Title: EVIDENCEBASED REVIEW: TREATMENT OF THE PATIENT WITH PERIPHERAL ARTERIAL DISEASE PHARMCOLOGIC AND NON
1EVIDENCE-BASED REVIEWTREATMENT OF THE PATIENT
WITH PERIPHERAL ARTERIAL DISEASEPHARMCOLOGIC AND
NONPHARMACOLOGIC MEASURES
2EVIDENCE 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
7A. 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.
8A. 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.
9A. 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.
10A. 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.
11A. 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
-
12B. 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.
13B. 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.
14B. 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).
15B. 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.
16B. 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.).
17B. 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).
18B. 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).
19B. 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. - .
20B. 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.
21C. 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).
22C. 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).
23C. 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.
24D. 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.
25D. 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.
26D. 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.
27E. 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
28E. 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.
29E. 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.
31II. PHARMACOLOGIC THERAPY
32A. 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.
33A. 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.
34A. 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.
35A. 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.
36B. 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.
37B. 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.
38B. TICLOPIDINE
- Cost
- 1. Ticlopidine 250mg PO bid 78.37 for 60 tabs
(250mg) - 2. Ticlid 250mg PO bid 120.58 for 60 tabs (250mg)
39C. 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.
40C. 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.
41C. 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
42C. 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
43C. 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
44C. 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
45D. 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
46D. 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....
47D. 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)
48D. 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)
49E. 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.
52E. 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.
53E. 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