New Approaches to and Indications for Antiplatelet Therapy

Joslin Diabetes Center
Primary Care Congress for Cardiometabolic Health 2013
New Approaches to and Indications for Antiplatelet Therapy
Disclosures
New Approaches to, and
Indications for, Antiplatelet Therapy
Kenneth A. Bauer, MD
Professor of Medicine, Harvard Medical School
Chief, Hematology Section, VA Boston Healthcare System
Director, Thrombosis Clinical Research,
Beth Israel Deaconess Medical Center
Consultant
Bayer Healthcare
Janssen Pharmaceuticals
Bristol Myers Squibb
Pfizer
Boehringer Ingelheim
Instrumentation Laboratory
Acknowledgement
Deepak Bhatt, MD
Atherothrombosis:
Clinical Manifestations
Platelet and Thrombus Formation:
Vascular Injury
Acute coronary
syndromes
– STEMI
– NSTEMI
– Unstable angina
Stable CAD
Angioplasty
Bare metal stent
Drug eluting stent
CABG
Abdominal aortic
aneurysm (AAA)
Stroke/TIA
Carotid artery disease
Renal artery stenosis
Peripheral arterial disease
Acute limb ischemia
Claudication
Endovascular stenting
Peripheral bypass
Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275. Meadows TA, Bhatt DL. Circ Res. 2007;100:1261
Antiplatelet Agents
Mechanism Of Aspirin In Reducing Risks
Of Cardiovascular Disease
Aspirin irreversibly acetylates the
active site of cyclooxygenase (COX-1
and COX-2), which is required for the
production of thromboxane A2 by
platelets, which promotes platelet
aggregation.
Desai NR, Bhatt DL. JACC Intervention 2010
Copyright © 2013 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only.
Any distribution or reuse of this presentation or any part of it in any form for other than personal use without the express
written permission of Joslin Diabetes Center is prohibited.
1

Joslin Diabetes Center
Primary Care Congress for Cardiometabolic Health 2013
New Approaches to and Indications for Antiplatelet Therapy
Efficacy of Aspirin at Various Doses in Reducing
Vascular Events in High-Risk Patients
Aspirin
(mg daily)
No. of
Trials
500-1500 34 19
160-325 19 26
75-150 12 32

Joslin Diabetes Center
Primary Care Congress for Cardiometabolic Health 2013
New Approaches to and Indications for Antiplatelet Therapy
Dual Antiplatelet Therapy
Clopidogrel adds to the benefit of aspirin in some
circumstances (coronary artery disease).
Benefits and risks:
Aspirin + Clopidogrel
Issues with Clopidogrel
Clopidogrel versus Prasugrel
Clopidogrel versus Ticagrelor
Cangrelor (investigational) – P2Y 12 receptor antagonist
Aspirin + Dipyrimadole (Aggrenox) – sustained release
ASA (25 mg bid)/dipyrimadole (200 mg bid)
Approved indication: ischemic stroke or TIA
Issues with Clopidogrel
Irreversible P2Y 12 receptor: dosage 75 mg qd
Pharmacokinetics: Oral absorption 1 h, t 1/2 8 h
Onset: 4-6 hours (after loading dose)
Offset: 5-7 days
Variable response: 25-30% of patients achieve
less than 25% inhibition of platelet activity
Undergoes 2 step metabolism (CYP3A4/2C19
mediated) to active agent (genetic variability)
Potential drug interaction (e.g., PPIs)
CURE: Primary Efficacy Results
(MI/Stroke/CV Death)
Randomized trial in acute MI
CURE: Clopidogrel in Patients with
ACS and Diabetes
Myocardial Infarction, Stroke, or Vascular Death
Cumulative Hazard Rate
0.14
0.12
0.10
0.08
0.06
0.04
0.02
Placebo *
(n = 6,303)
0.00
0 3 6 9 12
Months of follow-up
Clopidogrel *
(n = 6,259)
20% Relative
risk reduction
p = 0.00009
N=12,562
Cumulative event rate (%)
18
16
14
12
10
8
6
4
2
9.9%
20
*
7.9%
No previous diabetes
n = 9,721
16.7%
25
*
14.2%
Diabetes
n = 2,840
Placebo †
Clopidogrel †
*On top of standard therapy (including ASA)
Yusuf S et al. N Engl J Med 2001; 345: 494–502.
*Number of events prevented/1,000 patients treated/9 months
† On top of standard therapy (including ASA)
Yusuf S et al. N Engl J Med 2001; 345: 494–502.
CHARISMA
A randomized, double-blind placebo controlled trial of
15,603 patients (79% ) with established CVD and 21%
with multiple risk factors designed to test whether
clopidogrel should be continued beyond 1 year in
addition to aspirin.
All patients received daily aspirin (75-162 mg) and were
randomized to daily clopidogrel (75 mg) or placebo
Clopidogrel patients had an event rate of 6.8% and
placebo patients had an event rate of 7.3%.
CHARISMA demonstrated no significant benefit long
term when clopidogrel is added to aspirin.
Rates of severe bleeding were similar, but clopidogrel
patients experienced significantly higher rates of
moderate bleeding.
Bhatt DL, et al; N Engl J Med. 2006. 54: 1706-1717
CHARISMA: Proportion of Diabetic
Patients in Subgroups
N=15,613 N=12,153 N=3,284
Non
Diabetics
58%
Diabetics
42%
Overall
population
Non
Diabetics
69%
Diabetics
31%
Secondary
prevention
Diabetics
83%
Primary
prevention
Non
Diabetics
17%
Copyright © 2013 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only.
Any distribution or reuse of this presentation or any part of it in any form for other than personal use without the express
written permission of Joslin Diabetes Center is prohibited.
3

