a number of potential replacements or additions to aspirin have been introduced, with the workhorse being clopidogrel. Clopidogrel inhibits platelet activation by irreversibly blocking the P2Y12 site within the adenosine diphosphate receptor on the platelet surface, thus inhibiting platelet aggregation20. The 2012 ACCP guidelines make a strong recommendation for the use of clopidogrel 75 mg daily long-term, and actually less strongly recommends clopidogrel over aspirin (Grade 2B)17. This is largely the result of the CAPRIE trial (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events), which showed that in patients with a history of stroke, myocardial infarction, or peripheral vascular disease, clopidogrel significantly reduced the composite of ischemic stroke, MI, or cardiovascular death (5.32% vs. 5.83%, 95% CI 0.84-0.97; p = 0.043)21. Although insignificant, clopidogrel also resulted in 10 fewer nonfatal recurrent strokes per 1,000 patients when treated for two years, with little or no effect on mortality or major bleeding. Clopidogrel is also a good option for patients with an allergy to aspirin or another indication for antiplatelet therapy (e.g. history of MI, percutaneous coronary intervention, etc.).

    The PRoFESS trial (Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke) sought to compare clopidogrel to another agent approved for secondary prevention of ischemic stroke, extended-release dipyridamole plus aspirin22. In summary, there was no difference between the two drugs with regards to recurrent stroke, major bleeding, or overall mortality. However, headache was much more common with dipyridamole/aspirin than clopidogrel (30% vs. 10%); this along with the more inconvenient twice daily dosing than clopidogrel’s once daily are major reasons for why clopidogrel is used more often in practice.

    At this point, a number of clinical questions still exist. Firstly, the use of dual antiplatelet therapy is common in other acute cardiovascular events; what role does it play in the secondary prevention of ischemic stroke? For a long time, it appeared that this was not a useful strategy in any stroke patients. The Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke (MATCH) trial in 2004 showed no benefit in using clopidogrel plus aspirin over aspirin alone for reducing mortality, recurrent stroke, or MI, and did carry with it a significant increase in major bleeding23. The MATCH trial has been criticized by some, however, because a majority of its patients had lacunar infarcts, rather than atherothrombotic ischemia, which tend to benefit less from antiplatelet therapy.

    In 2013, the Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial compared the early use of aspirin/clopidogrel vs. aspirin24. The combination was continued for the first 21 days, and then the aspirin component was discontinued. At 90 days, there was a significantly reduced rate of recurrent strokes in the combination group (8.2% vs. 11.7%, number needed to treat = 29) and no difference in major bleeding.  CHANCE differs significantly from MATCH because patients were enrolled within 24 hours of acute stroke intervention, whereas MATCH allowed enrollment for the first six months after an acute event. In addition, CHANCE only enrolled Chinese patients, limiting its generalizability to other patient populations; Chinese patients tend to have a higher incidence of stroke and are known to have more polymorphisms that affect clopidogrel metabolism. However, the Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke (POINT) trial published in 2018 utilized similar methods and had similar outcomes, and enrolled patients in North America, Europe, Australia, and New Zealand25. Further study is needed to zone in on the most effective combination, duration, and patient population in which to utilize dual antiplatelet therapy. As a result of these trials, the 2018 AHA/ASA guideline recommended dual antiplatelet therapy with aspirin and clopidogrel for the first 21 days after acute treatment (Grade IIa)11.

    Unfortunately, recurrent stroke is all too common in the United States. This begs the question, how do we treat a patient who experiences a recurrent ischemic stroke despite adequate preventative antiplatelet therapy? Among those on preventative aspirin who fall into this population, a 2017 meta-analysis showed data supporting addition of or switching to a different antiplatelet agent was associated with reduced rates of recurrent stroke26. Data is less robust when the initial therapy in question is an agent other than aspirin. At this time, there isn’t enough information to make a high quality recommendation for any strategy, and will likely be the subject of more study in the future. As always, patient-specific factors need to be considered in order to make the most safe and efficacious decision possible.

