The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease
BMJ 2008; 337 doi: https://doi.org/10.1136/bmj.a1840 (Published 16 October 2008) Cite this as: BMJ 2008;337:a1840
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May I thank Professor Belch for her reply, which explained the
restricted nature of the study.
But if the group was aware of the haemorheological changes associated
with diabetes, the aging process, and cerebrovascular and cardiovascular
disease, was it ethical to select death and the manifestation of vascular
disorders as endpoints in patients who were not being treated ?
It is one thing to plan a study of the effects of a treatment, but it
is a very different matter if the study population has recognised risk
factors which are not treated during the course of the study. Given the
clear cut nature of the findings, one is left to wonder if the
significance of the results justified the deaths of 195 participants whose
lives might have been prolonged with appropriate treatment.
Competing interests:
None declared
Competing interests: No competing interests
Vas, Vas and Boncz in their rapid response to the article by Belch et
al (1) draw attention to a neglected aspect of the therapeutic and
preventative use of aspirin. I agree with their suggestion that the
confusing results from the many randomised trials of aspirin might be
related to the chronopharmacology of aspirin or to the chronobiology of
the pathological and physiological processes on which aspirin has an
effect. ie on the influence of biological rhythmicity. The references they
provide all ask the same question but do not provide an answer. In an
editorial 20 years ago in the BMJ (2) I asked the same question.
Almost all randomised controlled trials of aspirin have not controlled for
the possibility that there may be a best time of day for administration.
Vas, Vas and Boncz extrapolate observed circadian variations in
pathological events, eg myocardial infarction and in associated
haematological events eg platelet aggregation and in the pharmocokinetics
of aspirin. They suggest aspirin in the evening may be most effective in
preventing cardio-vascular events. They do not draw attention to the
potentially important randomised trials published from Hermida's group
(3,4) when the best time was found to be in the evening when studied in
randomised controlled trials of aspirin administration in pregnant women
at risk of eclampsia(3) and in hypertensives (4).
There is an extensive literature that indicates that circadian and other
time-dependant variations exist for many therapeutic substances. Some
trials still lack in the protocol a time of administration and randomised
trials to explore if there is a "best" time are infrequent. Outcome trials
should be set up to study aspirin as proposed by Vas, Vas and Boncz with a
design similar to that used by Hermida and colleagues. In conditions in
which the objective is symptom relief eg pain, or a surrogate marker for
outcome, a randomised blinded crossover design, as used in our studies in
rheumatoid arthritis (5,6), may provide support for there being a "best"
time of administration. Retrospective studies of the time that aspirin was
taken by participants in earlier trials of aspirin would be of interest,
especially if analysed in relation to events and outcomes. In a study of
time of taking medication for immunosuppression we were alarmed at the
lack of standardisation of time of administration and the wide range of
times when patients took the medication (7).
Belch J et al. The prevention of progression of arterial disease and
diabetes (POPADAD) trial: factorial randomised placebo controlled trial of
aspirin and antioxidants in patients with diabetes and asymptomatic
peripheral arterial disease. BMJ. 2008; 337: 1840-1850.
Knapp,MS. Chronotherapeutics, a new science (unattributed
editorial). Br Med J, 1978; 1376:1.
Hermida RC, Ayala DE, Iglesias M. Administration Time - Dependent
influence of aspirin on blood pressure in pregnant women. Hypertension.
2003; 41:651.
Hermida RC et al. Administration Time-dependant effects of aspirin on
blood pressure in untreated hypertensive patients Hypertension. 2003;
41(6): 1259-1267.
Kowanko IC et al, Time of day of prednisolone administration in
rheumatoid arthritis. Ann. Rheum Dis. 1982; 41: 447-452.
Kowanko IC et al, Circadian variations in the signs and symptoms of
rheumatoid arthritis and the therepuetic effectiveness of fluriprofen at
different times of day. 1981. Brit.J Clin Pharmac.11: 477- 484.
Knapp,MS et al. Time of day of administration of immunosuppressive
after renal transplantation, a possible influence of graft survival. Br
Med J. 1988; 281:1382-1385.
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir,
Dr Simpson discusses plasma viscosity in our study population. Whilst
we agree these factors which affect flow are of interest, the POPADAD
study was a pragmatic one, asking a simple question ie is aspirin at a
dose of 100mgs effective in preventing CV Events in this population? It
did not address the several haemorreological abnormalities of this patient
group, nor did it try to evaluate further any additional antithrombotic or
haemorrheological effects of the study medication. Thus, as the study did
not attempt to measure these, we made no mention of viscosity as this
would not have been relevant. We are aware of this literature quoted by Dr
Simpson but it was outwith the scope of our trial’s question: Does aspirin
work in this group?
