EVIDENCEBASED REVIEW: TREATMENT OF THE PATIENT WITH PERIPHERAL ARTERIAL DISEASE PHARMCOLOGIC AND NON

1
EVIDENCE-BASED REVIEWTREATMENT OF THE PATIENT
WITH PERIPHERAL ARTERIAL DISEASEPHARMCOLOGIC AND
NONPHARMACOLOGIC MEASURES

• 93?6?16?

2
EVIDENCE BASED APPROACH TO THE PATIENT
WITHPERIPHERAL VASCULAR DISEASE THE ASSIGNMENT

• BRIEF CASE
• A 65-year-old male presents to your office with
  classic intermittent claudication.
• Arterial dopplers and ABIs verify the clinical
  suspicion, based on history and physical
• examination, of peripheral arterial disease. He
  has no symptoms of rest pain or signs of
  ischaemic ulceration.

3

• GIVEN PAD is common. The age-adjusted prevalence
  of PAD is 12. Patients
• with PAD have excess cardiovascular morbidity and
  mortality.
• TO FIND What are the data on secondary
  prevention measures in patients with
• PAD?

4

• THE TASK What are the data re benefits to the
  following therapeutic options in the patient with
  PAD? Please review the primary data from
  appropriate studies in presenting your report and
  supporting your recommendations.
• Your report should include a summary of the
  relevant data that leads you to your
  recommendation for inclusion or exclusion. It
  should not just be a summary of a review article.
  It does not need to be lengthy. A onepage summary
  is sufficient. For example, if you were assigned
  to the clopidogrel data, you would review the
  data from the CAPRIE study, looking at ARR, RRR,
  NNT. Also, please include the cost of each
  pharmacological intervention. (e.g. 30 day
  supply of usual therapeutic dose).
• Finally, please include your references and how
  you searched for your data (e.g. UpToDate,
  Medline, references from review article, other)

5

• NONPHARMACOLOGIC MEASURES
• ? smoking cessation
• ? treatment of hyperlipidemia
• ? treatment of diabetes mellitus
• ? treatment of hypertension
• ? exercise
• PHARMACOLOGIC MEASURES
• ? aspirin
• ? ticlodipine
• ? clopidogrel
• ? pentoxifylline
• ? cilostazol

6

• I. NONPHARMACOLOGIC
• MEASURES

7
A. SMOKING CESSATION

• Recommendations I would recommend smoking
  cessation to a smoker presenting with classic
  intermittent claudication (and I would choose it
  as the answer to any board question where it is
  an available choice).
• Reasoning and Data
• Smoking cessation has been linked to many health
  benefits.

8
A. SMOKING CESSATION

• It has been shown to be associated with a
  decreased rate of limb amputation and a decreased
  rate of rest ischemia symptoms.
• There is some conflicting data regarding smoking
  cessation with respect to reduction of
  intermittent claudication.
• A few studies have been done which have claimed
  to show increased exercise tolerance and
  reduction in the progression of symptoms.

9
A. SMOKING CESSATION

• However, the point is made in a metaanalysis
  review article that the existing references are
  all cohort studies (not, for example, randomized
  blinded trials).
• An interesting point made in the meta-analysis is
  that smoking cessation is probably associated
  with other lifestyle changes, any one of which
  potentially could result in improved intermittent
  claudication symptoms.

10
A. SMOKING CESSATION

• Biochemically, smoking cessation seems to be a
  logical step in reducing the symptoms associated
  with intermittent claudication.
• The trends in most of the studies show that there
  is a potential benefit. Based on the trends of
  the studies and the other benefits of smoking
  cessation, I would recommend it for the patient
  in question.