    Tools for Clinicians
    Today, it seems as if there’s a mobile application for everything, and that holds true for decision-making tools for antiplatelet therapy. For primary prevention of stroke, the Aspirin Guide, created by researchers at Brigham and Women’s Hospital and Harvard Medical School helps clinicians decide which patients would experience ASCVD benefits, including the prevention of ischemic stroke, from low-dose aspirin. Another widely used primary prevention app is the ASCVD Risk Estimator Calculator, created by the American College of Cardiology. The algorithm used in this app collects several patient characteristics and gives a current 10-year ASCVD risk, lifetime risk (for those under 60), and gives advice for statin, antihypertensive, and aspirin therapy. The ACC also supports the Dual Antiplatelet Therapy (DAPT) Risk Calculator, which gives an approximate risk of major bleeding in patients on DAPT, and what that risk would be if they discontinued therapy. The app was created for patients with an FDA indication for DAPT (e.g. MI, PCI with stents, etc.), but as data for DAPT in secondary prevention of stroke becomes more robust and the number of patients utilizing this strategy increases, it may be a useful tool for clinicians taking care of this patient population as well. All of these apps are free and available in the app store.

    Conclusion
    Stroke is a huge source of morbidity and mortality in the United States, and as the population ages, current trends suggest incidence and related costs will rise significantly. Therefore, it’s important to ensure that these patients are being appropriately treated in order to prevent a recurrent event, and antiplatelet therapy is an important feature of that. The concept of the use of dual antiplatelet therapy in stroke patients is a great example of how new data is outpacing guideline recommendations, and the importance for clinicians to remain up to date on this data in order to adequately treat patients. This will likely be the topic of much study in the future, and may result in groundbreaking changes in how to prevent current stroke from current standard of practice.

    References

    1. Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, et al. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation. 2018;137(12):e67-e492. Epub 2018/01/31. PubMed PMID: 29386200.
    2. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29-322. Epub 2014/12/17. PubMed PMID: 25520374.
    3. Mohan KM, Wolfe CD, Rudd AG, Heuschmann PU, Kolominsky-Rabas PL, Grieve AP. Risk and cumulative risk of stroke recurrence: a systematic review and meta-analysis. Stroke. 2011;42(5):1489-94. Epub 2011/03/31. PubMed PMID: 21454819.
    4. Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Burvill PW, Anderson CS, et al. Long-term risk of first recurrent stroke in the Perth Community Stroke Study. Stroke. 1998;29(12):2491-500. PubMed PMID: 9836757.
    5. Jørgensen HS, Nakayama H, Reith J, Raaschou HO, Olsen TS. Stroke recurrence: predictors, severity, and prognosis. The Copenhagen Stroke Study. Neurology. 1997;48(4):891-5. PubMed PMID: 9109873.
    6. Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi S, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(12):3754-832. Epub 2014/10/28. PubMed PMID: 25355838.
    7. Flossmann E, Schulz UG, Rothwell PM. Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke. 2004;35(1):212-27. Epub 2003/12/18. PubMed PMID: 14684773.
    8. Whelton PK, Carey RM, Aronow WS, Casey DE, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(19):e127-e248. Epub 2017/11/13. PubMed PMID: 29146535.
    9. Ishida K, Messé SR. Antiplatelet strategies for secondary prevention of stroke and TIA. Curr Atheroscler Rep. 2014;16(11):449. PubMed PMID: 25204758.
    10. Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke. 2001;32(12):2735-40. PubMed PMID: 11739965.
    11. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110. Epub 2018/01/24. PubMed PMID: 29367334.
    12. Collaboration AT. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86. PubMed PMID: 11786451.
    13. Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry. 1991;54(12):1044-54. PubMed PMID: 1783914.
    14. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Antiplatelet Trialists' Collaboration. Br Med J (Clin Res Ed). 1988;296(6618):320-31. PubMed PMID: 3125883.
    15. The European Stroke Prevention Study (ESPS). Principal end-points. The ESPS Group. Lancet. 1987;2(8572):1351-4. PubMed PMID: 2890951.
    16. Johnson ES, Lanes SF, Wentworth CE, Satterfield MH, Abebe BL, Dicker LW. A metaregression analysis of the dose-response effect of aspirin on stroke. Arch Intern Med. 1999;159(11):1248-53. PubMed PMID: 10371234.
    17. Lansberg MG, O'Donnell MJ, Khatri P, Lang ES, Nguyen-Huynh MN, Schwartz NE, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e601S-e36S. doi: 10.1378/chest.11-2302. PubMed PMID: 22315273.
    18. Sandercock P, Gubitz G, Foley P, Counsell C. Antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev. 2003(2):CD000029. PubMed PMID: 12804384.
    19. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849-60. PubMed PMID: 19482214.
    20. Plavix (clopidogrel) [product monograph]. Laval, Quebec, Canada: Sanofi-Aventis Canada; March 2018.
    21. Committee CS. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348(9038):1329-39. PubMed PMID: 8918275.
    22. Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, Lawton WA, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359(12):1238-51. Epub 2008/08/27. PubMed PMID: 18753638.
    23. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331-7. PubMed PMID: 15276392.
    24. Wang Y, Zhao X, Liu L, Wang D, Wang C, Li H, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11-9. Epub 2013/06/26. PubMed PMID: 23803136.
    25. Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med. 2018;379(3):215-25. Epub 2018/05/16. PubMed PMID: 29766750.
    26. Lee M, Saver JL, Hong KS, Rao NM, Wu YL, Ovbiagele B. Antiplatelet Regimen for Patients With Breakthrough Strokes While on Aspirin: A Systematic Review and Meta-Analysis. Stroke. 2017;48(9):2610-3. Epub 2017/07/12. PubMed PMID: 28701574.


