Dual-antiplatelet Therapy Guidelines and Implications for Perioperative Management

Author’s Accepted Manuscript Dual Antiplatelet Therapy Guidelines Implications for Perioperative Management

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Kristin Stawiarski, Rachna Kataria, Claudio A Bravo, Pedro Villablanca, Divyanshu Mohananey, Seshasayee Narasimhan, Harish Ramakrishna www.elsevier.com/locate/buildenv

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S1053-0770(17)30575-X http://dx.doi.org/10.1053/j.jvca.2017.06.033 YJCAN4217

To appear in: Journal of Cardiothoracic and Vascular Anesthesia Cite this article as: Kristin Stawiarski, Rachna Kataria, Claudio A Bravo, Pedro Villablanca, Divyanshu Mohananey, Seshasayee Narasimhan and Harish Ramakrishna, Dual Antiplatelet Therapy Guidelines and Implications for Perioperative Management, Journal of Cardiothoracic and Vascular Anesthesia, http://dx.doi.org/10.1053/j.jvca.2017.06.033 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1 Category [Expert Review] Dual Antiplatelet Therapy Guidelines and Implications for Perioperative Management Kristin Stawiarskia,*, Rachna Katariaa,*, Claudio A Bravob,*, Pedro Villablancab, Divyanshu Mohananeyb, Seshasayee Narasimhand, e, f and Harish Ramakrishnac a

Department of Internal Medicine, Yale New Haven Health System, Bridgeport,

Connecticut, USA b

Montefiore Einstein Center for Heart & Vascular Care, Albert Einstein College of

Medicine, Montefiore Medical Center, Bronx, New York, USA c

Department of Anesthesiology, Mayo Clinic College of Medicine, Arizona, USA

d

Department of Cardiology, Manning Base Hospital, Taree, NSW, Australia

e

University of Newcastle, Callaghan, NSW, Australia

f

University of New England, Armidale NSW, Australia

* Equal contribution Address correspondence to: Harish Ramakrishna, MD, FASE, FACC, Division of Cardiovascular and Thoracic Anesthesiology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054. Telephone: 480-342-2447; Fax: 480-342-2319; E-mail: [email protected]. The authors have no conflict of interest or financial involvement with this manuscript.

2 Abstract

Dual antiplatelet therapy (DAPT) has become a mainstay of treatment for coronary artery disease. The recently updated 2016 American College of Cardiology/American Heart Association (ACC/AHA) guidelines have challenged the optimal duration of DAPT therapy. We discuss the currently available antiplatelet agents and the evidence in support of their combined use for both stable and acute ischemic heart disease. Further, the perioperative management of patients on DAPT will also be reviewed.

Dual Antiplatelet Therapy Guidelines and Their Implication on Perioperative Management Dual Antiplatelet therapy (DAPT) has become a key factor in the management of coronary artery disease (CAD). The combination of aspirin and a P2Y12-receptor inhibitor, especially after a percutaneous intervention (PCI), is recommended to prevent stent thrombosis and future ischemic events.1 In the past few years, DAPT guidelines have seen a number of updates largely owing to the effects of newer drug-eluting stent (DES) technology and the advent of more potent P2Y12-receptor antagonists. Current guidelines recommend at least 12 months of DAPT for patients with acute coronary syndrome (ACS), and between 6 and 12 months for those with stable ischemic heart disease (SIHD).2 The duration of DAPT is also dictated by the type of stent deployed; 12 months for DES and 1 month for Bare Metal Stents (BMS)2. Despite guideline consensus, the duration of DAPT is still a matter of debate. Real world registries,3 randomized clinical trials (RCT),4 and meta-analyses5 have been performed to compare the two strategies of abbreviated versus prolonged DAPT. As the optimal DAPT duration changes, so does the timing for elective surgical procedures.

3 In this review, we will discuss the various drugs available on the market that comprise a dual antiplatelet regimen and their role in both stable and acute ischemic heart disease. The current DAPT guidelines as outlined by the American College of Cardiology/American Heart Association (ACC/AHA) will be summarized along with the evidence in support of those recommendations. Further, the perioperative management of patients on DAPT for various indications will also be reviewed.

Antiplatelet Agents Currently, five antiplatelet agents are available for combined use in DAPT regimens (Table 1).6 Each has a unique pharmacologic profile including half-life and metabolic pathway that dictate their use in clinical practice.

Aspirin Aspirin or acetylsalicylic acid is an irreversible cyclooxygenase 1 (COX-1) inhibitor that was first developed as an analgesic in 1852. Several years later, aspirin’s antiplatelet effect was identified as a result of decreased prostaglandin H2 and thromboxane A2 production which inhibits platelet aggregation. Due to its irreversible binding, antiplatelet effect of aspirin persists for the life span of the platelets (7-10 days). However, the continuous generation of new platelets allows for a platelet recovery of around 10-15% per day starting right after the drug is discontinued. This response has been reported to be exaggerated as part of the rebound hyperactivity phenomenon predisposing patients to a higher risk of thrombotic events making this a key consideration in pre-operative settings.7 Further, one third of patients taking aspirin are

4 considered to be non-responders.8 Both of these variable patient responses were crucial the development of stronger and more predictable antiplatelet agents.

