The Optimal Management of Diffuse Vascular Disease: Clinical Implications of the REACH Registry

1
Primary Care Today Educational Conference and
Medical ExpositionToronto, Ontario / May 8-10,
2008
Adapted from a presentation by Alan D. Bell,
MD, MCFP Humber River Regional Hospital Toronto,
Ontario
2
The Optimal Management of Diffuse Vascular
Disease Clinical Implications of the Landmark
REACH Registry
3
Program Rationale
Atherothrombosis remains the leading cause of
death worldwide accounting for 47 of North
American Mortality
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
Suboptimal Risk Factor Management in C/V disease
42 of high risk atherothrombotic patients in
REACH were not on evidence based risk reduction
triple therapy
58 of Canadian high risk hypertensives NOT at
goal BP in REACH were on fewer than 3 drugs
4
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
5
Question 1

• Which of the following are typical
  characteristics a Registry?
• Registries examine the effects of a specific
  intervention
• Registries usually have more exclusion criteria
  compared to randomized trials
• Registries tell us about real world
  characteristics and outcomes
• Registry results are less reliable than
  randomized trial results
• All of the above

?
6
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
7
Example of a RegistryFramingham 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.
8
Framingham Heart StudyAtherothrombosis 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

9.2Feweryears
20
12 Feweryears
Life Expectancy (Years)
CVA cerebrovascular accident Adapted from Bakhai
A. Pharmacoeconomics 200422(suppl 4)11-18.
9
Framingham Heart Study
10
(No Transcript)
11
Cardiovascular Event Ratesin gt68,000 Outpatients
with AtherothrombosisRegistry Results
12
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
2006295(2)180-189.
13
Inclusion Criteria

• Documented cerebrovascular diseaseIschemic
  stroke orTIA
• Documentedcoronary diseaseAngina, MI,
  angioplasty/stent/bypass
• Documented historicalor current
  intermittentclaudication associatedwith ABI
  lt0.9

• Male ³65 yearsor female ³70 years
• Current smokinggt15 cigarettes/day
• Type I or II diabetes
• Hypercholesterolemia
• Diabetic nephropathy
• Hypertension
• ABI lt0.9 in eitherleg at rest
• Asymptomatic carotidstenosis ³70
• Presence of at leastone carotid plaque

Must include Signed Written Informed Consent Pat
ients aged 45 years
1
3
ABI Ankle Brachial Index Bhatt DL et al, on
behalf of the REACH Registry Investigators. JAMA
2006295(2)180-189.
14
REACH Registry gt67,000 Patients from 5,473
Sites in 44 Countries
5,656
17,886
27,746
5,048
5,903
846
North America
1,931
Latin America
Western Europe
Eastern Europe
2,872
Middle East
up to 15 patients/site (up to 20 in the US)
Asia (incl. Japan)
Australia
Adapted from Bhatt DL et al, on behalf of the
REACH Registry Investigators. JAMA
2006295(2)180-189.
15
REACH Registry Timeline
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
Dec 2003 to June 2004
June 2007 to June 2008
Bhatt DL et al, on behalf of the REACH Registry
Investigators. JAMA 2006295(2)180-189.
16
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 2006295(2)180-189.
17
Baseline Data

• Published 11th Jan 2006 Bhatt DL, et al, for the
  REACH Registry Investigators.
• JAMA 2006295(2)180-9.

