Transcript The Optimal Management of Diffuse Vascular Disease

Primary Care Today
Educational Conference and Medical Exposition
Toronto, Ontario / May 8-10, 2008
Adapted from a presentation by:
Alan D. Bell, MD, MCFP
Humber 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
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”
Atherothrombosis
remains the leading
cause of death
worldwide
accounting for 47%
of North American
Mortality
Suboptimal Risk
Factor Management
in C/V disease
58% of Canadian high risk
hypertensives NOT at goal BP in
REACH were on fewer than 3
drugs
Learning Objectives
At the end of this session, participants should be able to:

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
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
Life Expectancy (Years)
 Comparatively, patients with a history of MI lived 9.2 fewer years
 Those with a history of CVA lived 12 fewer years
20
9.2
Fewer
years
CVA: cerebrovascular accident
Adapted from Bakhai A. Pharmacoeconomics 2004;22(suppl 4):11-18.
12
Fewer
years
Framingham Heart Study:
Cardiovascular Event Rates
in >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.
Inclusion Criteria
•
Must include
Signed
Written
Informed
Consent
Patients aged
≥45 years
1
At least
of four
criteria
•
•
Documented
cerebrovascular disease
Ischemic stroke or
TIA
•
Male 65 years
or female 70 years
•
Current smoking
>15 cigarettes/day
Documented
coronary disease
Angina, MI, angioplasty/
stent/bypass
•
Type I or II diabetes
•
Hypercholesterolemia
•
Diabetic nephropathy
•
Hypertension
•
ABI <0.9 in either
leg at rest
•
Asymptomatic carotid
stenosis 70%
•
Presence of at least
one carotid plaque
Documented historical
or current intermittent
claudication associated
with ABI* <0.9
• At least
atherothrombotic
risk factors
3
*ABI: Ankle Brachial Index
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
REACH Registry:
>67,000 Patients from 5,473 Sites* in 44 Countries
5,656
1,976
17,886
27,746
5,048
5,903
846
North America
Latin America
1,931
Western Europe
Eastern Europe
2,872
Middle East
Asia (incl. Japan)
*up to 15 patients/site (up to 20 in the US)
Australia
Adapted from Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
REACH Registry Timeline
Baseline
Follow-up at 12 
3 months
Follow-up at 24
 3 months
Follow-up at 33
 3 months
Dec 2003 to
June 2004
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
Follow-up at 45
 3 months
June 2007 to
June 2008
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)
Single arterial bed: 65.9%
CAD Alone
CVD Alone
PAD Alone
44.6
16.6
4.7
Diffuse vascular disease: 15.9%
CAD + CVD
CAD + PAD
CVD + PAD
CAD + CVD + PAD
CAD: coronary artery disease
PAD: peripheral arterial disease
CVD: cerebrovascular disease
8.4
4.7
1.2
1.6
Multiple risk factors: 18.3%
0
10
20
30
40
Patients (%)
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
50
60
70
REACH: Patient Characteristics at Baseline
Total
% of population
Symptomatic
(n=67,888)
(n=55,499)
Multiple RF
only
(n=12,389)
Mean age (SD) yr
68.5 (10.1)
68.4 (10.1)
69.0 (9.8)
Men
63.7
66.9
49.5
Diabetes
44.3
37.5
74.9
Hypertension
81.8
80.0
90.3
Hypercholesterolemia
72.4
70.2
82.2
Overweight (BMI 25 to < 30)
39.8
40.9
35.0
Obesity (BMI ≥ 30)
30.2
27.4
42.4
Former smoker
41.6
44.6
28.4
Current smoker
15.3
14.4
19.2
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
Physician Profile
Physician profile
Follow-up available
(%) N=63,129
General practice (N=24,441)
74.7
36.7
Internist (N=22,244)
12.3
32.8
Cardiologist (N=9,390)
9.7
14.0
Angiologist (N=771)
1.1
Vascular surgeon (N=1,480)
2.2
Neurologist (N=6,353)
3.2
9.4
Endocrinologist (N=1,987)
3.0
Other (N=533)
0.8
REACH: Risk Factors are Consistently Found
Across All Disease Subpopulations*
Risk factor prevalence, by subpopulation (%)
100
Patients (%)
80
80.3
83.3 81
CAD population
CVD population
PAD population
77.0
66.7
58.2
60
44.2
38.3 37.4
40
29.9
23.7 23.8
20
24.5
13.0 14.3
0
Treated
hypertension
Treated hyper- Treated diabetes
cholesterolemia
Obesity
(BMI ≥ 30)
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
Current smoker
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
(%s are of total population)
Multiple risk
factors only
population
Patients with
CAD = 59.3% of
the REACH
Registry
population
CAD
44.6%
8.4%
1.6%
CVD
4.7%
PAD
1. Bhatt DL et al, on behalf of the REACH Registry Investigators.
JAMA 2006;295(2):180-189.
CAD=coronary artery disease
PAD=peripheral arterial disease
CVD=cerebrovascular disease
40% of the 18,843 patients with CVD also have
atherothrombotic disease in other arterial territories
(%s are of total population)
Multiple risk
factors only
population
Patients with CVD