Clopidogrel Clopidogrel is a thienopyridine pro-drug that irreversibly binds to the P2Y12 receptor on the platelet membrane blocking its effect. Normally, this receptor responds to the binding of extracellular nucleotides like ADP and in turn induces platelet activation and aggregation. As a pro-drug, 85% of the intestinally absorbed clopidogrel is hydrolyzed into an inactive metabolite. The remainder is metabolized to its active form by the liver cytochrome P450 system (CYP450). This necessary conversion step makes the response to clopidogrel variable with over 30% nonresponders due to either other drug-drug interaction at the level of CYP450 or to a genetic polymorphism of the hepatic enzyme complex i.e., cytochrome P450 2C19.9 As with aspirin, previous studies have also reported a potential rebound effect from clopidogrel discontinuation, however a RCT did not find support for this phenomenon.10 In the clinical setting, there are a number of landmark trials that have solidified clopidogrel’s use both alone and in conjunction with other antiplatelet therapy for cardiovascular events. The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial showed a modest superiority of clopidogrel over aspirin with an annual 8.7% relative risk reduction in the combined outcome of ischemic stroke, myocardial infarction, or vascular death in patients with previous cardiovascular events (stroke, myocardial infarction or symptomatic peripheral arterial disease).11 On the other hand, the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial showed that the addition of clopidogrel to aspirin in patients after an ACS, including unstable angina (UA) or non-ST elevation myocardial infarction (NSTEMI), resulted in a

5 reduction in the composite primary endpoint of cardiovascular mortality, nonfatal myocardial infarction, and stroke, largely due to fewer myocardial infarctions.12 Similar outcomes were seen in the PCI-CURE and the CREDO (Clopidogrel for the Reduction of Events During Observation) trials among patients who were receiving clopidogrel plus aspirin after elective PCI with stent placement.1, 13 Further, this DAPT regimen was associated with a reduction in the composite endpoint of an occluded infarct-related artery on angiography, recurrent myocardial infarction before angiography in patients, or death in patients with ST-elevation myocardial infarction (STEMI) treated with thrombolytic therapy.14 However, for SIHD, DAPT with clopidogrel did not outperform aspirin alone for the prevention of atherothrombotic events in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance) trial.15 This growing evidence has pushed clopidogrel into the forefront of antiplatelet therapy.

Prasugrel Prasugrel is another thienopyridine pro-drug that, like clopidogrel, irreversibly binds to the P2Y12 receptor. However, unlike clopidogrel it undergoes a more efficient conversion to its active form via CYP3A4 and CYP2B6 liver enzymes. Due to this alternate metabolic pathway, prasugrel evades common CYP450 polymorphism effects and possible drug-drug interactions. Compared to clopidogrel, the degree of platelet aggregation inhibition is greater in patients on prasugrel with a lower portion of non-responders.16 In the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel– Thrombolysis in Myocardial Infarction 38) trial, DAPT with aspirin and prasugrel was superior to aspirin and clopidogrel with regards to ischemic complications including stent thrombosis in patients with ACS undergoing elective PCI. However, the prasugrel combination was associated

6 with a higher rate of fatal bleeding.17 The TRILOGY-ACS trial, a similar study conducted in high-risk patients with ACS who were medically managed without revascularization revealed no differences between those treated with prasugrel and aspirin versus clopidogrel and aspirin with regards to composite endpoints including death.18

Ticagrelor Ticagrelor is an oral, reversible, direct-acting P2Y12 inhibitor that does not require conversion to an active form giving rise to its rapid onset of action.19 This novel antiplatelet agent was first brought to clinical attention after the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) trial. Patients with history of myocardial infarction 1-2 years prior were randomized to aspirin alone versus DAPT with aspirin and ticagrelor. The DAPT arm had a reduced composite outcome of cardiovascular death, myocardial infarction, or stroke with an increased rate of major bleeding events.20

Compared to clopidogrel, the PLATO (Platelet inhibition and Patient Outcomes) trial showed that DAPT with ticagrelor and aspirin was superior to clopidogrel and aspirin with regards to a decreased combined outcome of death from vascular causes, myocardial infarction, or stroke, without an increase in major bleeding.21 However, there was a significant interaction between geographic region and treatment effect. Clopidogrel was associated with a nonsignificant trend of better outcome in North America, whereas ticagrelor was associated with better outcome in the other regions combined. Statistical review suggested this could possibly be explained by use of higher dose aspirin in the United States.22

7

Cangrelor First approved by the FDA in June 2015, Cangrelor is the only available intravenous P2Y12 inhibitor. Due to its short half-life of 3-6 minutes, 90% of platelets are inhibited at the time of drug initiation and platelet function is completely restored 60 minutes after drug cessation. These pharmacokinetic properties make cangrelor an appealing option for bridging therapy in high-risk surgical patients in whom discontinuation of antiplatelet therapy is associated can precipitate life threatening thrombosis. The BRIDGE trial confirmed the safety of cangrelor infusion in patients with ACS or with stent that were planned for coronary artery bypass grafting (CABG) surgery in the next 48 hours. No significant difference in bleeding was found between the cangrelor and placebo groups however, the cangrelor group had a lower level of platelet inhibition.23

Cardiac Indications for DAPT Patients presenting with ACS are typically risk stratified to receive either PCI with or without stent placement or medical treatment alone. Extensive literature has been published in support of DAPT in both of these settings. However, it is the advances in coronary artery stent technology that have pushed the boundaries of DAPT and redefined treatment duration.