    Submit for CE

  • 27 Nov 2018 12:41 PM | MSHP Office (Administrator)

    Authors:  Abigail Cordia, student pharmacist1; Amber Laurent, student pharmacist1; Yvonne Burnett, PharmD1 ,1 St. Louis College of Pharmacy


    For many years, development of novel antimicrobials seemed to be at a standstill. This, combined with increasing rates antimicrobial resistance, left a very real threat that there may come a time when the antimicrobials in our arsenal will no longer be effective against deadly pathogens. Luckily, in the past year there have been quite a few new antimicrobials brought to market to combat multidrug resistant (MDR) pathogens. This article will focus on a few such agents. Below is a brief overview of Baxdela (delafloxacin) and Vabomere (meropenem/vaborbactam). While it is exciting to learn of these advances, it is important to understand where each of these fit in practice so that we may use them appropriately. As vital members of the healthcare team, pharmacists play crucial roles as antimicrobial stewards helping to keep antimicrobial use in check.

    Baxdela (delafloxacin)

    Baxdela is a fluoroquinolone antibiotic approved by the Food and Drug Administration (FDA) in June 2017 for the treatment of acute bacterial skin and skin structure infections (ABSSSI), and has broad activity against atypicals, gram positive and negative organisms, including anaerobes.1 Susceptible pathogens are similar to others in the class including Pseudomonas aeruginosa, Escherichia coli, Klebsiella spp., and Streptococcus spp., with the addition of Staphylococcus aureus, including methicillin-resistant (MRSA) strains, and Enterococcus faecalis. While there is broad gram negative coverage, Enterobacteriaceae and pseudomonal resistance to ciprofloxacin and levofloxacin already exists and is shared by delafloxacin. This antibiotic is available both orally (PO) and intravenously (IV), dosed at 450mg PO twice daily or 200mg IV twice daily. Doses should be renally adjusted for patients with CrCl <30 mL/min.1

    While the expanded spectrum of activity for MRSA is exciting, delafloxacin carries the same boxed warning as other fluoroquinolones, including tendinitis, tendon rupture, peripheral neuropathy, central nervous system effects, hypoglycemia, and exacerbation of myasthenia gravis. In studies, delafloxacin was generally well tolerated with the most common adverse effects reported as nausea (8%) and diarrhea (8%), headache (3%), transaminase elevations (3%), and vomiting (2%). 1 Uniquely, delafloxacin has not been associated with QT prolongation, as compared with other members of this class.3

    Two large phase 3 trials were conducted comparing delafloxacin, either 300mg IV q12 or 300mg IV q12 for 3 days followed by 450mg PO q12, to vancomycin 15 mg/kg plus aztreonam for 5-14 days for the treatment of ABSSSI.4,5 The primary endpoint for both trials was clinical response at 48-72 hours, defined as > 20% reduction in lesion size and no evidence of treatment failure (<20% reduction of erythema, additional antibiotic therapy, unplanned surgical intervention, or death within 72h after initiation). Results from both trials concluded that delafloxacin was non-inferior to vancomycin plus aztreonam. Additionally, the studies found a comparable response rate between the two groups for MRSA and gram-negative pathogens. It should be noted, that these studies included mostly white patients and had few burn and surgical wounds, infections due to gram-negative, or patients with diabetes.3 Interestingly, an additional study found increased cure rates in obese patients with delafloxacin compared to vancomycin, suggesting that it may have a place in therapy for obese patients.3