18
REACHSignificant Proportion of the Symptomatic
Population has Diffuse Vascular Disease
Prevalence of disease in arterial beds ( of
total)
Single arterial bed 65.9
CAD Alone
44.6
CVD Alone
16.6
PAD Alone
4.7
Diffuse vascular disease 15.9
CAD coronary artery disease PAD peripheral
arterial disease CVD cerebrovascular disease
CAD CVD
8.4
CAD PAD
4.7
CVD PAD
1.2
CAD CVD PAD
1.6
Multiple risk factors 18.3
0
10
20
30
40
50
60
70
Patients ()
Bhatt DL et al, on behalf of the REACH Registry
Investigators. JAMA 2006295(2)180-189.
19
REACH Patient Characteristics at Baseline
of population Symptomatic (n55,499)
Multiple RF only (n12,389)
Total (n67,888)
69.0 (9.8)
68.4 (10.1)
68.5 (10.1)
Mean age (SD) yr
49.5
66.9
63.7
Men
74.9
37.5
44.3
Diabetes
90.3
80.0
81.8
Hypertension
82.2
70.2
72.4
Hypercholesterolemia
35.0
40.9
39.8
Overweight (BMI 25 to lt 30)
42.4
27.4
30.2
Obesity (BMI 30)
28.4
44.6
41.6
Former smoker
19.2
14.4
15.3
Current smoker
Bhatt DL et al, on behalf of the REACH Registry
Investigators. JAMA 2006295(2)180-189.
20
Physician Profile
21
REACH Risk Factors are Consistently Found Across
All Disease Subpopulations
Risk factor prevalence, by subpopulation ()
100
CAD population
83.3
CVD population
81
80.3
77.0
80
PAD population
66.7
58.2
60
Patients ()
44.2
38.3
37.4
40
29.9
23.8
24.5
23.7
20
14.3
13.0
0
Treated
Treated hyper-
Treated diabetes
Obesity(BMI 30)
Current smoker
hypertension
cholesterolemia
Bhatt DL et al, on behalf of the REACH Registry
Investigators. JAMA 2006295(2)180-189.
22
Diffuse Vascular Disease

• How often do patients have manifest disease in
  more than one vascular bed?

23
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
CVD
1.6
4.7
PAD
CADcoronary artery disease PADperipheral
arterial disease CVDcerebrovascular disease

1. Bhatt DL et al, on behalf of the REACH Registry
   Investigators. JAMA 2006295(2)180-189.

24
40 of the 18,843 patients with CVD also
haveatherothrombotic 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
CVD
1.6
16.6
1.2
PAD
CADcoronary artery disease PADperipheral
arterial disease CVDcerebrovascular disease

1. Bhatt DL et al, on behalf of the REACH Registry
   Investigators. JAMA 2006295(2)180-189.

25
60 of the 8,273 patients with PAD also
haveatherothrombotic 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
CVD
1.6
4.7
1.2
PAD
CADcoronary artery disease PADperipheral
arterial disease CVDcerebrovascular disease
4.7

1. Bhatt DL et al, on behalf of the REACH Registry
   Investigators. JAMA 2006295(2)180-189.

26
1-Year Outcomes
27
REACH 1-year Event Curves for CV Death, MI,
Stroke Combined Endpoints
4.24 of these stable patients had an event
within 1 year
5.0
n64,977
4.5
Non-fatal stroke
Non-fatal MI infarction
4.0
CV death/MI/stroke
CV death
3.5
3.0
42 10 year risk
Event distribution function ()
2.5
2.0
1.5
1.0
0.5
0.0
1
2
3
4
5
6
7
8
9
10
11
12
0
Time in months

Steg PG et al, on behalf of the REACH Registry
Investigators. JAMA 2007297(11)1197-1206.
28
REACH 1-year CV Event Rates Symptomatic vs
Multiple Risk Factor Only
of population Symptomatic (n53,390)
Multiple RF only (n11,766)
Total (n64,977)
1.5
2.8
2.6
Death all cause
0.8
1.8
1.7
CV death
0.8
1.2
1.1
Non-fatal MI
0.8
1.9
1.7
Non-fatal stroke
2.2
4.7
4.2
CV death/MI/stroke
5.3
14.4
12.8
CV death/MI/stroke/ hospitalization for
atherothrombotic events
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 2007297(11)1197-1206.
29
1-year cardiovascular event rates as function of
number of symptomatic disease locations
All p values lt0.001 Pts with ³3 risk factors but
no symptoms are counted as 0, even in the
presence of asymptomatic carotid plaque or
reduced ABITIA, unstable angina, other
ischemic arterial event including worsening of
peripheral arterial disease
30
Other outcomes leading to hospitalization since
baseline
Multiple RF only (N11,444)
Symptomatic (N51,685)
Total (N63,129)
CVD (N17,451)
PAD (N7,674)
CAD (N37,542)
1.1
4.9
4.2
3.4
4.5
6.3
Unstable angina
0.6
1.8
3.2
1.2
1.5
1.4
TIA
0.5
4.1
1.5
1.5
1.5
1.3
Other ischemic arterial event (including
worsening of PAD)
1.4
4.1
3.2
4.2
3.4
3.1
Chronic heart failure
0.5
1.3
0.9
0.9
0.9
0.8
Bleeding (leading to hospitalization and
transfusion)
31
Major adverse event rates at one year as a
function of age total population
Rates adjusted for risk factors
32
Geographical Variation of 1-year Cardiovascular
Event Rates
TIA, unstable angina, other ischemic arterial
event including worsening of peripheral arterial
disease
33
Undertreatment of Risk Factors at Study Entry
Bhatt DL, et al. JAMA 2006295(2)180-9.
34
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)

