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RESEARCH: George Krasopoulos, Stephanie J Brister, W Scott Beattie, and Michael R Buchanan Aspirin "resistance" and risk of cardiovascular morbidity: systematic review and meta-analysis BMJ 2008; 0: bmj.39430.529549.BEv1 [Abstract] [Full text]

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Aspirin resistance and risk of cardiovascular morbidity

P C Elwood, Cardiff University   (24 January 2008)

Aspirin Resistance: Still a long way to go.

Sujoy Ghosh, Tarik Elhadd, Iqbal Malik   (24 January 2008)

Compliance is a double-confounder

David L. Sackett   (26 January 2008)

Aspirin"resistance". A problem in the problem

Roberto G Carbone, Giovanni Bottino and Riccardo Ghio, Dept. Internal Medicine and Haematology, University of Genoa, Italy   (27 January 2008)

The importance of aspirin resistance in renal failure

Jecko Thachil   (28 January 2008)

Aspirin"resistance" --a current problem, a future problem

José Máximo Carles Zerquera, Grace de Lara García,   (30 January 2008)

Re: The importance of aspirin resistance in renal failure

Les O. Simpson   (3 February 2008)

Non-compliance does not explain "aspirin resistance", which may (just) be a marker of increased risk.

Kjell Andersen   (5 February 2008)

Management of aspirin resistance

Burak Pamukcu, 34093 Capa / Istanbul / Turkey   (11 February 2008)

Aspirin "resistance" - still a misnomer?

Doson Chua, Chris Lo, Anita Lo   (20 February 2008)

Aspirin “resistance” and risk of cardiovascular morbidity

Jean-Luc Reny, Philippe de Moerloose, Jean-Christophe Gris, Pierre Fontana   (1 March 2008)

Chinese Herbs: A Probable Succedaneum of Aspirin

Hongcai Shang, Youping Li,Boli Zhang   (2 March 2008)

Hypothesis influences outcome

Yaozu Xiang   (6 March 2008)

Aspirin resistance: should we test it or not?

Gergely Feher, Andrea Feher, Gabriella Pusch   (20 March 2008)

