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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
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 (2)
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
731.4098398543471.3256941069
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 event00.10.1446614141717212128283030323241414545474750508181828285859090102102109109111111116116124124126126127127133133136136151151163163167167170170178178204204206206207207221221244244272272299299304304319319331331356356368368379379398398438438455455468468482482490490514514550550572572604604607607619619797797846846934934999999100110011434000.211193241799999990.211193241799999990.320971907100000010.320971907100000010.430750572399999980.430750572399999980.540650406200000040.540650406200000040.651038141599999950.651038141599999950.761918679400000020.761918679400000020.87329699740.87329699740.98555826920.98555826921.09820268531.09820268531.21188291210000011.21188291210000011.32569410689999991.32569410689999991.43950530169999991.43950530169999991.55344807011.55344807011.66981515281.66981515281.78618223540000011.78618223540000011.90268735731.90268735732.13653077252.13653077252.25472336810000012.25472336810000012.37377973430000022.37377973430000022.49298146852.49298146852.61276896052.61276896052.73314872690000012.73314872690000012.85352849339999982.85352849339999982.97390825982.97390825983.09488842410000013.09488842410000013.21601981353.21601981353.33760772830000013.33760772830000013.46012026610000013.46012026610000013.58310100463.58310100463.70639627180000013.70639627180000013.83080661263.83080661263.95852134479999983.95852134479999984.08640613664.08640613664.21446166920000034.21446166920000034.34303286160000024.34303286160000024.60226583479999984.60226583479999984.73312692419999964.73312692419999964.86599564544.86599564544.99905019689999994.99905019689999995.13342212029999975.13342212029999975.26933412300000015.26933412300000015.41286543489999965.41286543489999965.5646906915.5646906915.72287378870000035.72287378870000035.88798259120000015.88798259120000016.06488487950000016.06488487950000016.24622680059999976.24622680059999976.43261601180000046.43261601180000046.62474616370000026.62474616370000026.81887351049999966.81887351049999967.01926302990000037.01926302990000037.23752767059999967.23752767059999967.46657081219999967.46657081219999967.7062947227.7062947227.94727045379999997.94727045379999998.19274439930000048.19274439930000048.57848917069999938.57848917069999939.02663383159999999.02663383159999999.72108700849999969.721087008499999610.56481516700000110.56481516700000111.41657883200000111.416578832000001
Days since start of observations
Percentage of patients with event
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
Days since start of observations0 183 366 548 731 913 1096 1278 1461
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
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
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 (2)
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
731.4098398543471.3256941069
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 event00.10.1446614141717212128283030323241414545474750508181828285859090102102109109111111116116124124126126127127133133136136151151163163167167170170178178204204206206207207221221244244272272299299304304319319331331356356368368379379398398438438455455468468482482490490514514550550572572604604607607619619797797846846934934999999100110011434000.211193241799999990.211193241799999990.320971907100000010.320971907100000010.430750572399999980.430750572399999980.540650406200000040.540650406200000040.651038141599999950.651038141599999950.761918679400000020.761918679400000020.87329699740.87329699740.98555826920.98555826921.09820268531.09820268531.21188291210000011.21188291210000011.32569410689999991.32569410689999991.43950530169999991.43950530169999991.55344807011.55344807011.66981515281.66981515281.78618223540000011.78618223540000011.90268735731.90268735732.13653077252.13653077252.25472336810000012.25472336810000012.37377973430000022.37377973430000022.49298146852.49298146852.61276896052.61276896052.73314872690000012.73314872690000012.85352849339999982.85352849339999982.97390825982.97390825983.09488842410000013.09488842410000013.21601981353.21601981353.33760772830000013.33760772830000013.46012026610000013.46012026610000013.58310100463.58310100463.70639627180000013.70639627180000013.83080661263.83080661263.95852134479999983.95852134479999984.08640613664.08640613664.21446166920000034.21446166920000034.34303286160000024.34303286160000024.60226583479999984.60226583479999984.73312692419999964.73312692419999964.86599564544.86599564544.99905019689999994.99905019689999995.13342212029999975.13342212029999975.26933412300000015.26933412300000015.41286543489999965.41286543489999965.5646906915.5646906915.72287378870000035.72287378870000035.88798259120000015.88798259120000016.06488487950000016.06488487950000016.24622680059999976.24622680059999976.43261601180000046.43261601180000046.62474616370000026.62474616370000026.81887351049999966.81887351049999967.01926302990000037.01926302990000037.23752767059999967.23752767059999967.46657081219999967.46657081219999967.7062947227.7062947227.94727045379999997.94727045379999998.19274439930000048.19274439930000048.57848917069999938.57848917069999939.02663383159999999.02663383159999999.72108700849999969.721087008499999610.56481516700000110.56481516700000111.41657883200000111.416578832000001
Days since start of observations
Percentage of patients with event
Composite of stroke, MI & vascular death
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
Days since start of observations0 183 366 548 731 913 1096 1278 1461
21.4
6.2
