On the Pulse of What s Current: A Cardiovascular Pharmacotherapy Update

Transcription

1 On the Pulse of What s Current: A Cardiovascular Pharmacotherapy Update By Jason Williamson, Pharm.D., BCPS, clinical/staff pharmacist, Genesys Regional Medical Center Target Audience This continuing education activity was designed specifically for pharmacists. Disclosure Statement The author does not have any conflicts of interest, or financial relationships with a commercial interest, related to the activity. Learning Objectives At the end of this activity, participants should be able to: identify medications recently approved by the Food and Drug Administration (FDA) for use with cardiovascular disease states. select an appropriate dosing regimen and titration strategy for sacubitril/valsartan given a patient case. discuss appropriate dosing for ivabradine given a patient case, including specific actions to appropriately manage ivabradine-associated drug interactions. explain the appropriate use of vorapaxar in the presence of concomitant antiplatelet therapies. discuss the advances and shortcomings of the target-specific oral anticoagulants (TSOACs) relative to warfarin in the management of various thromboembolic disease states. The below table lists commonly used abbreviations for your reference while completing this home study. Commonly Used Abbreviations ACE angiotensin converting enzyme MI myocardial infarction ACS acute coronary syndrome NNT number needed to treat AF atrial fibrillation NSTEMI non-st segment elevation myocardial infarction ARB angiotensin receptor blocker NVAF nonvalvular atrial fibrillation AV atrioventricular NYHA New York Heart Association BPM beats per minute PAD peripheral arterial disease BUN blood urea nitrogen PAH pulmonary arterial hypertension CHF congestive heart failure PCI percutaneous coronary intervention CI confidence interval PE pulmonary embolism CrCl creatinine clearance RAAS renin-angiotensin-aldosterone system DVT deep venous thrombosis SA sinoatrial FDA Food and Drug Administration SCr serum creatinine HF heart failure STEMI ST segment elevation myocardial infarction HIV human immunodeficiency virus TIA transient ischemic attack HR hazard ratio TSOAC target-specific oral anticoagulant ICH intracranial hemorrhage LVEF left ventricular ejection fraction UA unstable angina VTE venous thromboembolism

2 Introduction The landscape of cardiovascular pharmacotherapy has significantly evolved and changed within the recent past. With many new medications approved by the Food and Drug Administration (FDA) within the last decade and several guideline updates recently published, pharmacy practitioners in a diverse array of settings may find it difficult to stay up-to-date with the most recent evidence-based therapies available. This article will review recently-approved medications used for the treatment of cardiovascular diseases and provide a focused update on selected cardiovascular medications and drug classes. Recently-approved Cardiovascular Medications A total of 20 new medications, medication combinations and novel dosage forms for the treatment of cardiovascular disease states have come to market in the United States since the beginning of ,2 Table 1 outlines medications approved by the FDA for the treatment of cardiovascular diseases within the last five years. Unless otherwise noted, medications are available as oral dosage forms. Despite many potential medications to discuss from those recently approved, several cardiovascular medications were selected to discuss based on clinical relevance to a diverse array of pharmacy practice settings. These selected medicaitons include sacubitril/valsartan (Entresto), ivabradine (Corlanor), vorapaxar (Zontivity) and the target-specific oral anticoagulants (TSOACs). Table 1. Cardiology/Vascular Medications Approved by the FDA from ,2 Azilsartan medoxomil (Edarbi) o Treatment of hypertension Azilsartan medoxomil and chlorthalidone (Edarbyclor) o Treatment of hypertension Rivaroxaban (Xarelto) o Reduction in the risk of stroke and systemic embolism from nonvavlular 2011 atrial fibrillation (NVAF) o Prevention of deep venous thrombosis (DVT) after knee or hip replacement surgery o Treatment of DVT/pulmonary embolism (PE) Ticagrelor (Brilinta) o Reduction of thrombotic events in patients with acute coronary syndrome (ACS) Apixaban (Eliquis) o Prevention of stroke and systemic embolism resulting from NVAF Icosapent ethyl (Vascepa) 2012 o Treatment of homozygous familial hypercholesterolemia Lomitapide (Juxtapid) o Treatment of hypertriglyceridemia Ezetimibe and atorvastatin (Liptruzet) o Treatment of hyperlipidemia Macitentan (Opsumit) o Treatment of pulmonary arterial hypertension (PAH) Mipomersen sodium subcutaneous injection (Kynamro) o Treatment of homozygous familial hypercholesterolemia 2013 Nimodipine oral solution (Nymalize) o Reduction in incidence and severity of ischemic deficits following subarachnoid hemorrhage Polidocanol injectable foam (Varithena) o Treatment of varicose veins