Role of Angioplasty in the Evolution of DAPT Historically, the first coronary balloon angioplasty was performed by Gruntzig and Myler in May 1977 as part of a coronary artery bypass surgery.24 However, the success of angioplasty was limited by the increased rates of acute artery closure from elastic recoil and late vascular remodeling. Thus, the development of coronary stents began shortly thereafter with the first

8 implantation in 1986.25 Since then, major refinements in stent design led to the implantation of the first drug-eluting stent (DES) in 1999 and its subsequent approval for use by the FDA in 2002.25 Despite this effort to delay stent endothelialization, safety reports of increasing stent thrombosis emerged along with a markedly high risk of mortality (up to 45%).26 This was combated with the adjunctive use of various anticoagulation and antiplatelet therapies in attempts to prevent stent thrombosis.

Alongside the birth of DAPT, DES technology advanced from first to second generation stents with the incorporation of new antiproliferative drugs. This led to a decreased risk of death, myocardial infarction, stent thrombosis and target lesion revascularization. The duration of DAPT is dictated by the type of stent deployed; 12 months for DES and 1 month for Bare Metal Stents (BMS) 2. With stent advancements, the duration of DAPT therapy may be safely shortened as the risk of thrombotic outcomes declines.25, 27.Further studies are being conducted to explore the appropriate shortened duration of DAPT. In March 2016, the ACC/AHA published a focused update of the previous DAPT recommendations in patients with SIHD and ACS.2 Most revisions pertained to both the selection of antiplatelet agents and the duration of DAPT as prior guidelines set recommendations based on the previous use of first generation DES compared to the newer generation DES now used.28-31 In regards to the duration of DAPT, the updated guidelines introduced the concept of evaluating a patient’s ischemic and bleeding risk when deciding on the termination of DAPT (Table 2). 2, 32

9 Choosing the Most Appropriate P2Y12 Inhibitor and its Dosage Successful DAPT with aspirin and clopidogrel, as evidenced by several large RCTs, entirely changed our management of ACS and percutaneous revascularization.1, 12-14 Newer P2Y12 inhibitors with more favorable pharmacokinetics, as discussed previously, were developed and proven superior. As a result, the 2016 ACC/AHA guidelines recommended preferential use of ticagrelor 90 mg twice daily over clopidogrel 75 mg once daily, for maintenance P2Y12 therapy, in patients with ACS treated with coronary stent implantation and consider it reasonable in patients with ACS treated with medical therapy alone (Class IIa, Level of Evidence (LOE) B).2 In patients with ACS who do not have a high bleeding or stroke/transient ischemic attack risk, prasugrel was recommended as a reasonable alternative to clopidogrel (Class IIa, LOE B). The guidelines strongly discourage the use of prasugrel in patients with prior history of stroke or transient ischemic attack because of its association with higher rates of bleeding rate as seen in the TRITON-TIMI 38 (Class III, LOE B).17 Determining the Optimal Duration of DAPT Despite years of clinical experience, the optimal duration of DAPT remains largely debatable. Previous DAPT guidelines have become outdated as newer generation DES have come into the market. The updated 2016 ACC/AHA guidelines reflect the fine balance that exists between the possibility of thromboembolic cardiovascular events and the increased risk of bleeding when making decisions regarding continuation or termination of DAPT (Table 2). There are several new RCTs that have emerged assessing the efficacy of shorter (3-6 months) and longer (18-48 months) duration of DAPT as compared with the more commonly prescribed 12-month time frame (Table 3).33-45

10 Several meta-analyses have attempted to summarize this evidence. Giustino et al 46 in in their analysis of 10 randomized trials showed that short term DAPT is associated with less clinically significant bleeding, all-cause mortality and a higher incidence of stent thrombosis. Villabalanca et al 5 reported no significant difference in cardiovascular and non-cardiovascular mortality, as well as stroke and target vessel revascularization between patients receiving <6 months or >12 months of DAPT. The relationship between increased bleeding with longer duration DAPT and mortality was studied in detail by a recent aggregate based meta-analysis of 12 RCTs. Palmerini et al 47 reported that patients with bleeding had significantly higher rates of all-cause mortality as compared to patients without bleeding. Bleeding itself was found to be an independent predictor of mortality. They also showed that in the intention-to-treat analysis, shorter DAPT was associated with significantly lower rates of bleeding-related deaths compared with longer DAPT, whereas no significant difference was apparent between the strategies in non-bleeding-related deaths.47

DAPT Duration in Patients with SIHD Treated with PCI The 2016 ACC/AHA guidelines strongly recommend a minimum duration of 1 month of DAPT for patients with SIHD following bare-metal stent (BMS) implantation (Class I, LOE A), and a minimum of 6 months of DAPT for patients with DES (Class I, LOE B).2 It may be reasonable to continue DAPT for a longer time as long as the patient is not at high risk of bleeding (Class IIb, LOE A).2

11 In contrast, the 2011 ACC/AHA guidelines for DAPT in a similar group of patients recommended a minimum duration of 1 month and an ideal duration of 12 months of clopidogrel and aspirin following BMS implantation, unless the patient was at high risk of bleeding complications in which case DAPT was recommended for at least 2 weeks (Class I, LOE B).28 On the other hand, following DES implantation, clopidogrel was recommended for a minimum duration of 12 months in patients without high risk of bleeding (Class I, LOE B). Early discontinuation of DAPT was considered reasonable if the risk of morbidity from bleeding outweighed the anticipated benefit of the added P2Y12 inhibitor (Class IIa, LOE C). A prolonged course of DAPT was reserved as a possible approach for patients undergoing DES placement (Class IIb, LOE C).

