Transcript CASE 1 (ACS)

Case Study: Diane Leary
Diffuse Vascular Disease
(Focus on Peripheral Arterial Disease [PAD])
Learning Objectives
At the end of this session, participants should be able to:
 Identify patients with peripheral arterial disease (PAD)
 Apply Canadian guidelines for the screening and
management of PAD
 Identify patients with diffuse vascular disease and
implement strategies for the prevention of
atherothrombotic events in these patients
Patient Presentation
▪
Diane is a 65-year-old retired school teacher
▪
She complains of left calf pain when
walking a couple of blocks; the pain goes
away after she rests for 5 minutes
▪
No other complaints
History
▪
NSTEMI 20 months ago
▪
Carotid bruit
▪
Hypertension
▪
Type 2 diabetes (diagnosed 5 years prior)
▪
Hyperlipidemia
▪
No family history of diabetes or cardiovascular
disease
▪
Former smoker
NSTEMI: non-ST-elevation myocardial infarction
Medications
▪
ASA 81 mg/day
▪
Ramipril 10 mg/day
▪
Metformin 500 mg tid
▪
Atorvastatin 20 mg/day
▪
Metoprolol 25 mg bid
ASA: acetylsalicylic acid
Physical Examination
▪
Height: 1.65 m
▪
Weight: 81.6 kg
▪
BMI: 29 kg/m2
▪
Waist circumference: 104 cm
▪
BP in-office: 128/72 mmHg
▪
Heart rate: 80 bpm
▪
Left femoral bruit
▪
Carotid bruit
▪
Bilateral reduced pedal pulses
BMI: body mass index; BP: blood pressure
Laboratory Investigations
▪
FPG: 6.2 mmol/L
▪
A1C: 7.5%
▪
Lipids at desired values
–
–
–
–
–
TC < 5.2 mmol/L
TG < 2.3 mmol/L
HDL-C > 1.20 mmol/L (female)
LDL-C < 2.0 mmol/L
TC/HDL-C < 4.0
▪
Urine ACR: 1.9 mg/mmol
▪
Complete blood count within normal limits
▪
ECG normal
FPG: fasting plasma glucose; A1C: hemoglobin A1C; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol;
HDL-C: high-density lipoprotein cholesterol; TG: triglycerides; ACR: albumin-to-creatinine ratio; ECG: electrocardiogram
Question 1
What is your initial diagnosis?
Key Points
▪ Patient presents with typical symptom of PAD
(intermittent claudication) and has a number of
risk factors for the disease
▪ Basic screening should include directed history
and physical exam focusing on femoral bruits
and pedal pulses
▪ Non-invasive evaluation should include an ABI
ABI: ankle-brachial index
Risk Factors for PAD
• Risk factors for PAD are similar to those for
atherosclerosis in other beds and include:
Non-Modifiable
Modifiable
▪ Age
▪ Male sex
▪ Family history
▪
▪
▪
▪
▪
▪
Elevated lipid levels
Cigarette smoking
Hypertension
Sedentary lifestyle
Obesity
Diabetes
• Smoking and diabetes are the most predictive for
development of symptomatic claudication
Teo KK. Can J Cardiol. 2005;21(12):997–1006.
Varied Presentation of PAD
PAD can be silent or cause symptoms ranging
from pain to critical limb ischemia
Typical
Intermittent claudication: pain,
ache, cramp, numbness, muscle
fatigue in calves, thighs or
buttocks; exacerbated by exercise
and relieved by rest
Atypical
Decreased walking ability:
(speed or distance) for reasons
other than classical symptoms of
intermittent claudication
Critical limb ischemia: rest pain,
ulcers, gangrene
Pain in other areas: e.g., general
aching
McDermott MM et al. JAMA 2001;286:1599-1606.
REACH Registry
Atherothrombosis: Overlapping Manifestations of Disease
The REACH Registry found overlapping manifestations of
disease in patients with CAD, CVD, and PAD
CVD
CAD
8.4%
44.6%
1.6%
1.2%
4.7%
PAD
16.6%
▪ 61% of PAD patients also had
symptomatic disease in the
coronary or cerebral circulation
▪ 40% of CVD patients also had
symptomatic disease in the
coronary or peripheral circulation
▪ 25% of CAD patients also had
symptomatic disease in the
cerebral or peripheral circulation
4.7%
18.3% of patients in the REACH Registry did not have
manifestations of atherothrombosis, but were included based on risk factors
CAD: coronary artery disease; CVD: cerebrovascular disease; PAD: peripheral arterial disease
Bhatt DL, et al; for the REACH Registry Investigators. JAMA. 2006;295:180-189.