3 Rioiciguat (Adempas) o Treatment of chronic thromboembolic pulmonary hypertension and PAH Apixaban (Eliquis) added indications o Prevention of DVT after knee or hip replacement surgery o Treatment of DVT/PE Omega-3 carboxylic acids (Epanova) 2014 o Treatment of severe hypertriglyceridemia Vorapaxar (Zontivity) o Reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD) Alirocumab for subcutaneous injection (Praluent) o Treatment of heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease Cangrelor powder for injection (Kengreal) o Adjunct to percutaneous coronary intervention (PCI) for the reduction of periprocedural thrombotic events (e.g., MI, repeat coronary revascularization, and stent thrombosis) Edoxaban (Savaysa) o Reduction in the risk of stroke and systemic embolism from NVAF 2015* o Treatment of DVT/PE Ivabradine (Corlanor) o Reduction in the risk of hospitalization for worsening heart failure (HF) in patients with stable, symptomatic chronic HF Perindopril arginine/amlodipine besylate (Prestalia) o Treatment of hypertension Sacubitril/valsartan (Entresto) o Reduction in the risk of cardiovascular death and hospitalization for HF in patients with chronic HF and reduced ejection fraction *Medications approved by the FDA through July 31, 2015 Sacubitril/Valsartan (Entresto) The combination of sacubitril/valsartan was approved in July 2015 by the FDA to reduce the risk of cardiovascular death and hospitalization related to HF in patients with chronic HF (classified as New York Heart Association [NYHA] Class II-IV) with reduced ejection fraction. 3 This new drug combination should typically be used in conjunction with other HF therapies and in place of an angiotensin-converting enzyme (ACE) inhibitor or other angiotensin II receptor blocker (ARB). Sacubitril, one component of Entresto, acts as a neprilysin inhibitor and represents the first agent of a new drug class. 4,5 Peptides (particularly natriuretic peptides, bradykinin and adrenomedullin, among other vasoactive compounds), which are normally degraded by neprilysin, start to accumulate due to the action of LBQ656, the active metabolite of the prodrug sacubitril. This accumulation, coupled with the simultaneous effects of valsartan on angiotensin II, provides beneficial cardiovascular and renal effects to patients with HF. The beneficial effects of these natriuretic peptides include improved regulation of sodium and water balance, blood volume and arterial pressure; decreased ventricular preload and systemic vascular resistance from direct vasodilator actions; an increased glomerular filtration rate, which results in natriuresis and diuresis; and a reduced release of renin from the kidneys. Previously referred to as LCZ696, sacubitril/valsartan demonstrated clinical benefit to HF patients in a multinational, randomized, double-blind trial, which compared the combination to enalapril in more than 8,000 patients with symptomatic chronic HF (NYHA class II-IV) and systolic dysfunction (defined as a left ventricular ejection fraction [LVEF] 40 percent). 4 Known as the PARADIGM-HF trial, the primary outcome (composite of death from cardiovascular causes or first

4 hospitalization for HF) occurred significantly less in patients treated with sacubitril/valsartan at a maximized dose of 200 mg PO BID (equivalent to 160 mg valsartan BID) compared to those treated with enalapril 10 mg PO BID (21.8 percent vs percent, hazard ratio [HR] in the sacubitril/valsartan group 0.80; 95 percent confidence interval [CI] 0.73 to 0.87; p < 0.001). The trial was halted early after a median follow-up of 27 months, as the boundary displaying an overwhelming benefit from sacubitril/valsartan had been crossed. In addition, fewer patients in the sacubitril/valsartan group experienced death from any cause (HR 0.84; 95 percent CI 0.76 to 0.93; p < 0.001) or death from cardiovascular diseases (HR 0.80; 95 percent CI 0.71 to 0.89; p < 0.001) relative to the enalapril group. The combination of sacubitril/valsartan also reduced the risk (relative to enalapril) of hospitalization for HF by 21 percent (p < 0.001) and decreased HF symptoms and physical limitations as well (p = 0.001). From the data collected, it was also determined that the number needed to treat (NNT) for sacubitril/valsartan to prevent one primary outcome event was 21, and the NNT to prevent one death from cardiovascular causes was 32. Sacubitril/valsartan is presently available as unscored, film-coated tablets in the following strengths: 24 mg sacubitril and 26 mg valsartan; 49 mg sacubitril and 51 mg valsartan; and 97 mg sacubitril and 103 mg of valsartan. 3 At times, pharmacy practitioners may be asked to assist with the transition of a patient presently treated with an ACE inhibitor or ARB to sacubitril/valsartan. Table 2 below is a useful resource that can help facilitate this transition in each patient-specific situation. Prior Use of ACE Inhibitor Stop ACE inhibitor 36 hours prior to starting sacubitril/valsartan Total daily dose > 10 mg of enalapril or equivalent dose of another ACE inhibitor: a start sacubitril/valsartan 49 mg/51 mg PO BID Total daily dose 10 mg of enalapril or equivalent dose of another ACE inhibitor: start sacubitril/valsartan 24 mg/26 mg PO BID o Double the dose after 2-4 weeks to 49 mg/51 mg PO BID, as tolerated Table 2. Initial Dose Selection of Sacubitril/Valsartan and Titration Strategy to Target Dose 3 Prior Use of ARB Total daily dose > 160 mg of valsartan or equivalent dose of another ARB: b start sacubitril/valsartan 49 mg/51 mg PO BID If treated with total daily dose 160 mg of valsartan or equivalent dose of another ARB: start sacubitril/valsartan 24 mg/26 mg PO BID o Double the dose after 2-4 weeks to 49 mg/51 mg PO BID, as tolerated ACE Inhibitor and/or ARB Naïve Not currently taking an ACE inhibitor or ARB: start sacubitril/valsartan 24 mg/26 mg PO BID o Double the dose after 2-4 weeks to 49 mg/51 mg PO BID, as tolerated Double the dose of sacubitril/valsartan after 2-4 weeks, as tolerated, to achieve the target dose of 97 mg/103 mg PO BID a Equivalent doses of other ACE inhibitors to enalapril 10 mg may include lisinopril 10 mg or ramipril 5 mg b Equivalent doses of ARBs to valsartan 160 mg may include losartan 50 mg or olmesartan 10 mg Considering dose adjustment for patients with severe renal impairment (estimated glomerular filtration rate < 30 ml/min/1.73 m 2 ) or patients with moderate hepatic impairment (Child-Pugh class B), sacubitril/valsartan should be started at 24/26 mg PO BID with a similar titration strategy, as previously discussed at 2-4 week intervals. Use of sacubitril/valsartan in patients with severe hepatic impairment (Child-Pugh class C) should be avoided. Adverse drug reactions reported by the prescribing information in 5 percent of patients treated with sacubitril/valsartan relative to enalapril include hypotension (18 percent vs. 12 percent),

