dual antiplatelet therapy using cilostazol for high-risk ...wcm/@sop/... · dual antiplatelet...

Dual Antiplatelet Therapy Using Cilostazol for High-Risk Ischemic Stroke: The Cilostazol Stroke Prevention Study for Antiplatelet Combination

(CSPS.com)

Kazunori Toyoda, MD (National Cerebral and Cardiovascular Center, Suita, Japan); Shinichiro Uchiyama, MD; Haruhiko Hoshino, MD; Kazumi Kimura, MD;

Kazuo Minematsu, MD; Hideki Origasa, PhD ; Hiroaki Naritomi, MD; Keiji Yamaguchi, MD; Masanori Isobe, MD; Yasushi Okada, MD;

Nobuyuki Sakai, MD; Kortaro Tanaka, MD; Takenori Yamaguchi, MD; for the CSPS.com Trial Investigators

International Stroke Conference 2019, 6th Feb, 2019 Honolulu

COIThe Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com)

CSPS.com was conducted under a trial contract between the study sponsor, Japan Cardiovascular Research Foundation (JCVRF), and the supporting company, Otsuka Pharmaceutical Co., Ltd.

JCVRF received funding for trial implementation and management from Otsuka Pharm.

The authors and each committee member received scientific consultancy fees for trial design and management, depending on their roles.

Otsuka Pharm. did not directly contribute to trial design, data management, or statistical analysis.

Background

Dual antiplatelet therapy with aspirin and clopidogrel reduces early recurrence of ischemic stroke. It was not effective and increased the risk of bleeding with long-term use.

Cilostazol, a phosphodiesterase 3 inhibitor, prevents stroke recurrence with relatively low incidence of serious bleeding. Dual antiplatelet therapy involving cilostazol may be safe and appropriate for long-term use.

Cilostazol Stroke Prevention Studies (CSPS)

Gotoh F, et al: J Stroke Cerebrovasc Dis 2000;9:147-57

CSPS: Cilostazol vs. placebo CSPS 2: Cilostazol vs. aspirin

Shinohara Y, et al: Lancet Neurol 2010;9:959-968

Recurrence of ischemic strokeRecurrence of

any stroke

Purpose

To determine if a combination of cilostazol with aspirin or clopidogrel reduces recurrence of ischemic stroke in the chronic stage without increasing the bleeding risk compared to aspirin or clopidogrel alone

Trial design

Multicenter, randomized, open-label, parallel-group Registration: Dec 2013 Mar 2017 (Initially planned -Mar 2016) Trial registration

Clinicaltrials. gov identifier: NCT01995370; UMIN 000012180 Protocol

Toyoda K, et al: Int J Stroke 2015;10:253-258

Trial population: Inclusion criteria 1

1. Non-cardioembolic ischemic stroke within 8-180 days 2. Identified on MRI3. Age 20-85 y4. Taking aspirin or clopidogrel alone as antiplatelet Tx

when providing IC

Trial population: Inclusion criteria 25. At least one of the following (a-c):

a. 50% stenosis of a major intracranial artery (to A2, M2, P2)b. 50% st. of an extracranial artery (CCA, ICA, VA, BCA, subclavian)c. 2 of the following risk factors Age 65 y DM HT CKD PAD Smoking (current)

Hx of IS (excluding the index IS for this trial) Hx of IHD

6. Considered to be able to visit the trial site for ambulatory care7. Written IC by the patient

Exclusion criteria1. High-risk sources of cardioembolism,

according to the TOAST classification 2. Using any anticoagulants3. Contraindication to MRI examination4. Scheduled to undergo any surgery during

the trial period5. Drug-eluting coronary stent implanted

within one year6. Hx of symptomatic non-traumatic ICH,

any other hemorrhagic disease, bleeding predisposition, blood clotting disorders

7. Hx of hypersensitivity to cilostazol8. CHF or uncontrolled AP

9. Thrombocytopenia ( 100,000/mm3)10. Severe liver or renal dysfunction11. Pregnant, breast-feeding, or of child-

bearing potential12. Malignant tumor requiring treatment13. For aspirin user: Hx of hypersensitivity to

aspirin or salicylic acid analogues / Current peptic ulcer / Aspirin-induced asthma or its history

14. For clopidogrel user: Hx of hypersensitivity to clopidogrel

15. Participating in any other clinical studies16. Unsuitable for trial enrollment, as

judged by the investigator

Trial treatment

Estimated sample size: 4000 patients

Aspirin 81~100 mg or Clopidogrel 50~75mg

Cilostazol (Pletaal) 100mg, BID + Aspirin orCilostazol (Pletaal) 100mg, BID + ClopidogrelR

Aspirin81~100 mg

or Clopidogrel50~75mg

MONOTHERAPY

DUAL THERAPY

Efficacy outcomesPrimary: Recurrence of ischemic strokeSecondary:

1. Any stroke (ischemic or hemorrhagic) 2. Hemorrhagic stroke (intracerebral or subarachnoid) 3. Ischemic stroke or TIA4. Death from any cause5. Composite of stroke, MI, and vascular death6. all vascular events, including stroke, MI, and others*

* aortic dissection; aortic rupture; PE; CHF, AP or PAD requiring hospitalization; revascularization of an aorta, coronary, cephalocervical, and peripheral arteries

Safety outcomes

1. Severe or life-threatening bleeding (GUSTO classification*)

2. Intracranial hemorrhage3. Any adverse events4. Serious adverse events5. Bleeding adverse events

ICH (hemorrhagic stroke, subdural or epidural hemorrhage) and bleeding resulting in substantial hemodynamic compromise requiring treatment

RESULTS

Flow Diagram

Baseline characteristics 1N (%), meanSD, or median (IQR)

Dual therapy(N=932)

Monotherapy(N=947)

Age, years 69.69.2 69.79.2Female sex 295 (31.7) 264 (27.9)Japanese 932 (100.0) 947 (100.0)BMI 23.93.6 23.73.4SBP, mm Hg 136 (126149) 138 (126151)DBP, mm Hg 78 (7087) 79 (7088)Hypertension 781 (83.8) 789 (83.3)Dyslipidemia 492 (52.8) 528 (55.8)Diabetes mellitus 346 (37.1) 355 (37.5)Chronic kidney disease 70 (7.5) 49 (5.2)Peripheral arterial disease 27 (2.9) 22 (2.3)Hx of ischemic stroke * 125 (13.4) 147 (15.5)Hx of ischemic heart disease 48 (5.2) 48 (5.1)Current smoking 259 (27.8) 275 (29.0)

* Except the qualifying one for this trial

Baseline characteristics 2N (%) or median (IQR)

Dual therapy(N=932)

Monotherapy(N=947)

Intracranial artery stenosis 275 (29.5) 272 (28.7)Extracranial artery stenosis 116 (12.4) 137 (14.5)mRS at randomization of 0-1 843 (90.5) 855 (90.3)Antiplatelets at randomization

Aspirin 383 (41.1) 380 (40.1)Clopidogrel 549 (58.9) 567 (59.9)

Stroke subtypeLacunar 464 (49.8) 461 (48.7)Atherothrombotic 389 (41.7) 399 (42.1)

Infarct locationSupratentorial 688 (73.8) 698 (73.7)Infratentorial 216 (23.2) 214 (22.6)

Median time to randomization after index events, days 27 (13-63) 25 (13-64)

Primary efficacy outcome: Recurrence of ischemic stroke

No. at risk

Monotherapy 947 764 628 426 283 152 79 22 0

0

5

10

15

20

25

Perc

enta

ge o

f pat

ient

s with

eve

nt

Days since start of observations0 183 366 548 731 913 1096 1278 1461

11.4Monotherapy

No. of patients947

No. of events64Monotherapy

Annual event rate4.5%/y

Even

t rat

e.

Days .

