|Year : 2018 | Volume
| Issue : 1 | Page : 3-8
Dual antiplatelet therapy after percutaneous coronary intervention and stenting: Customize your approach
Gagandeep S Wander1, K Sarat Chandra2
1 Department of Cardiology, Medanta-The Medicity, Gurgaon, Haryana, India
2 Department of Cardiology, Virinchi Hospital, Indo-US Super Speciality Hospital, Hyderabad, Telangana, India
|Date of Web Publication||24-Aug-2018|
Dr. Gagandeep S Wander
Department of Cardiology, Medanta-The Medicity, Sector 38, Gurgaon, Haryana 122011
Source of Support: None, Conflict of Interest: None
Dual antiplatelet therapy (DAPT), defined as a combination of aspirin with one other oral antiplatelet agent (among clopidogrel, prasugrel, and ticagrelor), has become an essential component of pharmacological management of patients who have undergone a percutaneous coronary intervention (PCI). Over the last few years, a vast amount of information has become available about the appropriate indications, choice, and duration of DAPT following PCI in different patient subsets. This review summarizes these evidences and provides a practical guidance for the selection of appropriate DAPT in different clinical settings.
Keywords: Aspirin, clopidogrel, PLATO, prasugrel, PRECISE DAPT, stent thrombosis, ticagrelor, TRITON-TIMI
|How to cite this article:|
Wander GS, Chandra K S. Dual antiplatelet therapy after percutaneous coronary intervention and stenting: Customize your approach. Indian Heart J Interv 2018;1:3-8
|How to cite this URL:|
Wander GS, Chandra K S. Dual antiplatelet therapy after percutaneous coronary intervention and stenting: Customize your approach. Indian Heart J Interv [serial online] 2018 [cited 2018 Nov 12];1:3-8. Available from: http://www.ihji.org/text.asp?2018/1/1/3/239778
Dual antiplatelet therapy (DAPT) refers to the combination of cyclooxygenase-1 inhibitor, aspirin, and oral inhibitor of the platelet P2Y12 receptor for adenosine 5’-diphosphate. A gradual evolution of platelet P2Y12 receptor inhibitors from ticlopidine to safer clopidogrel and finally to more potent molecules of ticagrelor and prasugrel with predictable action has been observed.
Routine DAPT is not recommended in medical treatment of stable coronary artery disease (CAD) and remains a Class III recommendation, but DAPT has an integral role in the treatment of patients after percutaneous coronary intervention (PCI). In this review on the essential topic of DAPT after PCI, we intend to discuss the choice and duration of DAPT in the light of newer guidelines.
| Choice of DAPT Regimes Post-PCI: Newer Concept of Risk Stratification for Ischemia and Bleeding|| |
Use of risk scores helps in maximizing ischemia protection and decreasing bleeding. It helps in tailoring of treatment and individualizing treatment.
DAPT score: It is calculated at 12 months of uneventful DAPT and helps to decide if a patient will benefit with prolonged (>30 months) DAPT. The score varies from –2 to 10, and a patient with a score of ≥2 can be considered for prolonged DAPT for 30 months.
PRECISE-DAPT score: This score gives baseline bleeding risk and shall be calculated at the time of stenting. It is calculated from five variables (age, creatinine clearance, hemoglobin, white blood cell count, and prior spontaneous bleeding), and the score ranges from 0 to 100. Patients with a score ≥25 are deemed to be at high-bleeding risk and shall be considered for short-term DAPT.
The online calculators are available for these scores. The use of these scores may be considered as a guidance for duration of DAPT, and as per the current European Society of Cardiology (ESC) guidelines, it is Class IIb recommendation.
| DAPT after PCI for Stable CAD|| |
After PCI with stent placement in stable CAD, DAPT (with aspirin and clopidogrel, with prior loading doses) has an established role and is the standard of care. In patients treated with DAPT, the recommended daily dosing of aspirin is 81mg (range, 75–100mg). There is a lack of evidence of use of more potent P2Y12 inhibitors in this stable low-risk subset and is not recommended. There is a paradigm shift in the treatment with DAPT as ESC has based its 2017 guidelines on bleeding risk and not on stent type (bare metal stent [BMS] or drug-eluting stent [DES]), but 2016 American College of Cardiology/American Heart Association (ACC/AHA) guidelines differentiate on stent type.