    Delafloxacin appears to be an effective broad spectrum treatment and results of the published trials support the use for treatment of ABSSSI caused by S. aureus (both methicillin susceptible (MSSA) and MRSA) and Streptococcus spp. Further study focusing on MDR gram negative pathogens is warranted to support treatment of these organisms. Additionally, caution should be exercised when considering fluoroquinolone antibiotics due to the myriad of adverse events associated with their use. With many other oral options available to treat ABSSSI due to gram-positive organisms, this drug may be useful when treating polymicrobial infections when additional gram negative and anaerobic coverage is warranted, but is unlikely to be a first line anti-MRSA drug. Additional studies will prove useful to better define delafloxacin’s place in clinical practice.

    Vabomere (meropenem/vaborbactam)

    Vabomere, a combination of a carbapenem, meropenem, and a non beta-lactam beta-lactamase inhibitor, vaborbactam, was approved by the FDA in August 2017 and is the first carbapenem/beta-lactamase inhibitor combination to be marketed in the United States. It is currently indicated for use in adult patients with a complicated urinary tract infections (cUTI), including pyelonephritis, caused by designated susceptible bacteria. This drug retains the broad spectrum activity of meropenem, including activity against MSSA, Streptococcus spp, Enterobacteriaceae, P. aeruginosa, and Bacteroides fragilis.  The addition of vaborbactam, a potent inhibitor of class A serine carbapenemases, restores meropenem’s activity against extended spectrum beta-lactamase (ESBL) producing organisms, including carbapenemase resistant Enterobacteriaceae (CRE). It should be noted, however, that vaborbactam does not improve the activity of meropenem against Acinetobacter baumannii, P. aeruginosa, Stenotrophomonas maltophilia, or organisms that produce metallo-beta lactamases. Meropenem/vaborbactam is administered as 4g IV (2g of meropenem, 2g vaborbactam) every 8 hours infused over 3 hours and must be renally adjusted for patients with CrCl < 50 mL/min. Common side effects include headache, phlebitis/infusion site reactions, and diarrhea.6

    In the phase 3 TANGO 1 study, meropenem/vaborbactam was compared to piperacillin-tazobactam for treatment of cUTI in 550 patients.8 Each medication was given for at least 5 days, for a median of 8 days. After 5 days, patients could be switched to an oral option to complete 10 days. Approximately 85% of patients grew one of the following Enterobacteriaceae species upon presentation: E. coli, K. pneumoniae, E. faecalis, Proteus mirabilis, and Enterobacter cloacae species complex. Meropenem/vaborbactam was found to be non-inferior to piperacillin-tazobactam for the primary composite endpoint of clinical cure or improvement and microbial eradication.  There were no significant differences in adverse events observed between the two drugs. Meropenem-vaborbactam is administered as an extended infusion, while piperacillin-tazobactam was not in this study, which may account for slightly higher success rates, this was not found to be statistically significant.8 The TANGO 2 trial evaluated meropenem/vaborbactam compared to best available therapy in patients with cUTI, acute pyelonephritis, hospital-acquired or ventilator-associated bacterial pneumonia, bacteremia, or complicated intra-abdominal infection, due to known or suspected CRE. Best available therapy included combination or monotherapy carbapenems, aminoglycosides, polymixin B, colistin, tigecycline, or ceftazidime-avibactam. While numbers were small in this study, only 72 patients, meropenem/vaborbactam demonstrated a higher rate of clinical cure versus best available therapy. 9 Additionally, meropenem/vaborbactam has demonstrated in vitro activity against 99% of CRE isolates.10

    Based on the available data, meropenem-vaborbactam is a promising antibiotic for CRE cUTIs. Further study is warranted to show meropenem/vaborbactam’s activity in the setting of additional severe drug-resistant gram-negative infections. Due to the lack of antibiotics with activity against CREs and the concern for the spread of emerging resistance, meropenem/vaborbactam should be reserved for only resistant infections to which it tests susceptible. It is also important to note that if an isolate of P. aeruginosa tests resistant to meropenem, the addition of vaborbactam will not provide additional coverage.

