Adjunctive Cilostazol Versus Double Dose Clopidogrel After Drug Eluting Stent Implantation

The HOST-ASSURE Randomized Trial

DR.N.PRAVEEN, PG

Kyung Woo Park ,MD,PhD ,Si Hyuck Kang ,MD. et al Seoul National University Hospital ,Seoul , Republic of Korea.

JACC –CARDIOVASCULAR INTERVENTIONS,Vol .6,No.9.,2013

HOST – ASSURE ( Harmonizing Optimal Strategy

for Treatment of Coronary Artery Stenosis – Safety & Effectiveness of DrUg Eluting Stents & Anti –Platelet REgimen)

ClincalTrials.gov number NCT01267734.

Background

• Antiplatelet regimen is an integral component of medical therapy after percutaneous coronary intervention (PCI).

• Inhibition of platelet reactivity in the first month post PCI is known to be critical in preventing thrombotic events,since higher on treatment platelet reactivity is reported to be associated with higher risk of hard endpoints.

• A 1-week duration of doubling the dose of clopidogrel was shown to improve outcome at 1 month compared with the conventional dose in ACS pts undergoing PCI.

• In Asia including Korea,the addition of cilostazol as a third antiplatelet agent is used in high risk patients,however no large-scale comparison has been done.

Objectives

To test the noninferiority of triple antiplatelet therapy (TAT) versus double-dose clopidogrel dual antiplatelet therapy (DDAT)in pts undergoing percutaneous coronary intervention(PCI).

Study design

• Prospective, randomized, blinded endpoint evaluation, multicenter trial conducted at 40 sites in the Republic of Korea.

• 2*2 factorial design – randomization for type of DES and type of APT .

• 1:1 to either TAT or DDAT. • 2:1 to either Platinum Chromium based Everolimus – eluting

stents or Cobalt Chromium based Zotarolimus – eluting stents.

Trial ProfileA total of 3,755 patients were randomly assigned to either triple antiplatlet therapy (n = 1,879) or double-dose clopidogrel dual antiplatelet therapy (n = 1,876). The analysis was performed on an intention-to-treat basis.DDAT = double-dose clopidogrel dual antiplatelet therapy; TAT = triple antiplatelet therapy.

• Participants were 18 yrs of age or older ,had atleast 1 clinically significant stenotic lesion amenable to PCI in the coronary artery or venous or arterial grafts.

• No exclusion criteria for lesion type,number of stents used,the no. of lesions treated,or the diagnosis at presentation –all comers’ study.

EXCLUSION CRITERIA

1. Severe Left ventricular systolic dysfunction (EF<25%)

2.Cardiogenic shock

3.H/o bleeding diathesis

4.coagulopathy

5.GI,GU bleeding within the previous 3 months

6.Major surgery within 2 months

• Before Index PCI - all pts received loading doses of 300 mg Aspirin

and 300 to 600 mg of Clopidogrel .

• TAT group – additional loading dose of 200 mg Cilostazol, followed

by 100mg bid *1 month.

• DDAT group – 150 mg/d maintenance dose of Clopidogrel *1month.

• UFH administered throughout the procedure (ACT > 250msec)

• GpIIb/IIIa inhibitors – at the discretion of treating physician.

• After PCI – all pts were recommended to receive optimal Rx.

Secondary per protocol analysis – pts adhering to allocated therapy at 1 month follow up and those with clinical events were included in analysis.

PRIMARY END POINT – (composite of the following at 1 month )

SECONDARY END POINT

Cardiac death All individual components of the primary composite end point

Non fatal Myocardial Infarction All death

Stent Thrombosis PLATO minor bleeding

Stroke Target vessel revascularization

PLATO major bleeding Target lesion revascularization

• Clinical events were defined as per ARC recommendations.

1. MI – clinical signs + CKMB or Trop T/I increase above upper normal limit.

2. Stent thrombosis – definite or probable .

3. Stroke – new neurological deficit,confirmed by Neurologist or imaging.

4. PLATO major bleeding Life threatening major bleeding - fatal , IC ,intrapericardial bleed

with cardiac tamponade or hypovolemic shock or severe hypotension requiring pressors or surgery, associated decrease in hemoglobin > 5g/dl or transfusion of >4U of whole blood or packed RBCs .

Disabling major bleeding - intraocular bleeding with permanent visual loss , decrease in Hb 3-5g/dl , transfusion of 2-3U whole blood or packed RBC.

• Subgroup of pts – platelet function tests using the Verify Now P2Y12 assay were performed– At baseline (12-24 h after loading dose of Clopidogrel 300-

600mg +/- Cilostazol 200 mg ) – At 1 month follow up under maintenance dose ( Clopidogrel

75-150mg/day +/- Cilostazol 100 mg bid) – At follow up after maintenance dose 2 -6 h after morning dose.

Statistical Analysis

• With assumption that the primary outcome rate would be 2% and 3% in the TAT and DDAT group respectively, an estimation of requirement of 3,750 pts for study was made to have > 90% power showing noninferiority margin of 0.75%.

• TAT would be considered to be noninferior to DDAT If the upper limit of a 1–sided 97.5% CI of the difference was less than the pre specified non inferiority margin.

Characteristics of Study Pts

• June 2010 to November 2011• TAT ( n = 1,879 );DDAT ( n = 1,876)• Baseline characteristics were well balanced• Mean age and frequency of h/o MI higher in DDAT , PAD lower

in DDAT.• No differences in Hb, Platelet count ,LDL levels in 2 groups.• Medications were also balanced• CCBs more in DDAT group.

