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Primary Care TodayEducational Conference and Medical Exposition
Toronto, Ontario / May 8-10, 2008
Adapted from a presentation by:
Alan D. Bell, MD, MCFPHumber River Regional Hospital
Toronto, Ontario
The Optimal Management of Diffuse Vascular Disease: Clinical Implications of the Landmark REACH Registry
Program Rationale
In Canada there is one stroke every 10 minutes and 1 heart attack every 7 minutes
Suboptimal Risk Factor Management in C/V disease
Atherothrombosis remains the leading cause of death worldwide accounting for 47% of North American Mortality
58% of Canadian high risk hypertensives NOT at goal BP in REACH were on fewer than 3 drugs
Need for Canadian primary care physicians to learn more about the management of patients with diffuse vascular disease
42% of high risk atherothrombotic patients in REACH were not on evidence based risk reduction “triple therapy”
Learning Objectives
Understand the epidemiology and burden of atherothrombosis
Understand the importance of registries and discuss the clinical implications of the REACH Registry
Describe the consequences of PAD and apply Canadian guidelines for the management of PAD
Identify patients with diffuse vascular disease and implement strategies for the prevention of atherothrombotic events in these patients
REACH: Reduction of Atherothrombosis for Continued Health; PAD: peripheral arterial disease
At the end of this session, participants should be able to:
Question 1
Which of the following are typical characteristics a Registry?
a) Registries examine the effects of a specific intervention
b) Registries usually have more exclusion criteria compared to randomized trials
c) Registries tell us about “real world” characteristics and outcomes
d) Registry results are less reliable than randomized trial results
e) All of the above
What is a Registry?
Organized system that collects data for scientific, clinical, or policy purposes
Complements RCTs by determining real-world outcomes
Generally do not: Have restrictive inclusion or exclusion criteria Specify what therapy the health care provider must
adhere to
Often used to evaluate outcomes for diverse purposes: Natural history of a disease Real-world effectiveness of therapies, etc.
RCTs: randomized controlled trials
Example of a Registry:Framingham Heart Study
Started in 1948
Objective: identify the common factors or characteristics that contribute to cardiovascular disease
5209 men and women, ages 30-62, from Framingham, Massachusetts
Examinations every 2 years
Over 50 years of follow-up
NHLBI. Framingham Heart Study. Available at: www.nhlbi.nih.gov/about/framingham Accessed January 22, 2008.
Framingham Heart Study:Atherothrombosis Reduces Life Expectancy
In the FHS, healthy individuals aged 60 years who did not have atherothrombosis were expected to live a further 20 years to the age of 80
Comparatively, patients with a history of MI lived 9.2 fewer years Those with a history of CVA lived 12 fewer years
In the FHS, healthy individuals aged 60 years who did not have atherothrombosis were expected to live a further 20 years to the age of 80
Comparatively, patients with a history of MI lived 9.2 fewer years Those with a history of CVA lived 12 fewer years
9.2Feweryears
12Feweryears
Lif
e E
xpec
tan
cy (
Yea
rs)
2020
CVA: cerebrovascular accidentAdapted from Bakhai A. Pharmacoeconomics 2004;22(suppl 4):11-18.
Framingham Heart Study:
Cardiovascular Event Ratesin >68,000 Outpatients with Atherothrombosis
Registry Results
REACH: Purpose
Describe the characteristics and management of patients at high risk of atherothrombosis with and without symptomatic manifestations in any vascular bed
Assess long-term risk of atherothrombotic events
Compare outcomes
Assess the amount of “cross-risk”
Assess the impact of “diffuse vascular disease”
Define predictors of risk
Adapted from Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
Must include
SignedWritten
InformedConsent
Patients aged≥45 years
At leastof four
criteria
• Documented cerebrovascular diseaseIschemic stroke orTIA
• Documentedcoronary diseaseAngina, MI, angioplasty/stent/bypass
• Documented historicalor current intermittentclaudication associatedwith ABI* <0.9
•
• Male 65 yearsor female 70 years
• Current smoking>15 cigarettes/day
• Type I or II diabetes
• Hypercholesterolemia
• Diabetic nephropathy
• Hypertension
• ABI <0.9 in eitherleg at rest
• Asymptomatic carotidstenosis 70%
• Presence of at leastone carotid plaque
1 At least
atherothrombotic risk factors3
Inclusion Criteria
*ABI: Ankle Brachial IndexBhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
North AmericaLatin America
Eastern Europe
Middle East
Asia (incl. Japan)
Australia
27,746
1,931
17,886
846
5,903
2,872
*up to 15 patients/site (up to 20 in the US)
Western Europe
REACH Registry: >67,000 Patients from 5,473 Sites* in 44 Countries
5,048
5,6561,976
Adapted from Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
Baseline Follow-up at 12 3 months
Follow-up at 24 3 months
Follow-up at 33 3 months
Follow-up at 45 3 months
REACH Registry Timeline
Dec 2003 to
June 2004
June 2007 to June 2008
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
What Does REACH Add to Our Current Understanding of Atherothrombosis?
