1. Treatment

2. Two Major Goals in Treating Patients With PAD
Cardiovascular morbidity and mortality outcomes
Limb outcomes
Improved ability to walk
Increase in peak walking distance
Improvement in quality-of-life (QoL)
Prevention of progression to CLI and amputation
Decrease in morbidity from non-fatal MI and stroke
Decrease in cardiovascular mortality from fatal MI and stroke

3. Treatment to Improve Cardiovascular Outcomes

4. Effect of Smoking Cessation on Survival
133 Patients observed after bypass graft or lumbar sympathectomy
Cumulative Survival (%)
Years Postoperative
Faulkner KW, et al. Med J Aust. 1983;1:

5. Smoking Cessation Therapy
IIa
IIb
III B
Individuals with lower extremity PAD who smoke cigarettes or use other forms of tobacco should be advised by each of their clinicians to stop smoking and should be offered comprehensive smoking cessation interventions, including behavior modification therapy, nicotine replacement therapy, or bupropion.

6. Heart Protection Study: Vascular Event by Prior Disease
Incidence of events
Risk vs Control
Statin
Control
Existing disease
(n=10,269)
(n=10,267)
Statin favored
Placebo
Previous MI
23.5
29.4
Other CHD
18.9
24.2
No prior CHD or CBV disease
18.7
23.6
PAD
24.7
30.5
24% Reduction (P<.0001)
Diabetes
13.8
18.6
All patients
19.8
25.2
0.4
0.6
0.8
1.0
1.2
1.4
CBD=cerebrovascular disease; CHD=congestive heart disease. Reprinted with permission from Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22 from Elsevier.

7. Atorvastatin in Patients With Claudication and PAD25 50 75
100
125
10 mg
Placebo
80 mg *
Mean change from baseline in PFWT (sec)
Baseline
Month 3
Month 6
Month 12
PFWT=pain-free walking time. *P=.03. No change in ABI over 12 months.
Reprinted with permission from Mohler ER et al. Circulation. 2003;108:

8. Considerations for the Treatment of Hypertension in PAD
Blood pressure lowering is indicated to reduce the risk of stroke, MI, CHF, CRF, and death.
Only major reductions in perfusion pressure may worsen claudication (21 mm Hg decrease in SBP resulted in a 9% decrease in absolute claudication distance).
Individuals with PAD should receive hypertension treatment according to current national guidelines (e.g., JNC-7).
CRF=chronic renal failure; CHF=congestive heart failure.

9. b- Blockers Are Not Contraindicated in PAD
In a meta analysis of 11 randomized controlled trials beta-blocker therapy did not worsen claudication in patients with PAD.
Beta blockers had no significant effect on pain-free walking distance compared with placebo in pooled analysis.
Radack K. Arch Intern Med. 1991;151:1769.

10. Intensive Antihypertensive Therapy in PAD: The ABCD Trial
Moderate treatment n = 227
Intensive treatment n = 227
*enalapril or nisoldipine 40
Odds of MI, Stroke or Vascular Death 30 20 10
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
Baseline ABI
Reprinted with permission from Mehler, et al. Circulation. 2003;107;

11. HOPE: Benefits in CV Risk Subgroups
Relative risk in ramipril group
No. of
Patients
Reduced
Increased
History of CAD 7477
No history of CAD 1820
Prior MI
No prior MI
CBV disease
No CBV disease
Peripheral vascular disease
No peripheral vascular disease
Microalbuminuria
No microalbuminuria
0.6
0.8
1.0
1.2
CAD=coronary artery disease; CBV=cerebrovascular disease; MI=myocardial infarction.
Adapted with permission. HOPE Study Investigators. N Engl J Med. 2000;342: Copyright © 2000 Massachusetts Medical Society. All rights reserved.