Mode of presentation –

• 65.5% - ACS • 53.8% - MVD • 3% - PCI for Left main disease • 16.2% - PCI for bifurcation lesion

Results

• 1end point - TAT 23 pts (1.2% ) , 27 pts (1.4%) DDAT• Non inferiority of TAT was confirmed with an upper limit of the 1-

sided 97.5% CI of 0.52% (prespecified noninferiority margin was 0.75%).

• Regarding superiority, no significant difference between two groups. (Hazards ratio :0.85 ,95% CI :0.49 to1.48)

• Rates of individual components of 1 end point –showed similar trends.

• PLATO major bleeding were the same in TAT ,DDAT groups. • PLATO minor bleeding were numerically higher in TAT group.

• No significant interaction between the antiplatelet regimen and stent randomization arms regarding any study outcome.

Cumulative Kaplan-Meier Estimates for the Primary Endpoint and PLATO Major Bleeding at 1 MonthKaplan-Meier curves show the cumulative incidence of the net clinical outcome (the primary endpoint), a composite of cardiac death, nonfatal myocardial infarction, stent thrombosis, stroke, or PLATO major bleeding (A) and PLATO major bleeding (B). Abbreviations as in Figure 1.

Figure Legend:

Compliance and per protocol analysis

• After randomization 97.4% were allocated TAT ,92.2% DDAT.• 5.2% refused the additional dose of clopidogrel in DDAT.• Upto 1 month follow up – 5.8% pts in TAT group , 5.7% DDAT

non adherent • At 1 month adherence rates were 91.6% TAT,86.5% DDAT.• Drug related adverse events led to discontinuation in

– TAT –Headache, easy bruisability, bleeding ,GI side effects,skin rash,tachycardia.

– DDAT – GI, easy bruisability.

Per protocol analysis • 1.2% TAT ,1.6% DDAT – primary outcome.• Spontaneous MI occured more frequently in DDAT group

Platelet function tests ( 36.1% pts ,n= 1,356)• Mean OPR was lower and % of inhibition significantly higher in

TAT group compared to DDAT group – no change after multivariable adjustment for baseline factors.

• Mean OPR > 228 PRU at 12-24 hrs after loading dose in all when plotted for thrombotic events.

On-treatment Platelet ReactivityScatterplot of on-treatment platelet reactivity in the TAT and DDAT groups at 12 to 24 h after a loading dose (A) and at 1 month after a maintenance dose (B). Abbreviations as in Figure 1.

Discussion

• Adjunctive use of cilostazol for 1 month in addition to conventional dual APT was noninferior to doubling the maintenance dose of clopidogrel with regard to net clinical outcome.

• No differences between the two treatment group regarding the individual components of primary outcome.

Potent inhibition of platelet reactivity during the first month after

PCI is one of the key factors in a successful outcome.

HOPR associated with increased risk of thrombotic outcomes –

most profound association seen in the first month post PCI .

Rate of HOPR exceeds 50% in East Asians.

Frequency of CYP2C19 LOF carriers > 60%

• Doubling the maintenance dose of Clopidogrel (150mg/d) - was

used in high risk pts - MI,increased platelet reactivity , CYP2C19

loss of function carriers.

This was proven benefit in following trials

– OPTIMUS ( Optimizing Antiplatelet Therapy in Diabetes) trial .

– ARYMDA (Antiplatelets for Reduction of Myocardial Damage

During Angioplasty ) DDAT – associated with higher platelet

inhibition,better flow mediated vasodilation ,low hsCRP .

– CURRENT –OASIS7 trial – 1 wk duration of DD Clopidogrel

– improve outcome at 1 month in pts undergoing PCI .

• Post PCI – Left main artery stenting ,multivessel stenting - cilostazol

is used as a third agent rather than an in maintenance dose of

clopidogrel - in East Asia.( TAT proven to be of benefit in

pharmacodynamics studies)

• In long lesion stenting ,diabetics – TAT >DDAT due to inhibition of

neointima formation ,decreased target lesion revascularization

• CILON – T ( influence of CILostazol based triple antiplatelet

therapy ON ischemic complications after drug eluting stenT

implantation) : mean OPR was less in TAT.

• TAT – more efficacious in pts with documented HOPR ,

Diabetics,Acute MI, CKD,CYP2C19 LOF allele .

• Stent thrombosis and non fatal MI – occurred less frequently in TAT group.

• Spontaneous MI in DDAT group ,no event in TAT group.• PLATO

– Major bleeding – similar in two groups.– Minor bleeding – more in TAT group ,not significant.(low OPR

in TAT group)

Limitations

1. The event rates were extremely lower than that expected from the original power calculation .

Occurrence of 1endpoint – 3%(expected) – 1.2% (result),1.4% control - 48% relative risk increase as being non inferior with no. of pts in study under powered to concretely prove that TAT is noninferior to DDAT.

2.Underreporting of events

Post PCI events are less in East Asia - genetic factors, IVUS usage during PCI.

3.Periprocedural rates - MI were low - cardiac enzymes measured only in pts with significant chest discomfort.

4.Adherence was only 91.6% TAT ,86.5% DDAT -may have affected the outcomes.

Take Home Message

• Adjunctive use of Cilostazol in addition to conventional dual

antiplatelet therapy is noninferior to doubling the maintenance dose

of clopidogrel in pts undergoing PCI with DES.

• HOPR associated with higher risk of thrombotic cardiovascular events

especially first month post PCI .

• HOPR > 50% in East Asian ,CYP2C19 LOF carriers >60%.

• DDAT beneficial proven in • Diabetics (OPTIMUS) ,• PCI pts(ARYMDA) ,• CURRENT OASIS 7 trial .

• Beneficial effects of Cilostazol – in DES pts - CILON –T.• TAT beneficial in pts with

• HOPR ,• Diabetics,• Acute MI, • CKD,• CYP2C19 LOF allele compared to DDAT .

• Post PCI rates low in East Asians – genetic factors.