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/m 2 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
▪ ▪ ▪
Age Male sex Family history Modifiable
▪ ▪ ▪ ▪ ▪ ▪
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 CAD 44.6% 8.4% 4.7% 1.6% 1.2% PAD 4.7% CVD 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 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
25 20 19.9
*
22.4
*
15 10 12.5
*
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.
Performing a directed examination focusing on physical findings that have been proven useful to detect PAD defined as an ABI<0.9.
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.
Ordering an ABI to diagnose PAD in asymptomatic patients with arterial bruits or diminished pulses.
Grade 1A 1A 1A 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-arm systolic pressure Left-arm systolic pressure RIGHT ABI Higher right-ankle pressure Higher arm pressure LEFT ABI Higher left-ankle pressure Higher arm pressure Right-ankle systolic pressure DP PT DP Left-ankle systolic pressure PT INTERPRETATION OF ABI >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
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 Reduced pedal pulses Femoral bruit
Slow venous filling Cold skin Abnormal colour Trophic changes
Sensitivity 68% 29% 23% 10% 35% 46% Specificity 95% 95% 95% 98% 87% 46% RR if present 27 5.7
4.1
5.8
2.8
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.
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
100 90 80 70 60 50 40 30 20 10
No diabetes Diabetes
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time (years)
Migliaccio-Walle K, et al
. Can J Diabetes.
2007;31(2):140-147.
CCS Guidelines for PAD:
Risk Reduction Strategies Non-pharmacologic
• Exercise • Blood pressure control • Lipid control • Habits
- Smoking Pharmacologic
• 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 Statins ACE inhibitors Oral hypoglycemics or insulin Antiplatelet GRADE 1A 1A 2B 1A
Anand SS, et al.
Can J Cardiol
. 2005;21(12):997 –1006.
CCS Guidelines: Antithrombotic Therapies
AGENTS ASA or Clopidogrel RECOMMENDATION 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.
Ticlopidine Cilostazol* ASA or clopidogrel recommended over ticlopidine.
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 Pentoxifylline Pentoxifylline is not recommended Vitamin K Antagonists Anticoagulant therapy is not recommended GRADE 1A 1B 1B 2B 2B
*Not available in Canada Anand SS, et al.
Can J Cardiol
. 2005;21(12):997 –1006.
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 MI, stroke, or CV death MI, stroke, CV death, or severe CAD– or PAD-related ischemia Ischemic stroke Hemorrhagic stroke Life-threatening bleeding Moderate bleeding Minor bleeding
WAVE Trial Investigators.
N Engl J Med.
2007;357(3):217-27.
COMBINATION n=1080 (%) 12.2
15.9
2.2
1.3
4.0
2.9
38.6
ANTIPLATELET ONLY n=1081 (%) 13.3
17.4
3.5
0 1.2
1.0
10.6
RELATIVE RISK (95% CI) 0.92 (0.73 - 1.16) 0.91 (0.74 - 1.12) 0.64 (0.38 - 1.06) 15.2 (2.0 - 115.6) 3.41 (1.84 - 6.35) 2.82 (1.43 - 5.58) 3.63 (3.01 - 4.38) P 0.48
0.37
0.09
0.001
<0.001
0.002
<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 disease 1 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 PAD 2
–
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 bleeding 3
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 CV Death Non-fatal MI Non-fatal stroke CV death/MI/stroke CV death/MI/stroke/ hospitalization* Overall 1.5
1.2
1.5
3.4
12.8
Single Arterial Bed CAD alone 1.5
1.4
0.9
CVD alone 1.4
0.5
† 3.5
† 3.1
4.5
† 13.3
10.0
† PAD alone 1.2
1.0
0.6
2.3
18.2
§ Polyvascular Disease Overall 2.4
1.5
3.1
CAD + CVD + PAD 3.6
1.8
4.0
6.0
7.4
22.0
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.
26.9
‡
CCS Guidelines: Antithrombotic Therapies
Agents ASA or Clopidogrel Ticlopidine Cilostazol Pentoxifylline Vitamin K Antagonists Recommendation 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.
ASA or clopidogrel recommended over ticlopidine.
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 Pentoxifylline is not recommended Anticoagulant therapy is not recommended Grade 1A 1B 1B 2B 2B
Anand SS, et al.
Can J Cardiol
. 2005;21(12):997 –1006.
