Stroke of Genius or Slight Miss: Evaluation
of the Updated Secondary Stroke Prevention
Guidelines
Jeffrey T. Lalama, Pharm.D., BCPS
Joel C. Marrs, Pharm.D., BCPS-AQ Cardiology, BCACP, CLS
Chad W. Martell, Pharm.D., BCPS
Colorado Pharmacists Society
2016 Winter CE and Ski Seminar
January 9th - 13th
Conflict of Interest Disclosure
We have no conflicts of interest to disclose.
Objectives
 Identify the difference between a cardioembolic and a
noncardioembolic stroke
 Discuss recommendations for the treatment of hypertension and
dyslipidemia after an ischemic stroke or transient ischemic attack
(TIA)
 Determine optimal antithrombotic therapy to prevent recurrent strokes
in patients with atrial fibrillation
 Describe when dual antiplatelet therapy (DAPT) with aspirin and
clopidogrel should or should not be used after an ischemic stroke or
TIA
 Compare and contrast antiplatelet therapy for the treatment of
noncardioembolic strokes
Stroke Types
 Hemorrhagic
– Intracerebral hemorrhage
10%
– Subarachnoid hemorrhage
3%
 Ischemic
87%
– Cardioembolic
– Noncardioembolic
Mozaffarian D, et al. Circulation. 2015;131:e29-e322.
WebMD: Stroke Health Center. Available at: www.webmd.com/stroke/ischemic-versushemorrhagic-stroke. Accessed 12/10/2015.
Pathophysiology of Ischemic Stroke
Noncardioembolic Origin
Cardioembolic Origin
Figure 446-3. Smith WS, et al. In: Harrison's Principles of Internal Medicine, 19e.
AccessPharmacy. Accessed 12/10/2015.
AHA Heart Disease and Stroke Statistics – 2015 Update
 Estimated 6.6 million Americans ≥ 20 years of age have had a stroke
– Overall stroke prevalence 2009–2012: estimated 2.6%
 Approximately 795,000 people experience a new or recurrent stroke
per year
 ≈ 610,000 (76.7%) first attacks; 185,000 (23.3%) recurrent attacks
– Stroke type: 87% ischemic, 10% ICH strokes, 3% SAH strokes
 Every 40 seconds, someone in the United States has a stroke
 Higher stroke prevalence: older adults, blacks, people with lower
levels of education, and people living in the southeastern United
States
 2030 projections: additional 3.4 million people aged ≥ 18 years will
have had a stroke
Mozaffarian D, et al. Circulation. 2015;131:e29-e322.
Stroke Death Rates, Total Population 35+
CDC. National Heart Disease and Stroke Maps. Available at:
www.cdc.gov/dhdsp/maps/national_maps/index.htm. Accessed 11/18/2015.
1-Year Mortality after First Stroke
Mozaffarian D, et al. Circulation. 2015;131:e29-e322. Chart 14-9.
5-Year Mortality after First Stroke
Mozaffarian D, et al. Circulation. 2015;131:e29-e322. Chart 14-10.
Temporal Trends in Mortality in the United States, 1969-2013
Age-Standardized Death Rate by Sex and Cause of Death in the United States
Ma J, et al. JAMA. 2015;314(16):1731-1739.
Guideline Summary: American Heart
Association/American Stroke Association
(AHA/ASA) – Secondary Stroke Prevention
Chad W. Martell, Pharm.D., BCPS
Jeffrey Lalama, Pharm.D., BCPS
Colorado Pharmacists Society
2016 Winter CE and Ski Seminar
January 9th - 13th
Applying Classification of Recommendations
and Level of Evidence: AHA/ACC
Kernan WN, et al. Stroke. 2014;45:2160-2236.
Applying Classification of Recommendations
and Level of Evidence: AHA/ACC
Kernan WN, et al. Stroke. 2014;45:2160-2236.
Determining the Cause of Stroke
2014 Recommendation
Summary of Change
For patients who have experienced an acute ischemic stroke or TIA
with no other apparent cause, prolonged rhythm monitoring (~30 days)
New recommendation
for AF is reasonable within 6 months of the index event (Class IIa;
Level of Evidence C).
AF= atrial fibrillation
Kernan WN, et al. Stroke. 2014;45:2160-2236.
AHA/ASA Recommendations: Hypertension
2014 Recommendation
Initiation of BP therapy is indicated for previously untreated patients with
ischemic stroke or TIA who, after the first several days, have an established BP
≥ 140 mm Hg systolic or ≥ 90 mm Hg diastolic (Class I; Level of Evidence B).
Initiation of therapy for patients with BP <140 mm Hg systolic and <90 mm Hg
diastolic is of uncertain benefit (Class IIb; Level of Evidence C).
Summary of Change
Clarification of
parameters for
initiating BP therapy
Resumption of BP therapy is indicated for previously treated patients with known
hypertension for both prevention of recurrent stroke and prevention of other
Clarification of
vascular events in those who have had an ischemic stroke or TIA and are
parameters for
beyond the first several days (Class I; Level of Evidence A).
resuming BP therapy
Goals for target BP level or reduction from pretreatment baseline are uncertain
and should be individualized, but it is reasonable to achieve a systolic pressure
<140 mm Hg and a diastolic pressure <90 mm Hg (Class IIa; Level of
Revised guidance for
Evidence B).
target values
For patients with a recent lacunar stroke, it might be reasonable to target a
systolic BP of <130 mm Hg (Class IIb; Level of Evidence B).