11
A. SMOKING CESSATION

• Cost
• 1. Nicoderm CQ Step I (14 patches, 21mg
• 
  each) 45.99
• Step II (14 patches, 14mg each) 45.99
• Step III (14 patches, 7mg each) 45.99
• 2. Zyban 150mg PO bid for 7-12 weeks
• 85.64 for 60
  tabs
• 3. Bupropion 150mg PO bid for 7-12 weeks
• (100mg each) 129.26 for 180 tabs

12
B. TREATMENT OF HYPERLIPIDEMIA

• Angiographic change
• In meta-analysis of 2 RCT trials (Blankenhorn
  DH et al, 1991 Duffield RGM, 1983) total n212
  about 2 years of follow-up cholestipol-niacin
  vs. diet and one of cholestyramine/nicotinic
  acid/clofibrate vs. usual care) a significant
  overall reduction in disease progression on
  angiogram (odds ratio 0.47, CI 0.29 to 0.77).
• In total, 14 of the treated subjects progressed
  compared with 25 of the controls.

13
B. TREATMENT OF HYPERLIPIDEMIA

• An additional trial in Sweden (Walldius et al,
  
• 1994 n274, probucol 0.5 g, twice daily vs.
• placebo with all patients given diet and
• cholestyramine, follow-up of 3 years)
• no difference.
• Another recent surgical trial (Buchwald H et
  al, 1996 n838, cholesterol reduction vs. not,
  5-yr. follow-up) showed no significant difference
  in progression.

14
B. TREATMENT OF HYPERLIPIDEMIA

• Ankle brachial pressure index
• One larger trial (Walldius et al, 1994 see
  above) showed no significant difference.
• A large, randomized surgical trial with good
  follow-up (Buchwald et al, 1996, see above)
  showed significantly larger percentage of
  untreated patient with decreased ABI (RR 0.55, CI
  0.36-0.86, p lt 0.01).

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B. TREATMENT OF HYPERLIPIDEMIA

• Two small RTCs were also done (Corsi et al, 1985
  Gans et al, 1990).
• In the first, (n30, glycosamineglycan as
  treatment, 6 months follow-up), there was a
  significant 28.3 increase in ABI in the
  treatment group.
• In the second (n32, fish oil vs. corn oil),
  there was no significant increase.

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B. TREATMENT OF HYPERLIPIDEMIA

• Claudication Three small trials done (Nye et al,
  1973 Davis et al, 1975 Corsi et al, 1985).
• First 8 of treated subjects reported worsening
  of claudication compared with 4 of controls
  (pgt0.05)
• second 24 of treated subjects experienced no
  effect compared with 88 of controls (plt0.001)
• third 0 of treated subjects were worse compared
  with 20 of controls.).

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B. TREATMENT OF HYPERLIPIDEMIA

• Claudication
• A sub-section of a recent large study in Sweden
  of Simvastatin (Pedersen et al, 1998 n4,444
  patients with prior MI/angina and high lipids,
  placebo vs. simvastatin, follow-up 5 years)
  showed the probability of new or worsening
  intermittent claudication was reduced by 38 (plt
  0.05).

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B. TREATMENT OF HYPERLIPIDEMIA

• Walking distance
• Pain-free walking distance was measured in the
  same two small trials as those which recorded the
  ABI.
• The first showed a significant improvement in
  walking distance in the treated group (plt0.01),
  while the second showed no significant
  difference.
• Cost Minimal to moderate. Simvastatin -
  100-199/mo. (plus LFT monitoring). Niacin-
  lt25/mo (but side-effects more likely).

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B. TREATMENT OF HYPERLIPIDEMIA

• Recommendation
• Probably treat, first with niacin, then with
  simvastatin. Considering objective, test-based
  criteria, the evidence is generally weak.
• It is weakest for change in angiographic
  advancement of lesions with lipid-lowering.
• .

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B. TREATMENT OF HYPERLIPIDEMIA

• Recommendation
• It is only mildly better, but present, for ABI
  improvement with sufficiently long follow-up.
• Considering the quality-of-life,
  clinically-relevant standards, the evidence is
  stronger.
• There is strong evidence that lipid-lowering
  reduces the incidence of claudication, while the
  evidence is essentially non-existent concerning
  the answer to the question of walking distance
  improvement.

