Curr Atheroscler Rep (2016) 18:45 DOI 10.1007/s11883-016-0595-0
CARDIOVASCULAR DISEASE AND STROKE (S. PRABHAKARAN, SECTION EDITOR)
Duration of Dual Antiplatelet Therapy in Coronary Artery Disease: a Review Article Alex D. Moseley 1 & Fareed M. Collado 1 & Annabelle Santos Volgman 1 & Gary L. Schaer 1 & R. Jeffrey Snell 1
# Springer Science+Business Media New York 2016
Abstract Dual antiplatelet therapy (DAPT) following an acute coronary syndrome or after placement of a coronary artery stent is superior to aspirin alone for prevention of atherothrombotic events but carries an increased bleeding risk. DAPT should be continued for at least 12 months based on current guidelines. Recent randomized trials demonstrate reduced ischemic events including myocardial infarction (MI), stroke, and death with continued DAPT for up to 30 months or longer, particularly in the post-MI population. However, this clinical benefit is accompanied by an increased risk of bleeding. Additional trials show mixed safety and efficacy with duration of DAPT of less than 12 months. The current data emphasizes the need to individualize DAPT duration at the patient level to balance the clinical benefits of a reduced risk of cardiovascular ischemic events with the greater risk of clinically significant bleeding. Patients at an increased risk of ischemic events and a lower risk of bleeding should be strongly considered for prolonged DAPT beyond the 1 year currently recommended in the practice guidelines. Keywords Dual antiplatelet therapy . Coronary artery disease
Introduction For the last 5 decades, the age-adjusted mortality rates for coronary artery disease (CAD) have been steadily declining This article is part of the Topical Collection on Cardiovascular Disease and Stroke * R. Jeffrey Snell
[email protected] 1
Rush University Medical Center, 1653 W Congress Parkway, Chicago, IL 60612, USA
in the USA. From 2006 to 2010 alone, the prevalence of CAD in the USA decreased from 6.7 to 6.0 % [1••]. The downtrend is primarily attributed to greater control of risk factors and improved medical treatment [2]. However, CAD remains a global health concern as the morbidity and mortality in patients with CAD remain elevated. Most patients with CAD who develop acute coronary syndromes (ACS), including unstable angina, non-ST elevation myocardial infarction (NSTEMI), and ST elevation myocardial infarction (STEMI), undergo revascularization with percutaneous coronary intervention (PCI) and occasionally coronary artery bypass graft surgery (CABG). All patients with CAD (whether or not they have ACS) should also receive intensive medical therapy, including treatment with a high intensity statin [3••]. The vast majority of patients undergoing PCI will be treated with a drug-eluting stent (DES), although some patients will receive a bare-metal stent (BMS) or balloon angioplasty alone. Subsequently, these patients, regardless of mode of treatment, are treated with dual antiplatelet therapy (DAPT). DAPT refers to the addition of a second platelet-inhibiting agent to aspirin. Oral P2Y12 inhibitors such as clopidogrel, prasugrel, and ticagrelor are the currently available medications used in DAPT [4]. The therapeutic goal of DAPT is to reduce the risk of atherothrombotic cardiovascular events (myocardial infarction (MI), stroke, and cardiovascular death) and in patients who have received a coronary artery stent, to reduce the risk of stent thrombosis. Although DAPT has been shown in several landmark studies to have superior antithrombotic benefits compared to aspirin alone, it is also known to increase bleeding risk. Bleeding complications related to antithrombotic therapy, although often minor, have been associated with increased risk of subsequent adverse outcomes including MI, stroke, and death in patients with ACS and also those undergoing PCI [5–7]. Therefore, it is prudent to balance the ischemic prevention
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benefits of antithrombotic therapy against its bleeding risk. The duration of antithrombotic therapy and the optimal agents to use are critical questions being answered in clinical trials over the last decade. Current recommendations from the American College of Cardiology/American Heart Association (ACC/AHA) practice guidelines state that DAPT should be continued for at least 12 months following coronary stenting for ACS followed by indefinite treatment with aspirin alone [3••]. Continued DAPT beyond 1 year may be considered if the risk of bleeding is low and the risk of an ischemic cardiovascular event (or stent thrombosis) is believed to be increased. In patients with ACS who receive medical management rather than PCI, 12 months of DAPT is still recommended [3••]. The ideal duration has not yet been established since the available antiplatelet agents have different proven risk-benefit profiles. The risk calculation between prevention of coronary artery thrombosis and bleeding events has led researchers to investigate the optimal length of DAPT therapy to maximize efficacy and safety before reverting to therapy with aspirin alone. Several studies that were reviewed produced conflicting results. It is the aim of this review to critically evaluate existing trials and studies and provide clinicians a framework for DAPT usage in patients with CAD.