Further statin use was recorded in all subjects. Stain therapy was
mentioned but specific details of this were not given as the aspirin did
not produce any effect (the statin use was random amongst the treatment
arms).
Finally, Dr Simpson suggests that he was surprised that the Trial
Investigators did not mention blood viscosity and the effects of sardine
oil. We would stress again, that our trial did not concern such issues,
and we believe that the study was conducted in a proper fashion addressing
the question asked of it.
Jill Belch
Competing interests:
None declared
Competing interests: No competing interests
We were lucky enough to receive the 100mg dose as a gift from Bayer.
The dose selected was based on the ATT (ref) evidence that at 75-100mgs
there was benefit and least harm in seondary prevention. Further the 100mg
dose is used across Europe. Thus we asked for, and were given, the higher
of the 2 lower doses to study.
Jill Belch
Ref 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
Competing interests:
None declared
Competing interests: No competing interests
Although the POPADAD trial seems to have determined satisfactorily
that aspirin and antioxidants are of no use in the prevention of
cardiovascular and cerebrovascular events in diabetes, there are several
peculiar aspects of the study.
1. Is it appropriate to consider events relating to blood flow in
diabetes without reference to the literature which records that blood
viscosity is increased in diabetes ?
2. Even though smoking status was recognised, there was no indication that
the smoking-induced increase in blood viscosity would be additive to the
diabetes-related blood viscosity and could have significant consequences.
3. Because statins lower plasma viscosity and increase red cell
deformability, the extent of statin use should have been recorded.
4. No information was provided about the age, type of diabetes, smoking
status and statin use of those who died.
5. The report made no reference to the extensive literature which records
the association of increased blood viscosity and altered blood rheology
with cardiovascular and cerebrovascular disorders. As the blood viscosity
problem is potentially correctable, this raises the moral issue of the use
of death as an endpoint, when the medical condition being studied was not
being treated.
In 1966, Skovberg et al (1) reported increased blood viscosity in
diabetes and there have been many subsequent confirmations. Schmid-
Schonbein and Vogel (2) discussed the significance of red cell
deformability in diabetes.
Having shown by a spin-label technique that poorly deformable diabetic red
cells had viscous membranes, Kamada et al (3) reported that sardine oil
improved the fluidity of the lipid bilayer in the diabetic red cell
membrane. Ferrari et al (4) reported a four year-long study of the
effects of pentoxifylline in diabetes. The drug lowers blood viscosity
and improves red cell deformability, and in the four year study, the drug
prevented the development of the complications of the diabetic state.
In a paper titled, "Hemorheological changes during human aging,"
Ajmani and Rifkind (5) cited 81 references and noted that the aging
process was associated with an increase in fibrinogen levels,blood
viscosity and red cell rigidity. They stated, "Many studies indicate that
hemorheological parameters change in a number of diseases prevalent during
aging including hypertension, stroke and diabetes." It is relevant that
in 1930 it was reported first that there is a direct association between
blood viscosity and blood pressure. So it is very likely that the
elevated systolic blood pressures recorded in the POPADAD trial reflected
a general increase in blood viscosity.
It seems strange that in such a large group of experts in various
fields of medicine, there was no recognition by the authors of the
published information concerning the clinical relevance of blood viscosity
changes in diabetes or in the aging process. The beneficial effects of
sardine oil reported by Kamada et al (3) had been foreshadowed by a Dutch
study which found that a daily intake of 34 grams of fatty fish resulted
in a 50% decrease in heart disease in a 20-year follow-up.
Therefore, as it had been shown that both fish oil and pentoxifylline
can lower blood viscosity, is it morally defensible to use death as an end
point without treating the increased blood viscosity associated with
diabetes and aging ?
References.
1. Skovberg F, Nielsen AAV, Schlichtkrull J, et al. Blood viscosity in
diabetic patients. Lancet 1966;i:127-31.
2. Schmid-Schonbein TH, Vogel E. Red cell aggregation and red cell
deformability in diabetes. Diabetes 1976;25 (Suppl 2):897-902.
3. Kamada T, Yamashita T, Baba Y, et al. Dietary sardine oil increases
erythrocyte fluidity in diabetic patients. Diabetes 1986; 35: 604-11.