F2A

A. Primary efficacy outcomeDays since start of observationsPercentage of patients with eventDays since start of observationsPercentage of patients with event

0000

0.100.10

0.10.10729613730.10.2111932418

10.107296137340.2111932418

10.2187835340.3209719071

20.2187835360.3209719071

20.330771427360.4307505724

40.3307714273140.4307505724

40.5565227944140.5406504062

80.5565227944170.5406504062

80.6712211534170.6510381416

170.6712211534210.6510381416

170.78890928210.7619186794

250.78890928280.7619186794

250.9082968741280.8732969974

340.9082968741300.8732969974

341.0310870886300.9855582692

411.0310870886320.9855582692

411.1557330746321.0982026853

471.1557330746411.0982026853

471.282132393411.2118829121

631.282132393451.2118829121

No. at risk631.4098398543451.3256941069

Dual therapy93269157641127615475250731.4098398543471.3256941069

Monotherapy94776462842628315279220731.5383798284471.4395053017

791.5383798284501.4395053017

Figure 2. Kaplan-Meier analysis of outcomes791.6674252022501.5534480701

Analysis Set: ITT871.6674252022811.5534480701

871.7978397576811.6698151528

1901.7978397576821.6698151528

1901.9414101673821.7861822354

1981.9414101673851.7861822354

1982.0856139759851.9026873573

2652.0856139759901.9026873573

2652.2344200337902.1365307725

3292.23442003371022.1365307725

3292.38741781141022.2547233681

3502.38741781141092.2547233681

3502.54639595831092.3737797343

3642.54639595831112.3737797343

3642.71213338011112.4929814685

4432.71213338011162.4929814685

4432.90289390291162.6127689605

4452.90289390291242.6127689605

4453.09365442571242.7331487269

4603.09365442571262.7331487269

4603.29101969161262.8535284934

4673.29101969161272.8535284934

4673.49083163441272.9739082598

4823.49083163441332.9739082598

4823.69358198811333.0948884241

4833.69358198811363.0948884241

4833.89676008521363.2160198135

6653.89676008521513.2160198135

6654.19429333571513.3376077283

8974.19429333571633.3376077283

8974.74490084531633.4601202661

14354.74490084531673.4601202661

1673.5831010046

1703.5831010046

1703.7063962718

1783.7063962718

1783.8308066126

2043.8308066126

2043.9585213448

2063.9585213448

2064.0864061366

2074.0864061366

2074.2144616692

2214.2144616692

2214.3430328616

2444.3430328616

2444.6022658348

2724.6022658348

2724.7331269242

2994.7331269242

2994.8659956454

3044.8659956454

3044.9990501969

3194.9990501969

3195.1334221203

3315.1334221203

3315.269334123

3565.269334123

3565.4128654349

3685.4128654349

3685.564690691

3795.564690691

3795.7228737887

3985.7228737887

3985.8879825912

4385.8879825912

4386.0648848795

4556.0648848795

4556.2462268006

4686.2462268006

4686.4326160118

4826.4326160118

4826.6247461637

4906.6247461637

4906.8188735105

5146.8188735105

5147.0192630299

5507.0192630299

5507.2375276706

5727.2375276706

5727.4665708122

6047.4665708122

6047.706294722

6077.706294722

6077.9472704538

6197.9472704538

6198.1927443993

7978.1927443993

7978.5784891707

8468.5784891707

8469.0266338316

9349.0266338316

9349.7210870085

9999.7210870085

99910.564815167

100110.564815167

100111.416578832

143411.416578832

&"Times New Roman," CSPS.com

&"Times New Roman"&9&F / &A&"Times New Roman"&9&P / &N&"Times New Roman"&9 2018/12/26

Percentage of patients with event00.10.1446614141717212128283030323241414545474750508181828285859090102102109109111111116116124124126126127127133133136136151151163163167167170170178178204204206206207207221221244244272272299299304304319319331331356356368368379379398398438438455455468468482482490490514514550550572572604604607607619619797797846846934934999999100110011434000.211193241799999990.211193241799999990.320971907100000010.320971907100000010.430750572399999980.430750572399999980.540650406200000040.540650406200000040.651038141599999950.651038141599999950.761918679400000020.761918679400000020.87329699740.87329699740.98555826920.98555826921.09820268531.09820268531.21188291210000011.21188291210000011.32569410689999991.32569410689999991.43950530169999991.43950530169999991.55344807011.55344807011.66981515281.66981515281.78618223540000011.78618223540000011.90268735731.90268735732.13653077252.13653077252.25472336810000012.25472336810000012.37377973430000022.37377973430000022.49298146852.49298146852.61276896052.61276896052.73314872690000012.73314872690000012.85352849339999982.85352849339999982.97390825982.97390825983.09488842410000013.09488842410000013.21601981353.21601981353.33760772830000013.33760772830000013.46012026610000013.46012026610000013.58310100463.58310100463.70639627180000013.70639627180000013.83080661263.83080661263.95852134479999983.95852134479999984.08640613664.08640613664.21446166920000034.21446166920000034.34303286160000024.34303286160000024.60226583479999984.60226583479999984.73312692419999964.73312692419999964.86599564544.86599564544.99905019689999994.99905019689999995.13342212029999975.13342212029999975.26933412300000015.26933412300000015.41286543489999965.41286543489999965.5646906915.5646906915.72287378870000035.72287378870000035.88798259120000015.88798259120000016.06488487950000016.06488487950000016.24622680059999976.24622680059999976.43261601180000046.43261601180000046.62474616370000026.62474616370000026.81887351049999966.81887351049999967.01926302990000037.01926302990000037.23752767059999967.23752767059999967.46657081219999967.46657081219999967.7062947227.7062947227.94727045379999997.94727045379999998.19274439930000048.19274439930000048.57848917069999938.57848917069999939.02663383159999999.02663383159999999.72108700849999969.721087008499999610.56481516700000110.56481516700000111.41657883200000111.41657883200000100.10.1112244881717252534344141474763637373797987871901901981982652653293293503503643644434434454454604604674674824824834836656658978971435000.10729613730.10729613730.218783530.218783530.330771427299999980.330771427299999980.556522794399999960.556522794399999960.671221153399999990.671221153399999990.788909280000000050.788909280000000050.908296874100000040.908296874100000041.03108708860000011.03108708860000011.15573307460000011.15573307460000011.28213239299999991.28213239299999991.40983985429999991.40983985429999991.53837982840000011.53837982840000011.66742520221.66742520221.79783975761.79783975761.94141016729999991.94141016729999992.08561397589999992.08561397589999992.23442003370000022.23442003370000022.38741781140000022.38741781140000022.54639595830000022.54639595830000022.71213338012.71213338012.90289390289999982.90289390289999983.09365442573.09365442573.29101969159999993.29101969159999993.49083163440000013.49083163440000013.69358198813.69358198813.89676008519999993.89676008519999994.19429333570000034.19429333570000034.74490084530000014.7449008453000001

Days since start of observations

Percentage of patients with event

Slide


0000

0.100.10

0.10.10729613730.10.2111932418

10.107296137340.2111932418

10.2187835340.3209719071

20.2187835360.3209719071

20.330771427360.4307505724

40.3307714273140.4307505724

40.5565227944140.5406504062

80.5565227944170.5406504062

80.6712211534170.6510381416

170.6712211534210.6510381416

170.78890928210.7619186794

250.78890928280.7619186794

250.9082968741280.8732969974

340.9082968741300.8732969974

341.0310870886300.9855582692

411.0310870886320.9855582692

411.1557330746321.0982026853

471.1557330746411.0982026853

471.282132393411.2118829121

631.282132393451.2118829121

No. at risk631.4098398543451.3256941069

Dual therapy93269157641127615475250731.4098398543471.3256941069

Monotherapy94776462842628315279220731.5383798284471.4395053017

791.5383798284501.4395053017


Analysis Set: ITT871.6674252022811.5534480701

871.7978397576811.6698151528

1901.7978397576821.6698151528

1901.9414101673821.7861822354

1981.9414101673851.7861822354

1982.0856139759851.9026873573

2652.0856139759901.9026873573

2652.2344200337902.1365307725

3292.23442003371022.1365307725

3292.38741781141022.2547233681

3502.38741781141092.2547233681

3502.54639595831092.3737797343

3642.54639595831112.3737797343

3642.71213338011112.4929814685

4432.71213338011162.4929814685

4432.90289390291162.6127689605

4452.90289390291242.6127689605

4453.09365442571242.7331487269

4603.09365442571262.7331487269

4603.29101969161262.8535284934

4673.29101969161272.8535284934

4673.49083163441272.9739082598

4823.49083163441332.9739082598

4823.69358198811333.0948884241

4833.69358198811363.0948884241

4833.89676008521363.2160198135

6653.89676008521513.2160198135

6654.19429333571513.3376077283

8974.19429333571633.3376077283

8974.74490084531633.4601202661

14354.74490084531673.4601202661

1673.5831010046

1703.5831010046

1703.7063962718

1783.7063962718

1783.8308066126

2043.8308066126

2043.9585213448

2063.9585213448

2064.0864061366

2074.0864061366

2074.2144616692

2214.2144616692

2214.3430328616

2444.3430328616

2444.6022658348

2724.6022658348

2724.7331269242

2994.7331269242

2994.8659956454

3044.8659956454

3044.9990501969

3194.9990501969

3195.1334221203

3315.1334221203

3315.269334123

3565.269334123

3565.4128654349

3685.4128654349

3685.564690691

3795.564690691

3795.7228737887

3985.7228737887

3985.8879825912

4385.8879825912

4386.0648848795

4556.0648848795

4556.2462268006

4686.2462268006

4686.4326160118

4826.4326160118

4826.6247461637

4906.6247461637

4906.8188735105

5146.8188735105

5147.0192630299

5507.0192630299

5507.2375276706

5727.2375276706

5727.4665708122

6047.4665708122

6047.706294722

6077.706294722

6077.9472704538

6197.9472704538

6198.1927443993

7978.1927443993

7978.5784891707

8468.5784891707

8469.0266338316

9349.0266338316

9349.7210870085

9999.7210870085

99910.564815167

100110.564815167

100111.416578832

143411.416578832






Slide (2)