• Global registry
• Stable outpatients
• Large number of primary-care patients
• Includes multiple risk factor and manifest vascular disease patients in all 3 vascular beds
• 4 years of follow-up
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
Baseline Data
Published 11th Jan 2006: Bhatt DL, et al, for the REACH Registry Investigators.
JAMA 2006;295(2):180-9.
REACH:Significant Proportion of the Symptomatic Population has Diffuse Vascular Disease*
Prevalence of disease in arterial beds (% of total)
CAD: coronary artery diseasePAD: peripheral arterial diseaseCVD: cerebrovascular disease
1.61.2
4.7
8.4
4.7
16.6
44.6
0 10 20 30 40 50 60 70
Multiple risk factors: 18.3%
CAD + CVD + PADCVD + PADCAD + PADCAD + CVD
Diffuse vascular disease: 15.9%
PAD AloneCVD AloneCAD Alone
Single arterial bed: 65.9%
Patients (%)Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
REACH: Patient Characteristics at Baseline
82.2
90.3
74.9
49.5
Multiple RF only
(n=12,389)
70.272.4Hypercholesterolemia
80.081.8Hypertension
37.544.3Diabetes
66.9
% of populationSymptomatic
(n=55,499)
63.7
Total(n=67,888)
Men
69.0 (9.8)68.4 (10.1)68.5 (10.1)Mean age (SD) yr
19.2
28.4
42.4
14.415.3Current smoker
44.641.6Former smoker
27.430.2Obesity (BMI ≥ 30)
35.040.939.8Overweight (BMI 25 to < 30)
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
Physician Profile
Follow-up available Follow-up available (%) N=63,129(%) N=63,129
0.8Other (N=533)
3.0Endocrinologist (N=1,987)
9.4Neurologist (N=6,353)
2.2Vascular surgeon (N=1,480)
1.1Angiologist (N=771)
14.0Cardiologist (N=9,390)
32.8Internist (N=22,244)
36.7General practice (N=24,441)
Physician profilePhysician profile
74.7
9.7
12.3
3.2
REACH: Risk Factors are Consistently Found Across All Disease Subpopulations*
Risk factor prevalence, by subpopulation (%)
80.3 77.0
38.329.9
13.0
83.3
58.2
37.4
23.7
14.3
81
66.7
44.2
23.8 24.5
0
20
40
60
80
100
Treatedhypertension
Treated hyper-cholesterolemia
Treated diabetes Obesity(BMI ≥ 30)
Current smoker
Pat
ien
ts (
%)
CAD population
CVD population
PAD population
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
Diffuse Vascular Disease
How often do patients have manifest disease in more than one vascular bed?
25% of the 40,258 patients with CAD also have atherothrombotic disease in other arterial territories
CAD
PAD
8.4%
1.6% CVD
44.6%
(%s are of total population)
Patients with CAD = 59.3% of
the REACH Registry
population
CAD=coronary artery diseasePAD=peripheral arterial
diseaseCVD=cerebrovascular disease
4.7%
Multiple risk factors only population
1. Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
40% of the 18,843 patients with CVD also haveatherothrombotic disease in other arterial territories
8.4%
1.6%
1.2%16.6%
Patients with CVD = 27.8% of the REACH Registry population
(%s are of total population)
CAD
PAD
CVD
CAD=coronary artery diseasePAD=peripheral arterial
diseaseCVD=cerebrovascular disease
Multiple risk factors only population
1. Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
CAD
PAD
CVD
60% of the 8,273 patients with PAD also haveatherothrombotic disease in other arterial territories
1.2%4.7%
1.6%
4.7%
Patients with PAD = 12.2% of
the total REACH Registry
population
(%s are of total population)
Multiple risk factors only population
CAD=coronary artery diseasePAD=peripheral arterial
diseaseCVD=cerebrovascular disease
1. Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
1-Year Outcomes
REACH: 1-year Event Curves for CV Death, MI, Stroke & Combined Endpoints
0.0
0.5
1.0
5.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Eve
nt
dis
trib
uti
on
fu
nct
ion
(%
)
Time in months
1 2 3 4 5 6 7 8 9 10 11 120
Non-fatal stroke
CV death
Non-fatal MI infarction
CV death/MI/stroke
Steg PG et al, on behalf of the REACH Registry Investigators. JAMA 2007;297(11):1197-1206.