4. Ferrari E, Fioravanti M, Patti AL, et al. Effect of long term
treatment (4yrs) with pentoxifylline on haemorheological changes and
vascular complications in diabetic patients. Pharmatherapeutica 1987; 5:
26-39.
5. Ajmani RS, Rifkind JM. Hemorheological changes during human aging.
Gerontology 1998; 44: 111-20.
Competing interests:
None declared
Competing interests: No competing interests
Dear Authors,
We were wondering why you used a 100mg dose of aspirin instead of the
widely accepted daily dose of 75mg? You don't seem to mention it in the
article.
The Hunters Bar Journal Club
Competing interests:
None declared
Competing interests: No competing interests
We read the article by Belch et al. (1) with great interest, in which
they investigated whether aspirin and antioxidants (combined or alone) can
reduce heart attacks and death in patients with diabetes and asymptomatic
peripheral arterial disease.
The incidence of myocardial infarction assessed by onset of clinical
symptoms exhibits a marked circadian variation with a peak period during
the morning. Acute myocardial infarction usually occurs unexpectedly or
more frequently in the early morning hours, between 5-12 a.m. In this
early morning period there is a higher aggregability of thrombocytes.
Patients usually take aspirin for prevention in the morning as the
treatment regimen is one tablet per day to be swallowed without chewing at
least 30 min before breakfast. The highest plasma level of the drug occurs
after the morning peak-incidence of the thromboembolic event, suggesting
lower prophylactic effect of Aspirin. Furthermore, this method of daily
Aspirin administration has its highest protective effect during the day,
when normal physical activity exerts a protective action, and has its
lowest protective value against cardiovascular events during the night and
early morning, when the lack of physical activity further augment the
cascade of haemorheological events favoring platelet aggregation and
subsequent ischemia.
In contrast, highest plasma level of Aspirin taken late evening would be
reached prior to the peak-incidence of thromboembolic disorders. We are
confident that Aspirin would better fit in the circadian scheme of the
occurrence of cardiovascular events and would result a significantly more
effective prevention with this time shift in the administration.
International, randomized multicenter studies are proposed to set up to
prove the viability of this concept.
Balint Vas1, Gabor Vas1, Imre Boncz2
1Institute of Nursing and Clinical Sciences, Faculty of Health
Sciences, University of Pécs, Hungary
2Department of Health Economics, Policy & Management, Faculty of
Health Sciences, University of Pécs, Hungary
Conflicts of Interest:
The authors have no conflicts of interest to declare
References:
1.Belch J, MacCuish A, Campbell I, and et al. The
prevention of progression of arterial disease and diabetes (POPADAD)
trial: factorial randomised placebo controlled trial of aspirin and
antioxidants in patients with diabetes and asymptomatic peripheral
arterial disease. BMJ. 2008;337:1840-1850.
2. Kriszbacher I, Koppan M,
Bodis J. Aspirin for stroke prevention taken in the evening? Stroke.
2004;35:2760-1.
3. Kriszbacher I, Ajtay Z, Koppan M, Bodis J. Can the
Time of Taking Aspirin Influence the Frequency of Cardiovascular Events?
Am J Cardiol. 2005;96:608-10.
4.Kriszbacher I, Koppan M, Bodis J. Would
it be more beneficial to take aspirin in the evening for prevention of
cardiovascular diseases? J Vasc Surg. 2005;41:375.
5. Kriszbacher I,
Koppan M, Bodis J. Inflammation, atherosclerosis, and coronary artery
disease. N Engl J Med. 2005;28;353:429-30.
Competing interests:
None declared
Competing interests: No competing interests
Belch et al (1) make a valuable contribution to the documentation
that there is little if any benefit from using long-term aspirin therapy
in patients who have or are at risk of atherosclerotic cardiovascular
disease (2). Few long-term trials of aspirin have shown a reduction in
mortality or major morbidity and those that did generally used doses of
about 1,000mg/day (3), including the sub-group analysis used to support of
using anti-platelet agents in diabetes for secondary prevention (3).