Increased Risk of PAD with Diabetes
Prevalence of PAD (%)
25
19.9*
20
15
22.4 *
12.5*
10
5
0
Normal glucose
tolerance
Impaired glucose
tolerance
Diabetes
Impaired glucose tolerance was defined as oral glucose tolerance test value ≥140 mg/dL <200 mg/dL.
* P≤0.05 vs. normal glucose tolerance.
Lee AJ, et al. Br J Haematol. 1999;105:648–654.
Question 2
What additional investigations would you
perform?
Key Points: Diagnosis of PAD
 History
 Edinburgh Questionnaire
 Physical examination
 Bruit
 Peripheral pulses
 Non-invasive tests
 ABI
 Arterial Duplex
Adapted from Roussin A, et al. Can J Cardiol. 2005;21(12):997–1006.
CCS Guidelines: Diagnosis of PAD
Recommendation
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.
Grade
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 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 your leg(s) when you walk?
• YES (If patient answers no, then stop here)
 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 (Answer may also be ‘no’ depending on severity of claudication)
 What happens to it if you stand still?
• Pain usually disappears in 10 minutes or less (pain continuing for more
than 10 minutes is not consistent with PAD)
 Where do you get this pain or discomfort?
• Patient marks calf and/or thigh and/or buttock
(A positive diagnosis of PAD requires the responses indicated in yellow for all questions)
Leng GC, et al. J Clin Epidemiol. 1992;45:1101–1109.
Measuring ABI
RIGHT ABI
Right-arm
systolic
pressure
Left-arm
systolic
pressure
LEFT ABI
Higher right-ankle pressure
Higher arm pressure
Higher left-ankle pressure
Higher arm pressure
INTERPRETATION OF ABI
Right-ankle
systolic pressure
DP
DP
PT
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
Left-ankle
systolic pressure
Adapted from Roussin A, et al. Can J Cardiol 2005;21(12):997-1006.
Question 3
What if the patient’s pedal pulses were
palpable and there were no bruits? Would
this change your diagnosis?
Key Point
▪ Palpable pedal pulses and an absence of
femoral bruits do not preclude PAD
PAD Regardless of Claudication
•
Value of physical examination relative to presence of PAD
ITEM
Sensitivity
Specificity
RR if present
Reduced pedal pulses
68%
95%
27
Femoral bruit
29%
95%
5.7
Slow venous filling
23%
95%
4.1
Cold skin
10%
98%
5.8
Abnormal colour
35%
87%
2.8
Trophic changes
46%
46%
1.5
McGee SR, et al. Arch Intern Med. 1998;158:1357–1364.
Case Evolution
▪
Based on your clinical examination, you
diagnose Diane with PAD. You perform further
investigations and find that she has an ABI of
0.65, which confirms your diagnosis.
Significance of ABI values ►
Question 4
How would you manage this patient’s:
a) claudication?
b) overall vascular risk?
Key Points:
Objectives of PAD Therapy
Prevent death and disability
 Reduce risk of MI (PAD quadruples MI risk)
 Reduce risk of stroke (PAD triples stroke risk)
Relieve symptoms
 Improve QOL
 Improve walking ability
Save limbs
 Prevent major amputations
 Avoid tissue loss
QOL: quality of life
Survival Following Diagnosis of PAD
by Diabetes Status
Proportion alive (%)
100
90
No diabetes
80
Diabetes
70
60
50
40
30
20
10
0
1
2
3
4
6
5
7
8
9 10 11 12 13 14
Time (years)
Migliaccio-Walle K, et al. Can J Diabetes. 2007;31(2):140-147.
15
CCS Guidelines for PAD:
Risk Reduction Strategies
Non-pharmacologic
Pharmacologic
• Exercise
• Blood pressure control
• Lipid control
• Habits
- Smoking
• Antiplatelet therapy
• Angiotensin converting enzyme
inhibitors (ACE-I)
• Diabetes control
• Hypertension control
• Statin use
Anand SS, et al. Can J Cardiol. 2005;21(12):997–1006.
