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Rapid Responses: Rapid Responses published:
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Aspirin ineffective in diabetic patients with PAD: it is not a novelty!
- Massimo Milani MD (18 October 2008)
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Will you trust guidelines again ?
- Paul Heath (19 October 2008)
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Re: Aspirin ineffective in diabetic patients with PAD: it is not a novelty!
- Jill JF Belch (20 October 2008)
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The POPADAD study
- Peter Elwood (21 October 2008)
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POPADAD Trial only shows that Aspirin can be given in too low a dose
- Michael A JAMES (22 October 2008)
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Re: The POPADAD study
- Jill JF Belch (24 October 2008)
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Aspirin for Priamary Prevention in Diabetes
- Richard L. Kennedy, Usman H. Malabu (26 October 2008)
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Practising evidence-based medicine: people with or at risk of atherosclerotic disease should not receive long-term aspirin.
- John GF Cleland (28 October 2008)
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Time of Taking Aspirin Can Have an Effect on the Frequency of Occurrence of Cardiovascular Events
- Balint Vas, Gabor Vas, Imre Boncz (5 November 2008)
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Why is the dose of aspirin 100mg?
- Margaret Warlow (6 November 2008)
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Diabetes, blood viscosity and the POPADAD trial
- Leslie O Simpson (8 November 2008)
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Re: Why is the dose of aspirin 100mg?
- Jill J Belch (11 November 2008)
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Re: Diabetes, blood viscosity and the POPADAD trial
- Jill J Belch (11 November 2008)
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Time of taking aspirin, blood pressure and cardiovascular events
- Martin S Knapp (13 November 2008)
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Re: Re: Diabetes, blood viscosity and the POPADAD trial
- Les O. Simpson (13 November 2008)
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Antiplatelet drugs for the prevention of cardiovascular events in patients with peripheral arterial disease – the confusion reaches new levels with the POPADAD trial
- Eric Wahlberg (24 November 2008)
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Massimo Milani MD, Solo practice Milan
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Dear Editor The efficacy of antiplatelet drugs (in particular, aspirin)in patients with type 2 diabetes, who are at high risk of vascular mortality and morbidity, is still a matter of debate.Although aspirin is generally considered effective in diabetic subjects, many of the results on which this belief is based originate from subgroup data of trials or meta- analyses including both diabetic and (mainly) non-diabetic patients, rather than from trials carried out in diabetics alone. The article of dr Belch did not give(seeing the reference list)any mention regarding that fact that several data, since late '90, were actually available in the literature regarding the lack of efficacy of aspirin in diabetic partients with PAD in reducing major cardiovascular events (Cimminiello and Milani, Diabetologia 1996; 39:1402). Diabetic patients have in general increased serum and urinary level of thromboxane metabolites (Davì, Circulation 1997). This increase is only partially corrected by aspirin administration. It is known, since 1986, that aspirin was ineffective in reducing major vascular events in diabetic patients (Colwell 1986). On the contrary there are in the literature several evidence-based available data regarding the rationale and the efficacy of antithromboxane agent such as picotamide (Gresele 2004 and Milani 1996)in diabetic patients with PAD. A randomised double blind multicenter trial conducted with picotamide in comparison with aspirin carried out in 1209 patients (Neri Serneri, Eur Hearth J 2004)has clearly shown that Picotamide is significantly more effective than aspirin in reducing overall mortality in type 2 diabetic patients with associated peripheral disease. It is strange to see that no mention of these relevant scientific works has been added in the discussion section of Belch article regarding this relevant clinical issue. Dr Massimo Milani MD Milan Italy Competing interests: None declared |
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Paul Heath, General Practice Grimsby