However, it seems that editors of journals persist in allowing papers on
aspirin to be published with conclusions designed to mislead health
professionals and the public. The New England Journal of Medicine must
take first place in this rogue’s gallery with publication of the US
Physician’s study (4) (stopped for futility but published as a positive
trial after retrospective rearrangement of the primary endpoint), followed
by the Lancet with the HOT (Hypertension Optimal Treatment) study (5),
that allowed the authors to make a recommendation in favour of aspirin
despite the study being neutral on its primary endpoint and
retrospectively redefining the criteria for myocardial infarction and the
PEP (Pulmonary Embolism Prevention) study (6) that showed a significant
excess of fatal and non-fatal myocardial infarction when aspirin was used
for prophylaxis of deep venous thrombosis after hip fracture but failed to
highlight this worrying finding in the papers conclusions. The short-
comings of the aspirin meta-analysis have not been well publicised,
although the BMJ has to be congratulated in not stifling the debate
totally (2). However, Belch et al’s conclusion that ‘Aspirin should,
however, still be given for secondary prevention of cardiovascular disease
in people with diabetes mellitus, when the evidence base is convincing,
and the results of this study must not detract from this important
standard of care.’ should have specified the duration of aspirin
prophylaxis after a vascular event for which there is evidence of benefit;
about 6-12 weeks. There is no evidence of a longer term benefit with
aspirin and some concern that there may be harm. We should assess aspirin
in the same way as any other therapeutic intervention. There is no trial
in any setting showing that contemporary doses of aspirin, used long-term,
reduce mortality. Is it not about time that an adequately powered study
comparing short versus long-term aspirin 75mg/day after a vascular event
was studied?
1. Belch J. J. F., MacCuish A., and et al. The prevention of
progression of arterial disease and diabetes (POPADAD) trial: factorial
randomised placebo controlled trial of aspirin and antioxidants in
patients with diabetes and asymptomatic peripheral arterial disease. BMJ
337:1840-1850, 2008.
2. Cleland J.G.. For Debate: Preventing atherosclerotic events with
aspirin. BMJ 324 (7329):103-105, 2002.
3. Sivenius J, Laakso M, Riekkinen P, Smets P, Lowenthal A. European
stroke prevention study: effectiveness of antiplatelet therapy in diabetic
patients in secondary prevention of stroke. Stroke 23:851-854, 1992.
4. Steering Committee of the Physicians' Health Study Research Group.
Final Report on the Aspirin Component of the Ongoing Physicians' Health
Study. N Engl J Med 321 (3):129-135, 1989.
5. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S
et al. Effect of intensive blood pressure lowering and low-dose aspirin in
patients with hypertension: principal results of the hypertension optimal
treatment (HOT) randomised trial. Lancet 351:1755-1762, 1998.
6. Pulmonary Embolism Prevention (PEP) Trial Collaborative Group.
Prevention of pulmonary embolism and deep vein thrombosis with low dose
aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 355 (9212):1295
-1302, 2000.
Competing interests:
None declared
Competing interests: No competing interests
Dear Editor
26 October 2008
The excellent study by Belch et al (BMJ 2008;337:a1840) suggests that
aspirin is not universally indicated for primary prevention of vascular
events in diabetic patients. Biologically, there is no difference in the
action of antiplatelet drugs for primary or secondary prevention – the
major difference is in the event rate and therefore the power of study
needed to show benefit. Arguably, the patients in the study had
atherosclerotic disease and were therefore secondary prevention patients.
With baseline risk factors (smoking, blood pressure, cholesterol) as
presented, many patients in this study would have been above the 1.5% per
year risk threshold where benefit of aspirin outweighs risk. 1 The event
rate documented was considerably short of that predicted, and this may
have been due to increased use of statins and other cardioprotective drugs
during the study – no data are given for this. Benefits of aspirin in high
-risk patients are significant, 2 but less than those projected for
statins. 3
Increased risk of haemorrhagic events is an inevitable consequence of
deriving benefit from the antiplatelet effects of aspirin. There was no
increased risk of dyspeptic symptoms or gastrointestinal haemorrhage with
aspirin in Belch’s study in spite of the fact that the numbers and length
of follow-up were sufficient to expect adverse effects to be detected. 4
Compliance and aspirin resistance are two factors not addressed in the
study, but which could affect response. At least a quarter of patients
treated with aspirin may be resistant, and this translates into decreased
protection from cardiovascular events. 5 Because of increased platelet
reactivity, aspirin resistance appears to be even more common in diabetic
patients and may be overcome by increasing the dose or prescribing an
additional antiplatelet drug. 6 Presumably, aspirin-resistant patients,
while not benefiting from treatment, are also not susceptible to
haemorrhagic side effects.