= 27.8% of the
REACH Registry
population
CAD
8.4%
1.6%
CVD
16.6%
1.2%
PAD
1. Bhatt DL et al, on behalf of the REACH Registry Investigators.
JAMA 2006;295(2):180-189.
CAD=coronary artery disease
PAD=peripheral arterial disease
CVD=cerebrovascular disease
60% of the 8,273 patients with PAD also have
atherothrombotic disease in other arterial territories
(%s are of total population)
Multiple risk
factors only
population
CAD
Patients with
PAD = 12.2% of
the total REACH
Registry
population
1.6%
4.7%
1. Bhatt DL et al, on behalf of the REACH Registry Investigators.
JAMA 2006;295(2):180-189.
PAD
4.7%
CVD
1.2%
CAD=coronary artery disease
PAD=peripheral arterial disease
CVD=cerebrovascular disease
1-Year Outcomes
REACH:
1-year Event Curves for CV Death,
MI, Stroke & Combined Endpoints
5.0
4.24% of these
stable patients had
an event within
1 year
n=64,977
Event distribution function (%)
4.5
4.0
Non-fatal stroke
Non-fatal MI infarction
3.5
CV death
CV death/MI/stroke
3.0
42% 10 year risk
2.5
2.0
1.5
1.0
0.5
0.0
0
1
2
3
4
5
6
7
8
9
Time in months
Steg PG et al, on behalf of the REACH Registry Investigators. JAMA 2007;297(11):1197-1206.
10
11
12
REACH 1-year CV Event Rates:
Symptomatic vs Multiple Risk Factor Only
Total
% of population
Symptomatic
(n=64,977)
(n=53,390)
Multiple RF
only
(n=11,766)
Death all cause
2.6
2.8
1.5
CV death
1.7
1.8
0.8
Non-fatal MI
1.1
1.2
0.8
Non-fatal stroke
1.7
1.9
0.8
CV death/MI/stroke
4.2
4.7
2.2
CV death/MI/stroke/
hospitalization for
atherothrombotic events*
12.8
14.4
5.3
*Such as TIA, unstable angina, worsening of PAD; adjusted for age and gender
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*
8
7,1
0
1
6
5,7
2
Percent
3
3,8
4
3,7
3,4
2,9
2,4
2
1,5
1,4
1,9
1,2
0,7
0,6
1,5
1,5
0,8
0
CV death
Non-fatal MI
Non-fatal stroke
CV death / MI / stroke
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
Other outcomes leading
to hospitalization since baseline
Multiple
RF only
Total
Symptomatic
CAD
CVD
PAD
(N=63,129)
(N=51,685)
(N=37,542)
(N=17,451)
(N=7,674)
Unstable angina
4.2
4.9
6.3
3.4
4.5
1.1
TIA
1.4
1.5
1.2
3.2
1.8
0.6
Other ischemic
arterial event
(including
worsening of PAD)
1.3
1.5
1.5
1.5
4.1
0.5
Chronic heart
failure
3.1
3.4
4.2
3.2
4.1
1.4
Bleeding (leading
to hospitalization
and transfusion)
0.8
0.9
0.9
0.9
1.3
0.5
(N=11,444)
Major adverse event rates at one year as a
function of age: total population
Rates adjusted for risk factors
5
4,1
Percent
4
3
45-60 yrs
60-70 yrs
70-80 yrs
80+ yrs
3,6
3,3
3,1
2,3
1,9
2
1,5
1,1
1,2
1,4
1,1
1,1
1,5
1,5
1,5
1,1
1
0
CV death
Non-fatal MI
Non-fatal stroke
CV death / MI / stroke
Geographical Variation of 1-year
Cardiovascular Event Rates
North
America
(N=25,302)
Latin
America
(N=1,718)
Western
Europe
(N=16,48
7)
CV death
1.4
1.8
1.5
2.2
2.4
1.5
1.5
0.7
Non-fatal MI
1.3
0.9
1.1
1.2
2.2
0.8
1.0
0.8
Non-fatal stroke
1.1
2.5
1.5
3.5
2.1
2.3
1.0
1.6
CV death/MI/ stroke
3.7
4.9
3.7
6.8
6.3
4.5
3.2
3.0
CV death/MI/
stroke/
hospitalization for
atherothrombotic
events*
11.4
13.6
14.2
21.6
18.0
10.0
11.3
6.3
Eastern
Europe
(N=5,579)
Middle
East
(N=818)
Asia
Australia
(N=5,559) (N=2,822)
*TIA, unstable angina, other ischemic arterial event including worsening of peripheral arterial disease
Japan
(N=4,844)
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
Ischemic stroke
Myocardial
infarction
(MI)
Rest pain
Gangrene
Necrosis
Adapted from Drouet L. Cerebrovasc Dis 2002;13(suppl 1):1–6.
Transient ischemic attack
(TIA)
Angina:
• Stable
• Unstable
Peripheral arterial disease (PAD):
• Intermittent claudication
Atherothrombosis:
A Generalized and Progressive Disease
Atherosclerosis
Thrombosis
Unstable
angina
MI
Ischemic
stroke/TIA
Critical leg
ischemia
Intermittent
claudication
Stable angina/Intermittent claudication
Adapted from Libby P. Circulation 2001;104(3):365-372.
CV death
ACS
What Types of Lesions Cause MI?
Coronary Events (%)
Coronary stenosis severity prior to MI
100
100
80
80
18%
60
60
68%
40
40
20
20
0
0
Ambrose
1988
Little
1988
<50%
Falk E et al. Circulation 1995;92:657-71.
Nobuyoshi
1991
Giroud
1992
50%-70%
14%
All 4
studies
>70%
Pathology: Plaque Fissuring
Vascular Disease* is a Leading
Cause of Death Worldwide†
Leading Causes Of Death, Worldwide
(% of all deaths)
AIDS
5.1
Pulmonary disease
6
Injuries
9.1
Cancer
12.6
Infectious disease
17.8
Vascular disease*
28.7
0
5
10
15
20
25
30
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
WHO. 2002. Available at: www.who.int/whr/2002/en/whr02_en.pdf
Atherothrombosis: Epidemiology
Epidemiology of Atherothrombotic
Manifestations in Canada
Peripheral Arterial Disease
and 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”
PAD: Epidemiology