0000

0.100.10

0.10.10729613730.10.2111932418

10.107296137340.2111932418

10.2187835340.3209719071

20.2187835360.3209719071

20.330771427360.4307505724

40.3307714273140.4307505724

40.5565227944140.5406504062

80.5565227944170.5406504062

80.6712211534170.6510381416

170.6712211534210.6510381416

170.78890928210.7619186794

250.78890928280.7619186794

250.9082968741280.8732969974

340.9082968741300.8732969974

341.0310870886300.9855582692

411.0310870886320.9855582692

411.1557330746321.0982026853

471.1557330746411.0982026853

471.282132393411.2118829121

631.282132393451.2118829121

No. at risk631.4098398543451.3256941069

731.4098398543471.3256941069

Monotherapy94776462842628315279220731.5383798284471.4395053017

791.5383798284501.4395053017


Analysis Set: ITT871.6674252022811.5534480701

871.7978397576811.6698151528

1901.7978397576821.6698151528

1901.9414101673821.7861822354

1981.9414101673851.7861822354

1982.0856139759851.9026873573

2652.0856139759901.9026873573

2652.2344200337902.1365307725

3292.23442003371022.1365307725

3292.38741781141022.2547233681

3502.38741781141092.2547233681

3502.54639595831092.3737797343

3642.54639595831112.3737797343

3642.71213338011112.4929814685

4432.71213338011162.4929814685

4432.90289390291162.6127689605

4452.90289390291242.6127689605

4453.09365442571242.7331487269

4603.09365442571262.7331487269

4603.29101969161262.8535284934

4673.29101969161272.8535284934

4673.49083163441272.9739082598

4823.49083163441332.9739082598

4823.69358198811333.0948884241

4833.69358198811363.0948884241

4833.89676008521363.2160198135

6653.89676008521513.2160198135

6654.19429333571513.3376077283

8974.19429333571633.3376077283

8974.74490084531633.4601202661

14354.74490084531673.4601202661

1673.5831010046

1703.5831010046

1703.7063962718

1783.7063962718

1783.8308066126

2043.8308066126

2043.9585213448

2063.9585213448

2064.0864061366

2074.0864061366

2074.2144616692

2214.2144616692

2214.3430328616

2444.3430328616

2444.6022658348

2724.6022658348

2724.7331269242

2994.7331269242

2994.8659956454

3044.8659956454

3044.9990501969

3194.9990501969

3195.1334221203

3315.1334221203

3315.269334123

3565.269334123

3565.4128654349

3685.4128654349

3685.564690691

3795.564690691

3795.7228737887

3985.7228737887

3985.8879825912

4385.8879825912

4386.0648848795

4556.0648848795

4556.2462268006

4686.2462268006

4686.4326160118

4826.4326160118

4826.6247461637

4906.6247461637

4906.8188735105

5146.8188735105

5147.0192630299

5507.0192630299

5507.2375276706

5727.2375276706

5727.4665708122

6047.4665708122

6047.706294722

6077.706294722

6077.9472704538

6197.9472704538

6198.1927443993

7978.1927443993

7978.5784891707

8468.5784891707

8469.0266338316

9349.0266338316

9349.7210870085

9999.7210870085

99910.564815167

100110.564815167

100111.416578832

143411.416578832



Percentage of patients with event00.10.1446614141717212128283030323241414545474750508181828285859090102102109109111111116116124124126126127127133133136136151151163163167167170170178178204204206206207207221221244244272272299299304304319319331331356356368368379379398398438438455455468468482482490490514514550550572572604604607607619619797797846846934934999999100110011434000.211193241799999990.211193241799999990.320971907100000010.320971907100000010.430750572399999980.430750572399999980.540650406200000040.540650406200000040.651038141599999950.651038141599999950.761918679400000020.761918679400000020.87329699740.87329699740.98555826920.98555826921.09820268531.09820268531.21188291210000011.21188291210000011.32569410689999991.32569410689999991.43950530169999991.43950530169999991.55344807011.55344807011.66981515281.66981515281.78618223540000011.78618223540000011.90268735731.90268735732.13653077252.13653077252.25472336810000012.25472336810000012.37377973430000022.37377973430000022.49298146852.49298146852.61276896052.61276896052.73314872690000012.73314872690000012.85352849339999982.85352849339999982.97390825982.97390825983.09488842410000013.09488842410000013.21601981353.21601981353.33760772830000013.33760772830000013.46012026610000013.46012026610000013.58310100463.58310100463.70639627180000013.70639627180000013.83080661263.83080661263.95852134479999983.95852134479999984.08640613664.08640613664.21446166920000034.21446166920000034.34303286160000024.34303286160000024.60226583479999984.60226583479999984.73312692419999964.73312692419999964.86599564544.86599564544.99905019689999994.99905019689999995.13342212029999975.13342212029999975.26933412300000015.26933412300000015.41286543489999965.41286543489999965.5646906915.5646906915.72287378870000035.72287378870000035.88798259120000015.88798259120000016.06488487950000016.06488487950000016.24622680059999976.24622680059999976.43261601180000046.43261601180000046.62474616370000026.62474616370000026.81887351049999966.81887351049999967.01926302990000037.01926302990000037.23752767059999967.23752767059999967.46657081219999967.46657081219999967.7062947227.7062947227.94727045379999997.94727045379999998.19274439930000048.19274439930000048.57848917069999938.57848917069999939.02663383159999999.02663383159999999.72108700849999969.721087008499999610.56481516700000110.56481516700000111.41657883200000111.416578832000001



Primary efficacy outcome: Recurrence of ischemic stroke

No. at riskDual therapy 932 691 576 411 276 154 75 25 0Monotherapy 947 764 628 426 283 152 79 22 0

0

5

10

15

20

25

Perc

enta

ge o

f pat

ient

s with

eve

nt


11.4

4.7

Monotherapy

Dual therapy

No. of patients932947

No. of events2964

Dual therapyMonotherapy

Hazard ratio: 0.49 (95%CI: 0.31-0.76)P=0.0010

Annual event rate2.2%/y4.5%/y

Even

t rat

e.

Days .

