Overview of Atherothrombotic Therapy: Secondary Prevention

1
Overview of Atherothrombotic Therapy Secondary
Prevention
2
2002 ACC/AHA UA/NSTEMI Guideline Update Risk
Factor Modification

• Class I
• Smoking cessation
• Achieving optimal weight
• Daily exercise
• AHA diet
• BP control to lt130/85 mm Hg
• Tight control of hyperglycemia in diabetes
• HMG-CoA reductase inhibitor for LDL-C gt130 mg/dL
• Lipid-lowering agent if LDL-C after diet is gt100
  mg/dL
• A fibrate or niacin if HDL-C lt40 mg/dL

Also known as nonQ-wave MI. ACC, American
College of Cardiology AHA, American Heart
Association UA, unstable angina NSTEMI,
nonST-segment myocardial infarction BP, blood
pressure HMG-GA, 3-hydroxy-3-methyl
glutaryl- coenzyme-A LDL-C, low-density
lipoprotein cholesterol HDL-C, high-denstiy
lipoprotein cholesterol. Braunwald E, et al. J
Am Col Cardiol. 200236970-1062.
3
Risk Reduction in Nonfatal MI When Patients With
CHD Stop Smoking
Study
RR (95 Cl)
10
0.1
1.0
Ceased smoking
Continued smoking
Adapted from Critchley JA, et al. JAMA.
200329086-97.
4
The Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure

• In persons older than 50 years, SBP of gt140 mm Hg
  is a much more important CVD risk factor than
  diastolic DBP.
• The risk of CVD, beginning at 115/75 mm Hg,
  doubles with each increment of 20/10 mm Hg.
• Individuals with a SBP of 120 to 139 mm Hg or a
  DBP of 80 to 89 mm Hg should be considered
  prehypertensive and require health-promoting
  lifestyle modifications to prevent CVD.

SBP, systolic blood pressure CVD, cardiovascular
disease DBP, diabolic blood pressure. Chobanian
AV, et al. JAMA. 20032892560-2572.
5
The Seventh Report of the Joint National
Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure

• Thiazide-type diuretics should be used in drug
  treatment for most patients with uncomplicated
  hypertension, either alone or combined with drugs
  from other classes
• Most patients with hypertension will require 2 or
  more antihypertensive medications to achieve goal
  BP (lt140/90 mm Hg, or lt130/80 mm Hg for patients
  with diabetes or chronic kidney disease)
• If BP is gt20/10 mm Hg above goal BP,
  consideration should be given to initiating
  therapy with 2 agents, 1 of which usually should
  be a thiazide-type diuretic
• The most effective therapy prescribed by the most
  careful clinician will control hypertension only
  if patients are motivated

SBP, systolic blood pressure CVD, cardiovascular
disease DBP, diabolic blood pressure. Chobanian
AV, et al. JAMA. 20032892560-2572.
6
Classification and Management of Adult Blood
Pressure
Chobanian A V, et al. JAMA. 20032892560-2572.
(with permission)
7
Algorithm for Treatment of Hypertension
Lifestyle Modifications
Not at Goal BP(lt140/90 mm HG or lt130/80 mm HG
for Those With Diabetes)
Initial Drug Choices
Hypertension Without Compelling Complications
Hypertension Without Compelling Complications
Stage 2 Hypertension(Systolic BP ?160 mm Hgor
Diastolic BP ?100 mm Hg) 2-Drug Combination for
Most(Usually Thiazide-Type Diuretic and ACE
Inhibitor or ARB or ?-Blocker or CCB)
Drug(s) for the Compelling IndicationsOther
Antihypertensive Drugs (Diuretics, ACE Inhibitor,
ARB, ?-Blocker, CCB) as Needed
Stage 1 Hypertension(Systolic BP 140-159 mm
Hgor Diastolic BP 90-99 mm Hg) Thiazide-Type
Diuretics for MostMay Consider ACE Inhibitor,
ARB, ?-Blocker, CCB, or Combination
Not at Goal BP
Optimize Dosages or Add Additional Drugs Until
Goal BP is AchievedConsider Consultation With
Hypertension Specialist
Chobanian AV, et al. JAMA. 20032892560-2572.
(with permission)
8
2002 ACC/AHA UA/NSTEMI Guidelines
Recommendations for Long-term Medical Therapy

• Class I
• Aspirin 75 to 325 mg/day
• Clopidogrel 75 mg daily (in the absence of
  contraindications) when aspirin is not tolerated
  because of hypersensitivity or gastrointestinal
  intolerance
• The combination of aspirin and clopidogrel for 9
  months after UA/NSTEMI
• ?-Blockers in the absence of contraindications
• Lipid-lowering agents and diet in post-ACS and
  postrevascularization patients with LDL-C gt130
  mg/dL
• Lipid-lowering agents if LDL-C level after diet
  is gt100 mg/dL
• ACE inhibitors for patients with CHF, LV
  dysfunction (EF lt0.40), hypertension, or diabetes