Kernan WN, et al. Stroke. 2014;45:2160-2236.
AHA/ASA Recommendations: Hypertension
2014 Recommendation
Summary of Change
The optimal drug regimen to achieve the recommended level of reductions is
uncertain because direct comparisons between regimens are limited. The
available data indicate that diuretics or the combination of diuretics and an
No change
angiotensin-converting enzyme inhibitor is useful (Class I; Level of Evidence A).
The choice of specific drugs and targets should be individualized on the basis of
pharmacological properties, mechanism of action, and consideration of specific
patient characteristics for which specific agents are probably indicated (eg,
No change
extracranial cerebrovascular occlusive disease, renal impairment, cardiac
disease, and DM) (Class IIa; Level of Evidence B).
Kernan WN, et al. Stroke. 2014;45:2160-2236.
AHA/ASA Recommendations: Dyslipidemia
2014 Recommendation
Summary of Change
Statin therapy with intensive lipid-lowering effects is recommended to reduce
Revised to be
risk of stroke and cardiovascular events among patients with ischemic stroke
consistent with 2013
or TIA presumed to be of atherosclerotic origin and an LDL-C level ≥100 mg/dL
ACC/AHA cholesterol
with or without evidence for other ASCVD (Class I; Level of Evidence B).
guideline
Statin therapy with intensive lipid-lowering effects is recommended to reduce
risk of stroke and cardiovascular events among patients with ischemic stroke
or TIA presumed to be of atherosclerotic origin, an LDL-C level <100 mg/dL,
and no evidence for other clinical ASCVD (Class I; Level of Evidence C).
New recommendation;
indicates a lower level
of evidence when LDLC <100 mg/dL
Patients with ischemic stroke or TIA and other comorbid ASCVD should be
otherwise managed according to the ACC/AHA 2013 guidelines, which include
lifestyle modification, dietary recommendations, and medication
recommendations (Class I; Level of Evidence A).
Revised to be
consistent with 2013
ACC/AHA cholesterol
guideline
ASCVD= atherosclerotic cardiovascular disease
Kernan WN, et al. Stroke. 2014;45:2160-2236.
Intensity of Statin Therapy for Stroke
High-Intensity Statin Therapy
Moderate-Intensity Statin Therapy
 Reduces LDL-C by ≥50%
 Reduces LDL-C by ~30% to <50%
 Individuals with clinical ASCVD
and age ≤75 years
 Individuals with clinical ASCVD and
age >75 years, OR if not candidate
for high-intensity statin
– Atorvastatin 40 – 80 mg
– Rosuvastatin 20 – 40 mg
– Atorvastatin 10 – 20 mg
– Rosuvastatin 5 – 10 mg
– Simvastatin 20 – 40 mg
– Pravastatin 40 – 80 mg
– Lovastatin 40 mg
– Fluvastatin XL 80 mg
– Fluvastatin 40 mg BID
Kernan WN, et al. Stroke. 2014;45:2160-2236.
Stone NJ, et al. Circulation. 2014;129(suppl 2):S1–S45.
– Pitavastatin 2 – 4 mg
AHA/ASA Recommendations: Antithrombotic Therapy for
Noncardioembolic Stroke or TIA
2014 Recommendation
Summary of Change
For patients with noncardioembolic ischemic stroke or TIA, the use of antiplatelet
agents rather than oral anticoagulation is recommended to reduce the risk of
recurrent stroke and other cardiovascular events (Class I; Level of Evidence A).
No change
Intracranial Atherosclerosis Recommendations
For patients with a stroke or TIA caused by 50% to 99% stenosis of a major
intracranial artery, aspirin 325 mg/d is recommended in preference to warfarin
(Class I; Level of Evidence B).
Revised
recommendation
For patients with recent stroke or TIA (within 30 days) attributable to severe
stenosis (70%–99%) of a major intracranial artery, the addition of clopidogrel 75
mg/d to aspirin for 90 days might be reasonable (Class IIb; Level of Evidence
B).
New
recommendation
Kernan WN, et al. Stroke. 2014;45:2160-2236.
AHA/ASA Recommendations: Antithrombotic Therapy for
Noncardioembolic Stroke or TIA
2011 Recommendation
Aspirin (50 mg/d to 325 mg/d) monotherapy (Class I; Level of Evidence A), the combination of
aspirin 25 mg and extended-release dipyridamole 200 mg twice daily (Class I; Level of
Evidence B), and clopidogrel 75 mg monotherapy (Class IIa; Level of Evidence B) are all
acceptable options for initial therapy. The selection of an antiplatelet agent should be
individualized on the basis of patient risk factor profiles, cost, tolerance, and other clinical
characteristics.
Furie KL, et al. Stroke. 2011;42:227–276.
AHA/ASA Recommendations: Antithrombotic Therapy for
Noncardioembolic Stroke or TIA
Summary of Change
2014 Recommendation
Aspirin (50–325 mg/d) monotherapy (Class I; Level of Evidence A) or the
combination of aspirin 25 mg and extended-release dipyridamole 200 mg twice
daily (Class I; Level of Evidence B) is indicated as initial therapy after TIA or
ischemic stroke for prevention of future stroke.