F2A


0000

0.100.10

0.10.10729613730.10.2111932418

10.107296137340.2111932418

10.2187835340.3209719071

20.2187835360.3209719071

20.330771427360.4307505724

40.3307714273140.4307505724

40.5565227944140.5406504062

80.5565227944170.5406504062

80.6712211534170.6510381416

170.6712211534210.6510381416

170.78890928210.7619186794

250.78890928280.7619186794

250.9082968741280.8732969974

340.9082968741300.8732969974

341.0310870886300.9855582692

411.0310870886320.9855582692

411.1557330746321.0982026853

471.1557330746411.0982026853

471.282132393411.2118829121

631.282132393451.2118829121

No. at risk631.4098398543451.3256941069

Dual therapy93269157641127615475250731.4098398543471.3256941069

Monotherapy94776462842628315279220731.5383798284471.4395053017

791.5383798284501.4395053017


Analysis Set: ITT871.6674252022811.5534480701

871.7978397576811.6698151528

1901.7978397576821.6698151528

1901.9414101673821.7861822354

1981.9414101673851.7861822354

1982.0856139759851.9026873573

2652.0856139759901.9026873573

2652.2344200337902.1365307725

3292.23442003371022.1365307725

3292.38741781141022.2547233681

3502.38741781141092.2547233681

3502.54639595831092.3737797343

3642.54639595831112.3737797343

3642.71213338011112.4929814685

4432.71213338011162.4929814685

4432.90289390291162.6127689605

4452.90289390291242.6127689605

4453.09365442571242.7331487269

4603.09365442571262.7331487269

4603.29101969161262.8535284934

4673.29101969161272.8535284934

4673.49083163441272.9739082598

4823.49083163441332.9739082598

4823.69358198811333.0948884241

4833.69358198811363.0948884241

4833.89676008521363.2160198135

6653.89676008521513.2160198135

6654.19429333571513.3376077283

8974.19429333571633.3376077283

8974.74490084531633.4601202661

14354.74490084531673.4601202661

1673.5831010046

1703.5831010046

1703.7063962718

1783.7063962718

1783.8308066126

2043.8308066126

2043.9585213448

2063.9585213448

2064.0864061366

2074.0864061366

2074.2144616692

2214.2144616692

2214.3430328616

2444.3430328616

2444.6022658348

2724.6022658348

2724.7331269242

2994.7331269242

2994.8659956454

3044.8659956454

3044.9990501969

3194.9990501969

3195.1334221203

3315.1334221203

3315.269334123

3565.269334123

3565.4128654349

3685.4128654349

3685.564690691

3795.564690691

3795.7228737887

3985.7228737887

3985.8879825912

4385.8879825912

4386.0648848795

4556.0648848795

4556.2462268006

4686.2462268006

4686.4326160118

4826.4326160118

4826.6247461637

4906.6247461637

4906.8188735105

5146.8188735105

5147.0192630299

5507.0192630299

5507.2375276706

5727.2375276706

5727.4665708122

6047.4665708122

6047.706294722

6077.706294722

6077.9472704538

6197.9472704538

6198.1927443993

7978.1927443993

7978.5784891707

8468.5784891707

8469.0266338316

9349.0266338316

9349.7210870085

9999.7210870085

99910.564815167

100110.564815167

100111.416578832

143411.416578832






Slide


0000

0.100.10

0.10.10729613730.10.2111932418

10.107296137340.2111932418

10.2187835340.3209719071

20.2187835360.3209719071

20.330771427360.4307505724

40.3307714273140.4307505724

40.5565227944140.5406504062

80.5565227944170.5406504062

80.6712211534170.6510381416

170.6712211534210.6510381416

170.78890928210.7619186794

250.78890928280.7619186794

250.9082968741280.8732969974

340.9082968741300.8732969974

341.0310870886300.9855582692

411.0310870886320.9855582692

411.1557330746321.0982026853

471.1557330746411.0982026853

471.282132393411.2118829121

631.282132393451.2118829121

No. at risk631.4098398543451.3256941069

Dual therapy93269157641127615475250731.4098398543471.3256941069

Monotherapy94776462842628315279220731.5383798284471.4395053017

791.5383798284501.4395053017


Analysis Set: ITT871.6674252022811.5534480701

871.7978397576811.6698151528

1901.7978397576821.6698151528

1901.9414101673821.7861822354

1981.9414101673851.7861822354

1982.0856139759851.9026873573

2652.0856139759901.9026873573

2652.2344200337902.1365307725

3292.23442003371022.1365307725

3292.38741781141022.2547233681

3502.38741781141092.2547233681

3502.54639595831092.3737797343

3642.54639595831112.3737797343

3642.71213338011112.4929814685

4432.71213338011162.4929814685

4432.90289390291162.6127689605

4452.90289390291242.6127689605

4453.09365442571242.7331487269

4603.09365442571262.7331487269

4603.29101969161262.8535284934

4673.29101969161272.8535284934

4673.49083163441272.9739082598

4823.49083163441332.9739082598

4823.69358198811333.0948884241

4833.69358198811363.0948884241

4833.89676008521363.2160198135

6653.89676008521513.2160198135

6654.19429333571513.3376077283

8974.19429333571633.3376077283

8974.74490084531633.4601202661

14354.74490084531673.4601202661

1673.5831010046

1703.5831010046

1703.7063962718

1783.7063962718

1783.8308066126

2043.8308066126

2043.9585213448

2063.9585213448

2064.0864061366

2074.0864061366

2074.2144616692

2214.2144616692

2214.3430328616

2444.3430328616

2444.6022658348

2724.6022658348

2724.7331269242

2994.7331269242

2994.8659956454

3044.8659956454

3044.9990501969

3194.9990501969

3195.1334221203

3315.1334221203

3315.269334123

3565.269334123

3565.4128654349

3685.4128654349

3685.564690691

3795.564690691

3795.7228737887

3985.7228737887

3985.8879825912

4385.8879825912

4386.0648848795

4556.0648848795

4556.2462268006

4686.2462268006

4686.4326160118

4826.4326160118

4826.6247461637

4906.6247461637

4906.8188735105

5146.8188735105

5147.0192630299

5507.0192630299

5507.2375276706

5727.2375276706

5727.4665708122

6047.4665708122

6047.706294722

6077.706294722

6077.9472704538

6197.9472704538

6198.1927443993

7978.1927443993

7978.5784891707

8468.5784891707

8469.0266338316

9349.0266338316

9349.7210870085

9999.7210870085

99910.564815167

100110.564815167

100111.416578832

143411.416578832






Slide (2)