Bare metal stent (BMS): The Intracoronary Stenting and Antithrombotic Regimen (ISAR) trial and two other trials, established treatment with 1 month of DAPT after BMS. As per the current 2016 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, at least 1-month treatment with DAPT is a Class I indication after BMS implantation in patients with stable CAD, and if there is no increased bleeding risk or significant overt bleed, DAPT >1 month may be reasonable (Class IIb). The ESC 2017 guidelines recommend DAPT for 6 months if low-bleeding risk (Class I) but DAPT > 6 months is class IIb recommendation. If bleeding risk is high (e.g., PRECISE-DAPT score ≥ 25), therapy may be shortened to 3 months (Class IIa) or 1 month (Class IIb).
Drug-eluting stent (DES): Newer generation DES has thinner struts, biodegradable polymers, and decreased antiproliferative drug doses, and it helps in better healing and lesser thrombotic events. This helps in shortening the duration of DAPT.
Many randomized controlled trials (RCTs) compared short-term (3–6 months) versus long-term (≥12 months) DAPT duration after DES. RCTs of 6-month duration of DAPT after DES implantation are EXCELLENT, PRODIGY, ITALIC, SECURITY, and ISAR-SAFE. RCTs of 3-month duration of DAPT are RESET and OPTIMISE. These studies reported similar ischemic outcomes but significantly reduced major bleeding rates with shorter (3 or 6 months) DAPT regimens compared with ≥12 months regimens after DES implantation.
Four RCTs (REAL-LATE/ZEST-LATE, ARCTIC-Interruption, DES-LATE, and OPTIDUAL) did not show any benefit in the reduction of ischemic events with DAPT prolongation beyond 12 months. The DAPT study randomly assigned patients to prolonged DAPT (30 months) or to placebo in addition to aspirin. Significantly reduced rates of stent thrombosis (0.4% vs. 1.4%; heart rate [HR], 0.29; P < 0.001), major adverse cardiovascular events (MACEs) (4.3% vs. 5.9%; HR, 0.71; P < 0.001), and myocardial infarction (MI) (2.1% vs. 4.1%; HR, 0.47; P < 0.001) were reported with 30-month DAPT regimen. At the same time, significantly increased risk of moderate or severe bleeding (2.5% vs. 1.6%; P = 0.001) and marginally increased risk of all-cause mortality (2.0% vs. 1.5%; HR, 1.36; P = 0.05) were observed.
As per the current 2016 ACC/AHA guidelines, DAPT shall be continued for at least 6 months after PCI with DES in patients with stable CAD (Class I). If no increased bleeding risk or overt bleed is observed, DAPT continuation beyond 6 months may be reasonable (Class IIb). If bleeding risk is high or significant overt bleeding occurs, it may be reasonable to discontinue DAPT after 3 months (Class IIb). The ESC 2017 guidelines recommend DAPT for 6 months after PCI in stable CAD (DES/BMS or drug coated balloon) if there is low-bleeding risk (Class I), and in this subset with low bleeding, DAPT > 6 months may be considered (Class IIb). If bleeding risk is high, therapy may be shortened to 3 months (Class IIa) or 1 month (Class IIb).