4.24% of these stable patients had an event within
1 year
n=64,977
42% 10 year risk
*Such as TIA, unstable angina, worsening of PAD; adjusted for age and gender
REACH 1-year CV Event Rates: Symptomatic vs Multiple Risk Factor Only
5.3
2.2
0.8
0.8
0.8
Multiple RF only
(n=11,766)
14.412.8CV death/MI/stroke/ hospitalization for atherothrombotic events*
4.74.2CV death/MI/stroke
1.91.7Non-fatal stroke
1.21.1Non-fatal MI
1.8
% of populationSymptomatic
(n=53,390)
1.7
Total(n=64,977)
CV death
1.52.82.6Death all cause
Steg PG et al, on behalf of the REACH Registry Investigators. JAMA 2007;297(11):1197-1206.
1-year cardiovascular event rates as function of number of symptomatic disease locations*
All p values <0.001*Pts with 3 risk factors but no symptoms are counted as 0, even in the presence of asymptomatic carotid plaque or reduced ABI**TIA, unstable angina, other ischemic arterial event including worsening of peripheral arterial disease
0,6 0,7 0,8
1,51,41,2
1,5
3,4
2,4
1,5
2,9
5,7
3,8
1,9
3,7
7,1
0
2
4
6
8
CV death Non-fatal MI Non-fatal stroke CV death / MI / stroke
Pe
rce
nt
0
1
2
3
Other outcomes leading to hospitalization since baseline
0.5
1.4
0.5
0.6
1.1
Multiple RF only(N=11,444)
1.30.90.90.90.8Bleeding (leading to hospitalization and transfusion)
4.13.24.23.43.1Chronic heart failure
4.11.51.51.51.3
Other ischemic arterial event (including worsening of PAD)
1.83.21.21.51.4TIA
4.9
Symptomatic (N=51,685)
4.2
Total(N=63,129)
3.4
CVD(N=17,451)
4.5
PAD(N=7,674)
6.3Unstable angina
CAD (N=37,542)
Major adverse event rates at one year as a function of age: total population
1,1 1,1
1,9
3,6
1,21,1
1,5
3,1
1,5
1,1
1,5
3,3
2,3
1,41,5
4,1
0
1
2
3
4
5
CV death Non-fatal MI Non-fatal stroke CV death / MI / stroke
Per
cen
t
45-60 yrs
60-70 yrs
70-80 yrs
80+ yrs
Rates adjusted for risk factors
Geographical Variation of 1-year Cardiovascular Event Rates
6.3
3.0
1.6
0.8
0.7
Japan (N=4,844)
11.3
3.2
1.0
1.0
1.5
Australia (N=2,822)
10.0
4.5
2.3
0.8
1.5
Asia (N=5,559)
18.0
6.3
2.1
2.2
2.4
Middle East
(N=818)
21.614.213.611.4
CV death/MI/ CV death/MI/ stroke/ stroke/ hospitalization for hospitalization for atherothrombotic atherothrombotic eventsevents**
6.83.74.93.7CV death/MI/ CV death/MI/ strokestroke
3.5 1.52.51.1Non-fatal strokeNon-fatal stroke
1.21.10.91.3Non-fatal MINon-fatal MI
1.4
North America
(N=25,302)
1.5
Western Europe
(N=16,487)
2.2
Eastern Europe
(N=5,579)
1.8CV deathCV death
Latin America
(N=1,718)
*TIA, unstable angina, other ischemic arterial event including worsening of peripheral arterial disease
Undertreatment of Risk Factors at Study Entry
Bhatt DL, et al. JAMA 2006;295(2):180-9.
Take-Home Messages
1-year REACH results reveal: High rate of CV death, MI, and stroke (4.24%) in this
“stable” outpatient population Similar risk factor profiles regardless of vascular bed
involved Significant proportion of symptomatic patients with
diffuse vascular disease Rates increase markedly with the number of
symptomatic disease locations (CV death/MI/stroke) 1.5% (risk factors only) 7.1% (triple location)
Atherothrombosis
Atherothrombosis has Multiple Manifestations
Adapted from Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6.
Transient ischemic attack (TIA)
Angina:• Stable• Unstable
Ischemic stroke
Myocardial infarction(MI)
Peripheral arterial disease (PAD):• Intermittent claudication
Rest pain Gangrene Necrosis
Atherothrombosis: A Generalized and Progressive Disease
Adapted from Libby P. Circulation 2001;104(3):365-372.
Atherosclerosis
Stable angina/Intermittent claudication
Unstable angina MI
Ischemic stroke/TIA
Critical leg ischemiaIntermittentclaudication
CV death
ACSThrombosis
What Types of Lesions Cause MI?
Falk E et al. Circulation 1995;92:657-71.