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As part of my GP training in the 1980s we were taught to critically appraise individual research papers and come to a conclusion ourselves about the validity of the results and to decide if they were applicable to the particular patients we might see . This was not an easy undertaking ,not least because (as the title of "Statistics made easy " suggests )it is a difficult subject for the non specialist. Also taken to its logical conclusion it may have resulted in individual doctors taking individual decisions about individual patients and this came to be seen as "undesirable" and producing "inequality". Evidence Based Medicine arrived . Then followed the rise of "The Guidelines". The idea is of course commendable and is aimed to produce advice on the most up to date effective interventions for patients. For the individual doctor it means putting your trust in the guideline and of course also relieves you of the impossible burden of reading and appraising individual research papers yourself . However I now feel my trust in guidelines has now been undermined somewhat by this paper and the accompanying editorial. It appears that the use of aspirin in "high risk patients" but without established cardiovascular disease is probably of no value . This is contrary to the advice of several previous guidelines but it now appears that these recommendations were not based on reliable sound evidence but on the murky world of subgroup analysis etc . The problem is this is not always made clear in the guidelines . Take for example the recent updated NICE guidance on type 2 diabetes . The brief summary guideline (which I suspect is all that most busy non specialists will read ) states that aspirin should be considered for all patients over 50ys and high risk patients below the age of 50ys . However if you look at the full guideline details it admits this is an arbitary choice of age with no evidence base . Also the detail regarding trials contains a bewildering array of references to a number of complicated trials concerning variations in antithromboitc treatment in differing populations and then makes a recommendation . The problem is I then accept the recommendation at face value and try to put it into practice as rapidly as possible. With our technology and systems we are able to rapidly identify and recall patients in these groups and make interventions on a large scale in a short time frame . I then find out four months later the recommendations were based on unsound evidence and in fact the editorial states that there has been "consistently negative evidence from trials " regarding aspirin usage in primary prevention . The detailed NICE guidance on type 2 diabetes (May 2008) stated "Antiplatlet therapy now has an established role in the managment of patients at high risk of a cardiovascular event " As a result I feel a little confused (as are my patients now ) and less likely to trust guidelines (as my patients may be of me next time I suggest an intervention ) Paul Heath (General Practitioner ) Competing interests: None declared |
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Jill JF Belch, Prof Vascular Medicine Dundee, DD1 9SY
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Dear Editor, Dr Milani comments about the use of aspirin in patients with Diabetes and PAD. However our study was in patients with Diabetes and a low ABPI ie in essence primary prevention as these patients had not yet had a clinical vascular event. Thus there was no direct comparison made in the paper with the papers cited by Dr Milani. In contrast Dr Milani's papers relate to the use of aspirin in secondary prevention, and whilst importantly calling into question the use of aspirin in a further population of patients with diabetes, this is different from our own work, Jill Belch, University of Dundee. Competing interests: None declared |
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Peter Elwood, Professor Cardiff University
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20th October 2008 To the Editor, BMJ From Professor Peter Elwood Dear Sir, The POPADAD study The POPADAD trial (BMJ 2008:337:a1840) presents important evidence on the use of aspirin by subjects who have diabetes together with early peripheral arterial disease. The results show no benefit from daily prophylactic aspirin (hazard ratio 0.98; P = 0.87). It is most important however that no firm conclusions are drawn from a single trial, but that this result is incorporated in a meta-analysis of all available evidence from relevant trials. The absence of evidence of benefit in POPADAD is not however surprising, the trial having been seriously underpowered. The annual cardiovascular event rate observed was only 2.9%, while the event rate expected is stated to have been 8%. In any case, the 95% confidence limits for the effect of aspirin (CI, 0.76-1.26) include a possible 24% reduction in vascular events, and this is consistent with the effect of aspirin in other trials of primary prevention. The result is also statistically homogeneous with results of the CLIPS trial, based on subjects with peripheral arterial disease, 76% of whom also had diabetes, in which low- dose aspirin prophylaxis was associated with a significant reduction in vascular events (P = 0.01). A further uncertainty concerns the effect of statins. The authors suggest that these drugs may have led to the low vascular event rate during the trial, giving little opportunity for the detection of additional benefit from the aspirin. This important hypothesis requires testing, and it is unfortunate that the authors give no data on a possible interaction between aspirin and statins in their data. The life-threatening consequences of diabetes – mainly heart disease and stroke – are at least twice as frequent in people with diabetes than in those without diabetes, and guidelines issued by expert bodies in the United Kingdom2,3 and in the United States4,5 therefore recommend low-dose aspirin prophylaxis in subjects with diabetes. Against this background, and in view of the evidence of benefit in other trials it would be most unfortunate if the results of POPADAD were to lead diabetic subjects discontinuing aspirin prophylaxis. At the very least, the results of yet another large trial in diabetic subjects, ASCEND, should be awaited. Hopefully, in due course appropriate overviews will ensure that recommendations about aspirin prophylaxis in diabetic patients will be consistent6. In the meantime older diabetic patients should keep taking daily low-dose aspirin. Yours sincerely, Peter Elwood, DSc, MD, FRCP, FFPHM, DUniv. Hon DSc Honorary Professor School of Medicine, Cardiff University. References 1. Critical Leg Ischaemia Prevention Study (CLIPS) Group. Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double-blind trial. J Int Med. 2007;261:276- 284. 2. British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, and British Diabetic Association. Joint recommendations on prevention of coronary heart disease in clinical practice: summary. BMJ. 2000;320:705-708. 3. 2002/055 NICE issues national guidelines for the management of blood pressure and lipids in people with type 2 diabetes. National Institute for Clinical Excellence. http://www.nice.org.uk/page.aspx?o=38701. Accessed January 9, 2008. 4. American Diabetes Association. Aspirin therapy in diabetes (position statement). Diabetes Care. 2004;27(suppl 1):S72-S73. 5. International Diabetes Federation Clinical Guidelines Task Force. Global guideline for type 2 diabetes. Brussels, Belgium; International Diabetes Foundation; 2005. 6. Nicolucci A, Berardis GD, Sacco M, Tognoni G. AHA / ADA vs ESC / EASD recommendations on aspirin as a primary prevention strategy in people with diabetes : how the same data generate divergent conclusions. European Heart Journal 2007;28(16):1925-1927. Competing interests: None declared |
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Michael A JAMES, consultant cardiologist Taunton & Somerset Hospital TA1 5DA
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Why have the authors concluded that the trial does not support the use of Aspirin? The trial has only demonstrated that Aspirin in the dose tested was ineffective. The correct dose of Aspirin has never been clear and has never been subjected to a proper dose ranging trial. As a consequence guidelines have always stated that "low dose" aspirin should be used in a dose of 75-150mg daily. However, 300mg is recommended in an acute myocardial infarction and Cardiac Surgeons have always recommended 300mg for post CABG prophylaxis. It would seem that the correct dose of Aspirin probably lies somewhere between 75-300mg daily. However as we have increasingly recognised the phenomenon of Aspirin tolerance this provides a rationale for why varaible results have been obtained with the lowest doses of Aspirin, trials with larger doses of Aspirin are less likely to be interefered with by Aspirin tolerance. Accordingly trials using 150mg or larger doses of Aspirin have mostly produced positive results, but many often quite large trials of 50 - 100mg daily have failed to show benefit. Such as the American Healthy Womens study of 39,876 subjects or the HOT trial in 18,790 subjects. Are we to conclude that aspirin does not have any effect after all? Clearly there is too much evidence of benefit to accept that conclusion, but most of that evidence comes from trials which have used at least 150mg of Aspirin. The HOT trial conducted a meta-analysis showing evidence of benefit in trials using doses from 75 - 325 mg daily but clearly none for doses < 75 or > 500mg. Unfortunately there was a lot of dosage overlap in the dose range from 75-150 mg. Clearly there is a need for a proper dose comparison study, but a meta-analysis of post CABG prophylaxis trials in the BMJ in 2003 found that doses of 325mg daily were almost twice as effective as doses of 100- 150mg. The dose of aspirin that is recommended is under constant pressure from groups who complain about the excess risk of bleeding complications. However, as we are repeatedly reminded - "there is no such thing as a free lunch". An effective dose of any anti-coagulant must increase risk of bleeding, doses that do not increase risk of bleeding are probably simply in-effective for anything. Yours sincerely M A James Competing interests: None declared |
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Jill JF Belch, Prof Vascular Medicine Dundee DD1 9SY
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To the Editor, BMJ From Prof JJF Belch Dear Sir, Prof Peter Elwood has much experience in the study of aspirin and CV disease, and we support his suggestion to include this study in a meta analysis of all aspirin primary prevention studies. We believe this may already be in draft form, but such an analysis has been already been completed albeit without inclusion of POPADAD, and was negative1. Further we agree that the event rate in the study was low, and is a testament to the efforts of the consultants involved to modify lipids and blood pressure optimally. We plan a sub-group analysis looking at the interactions with statins and this was pre-defined in our protocol. Nevertheless there is perhaps a good reason for aspirin being ineffective in primary prevention in this population. Once one has an