21
C. TREATMENT OF DIABETES MELLITUS

• DM has both macro- and microvascular effects
  tight control seems to differentially protect
  against the microvascular effects which are not
  associated with measurement of or symptoms from
  PVD.
• United Kingdom Prospective Diabetes Study
  compared intensive drug treatment vs. dietary
  treatment (n3867) had no effect on the risk of
  peripheral arterial disease relative risk 0.6,
  CI 0.4-1.2. (UKPDS 33, 1998).

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C. TREATMENT OF DIABETES MELLITUS

• Recent abstract (Florkowski et al, 2001 not yet
  available in our library except as on-line
  abstract) Independent predictors of increased
  CAD 10-yr. mortality for diabetics vs. controls
  with no CAD at entry to study include PVD with a
  relative risk of 2.4 and a confidence interval of
  1.3-4.5.
• This was greater than the risk for acceptable
  HbA1c (1.6, 1.1-2.3), HTN (1.9, 1.0- 3.7), and
  comparable to that of smoking (2.6, 1.2-5.8).

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C. TREATMENT OF DIABETES MELLITUS

• Recommendation
• Not supported by data if solely for PVD
  avoidance.
• Tight control of diabetes does not (directly)
  effect the likelihood of developing PVD as
  manifest by claudication and decreased ABI.
• Tight control does effect microvascular
  complications which may decrease the likelihood
  of infections and subsequent amputations.
• Most patients with DM have other reasons for
  maintaining tight control including the avoidance
  of retinopathy, neuropathy, and nephropathy.

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D. TREATMENT OF HYPERTENSION

• Data correlating the control of hypertension with
  alterations in the progression of PVD are quite
  sparse.
• One possible reason is that, once
  anti-hypertensive therapy was found to have a
  beneficial effect on mortality in patients with
  CAD, randomized controlled trials involving
  patients with PVD, which often exists in
  conjunction with other types of atherosclerotic
  disease, would be unethical.

25
D. TREATMENT OF HYPERTENSION

• The recent HOPE trial suggests that the reduction
  in cardiovascular mortality seen with the use of
  ACE-inhibition is similar in magnitude in
  patients with and without PVD.
• This effect is thought to be class-mediated and
  is out of proportion to the efficacy of
  blood-pressure control, per se.
• No comment is made about the effect of
  ACEinhibition on PVD symptoms or disease
  progression.

26
D. TREATMENT OF HYPERTENSION

• Many of the published data involving PVD and
  anti-hypertensive agents revolve around the use
  of beta-blockers.
• A few decades ago, scattered case reports
  suggested that betablockers worsened claudication
  symptoms.
• A meta-analysis of several subsequent small
  randomized controlled trials involving both
  selective and non-selective beta-blocking agents
  did not demonstrate a significant worsening of
  intermittent claudication or an increase in the
  rate of complications secondary to PVD.
• It is still advised to use beta-blockers with
  caution in patients with severe symptomatic
  claudication.

27
E. THE ROLE OF EXERCISE

• It has long been theorized that exercise
  rehabilitation improves the quality of life and
  functionality of patients with peripheral
  arterial disease.
• While a number of theories have been purported
  to explain this effect, it is likely that the
  benefit associated with exercise stems from
  multiple factors involving both systemic and
  local responses
• ? Overall improvement in central cardiovascular
  function
• ? Improved skeletal tone and intermediary
  metabolism
• ? Improved gait efficiency
• ? Decreased lower-extremity oxygen consumption
• ? Improved lower-extremity oxygen extraction

28
E. THE ROLE OF EXERCISE

• Interestingly enough, however, although it would
  make sense from a theoretical standpoint that the
  development of collateral circulation associated
  with sustained exercise would reduce
  lower-extremity ischemia, alterations in blood
  flow to the legs has not been reliably shown to
  either improve walking distance or decrease the
  progression of disease.

29
E. THE ROLE OF EXERCISE

• The current recommendation in terms of exercise
  therapy for patients with PVD includes a
  monitored and supervised walking program of at
  least 24 weeks duration consisting of at least
  three one-hour sessions per week.
• A meta-analysis of previously published studies
  demonstrated a consistent beneficial effect of
  structured treadmill exercise programs on both
  the functional status as well as the symptoms of
  patients with PVD a 179 increase in overall
  walking distance and a 122 increase in the
  distance walked prior to onset of maximal
  claudication pain.