| DAPT after PCI for Acute Coronary Syndrome|| |
In patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) undergoing PCI in CURE study, DAPT with clopidogrel versus aspirin monotherapy was found to decrease composite end point of cardiovascular death and MI by 31%. Subsequently, DAPT with more potent prasugrel or ticagrelor has shown to further improve outcomes in patients with ACS. In TRITON-TIMI 38 trial, prasugrel was compared with clopidogrel in 13,608 patients with ACS and scheduled for PCI. Prasugrel versus clopidogrel as a part of DAPT for up to 15 months decreased primary end point (CV death, nonfatal MI, stroke) by 19%, MI by 24%, stent thrombosis by 54%, but significantly increased the risk of major bleeding including fatal bleeding. Overall mortality did not differ between the groups. On subgroup analysis, prasugrel was found to clinically harm the patients with age >75 years, body weight <60kg, or a previous history of stroke or transient ischemic attack (TIA). In ACCOAST trial, pretreatment with prasugrel before angiography did not reduce the rate of primary outcome among patients undergoing PCI but increased the rate of bleeding. In PLATO trial, ticagrelor was compared with clopidogrel in addition to aspirin in 18,624 patients with ACS. At median follow-up of 12 months, ticagrelor significantly decreased the primary composite end point by 16%, MI by 16%, all-cause mortality by 22%, and CV mortality by 21%. No significant difference in overall incidence of major bleeding was observed, but non-coronary artery bypass grafting-related bleeding was increased. In PRAGUE-18 study, no difference in the treatment with prasugrel or ticagrelor was observed in the patients with ST-elevation MI treated with primary PCI. SMARTDATE trial compared 6 months of DAPT (aspirin and clopidogrel) with 12 months of DAPT in the patients with ACS. In this randomized trial, the major adverse cardiac and cerebrovascular events were similar in both groups, but there was a significant increase in MI in 6-month DAPT group. TOPIC trial is a randomized trial in which patients of ACS were switched at 1 month from aspirin and newer P2Y12 antagonist to aspirin and clopidogrel. Though it was a small trial of 645 patients, it showed that switched DAPT is superior to an unchanged DAPT strategy to prevent bleeding complications without any increase in ischemic events following ACS.
As per the current 2016 ACC/AHA guidelines, DAPT (clopidogrel, prasugrel, or ticagrelor) shall be given for 12 months (Class I, level of evidence (LOE) B) in patients with ACS. The daily dose of aspirin in DAPT is 81mg (75–100mg) (Class I, LOE B). After stent implantation, it is reasonable to use ticagrelor or prasugrel in preference to clopidogrel (Class IIa). In case of prasugrel, patient shall not be at high risk of bleeding complications and shall have no previous history of stroke or TIA.
The ESC 2017 guidelines give Class I recommendation, LOE B for use of ticagrelor and prasugrel in ACS (if undergoing PCI in case of prasugrel) unless there are contraindications. Patients on clopidogrel shall be switched to ticagrelor early after hospital admission at a loading dose of 180mg unless contraindications exist (Class I, LOE B). In patients who cannot receive ticagrelor or prasugrel (including those patients with prior intracranial bleed or indication of oral anticoagulant [OAC] therapy), clopidogrel can be used. In patients with NSTE-ACS in whom coronary anatomy is not known, it is not recommended to administer prasugrel (Class III). In post-stent implantation in ACS, DAPT is indicated for 12 months unless excessive risk of bleeding (e.g., PRECISE-DAPT ≥25) (Class I) is reported. If bleeding risk is high (e.g., PRECISE-DAPT ≥25), discontinuation of DAPT at 6 months should be considered (Class IIb). In patients who have tolerated DAPT without a bleeding complication, continuation of DAPT for more than 12 months may be considered (Class IIb).
| Algorithms for Switching between Oral P2Y12 Inhibitors|| |
Acute setting: Loading dose is to be administered in all cases. If switching from clopidogrel, loading dose of prasugrel or ticagrelor can be given irrespective of timing or dosing of last dose. In case of switch from ticagrelor or prasugrel, 24h shall elapse from the timing of last dose.
