aggregation, formation of a platelet plug, and, ultimately, leads to the formation of a thrombus. 14 The newly formed

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1 Introduction Heart disease impacts millions of Americans each year and is the leading cause of death among men and women. 1,2 While there are several diagnoses falling under the heart disease umbrella, acute coronary syndromes (ACS) account for more than half of these events and was responsible for 1 of every 7 deaths in The most recent 2015 statistics from the American Heart Association (AHA) estimates approximately 635,000 Americans will have a new coronary event and 300,000 will have a recurrent event each year. 3 This leads to a significant economic burden of disease. It is estimated that in 2011 the annual costs for cardiovascular disease (including stroke) were $320.1 billion with over $195 billion being in direct costs and $125 billion being related to lost productivity. 3 In clinical trials, treatment strategies for ACS, including percutaneous coronary intervention (PCI), pharmacotherapy, and dietary and lifestyle modification, e.g., cardiac rehabilitation, have been shown to reduce recurrent myocardial infarction (MI) and cardiac death. 4 6 However, up to 20% of patients hospitalized with ACS are readmitted within 30 days, commonly due to treatment failure or adverse events. 7 While there are multiple known contributors to treatment failure leading to recurrent ischemic events, poor medication adherence is the most frequent causative factor. 8 Particularly, interruption, or early discontinuation, of dual antiplatelet therapy (DAPT) leads to adverse effects including an increased risk of death. 9 Medication nonadherence is complex, but a consistent theme for preventing nonadherence is more effective transitions of care including patient education and close patient follow up. 8 Improvements in healthcare communities approach to caring for these patients could make large impacts on patient morbidity and mortality as well as the health systems economic burden. Pathophysiology Atherosclerosis is a complicated process that can take decades to develop. It begins with intimal thickening and xanthoma formation, which are often termed fatty streaks. Atherosclerosis continues to progress as cholesterol deposition progressively alters the entire arterial structure including the media and adventitia. Eventually, stable atherosclerotic plaques develop. These plaques are composed of cholesterol particles, extracellular matrix, and smooth muscle cells of the arterial vessel and are often times described using the term fibrous cap atheroma. Complicated biology, including an interaction of cholesterol plaques and chronic inflammation, leads to further progression of disease and remodeling of the vessel. Acute coronary syndrome occurs when the fibrous cap over a vulnerable atherosclerotic plaque in a coronary vessel ruptures. This disruption in the integrity of the endothelium exposes the necrotic core of the plaque to the lumen of the vessel and allows release of multiple pro thrombotic substances including von Willebrand Factor (vwf) and collagen from the sub endothelial layer. Release of these factors contributes to the recruitment of platelets to the site of vascular injury through binding of the glycoprotein 1B receptor on the platelet. 14 Once activated, platelet recruitment is propagated through various mechanisms, including the release of substances such as adenosine, fibrinogen, factor V, thromboxane A2, and others from the platelet s dense granule. These substances activate target specific receptors on the surface of the platelet. Through a series of g coupled proteins, agonism of their respective receptors leads to the activation and expression of the glycoprotein IIb/IIIa (GP IIb/IIIa) receptor. Cross linkage of the GP IIb/IIIa receptor leads to platelet aggregation, formation of a platelet plug, and, ultimately, leads to the formation of a thrombus. 14 The newly formed

2 thrombus may either completely or partially block the lumen of the coronary artery; thus, disrupting downstream blood flow and impairing oxygen delivery to the cardiac tissue. Complete occlusion results in ST segment elevation myocardial infarction (STEMI), while partial occlusion results in a non ST segment elevation acute coronary syndrome (NSTE ACS). NSTE ACS is a term introduced in the 2014 AHA/ACC guidelines that encompasses both non STsegment elevation myocardial infarction (NSTEMI) and unstable angina (UA). 5 The resulting myocardial ischemia leads to myocardial cell necrosis. Depending on the location and extent of damage, this leads to pump dysfunction and/or electrical instability (arrhythmia) which is responsible for a large portion of the morbidity and mortality associated with ACS. Antiplatelet therapy interrupts platelet aggregation, and subsequent thrombus formation and, thus, prevents, or minimizes, subsequent myocardial damage (see Figure 1). Figure 1. Antiplatelet Therapy Mechanism of Action Adapted from Minno MN, Guida A, Camera M, et al. Overcoming limitations of current antiplatelet drugs: a concerted effort for more profitable strategies of intervention. Ann Med. 2011;43(7): Patients at Risk and Presentation Symptoms Patients at greatest risk for an ACS event are smokers of advanced age with a family history of coronary heart disease and comorbid conditions such as: previous history of MI, diabetes, peripheral vascular disease, hyperlipidemia, obesity, and hypertension (see Table 1). 5, Presenting symptoms most commonly include a pressure like, substernal chest Table 1. discomfort, classically described as feeling like a heaviness or an elephant is sitting Risk Factors for Artherosclerosis 17,18 on my chest. The pain can radiate to one or both arms, the neck, jaw, back, or stomach. Additional symptoms may include diaphoresis, dyspnea, nausea, Non Modifiable lightheadedness, and syncope. 5 A differentiating characterization from chronic stable Advanced age angina is that it occurs with minimal exertion or even at rest. Duration of symptoms will typically exceed 10 minutes and, often times, may have a stuttering or waxing Male sex and waning course. 