5 hyperkalemia (12 percent vs. 14 percent), cough (9 percent vs. 13 percent), dizziness (6 percent vs. 5 percent) and renal failure/acute renal failure (5 percent vs. 5 percent). Though rare in general, angioedema was reported for both groups in 0.1 percent during the trial run-in period, but this rate increased to 0.5 percent in the sacubitril/valsartan group vs. 0.2 percent in the enalapril group during the double-blind period of the PARADIGM-HF trial. 4 Incidence of angioedema in black patients treated with sacubitril/valsartan was 2.4 percent compared to 0.5 percent for those treated with enalapril. Sacubitril/valsartan is contraindicated with concomitant use of an ACE inhibitor (regardless of comorbidities) or concomitant use of aliskiren specifically in patients with diabetes. 3 Additionally, this medication combination should not be used in patients with a documented hypersensitivity to any component in the formulation of sacubitril/valsartan and in patients with a history of angioedema related to previous ACE inhibitor or ARB use. As is the case with fetal toxicity warnings with agents affecting the renin-angiotensin-aldosterone system (RAAS), sacubitril/valsartan should be avoided in women of child bearing age due to the risks of fetal harm, morbidity, and mortality during the second and third trimesters of pregnancy. Pharmacists should be aware of several notable drug interactions that may affect patients treated with sacubitril/valsartan. When sacubitril/valsartan is coupled with potassium-sparing diuretics (e.g., spironolactone, eplerenone, amiloride or triamterene), potassium supplements or salt substitutes, the potential for hyperkalemia greatly increases. Pharmacists should realize the potential risks of hyperkalemia, review the present medication profile, confirm with prescribers that these therapies are desired together as appropriate, and assist with the development of an appropriate monitoring plan if one does not presently exist. Nonsteroidal anti-inflammatory drug (NSAID) use with sacubitril/valsartan may result in renal function impairment and potentially acute renal failure in certain patient populations. These populations include the elderly, volume-depleted patients (including patients treated with diuretic medications) or those with already compromised renal function. Though the effects of this interaction are typically reversible, renal function should be monitored regularly (e.g., blood urea nitrogen [BUN], serum creatinine [SCr]). Lithium also interacts with sacubitril/valsartan. Increased lithium concentrations and lithium toxicity have resulted from lithium use with an ARB or an ARB-containing therapy like sacubitril/valsartan. Management of this drug interaction usually involves evaluating lithium levels periodically and forewarning of signs and symptoms of lithium toxicity. Though not presently mentioned in the most recent guidelines for HF, one can anticipate an increase in the utilization of medications that target both neprilysin and the renin-angiotensinaldosterone system based on the promising results of the PARADIGM-HF trial. 4,6 Pharmacy practitioners should anticipate the future study and potential release of additional combination products coupling sacubitril or other neprilysin inhibitors with other RAAS-active medications. In future guideline updates, medications like sacubitril/valsartan will likely be viewed as first-line, mortality benefitting therapies in the treatment of HF sooner than stand-alone ACE inhibitors or ARBs.

6 STOP AND REFLECT Patient LR, a 77-year-old African American female, was recently admitted to your hospital for a HF exacerbation. Past medical history includes HF with her most LVEF at approximately 35 percent, hypertension, atrial fibrillation (AF), history of ST segment elevation myocardial infarction (STEMI), and coronary artery disease status post CABG in Present medications include metoprolol succinate 50 mg PO daily, enalapril 10 mg PO daily, spironolactone 25 mg PO daily, rivaroxaban 15 mg PO daily with dinner, furosemide 20 mg PO BID, hydralazine/isosorbide dinitrate 37.5 mg/25 mg PO TID, atorvastatin 40 mg PO daily, potassium chloride SR 20 meq PO daily and amiodarone 200 mg PO BID. The patient s cardiologist is preparing for her to be discharged home but has recently heard about the new combination of sacubitril/valsartan and wants to prescribe it for LR. What dose of sacubitril/valsartan should be used initially? What parameters should be monitored once sacubitril/valsartan is started? Ivabradine (Corlanor) Earlier this year, in April 2015, ivabradine gained FDA approval for the reduction in the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic HF. 7 This medication, however, has a specific place in therapy. Ivabradine must only be prescribed for patients with a LVEF 35 percent, who are in sinus rhythm with a resting heart rate 70 beats per minute (BPM), and who are either treated with maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. This medication selectively and specifically inhibits the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (f-channels) within the sinoatrial (SA) node of cardiac tissue. This action of ivabradine further disrupts I f ion current flow, prolongs diastolic depolarization, and subsequently slows the firing of the SA node and reduces heart rate. Ivabradine gained approval due to results from the SHIFT trial, a randomized, double-blind, placebo-controlled, parallel-group trial that studied ivabradine titrated to a maximum dose of 7.5 mg PO BID compared to placebo in more than 6,500 patients with symptomatic heart failure with a LVEF 35 percent, presently in sinus rhythm with a heart rate of 70 BPM or higher, and with a history of hospital admission for HF within the last year. 8 Concerning the primary endpoint of the composite of cardiovascular death or hospital admission for worsening heart failure, 793 patients (24 percent) in the ivabradine group had a primary endpoint event compared to 937 patients (29 percent) in the placebo group (HR 0.82, 95 percent CI 0.75 to 0.90, p < 0.001). However, the effects of this significant result were primarily driven by admissions for worsening heart failure and not for cardiovascular death, sudden cardiac death or all-cause deaths. The authors of the SHIFT trial concluded that their results support the role of heart rate reduction in the improvement of clinical outcomes of heart failure and point to the potential benefits of ivabradine in select populations. More recently, the SIGNIFY trial pitted ivabradine against placebo in more than 19,000 patients with stable coronary artery disease, without clinical heart failure, with a heart rate of 70 BPM or more, and with standard background therapy. 9 Though the trial seemed promising, there was no improvement in outcomes (e.g., primary outcome of composite of death from cardiovascular causes or nonfatal MI) relative to placebo, nor did ivabradine reliably reduce heart rate in patients treated. Ivabradine does have several contraindications to its use. 7 These include acute decompensated HF, blood pressure < 90/50 mmhg (e.g., hemodynamic instability), sick sinus syndrome, SA block, third degree atrioventricular (AV) block in the absence of a functioning demand pacemaker, resting heart rate < 60 BPM prior to treatment, severe hepatic impairment, pacemaker dependence (defined as a heart rate solely maintained by the pacemaker) and concomitant use of strong CYP3A4 inhibitors. Another notable warning for ivabradine concerns the potential for fetal harm based on animal studies. Though it may seem to be a rare situation, female patients of child-bearing age who are treated with ivabradine should be advised to use effective contraception to prevent pregnancy, according to the prescribing information.