100
80
60
40
20
0
14%
18%
68%
All 4studies
50%-70%<50% >70%
100
60
40
20
0Ambrose
1988Little1988
Nobuyoshi1991
Giroud1992
Cor
onar
y E
vent
s (%
)Coronary stenosis severity prior to MICoronary stenosis severity prior to MI
80
Pathology: Plaque Fissuring
0 5 10 15 20 25 30
28.7Vascular disease*
17.8Infectious disease
12.6Cancer
9.1Injuries
6Pulmonary disease
5.1AIDS
Vascular Disease* is a Leading Cause of Death Worldwide†
WHO. 2002. Available at: www.who.int/whr/2002/en/whr02_en.pdf
Mortality (%)
*Ischemic heart disease, cerebrovascular disease, inflammatory heart disease and hypertensive heart disease†Worldwide defined as Member States by World Health Organization (WHO) Region (Africa, Americas, Eastern Mediterranean, European, South-East Asia and Western Pacific)
AIDS: acquired immune deficiency syndrome
Leading Causes Of Death, Worldwide(% of all deaths)
Epidemiology of Atherothrombotic Manifestations in Canada
Atherothrombosis: Epidemiology
Peripheral Arterial Diseaseand the
Canadian PAD Guidelines
Question 2
How common is peripheral arterial disease (PAD) in your practice?
a) I hardly ever see it – It’s a specialist disease
b) I have a few patient’s, but it’s much less common than coronary disease
c) Since I’ve been screening for it I can’t believe how common it is!
d) I don’t know, because I have no way to test for it
e) I don’t look for it because none of my patients ever died of a “leg attack”
Often asymptomatic, under-diagnosed, under-recognized, and under-treated
16% of North America and Europe has PAD, corresponding to 27 million people
Of these, 16.5 million are asymptomatic
Gupta A. In: Abramson BL, et al. Can J Cardiol 2005;21(12):997-1006.
PAD: Epidemiology
CCS Guidelines: Diagnosis of PAD
Roussin A, et al. Can J Cardiol. 2005;21(12):997–1006.
Recommendation Grade
Taking a directed history for symptoms of PAD. A validated questionnaire, such as the Edinburgh Questionnaire, can help diagnose arterial claudication in patients suspected of suffering from PAD.
1A
Performing a directed examination focusing on physical findings that have been proven useful to detect PAD defined as an ABI<0.9.
1A
Ordering an ABI to help diagnose arterial claudication in patients suspected of claudication. An ABI below 0.9 is diagnostic of PAD with values below 0.4 associated with severe disease.
1A
Ordering an ABI to diagnose PAD in asymptomatic patients with arterial bruits or diminished pulses.
1A
Edinburgh Questionnaire
Do you get a pain or discomfort in you leg(s) when you walk?• YES
•Does this pain ever begin when you are standing still or sitting?• NO
Do you get it when you walk uphill or hurry?• YES
Do you get it when you walk at an ordinary pace on level ground?• YES
•What happens to it if you stand still?• Pain usually disappears in 10 minutes or less
Where do you get this pain or discomfort?• Patient marks calf and/or thigh and/or buttock
Leng GC, et al. J Clin Epidemiol. 1992;45:1101–1109.
91.3% Sensitive 99.3% specific
Measuring ABI
Adapted from Roussin A, et al. Can J Cardiol 2005;21(12):997-1006.
Right-arm
systolicpressure
Left-armsystolicpressure
Right-anklesystolic pressure
Left-anklesystolic pressure
DP
PT
DP
PT
INTERPRETATION OF ABI
>1.30
0.91-1.30
0.41-0.90
0.00-0.40
Noncompressible
Normal
Mild-to-moderate peripheral arterial disease
Severe peripheral arterial disease
Question 3
Which of the following are TRUE regarding symptomatic PAD?
a) 30% will suffer a fatal vascular event within 5 years
b) Ankle / Brachial Index (ABI) is sensitive and specific enough to make the diagnosis of PAD
c) Severity of disease and mortality may be predicted by ABI
d) Exercise programs can improve claudication symptoms
e) All of the above
• Local consequences in the leg include:– Intermittent claudication– Tissue loss including sepsis and major
amputations
• PAD is a marker of disease in other vascular beds– Fatal and non-fatal cerebral and coronary
vascular events
Consequences of PAD may be Local and Systemic
REACH: Reduction of Atherothrombosis for Continued Health
Patients with Previous Atherothrombotic Events are at Increased Risk of Further Events
Increased risk versus general population
MI Stroke
Ischemic stroke 2-3x(includes angina and
sudden death*)1
9x2
MI 5-7x(includes death)3
3-4x(includes TIA)1
PAD 4x(includes only fatal MI
and other CHD death†)4
2-3x(includes TIA)2
* Sudden death defined as death documented within 1 hour and attributed to coronary heart disease (CHD).† Includes only fatal MI and other coronary heart disease (CHD) death; does not include non-fatal MI.
1. Kannel WB. J Cardiovasc Risk1994;1(4):333–339.; 2. Wilterdink JL, et al. Arch Neurol 1992;49(8):857–863. 3. Adult Treatment Panel II. Circulation 1994;89(3):1333–1363. 4. Criqui MH, et al. N Engl J Med 1992;326(6):381–386.
