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					_______________________________________________
                   ACOFP 45th Annual Convention and Exhibition
                                                     Denver, Colorado
______________________________________________________________________________________________

Overview of Peripheral Artery Disease in the Primary Care Practice
                                          William R. Hiatt, MD, FACP
                                         Wednesday, March 12, 2008
                                                    2:00 pm – 3:00 pm

                                                          CME/CEU Information
The American College of Osteopathic Family Physicians is accredited by the American Osteopathic Association Council
                                        to sponsor continuing medical
                                                      education for osteopathic physicians.
                         The American College of Osteopathic Family Physicians designates the lectures
and workshops for Category 1A credit on an hour-for hour basis, pending approval by the AOA CCME. ACOFP is not
                                           responsible for the content.




 DISCLOSURE OF FINANCIAL RELATIONSHIPS WITHIN 12 MONTHS OF DATE OF THIS FORM
 Speaker Name: William R Hiatt, MD
          ACOFP1021D1
 Have you, or any of your immediate family, had a financial relationship or interest with any proprietary entity producing health care goods
          or services within the past 12 months? Yes
 If you answered Yes to the question above, please indicate the relationship(s):
 Relationships: Research Grants; Speakers' Bureau*
     If other:
 Organization/Clinical Area Involved: BMS-Sanofi-Aventis Partnership[br]Otsuka Japan
          *If you checked “Speakers’ Bureaus:
 Did you participate in company-provided speaker training related to your proposed topic? Yes
 Did you travel to participate in this training? No

 Did the company provide you with slides of the presentation in which you were trained as a speaker? Yes
 Did the company pay the travel/lodging/other expenses? No

 Did you receive an honorarium or consulting fee for participating in this training? Yes
 Have you received any other type of compensation from the company? Please specify:
 Yes
 Research grants
 _____________________________________________________________________
 When serving as faculty for ACOFP, will you use slides provided by a proprietary entity for your presentation/handout materials? No
 Will your topic involve information or data obtained from commercial speaker training?                     No
 DISCLOSURE OF UNLABELED/INVESTIGATIONAL USES OF PRODUCTS
 Will the content of your material(s)/presentation(s) in this CME activity include discussion of unapproved or investigational uses of
        products or devices?
 No
          _____________________________________________________________________________________________________
 I have read the ACOFP policy on full disclosure. If I have indicated a financial relationship or interest, I understand that this information
        will be reviewed to determine whether a conflict of interest may exist, and I may be asked to provide additional information. I
        understand that failure or refusal to disclose, false disclosure, or inability to resolve conflicts will require the ACOFP to identify a
        replacement.




                        Peripheral Arterial Disease
                      Pathophysiology and Treatment




                                                                           William R. Hiatt, MD
                                                                        Professor of Medicine
                                                              Section of Vascular Medicine
                                                                       University of Colorado
                       Atherothrombosis
                                                                                        MI
                                                                                        ACS
                                                                                        CVA / TIA
                                                                                        Acute Leg
                                                                                        Ischemia
                                                                                        CV death
                                                            Thrombosis
          Atherosclerosis
           (Arterial Stenosis)



           Stable angina
     Intermittent claudication
                                                                Stary HC. Circulation.1995;92:1355-1374.
       Critical Leg Ischemia                                    Fuster V et al. Vasc Med. 1998;3:231-239.




                         Distribution of PAD
      Aortoiliac                                    SFA                               Tibial




     Documented Prevalence of PAD
NHANES1
Age >40       4.3%

 San Diego2                           11.7%
 Mean Age=66

 NHANES1                                        14.5%
 Age ≥70

 Rotterdam4                                                   19.1%
 Age >55

 Diehm3
 Age ≥65                                                        19.8%
 PARTNERS5                                                                                29%
 Age >70, or between 50–69 with diabetes or smoking

0%          5%              10%             15%             20%             25%         30%            35%
             1.   Selvin E, Erlinger TP. NHANES. Circulation. 2004;110:738-743.
             2.   Criqui MH, et al. Circulation. 1985;71:510-515.
             3.   Meijer WT, et al. Arterioscler Thromb Vasc Biol. 1998;18:185-192.
             4.   Diehm C, et al. Atherosclerosis. 2004;172:95-105.
             5.   Hirsch AT, et al. JAMA. 2001;286:1317-1324.
                      Risk Factors for PAD
                                          Reduced Increased