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.
CCS Guidelines: Diagnosis of PAD
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
Roussin A, et al. Can J Cardiol. 2005;21(12):997–1006.
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
91.3% Sensitive 99.3% specific
Leng GC, et al. J Clin Epidemiol. 1992;45:1101–1109.
Measuring ABI
INTERPRETATION OF ABI
Rightarm
systolic
pressure
Left-arm
systolic
pressure
D
Right-ankle
systolic pressure P
PT
>1.30
Noncompressible
0.91-1.30
Normal
0.41-0.90
Mild-to-moderate
peripheral arterial
disease
0.00-0.40
Severe peripheral
arterial disease
D
Left-ankle
P systolic pressure
PT
Adapted from Roussin A, et al. Can J Cardiol 2005;21(12):997-1006.
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
Consequences of PAD may be
Local and Systemic
• 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
REACH: Reduction of Atherothrombosis for Continued Health
Patients with Previous Atherothrombotic Events are
at Increased Risk of Further Events
Increased risk versus general population
Ischemic stroke
MI
PAD
MI
Stroke
2-3x
(includes angina and
sudden death*)1
9x2
5-7x
(includes death)3
3-4x
(includes TIA)1
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
5-year natural history of intermittent claudication
Population > 55 years of age
Intermittent claudication 5%
5-year peripheral
vascular outcomes
Other cardiovascular
outcomes
Stable
claudication
Worsening
claudication
Surgery or
tissue loss
Major
amputation
~50%
~16%
>25%
<4%
5-year non-fatal
atherothrombotic
events (MI,
stroke, etc.)
20%
Adapted from Weitz JI, et al. Circulation 1996;94(11):3026-3049.
5-year mortality
30%
Risk of Death is Increased in Patients with Both
Asymptomatic and Symptomatic PAD
Survival (% of patients)
100
75
50
25
Normal subjects*
Symptomatic PAD†
Asymptomatic PAD†
Severe symptomatic PAD†
0
0
2
4
6
Year
* Kaplan-Meier survival curves based on mortality from all causes.
† Large-vessel PAD.
Criqui MH, et al. N Engl J Med 1992;326(6):381-386.
8
10
12
Proportion alive
GetABI:
Mortality (All-cause) by ABI Category
> 1.1
0.9 – 1.1
0.7 – 0.9
0.5 – 0.7
< 0.5
Diehm C. Presented at ESC Congress. Vienna, Austria. September 4, 2007.
PAD: A Major Health Burden