30

• However, because the inherent efficacy of any
  exercise regimen involving walking is limited by
  symptomatic lower-limb claudication, some
  attention has been paid to the effect of
  upper-limb exercise on PVD progression and
  symptomatology.
• A well-designed, albeit small, study demonstrated
  statistically significant improvement in
  lower-extremity claudication symptoms in a group
  of patients randomly assigned to receive only
  upper-extremity training in comparison with a
  group of patients undergoing a more standard
  walking regimen.

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II. PHARMACOLOGIC THERAPY
32
A. ASPIRIN

• 1. See clopidogrel vs ASA study below (CAPRIE) by
  Dr. Acharya 4 studies reviewed
• 1 Lancet 1985. Drug-induced inhibition of
  platelet function delays progression of PAD.
• 240 patients with PAD underwent serial angios.
  Results revealed a difference in the formation of
  new occlusions and in the increase and decrease
  of stenosing vascular changes.
• Significantly more occlusions occurred in the
  placebo group .
• In a paired comparison, the difference between
  the combined therapy group (ASA dipyradimole)
  and placebo group was statistically significant
  (plt0.001) but there was no difference between ASA
  and the placebo group.

33
A. ASPIRIN

• 2 NEJM 1989. Final report on the aspirin
  component of the ongoing Physicians Health Study
  R, DB, PCT among 22, 071 health US male
  physicians aged 40-84 designed to determine
  whether low dose ASA decreased cardiovascular
  mortality.
• Among 22 071 subjects, during an average of 60
  months of treatment and follow-up, there were 56
  participants who underwent peripheral arterial
  surgery (20 ASA 30 placebo. The RR of surgery in
  the ASA group was 0.54 (95 CI 0.3-0.95 p0.03).
• These data suggest that chronic administration of
  low-dose ASA to apparently healthy men may reduce
  the need for peripheral arterial surgery.

34
A. ASPIRIN

• 3 BMJ 1994 Aniplatelet Trialsist Collaboration.
• Meta-analysis of 142 trilas including gt 73000
  high risk patients in various disease categories,
  shows clearly that anitplatelet drugs, namely
  ASA, reduce the incidence of a composite outcome
  of ischemic stroke, MI and vascular death, the
  relative odds reduction being 27.

35
A. ASPIRIN

• 4 BMJ 1994 Antiplatelet Trialists Collaboration
  Maintenace of vascular graft or arterial patency
  by antiplatelet therapy.
• Metaanalysis of 46 RCTs of antiplatelet therapy
  vs control and 14 RCT comparing one antiplatelet
  regimen with another. Overall antiplatelet
  therapy produced a highly significant (plt0.0001)
  reduction in vascular occlusion with similar
  proportional reductions in several different
  types of patients.
• The absolute reduction tended to be largest among
  patients at highest risk of occlusion.

36
B. TICLOPIDINE

• Recommendations
• Ticlopidine would not be my first choice agent
  (or intervention) in the treatment of
  intermittent claudication despite proven
  efficacy.
• Reasoning and comments A 1999 metaanalysis of
  antithrombotic drugs in the management of
  claudication revealed that, The best evidence
  on efficacy of antithrombotic agents in patients
  with intermittent claudication is available for
  Ticlopidine.
• Several level 1 (randomized, double blind)
  studies have shown decreased need for
  revascularization, improved walking distance, and
  decreased mortality with Ticlopidine use.

37
B. TICLOPIDINE

• Nonetheless, the overall side effect profile is
  poor, with frequent GI symptoms and rash.
• More importantly, neutropenia occurs in 2.3 of
  patients and TTP in 1 in 2000-4000 patients. This
  hematalogic risk and the need for extensive
  monitoring, in my opinion outweighs the benefit
  especially when other potentially equally
  effective agents with better side effect profiles
  are available.