     Smoking
     Diabetes
     Hypertension
     Hypercholesterolemia
     Hyperhomocysteinemia
     Fibrinogen
     C-Reactive Protein
     Alcohol

            Relative Risk                    0        1        2        3       4        5       6

Newman AB, et al. Circulation. 1993;88:837-845; Hiatt WR, et al. Circulation. 1995;92:614-621;
Graham IM, et al. JAMA. 1997;277:1775-1781; TASC Working Group. J Vasc Surg.
2000;31(1 pt 2):S1-S288; Ridker PM, et al. Circulation. 1998;97:425-428.




        Identifying Patients at Risk for PAD

       Consider PAD in Patients with:
        – Exertional leg pain or exercise limitations
        – PARTNERS criteria of 50-69 years with diabetes or
        smoking or >70 years
        –Framingham risk 10%-20% in 10 years

                  • PARTNERS PAD prevalence = 29%


      JAMA 2001;286:1317-1324




                 Ankle-Brachial Index (ABI)
                                 ABI and Mortality
                70                         All-cause mortality
                60
  Percent (%)




                50
                40
                30
                20
                10
                0                                        //


                                         Baseline ABI


Circulation. 2004;109:733-739.




                               REACH Registry
   6.00%


   5.00%


   4.00%

                                                                                 A
                                                                                C D
   3.00%
                                                                                CVD
                                                                                PAD
   2.00%


   1.00%


   0.00%
                      V eath
                     C D            MI          CVA             VA eath
                                                            MI/C /D

                                                                 JAMA 2007;297:1197-1206




                Reducing CV Mortality in PAD

                     • Risk factor modification
                        –   Smoking cessation
                        –   Lipid-lowering drugs
                        –   Intensive treatment of diabetes
                        –   Antihypertensive therapy
                     • ACE inhibitors
                     • Antiplatelet therapy
           Smoking Cessation in PAD

         Survival                           Smoker       Abstinent
         1 year                                85%          100%
         3 year                                40%            67%
         5 year                                36%            66%

   • Decreased risk of amputation
   • Improved bypass graft patency

   Lassila R and Lepantalo M. Acta Chir Scand. 1988;154:635-640.
   Faulkner KW, et al. Med J Aust. 1983;1:217-219.




ACC/AHA PAD Management Guidelines
                            Smoking Cessation
     I IIa IIb III
    B                       Individuals with lower extremity PAD
                            who smoke cigarettes or use other
                            forms of tobacco should be advised
                            to stop smoking and should be
                            offered comprehensive smoking
                            cessation interventions, including
                            behavior modification therapy,
                            nicotine replacement therapy, or
                            bupropion.


Adapted from Hirsch AT, et al. Available at:
http://www.acc.org/clinical/guidelines/pad/summary.pdf




        Diabetes Treatment in PAD
        • Intensive glycemic control
              – HbA1c < 7.0%
              – Questionable benefit on CV events
        • Aggressive treatment of risk factors
              – Smoking, hyperlipidemia, hypertension
        • ACE inhibitors/ARB’s for CV and renal
          protection
                 ACC/AHA PAD Management Guidelines
                                                       Diabetes Therapies
                      I IIa IIb III
                            C                          Treatment of diabetes to lower
                                                       hemoglobin A1c to < 7% in patients
                                                       with PAD can reduce microvascular
                                                       complications and potentially
                                                       improve cardiovascular outcomes




                 Adapted from Hirsch AT, et al. Available at:
                 http://www.acc.org/clinical/guidelines/pad/summary.pdf




     I     s
T AT N w o r e




                     SIMVASTATIN: VASCULAR EVENT by PRIOR DISEASE
                    Baseline                           STATIN      PLACEBO                  Risk ratio and 95% CI
                    feature                            (10269)      (10267)              STATIN better STATIN worse

                     Previous MI                        1007            1255
                     Other CHD (not MI)                  452             597
                     No prior CHD
                           CVD                           182             215
                           PVD                           332             427
                           Diabetes                      279             369