0000

0.100.10

0.10.10729613730.10.2111932418

10.107296137340.2111932418

10.2187835340.3209719071

20.2187835360.3209719071

20.330771427360.4307505724

40.3307714273140.4307505724

40.5565227944140.5406504062

80.5565227944170.5406504062

80.6712211534170.6510381416

170.6712211534210.6510381416

170.78890928210.7619186794

250.78890928280.7619186794

250.9082968741280.8732969974

340.9082968741300.8732969974

341.0310870886300.9855582692

411.0310870886320.9855582692

411.1557330746321.0982026853

471.1557330746411.0982026853

471.282132393411.2118829121

631.282132393451.2118829121

No. at risk631.4098398543451.3256941069

731.4098398543471.3256941069

Monotherapy94776462842628315279220731.5383798284471.4395053017

791.5383798284501.4395053017


Analysis Set: ITT871.6674252022811.5534480701

871.7978397576811.6698151528

1901.7978397576821.6698151528

1901.9414101673821.7861822354

1981.9414101673851.7861822354

1982.0856139759851.9026873573

2652.0856139759901.9026873573

2652.2344200337902.1365307725

3292.23442003371022.1365307725

3292.38741781141022.2547233681

3502.38741781141092.2547233681

3502.54639595831092.3737797343

3642.54639595831112.3737797343

3642.71213338011112.4929814685

4432.71213338011162.4929814685

4432.90289390291162.6127689605

4452.90289390291242.6127689605

4453.09365442571242.7331487269

4603.09365442571262.7331487269

4603.29101969161262.8535284934

4673.29101969161272.8535284934

4673.49083163441272.9739082598

4823.49083163441332.9739082598

4823.69358198811333.0948884241

4833.69358198811363.0948884241

4833.89676008521363.2160198135

6653.89676008521513.2160198135

6654.19429333571513.3376077283

8974.19429333571633.3376077283

8974.74490084531633.4601202661

14354.74490084531673.4601202661

1673.5831010046

1703.5831010046

1703.7063962718

1783.7063962718

1783.8308066126

2043.8308066126

2043.9585213448

2063.9585213448

2064.0864061366

2074.0864061366

2074.2144616692

2214.2144616692

2214.3430328616

2444.3430328616

2444.6022658348

2724.6022658348

2724.7331269242

2994.7331269242

2994.8659956454

3044.8659956454

3044.9990501969

3194.9990501969

3195.1334221203

3315.1334221203

3315.269334123

3565.269334123

3565.4128654349

3685.4128654349

3685.564690691

3795.564690691

3795.7228737887

3985.7228737887

3985.8879825912

4385.8879825912

4386.0648848795

4556.0648848795

4556.2462268006

4686.2462268006

4686.4326160118

4826.4326160118

4826.6247461637

4906.6247461637

4906.8188735105

5146.8188735105

5147.0192630299

5507.0192630299

5507.2375276706

5727.2375276706

5727.4665708122

6047.4665708122

6047.706294722

6077.706294722

6077.9472704538

6197.9472704538

6198.1927443993

7978.1927443993

7978.5784891707

8468.5784891707

8469.0266338316

9349.0266338316

9349.7210870085

9999.7210870085

99910.564815167

100110.564815167

100111.416578832

143411.416578832



Percentage of patients with event00.10.1446614141717212128283030323241414545474750508181828285859090102102109109111111116116124124126126127127133133136136151151163163167167170170178178204204206206207207221221244244272272299299304304319319331331356356368368379379398398438438455455468468482482490490514514550550572572604604607607619619797797846846934934999999100110011434000.211193241799999990.211193241799999990.320971907100000010.320971907100000010.430750572399999980.430750572399999980.540650406200000040.540650406200000040.651038141599999950.651038141599999950.761918679400000020.761918679400000020.87329699740.87329699740.98555826920.98555826921.09820268531.09820268531.21188291210000011.21188291210000011.32569410689999991.32569410689999991.43950530169999991.43950530169999991.55344807011.55344807011.66981515281.66981515281.78618223540000011.78618223540000011.90268735731.90268735732.13653077252.13653077252.25472336810000012.25472336810000012.37377973430000022.37377973430000022.49298146852.49298146852.61276896052.61276896052.73314872690000012.73314872690000012.85352849339999982.85352849339999982.97390825982.97390825983.09488842410000013.09488842410000013.21601981353.21601981353.33760772830000013.33760772830000013.46012026610000013.46012026610000013.58310100463.58310100463.70639627180000013.70639627180000013.83080661263.83080661263.95852134479999983.95852134479999984.08640613664.08640613664.21446166920000034.21446166920000034.34303286160000024.34303286160000024.60226583479999984.60226583479999984.73312692419999964.73312692419999964.86599564544.86599564544.99905019689999994.99905019689999995.13342212029999975.13342212029999975.26933412300000015.26933412300000015.41286543489999965.41286543489999965.5646906915.5646906915.72287378870000035.72287378870000035.88798259120000015.88798259120000016.06488487950000016.06488487950000016.24622680059999976.24622680059999976.43261601180000046.43261601180000046.62474616370000026.62474616370000026.81887351049999966.81887351049999967.01926302990000037.01926302990000037.23752767059999967.23752767059999967.46657081219999967.46657081219999967.7062947227.7062947227.94727045379999997.94727045379999998.19274439930000048.19274439930000048.57848917069999938.57848917069999939.02663383159999999.02663383159999999.72108700849999969.721087008499999610.56481516700000110.56481516700000111.41657883200000111.416578832000001



Composite of stroke, MI & vascular death


0

5

10

15

20

25

Perc

enta

ge o

f pat

ient

s with

eve

nt


21.4

6.2

Monotherapy

Dual therapy


No. of events3878

Dual therapyMonotherapy

Hazard ratio: 0.52 (95%CI: 0.35-0.77)P=0.0008

Even

t rat

e.

Days .

F2B

B. A secondary efficacy outcome of a composite of stroke, myocardial infraction, and vascular deathDays since start of observationsPercentage of patients with eventDays since start of observationsPercentage of patients with event

0000

0.100.10

0.10.10729613730.10.3167898627

10.107296137340.3167898627

10.2187835340.4264523601

20.2187835360.4264523601

20.330771427360.5361148575

40.3307714273140.5361148575

40.5565227944140.6458983952

80.5565227944170.6458983952

80.6712211534170.8664402412

150.6712211534210.8664402412

150.7883541473210.9770803748

170.7883541473280.9770803748

170.9059034907281.0882172094

200.9059034907291.0882172094

201.0238726532291.1999819357

251.0238726532301.1999819357

251.1429774996301.3118732359

291.1429774996321.3118732359

291.2644234732321.4241464177

341.2644234732411.4241464177

No. at risk341.3867723908411.5374519965

Dual therapy93269157641127615475250411.3867723908451.5374519965

Monotherapy94776462842628315279220411.5109704105451.6508881117

471.5109704105471.6508881117


Analysis Set: ITT631.6369154611501.7643242269

631.7641639534501.8778914822

731.7641639534811.8778914822

731.8922419665811.993875062

791.8922419665821.993875062

792.0208235629822.1098586418

872.0208235629852.1098586418

872.1507694202852.2259798059

932.1507694202902.2259798059

932.2824642124902.4590525597

1212.28246421241022.4590525597

1212.41669159671022.5768556363

1772.41669159671092.5768556363

1772.55669634331092.6955196367

1902.55669634331112.6955196367

1902.69915731361112.814328526

1982.69915731361162.814328526

1982.84224678811162.9337212428

2652.84224678811242.9337212428

2652.9899029481243.0537042821

3292.9899029481263.0537042821

3293.14171843641263.1736873214

3503.14171843641273.1736873214

3503.29946808061273.2936703606

3643.29946808061333.2936703606

3643.46392476751333.414251819

3833.46392476751363.414251819

3833.63880896181363.5349840042

4433.63880896181513.5349840042

4433.82775247371513.6561712103

4453.82775247371543.6561712103

4454.01669598551543.7778174587

4604.01669598551633.7778174587

4604.21218132971633.8997720627

4674.21218132971673.8997720627

4674.4100900461674.0221927352

4824.4100900461704.0221927352

4824.61090918451704.1449265041

4834.61090918451784.1449265041

4834.81215199221784.2687702683

6654.81215199221914.2687702683

6655.1068512121914.3948983707

6885.1068512121954.3948983707

6885.40714598661954.5211930889

6895.40714598662044.5211930889

6895.70839711412044.6479909732

8975.70839711412064.6479909732

8976.25030287782064.7749576963

14356.25030287782074.7749576963

2074.9020939344

2214.9020939344

2215.0297421304

2325.0297421304

2325.1575621275

2445.1575621275

2445.4145877044

2725.4145877044

2725.5443344977

2995.5443344977

2995.6760718276

3045.6760718276

3045.8079934054

3195.8079934054

3195.9412211375

3315.9412211375

3316.075975835

3566.075975835

3566.2182849626

3686.2182849626

3686.3688174105

3796.3688174105

3796.5256535622

3986.5256535622

3986.6893564456

4046.6893564456

4046.8550947113

4386.8550947113

4387.0301791197

4557.0301791197

4557.2096575384

4687.2096575384

4687.3941313803

4727.3941313803

4727.5800869397

4827.5800869397

4827.7698608885

4907.7698608885

4907.9616075395

4917.9616075395

4918.1537544966

5148.1537544966

5148.3512733041

5508.3512733041

5508.5664111602

5528.5664111602

5528.7830784324

5728.7830784324

5729.0083053992

6049.0083053992

6049.244035178

6079.244035178

6079.4809959216

6199.4809959216

6199.7223799325

6559.7223799325

6559.9759687529

7979.9759687529

79710.354220985

84610.354220985

84610.793661078

86910.793661078

86911.265652289

93411.265652289

93411.943013722

99911.943013722

99912.765976211

100112.765976211

100113.596776438

133313.596776438

133321.451614943

143421.451614943



Percentage of patients with event00.10.1446614141717212128282929303032324141454547475050818182828585909010210210910911111111611612412412612612712713313313613615115115415416316316716717017017817819119119519520420420620620720722122123223224424427227229929930430431931933133135635636836837937939839840440443843845545546846847247248248249049049149151451455055055255257257260460460760761961965565579779784684686986993493499999910011001133313331434000.316789862699999980.316789862699999980.426452360099999980.426452360099999980.536114857499999990.536114857499999990.645898395200000030.645898395200000030.866440241199999960.866440241199999960.977080374799999980.977080374799999981.08821720941.08821720941.19998193569999991.19998193569999991.31187323591.31187323591.42414641770000011.42414641770000011.53745199651.53745199651.65088811171.65088811171.76432422689999991.76432422689999991.87789148219999991.87789148219999991.99387506200000011.99387506200000012.10985864179999982.10985864179999982.22597980590000022.22597980590000022.45905255969999992.45905255969999992.57685563629999992.57685563629999992.69551963669999982.69551963669999982.81432852600000022.81432852600000022.93372124279999992.93372124279999993.05370428213.05370428213.17368732140000013.17368732140000013.29367036060000023.29367036060000023.4142518193.4142518193.53498400423.53498400423.65617121030000013.65617121030000013.77781745873.77781745873.89977206269999993.89977206269999994.02219273524.02219273524.14492650409999994.14492650409999994.26877026829999994.26877026829999994.39489837074.39489837074.52119308889999964.52119308889999964.64799097319999984.64799097319999984.77495769630000044.77495769630000044.90209393439999994.90209393439999995.02974213039999985.02974213039999985.15756212750000035.15756212750000035.41458770439999975.41458770439999975.54433449770000045.54433449770000045.67607182760000045.67607182760000045.80799340540000045.80799340540000045.94122113750000045.94122113750000046.07597583500000046.07597583500000046.21828496260000036.21828496260000036.36881741050000026.36881741050000026.52565356219999966.52565356219999966.68935644559999966.68935644559999966.85509471129999966.85509471129999967.03017911969999967.03017911969999967.20965753840000017.20965753840000017.39413138030000027.39413138030000027.58008693970000017.58008693970000017.76986088850000027.76986088850000027.96160753950000017.96160753950000018.15375449659999958.15375449659999958.35127330409999948.35127330409999948.56641116019999958.56641116019999958.78307843248.78307843249.00830539919999939.00830539919999939.24403517800000079.24403517800000079.48099592159999999.48099592159999999.72237993250000099.72237993250000099.97596875290000019.975968752900000110.35422098510.35422098510.79366107810.79366107811.26565228911.26565228911.94301372211.94301372212.76597621112.76597621113.59677643799999913.59677643799999921.45161494299999921.45161494299999900.10.11122448815151717202025252929343441414747636373737979878793931211211771771901901981982652653293293503503643643833834434434454454604604674674824824834836656656886886896898978971435000.10729613730.10729613730.218783530.218783530.330771427299999980.330771427299999980.556522794399999960.556522794399999960.671221153399999990.671221153399999990.788354147299999970.788354147299999970.905903490699999980.905903490699999981.02387265321.02387265321.14297749959999991.14297749959999991.26442347319999991.26442347319999991.38677239081.38677239081.51097041049999991.51097041049999991.63691546110000011.63691546110000011.76416395341.76416395341.89224196650000011.89224196650000012.02082356292.02082356292.15076942020000012.15076942020000012.28246421239999992.28246421239999992.41669159670000022.41669159670000022.55669634330000012.55669634330000012.69915731360000022.69915731360000022.84224678810000022.84224678810000022.98990294800000012.98990294800000013.14171843640000013.14171843640000013.29946808060000013.29946808060000013.46392476753.46392476753.63880896180000013.63880896180000013.82775247369999993.82775247369999994.01669598550000024.01669598550000024.21218132969999994.21218132969999994.41009004599999974.41009004599999974.61090918449999964.61090918449999964.81215199219999964.81215199219999965.10685121199999965.10685121199999965.40714598659999985.40714598659999985.70839711410000035.70839711410000036.25030287780000036.2503028778000003