Revised
Clopidogrel (75 mg) monotherapy is a reasonable option for secondary prevention recommendations
of stroke in place of aspirin or combination aspirin/dipyridamole (Class IIa; Level
of Evidence B).
This recommendation also applies to patients who are allergic to aspirin.
The selection of an antiplatelet agent should be individualized on the basis of
patient risk factor profiles, cost, tolerance, relative known efficacy of the agents,
and other clinical characteristics (Class I; Level of Evidence C).
Recommendations will be topic of debate
Kernan WN, et al. Stroke. 2014;45:2160-2236.
Recommendation
assigned separate
COR;LOE
AHA/ASA Recommendations: Antithrombotic Therapy for
Noncardioembolic Stroke or TIA
2011 Recommendation
2014 Recommendation
The combination of aspirin and clopidogrel might
be considered for initiation within 24 hours of a
minor ischemic stroke or TIA and for continuation
for 21 days (Class IIb; Level of Evidence B).
The addition of aspirin to clopidogrel increases the
risk of hemorrhage and is not recommended for
routine secondary prevention after ischemic stroke
or TIA (Class III; Level of Evidence A).
New Recommendation
The combination of aspirin and clopidogrel, when
initiated days to years after a minor stroke or TIA
and continued for 2 to 3 years, increases the risk of
hemorrhage relative to either agent alone and is
not recommended for routine long-term secondary
prevention after ischemic stroke or TIA (Class III;
Level of Evidence A).
Recommendations will be topic of debate
Furie KL, et al. Stroke. 2011;42:227–276.
Kernan WN, et al. Stroke. 2014;45:2160-2236.
AHA/ASA Recommendations: Antithrombotic Therapy for
Noncardioembolic Stroke or TIA
2014 Recommendation
Summary of Change
For patients who have an ischemic stroke or TIA while taking aspirin, there is no
evidence that increasing the dose of aspirin provides additional benefit.
Although alternative antiplatelet agents are often considered, no single agent
No change
or combination has been adequately studied in patients who have had an
event while receiving aspirin (Class IIb; Level of Evidence C).
For patients with a history of ischemic stroke or TIA, AF, and CAD, the
usefulness of adding antiplatelet therapy to VKA therapy is uncertain for
purposes of reducing the risk of ischemic cardiovascular and cerebrovascular
events (Class IIb; Level of Evidence C).
Unstable angina and coronary artery stenting represent special circumstances
in which management may warrant DAPT/VKA therapy.
New recommendation
AF= atrial fibrillation; CAD= coronary artery disease; DAPT= dual-antiplatelet therapy; VKA= vitamin K antagonist
Kernan WN, et al. Stroke. 2014;45:2160-2236.
AHA/ASA Recommendations: Antithrombotic Therapy for
Cardioembolic Stroke or TIA
 Cardiogenic etiologies addressed in the Guidelines:
– Atrial Fibrillation
– Acute Myocardial Infarction and Left Ventricular Thrombus
– Cardiomyopathy
– Valvular Heart Disease
– Prosthetic Heart Valves
Kernan WN, et al. Stroke. 2014;45:2160-2236.
AHA/ASA Recommendations: Antithrombotic Therapy for
Cardioembolic Stroke or TIA
Atrial Fibrillation
 Class I anticoagulation recommendations
– Apixaban (Level of Evidence A)
– Dabigatran (Level of Evidence B)
– Warfarin (Level of Evidence A)
 Target INR of 2.5 recommended, range 2.0–3.0 (Level of Evidence A)
 Class IIa anticoagulation recommendations
– Rivaroxaban (Level of Evidence B)
 Anticoagulant approved after guideline publication
– Edoxaban
 Patients unable to take anticoagulation
– Aspirin monotherapy (Class I; Level of Evidence A)
– Aspirin with clopidogrel (Class IIb; Level of Evidence B)
Kernan WN, et al. Stroke. 2014;45:2160-2236.
Factors to Consider When Selecting an
Anticoagulant
 Risk factors
 Cost
 Tolerability
 Patient preference
 Potential for interactions
 Renal function
 Time in therapeutic range if patient already on warfarin
Kernan WN, et al. Stroke. 2014;45:2160-2236.
Warfarin Advantages and Disadvantages
 Advantages
 Disadvantages
– Low cost
– Drug interactions
– Reversal agent available
– Food interactions
– Most studied anticoagulant
– Requires routine INR
monitoring
– Ability to monitor
– Once daily dosing
– Can be used for valvular AF
– Not renally cleared
– Delayed onset and offset
– More intracerebral
hemorrhages compared to
the DOACs
DOACs= direct oral anticoagulants
Dabigatran Advantages and Disadvantages
 Advantages
 Disadvantages
– Superior to warfarin at
reducing ischemic strokes
– Twice daily dosing
– Reversal agent available
– Must be stored in original
container
– More clinical experience
(first DOAC approved)
– GI side effects
– Capsule must be swallowed
whole
– Renally cleared
– Cost
N Engl J Med. 2009;361:1139-1151.
Apixaban Advantages and Disadvantages
 Advantages
 Disadvantages
– Superior to warfarin
– Twice daily dosing
– Possible mortality benefit
compared to warfarin
– No reversal agent
– Risk of bleeding appears to
be low
– Unusual dose adjustments
– Cost
– Approved for use in
patients with hemodialysis
N Engl J Med. 2011;365:981-992.
N Engl J Med. 2011;364:806-817.
Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. 2015.