Consequences of PAD
Population > 55 years of age
Surgery or tissue loss
>25%
Adapted from Weitz JI, et al. Circulation 1996;94(11):3026-3049.
Stable claudication
~50%
5-year peripheral vascular outcomes
Worsening claudication
~16%
5-year natural history of intermittent claudication
Major amputation
<4%
Intermittent claudication 5%
Other cardiovascular outcomes
5-year non-fatal atherothrombotic
events (MI, stroke, etc.)
20%
5-year mortality
30%
Risk of Death is Increased in Patients with Both Asymptomatic and Symptomatic PAD
* Kaplan-Meier survival curves based on mortality from all causes.† Large-vessel PAD.
Year
0 2 4 6 8 10 12
100
75
50
25
0
Normal subjects*
Asymptomatic PAD†
Symptomatic PAD†
Severe symptomatic PAD†
Criqui MH, et al. N Engl J Med 1992;326(6):381-386.
GetABI: Mortality (All-cause) by ABI Category
Diehm C. Presented at ESC Congress. Vienna, Austria. September 4, 2007.
> 1.1
0.9 – 1.1
0.7 – 0.9
0.5 – 0.7
< 0.5
Pro
port
ion
aliv
e
Patients with symptomatic PAD have a
5-year mortality rate of 28%compared with 15% for breast
cancer and 18% for Hodgkin’s disease1
Patients with PAD are 6 X more likely to die within 10 years than those without PAD1
PAD: A Major Health Burden
1. Criqui MH, et al. N Eng J Med 1992;326(6):381-386. 2. Gupta A. In: Abramson BL, et al. Can J Cardiol 2005;21(12):997-1006.
Patients with PAD are 6 X more likely to die within 10 years than those without PAD1
Patients with PAD often have decreased quality of life because of pain during walking and limitations in mobility2
1. Criqui MH, et al. N Eng J Med 1992;326(6):381-386. 2. Belch JJ, et al. Arch Int Med 2003;163(8):884-892.
PAD: A Major Health Burden
Question 4
What are the most powerful risk factor(s) for development of PAD?
a) Risk factors for PAD are similar to those in all vascular beds
b) Smoking is more predictive for PAD than the other traditional risk factors
c) Diabetes is more predictive for PAD than the other traditional risk factors
d) All of the above
Risk Factors for PAD
Teo KK. In: Abramson BL, et al. Can J Cardiol 2005;21(12):997-1006.
• Risk factors for PAD are similar to those for atherosclerosis in other beds and include:
Non-Modifiable Modifiable
• Age
• Family history
• Male sex
• Cigarette smoking• Diabetes• Elevated lipid levels• Hypertension• Obesity• Sedentary lifestyle
REACH: Risk Factors are Consistently Found Across All Disease Subpopulations*
80.377.0
38.3
29.9
13.0
83.3
58.2
37.4
23.7
14.3
81
66.7
44.2
23.8 24.5
0
20
40
60
80
100
Treated
hypertension
Treated hyper-
cholesterolemia
Treated diabetes Obesity(BMI ≥ 30)
Current smoker
Pat
ien
ts (
%)
CAD population
CVD population
PAD population
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
Take-Home Messages
Atherothrombosis is a generalized and progressive disease
Acute vascular events are the result of sudden plaque rupture
PAD is associated with significant morbidity and mortality due to local and systemic complications
Currently, PAD is under-diagnosed and under-treated
Cigarette smoking and diabetes are the strongest risk factors for PAD
Hyperlinks to Patient Vignettes
Vignette 3: John63-year-old government employee with recently
diagnosed PAD
Vignette 1: Louise56-year-old female who experienced a mild ischemic stroke 6 months ago and has since made a full recovery
Vignette 2: Todd58-year-old retired executive with PAD who experienced a MI 6 months ago ( i.e., diffuse vascular disease)
Patient Vignette: Louise
Louise is a 56-year-old office manager6 months ago she experienced a mild ischemic
strokeShe has since made a full recovery with no
residual signs/symptomsHer current medications include anti-platelet
therapy, an ACE inhibitor and a statinLouise comes to your office today for a routine
visit and tells you that she would like to return to work
Question 5
Which of the following in NOT appropriate Anti-platelet therapy for Louise?
a) ER Dipyrdamole 200 mg plus ASA 25 mg BID
b) ECASA 81 mg plus clopidogrel 75 mg OD
c) ECASA 81 - 325 mg OD alone
d) Clopidogrel 75 mg OD alone
e) None of the above, all are reasonable
MATCH: Results
Cumulative Event Rate(Ischemic Stroke, MI, Vascular Death,
Rehospitalization due to Ischemic Event)
Months of follow-up
6.4% RRR1.03% ARR
P=0.244
0
6
12
18
0 1 3 6 12 18
Cu
mu
lati
ve e
ven
t ra
te (
%)
Placebo
ASA
On-Treatment Analysis: 9.6% RRR, 1.6% ARR, p=0.10
* All patients received clopidogrel background therapy
Diener HC, et al. Lancet. 2004; 364:331-337.