    Delafloxacin and meropenem/vaborbactam are just a few of the new antibiotics that have been brought to market recently. Antimicrobial resistance may be on the rise, but there is rejuvenated interest in development of new agents as well as conserving the use of current antimicrobials.  In the latter half of 2018, just prior to the publishing of this article, there were three additional antibiotics approved by the FDA: plazomicin (Zemdri), eravacycline (Xerava), and omadacycline (Nuzyra). Understanding each of their places in therapy is necessary to preserve their effectiveness and prevent the development of resistance. For now, these antimicrobials should be reserved for special cases, each for their own reason. Delafloxacin may prove useful for complicated polymicrobial infections with MRSA for which oral therapy is preferred, but does come with the risk of serious adverse effects. Meropenem/vaborbactam has potent activity against CREs, some of the most formidable pathogens, but should only be reserved for such cases and when susceptibility can be verified. For serious infections, patients are often treated with prolonged courses of therapy. Long term adverse effects, associated with such use for each of these agents, are unknown. By knowing when and how to use new antimicrobials, all pharmacists can play a central role in antimicrobial stewardship.

    References:

    1. Baxdela [package insert]. Lincolnshire, IL: Melinta Therapeutics Inc.; 2017.
    2. Hoover R, Hunt T, Benedict M, et al. Safety, tolerability, and pharmacokinetic properties of intravenous delafloxacin after single and multiple doses in healthy volunteers. Clin Ther. 2016;38(1):53-65.
    3. Kingsley J, Mehra P, Lawrence L, et al. A randomized, double-blind, phase 2 study to evaluate subjective and objective outcomes in patients with acute bacterial skin and skin structure infections treated with delafloxacin, linezolid or vancomycin. J Antimicrob Chemother. 2016;71:821-829.
    4. Pullman J, Gardovskis J, Farley B, et l. Efficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections: a phase 3, double-blind, randomized study. J Antimicrob Chemother. 2017;72:3471–3480.
    5. O’Riordan W, McManus A, Teras J, et al. A comparison of the efficacy and safety of intravenous followed by oral delafloxacin with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections: a phase 3, multinational, double-blind, randomized study. Clin Infect Dis. 2018;67(5):657-666.
    6. Vabomere [package insert]. Lincolnshire, IL: Melinta Therapeutics Inc.; 2017.
    7. Rubino CM, Bhavnani SM, Loutit JS, et al. Phase 1 study of the safety, tolerability, and pharmacokinetics of vaborbactam and meropenem alone and in combination following single and multiple doses in healthy adult subjects. Antimicrob Agents Chemother. 2018;62(4).
    8. Kaye KS, Bhowmick T, Metallidis S, et al. Effect of meropenem-vaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection: the TANGO I randomized clinical trial. JAMA. 2018;319(8):788-799.
    9. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant enterobacteriaceae infections: the TANGO II randomized clinical trial. Infect Dis Ther. 2018. [Epub ahead of print]
    10. Hackel MA, Lomovskaya O, Dudley MN, Karlowsky JA, Sahm DF. In vitro activity of meropenem-vaborbactam against clinical isolates of KPC-positive Enterobacteriaceae. Antimicrob Agents Chemother. 2018;62(1).
  • 26 Nov 2018 1:00 PM | MSHP Office (Administrator)

    Pharmacogenetic Testing to Predict Warfarin Response

    Author: Kristine Reckenberg, PharmD,  PGY1 Pharmacy Practice Resident
    Preceptor: Justinne Guyton, PharmD, BCACPPGY1 Pharmacy Practice Residency DirectorSt. Louis County Department of Public Health/St. Louis College of Pharmacy

    Program Number: 2018-11-05
    Approval Dates: December 1, 2018 - June 1, 2019
    Approved Contact Hours: One (1) CE(s) per LIVE session.

    Learning Objectives:

    1. Identify pharmacogenetic variables that impact warfarin dose requirements.
    2. Describe how warfarin genotypes impact warfarin metabolism.
    3. Use recommendations set forth by the Clinical Pharmacogenetics Implementation Consortium and the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
    4. Evaluate the current evidence for using pharmacogenetic testing prior to warfarin initiation.
    5. Identify an appropriate warfarin initiation strategy for a patient undergoing hip or knee arthroplasty given the results of the GIFT trial.