Rivaroxaban Advantages and Disadvantages
 Advantages
 Disadvantages
– Once daily dosing
– Non-inferior to warfarin
– Widespread use (more real
world clinical experience)
– Must be taken with food
– Preferred DOAC for CO
Medicaid (PA is required
however)
– Short half-life may be an
issue if a patient misses a
dose
– Renally dosed
– More GI bleeds compared
to warfarin
– No reversal agent
N Engl J Med. 2011;365:883-891.
Edoxaban Advantages and Disadvantages
 Advantages
 Disadvantages
– Once daily dosing
– Only non-inferior to warfarin
– Fewest drug interactions
– Avoid in patients with good
renal function (CrCl >95
mL/min)
– Can be administered with
or without food
– Renally dosed
– No reversal agent
– More GI bleeds compared
to warfarin
– Least clinical experience
N Engl J Med. 2013;369:2093-2104.
Savaysa [package insert]. Parsippanny, NJ: Daiichi Sankyo Inc. 2015.
AHA/ASA Recommendations: Antithrombotic Therapy for
Cardioembolic Stroke or TIA
Atrial Fibrillation
2014 Recommendation
For most patients with a stroke or TIA in the setting of AF, it is reasonable to
initiate oral anticoagulation within 14 days after the onset of neurological
symptoms (Class IIa; Level of Evidence B).
In the presence of high risk for hemorrhagic conversion (ie, large infarct,
hemorrhagic transformation on initial imaging, uncontrolled hypertension, or
hemorrhage tendency), it is reasonable to delay initiation of oral
anticoagulation beyond 14 days (Class IIa; Level of Evidence B).
For patients with AF and a history of stroke or TIA who require temporary
interruption of oral anticoagulation, bridging therapy with an LMWH (or
equivalent anticoagulant agent if intolerant to heparin) is reasonable,
depending on perceived risk for thromboembolism and bleeding (Class IIa;
Level of Evidence C).
LMWH= low-molecular-weight heparin
Kernan WN, et al. Stroke. 2014;45:2160-2236.
Summary of Change
New recommendation
New recommendation
Minor wording
revision regarding risk
assessment
Pro-Con Debates
Jeffrey T. Lalama, Pharm.D., BCPS
Joel C. Marrs, Pharm.D., BCPS-AQ Cardiology, BCACP, CLS
Chad W. Martell, Pharm.D., BCPS
Colorado Pharmacists Society
2016 Winter CE and Ski Seminar
January 9th - 13th
Case Scenario for Debate 1
FT is a 54-year-old male who presented to the hospital yesterday with
stroke-like symptoms which began 3 hours ago. His symptoms began to
resolve a few hours after arriving to the ED without any interventions
and was determined to have a TIA. A member of the medical team said
he heard of a trial discussing dual antiplatelet therapy after TIA or stroke
but was unable to remember the results. The team asks you to review
the evidence with them and to recommend a treatment plan. Which
regimen should you recommend?
A.
Aspirin and clopidogrel for 21 days
B.
Aspirin and clopidogrel for 90 days
C.
Aspirin monotherapy
Pro: Aspirin Plus Clopidogrel
Joel C. Marrs, Pharm.D., BCPS-AQ Cardiology, BCACP, CLS
Colorado Pharmacists Society
2016 Winter CE and Ski Seminar
January 9th - 13th
Patients with ASCVD
 CHARISMA subgroup analysis
– 9478 patients with prior MI, stroke or PAD
– Median follow-up of 2.3 years
– Treatment:
 Clopidogrel 75 mg daily + aspirin 75 to 162 mg daily
or
 Placebo + aspirin 75 to 162 mg daily
– Primary efficacy end point:
 Composite of myocardial infarction, stroke, or death from CV
causes
J Am Coll Cardiol. 2007;49:1982-8.
CHARISMA subgroup analysis
Patients with ASCVD
Components within the
composite endpoint
N = 9648
Study
Measure
of RR
Overall composite
endpoint
Myocardial
infarction
0.81 (0.63 – 1.03)
Stroke
CHARISMA
(Prior ASCVD)
Hazard
ratio
0.83 (0.72 – 0.96)
0.80 (0.64 – 0.99)
CHARISMA
(Prior MI)
Hazard
ratio
0.77 (0.61 – 0.98)
---
---
CHARISMA
(Prior Stroke)
Hazard
ratio
0.78 (0.62 – 0.98)
---
---
CHARISMA
(Prior PAD)
Hazard
ratio
0.87 (0.67 – 1.13)
---
---
CHARISMA = Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events; MI = myocardial infaction;
PAD = peripheral artery disease RR = relative risk
No difference in severe bleeding with DAPT: HR 1.11 (0.81 – 1.54)
Moderate bleeding increased with DAPT: HR 1.60 (1.16 – 2.20)
J Am Coll Cardiol. 2007;49:1982-8.
MATCH
 7599 patients with recent ischemic stroke or TIA (within last 3 months)
plus at least 1 CV risk factor already receiving clopidogrel 75 mg/day
 Mean follow-up of 1.5 years
 Treatment:
– Clopidogrel 75 mg daily + aspirin 75 mg daily
– or
– Clopidogrel 75 mg daily + Placebo
 Primary efficacy end point:
– Composite of myocardial infarction, ischemic stroke, vascular death, or
rehospitalization for acute ischemia
Lancet. 2004;364:331–337.