DAPT Duration in Patients with ACS Treated with PCI ACS are distinct in their pathophysiology when compared with SIHD. The 2016 ACC/AHA guidelines group both NSTEMI and STEMI under ACS. These guidelines strongly recommend DAPT for at least 12 months after either BMS or DES placement in ACS (Class I, LOE B).2 Furthermore, ticagrelor or prasugrel are the preferred choices over clopidogrel as maintenance P2Y12. Continuation of P2Y12 inhibitor therapy for longer than 12 months may be reasonable in patients who tolerate at least 12 months of DAPT and are not at high risk of bleeding (Class IIb, LOE A). However, for patients at high risk of bleeding or who actually develop overt bleeding, P2Y12 inhibitor may be discontinued after a minimum of 6 months (Class IIb, LOE C).

12 The 2013 ACC/AHA guidelines for management of STEMI 29 and the 2014 ACC/AHA guidelines for management of NSTEMI,48 made similar recommendations for a minimum duration of 12 months of DAPT following either BMS or DES implantation (Class I, LOE B). They also similarly recommended longer than 12 months duration of DAPT in patients who tolerate at least 12 months of DAPT, but the level of evidence is at most C (Class IIb). While the 2014 guidelines for management of NSTEMI 48 considered it reasonable to terminate DAPT earlier than 12 months in patients with high risk of bleeding (Class IIa, LOE C), the 2013 guidelines for management of STEMI made no recommendations in this regard.29

Overall, the 2016 ACC/AHA focused update on duration of DAPT makes stronger recommendations with better quality of evidence to support specific durations of DAPT after PCI in both SIHD and ACS settings (Table 4).

DAPT Duration in Patients with ACS Treated with Medical Therapy Alone For patients with ACS managed with medical therapy only (without revascularization or fibrinolytic therapy), the 2016 ACC/AHA focused update notes that P2Y12 inhibitor therapy (clopidogrel or ticagrelor) should be continued for at least 12 months (Class I, LOE B).2 In patients with NSTEMI who are managed with medical therapy alone and treated with DAPT, it is reasonable to use ticagrelor in preference to clopidogrel for maintenance P2Y12 inhibitor therapy (Class IIa, Level of evidence B). In patients with ACS treated with medical therapy alone who have tolerated DAPT without bleeding complication and who are not at high bleeding risk, DAPT continuation for longer than 12 months may be reasonable (Class IIb, LOE A).

13 Recommendations for Duration of DAPT in Patients Undergoing CABG The new 2016 ACC/AHA guidelines make specific recommendations for duration of DAPT in patients undergoing CABG in different scenarios.2 For patients with coronary stent implantation, post-CABG completion of DAPT for the entire original recommended duration based on the clinical indication for stent implantation and type of stent used, is strongly recommended (Class I, LOE C). Specifically, for patients with ACS being treated with DAPT and undergoing CABG, post-CABG DAPT is strongly recommended for a total duration of 12 months (Class I, LOE C). Even for patients with SIHD undergoing CABG, 12 months of DAPT may be reasonable to improve vein graft patency (Class IIb, LOE B).

Interruption of DAPT Despite guideline recommendations, in the real world up to 14% of patients discontinue DAPT earlier than expected mostly because of bleeding and surgical procedures.49 Other reasons to discontinue DAPT include the concomitant use of anticoagulants and the lack of instruction around medication use.49 However, only 2.4% of patients, largely immigrants and those with psychiatric illness, were found to have stopped DAPT without physician’s advice.49 At the bedside, the decision to discontinue DAPT is based on an individual patient’s cumulative risk profile for ischemic and bleeding events (Table 2).2, 32

Predictive Models - Implications for Perioperative Management

The question of DAPT continuation has become essential in planning the timing of non-elective surgical procedures for patients following a PCI. In attempts to stratify patients to DAPT continuation for more than 1 year after PCI, a novel scoring system was created to determine if

14 the ischemic benefit of continuing DAPT outweighed the potential bleeding risk. The DAPT score was derived from a study of 11,648 patients who received either a DES or BMS and were randomized to either 12 or 30 months of DAPT with a thienopyridine and aspirin. Of the 37 variables identified, those listed in Table 5 were identified to be most strongly associated with a significant benefit-risk difference and were allotted points accordingly on a scale of -2 to 10. The total score was further dichotomized at 2 points. Those patients with predictive scores of ≥ 2 had smaller increases in bleeding with the absolute risk reduction of myocardial infarction was 8.2 times greater than the absolute risk increase of moderate or severe bleeding. Conversely, those with score < 2 had an absolute risk increase in moderate or severe bleeding that was 2.4 times greater than the absolute risk reduction in myocardial infarction. This study did not include patients taking other anti-platelet combinations such as aspirin with other thienopyridine prodrugs (prasugrel or clopidogrel) or direct P2Y12 inhibitors (ticagrelor or cangrelor) for which a different risk -benefit profile may exist. Other peri-operative risk factors that could contribute to bleeding such as preexisting anemia, prior bleeding, and measures of the extent of atherosclerosis where also excluded making it difficult to generalize the score to all patient populations. Further external validation studies are required to support use of the score in guiding PCI specific bleeding risk evaluation in the pre-procedural period. 50