Monotherapy
Dual therapy
No. of patients932947
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
Figure 2. Kaplan-Meier analysis of outcomes471.6369154611471.7643242269
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
&"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 event00.10.1446614141717212128282929303032324141454547475050818182828585909010210210910911111111611612412412612612712713313313613615115115415416316316716717017017817819119119519520420420620620720722122123223224424427227229929930430431931933133135635636836837937939839840440443843845545546846847247248248249049049149151451455055055255257257260460460760761961965565579779784684686986993493499999910011001133313331434000.316789862699999980.316789862699999980.426452360099999980.426452360099999980.536114857499999990.536114857499999990.645898395200000030.645898395200000030.866440241199999960.866440241199999960.977080374799999980.977080374799999981.08821720941.08821720941.19998193569999991.19998193569999991.31187323591.31187323591.42414641770000011.42414641770000011.53745199651.53745199651.65088811171.65088811171.76432422689999991.76432422689999991.87789148219999991.87789148219999991.99387506200000011.99387506200000012.10985864179999982.10985864179999982.22597980590000022.22597980590000022.45905255969999992.45905255969999992.57685563629999992.57685563629999992.69551963669999982.69551963669999982.81432852600000022.81432852600000022.93372124279999992.93372124279999993.05370428213.05370428213.17368732140000013.17368732140000013.29367036060000023.29367036060000023.4142518193.4142518193.53498400423.53498400423.65617121030000013.65617121030000013.77781745873.77781745873.89977206269999993.89977206269999994.02219273524.02219273524.14492650409999994.14492650409999994.26877026829999994.26877026829999994.39489837074.39489837074.52119308889999964.52119308889999964.64799097319999984.64799097319999984.77495769630000044.77495769630000044.90209393439999994.90209393439999995.02974213039999985.02974213039999985.15756212750000035.15756212750000035.41458770439999975.41458770439999975.54433449770000045.54433449770000045.67607182760000045.67607182760000045.80799340540000045.80799340540000045.94122113750000045.94122113750000046.07597583500000046.07597583500000046.21828496260000036.21828496260000036.36881741050000026.36881741050000026.52565356219999966.52565356219999966.68935644559999966.68935644559999966.85509471129999966.85509471129999967.03017911969999967.03017911969999967.20965753840000017.20965753840000017.39413138030000027.39413138030000027.58008693970000017.58008693970000017.76986088850000027.76986088850000027.96160753950000017.96160753950000018.15375449659999958.15375449659999958.35127330409999948.35127330409999948.56641116019999958.56641116019999958.78307843248.78307843249.00830539919999939.00830539919999939.24403517800000079.24403517800000079.48099592159999999.48099592159999999.72237993250000099.72237993250000099.97596875290000019.975968752900000110.35422098510.35422098510.79366107810.79366107811.26565228911.26565228911.94301372211.94301372212.76597621112.76597621113.59677643799999913.59677643799999921.45161494299999921.45161494299999900.10.11122448815151717202025252929343441414747636373737979878793931211211771771901901981982652653293293503503643643833834434434454454604604674674824824834836656656886886896898978971435000.10729613730.10729613730.218783530.218783530.330771427299999980.330771427299999980.556522794399999960.556522794399999960.671221153399999990.671221153399999990.788354147299999970.788354147299999970.905903490699999980.905903490699999981.02387265321.02387265321.14297749959999991.14297749959999991.26442347319999991.26442347319999991.38677239081.38677239081.51097041049999991.51097041049999991.63691546110000011.63691546110000011.76416395341.76416395341.89224196650000011.89224196650000012.02082356292.02082356292.15076942020000012.15076942020000012.28246421239999992.28246421239999992.41669159670000022.41669159670000022.55669634330000012.55669634330000012.69915731360000022.69915731360000022.84224678810000022.84224678810000022.98990294800000012.98990294800000013.14171843640000013.14171843640000013.29946808060000013.29946808060000013.46392476753.46392476753.63880896180000013.63880896180000013.82775247369999993.82775247369999994.01669598550000024.01669598550000024.21218132969999994.21218132969999994.41009004599999974.41009004599999974.61090918449999964.61090918449999964.81215199219999964.81215199219999965.10685121199999965.10685121199999965.40714598659999985.40714598659999985.70839711410000035.70839711410000036.25030287780000036.2503028778000003
Days since start of observations
Percentage of patients with event
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
Figure 2. Kaplan-Meier analysis of outcomes471.6369154611471.7643242269
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
&"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 