                    ALL PATIENTS                         2042          2606                                                       24%SE 2.6
                                                       (19.9%)       (25.4%)                                                      reduction
                                                                                                                                  (2P<0.00001)
                                                                                 0.4       0.6     0.8     1.0       1.2    1.4




                                                 Niacin ER/Lovastatin
                             HDL                            TG                       LDL                             Lp(a)
                                                                                    34                                                         31
                     35                         30
                                         26
                     25            18
                                                                    4           8             12            16             52        100
                     15      11
                                                                  500/10      1000/20       1500/30       2000/40      2000/40      2000/40
                                                                 (n = 753)   (n = 706)     (n = 675)     (n = 656)    (n = 550)    (n = 393)
                       5
                                    -2
                      -5
                                         -10
                    -15            -19
                                               -16
                                                                                    -25
                    -25              -31
                             -25
                    -35                    -38
                                                                                                                                           -42
                                   -34                                           -43
                                                 -45
                    -45                  -41
                                                 -47                                 -44
                                                                                                                                           -45
                    -55
                             0
                             4
                             8
                            12
                            16
                            20
                            24
                            28
                            32
                            36
                            40
                            44
                            48
                            52
                            56
                            60
                            64
                            68
                            72
                            76
                            80
                            84
                            88
                            92
                            96
                           100




                                                                             Week
ACC/AHA PAD Management Guidelines
                     Lipid Lowering Therapies
     I IIa IIb III
                              Treatment with a statin medication is
    B
                              indicated for all patients with PAD to
                              achieve a low-density lipoprotein
                              (LDL) cholesterol level < 100 mg/dL

                               Treatment with a statin to achieve a
         B                     LDL cholesterol level < 70 mg/dL is
                               indicated in patients with PAD at a
                               very high risk of ischemic events


Adapted from Hirsch AT, et al. Available at:
http://www.acc.org/clinical/guidelines/pad/summary.pdf




      The HOPE Study: PAD Subgroup

                                Incidence of
                 No. of         Composite Outcome
                 Patients       in Placebo Group

  PAD             4046                   22.0

  No PAD          5251                   14.3


                                                0.6      0.8        1.0       1.2

                                                Relative Risk in Ramipril Group

   Yusuf S, et al. N Engl J Med. 2000;342:145-153.




ACC/AHA PAD Management Guidelines
                   Antihypertensive Therapies
     I IIa IIb III
                            Antihypertensive therapy should be
    A                       administered to hypertensive patients with
                            PAD to achieve a goal of < 140/90 mm Hg
                            (nondiabetics) or < 130/80 mm Hg
                            (diabetics and chronic renal disease)

                            Beta-adrenergic blocking drugs are
    A                       effective antihypertensive agents and are
                            not contra-indicated in PAD



Adapted from Hirsch AT, et al. Available at:
http://www.acc.org/clinical/guidelines/pad/summary.pdf
                Oral Antiplatelet Agents:
                 Mechanisms of Action

      Clopidogrel                                ADP                  dipyridamole
      ticlopidine
                                                                ADP           phosphodiesterase


                                               ADP


                                                                          Collagen
 GPIIb/IIIa                                                               Thrombin
                                                     Activation             TXA2
 (Fibrinogen
  Receptor)                           COX


                                        TXA2
                   aspirin


  ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.
  Schafer AI. Am J Med. 1996;101:199-209.




 Antithrombotic Trialist Collaboration

       • 287 randomized trials of antiplatelet Rx
       • 135,000 patients antiplatelet vs controls
       • 77,000 patients different antiplatelet Rx
       • Categorized as acute MI, prior MI, prior
         stroke/TIA, other high risk (PAD)
       • 25% odds reduction of MI, CVA, vascular
         death with aspirin
                                                      BMJ 2002;324:71-86




  Antithrombotic Trialists’ Collaboration
 MI, Stroke, CV Death in Patients With PAD
  Category                APT       CTRL                                   Reduction (%)
  Claudication            6.4%       7.9%                                       23±9


  Peripheral artery       5.4%       6.5%                                       22±16
  bypass graft

  Peripheral              2.5%       3.6%                                       29±35
  angioplasty

  All high-risk patients                                                  22±2 (P<.001)



                                      0.0       0.5      1.0        1.5        2.0


BMJ. 2002;324:71-86.
      CAPRIE Outcomes by Subgroup
                                                             Stroke

                                                MI

                                                                       PAD

                                                             All patients
          Mean & 95% CI


                 -40      -30      -20       -10         0      10     20    30   40

                         Aspirin Better                      Clopidogrel Better
    CAPRIE study. Lancet. 1996;348:1329-1339.




