Adisai Buakhamsri, MD Assistant Professor

Thammasat Heart Center & Univeristy Hospital Faculty of Medicine, Thammasat University

Dual Anti-Platelet Therapy (DAPT)

ESC guidelines for DAPT 2017

Role of platelet in coronary thrombosis

Wilson SJ, et al. Heart 2017;1:1–8

Platelet

Fibrin

Thrombusadhesion - activation - aggregation

Wilson SJ, et al. Heart 2017;1:1–8.

4 Wilson SJ, et al. Heart 2017;1:1–8. doi:10.1136/heartjnl-2016-309871

Review

or a first-generation drug-eluting stent (p=0.048). Similar trends were observed in DES-LATE25 and ARCTIC-INTERRUP-TION.26

Audit of the British Cardiovascular Society Intervention database indicates that in 2013/2014, a half of all percuta-neous coronary intervention procedures were associated with residual disease (≥1 stenosis of >50% severity), fulfilling the criteria for incomplete revascularisation. Patients with acute coronary syndrome and incomplete revascularisation have a residual burden of coronary disease that is a substrate for recur-rent plaque rupture, coronary thrombosis and future cardiac events.31 32 Prolonged dual antiplatelet treatment may mitigate this risk but whether this translates to a more favourable risk-to-benefit balance for patients with incomplete revascularisation remains an area for future research.

Bleeding and total mortalityLarge registries and trials have shown that major bleeding is associated with an increase in mortality that could potentially negate the benefits of dual antiplatelet therapy in acute coro-nary syndrome.33–36 Importantly, these bleeding risks are not confined to the initial hospitalisation phase.33 35 The association between bleeding and mortality has been a consistent feature of acute coronary syndrome trials irrespective of whether the intervention being assessed and improvements in outcome are seen with interventions that are associated with a lower bleeding risk. For example, in the OASIS-5 trial,33 fondaparinux had

similar antithrombotic benefits to enoxaparin but was associated with lower rates of major bleeding and marked reductions in all-cause mortality. Similar benefits have also been reported for randomised controlled trials of arterial access sites in patients treated with an invasive strategy for either ST-segment37 or non-ST-segment38 myocardial infarction. Again, because radial artery access was associated with less bleeding, overall all-cause mortality was lower.37 38 There have been various mechanisms proposed for the link between bleeding and mortality that include rebound hypercoagulability, discontinuation of anti-thrombotic treatments, inflammation and ischaemia.39 The European Society of Cardiology Working Group on Thrombosis has called for clinical trials to address bleeding in acute coronary syndrome including the exploration of the duration of dual anti-platelet therapy.39

Duration uncertaintyCurrently there are variations in local and regional dual anti-platelet therapy practices that are confusing for patients, primary care physicians and cardiologists. Indeed, while European13 and North American12 guidelines recommend dual antiplatelet therapy for 12 months after an acute coronary syndrome, both acknowledge that shorter or longer durations may be appro-priate. Duration of therapy is seen as a major priority for future research by numerous national and international guideline committees as well as having considerable financial implications, especially for the latest generation of P2Y12 receptor antagonists.

Figure 2 Platelet activation pathways and sites targeted by current and novel antiplatelet agents.  Arachidonic acid; ADP, adenosine diphosphate; c, cyclic; Ca2+, calcium; AMP, adenosinemonophosphate; COX-1, cyclo-oxygenase-1; DAG, diacylglycerol; GMP, guanosine monophosphate; GP, glycoprotein; IP3: inositol trisphosphate; PAR, protease activated receptor; PDE, phosphodiesterase; PI3K,phosphatidylinositol 3-kinase; PIP2: phosphatidylinositol 4,5-bisphosphate; PLC, phospholipase C; TP, thromboxane receptor; TRPC, transient receptor potential channel; TXA2, thromboxane A2; vWF, von Willebrand factor.

on 11 February 2019 by guest. Protected by copyright.http://heart.bm

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Antiplatelets commonly used in CAD

T H E LANCET

ResultsParticipants and follow-up19 185 patients from 384 clinical centres were randomisedbetween M arch, 1992, and February, 1995. Patientfollow-up was completed by February, 1996, resulting in36 731 patient-years at risk. Mean duration of follow-upwas 1·91 years.

During the study, 42 patients (0·22%) were lost tofollow-up, 22 in the clopidogrel group and 20 in theaspirin group (figure 2); the resulting loss in total patient-years at risk was 49 (0·13%). T hese 42 patients wereincluded in the analyses with their follow-up censored atthe time of last contact.