18 Positive family history ACC/AHA Guideline Therapy for Management of ACS Genetic disorders Patients with suspected ACS must be rapidly assessed to determine patient risk and prognosis. According to the 2014 AHA/ACC NSTE ACS guidelines, serial ECGs, cardiac Modifiable biomarkers, and risk assessment are class I recommendations. Upon presentation to Tobacco smoking the emergency department, an ECG should be obtained within 10 minutes followed by serial ECGs at 15 to 30 minute increments during the first hour. 5 High sensitivity Hypertension troponin assays offer a negative predictive value for MI of 99% and are a useful tool Dyslipidemia in the diagnosis and assessment of cardiac necrosis. Troponin should be obtained at baseline with serial measurements being utilized to identify the rise and fall pattern Diabetes mellitus consistent with the occurrence of an ACS event. Of note, CK MB is no longer recommended as it does not impart any additional information over the higher Obesity sensitive troponin assays. 5 Additionally, patients should be assessed using validated tools such as the Thrombolysis in Myocardial Infarction (TIMI) 19 and Global Registry of Acute Coronary Events (GRACE) 20 risk scores (See Table 2). Risk assessment tools can be particularly useful for determining the level of care required to adequately treat the patient including indication for certain interventions and medical therapy. Patients with higher GRACE or TIMI scores are more likely to benefit from invasive strategies over medical therapy alone. 5, 21 Based on level of perceived risk, patients are stratified into two possible treatment pathways: early invasive therapy or an ischemia guided 2

3 strategy. The updated guidelines replace the term initial conservative approach with ischemia guided strategy regarding the initial use of medication therapy alone. For patients with TIMI scores of 0 or 1 and/or GRACE scores <109, invasive therapy may not be indicated. This may especially be true in women who are at higher risk of complications with an invasive approach. 22 A change to an invasive evaluation for patients undergoing the ischemia guided strategy is appropriate for patients who fail medical therapy, have objective ischemic disease appreciated on a non invasive stress test, or who develop high risk features. Table 2. TIMI and GRACE Risk Scores TIMI Risk Score Calculations 19 TIMI Risk Score and Clinical Outcomes 19 Risk Factor Point Value Point Total Rate of Composite Endpoint (MACE) Risk Factor 1 0/1 4.7% Age >65 years % At least 3 risk factors for CAD % Significant coronary stenosis (e.g., prior coronary stenosis 50%) % ST deviation % Severe angina symptoms ( 2 events in last 24 1 hours) 6/7 40.9% Use of aspirin in last 7 days 1 Elevated serum cardiac markers 1 Grace Score Calculation 20 GRACE Score and Clinical Outcomes 20 Risk Factor Point Value Risk Factor Point Value Point Total Rate of Composite Endpoint (Probability of In hospital Death) Killip Class Age/Years % I % II % III % IV % SBP, mmhg % % % % Creatinine Level, mg/dl % % Heart Rate, beats/min % % % % % > % Cardiac Arrest at Admission ST Segment Deviation Elevated Cardiac Enzyme Levels % % % An invasive evaluation is done for two reasons: definitive risk stratification and revascularization. Revascularization is generally achieved through percutaneous intervention (PCI) or coronary artery bypass grafting (CABG). The choice between percutaneous and surgical revascularization is based upon coronary angiography features, the individualized risk to benefit ratio, and patient preference. While a complete discussion is beyond the scope of this CME activity, surgical revascularization may be preferred in patients with multi vessel coronary artery disease ( 3 vessels), especially in patients with left ventricular dysfunction and/or diabetes mellitus, or in patients with significant left main coronary artery stenosis. 23, 24 Still, the pharmacotherapy regimen is consistent regardless whether an invasive or noninvasive approach is selected and medical therapy for either strategy should be implemented in an efficient manner. 3

4 Standard medical therapy at the time of presentation should be initiated unless there is a contraindication present. These standard therapies include oxygen, aspirin (chewed, non enteric coated, mg), nitrates (sublingual x 3 doses initially followed by intravenous administration for persistent pain), anticoagulant, and, possibly, morphine therapy. Fibrinolytic therapy is only indicated in patients with STEMI who are unable to be revascularized urgently (within 90 minutes) in the catheterization laboratory and, if indicated, is given in addition to the standard treatment of ACS. Intravenous beta blockers are no longer indicated at the time of presentation with NSTE ACS due to a demonstrated increased risk of harm. 5 However, oral beta blockers should be started within the first 24 hours unless there are contraindications to beta blockade (e.g., heart failure, low output state, risk for cardiogenic shock). 5 A second antiplatelet medication should be started at the time of diagnosis (or suspected) ACS unless contraindicated. The 2014 AHA/ACC NSTE ACS guidelines recommend an oral P2Y 12 inhibitor as the second antiplatelet agent with a class I, level of evidence: B recommendation of using either clopidogrel or ticagrelor, in additional to aspirin, for up to twelve months for patients treated with either an early invasive or initial ischemia guided strategy, with preference given to ticagrelor over clopidogrel (class IIa, level of evidence: B). 5 For patients treated with coronary stenting, the 2014 AHA/ACC NSTE ACS guidelines recommend P2Y 12 inhibitor therapy with either clopidogrel, prasugrel, or ticagrelor for at least 12 months following PCI. 5 The 2013 AHA/ACC STEMI guidelines recommend DAPT with aspirin and a P2Y 12 inhibitor (clopidogrel, prasugrel, or ticagrelor) after PCI with drug eluting or bare metal stent placement for 12 months. 25 Aspirin (continued indefinitely), plus clopidogrel (continued for at least 14 days, and up to 1 year) is recommended in patients with STEMI who receive fibrinolytic therapy. 