7 Labeled safety information also warns of an increased risk of cardiac conduction disturbances and arrhythmias. Use of ivabradine can increase the risk of developing AF. In clinical trials, the rate of AF in patients treated with ivabradine compared to placebo was 5 percent versus 3.9 percent per patient-year, respectively. The patient s cardiac rhythm should be monitored regularly, and, if AF develops, ivabradine should be discontinued. Bradycardia, sinus arrest and heart block have also been documented with the use of ivabradine. Past clinical trial evidence noted that bradycardia occurred at a rate of 6.0 percent per patient-year (2.7 percent symptomatic, 3.4 percent asymptomatic) in patients treated with ivabradine and 1.3 percent per patient-year in patients treated with placebo. In general, use of ivabradine should be avoided in patients with second degree AV heart block (unless a functioning demand pacemaker is present), and additional risk factors for bradycardia should be carefully evaluated. These risk factors include sinus node dysfunction, conduction defects, ventricular dyssynchrony, and concomitant use of negative chronotropes. Ivabradine is typically started at 5 mg PO BID given with meals in most patients, but a more conservative dosing approach of 2.5 mg PO BID with meals should be used in patients with conduction defects or in whom bradycardia could lead to hemodynamic compromise or instability. After two weeks of treatment, the dose may be adjusted based on the patient s heart rate. The target resting heart rate range is BPM, and dose adjustment is not required if this target range is met. If the resting heart rate of the patient exceeds 60 BPM, the dose of ivabradine should be increased by 2.5 mg twice daily up to a maximum dose of 7.5 mg PO BID. In cases of symptomatic bradycardia or if the resting heart rate falls below 50 BPM, the dose of ivabradine should be decreased by 2.5 mg twice daily. Additionally, therapy should be discontinued in the previous situation if the dose is 2.5 mg PO BID. Ivabradine is available in 5 mg scored oral tablets and 7.5 mg non-scored oral tablets. Adverse drug reactions reported from the SHIFT trial include bradycardia (10 percent ivabradine vs. 2.2 percent placebo), hypertension (8.9 percent vs. 7.8 percent), AF (8.3 percent vs. 6.6 percent), and mild-to-moderate luminous phosphenes (2.8 percent vs. 0.5 percent). 8 Most notably, phosphenes are usually triggered by sudden changes in light intensity and are likely caused by the effects of ivabradine on retinal photoreceptors. Phosphenes secondary to the use of ivabradine will generally occur within the first two months of treatment and may occur more frequently thereafter. Fortunately, phosphenes have generally resolved during the course of treatment or after discontinuation. Several notable drug interactions that require intervention are well documented due to the effect of ivabradine on heart rate as well as the involvement of the cytochrome P450 3A4 enzyme in the metabolism of the drug. 7 Table 3 provides further guidance about managing ivabradine dosing in the presence of these interacting medications. Interacting Drug Class Strong CYP3A4 Inhibitors CYP3A4 Inducers Moderate CYP3A4 Inhibitors Table 3. Drug Interactions Involving Ivabradine 7 Members of Interacting Drug Class Azole antifungals (e.g., itraconazole), macrolide antibiotics (e.g., clarithromycin), HIV protease inhibitors (e.g., ritonavir) and nefazodone St. John s wort, rifampin, barbiturates (e.g., phenobarbital) and phenytoin Diltiazem, verapamil and grapefruit juice Drug Interaction Effect and Action Effect: increased ivabradine plasma concentration, which may exacerbate bradycardia and conduction disturbances Action: concomitant use is contraindicated Effect: decreased ivabradine plasma concentration Action: avoid concomitant use Effect: increased ivabradine plasma concentration, which may exacerbate bradycardia and conduction disturbances