    Introduction

    Pharmacogenetics is a subtype of pharmacogenomics in which polymorphisms in genes that encode drug metabolizing enzymes, transporters, and/or targets can impact drug effects, leading to variability among individuals in response to a medication.1 Warfarin, a vitamin K antagonist (VKA), is an oral anticoagulant commonly used for prevention of stroke in atrial fibrillation and prevention and treatment of venous thromboembolism.1 It is also an agent that displays pharmacogenetic variations between individuals that impact both pharmacokinetics and pharmacodynamics.2  Established pharmacogenetic variables are caused by variations in the cytochrome P450 system and the warfarin targets.1 These variables have the potential for a large impact as warfarin is an agent with a narrow therapeutic index that is associated with serious adverse events, notably bleeding. These differences are most significant during the dose finding stage of warfarin initiation. Based on these factors, warfarin can be initiated via a pharmacogenetic dosing algorithm, dosed clinically (dosing based off of clinical factors – age, medications, comorbidities, bleed risk, and social history), or using a standard dose approach.3

    Two guidelines provide recommendations regarding the use of warfarin pharmacogenetic testing prior to warfarin initiation. The Clinical Pharmacogenetics Implementation Consortium Guidelines (CPIC) has been updated with the results of newly published trials whereas the American College of Chest Physicians Guidelines (ACCP) have not.3-4 This continuing education article will focus on the factors that impact warfarin pharmacogenetics, current guideline recommendations, and recently published data regarding warfarin pharmacogenetics.

    Warfarin Pharmacogenetics

    There are two predominant genes, that have been studied extensively, that contribute to the interpatient variability in warfarin dose requirements. These include cytochrome P450 2C9 (CYP450 2C9) and vitamin K epoxide reductase complex 1 (VKORC1).5 CYP450 4F2 also plays a role in variability, however, it has demonstrated a smaller part in dose requirements during warfarin initiation.5

    CYP450 2C9 is associated with multiple different polymorphisms, however, the nonsynonymous single nucleotide polymorphisms (SNPs) that influence warfarin dose requirements the most are the *2 and *3 alleles.5-6 These SNPs lead to a reduction in the enzymatic activity of S-warfarin.5-6 The outcome is a decrease in warfarin requirements due to the slowed metabolism, as the S-enantiomer of warfarin has a greater anticoagulant effect as compared to the R-enantiomer. CYP450 2C9*2 is associated with only 70% activity as compared to the wild type allele, whereas CYP450 2C9*3 is associated with only 20% activity.6 These alleles are present most frequently in Europeans, and rarely in African Americans and Asians.5

    VKORC1 is an enzyme that is responsible for the regeneration of reduced vitamin K, and is the target of warfarin therapy.5-6  The SNPs that influence this enzyme include 1173 C>T and 1639 G>A.6 These alleles result in decreased translation of mRNA into proteins; ultimately leading to a lower level of expression of the VKORC1 enzyme.5 This decrease in VKORC1 is associated with lower warfarin dose requirements accounting for 25 + 8% of the variance in warfarin dose requirements.5-6 VKORC1 1639 A/A has been found to decrease initial warfarin dose requirements by approximately 40%.14 Those patients that have the wild-type haplotype (GG) have a higher rate of metabolism as compared to those that are homozygous for the variant allele (AA).6 Those that are heterozygous for the variant allele have an intermediate rate of metabolism.6 The A allele is present most frequently in patients of Asian ethnicity, followed by Europeans, and rarely in African Americans.5

    CYP450 4F2 is one of the CYP450 enzymes responsible for metabolism of vitamin K.5 Those patients with the CYP450 4F2 V433M SNP have decreased metabolism of vitamin K, resulting in higher warfarin dose requirements.5 Despite this finding, CYP450 4F2 V433M SNP only contributes to approximately one percent of variability in warfarin dose requirements.5 This polymorphism is present in Europeans and Asians, but rarely in African Americans.5

    Table 1 located in the appendix provides ranges of expected warfarin total daily doses based on CYP450 2C9 and VKORC1 polymorphisms, according to the manufacturer.