Aspirin resistance and risk of cardiovascular morbidity 24 January 2008
P C Elwood, Honorary Professor Department of Primary Care and Public Health, Cardiff University Send response to journal: Re: Aspirin resistance and risk of cardiovascular morbidity	To: the Editor of the BMJ From Peter Elwood and Gareth Morgan Aspirin resistance and risk of cardiovascular morbidity The finding of markedly raised risk for vascular disease in a subgroup of patients judged to be ‘resistant’ to aspirin, relative to patients sensitive to the drug is of very great interest. This led Krasopoulos et al. (BMJ 18th January 2008) to suggest that there could be a ‘potentially greater than 50% beneficial effect of aspirin in aspirin sensitive patients’. The problem is the identification of subjects ‘resistant’ to aspirin. Krasopoulos et al accepted evidence from the authors of 20 reports of randomised aspirin trials of an inhibition of the expected platelet response to aspirin ‘however measured’. They make the point that the platelet tests upon which the judgement of aspirin ‘resistance’ were based had been done in hospital before the admission of the patients to the trials. They therefore dismiss the possibility that the lack of benefit during the trial was simply due to poor compliance with aspirin taking. Despite this last, compliance could still be an explanation of the findings, at least in part. In one study of ‘resistance’ only one of seventeen patients who had been judged to be aspirin resistant (presumably in ‘a controlled environment’ within hospital) failed to show the expected platelet response to aspirin when aspirin was taken under close supervision.1 Then there is the paradox that although platelet aggregation, estimated by three methods, showed a large range in men within a large cohort, there was no evidence that the degree of platelet aggregation is predictive of subsequent heart disease events.2,3 Finally, the estimate the authors make of a greater than 50% beneficial effect of aspirin in sensitive patients is remarkably close to the 51% reduction reported for the doctors in the US Physicians Health Study who claimed that they had taken aspirin regularly, compared to a 17% reduction in the doctors who admitted that they had taken the drug on less than half the days.4 The finding by Krasopoulos et al should be followed up urgently. If so-called ‘sensitivity’ to aspirin can be identified, by any means whatever, the risk/benefit balance of the drug in vascular disease prevention could be greatly altered and ‘…the current strategies for antiplatelet therapy may need to be rethought’ to the great benefit of all. Perhaps however the one unfortunate item in this paper is the application of the term ‘increased risk’ to the patients with aspirin ‘resistance’ (at the foot of Fig 3). Whether or not aspirin ‘resistance’ carries an increased vascular risk cannot be judged in trials which included no placebo groups. Yours sincerely, Peter Elwood Honorary Professor, Department of Primary Care and Public Health, Cardiff University and Gareth Morgan, Welsh Aspirin Group. 1. Schwartz KA, Schwartz DE, Ghosheh K et al. Compliance as a critical consideration in patients who appear to be resistant to aspirin after healing of myocardial infarction. Amer J Cardiol 2005; 95:973-5 2. Elwood PC, Beswick A, Pickering J et al. Platelet tests in the prediction of myocardial infarction and stroke: evidence from the Caerphilly study. Brit J Haematol 2001;113:514-20 (2001) 3. Elwood PC, Pickering J, O’Brien J et al. Bleeding time, stroke and myocardial infarction: the Caerphilly prospective studyPlatelets 2003;14:139-41 4. Glynn RJ, Buring JE, Manson JE et al. Adherence to aspirin in the prevention of myocardial infarction: The Physicians Health Study. Arch Intern Med 1994;154:2649-57 Competing interests: None declared
Aspirin Resistance: Still a long way to go. 24 January 2008
Sujoy Ghosh, Clinical Teaching & Clinical Research Fellow The Ayr Hospital, Dalmellington Road, Ayr, Scotland, United Kingdom, Tarik Elhadd, Iqbal Malik Send response to journal: Re: Aspirin Resistance: Still a long way to go.	We have read with interest the article by Krasopoulos et al. and the accompanying editorial by Biondi-Zoccai G and Lotrionte M. [1-2]. The authors themselves highlight the limitations of the systematic review and meta-analysis. We are indeed grateful to the authors for highlighting the implications of ‘aspirin resistance’ and the need for more research to improve clinical outcome in our patients at risk of vascular events. The editorial however clouds the issue with some suggestions that we would like to comment on. As clinicians we are not sure when to suspect aspirin resistance in an individual patient. Antiplatelet therapy we know leads to relative risk reduction of vascular events. Therefore having a vascular event while on aspirin does not necessarily imply little or no effect of aspirin. Even if we did have any suspicion or aspirin resistance we are not sure which tests to use to confirm the same. At present there is no consensus on the tests [including