Patients with symptomatic PAD have a
5-year mortality rate of 28%
 compared with 15% for breast cancer
1
 and 18% for Hodgkin’s disease

Patients with PAD are 6 X more likely to
die within 10 years than those without
PAD1
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.
PAD: A Major Health Burden

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.
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
• Risk factors for PAD are similar to those for
atherosclerosis in other beds and include:
Non-Modifiable
• Age
• Family history
• Male sex
Modifiable
•
•
•
•
•
•
Cigarette smoking
Diabetes
Elevated lipid levels
Hypertension
Obesity
Sedentary lifestyle
Teo KK. In: Abramson BL, et al. Can J Cardiol 2005;21(12):997-1006.
REACH: Risk Factors are Consistently Found
Across All Disease Subpopulations*
100
83.3
80.3
81
80
CAD population
CVD population
PAD population
77.0
Patients (%)
66.7
58.2
60
44.2
38.3 37.4
40
29.9
23.7 23.8
20
24.5
13.0 14.3
0
Treated
hypertension
Treated hyper- Treated diabetes
cholesterolemia
Obesity
(BMI ≥ 30)
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
Current smoker
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 1: Louise
56-year-old female who experienced a mild ischemic stroke
6 months ago and has since made a full recovery
Vignette 2: Todd
58-year-old retired executive with PAD who experienced
a MI 6 months ago ( i.e., diffuse vascular disease)
Vignette 3: John
63-year-old government employee with recently
diagnosed PAD
Patient Vignette: Louise

Louise is a 56-year-old office manager

6 months ago she experienced a mild ischemic
stroke

She has since made a full recovery with no
residual signs/symptoms

Her current medications include anti-platelet
therapy, an ACE inhibitor and a statin