4059 patients (21·2%) had study drug permanentlydiscontinued early, for reasons other than the occurrenceof an outcome event; 21·3% in the clopidogrel and 21·1%in the aspirin group. Reasons for stopping study drug earlywere similar in the two groups: adverse events (11·4%);withdrawn consent (4·7%); contraindicated medications(2·4%); non-compliance (1·8%); and other (0·8%). Meanfollow-up while on study drug was 1·63 years for eachtreatment group.

With exclusion of follow-up after any early permanentdiscontinuation of study drug, mean compliance withclopidogrel and aspirin was similar at 91%. 46 patients inthe clopidogrel group and 40 in the aspirin group nevertook any study drug.

AnalysisBaseline characteristics of randomised patients are shownin table 4. T he treatment groups were well matched withrespect to age, sex, race, and cardiovascular risk factors.After randomisation, 16 patients, ten in the clopidogrelgroup and six in the aspirin group, were found not to havethe qualifying disease; most were entered as havingischaemic stroke but were subsequently found to bemisdiagnosed, (eg, as multiple sclerosis or primaryintracranial haemorrhage). T he study drug was terminatedwithin 4 months of randomisation for 13 of these patientsbut the other three patients were continued on study drug;all 16 continued to be followed as per protocol andincluded in the analyses.

T here were 2800 validated outcome events, of which1669 were non-fatal and 1131 were fatal (table 5). T herewere 1171 patients in the clopidogrel group and 1236patients in the aspirin group who had an outcome event of

whom 158 and 182, respectively, had more than oneevent.

T he primary analysis of efficacy was by intention-to-treat and based on the incidence of the first occurrence ofischaemic stroke, myocardial infarction, or vascular deathamong all patients randomised. T here were 939 events inthe clopidogrel group during 17 636 patient-years at risk,an average rate per year of 5·32%. T here were 1021 eventsin the aspirin group during 17 519 patient-years at risk, anaverage rate per year of 5·83%. Relative-risk reduction,estimated from a Cox proportional-hazard model, was8·7% (95% C I 0·3–16·5) in favour of clopidogrel(p= 0·043, table 6). T he cumulative proportions ofpatients who experienced an event in this primaryoutcome cluster over 3 years are shown in figure 3.

Results of the analyses of the four predefined secondaryoutcome clusters are also shown in table 6. T he estimatedrelative-risk reductions with clopidogrel were consistently7% to 8% when the outcomes were predominantlyvascular events but the relative-risk reduction was smallerfor all-cause mortality, of which 36% was non-vascular.

Estimated treatment effects for both the primary andsecondary outcome clusters remained virtually unchangedwhen adjusted for relevant prognostic baseline variables.

Main baseline characteristics for each of the subgroupsare shown in table 4. Patients in the ischaemic stroke andperipheral arterial disease groups were similar in age and 6

Vol 348 • November 16, 1996 1333

Outcome event cluster and treatment group First outcome events Event rate Relative-risk p

Non-fatal Fatal Total per year reduction (95% CI)

Ischaemic stroke, MI, or vascular death (primary cluster)Clopidogrel (nyrs=17636*) 631 308 939 5· 32% 8· 7% (0· 3 to 16· 5) 0· 043Aspirin (nyrs=17519) 700 321 1021 5· 83%

Ischaemic stroke, MI, amputation, or vascular deathClopidogrel (nyrs=17594) 677 302 979 5· 56% 7· 6% (!0· 8 to 15· 3) 0· 076Aspirin (nyrs=17482) 737 314 1051 6· 01%

Vascular deathClopidogrel (nyrs=17482) . . 350 350 1· 90% 7· 6% (!6· 9 to 20· 1) 0· 29Aspirin (nyrs=18354) . . 378 378 2· 06%

Any† stroke, MI, or death from any causeClopidogrel (nyrs=17622) 643 490 1133 6· 43% 7· 0% (!0· 9 to 14· 2) 0· 081Aspirin (nyrs=17501) 720 487 1207 6· 90%

Death from any causeClopidogrel (nyrs=18377) . . 560 560 3· 05% 2· 2% (!9· 9 to 12· 9) 0· 71Aspirin (nyrs=18354) . . 571 571 3· 11%

*Patient-years at risk for outcome cluster; †Includes primary intracranial hemorrhage; MI=myocardial infarction.

Table 6: Intention-to-treat analysis—primary and secondary outcome clusters

20

15

10

5

00 3 6 9 12 15 18 21 24 27 30 33 36

A: 9586C: 9599

91909247

80878131

61396160

39794053

21432170

542539

Time since randomisation (months)

p = 0.043

Clopidogrel

AspirinC

umul

ativ

e ris

k (%

)

Patientsat risk

Figure 3: Cumulative risk of Ischaemic stroke, myocardialinfarction, or vascular deathA=aspirin; C=clopidogrel.