ESPS 2:Risk Reduction for Stroke or Death
Str
oke
rela
tive
risk
redu
ctio
n (%
)
P<0.001
P<0.05 P<0.05
P=0.006
ER DP = extended release dipyridamole
n = 6602 within 3 months of stroke or TIA
2 years of follow-up
Diener HC, et al. J Neurol Sci. 1996;143:1-13.
Antithrombotic Trialists’ Collaboration
ASA dose
500 – 1500 mg daily
160 – 325 mg daily
75 – 150 mg daily
< 75 mg daily
Any ASA dose
0.0 0.5 1.0 1.5
ASA better Control better
% odds reduction*
Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86.
23% + 2
(P<0.0001)
*Vascular events = MI, stroke or vascular death
75-150 mg ASA daily is at least as effective as higher daily ASA doses which carry higher risk of GI bleeding
20 10 0 10 20 30 40
Outcome = IS, MI, vascular death
Clopidogrel better
8.7%
14.9%
CAPRIE:Clopidogrel vs ASA in Patients with Previous Acute Events
• Patients with previous acute events
• Entire CAPRIE sample
Outcome = IS, MI, rehospitalization for angina/ claudication/peripheral ischemia/TIA/MI
• Patients with previous acute events
• Entire CAPRIE sample
12.0%
9.0%
Ringleb PA, et al. Stroke. 2004;35:528-532.
ASA better
CAPRIE: Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events
2006 AHA/ASA Guidelines:Prevention of Stroke in Patients with Ischemic Stroke or TIA
Sacco RL, et al. Stroke. 2006;37:577–617.
Antithrombotic Therapy for Non-Cardioembolic Stroke or TIA
RecommendationClass, level of
evidence
Antiplatelet agents rather than oral anticoagulation I, A
ASA (50 to 325 mg/d)ASA + extended-release dipyridamoleClopidogrel } All acceptable options for
initial therapyIIa, A
ASA + extended-release dipyridamoleClopidogrel } Both safe compared with
ASA monotherapy IIa, A
Question 6
With regard to her future vascular risk:
a) Her greatest risk of death in the next 12 months is recurrent stroke
b) There is a high probability that she has atherothrombotic disease in the coronary and peripheral circulation
c) Long term she is more likely to die from recurrent stroke than cardiac disease
d) All of the above
e) None of the above
CVD
16.6%CAD
44.6%8.4%
1.2%4.7%
1.6%
PAD
4.7%
40% of CVD patients also have symptomatic disease in the coronary or peripheral circulation
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
REACH:Overlapping Manifestations of Disease
Cause of deathFirst stroke
Recurrent stroke
Cardiovascular disease
Nonvascular disease
Unknown
Hankey GJ, et al. Stroke 2000;31(9):2080-2086.
Long-Term Cause of Stroke Mortality Risk at 5 Years
Time since first-ever stroke
0
10
20
30
40
50
60
70
80
90
100
< 30d 30d–6m 6m–1yr 1-3yr 3-5yr
%
Question 7 - Suppose Louise also experienced an Acute Coronary Syndrome within the past year.
How would this impact her risk for subsequent atherothrombotic events?
a) She remains at equally high risk regardless of the presence of diffuse vascular disease
b) Her risk reduction strategies should remain unchanged
c) She would benefit from dual anti-platelet therapy with ASA 81 mg plus clopidogrel 75 mg
d) More aggressive lipid and blood pressure targets should be applied
e) All of the above
CURE Primary Endpoint: MI/Stroke/CV Death (n=12,562*)
The primary outcome occurred in 9.3% of
patients in the clopidogrel + ASA group and 11.4% in the placebo + ASA group
Months of Follow-up
Clopidogrel + ASA†
3 6 9
Placebo + ASA†
0 12
Cu
mu
lati
ve H
azar
d R
ate
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
20%20%Relative Relative
Risk ReductionRisk Reduction p=0.00009
*Study subjects had ACS (Acute Coronary Syndrome - UA/non–Q-wave MI). † Other standard therapies were used as appropriate.
CURE Trial Investigators. N Engl J Med 2001;345(7):494-502.
CURE: Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events
<100 mg 100-200 mg > 200 mg0.0
1.0
2.0
3.0
4.0
5.0
6.0
Ble
ed
ing
ra
te (
%)
ASA dose 75-325 mg
*In addition to standard therapy (including ASA).
2.0
2.62.3
3.54.0
4.9 Placebo*
Clopidogrel*
CURE: Major Bleeding by ASA Dose
CURE Trial Investigators. N Engl J Med 2001;345(7):494-502.