Individual and Composite Endpoints
Components within the
composite endpoint
Study
Measure
of RR
Overall composite
endpoint
Myocardial
infarction
Stroke
CHARISMA
Odds ratio 0.93 (0.83 – 1.05)*
0.92 (0.74 – 1.16)
0.82 (0.66 – 1.04)
MATCH
Odds ratio 0.93 (0.84 – 1.05)*
0.95 (0.66 – 1.36)
0.93 (0.79 – 1.10)
MATCH = Management of Atherothrombosis with Clopidogrel in High-risk Patients; CHARISMA = Clopidogrel and Aspirin versus
Aspirin Alone for the Prevention of Atherothrombotic Events; RR = relative risk
* Primary
Endpoint
N Engl J Med. 2006;354:1706-17.
Life threatening bleeding increased with DAPT: 1.26% (0.64 – 1.88)
Major bleeding increased with DAPT: 1.36% (0.86 – 1.86)
Minor bleeding increased with DAPT: 2.16% (1.51 – 2.81)
Lancet. 2004;364:331–337.
SPS3
 3020 patients with recent symptomatic lacunar infarct (within last 6
months)
 Mean follow-up of 3.4 years
 Treatment:
– Aspirin 325 mg daily + clopidogrel 75 mg daily
or
– Aspirin 325 mg daily + Placebo
 Primary efficacy end point:
– Any recurrent stroke including ischemic stroke and intracranial hemorrhage
N Engl J Med. 2012;367:817–825.
Individual and Composite Endpoints
Secondary Stroke Prevention
Components within the
composite endpoint
Study
MATCH
SPS3
Measure
of RR
Overall composite
endpoint
Odds ratio 0.93 (0.84 – 1.05)*
Hazard
ratio
---
Myocardial
infarction
Stroke
0.95 (0.66 – 1.36)
0.93 (0.79 – 1.10)
0.84 (0.52 – 1.35)
0.92 (0.72 – 1.09)*
MATCH = Management of Atherothrombosis with Clopidogrel in High-risk Patients; SPS3 = Secondary Prevention of Small
Subcortical Strokes; CHANCE = Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events; RR = relative
risk
* Primary
Endpoint
N Engl J Med. 2012;367:817–825.
Major hemorrhage increased with DAPT: HR 1.97 (1.41 – 2.71)
Extracranial hemorrhage increased with DAPT: HR 2.15 (1.49 – 3.11)
No difference intracranial hemorrhage with DAPT: HR 1.52 (0.79 – 2.93)
Lancet. 2004;364:331–337.
CHANCE
 5170 patients within 24 hrs after onset of minor ischemic stroke or highrisk TIA
 Follow-up at 90 days
 Treatment:
– Aspirin 75 mg daily (x 21 days) + clopidogrel 300 mg x 1 then 75 mg daily x 90
days
or
– Aspirin 75 mg daily + Placebo x 90 days
 Primary efficacy end point:
– Any recurrent stroke (ischemic or hemorrhagic)
N Engl J Med. 2013;369:11–19.
Individual and Composite Endpoints
Secondary Stroke Prevention
Components within the
composite endpoint
Study
MATCH
Measure
of RR
Overall composite
endpoint
Odds ratio 0.93 (0.84 – 1.05)*
Myocardial
infarction
Stroke
0.95 (0.66 – 1.36)
0.93 (0.79 – 1.10)
SPS3
Hazard
ratio
---
0.84 (0.52 – 1.35)
0.92 (0.72 – 1.09)*
CHANCE
Hazard
ratio
0.69 (0.58 – 0.82)
1.44 (0.24 – 8.63)
0.68 (0.57 – 0.81)*
MATCH = Management of Atherothrombosis with Clopidogrel in High-risk Patients; SPS3 = Secondary Prevention of Small
Subcortical Strokes; CHANCE = Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events; RR = relative
risk
* Primary Endpoint
No difference any bleeding with DAPT: HR 1.41 (0.95 – 2.10)
Lancet. 2004;364:331–337.
N Engl J Med. 2013;369:11–19.
N Engl J Med. 2012;367:817–825.
AHA/ASA 2014 Stroke/TIA Recommendations:
Antiplatelet Therapy
Class IIb Recommendations
Aspirin and clopidogrel combination might be considered for
initiation within 24 hours of a minor ischemic stroke or TIA and
for continuation for 21 days
Class III Recommendations
Aspirin and clopidogrel combination, initiated days to years
after a minor stroke or TIA and continued for 2 to 3 years,
increases the risk of hemorrhage relative to either agent
alone and is not recommended for routine long-term
secondary prevention after ischemic stroke or TIA
Kernan WN, et al. Stroke. 2014;45:2160-2236.
Kernan WN, et al. Stroke. 2015;46:e54.