35
Atherothrombosis
36
Atherothrombosis has Multiple Manifestations
Ischemic stroke
Transient ischemic attack (TIA)
Myocardial infarction (MI)

• Angina
• Stable
• Unstable

• Peripheral arterial disease (PAD)
• Intermittent claudication

Rest pain Gangrene Necrosis
Adapted from Drouet L. Cerebrovasc Dis
200213(suppl 1)16.
37
Atherothrombosis A Generalized and Progressive
Disease
Atherosclerosis
Unstable angina MI Ischemic stroke/TIA Critical
leg ischemia Intermittent claudication CV death
ACS
Thrombosis
Stable angina/Intermittent claudication
Adapted from Libby P. Circulation
2001104(3)365-372.
38
What Types of Lesions Cause MI?
Coronary stenosis severity prior to MI
100
100
14
80
80
18
60
68
60
Coronary Events ()
40
40
20
20
0
0
All 4studies
Ambrose1988
Little1988
Nobuyoshi1991
Giroud1992
50-70
lt50
gt70
Falk E et al. Circulation 199592657-71.
39
Pathology Plaque Fissuring
40
Vascular Disease is a Leading Cause of Death
Worldwide
Leading Causes Of Death, Worldwide ( of all
deaths)
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/w
hr02_en.pdf
41
Atherothrombosis Epidemiology
Epidemiology of Atherothrombotic Manifestations
in Canada
42
Peripheral Arterial Diseaseand theCanadian PAD
Guidelines
43
Question 2

• How common is peripheral arterial disease (PAD)
  in your practice?
• I hardly ever see it Its a specialist
  disease
• I have a few patients, but its much less
  common than coronary disease
• Since Ive been screening for it I cant
  believe how common it is!
• I dont know, because I have no way to test for
  it
• I dont look for it because none of my patients
  ever died of a leg attack

44
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
200521(12)997-1006.
45
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 ABIlt0.9. 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.
200521(12)9971006.
46
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.
19924511011109.
47
Measuring ABI
Adapted from Roussin A, et al. Can J Cardiol
200521(12)997-1006.
48
Question 3

• Which of the following are TRUE regarding
  symptomatic PAD?
• 30 will suffer a fatal vascular event within 5
  years
• Ankle / Brachial Index (ABI) is sensitive and
  specific enough to make the diagnosis of PAD
• Severity of disease and mortality may be
  predicted by ABI
• Exercise programs can improve claudication
  symptoms
• All of the above

?
49
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
50
Patients with Previous Atherothrombotic Events
are at Increased Risk of Further Events
Increased risk versus general population Increased risk versus general population 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 Risk19941(4)333339.
2. Wilterdink JL, et al. Arch Neurol
199249(8)857863. 3. Adult Treatment Panel II.
Circulation 199489(3)13331363. 4. Criqui MH,
et al. N Engl J Med 1992326(6)381386.
51
Consequences of PAD
5-year natural history of intermittent
claudication
Population gt 55 years of age
Intermittent claudication 5
5-year peripheral vascular outcomes
Other cardiovascular outcomes
Major amputation lt4
Surgery or tissue loss gt25
Stable claudication 50
Worsening claudication 16
5-year mortality 30
5-year non-fatal atherothrombotic events (MI,
stroke, etc.) 20
Adapted from Weitz JI, et al. Circulation
199694(11)3026-3049.
52
Risk of Death is Increased in Patients with Both
Asymptomatic and Symptomatic PAD
100
Survival ( of patients)
75
50
25
Normal subjects
Symptomatic PAD
Asymptomatic PAD
Severe symptomatic PAD
0
4
8
10
0
2
6
12
Year
Kaplan-Meier survival curves based on mortality
from all causes. Large-vessel PAD.
Criqui MH, et al. N Engl J Med 1992326(6)381-386
.
53
GetABI Mortality (All-cause) by ABI Category
Proportion alive
Diehm C. Presented at ESC Congress. Vienna,
Austria. September 4, 2007.
54
PAD A Major Health Burden

• Patients with symptomatic PAD have a
• 5-year mortality rate of 28
• compared with 15 for breast cancer
• and 18 for Hodgkins disease1
• 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 1992326(6)381-386
   .
2. Gupta A. In Abramson BL, et al. Can J Cardiol
   200521(12)997-1006.