25 A Focus on Antiplatelet Therapy in ACS As stated, platelets play a critical role in the pathogenesis of ACS. Aspirin and the P2Y 12 inhibitors work through unique mechanisms to minimize the reactivity of platelets and have demonstrated in clinical trials the ability to lower the risk of recurrent major adverse cardiovascular events (MACE) Various differences exist among the available antiplatelet therapies (see table 3 for selected differences in P2Y 12 inhibitors). We will discuss each of these agents individually. Table 3. Comparison of P2Y 12 Inhibitors Clopidogrel (Plavix ) Irreversible Inhibitor Loading Dose 300 mg 600 mg x 1 For patients undergoing PCI, 600 mg upfront loading recommended in guidelines Maintenance Dose 75 mg daily 10 mg daily Prasugrel (Effient ) Irreversible Inhibitor 60 mg x mg x 1 Ticagrelor (Brilinta ) Reversible Inhibitor 90 mg BID (60 mg BID for continued use beyond one year) Indication PCI, Medical Management PCI PCI, Medical Management Endpoints MACE MACE MACE, Mortality (with ASA <100mg) Safety Bleeding Fatal bleeding Bleeding, dyspnea, bradycardia Black Box 2C19 Genotypes, PPI TIA/Stroke Bleeding/ICH Washout 5 day 7 day Relevant Trial(s) CURE, CREDO TRITON, TRILOGY ACS Comments CYP 2C19 genotype testing; under metabolizers require switch to alternative agent (clopidogrel not activated) Patients with defined coronary anatomy Poor Candidates: <60 kg, active bleeding, age >75, hx of TIA or stroke FDA Label 5 days; in clinical trials hours 27 PLATO PEGASUS Only agent that showed a decrease in all cause mortality, NNT=300 Use with low dose ASA (<100 mg) per FDA labeling PPI=proton pump inhibitor; ICH=intracranial hemorrhage; NNT=number needed to treat 4

5 Aspirin 29, 30 For several decades aspirin has been known to have significant benefit in the treatment of coronary arterial disease. Beginning with the publication of the landmark ISIS 2 trial, it was established that aspirin therapy in AMI reduces cardiovascular death, non fatal myocardial re infarction, and non fatal stroke. The benefit of aspirin has been confirmed in other multiple large, randomized trials with aspirin offering a 30 50% reduction in the risk of MI among patients with ACS However, the ideal dose of aspirin has been a point of contention in the cardiovascular community. Clarification came for many with the 2010 publication of the randomized study coined the CURRENT OASIS This study enrolled over 17,000 patients who underwent PCI for ACS aiming to evaluate various doses of clopidogrel and aspirin. With respect to aspirin, high dose ( mg daily) versus low dose ( mg) did not differ for the primary outcome of CV death, MI or stroke (4.1% vs. 42%, P=.76). While major bleeding also did not differ, minor bleeding (which may lead to patient self discontinuation) was more common with the higher dose (5.0% vs 4.3%, P=.019). These findings were corroborated with a 2012 meta analysis that looked at the use of aspirin with, or without, P2Y 12 inhibitors in ACS patients who underwent PCI, CABG, or medical treatment. 35 The results of this review suggested that higher doses of aspirin were not associated with improved outcomes related to MACE or stroke, but was associated with increased risk of major bleeding in medical therapy patients. The conclusion is that higher doses of aspirin are not warranted in this patient population. 35 In addition, exploratory sub group analysis of the landmark ticagrelor clinical trial, PLATO, suggested that ticagrelor performance is enhanced when combined with low dose aspirin (<100 mg) compared to higher doses. 36 The Food and Drug Administration approved dosing recommendations for ticagrelor clearly suggest combination with only low dose aspirin. Further, both the ACC/AHA 2014 NSTE ACS and 2013 STEMI guideline updates specifically state that low dose 81 mg is preferred long term maintenance dose of aspirin (class IIa recommendation). 5, 25 However, most patients (greater than 60%) are discharged on 325 mg daily. 37 This practice continues to expose patients to unnecessary risk. Efforts should continue to be made to ensure that low dose aspirin is prescribed to all appropriate patients both at the time of discharge and continued at outpatient follow up for secondary prevention. Ticlopidine The first available P2Y 12 inhibitor, ticlopidine, is an irreversible inhibitor of the P2Y 12 component of the ADP receptor. Ticlopidine is usually given at the dose of 250 mg twice daily with a 500 mg dose given prior to PCI. Ticloplidine is associated with major safety concerns, most notably the occurrence of life threatening hematologic issues including neutropenia, aplastic anemia, and thrombotic thrombocytopenia purpura (TTP). Use of ticlopidine, therefore, requires frequent monitoring for TTP development including analyzing a complete blood count (CBC) with differential every two weeks for at least the first three months of therapy. Ticlopidine s use in the United States was supplanted upon the introduction of clopidogrel, an agent with an improved adverse effect profile and non inferior efficacy in coronary stenting. 38 Ticlopidine s use is no longer recommended and is no longer commercially available in the United States. Clopidogrel Clopidogrel is an irreversible inhibitor of the P2Y 12 receptor and was initially approved for the ACS indication in It is a prodrug that requires a two step activation through the hepatic cytochrome P450 (CYP) enzymes, notably CYP2C19 and CYP3A4. 39 Clopidogrel is, therefore, susceptible to polymorphisms and drug drug interactions. In ACS, a loading dose is recommended in order to achieve a quicker onset of action. 5 With a 600 mg versus 300 mg loading dose, the onset of action is reduced from 6 to 2 hours. 40 This difference is important, particularly in the setting of PCI, to reduce early stent thrombosis. 34 Maintenance dosing is 75 mg once daily. Clopidogrel has shown benefit in patients treated for ACS both in 26, 41 monotherapy and in combination with aspirin. Individuals with specific CYP enzyme polymorphisms may experience clopidogrel resistance. Because they lack the enzymes required to activate the clopidogrel prodrug, the agent is unable to block the action of adenosine diphosphate at the P2Y 12 receptor. 39 In this case, patients on therapy may continue to have high platelet reactivity putting the patient at risk for event recurrence and poor clinical outcomes. 42 Platelet aggregation testing is an ongoing area of research and innovation that seeks to identify patients who may experience clopidogrel resistance. 39 However, though there is true concern for clopidogrel resistance, the reality is that the majority of treatment failure is attributable to nonadherence. 8 Investigation of the possibility of noncompliance, before going down the path of expensive testing and treatment changes that have yet to demonstrate a benefit with regard to clinical outcomes, is reasonable. 5