Several other bleeding risk scores have also been validated in patients with atrial fibrillation and have been proposed for the use of quantifying bleeding risk for patients on DAPT following PCI. The utility of the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score, independent of atrial fibrillation, has also been explored for its role in decision making for DAPT

15 continuation past the one-year mark.51 One retrospective study found that higher bleeding after 12 months of DAPT was associated with a HAS-BLED score of > 2.51 However, prospective follow up studies are required for further validation. The study did find that patients with other modifiable factors such as renal dysfunction and alcohol use also had a higher incidence of bleed. Optimization of these other factors identified by the HAS-BLED score may improve operative outcomes. Other studies have supported the calculation of a HAS-BLED score prior to or at the time of DES placement.52 Unfortunately, due to the acuity of ACS treatment this is not always feasible. Continued exploration of the performance of existing bleeding risk scores in populations on DAPT is vital to assess surgical risk in this specific sub-population.

DAPT Duration Following PCI for Those Patients Needing Elective Non-cardiac Surgery

The guidelines for DAPT continuation peri-operatively are focused around the high risk of stent thrombosis in the 4-6 weeks after PCI.53 Some studies have proposed that the risk of stent thrombosis stabilizes at the 6-month mark following percutaneous coronary intervention.53 Nonetheless, elective surgery should be delayed for at least 30 days for patients with BMS placement and optimally 6 months for those with DES placement (Class I, LOE B).2 For more urgent procedures taking place in the 3-6 months of DES placement, DAPT can be discontinued and surgery can take place if the risk of delayed surgery outweighs the risk of stent thrombosis (Class IIb, LOE C).2 Once beyond the recommended waiting period, aspirin can be continued perioperatively while P2Y12 inhibitors are to be discontinued if warranted by the type of surgery and restarted as soon as possible after surgery (Class I, LOE C).2

16 The previous 2014 ACC/AHA guidelines on perioperative management had longer waiting restrictions prior to surgery with a recommended 12-month waiting period after DES placement (Class I, LOE B). However, this could be shortened to 6-months if surgery could not be delayed (Class IIb, LOE B). The 2014 and 2016 guidelines are largely in agreement on DAPT continuation perioperatively.31

Bleeding rates for the different P2Y12 inhibitors have been variably reported, but overall the risk of major bleeding in non-cardiac surgery is estimated to be at 21% for patients on DAPT and 4% in patients on a single antiplatelet agent.54

DAPT Duration Following PCI for Those Patients Needing Urgent or Emergent Noncardiac Surgery

Occasionally, emergent surgeries cannot be postponed until completion of the recommend DAPT course. An interdisciplinary approach to the benefits and potential harms of surgery needs to be discussed and implemented for each individual patient. It has been proposed that in these cases the approach to DAPT varies based on the risk of bleeding inherent to the type of surgery (Table 6). For low bleeding risk procedures DAPT can be continued. In contrast for intermediate to high risk procedures, DAPT discontinuation is largely inevitable and bridging therapy should be considered when appropriate. If possible, aspirin continuation is encouraged. However, there may not be enough time to stop DAPT therapy prior to surgery and the role for adjunctive platelet transfusion needs to be addressed on a case by case basis.6

17 DAPT Duration Following PCI for Those Patients Needing Elective Cardiac Surgery

For patients in need of CABG post-PCI, it is recommended that prasugrel be held 7 days prior to CABG whereas clopidogrel and ticagrelor are discontinued 5 days before. Parasugrel significantly increases the risk of major bleeding in patients undergoing CABG, ≥75 years of age, < 60kg body weight compared to those on clopidogrel.55

Future Implications

As the ideal DAPT duration continues to be debated, attention needs to be turned to subgroups of patients in whom longer or shorter DAPT duration is preferred. High risk patient populations such as those with complex or less than optimal PCI, or those with longer coronary lesions may achieve a greater benefit from longer DAPT therapy. The EXCELLENT trial (Table 3) has further identified that diabetic patients may benefit from prolonged DAPT given their increased proinflammatory and prothrombotic state.33 Likewise, those with advanced age or chronic kidney disease may also be focused populations that could benefit from a non-standardized DAPT duration. Individualized DAPT durations may be the future treatment approach.

Nearly all studies favoring shorter DAPT use clopidogrel as the P2Y12 inhibitor of choice (Table 3). However, given the proven superiority of prasugrel and ticagrelor in ACS, further studies using more potent P2Y12 inhibitors are required to assess the generalizability of bleeding risks. There are currently two ongoing studies that incorporate the use of ticagrelor into DAPT regimens (GLOBAL LEADERS and TWILIGHT trials). The GLOBAL LEADERS superiority trial randomizes patients to either DAPT with ticagrelor plus aspirin for 1 month followed by ticagrelor monotherapy for 23 months, or 12 months of standard DAPT with clopidogrel plus

18 aspirin for patients with SIHD, or ticagrelor plus aspirin for patients with ACS followed by aspirin monotherapy for the remainder of the 2-years post PCI. With recruitment completed and over 16,000 patients enrolled, results from the GLOBAL LEADERS trial are excepted in December 2017. The TWILIGHT trial aims to compare monotherapy with ticagrelor to DAPT with ticagrelor plus aspirin after both groups receive full DAPT for the initial 3-months post PCI. Patient recruitment is now underway. Further research on the use of monotherapy antiplatelet agents is also ongoing through the STOPDAPT-2 trial. Patients are being randomized to either 1-month of DAPT (aspirin plus P2Y12-receptor inhibitor), followed by 59 months of clopidogrel or 1-month of DAPT (aspirin plus P2Y12-receptor inhibitor), followed by 11-months aspirin plus clopidogrel, followed by 48 months aspirin. Expected study completion date is 2023. These studies aim to challenge our current use of DAPT and may provide evidence for antiplatelet monotherapy in both ACS and SIHD.

