primary care today

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



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


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)


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


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


CAD

PAD

CVD





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






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


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


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


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


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


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



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

(%)


(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


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


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


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

primary care today

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