CAPRIE (clopidogrel vs aspirin)

CAPRIE group. Lancet 1996; 348: 1329–39

patients with atherosclerotic vascular disease (n=19185 )

Clopidogrel

ASA

CURE study. N Engl J Med 2001;345: 494-502

CURE (clopidogrel vs aspirin)

patients with NSTE-ACS (n=12,562 )

Clopidogrel+ASA

ASA

678 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 83 • NUMBER 9 SEPTEMBER 2016

DUAL ANTIPLATELET THERAPY

each other and having additive effects (Figure 2, Table 1).5,16–21

Aspirin inhibits cyclo-oxygenase 1 Cyclo-oxygenase 1, found in platelets, endo-thelial cells, and other cells, catalyzes the con-version of arachidonic acid to thromboxane A2. Aspirin irreversibly inhibits cyclo-oxygenase 1 by acetylating its serine residue, preventing formation of thromboxane A2 and preventing platelet activation and aggregation.

P2Y12 ADP receptor antagonistsClopidogrel and prasugrel are thienopyridine agents that irreversibly inhibit the P2Y12 re-ceptor, thereby preventing binding of adenos-ine diphosphate and the subsequent platelet activation-aggregation cascade. They are both prodrugs and require conversion by cyto-chrome P450 enzymes to active metabolites. Prasugrel is 10 times more potent than clopi-dogrel due to more efficient formation of its

Techniques have evolved from balloon angioplasty to bare-metal stents to drug-eluting stents, but all pose a risk of thrombosis

FIGURE 2. Mechanism of action of antiplatelet agents.

AC = adenyl cyclase; cAMP = cyclic adenosine monophosphate; Ca2+ = calcium; CYP = cytochrome P450; Gs, Gi, Gq = G proteins; PDEIII = phos-phodiesterase III, PGR, P2Y12, P2Y1, P2X1 = platelet receptors; PKA= protein kinase A; VASP = vasodilator-stimulated phosphoprotein; VASP-P = phosphorylated VASP

βγαi

Hepatic CYPmetabolism

cAMP

VASP PKA VASP-P

Hepatic CYPmetabolism

Hepatic CYPmetabolism

Active metabolite

Inactive metaboliteEsterases

Extracellular

Intracellular

Ca2+ flux

5’-AMP

AC

AC

Ca2+ mobilization

Shape change

PGR P2Y12 P2Y1 P2X1

Granule secretion

PDEIIIPlatelet activation

Initiation of platelet aggregation

Stabilization of platelet aggregationPlatelet activation

Platelet activation

Intestinal absorption

ProdrugsClopidogrelPrasugrelCangrelor

Intestinal absorption

TicagrelorCilostazol

Direct-acting

GsGi Gq

CCF ©2016 Halkar et al CCJM 2017; 83(9),675-687

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 83 • NUMBER 9 SEPTEMBER 2016 679

HALKAR AND LINCOFF

active metabolite, and it achieves a compa-rable effect on platelet inhibition 30 minutes faster than the peak effect of clopidogrel at 6 hours. The overall peak inhibitory effect of prasugrel is twice that of clopidogrel.22

Ticagrelor, a cyclopentyl-triazolo-pyrimi-dine, directly and reversibly inhibits the P2Y12 ADP receptor. Unlike clopidogrel and prasu-grel, it does not need to be converted to an active metabolite, and it noncompetitively inhibits P2Y12 at a site different from the ad-enosine diphosphate binding site.23 Like prasu-grel, ticagrelor inhibits platelet function more rapidly and more completely than clopidogrel. Cangrelor, an intravenously administered analogue of adenosine triphosphate, revers-ibly inhibits the P2Y12 receptor. It has under-gone phase 3 trials but is not yet approved for clinical use.24

■ WHY DUAL ANTIPLATELET THERAPY?

Aspirin is good, clopidogrel is betterAspirin has a well-validated role in both pri-mary and secondary prevention of coronary and noncoronary atherosclerotic vascular disease. The CAPRIE trial found clopidogrel monotherapy to be superior to aspirin mono-

therapy in patients with established athero-sclerotic vascular disease.25

After stenting, short-term dual therapy is better than short-term warfarin Thrombotic complications in the early post-procedural period were a major limitation of stenting, and existing anticoagulation regi-mens were ineffective in preventing them.26,27

The ISAR trial studied the benefit of combined antiplatelet vs anticoagulant thera-py after stent placement. Patients randomized to receive combined aspirin plus ticlopidine (an early P2Y12 inhibitor) had significantly lower rates of primary cardiac, hemorrhagic, and vascular events at 30 days.9 Two other tri-als confirmed this finding.28,29

STARS10 also confirmed the benefit of as-pirin and ticlopidine after stenting. Patients were randomly assigned to aspirin alone, aspi-rin plus warfarin, or aspirin plus ticlopidine af-ter stent placement. The rate of stent throm-bosis at 30 days was significantly lower in the dual antiplatelet group than in the other two groups. The dual antiplatelet group had a higher rate of bleeding than the aspirin-alone group, but the rate was similar to that of the aspirin-plus-warfarin group.