6 Prasugrel Prasugrel is a potent, irreversible P2Y 12 inhibitor. It is also a prodrug, but, unlike clopidogrel, it is not known to be susceptible to polymorphisms and, therefore, provides more consistent platelet inhibition. It is dosed with a 60 mg loading dose followed by a maintenance dose of 10 mg once daily. Patient selection is an important consideration for this agent. In the TRITON TIMI 38 trial in patients who had defined coronary anatomy amenable to stenting, prasugrel reduced the risk of MACE versus clopidogrel. 28 However, prasugrel also increased the risk of spontaneous, life threatening, and fatal bleeding over clopidogrel. 28 Caution should also be used in patients that are over 75 years old and have a body weight of <60 kg. 28 Furthermore, prasugrel has an FDA black box warning prohibiting its use in patients with active pathologic bleeding or history of cerebral vascular accident (CVA) including transient ischemic attack (TIA). Prasugrel is not recommended for patients who are going to be managed medically (i.e., do not undergo revascularization) based on the results of the TRILOGY ACS trial, which showed prasugrel did not offer further MACE reduction over clopidogrel in patients not undergoing revascularization. 43 Additionally, upstream use of prasugrel does not seem to impart a reduction in the rate of early stent thrombosis and increases bleeding; therefore, pretreatment should not occur and administration of a loading dose should not take place until the time of PCI. 44 Providers in the community can ensure appropriate patient candidacy for prasugrel, specifically patients should be assessed for stent placement history within the last year, age (ideally <75), weight (ideally >60 kg), and comorbid conditions, specifically history of CVA (an absolute contraindication). Ticagrelor Ticagrelor is a reversibly binding P2Y 12 inhibitor with a more rapid onset and quicker recovery of platelet function as compared to the other agents in the class. The loading dose of ticagrelor is 180 mg. Due to the drug s reversibility and half life of 12 hours, the maintenance dose is 90 mg twice daily. The twice daily dosing regimen distinguishes ticagrelor from the once daily dosing regimens of clopidogrel and prasugrel. In the PLATO trial, as compared to clopidogrel, ticagrelor demonstrated a decrease (9.8% versus 11.7%; HR 0.84; P<.001) in the incidence of MACE (vascular death, stroke, or myocardial infarction) in both PCI and medically managed patients. 27 In STEMI patients, pretreatment with ticagrelor, prior to angiography and PCI, provides a decreased risk of early stent thrombosis without increasing bleeding risk. 27, 45 In the PLATO trial, major bleeding was not statistically different between study groups. However, in sub group analysis, there was more non CABG related bleeding in the ticagrelor group compared to the clopidogrel arm with no difference in CABG related bleeding. Still, ticagrelor demonstrates a significant reduction in all cause mortality, stroke, and MI compared to clopidogrel and, therefore, ticagrelor, used in combination with low dose aspirin, is now recommended as the first line antiplatelet agent as a class IIa, level of evidence B, indication in the 2014 NSTE ACS guideline update. 5 Adverse effects of ticagrelor include dyspnea, bradycardia, and non procedure related bleeding. Dyspnea incidence is greater than 10% in the treated population; however, it rarely requires drug discontinuation. 27, 46 Ticagrelor is also associated with an increased incidence of ventricular pauses, originating from the SA node; however, these had no apparent consequence and are not associated with need to discontinue therapy. 47 A final item to be aware of regarding ticagrelor therapy is the observation of a geographic discrepancy in the drug s effectiveness. In large clinical trials, patients in North America did not demonstrate the same benefit observed at testing centers outside the United States. 36 Further analysis attributed this discrepancy to a higher dose of aspirin use in the United States. Therefore, it is important to note that the benefit of ticagrelor over clopidogrel is limited to patients taking 75 mg to 100 mg of aspirin and higher doses of aspirin when used in combination with ticagrelor are not recommended. 36 A major concern relating to patient adherence is the twice daily dosing regimen of ticagrelor. It is logical that adherence to medications taken twice daily versus once daily dosing is likely worse. In evaluating the adherence of antiplatelet regimens, there was a significant drop off in adherence from once to twice daily dosing, with the greatest drop off occurring in the antiplatelet group from once daily clopidogrel to twice daily drugs such as aspirin/dipyridamole (a 41.7% greater adherence to once daily vs. twice daily agents). 48 While ticagrelor wasn t specifically included, results may be extrapolated. This is an important consideration in the development of transitions of care programs for post ACS patients especially in patients at highest risk for nonadherence. 6