12. PAD Guideline: Risk-factor Management with Antihypertensive Medications
IIa
IIb
III
Target BP < 140/90 mm Hg to reduce cardiovascular/cerebrovascular risk in all individuals with PAD
If comorbid diabetes or chronic renal disease is present, target BP < 130/80 mm Hg
- Blockers are effective and not contraindicated
Consider ACE inhibitors:
For patients with symptomatic PAD
For patients with asymptomatic PAD I
IIa
IIb
III I
IIa
IIb
III I
IIa
IIb
III B I
IIa
IIb
III
ACE=angiotensin-converting enzyme.
Hirsch AT et al. J Am Col Cardiol. 2006;47:

13. Antihypertensive Therapy
Antihypertensive therapy should be administered to hypertensive patients with lower extremity PAD to a goal of less than 140/90 mm Hg (non-diabetics) or less than 130/80 mm Hg (diabetics and individuals with chronic renal disease) to reduce the risk of myocardial infarction, stroke, congestive heart failure, and cardiovascular death.
Beta-adrenergic blocking drugs are effective antihypertensive agents and are not contraindicated in patients with PAD.

14. Lipid Lowering Therapy
IIa
IIb
III B
Treatment with a HMG coenzyme-A reductase inhibitor (statin) medication is indicated for all patients with peripheral arterial disease to achieve a target LDL cholesterol of less than 100 mg/dL. I
IIa
IIb
III B
Treatment with a HMG coenzyme-A reductase inhibitor (statin) medication to achieve a target LDL cholesterol level of less than 70 mg per dl is reasonable for patients with lower extremity PAD at very high risk of ischemic events†.
† Factors that define “very high risk” in individuals with established PAD are: (a) multiple major risk factors (especially diabetes), (b) severe and poorly controlled risk factors (especially continued cigarette smoking), (c) multiple risk factors of the metabolic syndrome and (d) individuals with acute coronary syndromes.
HMG coenzyme=3-hydroxy-3-methylglutaryl coenzyme

15. UKPDS: Intensive Blood-Glucose vs. Conventional Treatment
in Patients With Type 2 Diabetes
Favors
Intensive
Favors
Conventional
Log-rank
p-value
0.1 1 10
Clinical End Point
RR (95% CI)
Any diabetes-related end point
0.88 (0.79–0.99)
0.029
Diabetes-related deaths
0.90 (0.73–1.11)
0.34
All-cause mortality
0.94 (0.80–1.10)
0.44 MI
0.84 (0.71–1.00)
0.052
Stroke
1.11 (0.81–1.51)
0.52
Amputation or death from PAD
0.65 (0.36–1.18)
0.15
Microvascular disease
0.75 (0.60–0.93)
0.0099
PAD=peripheral arterial disease; RR=relative risk.
Reprinted with permission from UKPDS Group. Lancet. 1998;352: from Elsevier.

16. Diabetes Control and Complications Trial (DCCT):
Cumulative Incidence of the First of Any of the
Predefined Cardiovascular Disease Outcomes
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. N Engl J Med. 2005;353: Copyright © 2005 Massachusetts Medical Society. All rights reserved.

17. 10% Relative risk reduction
PROactive:
All-Cause Mortality, MI, ACS, Coronary or Peripheral Revascularization, Amputation, Stroke 25
10% Relative risk reduction
HR* 0.90 (0.80–1.02) P = 0.095
Placebo (572 events) 20
The primary outcome (all-cause mortality, nonfatal MI, stroke, acute coronary syndromes, leg amputation, coronary or peripheral revascularization) was reduced a nonsignificant 10% over 36 months in pioglitazone patients (compared with placebo).1
However, confirmed divergence in the survival curves suggests that significant risk reduction might have been achieved with longer treatment duration.
Pioglitazone (514 events) 15
Proportion of Events (%) 10 5 6 12 18 24 30 36
Time From Randomization
Number at risk
Pioglitazone
2488
2373
2302
2218
2146
348
Placebo
2530
2413
2317
2215
2122
345
*Unadjusted
Reprinted with permission from Dormandy JA, et al. Lancet. 2005;366:
1. Dormandy JA, Charbonnel B, Eckland DA, Erdmann E, Massi-Benedetti M, Moule IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet. 2005:366:

18. 16% Relative risk reduction Pioglitazone (301 events)
PROactive: Secondary Outcome All-cause mortality, MI (excluding silent MI), stroke 25 20
Placebo (358 events)
16% Relative risk reduction
HR* 0.84 (0.72–0.98) P = 0.027
The main secondary outcome of all-cause mortality, MI, or stroke was significantly reduced 16% in pioglitazone patients compared with placebo.1 15
Proportion of Events (%) 10
Pioglitazone (301 events) 5 6 12 18 24 30 36
Time From Randomization
Number at risk
Pioglitazone
2536
2487
2435
2381
2336
396
Placebo
2566
2504
2442
2371
2315
390
*Unadjusted
Reprinted with permission from Dormandy JA et al. Lancet. 2005;366:
1. Dormandy JA, Charbonnel B, Eckland DA, Erdmann E, Massi-Benedetti M, Moule IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet. 2005:366:

19. PAD Care Standards for Patients
With Diabetes
Proper foot care, including use of appropriate footwear, chiropody/podiatric medicine, daily foot inspection, skin cleansing, and use of topical moisturizing creams, should be encouraged and skin lesions and ulcerations should be addressed urgently in all diabetic patients with lower extremity PAD.
Treatment of diabetes in individuals with lower extremity PAD by administration of glucose control therapies to reduce the hemoglobin HbA1C to less than 7% can be effective to reduce microvascular complications and potentially improve cardiovascular outcomes. I
IIa
IIb
III B I
IIa
IIb
III c

20. Mechanisms of Action of Oral Antiplatelet Therapies
ASA=aspirin; COX=cyclooxygenase; PDE=phosphodiesterase.
Schafer AI. Am J Med. 1996;101:
1. Schrör K. The basic pharmacology of ticlopidine and clopidogrel. Platelets. 1993;4:
2. Plavix® (clopidogrel bisulfate) Prescribing Information.
3. Schafer AI. Antiplatelet therapy. Am J Med. 1996;101:

21. Patients Having MI, Stroke, or Vascular Death (%)
Antiplatelet Trialists’ Collaboration: Efficacy of Antiplatelet Therapy in Prevention of Ischemic Events
Odds Reduction 22
All antiplatelet therapy
control 5 10 15 20 25 25 29 27 25
Patients Having MI, Stroke, or Vascular Death (%) 32
Prior stroke/TIA
Acute MI
Prior MI
Other high risk*
All high- risk
trials
All trials
(high or low)
*Other high-risk patients include: unstable/stable angina, post-CABG, PAD, and diabetic patients. CABG=coronary artery bypass graft; PAD=peripheral arterial disease; TIA=transient ischemic attack.
Antiplatelet Trialists’ Collaboration. Brit Med J. 1994;308:
Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81–106.

22. Antithrombotic Trialists’ Collaboration (ATC): Meta-Analysis of Vascular Events in Antiplatelet Trials in Patients With PAD
Category APT CTRL Reduction (%)
Intermittent 6.4% 7.9% 23±9
claudication
Peripheral artery 5.4% 6.5% 22±16
bypass graft
Peripheral 2.5% 3.6% 29±35
angioplasty
All high-risk patients ±2
(P<.001)
0.0
0.5
1.0
1.5
2.0
N=9214. Data from 197 randomized trials comparing an antiplatelet agent (APT; aspirin, clopidogrel, dipyridamole, or a glycoprotein IIb/IIIa antagonist) vs control or another antiplatelet agent. APT=antiplatelet; CRTL=control.
Antithrombotic Trialists’ Collaboration. BMJ. 2002;324:71-86.