ACC/AHA PAD Management Guidelines
                            Antiplatelet Therapy
     I IIa IIb III
                            Antiplatelet therapy is indicated to
    A
                            reduce the risk of MI, stroke, or vascular
                            death in individuals with atherosclerotic
                            lower extremity PAD.
    A                       Aspirin, in daily doses of 75 to 325 mg,
                            is recommended as safe and effective
                            antiplatelet therapy to reduce the risk
                            of MI, stroke, or vascular death in
                            individuals with atherosclerotic lower
                            extremity PAD.


Adapted from Hirsch AT, et al. Available at:
http://www.acc.org/clinical/guidelines/pad/summary.pdf




                   TASC II PAD Guidelines
                            Antiplatelet Therapy
• All symptomatic patients with or without a history of other
cardiovascular disease should be prescribed an antiplatelet drug long
term to reduce the risk of cardiovascular morbidity and mortality [A].
• Aspirin/ASA is effective in patients with PAD who also have clinical
evidence of other forms of cardiovascular disease (coronary or
carotid) [A].
• The use of aspirin/ASA in patients with PAD who do not have clinical
evidence of other forms of cardiovascular disease can be considered
[C].
• Clopidogrel is effective in reducing cardiovascular events in a
subgroup of patients with symptomatic PAD, with or without other
clinical evidence of cardiovascular disease [B]


Norgren and Hiatt for the TASC II writing group
J Vasc Surg and Eur J Vasc Endovasc Surg 2007
ACC/AHA PAD Management Guidelines
                            Antiplatelet Therapy
     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 MI, stroke, or vascular death in
                            individuals with atherosclerotic PAD




Adapted from Hirsch AT, et al. Available at:
http://www.acc.org/clinical/guidelines/pad/summary.pdf




                     Results (MI/Stroke/
                    CV Death) by Category
Population                                                 N       RR (95% CI)         p value

Documented AT                                            12,153   0.88 (0.77, 0.998)   0.046

  Coronary                                               5,835    0.86 (0.71, 1.05)     0.13

  Cerebrovascular                                        4,320    0.84 (0.69, 1.03)     0.09

  PAD                                                    2,838    0.87 (0.67, 1.13)     0.29

Multiple RF                                              3,284    1.20 (0.91, 1.59)     0.20

Overall Population                                       15,603   0.93 (0.83, 1.05)     0.22

             0.4 0.6 0.8                 1.2 1.4 1.6
             Clopidogrel Better       Placebo Better

 Bhatt et al. NEJM 2006; 354:1-12




                    PAD Symptom Severity
    Maximal walking speed
          – Normal = 3-4 mph
          – PAD = 1-2 mph
    Maximal walking distance
          – Normal = unlimited
          – PAD, 31% difficulty walking in home
          – PAD, 66% difficulty walking 1/2 block
    Peak VO2
          – PAD reduced 50% (NYHA class III CHF)
                                       Otsuka data set, J Appl Physiol 1992;73:346
                    Pathophysiology of
                 Intermittent Claudication
            Reduced lower                               Supply-Demand mismatch
          extremity perfusion                                 With exercise




                                                                  Intermittent
 Ischemia-Reperfusion injury                                      Claudication
  -Denervation, muscle weakness
  -Impaired muscle metabolism
  -Reduced ATP production
                                                           Functional impairment
                                                             Walking limitation

Brass, EP, Hiatt WR. Acquired skeletal muscle metabolic myopathy in atherosclerotic peripheral
arterial disease. Vasc Med 2000;5:55-59




                 Intermittent Claudication
                     Exercise Therapy

         Frequency: 3-5 supervised sessions/week
         Duration: 35 to 50 minutes of exercise/session
         Type of exercise: treadmill or track walking to
             near-maximal claudication pain
         Length: 3 to 6 months
         Results: 100%-150% improvement in maximal
             walking distance, improved quality of life