CAPRIE:
Clopidogrel vs. ASA in Multi-bed Disease
15 10 5
10.74% 8.35%
164 events
22.7%
Relative Risk Reduction 196 events 0 Clopidogrel Events = ischemic stroke, MI or vascular death CAPRIE Steering Committee.
Lancet.
1996;348(9038):1329-39.
ASA
CHARISMA: Primary Endpoint (MI/Stroke/CV Death) in Patients with Previous MI, IS, or PAD 10 8 “CAPRIE-like Cohort” N=9,478 Placebo + ASA 8.8 % Clopidogrel + ASA 7.3 % 6 4 2 RRR: 17.1 % [95% CI: 4.4%, 28.1%] P=0.01
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 (%)
Severe bleeding Fatal bleeding Primary intracranial hemorrhage Moderate bleeding
Clopidogrel + ASA (n=4735)
79 (1.7) 15 (0.3)
Placebo + ASA (n=4743)
71 (1.5) 11 (0.2) 17 (0.4) 97 (2.0) 20 (0.4) 61 (1.3)
HR (95% CI)
1.114 (0.808
–1.535) 1.362 (0.626
–2.966) 0.849 (0.445
–1.621) 1.597 (1.159
–2.200)
P Value
0.509
0.434
0.619
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
0.00007
0.00006
0.00005
0.00004
0.00003
0.00002
0.00001
0 Placebo + ASA Clopidogrel + ASA 15 60 135 270 450 Days Since Randomization 630
Bhatt DL, et al.; CHARISMA Investigators.
J Am Coll Cardiol.
2007;49(19):1982-1988.
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
60 50 40 30 20 10 0
All-cause mortality Vascular disease mortality
*Mean participant follow-up 8.3 years Resnick HE, et al.
Circulation.
2004;109:733-739.
Baseline ABI*
Pathophysiology, Epidemiology & Burden of Atherothrombosis
Pathophysiology of Atherothrombosis
Atherosclerosis Normal artery Accumulation of lipids Inflammation Smooth muscle cell progression, plaque progression + Thrombus Formation Rupture of Fibrous Cap Erosion of Endothelium Erosion of Calcium Nodule Intraplaque Hemorrhage 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.
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) 14% 13% 9% 5% Peripheral Arterial Disease (PAD) Patients with > 1 manifestation = 41%
Aronow WS, Ahn C.
Am J Cardiol.
1994;74:64-65.
Epidemiology of Atherothrombotic Manifestations in Canada
Incidences per year Prevalence (Patients with disease history) Mortality Stroke 40,000 – 50,000 1 Stroke 1.0% 1 MI 75,000 1 PAD Variable depending on population 3 MI 2.7% (men) 2 1.5% (women) 2 PAD 3.0% (10.5 million †4 in North America) Patients with a history of atherothrombosis are most likely to die of a recurrent atherothrombotic event 5,6,7
MI=myocardial infarction; PAD=peripheral arterial disease.
† PAD patients in North America (USA and Canada): symptomatic (37.5%) and asymptomatic (62.5%).
1. Heart and Stroke Foundation of Canada.
5. Hardie K, et al.
Stroke.
2003;34:1842-1846.
2. Manuel DG, et al. 3. Ouriel K.
Lancet.
Can J Cardiol.
4. Weitz JI, et al.
Circulation.
2003;19:997-1004.
2001;358:1257-1264.
1996;94:3026-3049.
6. Taneja AK, et al.
Eur Heart J.
2004;25:2013-2018.
7. Hirsch AT, et al.
J Am Coll Cardiol.
2006;47:1239-1312.
Patients with Previous Atherothrombotic Events are at Increased Risk of Further Events Ischemic stroke MI PAD Increased risk versus general population MI 2-3x (includes angina and sudden death*) 1 Stroke 9x 2 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 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 20 15 20 9.2
Fewer years 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% 20 19.1% 15 10 12.5% 5 0 Athero thrombosis Infectious Disease
Bakhai A.
Pharmacoeconomics.
2004;22(suppl 4):11-18.
Cancer 9.1% Injuries 6.5% Pulmonary Disease 4.9% AIDS
Economic Burden of Atherothrombosis
500 The annual cost of CVD in 2006 was estimated to be higher than HIV and cancer in 2004
$403.1 billion
Indirect Costs Direct Costs 400 300
$190 billion
200 100 0 Cardiovascular Disease Cancer
$28.9 billion
HIV
American Heart Association.
Heart Disease and Stroke Statistics —2006 Update.
2006.