Epidemiology of Coronary Artery Disease The age-adjusted CAD prevalence in the USA is estimated between 6 and 6.7 % [2]. The incidence of MI has been estimated anywhere from 190 to 486 per 100,000 people with CAD depending on the statistics used and patient population examined [8]. These data reflect the incidence of reported coronary events with troponin elevations. They do not take into account the many cases of unstable angina, which are more difficult to standardize for reporting purposes. Because of this, the prevalence of ACS is likely underestimated. The most current data from the American Heart Association reports that in 2013, there were 370,213 Americans who died of CAD. An estimated 660,000 Americans have a new coronary attack (defined as first hospitalized MI or CAD death) and about 305,000 have a recurrent attack. In addition, an additional estimated 160,000 silent MIs occur each year [9]. It is well established that in ACS, including unstable angina, there is a mortality benefit and decreased risk of MI with PCI as compared to medical management [10, 11]. Anginal symptoms and resultant hospital readmission are also markedly reduced in patients treated with PCI compared to those receiving medical management. The most feared complication of PCI is stent thrombosis, which is estimated to occur in 1.9 % of real world patients in the first 9 months post-procedure and 0.7 % of patients overall [12]. The most powerful indicator for stent thrombosis risk
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was premature discontinuation of DAPT. The number of patients who undergo PCI after an ACS, the development of new antiplatelet agents, and bleeding risk associated with DAPT all make the duration of DAPT a paramount question.
Pharmacology of Antiplatelet Therapy The two drug combination that comprises DAPT prevents thrombosis by inhibiting two different steps in platelet activation and aggregation. Current guidelines require that all patients with an ACS without an allergy be treated with 81 to 325 mg of aspirin daily [1••, 3••]. Aspirin acts by inhibiting cyclooxygenase-1 (COX-1), which in turn decreases production of thromboxane A2. Thromboxane A2 is a protein that activates platelets and thereby initiates exposure of glycoprotein IIb/IIIa (GIIB/IIIa) receptors on the platelet surface. This receptor must be activated for fibrinogen to cross-link platelets and begin to form a thrombus. The inhibition of this pathway by aspirin, starting with COX-1, ultimately leads to reduced platelet aggregation. The class of antiplatelet agents often added to aspirin in DAPT is the oral P2Y12 antagonists that block the adenosine diphosphate (ADP) receptors. Drugs in this class include clopidogrel, prasugrel, and ticagrelor. These drugs prevent ADP binding to the P2Y12 receptor, which is required to activate platelets and thereby expose fibrin-binding sites on the GIIb/IIIa receptors on platelets. This reduces fibrin crosslinking of platelets thus decreases platelet aggregation. These drugs also have different pharmacokinetic profiles. Clopidogrel and prasugrel are pro-drugs requiring activation in the liver before achieving an antiplatelet effect. In addition, they are both irreversible antagonists of the P2Y12 receptor. Prasugrel has a faster peak onset and more potent antiplatelet effect and is also associated with less variability between patients. In contrast to clopidogrel and prasugrel, ticagrelor is not a prodrug and therefore does not require metabolic activation before exerting its antiplatelet effect. It is also a reversible antagonist of the P2Y12 receptor. Like prasugrel, ticagrelor is more potent and faster acting with less inter-patient variability compared to clopidogrel. Cangrelor is an intravenous P2Y12 inhibitor that was recently approved by the Food and Drug Administration (FDA) for use during PCI. Like ticagrelor, cangrelor is not a pro-drug and results in very rapid antiplatelet effects that are also rapidly reversible upon discontinuation of the infusion.
Atherosclerosis Pathophysiology and Dual Antiplatelet Therapy The pathogenesis of atherosclerosis is a complex process resulting from endothelial damage occurring in patients with hypertension, diabetes, smoking, or other traditional risk
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factors. This leads to low density lipoprotein (LDL) entering the intima of the vessel wall via the damaged endothelium. LDL particles then undergo oxidation and are taken up by macrophages resulting in formation of foam cells. Foam cells and migrating smooth muscle cells from the media result in atherosclerotic plaque formation [13]. An ACS event usually results from spontaneous rupture or erosion of an atherosclerotic plaque. This event exposes the plaque contents (i.e. tissue factor, collagen) to the blood pool resulting in platelet adherence to the vessel wall, platelet activation, aggregation, and further activation of the coagulation system. The resulting thrombus may progress to totally occlude the coronary artery causing a STEMI or may partially occlude the vessel or embolize platelet-fibrin fragments to the distal microcirculation causing an NSTEMI. Dual antiplatelet therapy can favorably impact this process by reducing the risk of coronary artery thrombus formation. Following such thrombotic events, patients who undergo PCI receive either a BMS, first generation DES (sirolimus or paclitaxel eluting stent), or a second generation DES. DAPT is used in patients who receive a stent both for the benefit in preventing future thrombosis at non-stented sites, and to prevent platelet aggregation to the stent itself, which until endothelialized, is a nidus for thrombosis. Stent thrombosis can lead to total occlusion of the recently stented vessel. The advancement of stent design has led to a decrease in stent thrombosis. A study of 18,334 patients by Tada et al. in 2013 demonstrated that the cumulative incidence of definite stent thrombosis at 3 years was 1.5 % with BMS, 2.2 % with first generation DES, and 1.0 % with second generation DES [12].