Risk Factor Management
 Smoking cessation
 Weight reduction
 Regular physical activity
 LDL-C < 2.0 mmol/L
 Glycosylated hemoglobin < 6.0%
 BP < 140/90 mmHg; < 130/80 mmHg in patients with diabetes
 Platelet inhibition
Hiatt WR. N Engl J Med. 2001;344:1608-1621.
McPherson R, et al. Can J Cardiol. 2006;22:913-927.
CDA 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Available at http://www.diabetes.ca/cpg2003
2007 CHEP Recommendations. Available at www.hypertensions.ca
CCS Guidelines for PAD:
Pharmacologic Approach
Medical therapies to reduce cardiovascular events in PAD
CLASS OF AGENTS
GRADE
Statins
1A
ACE inhibitors
1A
Oral hypoglycemics or insulin
2B
Antiplatelet
1A
Anand SS, et al. Can J Cardiol. 2005;21(12):997–1006.
CCS Guidelines:
Antithrombotic Therapies
AGENTS
RECOMMENDATION
ASA or
Clopidogrel
Lifelong antiplatelet therapy with ASA (75 to 325 mg/day)
or clopidogrel (75 mg/day) in patient 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 measure
(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, et al. Can J Cardiol. 2005;21(12):997–1006.
GRADE
Supervised Exercise in the
Management of Symptomatic PAD
 Exercise prescription is fundamental for all
patients with claudication
 Supervised programs have patients walk to the
point of moderate pain, followed by rest and
repeat exercise
 Benefit is observed as early as 4 weeks and
continues to improve for at least 1 year
Anand SS, Turpie AGG, et al. Can J Cardiol. 2005;21(12):997–1006.
Question 5
Could warfarin be added to antiplatelet
therapy in patients with PAD?
WAVE:
Warfarin Antiplatelet Vascular Evaluation
COMBINATION
n=1080 (%)
ANTIPLATELET
ONLY
n=1081 (%)
RELATIVE
RISK
(95% CI)
P
12.2
13.3
0.92
0.48
MI, stroke, or CV death
(0.73 - 1.16)
MI, stroke, CV death, or severe CAD– or
PAD-related ischemia
15.9
Ischemic stroke
2.2
17.4
0.91
0.37
(0.74 - 1.12)
3.5
0.64
0.09
(0.38 - 1.06)
Hemorrhagic stroke
1.3
0
15.2
0.001
(2.0 - 115.6)
Life-threatening bleeding
4.0
1.2
3.41
<0.001
(1.84 - 6.35)
Moderate bleeding
2.9
1.0
2.82
0.002
(1.43 - 5.58)
Minor bleeding
38.6
10.6
3.63
(3.01 - 4.38)
WAVE Trial Investigators. N Engl J Med. 2007;357(3):217-27.
<0.001
Question 6
Given this patient’s history of ACS and
current diagnosis of PAD (ie, diffuse vascular
disease), how long should she remain on the
prescribed antiplatelet regimen?
Review pathophysiology & epidemiology of polyvascular disease and atherothrombosis ►
Key Points
▪
▪
▪
High risk of CV death, MI, stroke or hospitalization in patients with diffuse
vascular disease1
Aggressive risk reduction strategies and dual antiplatelet therapy should
be considered for these patients
Currently no guideline recommendations on the optimal duration of
antiplatelet therapy in patients with diffuse vascular disease; however,
many experts would agree that this patient requires lifelong antiplatelet
therapy
– CCS recommends lifelong antiplatelet therapy in PAD2
– CHARISMA showed that patients with a prior atherothrombotic event
(MI, stroke or PAD) benefit from long-term dual antiplatelet therapy
(median follow-up 27 months), but at the cost of an increased rate of
bleeding3
CHARISMA: Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance
1. Steg PG, et al.; for the REACH Registry Investigators. JAMA. 2007;297:1197-206. 2. Abramson BL, et al. Can J Cardiol.
2005;21(12):997–1006. 3. Bhatt DL, et al.; CHARISMA Investigators. J Am Coll Cardiol. 2007;49(19):1982-8.