ACC, American College of Cardiology AHA,
American Heart Association UA, unstable angina
NSTEMI, nonST-segment elevation myocardial
infarction ACS, acute coronary syndrome LDL-C,
low-density lipoprotein cholesterol ACE,
angiotensin-converting enzyme CHF, coronary
heart failure LV, left-ventricular EF,
ejection-fraction. Braunwald E, et al. J Am
Cardiol.200036970-1062.
9
Antithrombotic Trialists Collaboration (ATC)
Efficacy of Antiplatelet Therapy on Vascular
Events

• Category OR
• Acute MI
• Acute stroke
• Prior MI
• Prior stroke/TIA
• Other high risk
• Coronary artery disease(unstable angina, heart
  failure)
• Peripheral arterial disease(intermittent
  claudication) 22 2
  
• High risk of embolism (atrial fibrillation)
• Other (diabetes mellitus)
• All trials

1.0
0.5
0.0
1.5
2.0
Antiplatelet Better
Control Better
Vascular events MI, stroke, or vascular
death. OR, odds reduction MI, myocardial
infarction TIA, tranient ischemic
attack. Antithrombotic Trialists Collaboration.
BMJ. 200232471-86. (with permission)
10
Effects of Various Antiplatelet Agents Combined
With Aspirin vs Aspirin Alone
OR Comparison () P Value
Antithrombotic Trialists Collaboration1 Dipyr
idamole 6 NS Ticlopidine 20 NS IV GP
IIb/IIIa-Inhibitor 19 P lt.0001 Subtotal 15 P
lt.0001
CURE2 Clopidogrel 20 P .00009
1.0
0.5
0.0
1.5
2.0
Aspirin Alone Better
Combined With Aspirin
In combination with aspirin vs aspirin alone.
CURE, Clopidogrel in Unstable angina to prevent
Recurrent Events. 1 Antithrombotic Trialists
Collaboration. BMJ. 200232471-86. 2 The CURE
Trial Investigators. N Engl J Med.
2001342494-502.
11
ATC Efficacy of Aspirin at Various Doses in
Reducing Vascular Events in High-Risk Patients
Aspirin Dose No. of Trials OR ()
Odds Ratio
500-1500 mg 34 19
160-325 mg 19 26
75-150 mg 12 32
lt75 mg 3 13
Any aspirin 65 23
0.5
1.5
2.0
0
1.0
Antiplatelet Better
Antiplatelet Worse
Vascular events included nonfatal MI, nonfatal
stroke, and death from vascular causes.
Treatment effect Plt.0001. Adapted with
permission from the BMJ Publishing Group. ATC,
Antithrombotic Trialists Collaboration, MI,
myocardial infarction Adapted from
Antithrombotic Trialists Collaboration. BMJ.
200232471-86.
12
Aspirin Resistance and the Risk ofCardiovacular
Events in High Risk Patients
Hypothesis Incomplete inhibition of thromboxane
B2 increases risk of cardiovascular event
5529 pts from HOPE study with baseline urine
samples
Case (n488) Pts with CV events after
randomization
Controls (n488) Pts without CV events after
randomization
MI, stroke or CV death (P.01)
1.8
Odd Ratio
1.4
Urinary 11-dehydro Thromboxane B2 (ng/mmol
creatinine)
1.3
1.0
lt15.1
15.1-21.8
21.9-33.8
gt33.8
Adapted from Eikelboom JW, et al. Circulation.
20021051650-1655.
13
Cholesterol Reduction Reduces Incidence of
Vascular Events in Diabetes
Log rank Plt.0001
Placebo-allocated
Major vascular events ()
Simvastatin-allocated
Follow-up (years)
Heart Protection Study Collaborative Group.
LANCET. 20033612005-2016. (with permission)
14
Cholesterol Reduction in Diabetes With or Without
Arterial Disease
Risk reduction (SE)Proportional 32.9
(9.1) 24.5 (3.1) 18.4 (5.7)Absolute/1000 44
(12) 62 (8) 66 (21)P-Value .0003 lt.0001 .002
36
SimvastatinPlacebo
31
25
20
13
9
Diabetes Occlusive Arterial Both
Arterial Alone Disease Alone Disease
and Diabetes
Heart Protection Study Collaborative Group.
Lancet. 20033612005-2016. (with permission)
15
CURE Benefit of Clopidogrel Therapy atVarious
Time Intervals
MI, stroke, CV Death 0-30 days
31 days-1 year
100
100
Clopidogrel ASA
98
98
Clopidogrel ASA
96
96
Event Free ()
Event Free ()
Placebo ASA
Placebo ASA
94
94
RRR 21 95 CI 0.670.92 P.003
RRR 18 95 CI 0.700.95 P.009
92
92
90
90
1
4
6
8
10
12
0
1
2
3
4
Weeks
Months
CURE, Clopidogrel in Unstable angina to prevent
Recurrent Events, MI, myocardial infarction CV,