Slide

B. A secondary efficacy outcome of a composite of stroke, myocardial infraction, and vascular deathDays since start of observationsPercentage of patients with eventDays since start of observationsPercentage of patients with event

0000

0.100.10

0.10.10729613730.10.3167898627

10.107296137340.3167898627

10.2187835340.4264523601

20.2187835360.4264523601

20.330771427360.5361148575

40.3307714273140.5361148575

40.5565227944140.6458983952

80.5565227944170.6458983952

80.6712211534170.8664402412

150.6712211534210.8664402412

150.7883541473210.9770803748

170.7883541473280.9770803748

170.9059034907281.0882172094

200.9059034907291.0882172094

201.0238726532291.1999819357

251.0238726532301.1999819357

251.1429774996301.3118732359

291.1429774996321.3118732359

291.2644234732321.4241464177

341.2644234732411.4241464177

No. at risk341.3867723908411.5374519965

Dual therapy93269157641127615475250411.3867723908451.5374519965

Monotherapy94776462842628315279220411.5109704105451.6508881117

471.5109704105471.6508881117


Analysis Set: ITT631.6369154611501.7643242269

631.7641639534501.8778914822

731.7641639534811.8778914822

731.8922419665811.993875062

791.8922419665821.993875062

792.0208235629822.1098586418

872.0208235629852.1098586418

872.1507694202852.2259798059

932.1507694202902.2259798059

932.2824642124902.4590525597

1212.28246421241022.4590525597

1212.41669159671022.5768556363

1772.41669159671092.5768556363

1772.55669634331092.6955196367

1902.55669634331112.6955196367

1902.69915731361112.814328526

1982.69915731361162.814328526

1982.84224678811162.9337212428

2652.84224678811242.9337212428

2652.9899029481243.0537042821

3292.9899029481263.0537042821

3293.14171843641263.1736873214

3503.14171843641273.1736873214

3503.29946808061273.2936703606

3643.29946808061333.2936703606

3643.46392476751333.414251819

3833.46392476751363.414251819

3833.63880896181363.5349840042

4433.63880896181513.5349840042

4433.82775247371513.6561712103

4453.82775247371543.6561712103

4454.01669598551543.7778174587

4604.01669598551633.7778174587

4604.21218132971633.8997720627

4674.21218132971673.8997720627

4674.4100900461674.0221927352

4824.4100900461704.0221927352

4824.61090918451704.1449265041

4834.61090918451784.1449265041

4834.81215199221784.2687702683

6654.81215199221914.2687702683

6655.1068512121914.3948983707

6885.1068512121954.3948983707

6885.40714598661954.5211930889

6895.40714598662044.5211930889

6895.70839711412044.6479909732

8975.70839711412064.6479909732

8976.25030287782064.7749576963

14356.25030287782074.7749576963

2074.9020939344

2214.9020939344

2215.0297421304

2325.0297421304

2325.1575621275

2445.1575621275

2445.4145877044

2725.4145877044

2725.5443344977

2995.5443344977

2995.6760718276

3045.6760718276

3045.8079934054

3195.8079934054

3195.9412211375

3315.9412211375

3316.075975835

3566.075975835

3566.2182849626

3686.2182849626

3686.3688174105

3796.3688174105

3796.5256535622

3986.5256535622

3986.6893564456

4046.6893564456

4046.8550947113

4386.8550947113

4387.0301791197

4557.0301791197

4557.2096575384

4687.2096575384

4687.3941313803

4727.3941313803

4727.5800869397

4827.5800869397

4827.7698608885

4907.7698608885

4907.9616075395

4917.9616075395

4918.1537544966

5148.1537544966

5148.3512733041

5508.3512733041

5508.5664111602

5528.5664111602

5528.7830784324

5728.7830784324

5729.0083053992

6049.0083053992

6049.244035178

6079.244035178

6079.4809959216

6199.4809959216

6199.7223799325

6559.7223799325

6559.9759687529

7979.9759687529

79710.354220985

84610.354220985

84610.793661078

86910.793661078

86911.265652289

93411.265652289

93411.943013722

99911.943013722

99912.765976211

100112.765976211

100113.596776438

133313.596776438

133321.451614943

143421.451614943



Percentage of patients with event00.10.1446614141717212128282929303032324141454547475050818182828585909010210210910911111111611612412412612612712713313313613615115115415416316316716717017017817819119119519520420420620620720722122123223224424427227229929930430431931933133135635636836837937939839840440443843845545546846847247248248249049049149151451455055055255257257260460460760761961965565579779784684686986993493499999910011001133313331434000.316789862699999980.316789862699999980.426452360099999980.426452360099999980.536114857499999990.536114857499999990.645898395200000030.645898395200000030.866440241199999960.866440241199999960.977080374799999980.977080374799999981.08821720941.08821720941.19998193569999991.19998193569999991.31187323591.31187323591.42414641770000011.42414641770000011.53745199651.53745199651.65088811171.65088811171.76432422689999991.76432422689999991.87789148219999991.87789148219999991.99387506200000011.99387506200000012.10985864179999982.10985864179999982.22597980590000022.22597980590000022.45905255969999992.45905255969999992.57685563629999992.57685563629999992.69551963669999982.69551963669999982.81432852600000022.81432852600000022.93372124279999992.93372124279999993.05370428213.05370428213.17368732140000013.17368732140000013.29367036060000023.29367036060000023.4142518193.4142518193.53498400423.53498400423.65617121030000013.65617121030000013.77781745873.77781745873.89977206269999993.89977206269999994.02219273524.02219273524.14492650409999994.14492650409999994.26877026829999994.26877026829999994.39489837074.39489837074.52119308889999964.52119308889999964.64799097319999984.64799097319999984.77495769630000044.77495769630000044.90209393439999994.90209393439999995.02974213039999985.02974213039999985.15756212750000035.15756212750000035.41458770439999975.41458770439999975.54433449770000045.54433449770000045.67607182760000045.67607182760000045.80799340540000045.80799340540000045.94122113750000045.94122113750000046.07597583500000046.07597583500000046.21828496260000036.21828496260000036.36881741050000026.36881741050000026.52565356219999966.52565356219999966.68935644559999966.68935644559999966.85509471129999966.85509471129999967.03017911969999967.03017911969999967.20965753840000017.20965753840000017.39413138030000027.39413138030000027.58008693970000017.58008693970000017.76986088850000027.76986088850000027.96160753950000017.96160753950000018.15375449659999958.15375449659999958.35127330409999948.35127330409999948.56641116019999958.56641116019999958.78307843248.78307843249.00830539919999939.00830539919999939.24403517800000079.24403517800000079.48099592159999999.48099592159999999.72237993250000099.72237993250000099.97596875290000019.975968752900000110.35422098510.35422098510.79366107810.79366107811.26565228911.26565228911.94301372211.94301372212.76597621112.76597621113.59677643799999913.59677643799999921.45161494299999921.45161494299999900.10.11122448815151717202025252929343441414747636373737979878793931211211771771901901981982652653293293503503643643833834434434454454604604674674824824834836656656886886896898978971435000.10729613730.10729613730.218783530.218783530.330771427299999980.330771427299999980.556522794399999960.556522794399999960.671221153399999990.671221153399999990.788354147299999970.788354147299999970.905903490699999980.905903490699999981.02387265321.02387265321.14297749959999991.14297749959999991.26442347319999991.26442347319999991.38677239081.38677239081.51097041049999991.51097041049999991.63691546110000011.63691546110000011.76416395341.76416395341.89224196650000011.89224196650000012.02082356292.02082356292.15076942020000012.15076942020000012.28246421239999992.28246421239999992.41669159670000022.41669159670000022.55669634330000012.55669634330000012.69915731360000022.69915731360000022.84224678810000022.84224678810000022.98990294800000012.98990294800000013.14171843640000013.14171843640000013.29946808060000013.29946808060000013.46392476753.46392476753.63880896180000013.63880896180000013.82775247369999993.82775247369999994.01669598550000024.01669598550000024.21218132969999994.21218132969999994.41009004599999974.41009004599999974.61090918449999964.61090918449999964.81215199219999964.81215199219999965.10685121199999965.10685121199999965.40714598659999985.40714598659999985.70839711410000035.70839711410000036.25030287780000036.2503028778000003