REACH
Major endpoints as a Function of Single vs
Multiple and Overlapping Locations
Single Arterial Bed
Polyvascular Disease
Overall
CAD
alone
CVD
alone
PAD
alone
Overall
CAD + CVD +
PAD
CV Death
1.5
1.5
1.4
1.2
2.4
3.6
Non-fatal MI
Non-fatal stroke
CV
death/MI/stroke
CV
death/MI/stroke/
hospitalization*
1.2
1.5
1.4
0.9
0.5†
3.5†
1.0
0.6
1.5
3.1
1.8
4.0
3.4
3.1
4.5†
2.3
6.0
7.4
12.8
13.3
10.0†
18.2§
22.0
26.9‡
Risk doubles with diffuse vascular disease
†
P<0.001 (ref class: CAD alone)
P<0.001 (ref class: PAD alone)
‡ P<0.001 (ref class: CAD + CVD)
§
Steg PG, et al.; for the REACH Registry Investigators. JAMA. 2007;297:1197-206.
CCS Guidelines:
Antithrombotic Therapies
Agents
Recommendation
ASA or
Clopidogrel
Lifelong antiplatelet therapy with ASA (75 to 325 mg/day) or
clopidogrel (75 mg/day) in patient 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 measure
(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
Anand SS, et al. Can J Cardiol. 2005;21(12):997–1006.
Grade
CAPRIE:
Clopidogrel vs. ASA in Multi-bed Disease
Annual event rate (%)
15
10.74%
10
8.35%
22.7%
Relative Risk
Reduction
5
0
164 events
Clopidogrel
Events = ischemic stroke, MI or vascular death
CAPRIE Steering Committee. Lancet. 1996;348(9038):1329-39.
196 events
ASA
CHARISMA:
Primary Endpoint (MI/Stroke/CV Death) in Patients with
Previous MI, IS, or PAD
“CAPRIE-like Cohort”
Primary outcome event rate (%)
10
Placebo + ASA
8.8 %
N=9,478
8
Clopidogrel + ASA
7.3 %
6
4
RRR: 17.1 % [95% CI: 4.4%, 28.1%]
P=0.01
2
0
0
6
12
18
24
Months since randomization
Bhatt DL, et al.; CHARISMA Investigators. J Am Coll Cardiol. 2007;49(19):1982-1988.
30
CHARISMA:
Primary and Secondary Safety Endpoints
Endpoint, n (%)
Clopidogrel +
ASA
(n=4735)
Placebo + ASA
(n=4743)
HR (95% CI)
P Value
Severe bleeding
79 (1.7)
71 (1.5)
1.114 (0.808–1.535)
0.509
Fatal bleeding
15 (0.3)
11 (0.2)
1.362 (0.626–2.966)
0.434
Primary intracranial
hemorrhage
Moderate bleeding
17 (0.4)
20 (0.4)
0.849 (0.445–1.621)
0.619
97 (2.0)
61 (1.3)
1.597 (1.159–2.200)
0.004
Bhatt DL, et al.; CHARISMA Investigators. J Am Coll Cardiol. 2007;49(19):1982-1988.
CHARISMA:
Timing of Severe or Moderate Bleeding
0.00008
Placebo + ASA
Clopidogrel + ASA
Hazard Function/d
0.00007
0.00006
0.00005
0.00004
0.00003
0.00002
0.00001
0
15 60
135
270
450
Days Since Randomization
Bhatt DL, et al.; CHARISMA Investigators. J Am Coll Cardiol. 2007;49(19):1982-1988.
630
810
Take-Home Messages
▪ Patients with PAD are at increased risk of diffuse vascular
disease (ie, CAD and CVD)
▪ Screen for PAD through history (Edinburgh Questionnaire)
and physical examination (femoral bruits and pedal pulses)
▪ Definitive diagnosis of PAD requires an ABI < 0.9
▪ Aggressive risk factor management should be considered
for patients with diffuse vascular disease
▪ Long-term dual antiplatelet therapy can also be considered
in selected cases but it is important to weigh the benefits
against the higher risk of bleeding
HYPERLINKS
Significance of ABI Values
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.
Strong Association Between Decreased
ABI & Increased Risk for Vascular Death
Percent (%)
60
All-cause mortality
50
Vascular disease mortality
40
30
20
10
0
*Mean participant follow-up 8.3 years
Resnick HE, et al. Circulation. 2004;109:733-739.