cardiovascular ASA, acetylsalicylic acid RRR,
relative risk ratio.Yusuf S, et al. For THE CURE
Trial Investigators. Circulation.
2003107966-972. (with permission)
16
CAPRIE Efficacy of Clopidogrel vs Aspirin in
MI, Ischemic Stroke, or Vascular Death (N
19,185)
Median Follow-up 1.91 years
Aspirin
8.7
16
Overall RRR2
Aspirin 5.831
Clopidogrel
12
Cumulative Event Rate ()
P .0452
5.321 Clopidogrel
8
4
0
0
3
6
9
12
15
18
21
24
27
30
33
36
Follow-up (mo)
ITT analysis. CAPRIE, Clopidogrel vs aspirin
in Patients at Risk of Ischemic Events MI,
myocardial infarction RRR, relative risk
ratio. CAPRIE Steering Committee. Lancet.
19963481329-1339. (with permission) Plavix
(clopidogrel bisulfate) prescribing information.
17
CAPRIE Reduction in Fatal or Nonfatal MI
N19,185
19.2
5
RRR
Aspirin
4
P.008
3
Clopidogrel
Cumulative MI Event Rate ()
2
1
0
21
24
27
33
36
3
9
12
15
18
30
0
6
Follow-up (mo)
CAPRIE, Clopidogrel vs aspirin in Patients at
Risk of Ischemic Events MI, myocardial
infarction RRR, relative risk ratio. Cannon
CP. Am J Cardiol. 200290760-762. (with
permission)
18
CAPRIE Patients With Prior Cardiac Surgery
Primary Endpoint MI, Stroke, Vascular Death
CAPRIE, Clopidogrel vs Aspirin in Patients at
Risk of Ischemic Events MI, myocardial
infarction RRR, relative risk ratio. Bhatt DL,
et al. Circulation. 2001103363-368.
19
CAPRIE Clopidogrel in Diabetes
Ischemic Stroke, MI, Vascular Death,
Hospitalization for Ischemic Events/Bleeding
Overall Benefit P.032 Multivariate Analysis
CAPRIE, Clopidogrel vs Aspirin in Patients at
Risk of Ischemic Events MI, myocardial
infarction. Bhatt DL, et al. Am J Cardiol.
200290625-628. (with permission)
20
CAPRIE Safety
Patients with a history of aspirin intolerance
were excluded from CAPRIE. CAPRIE, Clopidogrel
versus aspirin in patients at risk of ischemic
events GI, gastrointestinal. Plavix
(clopidogrel bisulfate) prescribing information.
21
Cumulative Risk of Death, MI, and Severe
Recurrent Ischema
20
16
Placebo
12
Ximelagatran
Cumulative Risk ()
8
4
P.317
0
0
180
180
150
120
60
30
Wallentin L, et al. Lancet. 2003362789-797.
(with permission)
22
Esteem Outcomes
Oral Xlmelagatran
Placebo
(n638) 24 mg (n307) 36 mg (n303) 48 mg
(n311) 60 mg (n324)
CV-death/MI/ 110 37 68 44 0.84 34 0.61 40 0.71
ischaemic stroke/SRI (18) (12) (0.47-0.99) (15
) (0.59-1.19) (11) (0.42-0.90) (13) (0.47-1.01)
6 6 2.07 2 0.70 10 3.42 5 1.67 Major
bleeding (1) (2) (0.67-6.41) (1) (0.14-3.48) (3
) (1.24-9.42) (2) (0.51-5.46)
Bilirubin gt2X upper limit of normal 3 (1)
2 (1) 2 (1) 2 (1) 3 (1)
ALP gt1-5X upper limit of normal 10
(2) 10 (3) 12 (4) 11 (4) 19 (6)
Wallentin L, et al. Lancet. 2003362789-797.
(with permission)
23
Warfarin With or Without Aspirin Post ACS/MI
ASPECT II WARIS II
Death,MI,CVA
0.14 0.12 0.10 0.08 0.06 0.04 0.02 0
Logrank test P.03
1.0 0.9 0.8 0.7
Aspirin
P.003
Cumulative Treatment Failure ()
Coumadin
Event-free Survival
Warfarinplus aspirin
Combination
Warfarin
Aspirin
Patients at risk
0 1000 2000 3000
325 325 233 188 159 105 54 336 282 233 186 159 100
56 332 293 243 197 161 102 60
Comb.AspirinCoumadin
Follow up (days)
van Es, et al. Lancet. 2002360109-113. (with
permission)
Hurlen M, et al. NEJM. 2002347969-974. (with
permission)
24
Conclusions ACS Atherothrombosis

• ACS is a manifestation of diffuse
  atherothrombosis
• Multiple plaques, inflammation, and thrombosis.
• Patients with ACS and post-PCI remain at
  increased risk for long-term ischemic events.
• Management of ACS
• Focal Rx of ruptured culprit lesion (stents).
• Systemic Rx to prevent future ischemic events.
• Risk factor modification 5 drugs for long-term
  medical therapy to treat Athero thrombosis
• Statins ASA
• ACE inhibitor Clopidogrel
• ?-blocker

ACS, acute coronary syndrome PCI, percutaneous
coronary intervention ASA, acetylsalicyclic
acid ACE, angiotensin-converting enzyme.