55
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 1992326(6)381-386
   .
2. Belch JJ, et al. Arch Int Med 2003163(8)884-892
   .

56
Question 4

• What are the most powerful risk factor(s) for
  development of PAD?
• Risk factors for PAD are similar to those in
  all vascular beds
• Smoking is more predictive for PAD than the
  other traditional risk factors
• Diabetes is more predictive for PAD than the
  other traditional risk factors
• All of the above

?
57
Risk Factors for PAD

• 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

Teo KK. In Abramson BL, et al. Can J Cardiol
200521(12)997-1006.
58
REACH Risk Factors are Consistently Found Across
All Disease Subpopulations
Bhatt DL et al, on behalf of the REACH Registry
Investigators. JAMA 2006295(2)180-189.
59
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

60
Hyperlinks to Patient Vignettes
61
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

62
Question 5

• Which of the following in NOT appropriate
  Anti-platelet therapy for Louise?
• ER Dipyrdamole 200 mg plus ASA 25 mg BID
• ECASA 81 mg plus clopidogrel 75 mg OD
• ECASA 81 - 325 mg OD alone
• Clopidogrel 75 mg OD alone
• None of the above, all are reasonable

?
63
MATCH Results
Cumulative Event Rate (Ischemic Stroke, MI,
Vascular Death, Rehospitalization due to
Ischemic Event)
Placebo
6.4 RRR 1.03 ARR P0.244
ASA
Cumulative event rate ()
On-Treatment Analysis 9.6 RRR, 1.6 ARR, p0.10
0
1
3
6
12
18
Months of follow-up
All patients received clopidogrel background
therapy
Diener HC, et al. Lancet. 2004 364331-337.
64
ESPS 2Risk Reduction for Stroke or Death
Plt0.001
P0.006
Plt0.05
Stroke relative risk reduction ()
Plt0.05
n 6602 within 3 months of stroke or TIA 2
years of follow-up
ER DP extended release dipyridamole
Diener HC, et al. J Neurol Sci. 19961431-13.
65
Antithrombotic Trialists Collaboration
ASA dose 500 1500 mg daily 160 325 mg
daily 75 150 mg daily lt 75 mg daily Any ASA
dose
odds reduction
75-150 mg ASA daily is at least as effective as
higher daily ASA doses which carry higher risk of
GI bleeding
23 2
(Plt0.0001)
0.0
0.5
1.0
1.5
ASA better
Control better
Vascular events MI, stroke or vascular death
Antithrombotic Trialists Collaboration. BMJ.
200232471-86.
66
CAPRIEClopidogrel vs ASA in Patients with
Previous Acute Events
Outcome IS, MI, vascular death
14.9

• Patients with previous acute events

• Entire CAPRIE sample

8.7
Outcome IS, MI, rehospitalization for angina/
claudication/peripheral ischemia/TIA/MI
12.0

• Patients with previous acute events

• Entire CAPRIE sample

9.0
30
20
0
10
20
40
10
Clopidogrel better
ASA better
CAPRIE Clopidogrel vs Aspirin in Patients at
Risk of Ischemic Events
Ringleb PA, et al. Stroke. 200435528-532.
67
2006 AHA/ASA GuidelinesPrevention of Stroke in
Patients with Ischemic Stroke or TIA
Antithrombotic Therapy for Non-Cardioembolic
Stroke or TIA
Recommendation Recommendation Recommendation Class, level of evidence
Antiplatelet agents rather than oral anticoagulation Antiplatelet agents rather than oral anticoagulation Antiplatelet agents rather than oral anticoagulation I, A
ASA (50 to 325 mg/d) ASA extended-release dipyridamole Clopidogrel All acceptable options for initial therapy IIa, A
ASA extended-release dipyridamole Clopidogrel Both safe compared with ASA monotherapy IIa, A
Sacco RL, et al. Stroke. 200637577617.
68
Question 6

• With regard to her future vascular risk
• Her greatest risk of death in the next 12 months
  is recurrent stroke
• There is a high probability that she has
  atherothrombotic disease in the coronary and
  peripheral circulation
• Long term she is more likely to die from
  recurrent stroke than cardiac disease
• All of the above
• None of the above