Baseline ABI*
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Pathophysiology, Epidemiology & Burden
of Atherothrombosis
Pathophysiology of Atherothrombosis
+
Atherosclerosis
Thrombus Formation
Rupture of Fibrous Cap
Normal
artery
Accumulation
of lipids
Inflammation
Smooth muscle
cell progression,
plaque progression
Erosion of Endothelium
Erosion of Calcium Nodule
Atherosclerosis leads to any number
of four possible types of thrombus formation
1. Munger MA et al. J Am Pharm Assoc. 2004;44(suppl 1):s5-s13.
2. Libby P et al. Circulation. 2005;111:3481-3488.
Intraplaque Hemorrhage
Atherothrombosis Can Manifest in
Multiple Vascular Beds
▪ Atherothrombosis is a process that includes the
following clinical consequences:
– Ischemic stroke, MI, and PAD
▪ Patients with atherothrombosis have
thrombus formations that can manifest in
multiple vascular beds throughout the body
Munger MA et al. J Am Pharm Assoc. 2004;44(suppl 1):s5-s13.
Atherothrombosis: Disease Overlap
Coronary artery disease
(CAD)
Cerebrovascular
disease (CVD)
13%
9%
14%
5%
Peripheral Arterial Disease
(PAD)
Patients with > 1 manifestation = 41%
Aronow WS, Ahn C. Am J Cardiol. 1994;74:64-65.
1.
2.
3.
4.
Epidemiology of Atherothrombotic
Manifestations in Canada
Incidences per year
Stroke
40,000 –
50,0001
MI
75,0001
PAD
Variable depending
on population3
Prevalence
(Patients with
disease history)
Stroke
1.0%1
MI
2.7% (men)2
1.5% (women)2
PAD
3.0%
(10.5 million†4
in North America)
MI=myocardial infarction; PAD=peripheral arterial disease.
†PAD patients in North America (USA and Canada): symptomatic (37.5%) and asymptomatic (62.5%).
Heart and Stroke Foundation of Canada.
5. Hardie K, et al. Stroke. 2003;34:1842-1846.
Manuel DG, et al. Can J Cardiol. 2003;19:997-1004.
6. Taneja AK, et al. Eur Heart J. 2004;25:2013-2018.
Ouriel K. Lancet. 2001;358:1257-1264.
7. Hirsch AT, et al. J Am Coll Cardiol. 2006;47:1239-1312.
Weitz JI, et al. Circulation. 1996;94:3026-3049.
Mortality
Patients with a
history of
atherothrombosis
are most likely to
die of a recurrent
atherothrombotic
event5,6,7
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 one hour and attributed to coronary heart disease (CHD).
† Includes only fatal MI and other CHD death; does not include non-fatal MI.
1. Kannel WB. J Cardiovasc Risk.1994;1:333–339.; 2. Wilterdink JL, et al. Arch Neurol. 1992;49:857–863. 3. Adult
Treatment Panel II. Circulation. 1994;89:1333–1363. 4. Criqui MH, et al. N Engl J Med. 1992;326:381–386.
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
Life Expectancy (Years)
20
20
9.2
Fewer
years
15
12
Fewer
years
10
5
0
Healthy
History of MI
MI=myocardial infarction; CVA=cerebrovascular accident.
Adapted from Bakhai A. Pharmacoeconomics. 2004;22(suppl 4):11-18.
History of CVA
Atherothrombosis as a Cause of Death
According to the World Health Organization in 2004 atherothrombosis was the
leading cause of death worldwide—more than AIDS and cancer
25
22.3%
19.1%
Mortality (%)
20
15
12.5%
9.1%
10
6.5%
4.9%
5
0
Atherothrombosis
Infectious
Disease
Bakhai A. Pharmacoeconomics. 2004;22(suppl 4):11-18.
Cancer
Injuries
Pulmonary
Disease
AIDS
Economic Burden of Atherothrombosis
The annual cost of CVD in 2006 was estimated to
be higher than HIV and cancer in 2004
Estimated Cost (in billions)
500
Indirect Costs
$403.1 billion
Direct Costs
400
300
$190 billion
200
100
$28.9 billion
0
Cardiovascular Disease
Cancer
American Heart Association. Heart Disease and Stroke Statistics—2006 Update. 2006.
HIV
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