History of Dual Antiplatelet Therapy In 1988, the second International Study of Infarct Survival (ISIS-2) trial placed aspirin as the mainstay of therapy in STEMI patients. This study randomized 17,187 patients within 24 hours of the onset of suspected MI to streptokinase, aspirin 160 mg per day, both, or neither. Streptokinase alone and aspirin alone each produced a highly significant reduction in mortality. The combination of streptokinase and aspirin was significantly better than either agent alone. Aspirin also significantly reduced non-fatal reinfarction and non-fatal stroke and was not associated with any significant increase in cerebral hemorrhage or bleeding requiring transfusion [14]. In the pre-stent era of interventional cardiology, patients who underwent balloon angioplasty or atherectomy were treated with aspirin alone following the procedure. It was subsequently demonstrated in 1996 that patients who were postMI, post-stroke, or had peripheral arterial disease had fewer thrombotic events following treatment with clopidogrel, a P2Y12 inhibitor, compared to aspirin [15]. In 2001, the CURE trial (Clopidogrel in Unstable angina to prevent
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Recurrent Events) demonstrated that treatment of patients with an ACS without ST elevation with both aspirin and clopidogrel within 24 hours and continued for 1 year was superior to aspirin alone. Of note, however, the risk of major bleeding was increased among patients treated with clopidogrel in this trial [16]. Subsequently, pharmaceutical companies developed new P2Y12 inhibitors, and their comparative efficacy and safety became a new focus of research. Prasugrel was demonstrated to have superior efficacy compared to clopidogrel but significantly more bleeding in TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38). In this study, 13,608 patients with moderate to high risk ACS with scheduled PCI received either prasugrel (60 mg loading dose followed by 10 mg daily) or clopidogrel (300 mg loading dose followed by 75 mg daily) in addition to aspirin. The prasugrel group had significantly reduced ischemic events including stent thrombosis. However, the prasugrel group also had a significant increase in major bleeding, and there was no difference in overall mortality [17]. In 2009, ticagrelor was studied in patients with non-ST elevation-acute coronary syndrome (NSTE-ACS) or STEMI in the PLATO (Platelet Inhibition and Patient Outcomes) trial. At 12 months, treatment with ticagrelor (180 mg loading dose then 90 mg twice daily) compared to clopidogrel (300– 600 mg loading dose then 75 mg daily) resulted in a lower incidence of the primary end point (a composite of death from vascular causes, MI, or stroke). This end point occurred in 9.8 % of patients receiving ticagrelor as compared with 11.7 % of those receiving clopidogrel (hazard ratio, 0.84; 95 % confidence interval [CI], 0.77 to 0.92; P < 0.001) [18]. Ticagrelor was also associated with a higher rate of major bleeding not related to CABG (4.5 % vs. 3.8 %, P = 0.03). Although all patients in the trial were treated with aspirin (75 to 325 mg each day at the discretion of the treating physician), a post-hoc analysis demonstrated that only low doses of aspirin in combination with ticagrelor was beneficial. The beneficial effects of ticagrelor compared to clopidogrel were least prominent in the USA cohort (hazard ratio 1.27; 95 % [CI] 0.92 to 1.75). Conversely, high-dose aspirin use (>300 mg) was much more prominent (53.6 %) versus the international cohort (1.7 %). In the post-hoc analysis, only aspirin dose could account for the difference in ticagrelor effectiveness between the USA and international cohort [19]. As of today, there is no definitive rationale that explains why ticagrelor is less effective than clopidogrel when using a higher aspirin dose. Several hypotheses exist that may explain this phenomenon. One of the hypotheses focus on the reduction of prostacyclin release by higher aspirin doses in the presence of a strong P2Y12 inhibitor, thus potentially shifting the influence of aspirin into a prothrombotic effect. However, since there is no strong biological rationale for this
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phenomenon, it is suggested that chance alone rather than aspirin dose must remain a potential explanation [19]. Therefore, the FDA approved labeling for ticagrelor in the USA mandates that only 81 mg each day of aspirin be used in combination with ticagrelor. Table 1 summarizes the results of the landmark trials of the different antiplatelet agents.