7 Cangrelor Cangrelor is an intravenous, nonthienopyridine adenosine triphosphate analogue that is a direct inhibitor of the P2Y 12 receptor. It is typically given prior to PCI as a 30 mcg/kg bolus followed by an infusion of 4 mcg/kg/min during, and up to 2 hours after, the PCI procedure. 49 In a study of over 11,000 patients, cangrelor was shown to decrease the composite endpoint of death, MI, ischemia driven revascularization, or stent thrombosis (4.7% vs. 5.9%, OR 0.78, P=.005) at 48 hours compared to a loading dose of 300 mg or 600 mg of clopidogrel. 50 It did this without a significant increase in bleeding. For the time being, the role of this therapy will likely be restricted to the catheterization laboratory. Vorapaxar Vorapaxar has recently been approved by the FDA as therapy for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. Vorapaxar reduces platelet activity by inhibiting thrombin related platelet aggregation via antagonism of the platelet s protease activated receptor 1 (PAR 1). 51, 52 In the TRACER trial, vorapaxar (40 mg load with daily maintenance dose of 2.5 mg) was studied as add on to standard therapy (clopidogrel plus aspirin) in the setting of ACS without STEMI. 53 This study of nearly 13,000 patients failed to show a statistical decrease in the composite endpoint of cardiovascular death, myocardial infarction, stroke, rehospitalization due to recurrent ischemia, or urgent coronary artery revascularization (18.5% vs. 19.9%, HR 0.92, P=.07). The study was stopped prematurely as there was a significant increase in bleeding (defined moderate or severe) in the vorapaxar group compared to standard therapy (7.2% vs. 5.2% HR 1.35, P<.001) and included intracranial hemorrhage 53, 54 (1.1% vs. 0.2%, HR 3.39, P<.001). Vorapaxar has also been studied for secondary prevention in patients with a history of MI, stroke, or peripheral arterial disease. Morrow and colleagues randomly assigned 26,449 patients with stable atherosclerosis to receive vorapaxar or placebo in addition to standard therapy. 54 At three years there was a statistically significant decrease in the composite endpoint of cardiovascular death, myocardial infarction, or stroke (9.3% vs. 10.5%, HR=0.87, P<.001). However, there was also a significant increase in moderate or severe bleeding (4.2% vs. 2.5%, HR=1.66, P<.001) with an increase in the rate of intracranial hemorrhage (1.0% vs. 0.5%, P<.001). Unless new data becomes available, the role of vorapaxar will be limited due to the risk of bleeding. Dual Antiplatelet Therapy Currently, stent thrombosis is a rare, but life threatening, complication of PCI. 55 Stent thrombosis is usually diagnosed during angiography, or at autopsy, by the presence of thrombus inside a segment of stented coronary artery. This thrombus is comprised of activated platelets in addition to thrombus, leukocytes, and other inflammatory cells. 56 Thrombus is more likely to form in a stented area as platelet activation is stimulated by the non endothelialized stent. At the start of the interventional era, stent thrombosis was much more common and occurred in up to 24% of procedures despite the procedure being performed with high dose anticoagulation that resulted in significant bleeding complications. 57 The discovery that dual antiplatelet therapy (DAPT) could reduce the risk of stent thrombosis without a prohibitively high rate of bleeding was fundamental in allowing PCI to become a mainstream therapy to treat cardiovascular disease. Indeed, though DAPT is associated with an increased risk of bleeding, the decrease in ischemic events provides a favorable net clinical benefit supporting its use. The STARS trial is one of the first DAPT trials. In this three arm trial of nearly 2,000 patients, aspirin monotherapy was compared to warfarin in addition to aspirin and with ticlopidine in addition to aspirin in patients receiving bare metal stenting. There was a significant reduction in the primary endpoint which reflected the occurrence of stent thrombosis (3.6% vs. 2.7% vs. 0.5%, P=.001). 58 Due to the limiting side effects of ticlopidine, clopidogrel quickly replaced ticlopidine as the DAPT agent of choice. Early clopidogrel studies also demonstrated that the use of dual antiplatelet therapy with clopidogrel and aspirin is better than aspirin alone in the management of post ACS patients who received either invasive PCI therapy or medical management alone. 26, 59 There are no studies that have been performed comparing DAPT with prasugrel or ticagrelor vs. aspirin monotherapy. Also, there are no studies of any agents comparing DAPT vs. monotherapy in drug eluting stents. This is due to ethical concerns of randomizing patients to a likely inferior treatment strategy. Currently, it is a class I recommendation that all patients, without contraindication, being treated for ACS (either an invasive or ischemia driven approach) receive DAPT for one year. 5 7

8 Duration of DAPT Following an ACS event, aspirin should be continued indefinitely unless there is a contraindication. For ACS patients with, or without, PCI, the guideline recommended duration of dual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 inhibitor is 12 months. 5 However, it has long been speculated that, for some patients, therapy longer than 12 months could be beneficial. 60 Two recently published prospective studies add needed information to this topic. The Twelve or 30 Months of Dual Antiplatelet Therapy after Drug Eluting Stents (referred to as the DAPT trial), was a study of 9,961 patients who received PCI (slightly over 40% of the patients were treated for an ACS indication). 61 They were randomized to either receive twelve versus thirty months of treatment. Clopidogrel was the second antiplatelet agent 65% of the time with prasugrel being utilized 35% of the time. In the group that continued P2Y 12 inhibitory therapy for thirty months, there was a significant decrease in adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%, HR 0.79, P<.001), in MI (2.1% vs. 4.1%, P<.001) and in stent thrombosis (0.4% vs. 1.4%, HR 0.29, P<.001). There was a significant increase in moderate or severe bleeding in the group with extended P2Y 12 therapy (2.5% vs. 1.6%, HR 1.61, P=.001). There was no difference in the rate of death from cardiac causes (0.9% vs. 1.0%, P=.98). However, the rate of death from any cause was increased in the extended treatment group (2.0% vs. 1.5%, HR 1.36, P=.05) which was driven primarily by deaths due to cancer. The Long Term Use of Ticagrelor in Patients with Prior Myocardial Infarction (PEGASUS TIMI 54) trial was a study conducted in 21,162 patients with a history of MI 1 3 years prior to randomization. 