Joslin Diabetes Center
Primary Care Congress for Cardiometabolic Health 2013
New Approaches to and Indications for Antiplatelet Therapy
Primary Efficacy Results (MI/Stroke/CV
Death) by Pre-Specified Entry Category
Population RR (95% CI) p value
Primary Efficacy – Diabetics vs Non Diabetics
Overall population
N=15,603
p-value for interaction: 0.283
Secondary prevention
N=12,152
p-value for interaction: 0.923
Primary prevention
N=3,284
p-value for interaction: 0.255
Qualifying CAD, CVD or PAD * 0.88 (0.77, 0.998) 0.046
(n=12,153)
Multiple Risk Factors * 1.20 (0.91, 1.59) 0.20
(n=3,284)
10%
8%
6%
10.04%
8.24%
9.23%
8.17%
6.73%
6.7%
5.87%
5.89%
6.98%
5.97%
6.69%
5.14%
Overall Population † 0.93 (0.83, 1.05) 0.22
(n=15,603)
4%
0.4
0.6 0.8 1.2 1.4
Clopidogrel + ASA
Better
1.6
Placebo + ASA
Better
* A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for these prespecified
subgroups of patients
† 166 patients did not meet any of the main inclusion criteria
2%
0%
Non Diabetics Diabetics
N=9,047 N=6,556
Placebo + ASA
Non Diabetics Diabetics
N=8,380 N=3,773
Clopidogrel + ASA
Non Diabetics Diabetics
N=569 N=2,715
Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.
Mechanism of Action of Prasugrel
15
Primary Endpoint
CV Death,MI,Stroke
Primary Endpoint (%)
10
5
HR 0.77
P=0.0001
HR 0.80
P=0.0003
Clopidogrel
Prasugrel
12.1
(781)
9.9
(643)
HR 0.81
(0.73-0.90)
P=0.0004
NNT= 46
Bhatt DL. N Engl J Med 2009.
ITT= 13,608 LTFU = 14 (0.1%)
0
0 30 60 90 180 270 360 450
Wiviott et al. NEJM 2007.
Days
Endpoint (%)
3
2
1
Stent Thrombosis
(ARC Definite + Probable)
Any Stent at Index PCI
N= 12,844
Clopidogrel
Prasugrel
2.4
(142)
1.1
(68)
HR 0.48
P

Joslin Diabetes Center
Primary Care Congress for Cardiometabolic Health 2013
New Approaches to and Indications for Antiplatelet Therapy
Endpoint (%)
18
16
14
12
10
8
Diabetic Subgroup
N=3146
Clopidogrel
CV Death / MI / Stroke
Prasugrel
17.0
12.2
HR 0.70
P

Joslin Diabetes Center
Primary Care Congress for Cardiometabolic Health 2013
New Approaches to and Indications for Antiplatelet Therapy
DUAL ANTIPLATELET THERAPY AND
INCREASED RISKS OF BLEEDING
In a meta-analysis of 18 randomized trials which
included 129,314 patients
Those assigned to dual antiplatelet therapy have about a 50%
increase in risk of major bleeding compared with those given
single agent therapy
The magnitude of this excess risk is about as high as the
approximately 60% increase observed in the trials comparing
single antiplatelet agents to placebo
These excess risks of major bleeding should be considered in
relation to the benefits on occlusive CVD events in choosing
the optimal antiplatelet strategy, especially for long-term
treatment of patients with prior events or those at high risk of
developing CVD.
Conclusions
Increased platelet activation/aggregation in diabetic patient
contributes to their increased rate of ischemic events
Clear role for aspirin in secondary prevention, “primary” prevention
Dual antiplatelet therapy indicated for at least 1 year after ACS or PCI
More potent P2Y12 receptor antagonists likely of greater benefit in
diabetics, if bleeding risk not too high
Fund Clin Pharm 2008; 22:315-321
Copyright © 2013 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only.
Any distribution or reuse of this presentation or any part of it in any form for other than personal use without the express
written permission of Joslin Diabetes Center is prohibited.
6