8 Negative chronotropes Digoxin, amiodarone, beta-blockers (e.g., bisoprolol, carvedilol, metoprolol) Action: avoid concomitant use Effect: increased risk of bradycardia Action: monitor heart rate in patients taking ivabradine with other negative chronotropes Each prescription of ivabradine should be dispensed with the corresponding medication guide (please follow this link for a copy of the medication guide for ivabradine). The medication guide forewarns patients about some of the most important information about ivabradine, including the potential risks when ivabradine is used during pregnancy, increased risk for arrhythmias and bradycardia as a potential adverse drug reaction. Ivabradine may not be recommended within the most recently published treatment guidelines for the management of HF, but this medication will likely be useful for patients who are unable to attain their goal heart rate on maximally tolerated doses of beta blockers or in patients who are unable to take a beta blocker. 6-9 Despite a lack of evidence pointing to a mortality benefit with ivabradine for the general HF population, the medication does reduce the risk of hospitalization and, therefore, may prove useful in patient-specific situations where ivabradine is appropriately indicated. Vorapaxar (Zontivity) Vorapaxar was recently approved to reduce thrombotic cardiovascular events (including cardiovascular death, MI, stroke and urgent coronary revascularization procedures) in patients with a history of MI or with PAD. 10 As the first in a new class of agents, the drug is a protease-activated receptor-1 (PAR-1) antagonist that acts on platelets and irreversibly inhibits thrombin-induced and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation. One phase 3 clinical trial studied vorapaxar 2.5 mg by mouth daily against matching placebo in more than 26,000 patients with a history of MI, ischemic stroke or PAD. 11 In the TRA 2P-TIMI 50 trial, the primary efficacy endpoint, which was a composite of death from cardiovascular causes, MI or stroke, occurred in 1,028 patients (9.3 percent) treated with vorapaxar 2.5 mg PO daily compared to 1,176 patients (10.5 percent) in the placebo group (HR 0.87; 95 percent CI 0.80 to 0.94; p < 0.001). The secondary endpoint, which included cardiovascular death, MI, stroke or urgent coronary revascularization, occurred in 1,259 patients (11.2 percent) treated with vorapaxar and 1,417 patients (12.4 percent) treated with placebo (HR 0.88; 95 percent CI 0.82 to 0.95; p = 0.001). Despite significant results in the main efficacy end points of the trial, moderate-to-severe bleeding (according to GUSTO criteria) occurred more frequently in patients treated with vorapaxar compared to placebo (4.2 percent vs. 2.5 percent; HR 1.66; 95 percent CI 1.43 to 1.93; p < 0.001). This was also true of incidence of intracranial hemorrhage (1.0 percent vs. 0.5 percent; HR 1.94; 95 percent CI 1.39 to 2.70; p < 0.001), which also occurred more frequently in patients with a history of stroke. Vorapaxar should be prescribed at a dose of 2.08 mg PO daily with aspirin and/or clopidogrel, according to their indications or standards of care. 10 Considering other antiplatelet drugs (e.g., prasugrel, ticagrelor, dipyridamole), there is limited clinical experience with concomitant vorapaxar, and combination with alternative antiplatelet drugs outside of aspirin and/or clopidogrel should be avoided. Additionally, vorapaxar should not be used as a stand-alone antiplatelet agent. Vorapaxar is primarily eliminated through metabolism from CYP3A4 and CYP2J2, and use of the drug with strong CYP3A inhibitors or inducers should be avoided. Renal dose adjustment and hepatic dose adjustment for patients with mild-to-moderate hepatic impairment are not required. However, based on the increased risk of bleeding in patients with severe hepatic impairment, vorapaxar should be avoided in this population. Consistent with labeled dosing information for other blood thinners, patient age should be thoroughly considered before starting vorapaxar due to an increased risk of bleeding in older patients.

9 There are several contraindications to the use of vorapaxar. These include history of a stroke, transient ischemic attack (TIA) or intracranial hemorrhage (ICH) due to the increased risk of ICH in this population. If a patient is experiencing active pathologic bleeding (e.g., ICH, peptic ulcer), use of vorapaxar is also contraindicated. Additionally, a medication guide that discusses these bleeding-related adverse drug reactions should be given to the patient with each dispensing of the medication (please follow this link for a copy of the medication guide for vorapaxar). Other nonbleeding-related adverse drug reactions documented in clinical trials include depression (2.4 percent vorapaxar vs. 2.1 percent placebo) as well as rashes, eruptions and exanthemas (2.2 percent vorapaxar vs. 2.0 percent placebo) At present, it appears difficult to determine the exact place in therapy for vorapaxar in patients with past MI or with PAD. Though guidelines for the treatment of non-st segment elevation myocardial infarction (NSTEMI)/unstable angina (UA) or PAD do not presently mention vorapaxar, STEMI guidelines recognize vorapaxar as a potential component of care that needs more evidence before major recommendations can be made One publication suggests that the potential place in therapy for vorapaxar is adjunctive use with standard care in patients at high risk of thrombotic events and low risk of bleeding. 16 However, the best tool that allows for reliable and individualized risk stratification for thrombosis and bleeding risk assessment in this patient population has not been discerned. This has, in general, led to limited use of vorapaxar in clinical practice. Further study of risk assessment and stratification tools for potential candidates for treatment with vorapaxar should be anticipated. An Update on Target-specific Oral Anticoagulants (TSOACs) Added Indications, Recently-approved Agents and Complex Dosing Strategies The TSOACs (synonymously referred to as novel oral anticoagulants [NOACs] and direct oral anticoagulants [DOACs]) have been heralded by many as the replacement to warfarin and vitamin K antagonists in general. However, these therapy options require thorough scrutiny and evaluation from the prescribing health care provider and pharmacy staff member prior to initiation. The drug class includes the following medications: Apixaban (Eliquis) Dabigatran (Pradaxa) Edoxaban (Savaysa) Rivaroxaban (Xarelto) All of the medications within the drug class are approved for use in the prevention of thromboembolic stroke and systemic embolism in patients with NVAF as well as the treatment of DVT/PE Additionally, both apixaban and rivaroxaban are approved for the prophylaxis of DVT after a patient undergoes a hip or knee replacement surgery. The drug class holds many different advantages to the use of warfarin. 21,22 From a pharmacokinetic/pharmacodynamic standpoint, the drug class has a wider therapeutic window, more rapid onset of action and shorter half-lives than warfarin. Convenient for patients and practitioners, laboratory monitoring is not required for the TSOACs, and fixed doses are normally utilized. As the class does not affect vitamin K epoxide reductase, the dietary considerations with vitamin K intake that warfarin requires are of no concern with the TSOACs. Despite a number of improvements on many of the shortcomings of warfarin and other vitamin K antagonists, the TSOACs also present their own unique risks with regard to medication and patient safety With many complex dosing regimens, multiple dosage strengths available for many different indications, and (for some) an overall lack of familiarity with the drug class, the TSOACs are particularly prone to dosing errors. Additionally, a variety of dose adjustment criteria are utilized to guide therapy, including a multitude of renal function dose adjustment thresholds, patient age cut-offs, weight adjustment criteria and dosing criteria based on P450-mediated and P- glycoprotein-mediated drug interactions. Unlike warfarin, which has a specific antidote for its reversal, there are no approved TSOAC-specific agents for reversal in cases of life-threatening bleeding (though some are in the pipeline) The importance of pharmacy staff, health care