?
69
REACHOverlapping Manifestations of Disease
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 2006295(2)180-189.
70
Long-Term Cause of Stroke Mortality Risk at 5
Years
Cause of death First stroke Recurrent
stroke Cardiovascular disease Nonvascular
disease Unknown
100
90
80
70
60
50

40
30
20
10
0
lt 30d
30d6m
6m1yr
1-3yr
3-5yr
Time since first-ever stroke
Hankey GJ, et al. Stroke 200031(9)2080-2086.
71
Question 7 - Suppose Louise also experienced an
Acute Coronary Syndrome within the past year.

• How would this impact her risk for subsequent
  atherothrombotic events?
• She remains at equally high risk regardless of
  the presence of diffuse vascular disease
• Her risk reduction strategies should remain
  unchanged
• She would benefit from dual anti-platelet
  therapy with ASA 81 mg plus clopidogrel 75 mg
• More aggressive lipid and blood pressure targets
  should be applied
• All of the above

?
72
CURE Primary Endpoint MI/Stroke/CV Death
(n12,562)
0.14
Placebo ASA
20 Relative Risk Reduction p0.00009
0.12
0.10
Clopidogrel ASA
0.08
Cumulative Hazard Rate
0.06
The primary outcome occurred in 9.3 of patients
in the clopidogrel ASA group and 11.4 in the
placebo ASA group
0.04
0.02
0.00
6
9
0
12
3
Months of Follow-up
CURE Clopidogrel in Unstable Angina to Prevent
Recurrent Ischemic Events
Study subjects had ACS (Acute Coronary
Syndrome - UA/nonQ-wave MI). Other
standard therapies were used as
appropriate. CURE Trial Investigators. N Engl J
Med 2001345(7)494-502.
73
CURE Major Bleeding by ASA Dose
6.0
5.0
Placebo
4.9
4.0
Clopidogrel
4.0
3.5
Bleeding rate ()
3.0
2.6
2.3
2.0
2.0
1.0
0.0
lt100 mg
100-200 mg
gt 200 mg
ASA dose 75-325 mg
In addition to standard therapy (including ASA).
CURE Trial Investigators. N Engl J Med
2001345(7)494-502.
74
REACH 1-year CV Event Rates as a Function of the
Number of Symptomatic Disease Locations
Plt0.001
Risk sharply increases with diffuse vascular
disease
CV death/MI/stroke/hospitalization ()

Number of disease locations
Multiple risk factor group
Steg PG et al, on behalf of the REACH Registry
Investigators. JAMA 2007297(11)1197-1206.
75
HOPE Risk Reduction with ACE Inhibition
CVD death
Stroke
Non-fatal MI
Total morality
16
20
p0.005
plt0.001
26
plt0.001
32
plt0.001
Minimal changes in BP non-hypertensive sub-group
noted similar benefit
HOPE Heart Outcomes Prevention Evaluation
Yusuf S, et al. N Engl J Med 2000342(3)145-153.
76
PROGRESS Stroke Reduction
0.20
6,105 subjects with cerebrovascular event within
past 5 years No BP entry requirement
0.15
Proportion with event
0.10
28 risk reduction 95 CI 1738 Plt0.0001 ARR
() 4.0
0.05
placebo perindopril-based treatment
1
2
3
4
Follow-up time (years)
PROGRESS Perindopril Protection Against
Recurrent Stroke Study
PROGRESS Collaborative Group. Lancet
2001358(9287)1033-1041.
77
SPARCL Primary End-point Fatal or Non-fatal
Stroke
16 RRR HR 0.84 (0.710.99) P0.03
Placebo
16
12
Atorvastatin
8
Fatal/ nonfatal stroke()
4
0
0
1
2
3
4
5
6
Time since randomization (years)
SPARCL Stroke Prevention by Aggressive Reduction
in Cholesterol Levels
Adjusted
The SPARCL Investigators. N Eng J Med
2006355(6)549-559.
78
CAPRIEClopidogrel vs. ASA in Multi-bed Disease
15
10.74
22.7
10
8.35
Annual event rate ()
Relative Risk Reduction
164 events
196 events
5
0
ASA
Clopidogrel
Events ischemic stroke, MI or vascular death
CAPRIE Clopidogrel vs Aspirin in Patients at
Risk of Ischemic Events
CAPRIE Steering Committee. Lancet
1996348(9038)1329-1339.
79
CHARISMA Treatment Effect by Inclusion Criteria
Combined endpoint MI, stroke, CV death
Hazard ratio
RR (95 CI)
n3284
Asymptomatic
1.20 (0.911.59)
P0.20
n12,153
Symptomatic
0.88 (0.770.998)
P0.046
n15,603
All patients
0.93 (0.831.05)
P0.22
0.5
1.0
1.5
Placebo
Clopidogrel
better
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 2006354(16)1706-17
17.
80
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)