methodology, agonists used and cut offs] for routine clinical use to establish aspirin resistance. Finally there is little evidence to suggest that in cases of aspirin resistance, an alternative antiplatelet agent (probably working through a different mechanism of action) would be able to do the job. A lot more research needs to be done before the problem of so called ‘aspirin resistance’ could have implications for change in our current clinical practice. REFERENCE: [1] Krasopoulos G, Brister S J, Beattie W S, Buchanan M R. Aspirin "resistance" and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ, doi:10.1136/bmj.39430.529549.BE (published 17 January 2008) [2] Biondi-Zoccai G, Lotrionte M. Aspirin resistance in cardiovascular disease. BMJ, doi:10.1136/bmj.39405.635498.80 (published 17 January 2008) Competing interests: None declared
Compliance is a double-confounder 26 January 2008
David L. Sackett, Trialist Trout Centre, 303-28 Duke Street, Hamilton, Ontario, Canada, L8P1X1 Send response to journal: Re: Compliance is a double-confounder	As Peter Elwood nicely shows, aspirin "resistance" may merely represent aspirin-noncompliance. Moreover, this noncompliance can distort the results of this meta-analysis as well. In 1980, a report from the Coronary Drug Project documented about a 50% relative risk reduction in 5- year mortality for "good adherers," regardless of whether they were assigned to clofibrate or to the corresponding placebo (1). This often- reported confounding of compliance with outcome, regardless of active or placebo treatment, provides a second reason to question the authors' conclusions. (1) Coronary Drug Project. Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project. N Engl J Med 1980;303:1038-41. Competing interests: Dave Sackett was a PI in the first trials of aspirin in TIAs and unstable angina.
Aspirin"resistance". A problem in the problem 27 January 2008
Roberto G Carbone, Vice - head Respiratory Unit Regional Hospital, 11100, Aosta , Italy, Giovanni Bottino and Riccardo Ghio, Dept. Internal Medicine and Haematology, University of Genoa, Italy Send response to journal: Re: Aspirin"resistance". A problem in the problem	We read with interest the review written by Krasopoulos and Colleagues.1 In the hypothesis of aspirin non- responsiveness we would like to ask to the Authors what are the clinical approaches into prevention of recurrent pregnancy loss in women with co morbidity as prosthetic valves and antiphospholipids (APLs), with high risk of thrombo- embolisms.In addition, based on the literature we suggest to pregnant women with complications an anticoagulant treatment or heparin low weight in combination with low dose aspirin 75 to 100 mg/d, but in this case, we doubt that the dose of the latter can be satisfying. Future works should explore potentially modifiable risk factors as well as age, gender,race, and especially co morbidity conditions in aspirin non-responsiveness, because these may be important modifiers of death, and we should examine these findings with more detailed clinical information. 1. Krasopoulos G, Brister SJ, Beattle WS, Buchanan MR. Aspirin "resistance" and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ 2008;336:195-198 Competing interests: None declared
The importance of aspirin resistance in renal failure 28 January 2008
Jecko Thachil, Haematology SpR Liverpool Send response to journal: Re: The importance of aspirin resistance in renal failure	In the systematic review by Krasopoulos et al, the relation between resistance to aspirin and a history of renal impairment has been considered as possibly an anomaly mainly because of dearth of data. However, an abnormality of platelet arachidonic acid metabolism has been well documented to exist in patients with uraemia [1]. This leads to altered thromboxane synthesis which is a key factor for the development of resistance to aspirin. Initially thought to be due to a 'functional cyclooxygenase defect', it is now thought to be due to the increased activity of phospholipase A2 in the platelets of patients with uraemia [1, 2]. Enhanced production of thromboxane in the kidney has been demonstrated in several diseases including lupus nephritis, ureteral obstruction, and nephrotoxic renal injury [3, 4, 5]. The administration of thromboxane antagonists interestingly decreased the severity of these kidney diseases as well. Chronic kidney disease is now recognized as an independent risk factor for cardiovascular events, and cardiovascular disease is the major cause of mortality in patients with the disease [6]. Possibly, the increased aspirin resistance in patients with chronic renal failure may indicate a similar vascular pathology in the two beds and serve as a useful indicator for increased cardiovascular morbidity, as shown by the systematic review. References 1. Bloom A, Greaves M, Preston FE, Brown CB.Evidence against a platelet cyclooxygenase defect in uraemic subjects on chronic haemodialysis. Br J Haematol. 1986 ; 62: 143-9. 2. Vecino AM, Teruel JL, Navarro JL, Cesar JM. Phospholipase A2 activity in platelets of patients with uremia. Platelets. 