Conclusions

Optimal duration of DAPT should be individualized to each patient weighing the bleeding versus thrombotic risk in both surgical and non-surgical settings. Current evidence supports shorter duration DAPT ≤ 6-months in SIHD. However, futures RCTs are required to define the best strategy for ACS. Perioperative management of DAPT will continue to evolve as these recommendations are challenged.

19 References 1.

Steinhubl SR, Berger PB, Mann JT, 3rd, et al. Early and sustained dual oral

antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411-2420. 2.

Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on

duration of dual antiplatelet therapy in patients with coronary artery disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. The Journal of thoracic and cardiovascular surgery. 2016;152(5):12431275. 3.

Pfisterer M, Brunner-La Rocca HP, Buser PT, et al. Late clinical events after

clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. Journal of the American College of Cardiology. 2006;48(12):2584-2591. 4.

Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet

therapy after drug-eluting stents. N Engl J Med. 2014;371(23):2155-2166. 5.

Villablanca PA, Massera D, Mathew V, et al. Outcomes of
month dual antiplatelet therapy after drug-eluting stent implantation: A meta-analysis and meta-regression. Medicine (Baltimore). 2016;95(52):e5819. 6.

Song JW, Soh S, Shim JK. Dual antiplatelet therapy and non-cardiac surgery: evolving

issues and anesthetic implications. Korean journal of anesthesiology. 2017;70(1):13-21. 7.

Beving H, Eksborg S, Malmgren RS, et al. Inter-individual variations of the effect of

low dose aspirin regime on platelet cyclooxygenase activity. Thromb Res. 1994;74(1):3951.

20 8.

Antithrombotic Trialists C. Collaborative meta-analysis of randomised trials of

antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86. 9.

Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response

to clopidogrel. N Engl J Med. 2009;360(4):354-362. 10.

Ford I, Scott NW, Herd V, et al. A randomized controlled trial of platelet activity

before and after cessation of clopidogrel therapy in patients with stable cardiovascular disease. Journal of the American College of Cardiology. 2014;63(3):233-239. 11.

Committee CS. A randomised, blinded, trial of clopidogrel versus aspirin in patients

at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348(9038):1329-1339. 12.

Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in

patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502. 13.

Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and

aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358(9281):527-533. 14.

Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and

fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352(12):1179-1189. 15.

Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the

prevention of atherothrombotic events. N Engl J Med. 2006;354(16):1706-1717.

21 16.

Jernberg T, Payne CD, Winters KJ, et al. Prasugrel achieves greater inhibition of

platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J. 2006;27(10):1166-1173. 17.

Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients

with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015. 18.

Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel for acute

coronary syndromes without revascularization. N Engl J Med. 2012;367(14):1297-1309. 19.

Husted S, Emanuelsson H, Heptinstall S, et al. Pharmacodynamics, pharmacokinetics,

and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27(9):1038-1047. 20.

Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with

prior myocardial infarction. N Engl J Med. 2015;372(19):1791-1800. 21.

Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with

acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057. 22.

Mahaffey KW, Wojdyla DM, Carroll K, et al. Ticagrelor compared with clopidogrel by

geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2011;124(5):544-554. 23.

Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging antiplatelet therapy with

cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA. 2012;307(3):265-274.

22 24.

Iqbal J, Gunn J, Serruys PW. Coronary stents: historical development, current status

and future directions. British medical bulletin. 2013;106:193-211. 25.

Bennett J, Dubois C. Percutaneous coronary intervention, a historical perspective

looking to the future. Journal of thoracic disease. 2013;5(3):367-370. 26.

Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of

thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293(17):21262130. 27.

Tada T, Byrne RA, Simunovic I, et al. Risk of stent thrombosis among bare-metal

stents, first-generation drug-eluting stents, and second-generation drug-eluting stents: results from a registry of 18,334 patients. JACC Cardiovasc Interv. 2013;6(12):1267-1274. 28.

Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for

Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124(23):e574-651. 29.

O'Gara PT, Kushner FG, Ascheim DD, 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. Circulation. 2013;127(4):e362-425. 30.

Amsterdam EA, Wenger NK, Brindis RG, 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. Circulation. 2014;130(25):e344-426.

23 31.

Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on

perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(24):e278-333. 32.

Manoukian SV. Predictors and impact of bleeding complications in percutaneous

coronary intervention, acute coronary syndromes, and ST-segment elevation myocardial infarction. The American journal of cardiology. 2009;104(5 Suppl):9c-15c. 33.

Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet

therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation. 2012;125(3):505-513. 34.

Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-

antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation. 2012;125(16):2015-2026. 35.

Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet

therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA. 2013;310(23):2510-2522. 36.

Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after

drug-eluting stent implantation: a randomized, controlled trial. Circulation. 2014;129(3):304-312. 37.

Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 Months of Dual Antiplatelet

Therapy after Drug-Eluting Stents. New England Journal of Medicine. 2014;371(23):21552166.