Other secondary efficacy outcomes

*The number of events per 100 person-year

Outcome

Dual therapy (N=932)

Monotherapy(N=947)

HR (95% CI) PN (%) Annual event rate* N (%)

Annual event rate*

Any stroke 34 (3.6) 2.6 71 (7.5) 5.0 0.51 (0.34-0.77) 0.001

Ischemic stroke or TIA 32 (3.4) 2.4 69 (7.3) 4.9 0.50 (0.33-0.76)

Primary efficacy outcome according to subgroups 1

Primary efficacy outcome according to subgroups 2

Severe or life-threatening bleeding


0

5

10

15

20

25

Perc

enta

ge o

f pat

ient

s with

eve

nt


2.72.0

Monotherapy

Dual therapy


No. of events8

13Dual therapyMonotherapy

Hazard ratio: 0.66 (95%CI: 0.27-1.60)P=0.3539

Even

t rat

e.

Days .


F2C

C. Severe or life-threatening bleedingDays since start of observationsPercentage of patients with eventDays since start of observationsPercentage of patients with event

0000

150150

150.1179245283150.1107419712

220.1179245283290.1107419712

220.2375437804290.2237388694

930.23754378041070.2237388694

930.37181357341070.3452690292

1020.37181357341190.3452690292

1020.50773197231190.468147859

1210.50773197231490.468147859

1210.64439717571490.5933451572

1770.64439717571950.5933451572

1770.7869446691950.7246617422

4060.7869446692940.7246617422

4060.97273690742940.8627359262

10460.97273690744040.8627359262

10462.01512915054041.0391367519

14352.01512915054711.0391367519

4711.2378533448

5521.2378533448

5521.4718868677

6551.4718868677

No. at risk6551.7486512304

Dual therapy932691576411276154752508111.7486512304

Monotherapy947763627426283152792208112.1739817446

8692.1739817446

Figure 2. Kaplan-Meier analysis of outcomes8692.6915797248

Analysis Set: ITT14342.6915797248



Percentage of patients with event0151529291071071191191491491951952942944044044714715525526556558118118698691434000.11074197120.11074197120.223738869400000010.223738869400000010.345269029200000020.345269029200000020.4681478590.4681478590.593345157200000030.593345157200000030.724661742200000010.724661742200000010.862735926199999950.862735926199999951.03913675190000011.03913675190000011.23785334481.23785334481.47188686770000011.47188686770000011.74865123039999991.74865123039999992.17398174459999982.17398174459999982.69157972482.69157972480151522229393102102121121177177406406104610461435000.11792452830.11792452830.237543780399999990.237543780399999990.371813573399999990.371813573399999990.50773197230.50773197230.644397175699999990.644397175699999990.786944669000000040.786944669000000040.972736907399999960.972736907399999962.01512915052.0151291505



Slide


0000

150150

150.1179245283150.1107419712

220.1179245283290.1107419712

220.2375437804290.2237388694

930.23754378041070.2237388694

930.37181357341070.3452690292

1020.37181357341190.3452690292

1020.50773197231190.468147859

1210.50773197231490.468147859

1210.64439717571490.5933451572

1770.64439717571950.5933451572

1770.7869446691950.7246617422

4060.7869446692940.7246617422

4060.97273690742940.8627359262

10460.97273690744040.8627359262

10462.01512915054041.0391367519

14352.01512915054711.0391367519

4711.2378533448

5521.2378533448

5521.4718868677

6551.4718868677

No. at risk6551.7486512304

Dual therapy932691576411276154752508111.7486512304

Monotherapy947763627426283152792208112.1739817446

8692.1739817446








Severe or life-threatening bleeding


0

5

10

15

20

25

Perc

enta

ge o

f pat

ient

s with

eve

nt


2.72.0

Monotherapy

Dual therapy


No. of events8

13Dual therapyMonotherapy

Hazard ratio: 0.66 (95%CI: 0.27-1.60)P=0.3539

Even

t rat

e.

Days .


= Intracranial hemorrhage

F2C


0000

150150

150.1179245283150.1107419712

220.1179245283290.1107419712

220.2375437804290.2237388694

930.23754378041070.2237388694

930.37181357341070.3452690292

1020.37181357341190.3452690292

1020.50773197231190.468147859

1210.50773197231490.468147859

1210.64439717571490.5933451572

1770.64439717571950.5933451572

1770.7869446691950.7246617422

4060.7869446692940.7246617422

4060.97273690742940.8627359262

10460.97273690744040.8627359262

10462.01512915054041.0391367519

14352.01512915054711.0391367519

4711.2378533448

5521.2378533448

5521.4718868677

6551.4718868677

No. at risk6551.7486512304

Dual therapy932691576411276154752508111.7486512304

Monotherapy947763627426283152792208112.1739817446

8692.1739817446








Slide


0000

150150

150.1179245283150.1107419712

220.1179245283290.1107419712

220.2375437804290.2237388694

930.23754378041070.2237388694

930.37181357341070.3452690292

1020.37181357341190.3452690292

1020.50773197231190.468147859

1210.50773197231490.468147859

1210.64439717571490.5933451572

1770.64439717571950.5933451572

1770.7869446691950.7246617422

4060.7869446692940.7246617422

4060.97273690742940.8627359262

10460.97273690744040.8627359262

10462.01512915054041.0391367519

14352.01512915054711.0391367519

4711.2378533448

5521.2378533448

5521.4718868677

6551.4718868677

No. at risk6551.7486512304

Dual therapy932691576411276154752508111.7486512304

Monotherapy947763627426283152792208112.1739817446

8692.1739817446








Any adverse events

Including 26 pts with headache (all belonging to the dual therapy group) Including 59 pts with palpitation/tachycardia (all belonging to the dual therapy group)

System organ class (MedDRA)Efficacy endpoints such as stroke are included in adverse events.

Dual therapy Monotherapy(N=932) (N=947)

Total 255 (27.4%) 219 (23.1%)Nervous system 83 (8.9%) 91 (9.6%)Cardiac 78 (8.4%) 17 (1.8%)Gastrointestinal 27 (2.9%) 21 (2.2%)Infections and infestations 16 (1.7%) 20 (2.1%)Injury, poisoning and procedural complications 13 (1.4%) 17 (1.8%)Neoplasms benign, malignant & unspecified 16 (1.7%) 12 (1.3%)Skin and subcutaneous tissue 15 (1.6%) 12 (1.3%)Respiratory, thoracic and mediastinal 12 (1.3%) 11 (1.2%)Others 53 (5.7%) 55 (5.8%)

P=0.038

P

Serious adverse events



Total 87 (9.3%) 142 (15.0%)Nervous system 44 (4.7%) 79 (8.3%)Neoplasms benign, malignant & unspecified 12 (1.3%) 9 (1.0%)Infections and infestations 8 (0.9%) 12 (1.3%)Cardiac 9 (1.0%) 10 (1.1%)Injury, poisoning and procedural complications 8 (0.9%) 7 (0.7%)Gastrointestinal 2 (0.2%) 11 (1.2%)Others 13 (1.4%) 29 (3.1%)

p

Bleeding adverse events



Total 38 (4.1%) 33 (3.5%)Gastrointestinal 9 (1.0%) 9 (1.0%)Respiratory, thoracic and mediastinal 10 (1.1%) 6 (0.6%)Nervous system 5 (0.5%) 8 (0.8%)Injury, poisoning and procedural complications 4 (0.4%) 5 (0.5%)Skin and subcutaneous tissue 5 (0.5%) 3 (0.3%)Renal and urinary 5 (0.5%) 1 (0.1%)Blood and lymphatic system 1 (0.1%) 0 (0.0%)Eye 0 (0.0%) 1 (0.1%)

Summary of Results

Outcome HR (95% CI) P

Ischemic stroke 0.49 (0.31-0.76) 0.001

Composite of stroke, MI, & vascular death 0.52 (0.35-0.77)

Strength1. Routine use of MRI/MRA to identify infarct distribution and for

intracranial vascular imaging2. The first successful RCT of cilostazol + thienopyridines for stroke

Strength1. Routine use of MRI/MRA to identify infarct distribution and for

intracranial vascular imaging2. The first successful RCT of cilostazol + thienopyridines for stroke

Limitations

1. Enrollment: 47% of the planned number (1879/4000) 2. Open trial treatment 3. Ethnicity: limited to Japanese4. Discontinuation of trial medication within half a year

occurred in 1/5 of patients receiving the dual therapy

Conclusions In patients with high-risk stroke recurrence, the combination

of cilostazol with aspirin or clopidogrel had a lower risk of ischemic stroke and a similar risk of severe or life-threatening bleeding compared to aspirin or clopidogrel alone.