CV
dea
th/M
I/str
oke/
hosp
italiz
atio
n (%
)
Number of disease locations
P<0.001
*
*Multiple risk factor group
REACH: 1-year CV Event Rates as a Function of the Number of Symptomatic Disease Locations
Steg PG et al, on behalf of the REACH Registry Investigators. JAMA 2007;297(11):1197-1206.
Risk sharply increases with
diffuse vascular disease
HOPE: Risk Reduction with ACE Inhibition
Minimal changes in BP; non-hypertensive sub-group noted similar benefit
Yusuf S, et al. N Engl J Med 2000;342(3):145-153.
CVD death Stroke Non-fatal MI Total morality
26%32%
20%16%
p<0.001
p<0.001
p<0.001p=0.005
HOPE: Heart Outcomes Prevention Evaluation
0.05
0.10
0.15
0.20
1 2 3 4Follow-up time (years)
Pro
port
ion
with
eve
nt
28% risk reduction95% CI 17–38%
P<0.0001ARR (%) = 4.0placebo
perindopril-based treatment
6,105 subjects with cerebrovascular event within past 5 years
No BP entry requirement
PROGRESS: Stroke Reduction
PROGRESS Collaborative Group. Lancet 2001;358(9287):1033-1041.
PROGRESS: Perindopril Protection Against Recurrent Stroke Study
SPARCL: Primary End-point: Fatal or Non-fatal Stroke
The SPARCL Investigators. N Eng J Med 2006;355(6):549-559.
Time since randomization (years)
*Adjusted
Fat
al/ n
on
fata
l str
oke
(%)
00 1 2 3 4 5 6
16
12
8
4
Placebo
Atorvastatin
16% RRR*
HR 0.84 (0.71–0.99)
P=0.03
SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels
CAPRIE:Clopidogrel vs. ASA in Multi-bed Disease
15
5
0
Ann
ual e
vent
rat
e (%
)
Clopidogrel ASA
Events = ischemic stroke, MI or vascular death
CAPRIE Steering Committee. Lancet 1996;348(9038):1329-1339.
108.35%
10.74%
164 events 196 events
22.7%
Relative RiskReduction
CAPRIE: Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events
n=3284
n=12,153
n=15,603
CHARISMA: Treatment Effect by Inclusion Criteria
Combined endpoint: MI, stroke, CV death
*Multiple atherothrombotic risk factors†Documented CAD, CVD and/or PAD
0.5 1.0 1.5Placebobetter
Clopidogrelbetter
Asymptomatic*
Symptomatic†
All patients
Hazard ratio RR (95% CI)
1.20 (0.91–1.59)
0.88 (0.77–0.998)
0.93 (0.83–1.05)
Bhatt DL, et al. N Engl J Med 2006;354(16):1706-1717.
P=0.20
P=0.046
P=0.22
CHARISMA: Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance
Take-Home Messages
Approximately 40% of patients with CVD in the REACH Registry had diffuse vascular disease
Compared with a history of disease in a single vascular bed, diffuse vascular disease doubles the risk of a major CV event or hospitalization within 1 year
Aggressive risk reduction strategies including ACE inhibition, statins and antiplatelet therapy should be considered for patients with diffuse vascular disease
CHARISMA showed that patients with a prior atherothrombotic event benefit from long-term dual antiplatelet therapy (median follow-up 27 months)
Patient Vignette: John
John is a 63-year-old government employeeLast month, he came to your office complaining
of left calf pain when walking a couple of blocks; the pain went away after a few minutes
Based on your history and clinical examination at this time, you suspected John had symptomatic PAD and sent him for an ABI
John’s ABI was 0.90 (R) 0.77 (L), which confirmed your diagnosis
ABI: ankle brachial index
Question 8
Unless contraindicated, which of the following are necessary risk reduction strategies for John?
a) Statin therapy to reduce LDL to < 2.0 mmol/L
b) RAA inhibition with an ACEI or ARB
c) Anti-platelet agent
d) Referral to a vascular surgeon
e) All of the above
f) a, b and c only
CCS Guidelines for PAD: Risk Reduction Strategies
Anand SS, Turpie AGG. In: Abramson BL, et al. Can J Cardiol 2005;21(12):997-1006.
Non-pharmacologic Pharmacologic
• Exercise• Blood pressure control• Lipid control• Habits
- Smoking
• Antiplatelet therapy• ACE inhibitors • Diabetes control• Hypertension control• Statin use
CCS: Canadian Cardiovascular Society; ACE: angiotensin-converting enzyme
Medical therapies to reduce cardiovascular events in PAD
CCS Guidelines for PAD: Pharmacological Approach
CLASS OF AGENT GRADE
Statins 1A
ACE inhibitors 1A
Oral hypoglycemics or insulin 2B
Antiplatelet 1A
Anand SS, Turpie AGG. In: Abramson BL, et al. Can J Cardiol 2005;21(12):997-1006.