62 Patients did not have to currently be on DAPT. Unlike the clopidogrel trial, patients may have had a break in DAPT therapy for a period of time prior to initiation of DAPT for the extended use arm of the trial. Patients were then randomized to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or aspirin monotherapy. Both doses achieved statistical significance at reducing the composite endpoint of cardiovascular death, MI, or stroke compared to aspirin alone (ticagrelor 90 mg twice daily rate =7.85% ticagrelor 60 mg twice daily rate=7.77% and aspirin alone rate=9.04%) The two ticagrelor doses had similar rates of major bleeding (ticagrelor 90 mg twice daily=2.6%, ticagrelor 60 mg twice daily=2.3%) which were increased compared to aspirin (1.06%). The risk of minor bleeding was also higher in the ticagrelor groups. The rate of fatal bleeding, or nonfatal intracranial bleeding, was similar between groups. The net clinical benefit was achieved, though with a narrow margin, leading to the September 2015 FDA approval of ticagrelor 60 mg twice daily for long term prevention of myocardial infarction, stroke, or death in patients continuing antiplatelet therapy beyond one year. In a meta analysis of 10 randomized trials, including over 32,000 patients, the optimal duration of DAPT following PCI was evaluated. 63 Compared to the standard twelve month therapy, a shorter duration is associated with less major bleeding (OR 0.58, P=.02). In patients receiving extended therapy, they have a significantly reduced risk of MI (OR 0.53, P<.001) and stent thrombosis (OR 0.33, P<.001) compared to twelve months of DAPT. Extended therapy was associated with a higher risk of major bleeding (OR 1.62, P<.001) and for all cause mortality (OR 1.3, P=.03), but not for cardiovascular mortality. As is the case with most clinical medicine, DAPT duration should be customized to the individual. Considerations for duration of therapy include: ischemic risk, bleeding risk, stent related factors, and anatomy related factors. 60 For most patients, twelve months of DAPT is appropriate. For patients at highest risk of recurrent MI or stent thrombosis, and with low bleeding risk, an extended course of DAPT may be appropriate. Patients with increased risk of bleeding likely should not receive extended duration of therapy. Indeed, it is possible that patients with significantly increased risk of bleeding may benefit from shorter therapy. With newer generations of drug eluting stents (DES) or when bare metal stents (BMS) are placed, the risk of in stent thrombosis is significantly lower than what was observed with first generation DES. Therefore, in cases of significantly elevated bleeding risk or the need of urgent surgery, DAPT duration may be shortened to as brief as six months (or for one month following BMS) without an overall increase in late and very late stent 63, 64 thrombosis. Other Secondary Prevention Strategies In addition to DAPT therapy, it is well known that there are multiple other secondary prevention therapies recognized to prevent mortality and future cardiac events. These drug therapies include oral beta blocker, early high intensity statin, and, in qualifying patients, angiotensin converting inhibitor (ACE I), or angiotensin receptor blocker (ARB) and, possibly, aldosterone antagonists. ACE I/ARB therapy is a class I, level of evidence: A recommendation for patients with comorbid conditions of: reduced ejection fraction (EF <40%), chronic kidney disease (CKD), diabetes mellitus (DM), or hypertension (HTN). For patients without these co morbid conditions, use of ACE I/ARB is suggested with level of evidence IIb/B. 8

9 Aldosterone antagonist therapy is indicated only in patients with reduced ejection fraction (EF 40%) plus DM or symptoms of heart failure. 5, 65 Unfortunately, this can lead to a very complicated pharmacotherapy regimen. As previously mentioned, medication nonadherence is a contributor to hospital readmissions and medication regimen complexity is a known risk factor for nonadherence. 8 In the case of ACS, patients are being prescribed potentially 5 or 6 new chronic medications which can be overwhelming and should require thoughtful consideration during transitions of care. Adding further complexity, but an essential component of the ACS hospitalization and safe transitions of care, is developing a post hospital system and individualized plan of care. Class I recommendations in the NSTE ACS guidelines include coordinated outpatient care, including not only an evidence based medication regimen, but a system that promotes adherence, timely follow up, and supportive education and instruction for lifestyle modifications. Guidelines state that the plan of care should include specifics about daily exercise and activities of daily living to avoid (or resume) with education materials to support patient and family understanding. Guidelines stress the importance of paying close attention to all psychosocial and socioeconomic issues, including risk of depression, barriers to adherence, and patient understanding, as vital to successful transition in this high risk patient population. Finally, annual influenza vaccination is recommended for all patients with cardiovascular disease and is addressed in the plan of care section of the NSTE ACS guidelines. Medication Adherence Medication adherence is not just a challenge for patients with ACS and clinicians in the cardiology community; medication nonadherence has been identified as the leading cause of morbidity and mortality in the United States. Genetic polymorphisms, interpatient variability, and drug interactions are often implicated in patients who have poor response to antiplatelet therapy, though poor adherence is the biggest culprit. 8 The term adherence is widely preferred to compliance, as the later suggests a passive role in following dictated instructions, while adherence implies an established patient/provider relationship with patient s agreement to the recommendations. 66 Admittedly, both terms are imperfect in describing patients medication taking behaviors and opportunities for improvement. In 2001, the World Health Organization defined adherence as the extent to which the patient follows medical instructions and is often described as a percentage of medications taken compared to those prescribed during the same time period. 