38
B. TICLOPIDINE

• Cost
• 1. Ticlopidine 250mg PO bid 78.37 for 60 tabs
  (250mg)
• 2. Ticlid 250mg PO bid 120.58 for 60 tabs (250mg)

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C. CLOPIDOGREL

• Clopidogrel is a thienopyridine derivative.
• It presents the activation of platelets by ADP by
  irreversible inhibiting the binding of ADP to its
  platetet receptors, thereby preventing activation
  of the BpIIb-IIIa complex which is necessary to
  bind fibrinogen and form clots.

40
C. CLOPIDOGREL

• The trial compared the effects of daily aspirin
  vs daily clopidogrel in patients with known
  vascular disease, or ischemic stroke, or known
  MI. It was a randomized, blinded multicenter
  trial that sought to assess the benefit of the2
  agents in reducing the risk of ischemic stroke,
  MI, or vascular death.

41
C. CLOPIDOGREL

• INCLUSION CRITERIA
• Atherosclerotic PVD Intermittent claudication
  and ABI lt 0.85 or a history of IC with previous
  leg amputation, reconstructive surgery or
  angioplasty MI onset lt35 days before
  randomization Ischemic stroke focal neuro
  deficit likely to be atherothrombotic in origin.
  Onset between 1 week and 6 months before
  randomization

42
C. CLOPIDOGREL

• EXLCUSION CRITERIA
• age lt21, uncontrolled HTN, severe cerebral
  deficits, stroke induced by vascular
  intervention, severe comorbidity causing a life
  expectancy lt3 years, contraindication to the
  study drugs, severe renal or hepatic disease,
  bleeding disorder, history of thrombocytopenia,
  women of childbearing age not on reliable
  contraception, people in prior clopidogrel studies

43
C. CLOPIDOGREL

• TREATMENT 75 mg clopidogrel placebo or 325 mg
  ASA placebo
• PRIMARY OUTOMCE cluster endpoint of ischemic
  stroke, MI or vascular death.
• Intention to treat analysis
• MAIN RESULTS
• Clopidogrel group had 939 events corresponding to
  an average rate of 5.3/year
• ASA group had 1021 events corresponding to an
  average rate of 5.8/year
• RRR 8.7 in favor of clopidogrel. NNT
  approximately 200

44
C. CLOPIDOGREL

• ADVERSE EFFECTS
• higher incidence of hemorrhage in the ASA group
  cf clopidogrel
• higher incidence of severe rash and diarrhea in
  the clopidogrel group incidence of hematologic
  abnormalities roughly identical

45
D. PENTOXIFYLLINE

• Background info
• Pentoxifylline was approved by the FDA in 1984
  for the SYMPTOMATIC treatment of PVD.
• Putative mechanism Increases rbc flexibility
  decreases blood viscosity
• RHEOLOGY science dealing with the deformation
  and flow of matter
• Usual dose 400 mg TID with meals
• Cost not in ePocrates
• Common SE dyspepsia, nausea, vomiting

46
D. PENTOXIFYLLINE

• Two Studies Summarized Extremely Briefly
• Lindgarde, et al.
• RDBPCT, multicenter, n150, intention-to-treat
  analysis.
• Assessed stability of claudication sx x 6 wks,
  then randomized and followed x 6 months.
• Inclusion dx established clinically, doppler
  pressure assessments, confirmed by
  angiography.ICD between 50-200m, at least 40
  years old, h/o intermittent claudication for at
  least 6 mos.
• Exclusion ALL DIABETICS, peripheral neuropathy,
  cardiac failure or severe rhythm d/o, vascular
  reconstruction wi last 6 mos., addiction to
  analgesics, malignancy, other conditions
  affecting ability to walk, certain vessels fully
  occluded....