CAD
PAD
CVD
~ 3/5 of the 8,273 patients with PAD also haveatherothrombotic disease in other arterial territories
1.2%4.7%
1.6%
REACH: ~ 3/5 of Patients with Symptomatic PAD have Diffuse Vascular Disease
4.7%
Patients with PAD = 12.2% of
the total REACH Registry
population
(%s are of total population)
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
Consequences of PAD
Population > 55 years of age
Surgery or tissue loss
>25%
Adapted from Weitz JI, et al. Circulation 1996;94(11):3026-3049.
Stable claudication
~50%
5-year peripheral vascular outcomes
Worsening claudication
~16%
5-year natural history of intermittent claudication
Major amputation
<4%
Intermittent claudication 5%
Other cardiovascular outcomes
5-year non-fatal atherothrombotic
events (MI, stroke, etc.)
20%
5-year mortality
30%
REACH:Vascular Interventions at 1 Year
0.31.60.30.30.4Amputation
0.45.00.91.01.2PAD angioplasty/ stenting
0.2
0.3
0.2
0.5
0.9
Multiple RF only(n=11,966)
3.70.50.60.8Peripheral bypass graft
1.00.70.40.5Carotid surgery
0.60.40.30.3Carotid angioplasty/ stenting
1.00.71.41.1CABG
2.9
Total symptomatic
(n=53,390)
1.5
CVD(n=18,013)
2.4
PAD(n=8,581)
3.8Coronary angioplasty/ stenting
CAD (n=38,602)
CABG: coronary artery bypass graft; adjusted for age and genderSteg PG et al, on behalf of the REACH Registry Investigators. JAMA 2007;297(11):1197-1206.
Local Systemic
REACH:Vascular Interventions at 1 Year
Rev
ascu
lariz
atio
n at
1 y
ear
(%)
Steg PG et al, on behalf of the REACH Registry Investigators. JAMA 2007;297(11):1197-1206.
(n=18,013) (n=38,602) (n=8,581)
Question 9
Which of the following anti-platelet strategies are NOT appropriate for John?
a) ASA 81 mg OD
b) Clopidogrel 75 mg OD
c) ASA 81 mg OD plus Clopidogrel 75 mg OD
d) ER Dipyrdamole 200 mg plus ASA 25 mg BID
e) None of the above (all are appropriate)
CCS Guidelines:Antithrombotic Therapies
AGENT RECOMMENDATION GRADE
ASA or Clopidogrel
Lifelong antiplatelet therapy with ASA (75 to 325 mg/day) or clopidogrel (75 mg/day) in patients with or without clinically manifest coronary or cerebrovascular disease
1A
Ticlopidine ASA or clopidogrel recommended over ticlopidine 1B
Cilostazol* Recommendation for patients with disabling intermittent claudication who do not respond to conservative measures (risk factor modification and exercise therapy) and who are not candidates for surgical or catheter-based intervention
1B
Pentoxifylline Pentoxifylline is not recommended 2B
Vitamin K Antagonists
Anticoagulant therapy is not recommended 2B
*Not available in Canada
Anand SS, Turpie AGG. In: Abramson BL, et al. Can J Cardiol 2005;21(12):997-1006.
Question 10
What percentage of symptomatic Canadian REACH Registry patients are currently on “Triple Therapy” (ACE or ARB + Statin + Anti-platelet agent)
a) 95 %
b) 80 %
c) 75 %
d) 70 %
e) < 60 %
REACH: Proven Therapies are Consistently Underused in All Patient Types*
(n=12,389) (n=8,273) (n=18,843)(n=40,258)
Pat
ien
ts r
ecei
vin
g p
rov
en t
her
apy
(%)
ARB: angiotensin II receptor blocker*Data shown may differ slightly from published abstracts owing to a subsequent database lock
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
CRUSADE: Link Between Guideline Adherence and In-hospital Mortality
• Adjusted figures
Peterson ED, et al. ACC Annual Scientific Session. 2004. Available at: http://www.crusadeqi.com
Improved Guideline AdherenceImproved Guideline Adherence
CRUSADE : Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines
Approximately 1 in 5 patients with PAD will experience CV death, MI, stroke, or hospitalization within 1 year
Breakdown of event rates
PAD
CAD
CVD
21.1% 1 in ~5
15.2% 1 in ~6
14.5% 1 in ~7
Steg PG et al, on behalf of the REACH Registry Investigators. JAMA 2007;297(11):1197-1206.
Take-Home Messages
Take-Home Messages (continued)
• ~ 60% of patients with PAD have diffuse vascular disease
• ~ 15% of patients with PAD will require a vascular
intervention at 1 year
• Lifelong antiplatelet therapy with ASA or clopidogrel is
recommended for patients with PAD
• Adherence to guideline recommendations may lead to
reduced mortality in PAD