    Current Guideline Recommendations

    There are two main sources that provide recommendations regarding warfarin pharmacogenetic testing for initiation of warfarin therapy. These include guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the American College of Chest Physicians (ACCP).3-4

    The CPIC Guidelines, prepared by an international consortium of volunteers, released an update in 2017 following release of results of the Genetics-Informatics Trial (GIFT).3 The CPIC recommends that in patients of non-African ancestry, warfarin dosing should be calculated using a published pharmacogenetic algorithm including genotype information for VKORC1 1639 C>A, CYP450 2C9*2 and *3.3 If this genetic information is not available, warfarin should be initiated based on clinical factors; this has a strong recommendation rating.3 In patients of African ancestry it is important to know the additional genotypes of CYP2C9*5, *6, *8, and *11.3 If available, the warfarin dose should be calculated using a validated pharmacogenetic algorithm including the variables of VKORC1 1639 C>A, CYP2C9*2 and *3.3 If the patient carries CYP2C9*5, *6, *8, or *11 alleles, the dose should be decreased by 15-30%; with a moderate recommendation rating by the CPIC.3 If this genetic information is unavailable, warfarin should be dosed clinically.3

    The ACCP Guidelines published in 2012 recommend against the routine use of pharmacogenetic testing for guiding doses of vitamin K antagonists with a grade of 1B.4 This is due to the limited availability of four small randomized controlled trials, availability of a single systematic review concluding lack of evidence to support using pharmacogenetic testing to guide therapy, and multiple cost effectiveness analyses indicating lack of cost-effectiveness at the time of guideline update.4

    Summary of Evidence

    Before pharmacogenetic dosing of warfarin can be considered as a potential for adoption in routine clinical practice, there must be sufficient evidence provided by large randomized controlled trials. To date most randomized controlled trials have had small sample sizes with the most recent study being the largest to date. Here the three major landmark clinical trials and one systematic review exploring pharmacogenetic-guided warfarin dosing versus clinically-guided warfarin dosing will be reviewed.

    The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial by Verhoef and colleagues was published first in 2013.8 This study combined data from two single-blind, randomized trials for the initiation of VKAs, acenocoumarol or phenprocoumon, in the treatment of 548 patients with atrial fibrillation or venous thromboembolism. VKAs were initiated with either a genotype-guided algorithm or clinically-guided algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1, or a dosing algorithm that included only clinical variables for the first 5-7 days. After the first 5-7 days, the patients were treated based on international normalized ration (INR) and local clinical practice with intended follow-up for 12 weeks.8 The primary outcome, percent of time in therapeutic INR, was observed in 61.6% of patients in the genotype-guided group and 60.2% in the clinically-guided group (p = 0.52) during the first 12 weeks.8 However, the percentage of time in therapeutic range after the first four weeks of treatment was 52.8% in the genotype-guided group versus 47.5% in the clinically-guided group (p = 0.02). There were no differences in bleeding event rates or thromboembolic events.8

    The Clarification of Optimal Anticoagulation Through Genetics (COAG) trial by Kimmel and colleagues was published in 2013.9 This was a multicenter, double blind trial comparing a warfarin dosing algorithm including  genotype-guided therapy versus clinically-guided therapy during the first 5 days of warfarin therapy in 1015 patients.9 The patients received follow-up through the first 4 weeks of therapy.9 The primary outcome (percent of time in therapeutic INR from day 4 or 5 through day 28 of therapy) was observed in 45.2% in the genotype-guided group and 45.4% in the clinically guided group, with an adjusted mean difference of -0.2 (95% CI -3.4 to 3.1, p = 0.91).9 Statistically significant findings were reported with subgroups; black patients had a lower mean percentage of time in the therapeutic range in the genotype-guided group as compared to the clinically-guided group.9 There were no significant differences with regard to INR > 4, major bleeding, or thromboembolism.9

    The most recent warfarin pharmacogenetic study is the Genetic Informatics Trial (GIFT) published by Gage and colleagues in 2017.10 This was a multicenter randomized clinical trial in patients initiating warfarin at the time of elective hip or knee arthroplasty. A total of 1597 patients were randomized to receive genotype-guided dosing of warfarin during the first 11 days or clinically-guided dosing of warfarin with follow-up for 90 days.10 The primary outcome (a composite of major bleeding within 30 days, INR of 4 or greater within 30 days, death within 30 days, and symptomatic or asymptomatic venous thromboembolism within 60 days of arthroplasty) was observed in 10.8% of patients in the genotype-guided group versus 14.7% in the clinically-guided group with an absolute difference of 3.9% (95% CI 0.7-7.2%, p = 0.02).10