81
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
• Johns ABI was 0.90 (R) 0.77 (L), which
  confirmed your diagnosis

ABI ankle brachial index
82
Question 8

• Unless contraindicated, which of the following
  are necessary risk reduction strategies for John?
• Statin therapy to reduce LDL to lt 2.0 mmol/L
• RAA inhibition with an ACEI or ARB
• Anti-platelet agent
• Referral to a vascular surgeon
• All of the above
• a, b and c only

?
83
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 200521(12)997-1006.
84
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 200521(12)997-1006.
85
REACH 3/5 of Patients with Symptomatic PAD
have Diffuse Vascular Disease
3/5 of the 8,273 patients with PAD also
haveatherothrombotic disease in other arterial
territories
(s are of total population)
CAD
Patients with PAD 12.2 of the total REACH
Registry population
CVD
1.6
4.7
1.2
PAD
4.7
Bhatt DL et al, on behalf of the REACH Registry
Investigators. JAMA 2006295(2)180-189.
86
Consequences of PAD
5-year natural history of intermittent
claudication
Population gt 55 years of age
Intermittent claudication 5
5-year peripheral vascular outcomes
Other cardiovascular outcomes
Major amputation lt4
Surgery or tissue loss gt25
Stable claudication 50
Worsening claudication 16
5-year mortality 30
5-year non-fatal atherothrombotic events (MI,
stroke, etc.) 20
Adapted from Weitz JI, et al. Circulation
199694(11)3026-3049.
87
REACHVascular Interventions at 1 Year
Multiple RF only (n11,966)
Total symptomatic (n53,390)
CVD (n18,013)
PAD (n8,581)
CAD (n38,602)
0.9
2.9
1.5
2.4
3.8
Coronary angioplasty/ stenting
0.5
1.0
0.7
1.4
1.1
CABG
0.2
0.6
0.4
0.3
0.3
Carotid angioplasty/ stenting
0.3
1.0
0.7
0.4
0.5
Carotid surgery
0.2
3.7
0.5
0.6
0.8
Peripheral bypass graft
0.4
5.0
0.9
1.0
1.2
PAD angioplasty/ stenting
0.3
1.6
0.3
0.3
0.4
Amputation
Local Systemic
CABG coronary artery bypass graft adjusted for
age and gender
Steg PG et al, on behalf of the REACH Registry
Investigators. JAMA 2007297(11)1197-1206.
88
REACHVascular Interventions at 1 Year
Revascularization at 1 year ()
(n18,013)
(n38,602)
(n8,581)
Steg PG et al, on behalf of the REACH Registry
Investigators. JAMA 2007297(11)1197-1206.
89
Question 9

• Which of the following anti-platelet strategies
  are NOT appropriate for John?
• ASA 81 mg OD
• Clopidogrel 75 mg OD
• ASA 81 mg OD plus Clopidogrel 75 mg OD
• ER Dipyrdamole 200 mg plus ASA 25 mg BID
• None of the above (all are appropriate)

?
90
CCS GuidelinesAntithrombotic 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 200521(12)997-1006.
91
Question 10

• What percentage of symptomatic Canadian REACH
  Registry patients are currently on Triple
  Therapy (ACE or ARB Statin Anti-platelet
  agent)
• 95
• 80
• 75
• 70
• lt 60

?
92
REACH Proven Therapies are Consistently
Underused in All Patient Types
Patients receiving proven therapy ()
(n12,389)
(n8,273)
(n18,843)
(n40,258)
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 2006295(2)180-189.
93
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

94
Approximately 1 in 5 patients with PAD will
experience CV death, MI, stroke, or
hospitalization within 1 year
Take-Home Messages
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 2007297(11)1197-1206.
95
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