24 38.

Collet J-P, Silvain J, Barthélémy O, et al. Dual-antiplatelet treatment beyond 1 year

after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. The Lancet.384(9954):1577-1585. 39.

Helft G, Steg PG, Le Feuvre C, et al. Stopping or continuing clopidogrel 12 months

after drug-eluting stent placement: the OPTIDUAL randomized trial. European Heart Journal. 2016;37(4):365-374. 40.

Colombo A, Chieffo A, Frasheri A, et al. Second-generation drug-eluting stent

implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. Journal of the American College of Cardiology. 2014;64(20):20862097. 41.

Gilard M, Barragan P, Noryani AA, et al. 6- versus 24-month dual antiplatelet therapy

after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial. Journal of the American College of Cardiology. 2015;65(8):777-786. 42.

Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual

antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). Journal of the American College of Cardiology. 2012;60(15):1340-1348. 43.

Schulz-Schupke S, Byrne RA, Ten Berg JM, et al. ISAR-SAFE: a randomized, double-

blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J. 2015;36(20):1252-1263.

25 44.

Hong SJ, Shin DH, Kim JS, et al. 6-Month Versus 12-Month Dual-Antiplatelet Therapy

Following Long Everolimus-Eluting Stent Implantation: The IVUS-XPL Randomized Clinical Trial. JACC Cardiovasc Interv. 2016;9(14):1438-1446. 45.

Han Y, Xu B, Xu K, et al. Six Versus 12 Months of Dual Antiplatelet Therapy After

Implantation of Biodegradable Polymer Sirolimus-Eluting Stent: Randomized Substudy of the I-LOVE-IT 2 Trial. Circulation Cardiovascular interventions. 2016;9(2):e003145. 46.

Giustino G, Baber U, Sartori S, et al. Duration of dual antiplatelet therapy after drug-

eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials. Journal of the American College of Cardiology. 2015;65(13):1298-1310. 47.

Palmerini T, Bacchi Reggiani L, Della Riva D, et al. Bleeding-Related Deaths in

Relation to the Duration of Dual-Antiplatelet Therapy After Coronary Stenting. Journal of the American College of Cardiology. 2017;69(16):2011-2022. 48.

Amsterdam EA, Wenger NK, Brindis RG, 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 the American College of Cardiology. 2014;64(24):e139-228. 49.

Ferreira-Gonzalez I, Marsal JR, Ribera A, et al. Background, incidence, and predictors

of antiplatelet therapy discontinuation during the first year after drug-eluting stent implantation. Circulation. 2010;122(10):1017-1025. 50.

Yeh RW, Secemsky EA, Kereiakes DJ, et al. Development and Validation of a

Prediction Rule for Benefit and Harm of Dual Antiplatelet Therapy Beyond 1 Year After Percutaneous Coronary Intervention. Jama. 2016;315(16):1735-1749.

26 51.

Shah RR, Pillai A, Omar A, et al. Utility of the HAS-BLED Score in Risk Stratifying

Patients on Dual Antiplatelet Therapy Post 12 Months After Drug-Eluting Stent Placement. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 2016. 52.

Konishi H, Miyauchi K, Tsuboi S, et al. Impact of the HAS-BLED Score on Long-Term

Outcomes After Percutaneous Coronary Intervention. The American journal of cardiology. 2015;116(4):527-531. 53.

Wijeysundera DN, Wijeysundera HC, Yun L, et al. Risk of elective major noncardiac

surgery after coronary stent insertion: a population-based study. Circulation. 2012;126(11):1355-1362. 54.

van Kuijk JP, Flu WJ, Schouten O, et al. Timing of noncardiac surgery after coronary

artery stenting with bare metal or drug-eluting stents. The American journal of cardiology. 2009;104(9):1229-1234. 55.

Briasoulis A, Telila T, Palla M, et al. P2Y12 Receptor Antagonists: Which One to

Choose? A Systematic Review and Meta-Analysis. Current pharmaceutical design. 2016;22(29):4568-4576.

27 Table Legends

Table 1. Antiplatelet Agents

Table 2. Procedural and patient factors associated with an increased bleeding and ischemic risk

Table 3. RCTs of short versus long DAPT duration after drug-eluting stent placement

Table 4. Summary of 2016 Guidelines on Dual Antiplatelet Therapy after PCI

Table 5. DAPT score calculation

Table 6. Bleeding risk based on type of surgery

Table 1. Antiplatelet Agents Antiplatelet Agents

Aspirin

Clopidogrel

Prasugrel

Ticagrelor

Class

NSAID

Mechanism of Action

Irreversible COX-1 inhibitor Oral/rectal 160-325 mg

Second generation thienopyridine (Prodrug) Irreversible P2Y12 inhibitor Oral 300-600 mg

Third generation thienopyridine (Prodrug) Irreversible P2Y12 inhibitor Oral 60 mg

Cytopentyltriazolopyrimidine Reversible P2Y12 inhibitor Oral 180 mg

75 mg QD

10 mg QD

90 mg BID

CYP2C19

CYP3A4, CYP2B6

CYP3A4/5

0.5 hrs

7 hrs (range 2-15 hr)

9 hrs (range 6.79.1 hrs)

Formulation Loading Dose Maintenance Dose Metabolism

Half Life

80 or 81 mg QD Hepative microsomal enzyme system Low dose: 3-5 hrs High dose: 15-30 hrs