23. Risk of Occlusive Vascular Events in High-Risk Patients: Antithrombotic Trialists’ Collaboration
Risk category
Patients with event (%)
Reduced
Increased
Risk vs control
(No. of trials with data)
APT
Control
Reduced
Reduced
Increased
Increased
N=9706
IC (n=26)
6.4
7.9
Peripheral
5.4
6.5
grafting (n=12)
Peripheral
2.5
3.6
angioplasty (n=4)
All PAD trials (n=42)
5.8
7.1
0.0
0.5
1.0
1.5
2.0
APT=antiplatelet therapy with aspirin, clopidogrel, dipyridamide, or a glycoprotein IIb/IIIa antagonist; IC=intermittent claudication.
Reprinted with permission Antithrombotic Trialists’ Collaboration. Brit Med J. 2002;324:71-86.
Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86

24. Overall Relative Risk Reduction
Efficacy of Clopidogrel vs. Aspirin in MI, Ischemic Stroke, or Vascular Death
8.7%* 16
Overall Relative Risk Reduction
ASA
5.83% 12
Event Rate (%)
Cumulative 8
5.32%
Clopidogrel 4
N=19,185 3 6 9 12 15 18 21 24 27 30 33 36
Months of Follow-Up
ASA=aspirin. Mean follow-up=1.91 years. *ITT analysis.
Reprinted with permission from CAPRIE Steering Committee. Lancet. 1996;348:
CAPRIE Steering Committee. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:

25. Risk Reduction of Clopidogrel vs
Risk Reduction of Clopidogrel vs. Aspirin in Patients With Atherosclerotic Vascular Disease
Aspirin favored
Clopidogrel favored
Stroke
N=19,185 MI
PAD
All patients
-30
-20
-10 10 20 30 40
Reprinted with permission from CAPRIE Steering Committee. Lancet. 1996;348:
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:

26. CHARISMA: Affect of Clopidogrel Plus Aspirin vs
CHARISMA: Affect of Clopidogrel Plus Aspirin vs. Aspirin Alone on MI, Stroke, or CV Death
First occurrence of MI (fatal or nonfatal), stroke (fatal or nonfatal), or CV death† 8
Placebo + ASA
7.3% 6
Clopidogrel + ASA
6.8%
Cumulative Event Rate* (%) 4
RRR 7.1% (95% CI: -4.5%, 17.5%)
P=0.22 2 6 12 18 24 30
Months Since Randomization§
ASA=aspirin; CI=confidence interval; MI=myocardial infarction; RRR=relative risk ratio. *All patients received ASA mg/day; †The number of patients followed beyond 30 months decreases rapidly to zero; only 21 primary efficacy events occurred beyond this time (13 clopidogrel and 8 placebo).
Bhatt DL, Fox KA, Hacke W, et al. N Engl J Med 2006;354:1706.

27. CHARISMA: Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category
Population RRR (95% CI) P
Qualifying CAD, CVD, or PAD (0.77, 0.998) (n=12,153)
Multiple risk factors (0.91, 1.59) (n=3,284)
Overall population* 0.93 (0.83, 1.05) (N=15,603)
0.4
0.6
0.8
1.2
1.4
1.6
Clopidogrel better
Placebo better
CAD=coronary artery disease; CI=confidence interval; CVD=cardiovascular disease; MI=myocardial infarction; RRR=relative risk ratio.
*A statistical test for interaction showed marginally significant heterogeneity (P=0.045) in treatment response for these prespecified subgroups of patients.
Adapted from Bhatt DL, Fox KA, Hacke W, et al. N Engl J Med 2006;354:1706..

28. B Antiplatelet Therapy
Antiplatelet therapy is indicated to reduce the risk of myocardial infarction, stroke, or vascular death in individuals with atherosclerotic lower extremity PAD.
Aspirin, in daily doses of 75 to 325 mg, is recommended as safe and effective antiplatelet therapy to reduce the risk of myocardial infarction, stroke, or vascular death in individuals with atherosclerotic lower extremity PAD. I
IIa
IIb
III B
Clopidogrel (75 mg per day) is recommended as an effective alternative antiplatelet therapy to aspirin to reduce the risk of myocardial infarction, stroke, or vascular death in individuals with atherosclerotic lower extremity PAD.

29. Treatment of the Asymptomatic Patient With PAD
IIa
IIb
III B
Smoking cessation, lipid lowering, and diabetes and hypertension treatment according to current national treatment guidelines are recommended for individuals with asymptomatic lower extremity PAD.
Antiplatelet therapy is indicated for individuals with asymptomatic lower extremity PAD to reduce the risk of adverse cardiovascular ischemic events. I
IIa
IIb
III c