Level of
Evidence
B
Level of
Evidence
A
Pro: Aspirin Plus Clopidogrel
 The combination of clopidogrel and aspirin (1st 21 days only) was
superior to aspirin alone in reducing risk of recurrent stroke at 90 day
and showed no increased risk of bleeding vs aspirin monotherapy
(CHANCE)
 The combination of clopidogrel and aspirin was superior to aspirin
alone in reducing risk of MI/Stroke in subgroup of patients with a
previous stroke at with a small increase risk of moderate bleeding vs
aspirin monotherapy (CHARISMA subanalysis)
Con: Aspirin Plus Clopidogrel
Jeffrey T. Lalama, Pharm.D., BCPS
Colorado Pharmacists Society
2016 Winter CE and Ski Seminar
January 9th - 13th
MATCH Trial
 Randomized 7,599 patients with recent ischemic stroke or TIA and
one additional vascular risk factor to clopidogrel vs. placebo in
addition to ASA 75 mg daily
 Stroke or TIA must have occurred within the past 3 months
 Patients were followed for 18 months
 No difference was seen in the primary composite endpoint of
ischemic stroke, myocardial infarction, vascular death, or
hospitalization for acute ischemia (15.7% vs. 16.7%, p=0.244)
 Life threatening bleeds and major bleeds were increased in the
clopidogrel group compared to the placebo group (see on next slide)
 No differences were observed for mortality
Lancet. 2004;364:331–337.
Lancet. 2004;364:331–337.
Lancet. 2004;364:331–337.
SPS3 Trial
 3,020 patients with lacunar stroke randomized to receive clopidogrel
75 mg daily vs. placebo in addition to ASA 325 mg daily
 Randomization took place after at least 2 weeks after stroke
 Mean follow up of 3.4 years
 No difference seen in the primary endpoint of recurrent stroke (both
ischemic and hemorrhagic) [2.5%/year vs. 2.7%/year, HR 0.92, CI
0.72-1.16]
 Major bleeding was increased in the DAPT arm (2.1%/year vs.
1.1%/year, HR 1.97, CI 1.41-1.71, P=<0.001)
N Engl J Med. 2012;367:817–825.
SPS3 Trial Results
N Engl J Med. 2012;367:817–825.
FASTER Trial
 392 patients with TIA or minor strokes randomized in a factorial
design to receive clopidogrel 300 mg loading dose followed by 75 mg
daily or placebo within 24 hours of symptom onset
 All patients received ASA 81 mg daily with ASA naïve patients
receiving an initial loading dose of 162 mg
 Patients were followed for 90 days
 No difference was seen for the primary endpoint of total stroke (both
ischemic and hemorrhagic) [7.1% for clopidogrel vs. 10.8% for
placebo, CI 0.3-1.2, P=0.19]
 Two hemorrhagic strokes seen in clopidogrel arm while none were
seen in the placebo arm
Lancet Neurol. 2007;6:961-969.
Acknowledgement of CHARISMA and CHANCE
 Data presented from the CHARISMA trial comes from a post-hoc
subgroup analysis
– While compelling, these results should only be considered hypothesis
generating
– Analysis was also not pre-specified so the two groups may not have been
optimally randomized
 Results from CHANCE trial may be difficult to generalize to a broader
population
– Study was entirely conducted in China and patient characteristics may not
match Colorado demographics
– CHANCE only enrolled patients with “high risk” TIAs or minor strokes
 TIA patients needed ≥4 on ABCD2 score to qualify for enrollment
 Strokes needed to score ≤3 on NIHSS
J Am Coll Cardiol. 2007;49:1982-8.
N Engl J Med. 2013;369:11–19.
Con: Aspirin Plus Clopidogrel
 Adding clopidogrel to aspirin significantly increases the risk of
bleeding (MATCH, SPS3)
 Adding clopidogrel to aspirin did not significantly decrease the risk of
thrombotic events for most trials (MATCH, SPS3, FASTER)
 Positive results from CHARISMA and CHANCE either need to be
validated or are difficult to generalize
Pro: Rebuttal
Con: Rebuttal
Case Scenario for Debate 1
FT is a 54-year-old male who presented to the hospital yesterday with
stroke-like symptoms which began 3 hours ago. His symptoms began to
resolve a few hours after arriving to the ED without any interventions
and was determined to have a TIA. A member of the medical team said
he heard of a trial discussing dual antiplatelet therapy after TIA or stroke
but was unable to remember the results. The team asks you to review
the evidence with them and to recommend a treatment plan. Which
regimen should you recommend?
A.
Aspirin and clopidogrel for 21 days
B.
Aspirin and clopidogrel for 90 days
C.
Aspirin monotherapy
Summary from Debate 1
 Results from CHANCE trial are encouraging
 Risk for bleeding outweighs potential benefits for aspirin with
clopidogrel when continued for prolonged periods of time
 Therapy should be initiated shortly after stroke has occurred if
clopidogrel is to be added to aspirin
 Optimal duration is still unknown
 POINT and TARDIS trials are still ongoing and will hopefully provide
us with some more definitive answers
Case Scenario for Debate 2
BB is a 61-year-old female who presented to the hospital yesterday with
a noncardioembolic stroke. She was taking no antiplatelet therapy prior
to her stroke. The medical team would like to send her home with
clopidogrel monotherapy for secondary prevention of stroke. How
should you respond to this recommendation?
A.
Agree, using clopidogrel monotherapy is reasonable
B.
Disagree, switch to aspirin instead
C.
Disagree, switch to aspirin/dipyridamole ER instead
Pro: Aspirin Plus ER Dipyridamole (Aggrenox)
Joel C. Marrs, Pharm.D., BCPS-AQ Cardiology, BCACP, CLS
Colorado Pharmacists Society
2016 Winter CE and Ski Seminar
January 9th - 13th
30 years ago….