Cangrelor

Reversible P2Y12 inhibitor Intravenous 30 mcg/kg over 1 min 4 mcg/kg/min Hepatic independentcirculatory dephosphorylation 3-6 min

28

Table 2. Procedural and Patient Factors Associated with an Increased Bleeding and Ischemic Risk Factors Increasing Bleeding Risk

Factors Increasing Ischemic Risk

Procedural Characteristics Placement in the setting of STEMI Use of parasugrel (in patients undergoing CABG, ≥75 years of age, < 60 kg body weight)

Procedural Characteristics First generation DES Smaller diameter stents

Patient Characteristics Advanced age Female sex Low body weight Hypertension Diabetes mellitus Chronic kidney disease Anemia Prior bleeding episode Use of anticoagulants/NSAIDS/chronic steroids

Patient Characteristics Advanced age Coronary artery disease Prior myocardial infarction Diabetes mellitus Chronic kidney disease Left ventricular ejection fraction < 40%

Longer length stents Undersized stents Under-deployed stents Bifurcation stents Double stent placement in bifurcation lesions Placement in the setting of ACS Use of clopidogrel

29

Table 3. RCTs of Short versus Long DAPT Duration after Drug-eluting Stent Placement Study, year (location)

DAPT Duration Comparison

Primary Endpoint

RESET, 2012 (Korea)

3 vs. 12 mo

OPTIMIZE, 2013 (Brazil) EXCELLENT, 2012 (Korea) ISAR – SAFE, 2015 (International) SECURITY, 2016 (International) I-LOVE-IT 2 (China)

3 vs. 12 mo

6 vs. 12 mo

Cardiac death, MI, ST, revascularization, or bleeding NACCE-death, MI, stroke, or bleed Cardiac death, MI or ischemia driven TVR Death, MI, stroke, or TIMI major bleeding Cardiac death, MI, ST, or stroke Cardiac death, MI, TVR

PRODIGY, 2012 (Italy) ITALIC, 2015 (Europe & Middle East) IVUS-XPL (Korea)

6 vs. 24 mo

Death, MI or stroke

6 vs. 24 mo

100

P < 0.00002 for non-inferiority

100

p = 0.854

ARCTIC, 2014 (France) DAPT, 2015 (International) DES-LATE, 2010 (Korea) OPTIDUAL, 2015 (France)

12 vs. 18 mo

Death, MI, urgent TVR, stroke or major bleeding Cardiac death, MI, stroke, or TIMI major bleeding Death, MI, ST, stroke, or urgent TVR ST and MACCE

63

p = 0.58

59

p = 0.001

Cardiac death, MI or stroke < 24 hrs Death, MI, CVA, or major bleeding

30

p = 0.75

59

p = 0.17

6 vs. 12 mo 6 vs. 12 mo 6 vs. 12 mo

6 vs. 24 mo

12 vs. 30 mo 12 vs. 36 mo 12 vs. 48 mo

Patients with new generation DES [%] 85

Conclusion

P < 0.001 for non-inferiority

100

P = 0.002 for non-inferiority 75 P = 0.001 for non-inferiority 72 P < 0.001 for non-inferiority 100 P < 0.05 for non-inferiority 100 P = 0.0065 for (Biodegradable non-inferiority Stent) 67 P = 0.91

CVA = cerebral vascular accident MACCE = major adverse cardiac and cerebrovascular events MI = myocardial infarction NACCE = net adverse cardiac and cerebrovascular events ST = stent thrombosis TIMI = thrombolysis in myocardial infarction TVR = target vessel revascularization

30 Table 4. Summary of 2016 Guidelines on Dual Antiplatelet Therapy after PCI SIHD

BMS

1 month with clopidogrel (Class I, LOA) >1 month might be reasonable, if not at high risk of bleeding (Class IIB, LOA)

SIHD

DES

6 months with clopidogrel (Class I, LOB) >6 months might be reasonable, if not at high risk of bleeding (Class IIB, LOA) 3 months with P2Y12 inhibitor then additional 3 months of aspirin, if high risk of bleeding or overt bleed (Class IIB, LOEC)

ACS

BMS & DES

12 months with ticagrelor or prasugrel (Class I, LOB) > 12 months might be reasonable, if not at high risk of bleeding (Class IIB, LOA) 6 months with P2Y12 inhibitor then additional 6 months of aspirin, if high risk of bleeding or overt bleed (Class IIB, LOEC)

SIHD = stable ischemic heart disease ACS = STEMI and NSTEMI

Table 5. DAPT Score Calculation Variable Age (Years) ≥75 65-<75 <65

Points

Current Cigarette Smoker

1

Diabetes Mellitus

1

MI at Presentation

1

Prior PCI or Prior MI

1

Paclitaxel – eluting stent

1

Stent Diameter < 3mm

1

CHG or LVEF < 30%

2

Vein Graft PCI

2

Total Score Range:

-2 to 10

-2 -1 0

31

Table 6. Bleeding Risk Based on Type of Surgery Surgical Bleeding Risk

Type of Surgery

Low

Breast biopsy Endoscopy Cataract surgery Dental extraction and surgery

Intermediate

Intrathoracic and intraperitoneal surgery Carotid endarterectomy Orthopaedic surgery Urological surgery

High

Intracranial or spinal surgery Major cardiac or vascular surgery