67 Patients are considered adherent if this is greater or equal to 80%. This is sometimes referred to as the proportion of days covered (PDC). For example, taking 24 pills in 30 days of a medication prescribed as 1 pill once daily (or 80% PDC) would be considered adherent. Recent analyses from the TReatment with ADP receptor inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE ACS) study, revealed that, early after myocardial infarction, medication nonadherence is common. 68 The TRANSLATE ACS study evaluated adherence to cardiovascular medications in 7,425 acute MI patients within 6 weeks of PCI using the self assessment 8 question Morisky Medication Adherence Scale. Results showed over 30% of patients had moderate or low adherence (25% and 4% respectively). 68 Given the selfreporting bias, this likely underestimates adherence issues and further demonstrates the epidemic challenge of getting patients to appropriately, and consistently, take their prescribed medications. Similarly, Benner and colleagues evaluated statin use amongst elderly patients and found that only 1 in 4 elderly patients had a PDC greater than 80% at 5 years. 69 Further, premature discontinuation of certain cardiac medications in certain patients has significant clinical consequences. Early discontinuation of DAPT leads to a 9 fold increase in risk of death and 90 fold increase in risk of stent thrombosis. 70,71 This statistic is concerning, especially since almost 50% of patients in the United States do not take their medications as prescribed. 72 The PARIS (Patterns of Nonadherence to Antiplatelet Regimens in Stented Patients) registry was a prospective observational study of adult patients undergoing stent placement with pre specified follow up at 1, 6, 12, and 24 months to evaluate the clinical consequences of DAPT disruption, interruption, or discontinuation. 73 Investigators enrolled 5,031 patients and, by the 30 day follow up, researchers found a 6 fold increase in odds of stent thrombosis in patients with nonadherence. The association of stent thrombosis and early nonadherence to DAPT has also been observed in the EDUCATE registry and a VA cohort. 74, 75 Given the clinical implications of nonadherence post PCI, identification of patients who are nonadherent or are at risk and providing systematic, or targeted, interventions to improve medication use is vital in this patient population. 76 We know that patients have trouble discussing adherence issues with physicians. In 2013, a publication in Family Practice Management highlighted this disconnect with 85% of physicians believing their patients were adherent and 85% of 9

10 patients stating that they would not tell their doctor if they were not planning on buying a medicine. 77, 78 With these results, the need to address patient adherence is obvious, but the task can seem daunting. Identifying nonadherence can be done through procession ratios (based on days between refills), pill counts, memory caps, risk factor screening, and selfreporting. While none of these are perfect, each offers some insight into patients approximate adherence. As previously mentioned, one tool which can readily be used by providers is the validated 8 question Morisky Medication Adherence Scale (see Table 4). 79 Table 4. Morisky 8 Item Medication Adherence Questionnaire 79 Total Score >2=low adherence 1 2=medium adherence 0=high adherence Score A=0 B E=1 Another tool that can be used to identify medication nonadherence is The Adherence Estimator (see Figure 2). 78 This three item tool uses a Likert scale and asks patients to indicate whether or not they agree or disagree with the following three statements related to medication use: 1) I am convinced of the importance of my prescription medications, 2) I worry that my medication will do more harm than good to me, 3) I feel financially burdened by my out of pocket expenses for my prescription medication. A score of zero suggests there is low risk for adherence problems, while a score of 8 or more indicates a high risk of adherence problems (<32% Figure 2. The Adherence Estimator 78 probability of adherence). Both assessments are brief and practical for everyday use and can aid providers in identifying patients at the highest risk to target interventions when resources limit more systematic approaches. When screening tools cannot be employed, it may be helpful to know that Czrany and colleagues performed a systematic review and identified that adherence to DAPT is particularly low in patients with lower education levels or immigrant status

11 The medical community has a lot of work to do to better understand medication taking behaviors to improve patient adherence. Many assume the biggest barrier to medication adherence is medication cost or drug access issues. However, in the MI FREEE study, the elimination of out of pocket costs was only associated with a modest improvement in adherence rates (35.9 to 49.0%) indicating the issues surrounding medication nonadherence is much more complex. 81 Expertly discussed in an essay that appeared in January 2015, in the New England Journal of Medicine, Dr. Rosenbaum sought to understand how 20 post MI patients felt about taking medications for heart disease. In this piece, she described what many practitioners have anecdotally observed that, in addition to known risk factors (white race, depression, and female sex), there are MANY emotional reasons patients deliberately do not take their medications. Amongst others, these include intrinsically negative views of medicines and potential side effects, that taking medications reinforces that they are sick, that prescription medicines, unlike herbals (which are organic ) are chemicals, and that the benefits are often imperceptible. 