47
D. PENTOXIFYLLINE

• Outcomes studied ICD ACD. Baseline ICD was
  approx. 80m, baseline ACD was
• approx. 140m.
• Results ACD improved 50 vs 26 with trental
  (210 vs. 175m total) for all.
• Subgroup analysis
• If ABI lt 0.8 Trental group had significantly
  improved ACD ICD
• If PVD gt 1 yr
• If Both
• This means ACD improved 60 vs 20-30 with
  trental (220 vs. 175m)
• ICD improved 80 vs. 50 (140m vs. 120m)

48
D. PENTOXIFYLLINE

• RDBPCT, multicenter, n128, intention-to-treat
  analysis, followed x 6 months. 46 pts withdrew
• Assessed stability of claudication sx x 6 wks,
  then randomized.
• Inclusion dx established by diminished pulses OR
  by angio, supporting evidence by dependent rubor,
  cyanosis, decreased ABI after exercise h/o
  intermittent claudication for at least 6 mos.
• Exclusion Rest pain, ulcers, gangrene, severe
  peripheral neuropathy, unstable claudication,
  pregnant...
• Outcomes studied ICD ACD. Baseline ICD was
  approx. 110m, baseline ACD was approx. 175m.
• Results ACD improved 32 vs 20 with trental
  (230 vs. 210m)
• ICD improved 59 vs. 36 (175m vs. 150m)

49
E. CILOSTAZOL

• Trade name Pletal
• Indication Symptomatic relief of claudication in
  PVD
• Mechanism of action inhibits type III
  phosphodiesterase activity in platetes, leading
  to increase in intracellular cAMP, which inhibits
  thromboxane A2 production and platelet
  aggregation by inhibiting phospholipase and
  cyclooxygenase. Cilostazol also has a direct
  arterial vasodilatation effect. The role of
  vasodilatation in PVD is unclear, as it is
  thought that resistance bes are already maximally
  vasodilated in ischemic limbs.
• Dosage 100mg po BID (studied dose), or 50mg po
  bid.
• Cost 170 for a month supply of 100mg po bid.

50

• Money et al., 2000 (2) a multicenter,
  randomized, prospective, double-blind, placebo
  controlled trial involving 239 subjects,
  randomized to cilostazol 100 mg po bid vs.
  placebo for 16 weeks. Subjects were assessed at
  8, 10, 12 weeks after initiation of treatment,
  and results show a 47 increase in absolute
  claudication distance in the treatment group at
• week 16 (plt0.001.)
• There is also statistically significant
  improvement at 8 and 10 weeks.
• Unfortunately, I could only obtain the
  abstract from this paper and cannot give further
  details.

51

• Beebe et al., 1999 (3) a multicenter,
  randomized, prospective, double-blind, placebo
  controlled trial. 561 subjects were randomized to
  3 groups one treated with cilostazol 100mg po
  bid, one with cilostazol 50mg bid and one with
  placebo.
• This study shows significant benefit of
  cilostazol vs. placebo 59 increase in the
  pain-free walking
• distance of the 100mg bid group, 48 increase
  in the 50mg bid group, compared to 20 increase
  in the placebo group (plt0.001 in both treatment
  groups.)
• Treatment groups had significantly greater
  incidence of side effects than placebo (plt0.05).
• Most common side effects include headache,
  diarrhea, palpitation and dizziness.

52
E. CILOSTAZOL

• My recommendations Based on the studies above,
  and despite a few minor flaws in the design, I
  feel that there is a clear benefit of cilostazol
  in patients with PVD.
• The drawbacks are its cost and the time it takes
  to achieve a meaningful improvement.
• It should also be noted that there has been no
  studies to compare cilostazol to pentoxifylline
  or to surgical interventions.

53
E. CILOSTAZOL

• Therefore, my recommendations are as follow
• - for the severe, debilitating PVD patients
  surgery is the treatment of choice
• - for the mild to moderate cases, try
  modification of risk factors, such as smoking
  cessation, exercise, diet, blood pressure control
  etc.
• - if those modifications cannot be achieved,
  either by reasonable effort or common-sense
  prediction, especially if claudication is a
  limiting factor in exercise, a trial of
  pentoxifylline can be used to improve exercise
  capacity
• - if patient fails pentoxifylline, a trial of
  cilostazol is warranted.

54

• Thanks for your attention