Dual Antiplatelet Therapy Duration in Recent Literature Although DAPT led to less major adverse coronary events, especially in patients treated with stents, DAPT was associated with increased bleeding events in most clinical trials. According to current guidelines, at least 12 months of DAPT is recommended following coronary artery stenting for ACS. In patients receiving a DES for non-ACS indications, DAPT with clopidogrel should be given for at least 12 months. In those receiving a BMS for a non-ACS indication, DAPT with clopidogrel should be given for at least 1 month [1••]. Premature discontinuation of DAPT, especially within the first 3 months after implantation, is associated with a marked increase in the risk of stent thrombosis (hazard ratio 152; 95 % CI 52 to 442, P < 0.001) [20]. Patients and caregivers should be educated about the critical importance of continuing DAPT and the dangers of premature discontinuation. Practice guidelines also emphasize that if the risk of morbidity from bleeding outweighs the anticipated benefit afforded by a recommended duration of P2Y 12 inhibitor therapy after stent implantation, earlier discontinuation of P2Y 12 inhibitor therapy is reasonable. Figure 1 and Table 2 summarize the conflicting results of multiple recent trials comparing different durations of DAPT.
12-Month Dual Antiplatelet Therapy Versus Increased Duration The DAPT trial randomized patients after successful coronary artery stenting to 12 versus 30 months of DAPT (clopidogrel or prasugrel in addition to aspirin). The co-primary efficacy endpoint was stent thrombosis or the composite of death, stroke, or myocardial infarction during the period from 12 to 30 months. The primary safety endpoint was moderate or severe bleeding. The group that received 30 months of DAPT had a statistically significant reduction in stent thrombosis (0.4 % vs. 1.4 %; hazard ratio 0.29 [95 % CI, 0.17 to 0.48]; P < 0.001), as well as a statistically significant reduction in composite cardiovascular events (4.3 % vs. 5.9 %; hazard ratio 0.71 [95 % CI, 0.59 to 0.85]; P < 0.001). The rate of moderate or severe
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bleeding was increased with continued DAPT (2.5 % vs. 1.6 %, P = 0.001). The results of the trial were encouraging to advocates of extended duration DAPT, but there were several limitations. First, there were very low event rates in both arms of the study. Second, patients who were adherent to 12 months of DAPT were then randomized to the aspirin versus 30 months DAPT groups. This creates selection bias toward more adherent and highly motivated patients [21•]. ARCTIC-Interruption was the next study to compare longer duration DAPT with standard 12-month treatment. Clopidogrel or prasugrel in addition to aspirin was compared in 12 and 24 months treatment groups. In this study, there was no significant difference found in efficacy endpoints but an increased number of bleeding events occurred in the 24-month arm. Similar to the DAPT trial, ARCTIC-Interruption was limited by its use of a predominantly low risk population in conjunction with lower than expected event rates, leading to wide confidence intervals for safety and efficacy endpoints [22]. Most of the trials evaluating the duration of DAPT included a cohort of patients who recently had a PCI, ACS, or both. The appropriate treatment and outcomes of patients beyond 1 year after having an MI remain unclear. In 2015, the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of AspirinThrombolysis in Myocardial Infarction 54 (PEGASUSTIMI 54) trial was published to answer this clinical question. A robust number of patients (n = 21,162) were included in this multicenter, double-blind, randomized, and placebo-controlled study. The cohort of patients studied had an MI 1 to 3 years prior to enrollment. They were randomized into three groups: ticagrelor 90 mg twice daily (n = 7050), ticagrelor 60 mg twice daily (n = 7045), and placebo (n = 7067). All groups were taking aspirin 75 to 150 mg daily. The groups had a median follow up of 33 months with a primary endpoint of cardiovascular (CV) mortality, MI, or stroke. At 3 years, the study demonstrated a significant reduction of the rate of the primary endpoint with the two ticagrelor doses when compared with placebo. However, the rates of Thrombolysis In Myocardial Infarction (TIMI) major bleeding were also higher in both ticagrelor groups when compared to placebo [23•]. In contrast to other trials, however, the patients in the trial were at high risk for ischemic events (age >50 years, diabetes mellitus, multi-vessel CAD, history of prior MI, and creatinine clearance of