10 provider and patient education about this relatively new and continuously developing class of medications cannot be emphasized enough. At some institutions, reference tables or pocket cards have been developed to assist with dosing selection on a patient-to-patient basis. Table 4, which can be found on the next pages, organizes the TSOACs presently on the market and includes many of the dosing considerations a practitioner should think through when initiating or evaluating therapy (e.g., renal function, drug interactions, timing around discontinuation or initiation of other anticoagulants). Methods of anticoagulation reversal included in this type of table may also be useful, but this component was excluded in this example, as anticoagulation reversal is often formulary or institution specific. Though a table like this may be a useful tool for clinicians, a pharmacist must constantly review and update the resource for purposes of accuracy. STOP AND REFLECT Patient MW is an 84-year-old patient and regular to your community pharmacy. She has an extensive history of warfarin use for her NVAF. She has grown tired of the lab draws and dietary restrictions associated with the drug. MW recently saw a commercial about a drug she refers to as Eloquent and is now interested in using one of the TSOACs. She had a pacemaker placed in 2011 and has had recurrent issues with epistaxis since she was hit in the nose with a hardball as a teenager. Prior to retirement, MW was heavily involved in local politics and was the mayor of the town where your pharmacy is located. What information would you provide MW about the drug class and the specific agent MW saw advertised? Conclusion This article provided an update of several recently-approved medications for the treatment of cardiovascular disease states and reviewed the TSOACs, a continuously evolving drug class with potential medication safety concerns. Pharmacotherapy for cardiovascular disease states will continue to advance and improve the lives of impacted patients. However, this can only occur if the pharmacy practitioners involved maintain a keen awareness of the ever-changing environment of evidence-based cardiovascular medicine.

11 Available Strengths Dosing for DVT/PE Treatment Dosing for NVAF Dosing for post-op DVT prophylaxis Dose Adjustment Converting from Warfarin Table 4. Target-specific Oral Anticoagulants (TSOACs) Reference Table (Updated July 31, 2015) 17-20,25-40 Apixaban (Eliquis) Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Edoxaban (Savaysa) 10 mg, 15 mg and 20 mg oral 15 mg, 30 mg and 60 mg oral 2.5 mg and 5 mg oral tablet 75 mg and 150 mg oral capsule tablet tablet 10 mg PO BID X 7 days, then 5 mg PO BID After six months treatment, give 2.5 mg PO BID to reduce risk of recurrence 150 mg PO BID (after 5-10 days of parenteral anticoagulation) 5 mg PO BID 150 mg PO BID* 2.5 mg PO BID Start hrs post-op Knee replacement at least 12 days duration Hip replacement at least 35 days duration When used for NVAF, reduce the dose to 2.5 mg PO BID if the patient has two of the following: Age 80 years Actual body weight 60 kg Serum creatinine 1.5 mg/dl Dual strong CYP3A4 inhibitors and P-glycoprotein inhibitors (e.g., clarithromycin, ketoconazole, itraconazole, ritonavir): 2.5 mg PO BID Discontinue warfarin and start apixaban when INR < two Not FDA approved CrCl ml/min 75 mg PO BID Avoid use if given with concomitant P- glycoprotein inhibitors (e.g., amiodarone, clarithromycin, dronedarone, quinidine, verapamil, etc) CrCl ml/min and concomitant PO ketoconazole or dronedarone Consider75 mg PO BID Avoid use with any P- glycoprotein inducer (e.g., rifampin) Discontinue warfarin and start dabigatran when INR < two 15 mg PO BID with food X 21 days, then 20 mg PO daily with food thereafter for at least three months 20 mg PO daily with evening meal 10 mg PO daily Knee replacement at least 12 days Hip replacement at least 35 days DVT/PE treatment or post-op DVT prophylaxis CrCl < 30 ml/min: avoid use ESRD: avoid use NVAF CrCl ml/min: 15 mg PO daily with evening meal CrCl < 15 ml/min: avoid use ESRD: avoid use (Child-Pugh class B or C): avoid use Hepatic disease with coagulopathy: avoid use Discontinue warfarin and start rivaroxaban when INR < three 60 mg PO daily (after 5-10 days of parenteral anticoagulation) 60 mg PO daily Not FDA approved CrCl ml/min, weight < 60 kg, concomitant use of P- glycoprotein inhibitors 30 mg PO daily CrCl > 95 ml/min Avoid use Discontinue warfarin and start edoxaban when INR 2.5

12 Converting to Warfarin Converting from Parenteral Anticoagulants Converting to Parenteral Anticoagulants Surgical Discontinuation Clinical Trials Apixaban (Eliquis) Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Edoxaban (Savaysa) If continuous anticoagulation is needed, discontinue apixaban and initiate both a parenteral anticoagulant and warfarin when the next apixaban dose is due. The parenteral anticoagulant can be discontinued when the INR is therapeutic. Discontinue the parenteral anticoagulant and start apixaban at the time of the next scheduled dose. Discontinue apixaban and begin the parenteral anticoagulant at the time of the next scheduled dose. If major procedure, stop at least 48 hours before. If minor procedure (e.g., low bleeding risk), stop at least 24 hours before. NVAF: ARISTOTLE, AVERROES DVT/PE Treatment: AMPLIFY, PLIFY-EXT CrCl > 50 ml/min: start warfarin three days before stopping dabigatran CrCl ml/min: start warfarin two days before stopping dabigatran CrCl ml/min: start warfarin one day before stopping dabigatran Start dabigatran two hours prior to the time of the next scheduled parenteral anticoagulant dose or at the time of discontinuation of the continuously-administered parenteral drug. Wait 12 hours (CrCl 30 ml/min) or 24 hours (CrCl < 30 ml/min) after the last dose of dabigatran before initiating a parenteral anticoagulant. CrCl 50 ml/min: stop 1-2 days before procedure CrCl < 50 ml/min: stop 3-5 days before procedure NVAF: RE-LY Initiate warfarin and a parenteral anticoagulant 24 hours after discontinuation of rivaroxaban. Discontinue current anticoagulant and start rivaroxaban two hours prior to the next scheduled evening dose of the anticoagulant. If converting from heparin drip, start rivaroxaban at the time of UFH discontinuation. Initiate the parenteral anticoagulant 24 hours after the discontinuation of rivaroxaban. If converting to heparin drip, start continuous infusion UFH 24 hours after discontinuing rivaroxaban. Stop at least 24 hours before the procedure and restart as soon as adequate hemostasis has been established NVAF: ROCKET-AF DVT/PE Treatment: EINSTEIN, EINSTEIN-PE DVT/PE Treatment: RE-COVER DVT/PE Prophy: RECORD1, DVT/PE Prophy: 2009 Trials RECORD3 *Not to be used in patients with AF who also have a mechanical heart valve due to results of RE-ALIGN trial If taking 60 mg PO daily, reduce to 30 mg PO daily and begin warfarin concomitantly. If taking 30 mg PO daily, reduce to 15 mg PO daily and begin warfarin concomitantly. Measure INR weekly just prior to dose. Stop edoxaban when stable INR 2.0. Discontinue the parenteral anticoagulant and start edoxaban at the time of the next dose of the parenteral anticoagulant. If converting from heparin drip, start edoxaban four hours after discontinuation. Discontinue edoxaban and start the parenteral anticoagulant at the time of the next dose of edoxaban Stop at least 24 hours before the procedure and restart as soon as adequate hemostasis has been established. NVAF: ENGAGE AF-TIMI 48 DVT/PE Treatment: HOKUSAI-VTE