Addition of cilostazol to aspirin or clopidogrel is recommendable for the long-term use in the chronic stage of high-risk non-cardioembolic stroke for patients who are tolerable to headache and palpitation.

Committees Principal Investigator

Takenori Yamaguchi

Steering CommitteeShinichirou Uchiyama (CHAIR) Haruhiko HoshinoKazumi KimuraYasushi OkadaNobuyuki SakaiKotaro TanakaKazunori Toyoda

Protocol Authoring Committee

Kazunori Toyoda (CHAIR) Haruhiko Hoshino, Kazumi Kimura

Independent Data Monitoring Committee

Hiroaki Naritomi (CHAIR) Shinya GotoTatsuya Isomura

Event Evaluation CommitteeKazuo Minematsu (CHAIR) Kiyohiro HoukinMasayasu MatsumotoYasuo TerayamaHidekazu TomimotoTeiji TominagaSatoshi Yasuda

Statistical Analysis CommitteeHideki Orikasa (CHAIR)Naoko Kumagai

Clinical Sites by Enrollment58 Ichinomiya Nishi Hospital49 Kushiro Rosai Hospital36 Yuri Kumiai General Hospital34 Tokyo Women's Medical University Hospital

National Cerebral and Cardiovascular CenterNitobe Memorial Nakano General Hospital

32 Doutou neurosurgery30 Kobe City Medical Center General Hospital29 Shiroyama Hospital22 Ube Kohsan Central Hospital

Kobe Ekisaikai Hospital20 Seirei Memorial Hospital

Kurobe City HospitalSakurakai Hospital

19 NHO Kagoshima Medical Center18 Otaru General Hospital

Saga University Hospital17 Kashiwaba Neurosurgical Hospital

Date Red Cross HospitalMunicipal Tsuruga Hospital

16 Toho University Omori Medical CenterDaido HospitalJapanese Red Cross Society Himeji HospitalSt.Mary's Hospital

15 Sendai Medical CenterJCHO Tokyo Yamate Medical CenterTakagi Hospital

14 Sumoto Itsuki HospitalShimane University HospitalNHO Asahikawa Meidical CenterNakamura Memorial Hospital

13 NHO Kyushu Medical CenterJapan Red Cross Okayama Hospital

12 Sapporo Shiroishi Memorial HospitalAsahikawa Rehabilitation HospitalSouthern TOHOKU General HospitalSaiseikai Yokohamashi Tobu HospitalToyama University HospitalFujieda Heisei Memorial Hospital

11 Japanese Red Cross Asahikawa HospitalJikei UniversityYokohamashintoshi Neurosurgical Hospital

11 Hyogo College of Medicine HospitalSteel Memorial Yawata HospitalKawasaki Hospital

10 Ohkawara Neurosurgical HospitalRumoi Central ClinicIwate Medical UniversityJapanese Red Cross Fukushima HospitalTokyo Medical CenterJuntendo University HospitalJuntendo University Shizuoka HospitalAnjo Kosei HospitaTOYOTA Memorial HospitalToyota Kosei HospitalKanazawa Neurosurgical HospitalJCHO Hoshigaoka Medical CenterJOHAS Kyushu Rosai HospitalImamura General HospitalKita-Harima Medical CenterAtsuchi Neurosurgical HospitalShunan Memorial Hospital

9 Muroran City General HospitalShizuoka General HospitalNagoya Medical CenterSuzuka Kaisei HospitalYokkaichi Municipal HospitalMihara Memorial HospitalJapanese Red Cross Osaka HospitalYamaguchi University HospitalYame General HospitalKagoshima City Hospital

8 Hokkaido Neurosurgical Memorial HospitalResearch I. for Brain & Blood Vessels-AkitaOgaki Tokushukai HospitalJOHAS Chubu Rosai HospitalToyokawa City HospitalJapanese Red Cross Ise HospitalNHO Kyoto Medical CenterKansai Electric Power HospitalOsaka Medical College HospitalNHO Fukuoka-higashi Medical CenterTokushima Prefectural Central HospitalYamaga Chuo Hospital

7 NHO Kanagawa HospitalInuyama Chuo General HospitalKindai University HospitalOkayama University HospitalFukuoka Shin Mizumaki HospitalTobata Kyoritsu HospitalKokura Kinen HospitalFukuoka University Hospital

6 Iwate Prefectural Iwai HospitalAkita University HospitalSaitama Medical University HospitalShizuoka City Shimizu HospitalAoyama General HospitalToyama Red Cross HospitalNanto Municipal HospitalKanazawa Nishi HospitalHigashiosaka City Medical CenterIshinkai Yao General HospitalNHO Osaka National HospitalTakarazuka City HospitalHyogo Prefectural Awaji Medical CenterOnomichi Municipal HospitalJapanese Red Cross Fukoka HospitalSasebo City General HospitalObase HospitalMiyakonojo Medical Assocciation HospitalOsaka Neurosurgical HospitalJOHAS Yokohama Rosai HospitalOgachi Central Hospital

5 Kohnan HospitalIbaraki Prefectural Central HospitalItabashi Chuo Medical CenterShioda HospitalJapanese Red Cross Shizuoka HospitalJapanese Red Cross Nagoya Daini HospitalAsuke HospitalSaiseikai Matsusaka General HospitalShiga Univ. of Medical Science HospitalJapanese Red Cross Osaka HospitalIseikai HospitalNishiwaki Municipal HospitalShimane Prefectural Central HospitalSeiai Rehabilitation HospitalNishida HospitalUrazoe General HospitalShirakawa HospitalIzumino Hospital, BouchikaiJINSEI-KAI Hosogi Hospital

4 Kushiro City General HospitalNational Defense Medical CollegeKeio University HospitalNihon University School of MedicineOhkubo HospitalTokai UniversityNagoya City East Medical CenterKomaki City HospitalFukui Prefectural HospitalNagahama City HospitalUji-Tokushukai Medical CenterSakai City Medical CenterHyogo Prefectural Nishinomiya HospitalNishinomiya Kyouritsu Neurosurgical HpKitakyushu General HospitalShin Koga HospitalSato Daiichi HospitalKagawa University HospitalNoichi Chuo HospitalJA Onomichi General HospitalShinonoi General HospitalIwate Prefectural Kuji HospitalJunwakai Memorial HospitalMominoki HospitalKyoto Okamoto Memorial Hospital

Total 292 sitesover Japan joinedthe CSPS.com

Slide Number 1COIThe Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com)BackgroundCilostazol Stroke Prevention Studies (CSPS)PurposeTrial designTrial population: Inclusion criteria 1Trial population: Inclusion criteria 2Exclusion criteriaTrial treatmentEfficacy outcomesSafety outcomesSlide Number 13Flow DiagramBaseline characteristics 1Baseline characteristics 2Primary efficacy outcome: Recurrence of ischemic strokePrimary efficacy outcome: Recurrence of ischemic strokeComposite of stroke, MI & vascular deathOther secondary efficacy outcomesPrimary efficacy outcome according to subgroups 1Primary efficacy outcome according to subgroups 2Severe or life-threatening bleedingSevere or life-threatening bleedingAny adverse eventsSerious adverse eventsBleeding adverse eventsSummary of ResultsStrengthStrengthLimitationsConclusionsCommitteesClinical Sites by Enrollment

dual antiplatelet therapy using cilostazol for high-risk ...wcm/@sop/... · dual antiplatelet...

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