Diabetic patients are at high risk of macrovascular complications,
but trials must take account of the interaction between drugs and changing
clinical practice. Although aspirin is cheap and safe, it is not always
effective. The time may have come to consider monitoring platelet function
in patients with aspirin – as other forms of anticoagulation are
monitored. Aggregrometry is simple and cheap, but requires
standardisation. Current evidence does not allow us to preclude an effect
of aspirin in primary prevention of vascular events in diabetes, but
neither does it support universal prescription of aspirin despite the very
high risk experienced by diabetic patients.
Conflicts of Interest:
The authors have no conflicts of interest to declare
References
1. Sanmuganathan PS, Ghahramani P, Jackson PR, Wallis EJ, Ramsay LE.
Aspirin for primary prevention of coronary heart disease: safety and
absolute benefit related to coronary risk derived from meta-analysis of
randomised trials. Heart 2001;85(3):265-71.
2. Antithrombotic Trialists C. Collaborative meta-analysis of randomised
trials of antiplatelet therapy for prevention of death, myocardial
infarction, and stroke in high risk patients. BMJ 2002;324(7329):71-86.
3. Cholesterol Treatment Trialists C, Kearney PM, Blackwell L, Collins R,
Keech A, Simes J, et al. Efficacy of cholesterol-lowering therapy in
18,686 people with diabetes in 14 randomised trials of statins: a meta-
analysis. Lancet 2008;371(9607):117-25.
4. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term
use of aspirin: meta-analysis. BMJ 2000;321(7270):1183-7.
5. Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin
"resistance" and risk of cardiovascular morbidity: systematic review and
meta-analysis. BMJ 2008;336(7637):195-8.
6. Duzenli MA, Ozdemir K, Aygul N, Soylu A, Tokac M. Comparison of
increased aspirin dose versus combined aspirin plus clopidogrel therapy in
patients with diabetes mellitus and coronary heart disease and impaired
antiplatelet response to low-dose aspirin. American Journal of
Cardiology 2008;102(4):396-400.
Competing interests:
None declared
Competing interests: No competing interests
Antiplatelet drugs for the prevention of cardiovascular events in patients with peripheral arterial disease – the confusion reaches new levels with the POPADAD trial
Peripheral arterial disease (PAD), which includes claudication and
asymptomatic PAD defined by a reduced ankle-brachial index (ABI <_0.9 is="is" highly="highly" prevalent="prevalent" among="among" the="the" elderly="elderly" with="with" _1="_1" in="in" _5="_5" people="people" over="over" age="age" of="of" _59="_59" years="years" suffering="suffering" from="from" pad="pad" population="population" surveys1.="surveys1." importantly="importantly" patients="patients" have="have" a="a" high="high" risk="risk" cardiovascular="cardiovascular" events2.="events2." both="both" aha="aha" acc3="acc3" and="and" tasc="tasc" ii4="ii4" guidelines="guidelines" recommend="recommend" prescription="prescription" statins="statins" for="for" lipid-="lipid-" lowering="lowering" aspirin="aspirin" as="as" antiplatelet="antiplatelet" agent="agent" prevention="prevention" events="events" symptomatic="symptomatic" asymptomatic="asymptomatic" lower="lower" extremity="extremity" pad.="pad." good="good" quality="quality" data="data" exist="exist" to="to" support="support" use="use" including="including" subgroup="subgroup" analysis="analysis" enrolled="enrolled" heart="heart" protection="protection" study5="study5" well="well" several="several" smaller="smaller" studies6-9.="studies6-9." these="these" demonstrate="demonstrate" that="that" statin="statin" beneficial="beneficial" but="but" may="may" also="also" lead="lead" an="an" improvement="improvement" symptoms78.="symptoms78." contrast="contrast" evidence-base="evidence-base" becoming="becoming" increasingly="increasingly" uncertain.="uncertain." p="p"/>Most guidelines propose aspirin as first line therapy for risk prevention
in PAD and base this recommendation on scientific support from the
Antithrombotic Trialists’ Collaboration (ATC) meta-analysis10. Among the
9214 patients with PAD investigated, there was a 23% reduction in serious
vascular events in those receiving antiplatelet therapy. However, on
closer inspection of these data, it appears that the benefits observed in
the PAD subgroup were largely driven by non-aspirin antiplatelet drugs11.
Some additional, but also weak, support came from the CLIPS trial12. This
study focused on aspirin use in PAD solely and reported a 64% reduction in
vascular events. Unfortunately the trial was terminated early and the
enrolled population consisted of only 366 patients in total, which
consequently resulted in the 95% confidence interval for the odds ratio
passing a value of 1.0.