13 References: 1. Food and Drug Administration, FDA Approved Drug Products, Aug. 9, CenterWatch, FDA Approved Drugs by Year, Aug. 9, Entresto (sacubitril and valsartan) [prescribing information], East Hanover, NJ: Novartis; July McMurray, J.J., Packer, M., Desai, A.S., et al., Angiotensin-neprilysin Inhibition Versus Enalapril in Heart Failure, New England Journal of Medicine, 2014, Vol. 371, No. 11, pp Vardeny, O., Miller, R., Solomon, S.D., Combined Neprilysin and Renin-angiotensin System Inhibition for the Treatment of Heart Failure, JACC Heart Failure, 2014, Vol. 2, No. 6, pp Yancy, C.W., Jessup, M., Bozkurt, B., et al., 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, Journal of American College of Cardiology, 2013, Vol. 62, No. 16, pp. e Corlanor (ivabradine) [prescribing information], Thousand Oaks, Calif.: Amgen Inc; April Swedberg, K., Komajda, M., Böhm, M., et al., Ivabradine and Outcomes in Chronic Heart Failure (SHIFT): A Randomized Placebo-controlled Study, Lancet, 2010, Vol. 376, No. 9744, pp Fox, K., Ford, I., Steg, P.G., et al., Ivabradine in Stable Coronary Artery Disease without Clinical Heart Failure, New England Journal of Medicine, 2014, Vol. 371, No. 12, pp Zontivity (vorapaxar) [prescribing information], Whitehouse Station, NJ: Merck & Co, Inc; April Morrow, D.A., Braunwald, E., Bonaca, M.P., et al., Vorapaxar in the Secondary Prevention of Atherothrombotic Events, New England Journal of Medicine, 2012, Vol. 366, No. 15, pp Tricoci, P., Huang, Z., Held, C., et al., Thrombin-receptor Antagonist Vorapaxar in Acute Coronary Syndromes, New England Journal of Medicine, 2012, Vol. 366, No. 1, pp Amsterdam, E.A., Wenger, N.K., Brindis, R.G., et al., 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, Journal of American College of Cardiology, 2014, Vol. 64, No. 24, pp. e O Gara, P.T., Kushner, F.G., Ascheim, D.D., et al., 2013 ACCF/AHA Guideline for the Management of ST-elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, Journal of American College of Cardiology, 2013, Vol. 61, No. 4, pp. e Rooke, T.W., Hirsch, A.T., Misra, S., et al., Management of Patients with Peripheral Artery Disease (Compilation of 2005 and 2011 ACCF/AHA Guideline Recommendations: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, Journal of American College of Cardiology, 2013, Vol. 61, No. 14, pp Farag, M., Patel, H., Gorog, D.A., Adjunctive Therapies to Reduce Thrombotic Events in Patients with a History of Myocardial Infarction: Role of Vorapaxar, Drug Design, Development and Therapy, 2015, No. 9, pp Eliquis (apixaban) [prescribing information], Princeton, NJ: Bristol-Myers Squibb, June Pradaxa (dabigatran etexilate) [prescribing information], Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals Inc., September Savaysa (edoxaban) [prescribing information], Parsippany, NJ: Daiichi Sankyo, January Xarelto (rivaroxaban) [prescribing information], Gurabo, PR: Janssen Pharmaceuticals Inc., September Wild, D., ISMP Urges Caution with New Oral Anticoagulants, Pharmacy Practice News, =32460, Aug. 9, Bauer, K.A., Targeted Anti-anticoagulants, New England Journal of Medicine, 2015, Vol. 373, No. 6, pp Crowther, M., Crowther, M.A., Antidotes for Novel Oral Anticoagulants: Current Status and Future Potential, Arteriosclerosis, Thrombosis, and Vascular Biology, 2015, Vol. 35, No. 8, pp