                  Stewart, Hiatt, Regensteiner, Hirsch. N Eng J Med. 2002;347:1941-1951




           Exercise Training Mechanism
        Better walking efficiency
              – Decreased VO2 for submax exercise
        Improved microcirculation
              – Decreased blood viscosity
        Improved muscle metabolism
              – ↑ tissue oxygen extraction
              – Improved muscle carnitine metabolism
        Minimal change in blood flow, O2 delivery
ACC/AHA PAD Management Guidelines
                               Exercise Therapy
     I IIa IIb III
    A                       A program of supervised exercise training
                            is recommended as initial treatment for
                            patients with claudication


                            Supervised exercise training should be
    A                       performed for a minimum of 30-45 minutes,
                            3-times a week for 12 weeks



Adapted from Hirsch AT, et al. Available at:
http://www.acc.org/clinical/guidelines/pad/summary.pdf




          TASC II PAD Guidelines
      Revascularization for Claudication
Patients with intermittent claudication who continue to
  experience limitations to their quality of life after
  appropriate medical therapy (exercise rehabilitation
  and/or pharmacotherapy) or patients with critical limb
  ischemia, may be considered candidates for
  revascularization if they meet the following additional
  criteria:
• A suitable lesion for revascularization is identified
• The patient does not have any systemic contraindications
  for the procedure; and
• The patient desires additional therapy [B].

Norgren and Hiatt for the TASC II writing group
J Vasc Surg and Eur J Vasc Endovasc Surg 2007




                  TASC II Aorto-iliac lesions
                               Type A and Type B
    TASC II Aorto-iliac lesions
        Type C and Type D




TASC II Femoral Popliteal Lesions
        Type A and Type B




TASC II Femoral Popliteal Lesions
        Type C and Type D
     Drugs with insufficient evidence of
    clinical utility in treating claudication

• Pentoxifylline
• Antiplatelet drugs (Aspirin, Clopidogrel)
• Vasodilators
• L-Arginine
• ACAT (acyl coenzyme A-cholesterol acyltransferase) inhibitors
• 5-Hydroxytryptamine antagonists (ketanserine, AT-1015,
  Sarpogrelate
• Prostaglandins: Iloprost, Beraprost
• Buflomedil, defibrotide
• Other agents (Chelation, omega-3 fatty acids, ginko-biloba)




                             Pharmacologic Effects
                                 of Cilostazol
    Phosphodiesterase-3 (PDE-3) inhibitor
    -Inhibition of platelet aggregation
    -Vasodilation
    -Inhibition of smooth muscle cell proliferation
    -Improvement of EC
    -Lower TG, Raise HDL cholesterol levels
    -Less positive inotropic and chronotropic effects than milrinone
       (due to PDE-3 selectivity and adenosine uptake inhibition)




                            Cilostazol vs Pentoxifylline
                            Walking Distance in Claudication

                                         Cilostazol 100 mg bid po
                            50           Pentoxifylline 400 mg tid
                                                                          *
      Baseline MWD (mean)
      Percent Change from




                                         Placebo
                            40

                            30

                            20

                            10
                                                     * P <0.05
                             0
                                 0   4        8       12     16      20   24
                                           Weeks of Treatment
     Dawson, et al. Am J Med 2000;109:523-30
ACC/AHA PAD Management Guidelines
           Pharmacotherapy of Claudication
     I IIa IIb III
    A                         Cilostazol (100 mg orally 2 times per
                              day) is indicated as an effective therapy
                              to improve symptoms and increase
                              walking distance in patients with lower
                              extremity PAD and intermittent
                              claudication (in the absence of heart
                              failure).




Adapted from Hirsch AT, et al. Available at:
http://www.acc.org/clinical/guidelines/pad/summary.pdf




         Claudication Treatment Options
Treatment                         Mechanism              ACC-AHA-TASC

 Exercise                         Metabolic,
                                  Walking efficiency          1-A
                                  Endothelial


 Angioplasty                      Hemodynamic                 1-A


 Cilostazol                       Metabolic,
                                  Hemodynamic                 1-A
                                  Vascular smooth muscle

				
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