The POPADAD trial13, which was published in the October 17th issue of BMJ,
was anticipated to provide the final support for aspirin use in PAD, but
the results were disappointing. There was no statistical difference
between the aspirin and placebo arms for both the two hierarchical primary
endpoints, as well as the secondary endpoints. This trial enrolled
asymptomatic PAD patients with diabetes – an asymptomatic PAD population
of particularly high risk that should have provided a reasonable target
for primary prevention. When scrutinizing the data, the only indication of
a positive aspirin effect appears to be a tendency toward a small
reduction in cardiovascular events in the subgroup with the lowest ABI at
baseline. However, on the negative side there was also a similar tendency
toward adverse events such as gastrointestinal problems or dyspepsia in
the aspirin group compared with placebo.
Consequently, while statin use is justifiable for the prevention of
cardiovascular events in patients with PAD, the basis for using aspirin
has become further weakened by the additional findings of the POPADAD
trial. In fact, it is unclear if the use of aspirin benefits our patients
at all, especially when considering its side effects. Hesitancy caused by
the more expensive alternative medications should not make us avoid the
question of whether aspirin should be used in the management of PAD, and
we should definitely re-examine the current guideline recommendations.
Therefore, at this time, without stronger supporting data, would it be
better to not recommend any antiplatelet therapy to patients with PAD?
Eric Wahlberg,
Professor of Vascular Surgery
The Heart Center,
Linköping University Hospital, Sweden
eric.wahlberg@lio.se
References
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B, Persson E, et al. A population-based study of peripheral arterial
disease prevalence with special focus on critical limb ischemia and sex
differences. J Vasc Surg. 2007 Jun;45(6):1185-91.
2. Steg PG, Bhatt DL, Wilson PW, D'Agostino R, Sr., Ohman EM, Rother
J, et al. One-year cardiovascular event rates in outpatients with
atherothrombosis. JAMA 2007;297:1197-206.
3. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin
JL, et al. ACC/AHA 2005 Practice Guidelines for the management of patients
with peripheral arterial disease (lower extremity, renal, mesenteric, and
abdominal aortic): a collaborative report from the American Association
for Vascular Surgery/Society for Vascular Surgery, Society for
Cardiovascular Angiography and Interventions, Society for Vascular
Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA
Task Force on Practice Guidelines (Writing Committee to Develop Guidelines
for the Management of Patients With Peripheral Arterial Disease): endorsed
by the American Association of Cardiovascular and Pulmonary
Rehabilitation; National Heart, Lung, and Blood Institute; Society for
Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular
Disease Foundation. Circulation 2006;113:e463-e654.
4. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes
FG. Inter-Society Consensus for the Management of Peripheral Arterial
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5. Heart Protection Study Collaborative Group. MRC/BHF Heart
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risk individuals: a randomised placebo-controlled trial. The Lancet
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6. Meade T, Zuhrie R, Cook C, Cooper J. Bezafibrate in men with
lower extremity arterial disease: randomised controlled trial. BMJ
2002;325:1139.
7. Mondillo S, Ballo P, Barbati R, Guerrini F, Ammaturo T, Agricola
E, et al. Effects of simvastatin on walking performance and symptoms of
intermittent claudication in hypercholesterolemic patients with peripheral
vascular disease. Am J Med 2003;114:359-64.
8. Mohler ER, III, Hiatt WR, Creager MA. Cholesterol reduction with
atorvastatin improves walking distance in patients with peripheral
arterial disease. Circulation 2003;108:1481-6.
9. Blankenhorn DH, Azen SP, Crawford DW, Nessim SA, Sanmarco ME,
Selzer RH, et al. Effects of colestipol-niacin therapy on human femoral
atherosclerosis. Circulation 1991;83:438-47.
10. 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.
11. Hiatt WR,.Krantz MJ. The efficacy of aspirin in peripheral
arterial disease: an unresolved question. J Mal Vasc 2007;32:71-2.
12. Catalano M, Born G, Peto R. Prevention of serious vascular
events by aspirin amongst patients with peripheral arterial disease:
randomized, double-blind trial. J Intern Med 2007;261:276-84.
13. Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R,
et al. The prevention of progression of arterial disease and diabetes
(POPADAD) trial: factorial randomised placebo controlled trial of aspirin
and antioxidants in patients with diabetes and asymptomatic peripheral
arterial disease. BMJ 2008;337:a1840.
Competing interests:
Independent research grants from Shering AG, Sanofi-Aventis, and Pfizer, and fees for lecturing from Schering Plough, Merck and Otsuka
Competing interests: No competing interests