 Multicenter, RCT
 2500 patients with recent Stroke, TIA, or reversible ischemic
neurological deficit
 Treatment:
– ASA 325 mg + Dipyridamole 75 mg TID
– Placebo
 Primary Outcome (Stroke or all cause mortality)
– 15.2% (A+D) vs 22.6% (Placebo); p < 0.001
 Secondary Outcome (all cause mortality)
– 8.6% (A+D) vs 12.5% (Placebo); p < 0.01
Lancet. 1987;2:1351–1354.
20 years ago….
 Multicenter RCT of 6602 patients with prior Stroke or TIA
 Treatment:
– ASA 50 mg daily
– Dipyridamole MR 400 mg daily
– ASA 50 mg + Dipyridamole MR 400 mg daily
– Placebo
 Primary Outcome (Stroke or all cause mortality)
– 20.0% (A) vs 22.9% (Placebo)
[RRR 16%]
– 19.4% (D) vs 22.9% (Placebo)
[RRR 19%]
– 17.3% (A+D) vs 22.6% (Placebo) [RRR 29%]
J Neurol Sci.1996;143:1–13.
10 years ago….
 Multicenter, RCT (mean follow-up 3.5 years)
 2739 patients with recent Stroke, TIA, or reversible ischemic
neurological deficit
 Treatment:
– ASA 30-325 mg daily + Dipyridamole 200 mg BID
– ASA 30-325 mg daily
 Primary Outcome (CV death, nonfatal Stroke, nonfatal MI, major
bleeding)
– 13% (A+D) vs 16% (A); p < 0.001
Lancet. 2006;367:1665–1673.
8 years ago….
 Double-blind, 2x2 factorial trial (mean follow-up 2.5 years)
 20,332 patients with recent Stroke (< 90 days prior to enrollment)
 Treatment:
– ASA 25 mg + Dipyridamole ER 200 mg BID
– Clopidogrel 75 mg daily
 Primary Outcome (Stroke)
– 9% (A+D) vs 8.8% (C)
 Secondary Outcome (Stroke, MI or CV death)
– 13.1% (A+D) vs 13.1% (C)
 Did not meet pre-defined criteria for noninferiority
N Engl J Med. 2008;359:1238–51.
AHA/ASA 2014 Stroke/TIA Recommendations:
Antiplatelet Therapy
Class I Recommendations
Aspirin 50 to 325 mg daily (LOE: A) or the combination of aspirin 25
mg and extended-release dipyridamole 200 mg twice daily (LOE: B) is
indicated as initial therapy after TIA or ischemic stroke for prevention
of future stroke
Kernan WN, et al. Stroke. 2014; 45:2160-2236.
Level of
Evidence
A/B
Pro: Aspirin Plus ER Dipyridamole (Aggrenox)
 Combination of aspirin plus dipyridamole shown to be more effective
than aspirin alone for prevention of recurrent stroke (ESPRIT)
 No studies have compared clopidogrel to placebo in the secondary
stroke prevention population
 Only trial to compare clopidogrel to aspirin plus dipyridamole for
secondary stroke prevention did not establish superiority to aspirin
plus dipyridamole (PRoFESS)
Con: Aspirin Plus ER Dipyridamole (Aggrenox)
Chad W. Martell, Pharm.D., BCPS
Colorado Pharmacists Society
2016 Winter CE and Ski Seminar
January 9th - 13th
AHA/ASA 2014 Stroke/TIA Recommendations:
Antiplatelet Therapy
Class I Recommendations
Aspirin 50 to 325 mg daily (LOE: A) or the combination of aspirin 25 mg and
extended-release dipyridamole 200 mg twice daily (LOE: B) is indicated as
initial therapy after TIA or ischemic stroke for prevention of future stroke
Class IIa Recommendation
Clopidogrel (75 mg) monotherapy is a reasonable option for secondary
prevention of stroke in place of aspirin or combination aspirin/dipyridamole
(LOE: B). This recommendation also applies to patients who are allergic to
aspirin.
Kernan WN, et al. Stroke. 2014;45:2160-2236.
Level of
Evidence
A/B
Level of
Evidence
B
CAPRIE
 Randomized, blinded, international trial at 384 clinical centers
 19,185 patients with recent ischemic stroke (n=6431), recent MI (n=6302), or
symptomatic PAD (n=6452)
 ASA 325 mg/day vs. Clopidogrel 75 mg/day
 Treatment duration 1-3 years (mean 1.9 years)
 Primary outcome: composite of
ischemic stroke, MI, or vascular death
 Other analyses: event-type subgroups,
all-cause mortality, safety/adverse
events
Lancet.1996;348:1329-1339.
CAPRIE- Outcomes
Clopidogrel
ASA
Event rate per year
Clopidogrel vs. ASA
RRR (95% CI)
p-value
Composite Outcome:
Total Population
5.32%
5.83%
8.7% (0.3%–16.5%)
0.043
Composite Outcome:
Stroke Subgroup
7.15%
7.71%
7.3% (-5.7%–18.7%)
0.26
Safety
% of patients
Any bleeding
9.27%
9.28%
NS
ICH
0.35%
0.49%
NS
GI bleeding
1.99%
2.66%
< 0.05
RRR= relative-risk reduction; ICH= Intracranial hemorrhage; GI= gastrointestinal; NS= not significant
Lancet.1996;348:1329-1339.