Prasugrel is 10 times more potent than clopidogrel due to more efficient formation of its active metabolite

TABLE 1

Antiplatelet agents

DrugMetabolic activation

Revers-ibility

Time to peak activity

Elimina-tion half-life

Duration of effect

Elimina-tion Dosage

Aspirin By esterases in gastro-intestinal mucosa

No 1–2 hours 3 hours 7–10 days Renal 162–325 mg loading dose, then 81–162 mg daily

Clopidogrel By CYP450 No 2–6 hours 6 hours 5–7 days Renal and gastrointes-tinal

300–600 mg loading dose, then 75 mg daily

Prasugrel By CYP450 No 0.5–4 hours

2–15 hours

5–9 days Renal and gastrointes-tinal

60 mg loading dose, then 10 mg daily

Ticagrelor No Yes 0.5–2 hours

7–9 hours

3–5 days Gastroin-testinal and renal

180 mg loading dose, then 90 mg twice a day

Cangrelor No Yes 2–30 minutes

3–5 minutes

0–30 minutes

Renal and gastrointes-tinal

4 µg/kg/min intravenous infusion

Properties of current antiplatelets

Halkar et al CCJM 2017; 83(9),675-687

Balancing the ischemic and bleeding risk

Recommendations

ESC guidelines for DAPT 2017

ESC guidelines for DAPT 2017

ESC guidelines for DAPT 2017

ESC guidelines for DAPT 2017

Recommendation on reducing risk of bleeding

ESC guidelines for DAPT 2017

If a patient with DAPT is going to have a surgery

Banerjee et al Am Coll Cardiol 2017;69:1861–70

Patient with coronary stent undergoing non-cardiac surgery

P2Y12 inhibitor interruption before elective non-cardiac surgery

Ischemic RiskBleeding Risk

Risk of thrombotic events

Banerjee et al Am Coll Cardiol 2017;69:1861–70

Risk of bleeding events

Banerjee et al Am Coll Cardiol 2017;69:1861–70

Banerjee et al Am Coll Cardiol 2017;69:1861–70

Perioperative management of DAPT

P2Y12 inhibitor interruption before elective non-cardiac surgery

1. Multidisciplinary expert team for preoperative evaluation

2. If a P2Y12 inhibitor has to be discontinued perioperatively, surgery should be considered after at least 1 month of PCI, irrespective of the stent type and aspirin must be maintained throughout the perioperative period.

3. If both ASA and P2Y12 inhibitor has to be discontinued perioperatively, a bridging strategy with cangrelor, tirofiban, or eptifibatide may be considered (especially Sx within 1 month after stent implantation)

Patient with PCI+DAPT, undergoing non-cardiac surgery

Points to remember

1. Benefits of prolonged DAPT (>1yr) depend on baseline risk

2. Try to reduce bleeding risk during DAPT(low-dose, access site, PPI, other modifiable risk factors)

3. Clopidogrel as a default P2Y12 inhibitor(PCI in stable CAD, on OAC, contraindicated for other inhibitors)

4. Prasugrel or ticagrelor is recommended in ACS

Points to remember

5. PCI in stable CAD with any stent type, DAPT for 1-6 mo or longer

6. For ACS with any revascularization, default DAPT duration is 12 months (6 months if high bleeding risk, >12 months if DAPT tolerable and no bleeding)

7. DAPT duration should be based on ischemic versus bleeding risk assessment and not by the stent type

Points to remember

8. Duration of triple therapy (DAPT+OAC) is limited to hospital discharge or no longer than 6 months (clopidogrel is P2Y12 inhibitor of choice, not prasugrel or ticagrelor)

9. DAPT with active bleeding, decision to stop both antiplatelets agents, especially if shortly after PCI, should be taken only if the bleeding is life-threatening and the source has not been or cannot be treated

ESC guidelines for DAPT 2017

Adisai Buakhamsri, MD Assistant Professor

Thammasat Heart Center & Univeristy Hospital Faculty of Medicine, Thammasat University

Dual Anti-Platelet Therapy (DAPT)