event00.10.1446614141717212128282929303032324141454547475050818182828585909010210210910911111111611612412412612612712713313313613615115115415416316316716717017017817819119119519520420420620620720722122123223224424427227229929930430431931933133135635636836837937939839840440443843845545546846847247248248249049049149151451455055055255257257260460460760761961965565579779784684686986993493499999910011001133313331434000.316789862699999980.316789862699999980.426452360099999980.426452360099999980.536114857499999990.536114857499999990.645898395200000030.645898395200000030.866440241199999960.866440241199999960.977080374799999980.977080374799999981.08821720941.08821720941.19998193569999991.19998193569999991.31187323591.31187323591.42414641770000011.42414641770000011.53745199651.53745199651.65088811171.65088811171.76432422689999991.76432422689999991.87789148219999991.87789148219999991.99387506200000011.99387506200000012.10985864179999982.10985864179999982.22597980590000022.22597980590000022.45905255969999992.45905255969999992.57685563629999992.57685563629999992.69551963669999982.69551963669999982.81432852600000022.81432852600000022.93372124279999992.93372124279999993.05370428213.05370428213.17368732140000013.17368732140000013.29367036060000023.29367036060000023.4142518193.4142518193.53498400423.53498400423.65617121030000013.65617121030000013.77781745873.77781745873.89977206269999993.89977206269999994.02219273524.02219273524.14492650409999994.14492650409999994.26877026829999994.26877026829999994.39489837074.39489837074.52119308889999964.52119308889999964.64799097319999984.64799097319999984.77495769630000044.77495769630000044.90209393439999994.90209393439999995.02974213039999985.02974213039999985.15756212750000035.15756212750000035.41458770439999975.41458770439999975.54433449770000045.54433449770000045.67607182760000045.67607182760000045.80799340540000045.80799340540000045.94122113750000045.94122113750000046.07597583500000046.07597583500000046.21828496260000036.21828496260000036.36881741050000026.36881741050000026.52565356219999966.52565356219999966.68935644559999966.68935644559999966.85509471129999966.85509471129999967.03017911969999967.03017911969999967.20965753840000017.20965753840000017.39413138030000027.39413138030000027.58008693970000017.58008693970000017.76986088850000027.76986088850000027.96160753950000017.96160753950000018.15375449659999958.15375449659999958.35127330409999948.35127330409999948.56641116019999958.56641116019999958.78307843248.78307843249.00830539919999939.00830539919999939.24403517800000079.24403517800000079.48099592159999999.48099592159999999.72237993250000099.72237993250000099.97596875290000019.975968752900000110.35422098510.35422098510.79366107810.79366107811.26565228911.26565228911.94301372211.94301372212.76597621112.76597621113.59677643799999913.59677643799999921.45161494299999921.45161494299999900.10.11122448815151717202025252929343441414747636373737979878793931211211771771901901981982652653293293503503643643833834434434454454604604674674824824834836656656886886896898978971435000.10729613730.10729613730.218783530.218783530.330771427299999980.330771427299999980.556522794399999960.556522794399999960.671221153399999990.671221153399999990.788354147299999970.788354147299999970.905903490699999980.905903490699999981.02387265321.02387265321.14297749959999991.14297749959999991.26442347319999991.26442347319999991.38677239081.38677239081.51097041049999991.51097041049999991.63691546110000011.63691546110000011.76416395341.76416395341.89224196650000011.89224196650000012.02082356292.02082356292.15076942020000012.15076942020000012.28246421239999992.28246421239999992.41669159670000022.41669159670000022.55669634330000012.55669634330000012.69915731360000022.69915731360000022.84224678810000022.84224678810000022.98990294800000012.98990294800000013.14171843640000013.14171843640000013.29946808060000013.29946808060000013.46392476753.46392476753.63880896180000013.63880896180000013.82775247369999993.82775247369999994.01669598550000024.01669598550000024.21218132969999994.21218132969999994.41009004599999974.41009004599999974.61090918449999964.61090918449999964.81215199219999964.81215199219999965.10685121199999965.10685121199999965.40714598659999985.40714598659999985.70839711410000035.70839711410000036.25030287780000036.2503028778000003
Days since start of observations
Percentage of patients with event
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
No. at riskDual therapy 932 691 576 411 276 154 75 25 0Monotherapy 947 763 627 426 283 152 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
2.72.0
Monotherapy
Dual therapy
No. of patients932947
No. of events8
13Dual therapyMonotherapy
Hazard ratio: 0.66 (95%CI: 0.27-1.60)P=0.3539
Even
t rat
e.
Days .
Annual event rate0.6%/y0.9%/y
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
&"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 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
Days since start of observations
Percentage of patients with event
Slide
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
&"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 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
Days since start of observations
Percentage of patients with event
Severe or life-threatening bleeding
No. at riskDual therapy 932 691 576 411 276 154 75 25 0Monotherapy 947 763 627 426 283 152 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
2.72.0
Monotherapy
Dual therapy
No. of patients932947
No. of events8
13Dual therapyMonotherapy
Hazard ratio: 0.66 (95%CI: 0.27-1.60)P=0.3539
Even
t rat
e.
Days .
Annual event rate0.6%/y0.9%/y
= Intracranial hemorrhage
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
&"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 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
Days since start of observations
Percentage of patients with event
Slide
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
&"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 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
Days since start of observations
Percentage of patients with event
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
System organ class (MedDRA)Efficacy endpoints such as stroke are included in adverse events.
Dual therapy Monotherapy(N=932) (N=947)
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
System organ class (MedDRA)Efficacy endpoints such as stroke are included in adverse events.
Dual therapy Monotherapy(N=932) (N=947)
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
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