    Lastly, a meta-analysis was published in 2014 by Stergiopoulos and colleagues, which included nine randomized controlled trials and 2812 patients, and compared genotype-guided initial dosing of warfarin and its analogues to clinical dosing protocols.11 In this study, the standardized difference in means of the percent of time that the INR was therapeutic was 0.14 (95% CI -0.10-0.39, p = 0.25).11 There was not a significant difference found for risk ratio for an INR greater than 4, major bleeding, or thromboembolic events.11

    With regards to pharmacoeconomic studies, varying results have been presented. Three studies found pharmacogenetic-guided warfarin dosing to be cost effective, whereas four studies were inconclusive, and five studies found pharmacogenetic-guided warfarin dosing to not be cost effective.12 Furthermore, coverage of pharmacogenetic testing for warfarin initiation varies based on insurance company. The Centers for Medicare and Medicaid Services (CMS) released an update regarding their organization’s coverage of this testing. As of January 25th, 2018, CMS does not believe that current evidence supports pharmacogenetic testing for CYP2C9 or VKORC1 for warfarin initiation due to limited studies indicating a benefit in health outcomes.12 Testing will not be covered under the Social Security Act, but may be covered under the Coverage with Evidence Development (CED) section of the Social Security Act if specific requirements are meant.12 According to CMS, these include patients who are “candidates for anticoagulation with warfarin who: have not been previously tested for CYP2C9 or VKORC1 alleles; and have received fewer than 5 days of warfarin in the anticoagulation regimen for which the testing is ordered; and are enrolled in a prospective, randomized, controlled clinical study when that study meets the standards specified in the decision memorandum.”12

    Conclusion

    Pharmacogenomic studies have indicated that warfarin pharmacogenetics can play a role in warfarin dose requirements through polymorphisms in CYP450 2C9 and VKORC1. A number of randomized controlled trials, each with their own limitations have presented variable results with regards to the benefit of pharmacogenetic versus clinically guided dosing of warfarin. In addition, cost-effectiveness studies have also produced opposing results. Therefore, clinicians should be aware of the impact pharmacogenetic testing results can have on warfarin dose adjustments and use this information, should it be available. Pharmacists should be aware of advances in pharmacogenetic dose adjustments of medications to serve as a resource for both other healthcare providers and patients.

    References

    1. Cavallari LH. Tailoring drug therapy based on genotype. J Pharm Pract. 2012;25(4):413-416.
    2. Lexi-Comp, Inc. (Lexi-DrugsTM). Lexi-Comp, Inc. Accessed 17 Sep 2018.
    3. Johnson J.A., Caudle K.E., Gong L., Whirl-Carrillo M., et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clin Pharmacol Ther. 2017 Feb 15;102(3):397–404.Holbrook A, Schulman S, Witt DM, et al. American College of Chest P. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e152S–e184S.
    4. Johnson JA, Cavallari LH. Warfarin pharmacogenetics. Trends Cardiovasc Med. 2015;25(1):33-41.
    5. Li J, Wang S, Barone J, et al. Warfarin pharmacogenomics. P T. 2009;34(8):422-427.
    6. Coumadin [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; Oct 2011. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009218s107lbl.pdf. Accessed 17 Sep 2018.
    7. Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013;369:2294–2303.
    8. Kimmel SE, French B, Kasner SE, Johnson JA, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. 2013;369:2283–2293.
    9. Gage BF, Bass AR, Lin H. Effect of genotype-guided warfarin dosing on clinical events and anticoagulation control among patients undergoing hip or knee arthroplasty: the GIFT randomized clinical trial. JAMA. 2017;318(12):1115-1124.
    10. Stergiopoilos K, Brown DL. Genotype-guided vs clinical dosing of warfarin and its analogues meta-analysis of randomized clinical trials. JAMA. 2014;174(8):1330-1338.
    11. Verbelen M, Weale ME, Lewis CM. Cost-effectiveness of pharmacogenetic-guided treatment: are we there yet? Pharmacogenomics J. 2017(5):395-402.
    12. Pharmacogenomic testing for warfarin response. CMS; Jan 2018. Available at: https://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence-Development/Pharmacogenomic-Testing-for-Warfarin-Response.html. Accessed 17 Sep 2018.
    13. Dean L. Warfarin therapy and VKORC1 and CYP genotype. 2012 Mar 8 [Updated 2018 Jun 11]. In: Pratt V, McLeod H, Rubinstein W, et al., editors. Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK84174/.


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