atherothrombotic event eg MI, clot is formed and ruptured plaque is a huge stimulus for platelet aggregation. However in primary prevention, where there has been no event, thrombus is not routinely formed. In primary prevention the prophylaxes shown to be effective are statins2 and antihypertensives3. These latter 2 therapies target vessel wall rather than thrombus, and thus might be expected to be more efficacious than an antiplatelet agent. In contrast in secondary prevention, such as in CLIPS, as referenced by Prof Elwood, aspirin does have a role in preventing secondary events. This remains speculative, however, but there are a number of other trials in which aspirin, as primary prevention, has been ineffective1,4. As Prof Elwood suggests the results from ASCEND are eagerly awaited. Jill Belch, Professor of Vascular Medicine. 1. Fleming T, Nissen SE, Borer JS, Armstrong PW. Report from the 100th cardiovascular and renal drugs advisory committee meeting: US Food and Drug Administration: December 8-9, 2003 Gaithersburg, MD. Circulation 2004;109:e9004-5 2. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301- 1307 3. Dahlöf B, Sever PS, Poulter NR, for the ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366:895-906. 4. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293-304. Competing interests: None declared |
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Richard L. Kennedy, Professor of Medicine James Cook University, Douglas, Queensland QLD 4814, Australia, Usman H. Malabu
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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 |
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John GF Cleland, Professor of Cardiology Castle Hill Hospital, University of Hull, Kinsgton-upo-Hull HU16 5JQ
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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 |
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Balint Vas, medical doctor Institute of Nursing and Clinical Sciences, Faculty of Health Sciences, University of Pécs, H-7621, Gabor Vas, Imre Boncz
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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
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 |
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Margaret Warlow, FY2 Doctor Royal Hallamshire Hospital, Sheffield
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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 |
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Leslie O Simpson, retired experimental pathologist Dunedin, New Zealand 9077
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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 |
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Jill J Belch, Prof Vascular Medicine Dundee DD1 9SY
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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 |
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Jill J Belch, Prof Vascular Medicine Dundee DD1 9SY
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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 |
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Martin S Knapp, Nephrologist, Mildura Nephrology, 12 Townsend St., 3079, Australia
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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 |
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Les O. Simpson, retired experimental pathologist Dunedin, New Zealand 9077
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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 |
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Eric Wahlberg, Professor of Vascular Surgery The Heart Center, Linköping University Hospital, 585 99 Sweden
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Peripheral arterial disease (PAD), which includes claudication and asymptomatic PAD defined by a reduced ankle-brachial index (ABI <0.9), is highly prevalent among the elderly, with 1 in 5 people over the age of 59 years suffering from PAD in population surveys1. Importantly, patients with PAD have a high risk of cardiovascular events2. Both the AHA/ACC3 and TASC II4 guidelines recommend the prescription of statins (for lipid- lowering) and aspirin (as the antiplatelet agent) for the prevention of cardiovascular events in both symptomatic and asymptomatic patients with lower extremity PAD. Good quality data exist to support the use of statins in patients with PAD, including a subgroup analysis of patients with PAD enrolled in the Heart Protection Study5 as well as several smaller studies6-9. These data demonstrate that in patients with PAD, statin use is beneficial for risk prevention but may also lead to an improvement in symptoms7,8. In contrast, the evidence-base for aspirin use is becoming increasingly uncertain. 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,
References 1. Sigvant B, Wiberg-Hedman K, Bergqvist D, Rolandsson O, Andersson 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 Disease (TASC II). Eur J Vasc Endovasc Surg 2007;33:S1-S75. 5. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high- risk individuals: a randomised placebo-controlled trial. The Lancet 2002;360:7-22. 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 |
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