14 24. Pollack, C.V., Jr., Reilly, P.A., Eikelboom, J., et al., Idarucizumab for Dabigatran Reversal, New England Journal of Medicine, 2015, Vol. 373, No. 6, pp Granger, C.B., Alexander, J.H., McMurray, J.J., et al., Apixaban Versus Warfarin in Patients with Atrial Fibrillation, New England Journal of Medicine, 2011, Vol. 365, No. 11, pp Connolly, S.J., Eikelboom, J., Joyner, C., et al., Apixaban in Patients with Atrial Fibrillation, New England Journal of Medicine, 2011, Vol. 64, No. 9, pp Agnelli, G., Büller, H.R., Cohen, A., et al., Oral Apixaban for the Treatment of Acute Venous Thromboembolism, New England Journal of Medicine, 2013, Vol. 369, No. 9, pp Agnelli, G., Büller, H.R., Cohen, A., et al., Apixaban for Extended Treatment of Venous Thromboembolism, New England Journal of Medicine, 2013, Vol. 368, No. 8, pp Lassen, M.R., Raskob, G.E., Gallus, A., et al., Apixaban or Enoxaparin for Thromboprophylaxis After Knee Replacement, New England Journal of Medicine, 2009, Vol. 361, No. 6, pp Lassen, M.R., Gallus, A., Raskob, G.E., et al., Apixaban Versus Enoxaparin for Thromboprophylaxis After Hip Replacement, New England Journal of Medicine, 2009, Vol. 363, No. 26, pp Connolly, S.J., Ezekowitz, M.D., Yusuf, S., et al., Dabigatran Versus Warfarin in Patients with Atrial Fibrillation, New England Journal of Medicine, 2009, Vol. 361, No. 12, pp Schulman, S., Kearon, C., Kakkar, A.K., et al., Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism, New England Journal of Medicine, 2009, Vol. 361, No. 24, pp Patel, M.R., Mahaffey, K.W., Garg, J., et al., Rivaroxaban Versus Warfarin in Nonvalvular Atrial Fibrillation, New England Journal of Medicine, 2011, Vol. 365, No. 10, pp Bauersachs, R., Berkowitz, S.D., Brenner, B., et al., Oral Rivaroxaban for Symptomatic Venous Thromboembolism, New England Journal of Medicine, 2010, Vol. 363, No. 26, pp Büller, H.R., Prins, M.H., Lensin, A.W., et al., Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism, New England Journal of Medicine, 2012, Vol. 366, No. 14, pp Eriksson, B.I., Borris, L.C., Friedman, R.J., et al., Rivaroxaban Versus Enoxaparin for Thromboprophylaxis After Hip Arthroplasty, New England Journal of Medicine, 2008, Vol. 358 No. 26, pp Lassen, M.R., Ageno, W., Borris, L.C., et al., Rivaroxaban Versus Enoxaparin for Thromboprophylaxis After Total Knee Arthroplasty, New England Journal of Medicine, 2008, Vol. 358, No. 26, pp Giugliano, R.P., Ruff, C.T., Braunwald, E., et al., Edoxaban Versus Warfarin in Patients with Atrial Fibrillation, New England Journal of Medicine, 2013, Vol. 369, No. 22, pp Büller, H.R., Décousus, H., Grosso, M.A., et al., Edoxaban Versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism, New England Journal of Medicine, 2013, Vol. 369, No. 15, pp Eikelboom, J.W., Connolly, S.J., Brueckmann, M., et al., Dabigatran Versus Warfarin in Patients with Mechanical Heart Valves, New England Journal of Medicine, 2013, Vol. 369, No. 13, pp

15 Continuing Education Self-assessment Questions 1., the first ADP receptor antagonist available as an injectable formulation, was approved by the U.S. Food and Drug Administration (FDA) in 2015 as an adjunct to percutaneous coronary intervention (PCI) for the reduction of periprocedural thrombotic events. a. Ticagrelor (Brilinta) b. Prasugrel (Effient) c. Cangrelor (Kengreal) d. Clopidogrel (Plavix) Questions 2 and 3 pertain to the following case: Patient FM is a 68-year-old man who was just discharged from the hospital for an acute heart failure (HF) exacerbation. Other past medical history (PMH) includes coronary artery disease, hypertension, congestive heart failure (CHF), asthma, type 2 diabetes mellitus, gout and vertigo. Pertinent medications prescribed at discharge for this patient s cardiovascular disease states include bisoprolol 5 mg PO daily, niacin SR 1000 mg PO every bedtime, ezetimibe/atorvastatin 10 mg/40 mg PO daily, torsemide 10 mg PO daily, spironolactone 25 mg PO daily, digoxin mg PO daily and sacubitril/valsartan 24 mg/26 mg PO BID. Upon review of the patient s prior medication profile at your pharmacy, you note that the patient was treated with lisinopril 40 mg PO daily, and their last refill was picked up just a couple of weeks prior to being hospitalized. FM is persistent that he hasn t used another pharmacy to fill his prescriptions. 2. What action should be taken with the current prescription you ve received? a. No action is required, as the dose of sacubitril/valsartan is appropriate considering the previous prescription for lisinopril 40 mg PO daily. b. Call the ordering prescriber to change the dose of sacubitril/valsartan to 49 mg/51 mg PO BID. c. No action is required; the dose of sacubitril/valsartan is independent of any past lisinopril dosing. d. Call the ordering prescriber to change the dose of sacubitril/valsartan to 97 mg/103 mg PO BID. 3. Which of following titration strategies is the most appropriate for patient FM? a. Maintain sacubitril/valsartan at the dose previously selected, as there is no dose titration required. b. Double the dose of sacubitril/valsartan every two to four weeks, as tolerated, to a target dose of 49 mg /51 mg PO BID c. Double the dose of sacubitril/valsartan every two to four weeks, as tolerated, to a target dose of 97 mg /103 mg PO BID. d. Double the dose of sacubitril/valsartan every one to two weeks, as tolerated, to a target dose of 97 mg/103 mg PO BID. 4. Vorapaxar is best utilized when coupled with which of the following antiplatelet agent(s)? a. Aspirin alone b. Aspirin and clopidogrel (Plavix) c. Aspirin and dipyridamole (Aggrenox) d. A and B 5. Omega-3 carboxylic acids (Epanova) gained approval from the FDA in 2014 for which of the following indications? a. Treatment of severe hypertriglyceridemia b. Treatment of homozygous familial hypercholesterolemia c. Treatment of primary hyperlipidemia d. None of the above 6. Patient LC is a 53-year-old African American male who is well known to your outpatient HF clinic. Upon seeing the patient for their medication management appointment, you note that the cardiologist has started LC on ivabradine 5 mg PO twice daily with food. PMH includes HF, HIV infection, depression, hypertension and