82 Understanding and combating the individual patient s barriers to adherence is a vital component of successful management of coronary artery disease (or any illness for that matter). Evidence, especially to the post ACS patient population, continues to prove that prescribing guideline recommended therapy is only part of the solution to management of ACS. Helping patients to become engaged in their health and adherent to prescribed regimens is an essential component in influencing individual patient and population health outcomes. Medication adherence, despite increased direct drug cost, is associated with decreased healthcare costs, owing to reductions in hospitalizations and emergency department use. 83 Education to Improve Adherence Several of the evaluations discussed have given healthcare professionals some hints to improve patient adherence. Two key components to successful transitions of care (and related DAPT adherence) for ACS patients is medication education and close follow up. 68, 80 Specifically, when patients are given follow up appointments prior to discharge, there is an observed decrease in readmission and emergency Figure 3. Teach Back Cycle department visits. Medication education, that includes the use for each medication and the potential side effects, has been shown to improve adherence as well as patient satisfaction. In addition to indication, rationale, or anticipated benefit, the medication name, dose, dosing schedule, and what to do if a dose is missed should also be reviewed. 84 Further, medication education should include potential adverse effects, anticipated dose changes, therapy duration, and drug drug or drugdisease interactions. Providing patients with a complete list of their medications and instructing them to carry it with them can Adapted from Schillinger D, et al. Arch Intern Med help improve provider continuity and proves useful in cases of emergency. Reinforcement of this information by multiple members of the healthcare team and with patients care providers present can help retention. Ideally, education will be delivered with multiple formats (e.g., written and verbal) and in a level appropriate for patient education. 84 Whenever possible teach back techniques should be employed to ensure patient comprehension of the education provided (see Figure 3). Although not specifically proven in ACS patients, providing the patient with information and asking them to teach back has been shown to be effective in other chronic diseases. 85 Given the well described consequences, particularly with early interruption, or delays, in filling DAPT prescriptions post ACS, institutions should ensure affordability of discharge regimens and, if possible, employ bedside discharge prescriptions delivery services to eliminate early access barriers to adherence. The discharge counseling session should also address any patient specific barriers to 11

12 adherence and stress the importance of adherence (and consequences of nonadherence) including the need for timely refills. Related to ACS, and antiplatelet therapy specifically, it is important to ensure patients understand the vital role dual antiplatelet therapy plays in preventing thrombosis. Because aspirin is over the counter, it is often misinterpreted by patients to be unimportant. They should know that their doctor is prescribing them to use low dose aspirin and that it is often used in conjunction with P2Y 12 inhibitors in patients with cardiovascular disease. They should be told that this combination has been well studied to prevent CV death, recurrent MI, and stroke. Patients should be informed that these medications should never be discontinued without consulting their cardiologist or prescribing provider. The patient and care providers should be informed upfront about the anticipated duration of DAPT in their specific clinical scenario to prevent stent thrombosis and recurrent heart attacks. Recall that, in all patients post ACS, this will ideally be one year, but this is particularly important in those with drug eluting stents. Medically managed patients and those status post bare metal stent placement may have shorter durations for various reasons. It is also important that this information be balanced and that the patient understands that these medications can increase their chance of both major and minor bleeding events. The patient understanding that you have evaluated the risk and benefits in them individually and recommend taking DAPT will likely improve their engagement and adherence. Patients should be instructed to notify their provider if they experience uncontrolled bleeding of the gums or nose, excessive bruising, dark urine or stools, or coughing up blood. If any of these are problems at baseline, the patient should be given strategies to prevent worsening (e.g., saline nasal spray to prevent dry nose in the winter months or GI prophylaxis in patients with reflux). Finally, it is very important that patients on DAPT understand the importance of telling all of their care providers that they are taking aspirin and a P2Y 12 inhibitor. Multiple over the counter medications (e.g., fish oil) can increase bleeding and should be avoided while on DAPT. The addition of anticoagulation (i.e., warfarin or a non vitamin K oral anticoagulant) should be considered very cautiously and in conjunction with their cardiologist as triple therapy greatly increases the risk of major bleeding. Conclusion According to clinical guidelines, following acute coronary syndrome pharmacotherapy regimens for secondary prevention should include high potency statins, beta blockers, ACE inhibitors (in select patients), and dual antiplatelet therapy. Particularly, in patients who are managed with percutaneous interventions, aspirin plus a P2Y 12 inhibitor has been shown to decrease recurrent MI, stroke, and death. Unless there is a significant contraindication or complication, all ACS patients should be treated with DAPT for at least one year with more recent studies demonstrating a long term benefit (beyond a year) in some patients. It has been well established that poor adherence, early discontinuation, or failure to fill prescriptions for DAPT lead to recurrent stent thrombosis events at an alarming rate. Nonadherence in this patient population is unacceptably high, but may be prevented with improved provider identification, patient education, and close patient follow up. Medication taking behaviors are complex and barriers to full compliance are varied, requiring care providers to understand not only evidence based medicine recommendations, but how to support their patients with adherence to prescribed regimens. 12