Chronic setting: Loading dose is to be administered at 24h from the timing of last dose if switching from ticagrelor (600mg if switching to clopidogrel and 60mg if switching to prasugrel). In all other cases, maintenance dose at 24h from the timing of last dose is enough.
| Special Conditions|| |
DAPT shall be given for at least 12 months whether stable CAD or ACS. As there is twofold higher rate of stent thrombosis, especially in the first 30 days, a basis for considering the use of more potent P2Y12 inhibitors is considered. In view of concerns for late stent thrombosis, a longer duration of DAPT may be reasonable.
DAPT for long-term secondary prevention after prior MI
Patients with prior MI remain at increased long-term risk for ischemic events on follow-up. They may have benefit of extended duration of DAPT. PEGASUS-TIMI 54 trial randomized 21,162 patients with a history of spontaneous MI 1–3 years before enrollment, age ≥50 years, and at least one additional high-risk feature (age ≥65 years, diabetes mellitus, a second spontaneous MI, multivessel CAD, or chronic renal dysfunction). In this trial, 83% patients were previously treated with PCI. The patients were randomly assigned ticagrelor (90 or 60mg) twice a day or placebo in addition to low-dose aspirin. The primary efficacy of end point (CV death, MI, or stroke) was significantly lesser with ticagrelor (90mg; 7.85%, P = 0.008 and 60mg; 7.77%, P = 0.004) as compared with placebo (9.04%). Statistically significant reduction of MI with both doses and of stroke with lower dose was observed. The rates of thrombolysis in myocardial infarction (TIMI) major bleeding were higher, but no difference between nonfatal bleed and intracranial hemorrhage was observed. The data suggest greater benefit in continuation of therapy after MI rather than disruption and reinitiating of therapy in patients who have remained stable for an extended period.
In patients with high-ischemic risk after prior MI, prolongation of DAPT (preferably with ticagrelor, 60mg twice daily) in addition to low-dose aspirin beyond 1 year may be considered after careful evaluation of ischemic and bleeding risks (Class IIb).
DAPT in patients with complex PCI
In a meta-analysis, complex PCI was defined as at least three stents implanted, at least three lesions treated, total stent length >60mm, bifurcation with two stents implanted, and chronic total occlusion. It was seen that patients who had complex PCI had twofold increased risk of MACE. Long-term DAPT (≥12 months) as compared to short-term DAPT (≤6 months) was associated with a significant reduction in the MACE in the complex PCI group (4% vs. 6%; HR, 0.56%).
DAPT in patients with stent thrombosis
A substantial risk of recurrence of stent thrombosis after first episode was observed. In a study, the cumulative hazard of definite or probable stent thrombosis was 16% at 1 year and 24% at 5 years. The recurrent events significantly decrease with ticagrelor or prasugrel. In view of long-term risk of recurrent stent thrombosis, it is reasonable to maintain DAPT for a very long term, especially in the absence of correctable causes.
DAPT in patients with post-PCI requiring long-term OAC therapy
Approximately 6%–8% of patients with PCI require OAC therapy with a vitamin K antagonist (VKA) or non-VKA antagonist. Addition of DAPT to OAC therapy increases the risk of bleeding two- to threefold, including major fatal or nonfatal bleeding. The need of OAC therapy should be reassessed (e.g., CHA2DS2-VASc score for atrial fibrillation [AF]) and bleeding risk should be calculated by HAS-BLED score. Triple-therapy duration shall be kept as short as possible. Low-dose aspirin shall be used and clopidogrel is the P2Y12 inhibitor of choice. Use of novel OAC shall be considered in place of VKA. If VKA is used, target international normalized ratio in the lower range shall be maintained.
In WOEST trial, 573 patients on OAC therapy were randomized to dual therapy (with clopidogrel) or triple therapy (with OAC, clopidogrel, and aspirin). Treatment was continued for 1 month after BMS placement and 1 year after DES placement. TIMI bleeds were significantly less at 1 year in dual-therapy arm. The rates of ischemic end points were similar, but all-cause mortality was lower in dual-therapy arm at 1 year (P = 0.027).