Louise 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)
18
Placebo
Cumulative event rate (%)
ASA
6.4% RRR
1.03% ARR
P=0.244
12
6
On-Treatment Analysis: 9.6% RRR, 1.6% ARR, p=0.10
0
0
1
3
6
Months of follow-up
* All patients received clopidogrel background therapy
Diener HC, et al. Lancet. 2004; 364:331-337.
12
18
ESPS 2:
Risk Reduction for Stroke or Death
Stroke relative risk reduction (%)
P<0.001
P=0.006
P<0.05
P<0.05
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.
ER DP = extended release dipyridamole
Antithrombotic Trialists’ Collaboration
ASA dose
% odds reduction*
500 – 1500 mg daily
75-150 mg ASA
daily is at least as
effective as higher
daily ASA doses
which carry higher
risk of GI bleeding
160 – 325 mg daily
75 – 150 mg daily
< 75 mg daily
Any ASA dose
23% + 2
(P<0.0001)
0.0
0.5
ASA better
*Vascular events = MI, stroke or vascular death
Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86.
1.0
1.5
Control better
CAPRIE:
Clopidogrel vs ASA in Patients with Previous Acute Events
Outcome = IS, MI, vascular death
• Patients with previous acute events
14.9%
• Entire CAPRIE sample
8.7%
Outcome = IS, MI, rehospitalization for
angina/ claudication/peripheral
ischemia/TIA/MI
• Patients with previous acute events
12.0%
• Entire CAPRIE sample
9.0%
20
ASA better
10
0
10
20
30
40
Clopidogrel better
CAPRIE: Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events
Ringleb PA, et al. Stroke. 2004;35:528-532.
2006 AHA/ASA Guidelines:
Prevention of Stroke in Patients with Ischemic Stroke or TIA
Antithrombotic Therapy for Non-Cardioembolic Stroke or TIA
Class, level of
evidence
Recommendation
Antiplatelet agents rather than oral anticoagulation
ASA (50 to 325 mg/d)
ASA + extended-release dipyridamole
Clopidogrel
}
All acceptable options for
initial therapy
ASA + extended-release dipyridamole
Clopidogrel
}
Both safe compared with
ASA monotherapy
Sacco RL, et al. Stroke. 2006;37:577–617.
I, A
IIa, A
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
REACH:
Overlapping Manifestations of Disease
40% of CVD patients also have symptomatic disease
in the coronary or peripheral circulation
CVD
CAD
8.4%
44.6%
16.6%
1.6%
1.2%
4.7%
PAD
4.7%
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
Long-Term Cause of Stroke
Mortality Risk at 5 Years
Cause of death
First stroke
100
90
Recurrent
stroke
80
70
Cardiovascular
disease
%
60
50
Nonvascular
disease
40
30
20
Unknown
10
0
< 30d
30d–6m 6m–1yr
1-3yr
3-5yr
Time since first-ever stroke
Hankey GJ, et al. Stroke 2000;31(9):2080-2086.
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*)
0.14
Placebo
+ ASA†
Cumulative Hazard Rate
0.12
20%
Relative
Risk Reduction
p=0.00009
0.10
Clopidogrel
+ ASA†
0.08
0.06
0.04
The primary outcome
occurred in 9.3% of
patients in the clopidogrel +
ASA group and 11.4% in
the placebo + ASA group
0.02
0.00
0
3
6
9
12
Months of Follow-up
CURE: Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events
*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:
Major Bleeding by ASA Dose
6.0
5.0
Bleeding rate (%)
4.9
4.0
4.0
3.5
3.0
2.6
2.0
2.3
2.0
1.0
0.0
<100 mg
> 200 mg
100-200 mg
ASA dose 75-325 mg
*In addition to standard therapy (including ASA).
CURE Trial Investigators. N Engl J Med 2001;345(7):494-502.
Placebo*
Clopidogrel*
REACH: 1-year CV Event Rates as a Function of
the Number of Symptomatic Disease Locations
CV death/MI/stroke/hospitalization (%)
P<0.001
Risk sharply increases with
diffuse vascular disease
*
*Multiple risk factor group
Number of disease locations
Steg PG et al, on behalf of the REACH Registry Investigators. JAMA 2007;297(11):1197-1206.
HOPE: Risk Reduction with ACE Inhibition
CVD death
Stroke
Non-fatal MI
20%
Total morality
16%
p=0.005
p<0.001
26%
p<0.001
32%
p<0.001
Minimal changes in BP; non-hypertensive sub-group noted similar benefit
HOPE: Heart Outcomes Prevention Evaluation
Yusuf S, et al. N Engl J Med 2000;342(3):145-153.
PROGRESS: Stroke Reduction
Proportion with event
0.20
0.15
6,105 subjects with cerebrovascular event within
past 5 years
No BP entry requirement
0.10
28% risk reduction
95% CI 17–38%
P<0.0001
ARR (%) = 4.0
0.05
placebo
perindopril-based treatment
1
2
3
Follow-up time (years)
PROGRESS: Perindopril Protection
Against Recurrent Stroke Study
PROGRESS Collaborative Group. Lancet 2001;358(9287):1033-1041.
4
SPARCL:
Primary End-point: Fatal or Non-fatal Stroke
16
Fatal/ nonfatal stroke
(%)
16% RRR*
Placebo
HR 0.84 (0.71–0.99)
P=0.03
12
Atorvastatin
8
4
0
0
1
2
3
4
5
Time since randomization (years)
6
SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels
*Adjusted
The SPARCL Investigators. N Eng J Med 2006;355(6):549-559.
CAPRIE:
Clopidogrel vs. ASA in Multi-bed Disease
Annual event rate (%)
15
10.74%
10
8.35%
22.7%
Relative Risk
Reduction
5
164 events
196 events
0
Clopidogrel
ASA
Events = ischemic stroke, MI or vascular death
CAPRIE: Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events
CAPRIE Steering Committee. Lancet 1996;348(9038):1329-1339.
CHARISMA:
Treatment Effect by Inclusion Criteria
Combined endpoint: MI, stroke, CV death
Hazard ratio
RR (95% CI)
Asymptomatic*
n=3284
1.20 (0.91–1.59)
P=0.20
Symptomatic†
n=12,153
0.88 (0.77–0.998)
P=0.046
All patients
n=15,603
0.93 (0.83–1.05)
P=0.22
0.5
1.0
Clopidogrel
better
1.5
Placebo
better
CHARISMA: Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance
*Multiple atherothrombotic risk factors
†Documented CAD, CVD and/or PAD
Bhatt DL, et al. N Engl J Med 2006;354(16):1706-1717.
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 employee

