Adjunctive Cilostazol Versus
Double Dose Clopidogrel After
Drug Eluting Stent Implantation
The HOST-ASSURE Randomized Trial
HOST – ASSURE ( Harmonizing Optimal Strategy
for Treatment of Coronary Artery Stenosis – Safety
& Effectiveness of DrUg Eluting Stents & Anti –
ClincalTrials.gov number NCT01267734.
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
• 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.
To test the noninferiority of triple antiplatelet therapy (TAT) versus
double-dose clopidogrel dual antiplatelet therapy (DDAT)in pts
undergoing percutaneous coronary intervention(PCI).
• 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
• 1:1 to either TAT or DDAT.
• 2:1 to either Platinum Chromium based Everolimus – eluting
stents or Cobalt Chromium based Zotarolimus – eluting stents.
A 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.
1. Severe Left ventricular systolic dysfunction (EF<25%)
3.H/o bleeding diathesis
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.
PRIMARY END POINT –
(composite of the following at 1
SECONDARY END POINT
All individual components of the
primary composite end point
Non fatal Myocardial Infarction
PLATO minor bleeding
Target vessel revascularization
PLATO major bleeding
Target lesion revascularization
Secondary per protocol analysis – pts adhering to allocated therapy at 1
month follow up and those with clinical events were included in analysis.
• Clinical events were defined as per ARC recommendations.
1. MI – clinical signs + CKMB or Trop T/I increase above upper
2. Stent thrombosis – definite or probable .
3. Stroke – new neurological deficit,confirmed by Neurologist or
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 300600mg +/- 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.
• 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
• 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
- PCI for Left main disease
16.2% - PCI for bifurcation lesion
• 1 end point - TAT 23 pts (1.2% ) , 27 pts (1.4%) DDAT
• Non inferiority of TAT was confirmed with an upper limit of the 1sided 97.5% CI of 0.52% (prespecified noninferiority margin was
• 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
• 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 Month
Kaplan-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.
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
• 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
– 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 Reactivity
Scatterplot 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.
• 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
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
• 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
• Spontaneous MI in DDAT group ,no event in TAT group.
– Major bleeding – similar in two groups.
– Minor bleeding – more in TAT group ,not significant.(low OPR
in TAT group)
1. The event rates were extremely lower than that expected from the
original power calculation .
Occurrence of 1 endpoint – 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
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
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
CYP2C19 LOF allele compared to DDAT .
• Post PCI rates low in East Asians – genetic factors.