PIONEER AF-PCI trial randomized 2124 patients with non-valvular AF who underwent PCI to receive low-dose rivaroxaban (15mg once daily) plus a P2Y12 inhibitor, very low-dose rivaroxaban (2.5mg twice daily) plus DAPT, or standard therapy (VKA plus DAPT) for 1, 6, or 12 months. At 12 months, bleeding was 16.8% and 18% in rivaroxaban groups and significantly higher 26.7% in standard therapy group (P < 0.001). The three groups had similar efficacy rates.
REDUAL-PCI trial randomly assigned 2725 patients with AF who had undergone PCI to triple therapy with warfarin plus P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin or dual therapy with dabigatran (110 or 150mg twice daily) plus P2Y12 inhibitor (clopidogrel or ticagrelor) and no aspirin. The incidence of major or clinically relevant nonmajor bleeding was 15.4% in 110-mg dual-therapy group (P < 0.001% for superiority), 20.2% in 150-mg dual-therapy group (P < 0.001% for non-inferiority), and 26.9% in triple-therapy group. Dual therapy was non-inferior to triple therapy with respect to the risk of thromboembolic events.
As per the ESC 2017 guidelines, it is recommended to administer aspirin and clopidogrel periprocedurally in patients undergoing coronary stent implantation (Class I). In patients treated with coronary stent implantation, triple therapy with aspirin, clopidogrel, and OAC should be considered for 1 month irrespective of the stent used (if ischemic risk is more, e.g., ACS, then triple therapy may be given for 6 months. If bleeding risk is more, then dual therapy may be considered in 1st month itself). After triple therapy, patient shall be maintained on dual therapy (OAC plus aspirin or clopidogrel) till 1 year and after 1 year, all antiplatelet be stopped and OAC alone shall be continued (Class IIa). The use of ticagrelor or prasugrel is not recommended as a part of triple-antithrombotic therapy with aspirin and OAC (Class III).
Elective noncardiac surgery in patients on DAPT
As per estimates, 5%–25% of patients with coronary stents may require noncardiac surgery within 5 years after stent implantation. To choose the best management strategy for such patients, a multidisciplinary approach is advisable (ESC Class IIa).
Discontinuation of DAPT within the 1st month of coronary stenting in patients undergoing elective noncardiac surgery is not recommended (Class III). Elective surgery after 6 months is a safe Class I recommendation. Elective surgery between 1 and 6 months after stenting in stable CAD is Class IIa recommendation, but Class IIb after stenting in cases of ACS.
In surgical procedures with low-bleeding risk, continue DAPT perioperatively. It is recommended to continue aspirin perioperatively if the bleeding risk allows (moderate-bleeding risk), and to resume DAPT as soon as possible postoperatively (ESC Class I). Discontinuation of P2Y12 inhibitors should be considered at least 3 days before surgery for ticagrelor, at least 5 days for clopidogrel, and at least 7 days for prasugrel (ESC Class IIa).
Patients with bleeding on DAPT
In cases of moderate and severe bleeding, consider stopping DAPT and switching to single-antiplatelet regime (preferably with P2Y12 inhibitor, especially in case of upper gastrointestinal bleeding). If severe bleeding persists despite treatment or if it is life-threatening bleed, all antithrombotic medicines need to be discontinued.
| Conclusion and Future Directions|| |
As per newer evidence and current guidelines, to optimize DAPT regimen and duration, tailored approach is better. We shall customize our treatment based on clinical presentation and ischemic and bleeding risks of patient. Novel strategies are being explored in multiple large ongoing trials. GLOBAL LEADERS and TWILIGHT trials are investigating ticagrelor monotherapy after short-term duration of DAPT (1–3 months). In patients with high-bleeding risk, 1-month DAPT is being compared with standard DAPT duration (6–12 months) in SENIOR and MASTER DAPT trials. These trials and many more will generate newer evidence to challenge present concepts and provide optimal balance between efficacy and safety.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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