Last 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)
c)
d)
e)
 f)
RAA inhibition with an ACEI or ARB
Anti-platelet agent
Referral to a vascular surgeon
All of the above
a, b and c only
CCS Guidelines for PAD:
Risk Reduction Strategies
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
Anand SS, Turpie AGG. In: Abramson BL, et al. Can J Cardiol 2005;21(12):997-1006.
CCS Guidelines for PAD:
Pharmacological Approach
Medical therapies to reduce cardiovascular events in PAD
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.
REACH: ~ 3/5 of Patients with Symptomatic PAD have
Diffuse Vascular Disease
~ 3/5 of the 8,273 patients with PAD also have
atherothrombotic disease in other arterial territories
(%s are of total population)
CAD
Patients with
PAD = 12.2% of
the total REACH
Registry
population
1.6%
4.7%
CVD
1.2%
PAD
4.7%
Bhatt DL et al, on behalf of the REACH Registry Investigators. JAMA 2006;295(2):180-189.
Consequences of PAD
5-year natural history of intermittent claudication
Population > 55 years of age
Intermittent claudication 5%
5-year peripheral
vascular outcomes
Other cardiovascular
outcomes
Stable
claudication
Worsening
claudication
Surgery or
tissue loss
Major
amputation
~50%
~16%
>25%
<4%
5-year non-fatal
atherothrombotic
events (MI,
stroke, etc.)
20%
Adapted from Weitz JI, et al. Circulation 1996;94(11):3026-3049.
5-year mortality
30%
REACH:
Vascular Interventions at 1 Year
Total
symptomatic
CAD
CVD
PAD
(n=38,602)
(n=18,013)
(n=8,581)
(n=53,390)
Multiple
RF only
(n=11,966)
Coronary angioplasty/
stenting
2.9
3.8
1.5
2.4
0.9
CABG
1.1
1.4
0.7
1.0
0.5
Carotid angioplasty/
stenting
0.3
0.3
0.4
0.6
0.2
Carotid surgery
0.5
0.4
0.7
1.0
0.3
Peripheral bypass graft
0.8
0.6
0.5
3.7
0.2
PAD angioplasty/
stenting
1.2
1.0
0.9
5.0
0.4
Amputation
0.4
0.3
0.3
1.6
0.3
Local
Systemic
CABG: coronary artery bypass graft; adjusted for age and gender
Steg PG et al, on behalf of the REACH Registry Investigators. JAMA 2007;297(11):1197-1206.
Revascularization at 1 year (%)
REACH:
Vascular Interventions at 1 Year
(n=18,013)
(n=38,602)
(n=8,581)
Steg PG et al, on behalf of the REACH Registry Investigators. JAMA 2007;297(11):1197-1206.
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
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 catheterbased 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.
GRADE
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 %
Patients receiving proven therapy (%)
REACH: Proven Therapies are Consistently
Underused in All Patient Types*
(n=40,258)
(n=18,843)
(n=8,273)
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.
(n=12,389)
CRUSADE: Link Between Guideline Adherence
and In-hospital Mortality
Improved Guideline Adherence
CRUSADE : Can Rapid Risk Stratification of Unstable Angina Patients Suppress
ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines
• Adjusted figures
Peterson ED, et al. ACC Annual Scientific Session. 2004. Available at: http://www.crusadeqi.com
Take-Home Messages
Approximately 1 in 5 patients with PAD will experience CV
death, MI, stroke, or hospitalization within 1 year
Breakdown of event rates
PAD
21.1%
1 in ~5

CAD
15.2%
1 in ~6

CVD
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 (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