PRoFESS
 20,332 patients with recent ischemic stroke
 ASA 25 mg + ER Dipyridamole 200 mg twice daily vs. Clopidogrel 75
mg daily
– Mean duration 2.5 years
 Primary Outcome: recurrent stroke
 Secondary Outcome: stroke, MI, or CV death
 Outcome analysis- sequential testing for noninferiority, then superiority
– Noninferiority margin set at 1.075 (i.e., upper boundary of 95% CI for the HR
must lie below 1.075)
N Engl J Med. 2008;359:1238-51.
PRoFESS- Outcomes
Primary Outcome:
 9.0% (ASA + ERDP) vs. 8.8% (clopidogrel)
 HR (95% CI): 1.01 (0.92 – 1.11)
noninferiority not met
– ASA + ERDP ‘not noninferior’ to clopidogrel, but ‘similar’
ASA + ERDP
Safety Outcomes
Clopidogrel
% of patients
HR (95% CI)
Major hemorrhagic event
4.1%
3.6%
1.15 (1.00 – 1.32)
Hemorrhagic event (minor or major)
5.3%
4.9%
1.08 (0.96 – 1.22)
Intracranial hemorrhage
1.4%
1.0%
1.42 (1.11 – 1.83)
ERDP=Extended-release dipyridamole; HR= hazard ratio
Premature discontinuation of drug:
 ASA + ERDP (29.1%) vs. clopidogrel (22.6%); p<0.001
N Engl J Med. 2008;359:1238-51.
ESPRIT Revisited
 2739 patients with recent stroke, TIA, or reversible ischemic
neurological deficit
 Primary Outcome: CV death, nonfatal stroke, nonfatal MI, major
bleeding
– 13% (ASA 30-325 mg daily + Dipyridamole 200 mg BID) vs. 16% (ASA 30-325
mg daily); p < 0.001
 ESPRIT therapy ≠ Aggrenox®
– ESPRIT used ER dipyridamole (83%) or IR dipyridamole (17%)
– ESPRIT median ASA dose 75 mg daily
– Aggrenox= ASA 25 mg + ER dipyridamole 200 mg BID (TDD ASA = 50 mg)
 ESPRIT drug discontinuation: 34% (combination) vs. 13% (ASA)
– Main reason cited- headache
Lancet. 2006;367:1665–1673.
Extra Commentary from the 2014 AHA/ASA Guideline
 “Observation of the survival curves from CAPRIE and PRoFESS
indicate that clopidogrel is probably as effective as the combination of
aspirin/dipyridamole and, by inference, aspirin. Clopidogrel appears
to be safer than the aspirin/dipyridamole combination.”
 “Risk for gastrointestinal hemorrhage or other major hemorrhage may
be greater with aspirin or combination aspirin/dipyridamole than with
clopidogrel.”
Kernan WN, et al. Stroke. 2014;45:2160-2236.
AHA/ASA 2014 Stroke/TIA Recommendations:
Antiplatelet Therapy
Class I Recommendations
Aspirin 50 to 325 mg daily (LOE: A) or the combination of aspirin 25 mg and
extended-release dipyridamole 200 mg twice daily (LOE: B) is indicated as
initial therapy after TIA or ischemic stroke for prevention of future stroke
Class IIa Recommendation
Clopidogrel (75 mg) monotherapy is a reasonable option for secondary
prevention of stroke in place of aspirin or combination aspirin/dipyridamole
(LOE: B). This recommendation also applies to patients who are allergic to
aspirin.
Kernan WN, et al. Stroke. 2014;45:2160-2236.
Level of
Evidence
A/B
Level of
Evidence
B
Con: Aspirin Plus ER Dipyridamole (Aggrenox)
 Clopidogrel monotherapy shown to reduce recurrent ischemic stroke,
MI, or vascular death compared to aspirin alone (CAPRIE)
 Combination of aspirin plus dipyridamole was not found to be
noninferior to clopidogrel monotherapy to prevent recurrent stroke,
and trend toward less bleeding with clopidogrel (PRoFESS)
 Unlike aspirin plus dipyridamole, the clopidogrel dosage used in
clinical outcomes trials is available as an FDA approved product
 Clopidogrel discontinuation rates in clinical trials were significantly
lower compared to aspirin plus dipyridamole (PRoFESS, ESPRIT)
 Clopidogrel administered as a single tablet, once daily
Pro: Rebuttal
Con: Rebuttal
Case Scenario for Debate 2
BB is a 61-year-old female who presented to the hospital yesterday with
a noncardioembolic stroke. She was taking no antiplatelet therapy prior
to her stroke. The medical team would like to send her home with
clopidogrel monotherapy for secondary prevention of stroke. How
should you respond to this recommendation?
A.
Agree, using clopidogrel monotherapy is reasonable
B.
Disagree, switch to aspirin instead
C.
Disagree, switch to aspirin/dipyridamole ER instead
Summary from Debate 2
 Three acceptable antiplatelet therapy options for patients with
noncardioembolic ischemic stroke/TIA
 However, no conclusively superior therapy based on risks/benefits
 Probably more clinical data to support aspirin plus dipyridamole, but
efficacy data appears ‘similar’ with clopidogrel
 Clopidogrel is better tolerated than aspirin plus dipyridamole, and
may be associated with lower risk of bleeding
 Patient characteristics should guide selection of drug therapy (e.g.,
comorbid illness, history of bleeding, tolerance, concomitant
cardiovascular disorders)
Questions?