2002; 13: 415-8. 3. Spurney RF, Fan PY, Ruiz P, Sanfilippo F, Pisetsky DS, Coffman TM. Thromboxane receptor blockade reduces renal injury in murine lupus nephritis. Kidney Int. 1992 ;41: 973-82. 4. Yarger W, Schocken D, Harris R. Obstructive nephropathy in the rat: possible roles for the renin-angiotensin system, prostaglandins, and thromboxanes in post-obstructive renal failure. J. Clin. Invest. 1980; 65: 400-412. 5. Lianos E, Andres G, Dunn M. Glomerular prostaglandin and thromboxane synthesis in rat nephrotoxic serum nephritis. J. Clin. Invest. 72: 1439- 1448, 1983. 6. Rubin C, Nolin TD, Himmelfarb J. Are biomarkers useful for assessing cardiovascular risk in patients with chronic kidney disease? Curr Opin Nephrol Hypertens. 2007; 16: 506-11. Competing interests: None declared
Aspirin"resistance" --a current problem, a future problem 30 January 2008
José Máximo Carles Zerquera, professor Internal Medicine General Hospital Trinidad. Cuba, Grace de Lara García, Send response to journal: Re: Aspirin"resistance" --a current problem, a future problem	We have read with interest the article by Krasopoulos et al. Aspirin therapy in patients with different cardiovascular, cerebrovascular disease is very important. Doctors' use general ranges from 75-325 mg daily. In our practice the effect of aspirin resistance and its effect on adverse cardiovascular outcomes ocurred in 32% ( for example fatal myocardial infarction, unstable angina, vascular restenosis, stroke, death in antiphospholipid syndrome). The use of other antiplatelet agents ( dipiridamol, ticlopidina, trifusal, clopidogrel) did not provide any benefit to aspirin resistant patients. Future problem. Every day increase disorders, risk factors for cardiovascular, cerebral, renal, and peripheral atherosclerotic vascular disease ( diabetes, hypertension, dyslipidemia, obesity, physical inactivity). Life style modification is the most important treatment. 1. Krasopoulos G, Brister SJ, Beattle WS, Buchanan MR. Aspirin "resistance" and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ 2008;336:195-198 Competing interests: None declared
Re: The importance of aspirin resistance in renal failure 3 February 2008
Les O. Simpson, retired experimental pathologist Dunedin, New Zealand 9077 Send response to journal: Re: Re: The importance of aspirin resistance in renal failure	According to Dr.Thachiel, "Chronic kidney disease is now recognised as an independent risk factor for cardiovascular events and cardiovascular disease is the main cause of mortality in patients with the disease." However, such a concept does not recognise the possibility that both chronic kidney disease and cardiovascular events are manifestations of a single event, an increase in blood viscosity. Such a suggestion is based upon the existence of two models which show that increased blood viscosity influences kidney function. The first model is hyperproteinemic proteinuria; the second model is the proteinuria associated with polycythemia. Hyperproteinemic proteinemia can be induced in normal mice by the daily i.p. injection of at least 150mg of human serum albumin. High molecular weight proteinuria (as determined by electrophoresis in 6% SDS- polyacrylamide gels)develops by 16 hours and persists for as long as the injections continue. By 3 days after the last injection, normal urine has returned.(1) Polycythemia is associated with increased blood viscosity and accompanied by albuminemia, but when the patient is bled down to a haematocrit of 42, renal function is normal. The effects of blood viscosity on renal function were hypothesised in 1982.(2) The crucial factor is that when there is increased blood viscosity in the afferent glomerular arteriole, the effects of glomerular filtration will render the blood in the efferent arteriole hyperviscous and impair blood flow in the peritubular plexus. In a 1994 contribution(3) it was concluded, "...when faced with the haemoconcentrating effects of glomerular filtration, nephrologists need to cogitate on whether or not renal function can be expected to proceed unaffected when blood rheology is abnormal." Therefore it can be expected that the reported changes in blood rheology which accompany cardiovascular disease (and diabetes, dyslipidemia, hypertension, physical inactivity, etc) can be expected to interfere with renal function. What needs to be known is whether or not aspirin resistance is associated with altered blood rheology. References. 1. Simpson LO, Shand BI. The implications of the nature of the urinary proteins which occur in albumin overload-induced proteinuria in normal mice. Br J exp Path 1983;64:64-78. 2. Simpson LO. A hypothesis proposing increased blood viscosity as a cause proterinuria and increased vascular permeability. Nephron 1982;331:89-93. 3. Simpson LO. Abnormal protein excretion. Clin Nephrol 1994;41:57-8. (letter) Competing interests: None declared
Non-compliance does not explain "aspirin resistance", which may (just) be a marker of increased risk. 5 February 2008
Kjell Andersen, Cardiologist Medical Department, Central Hospital of Hedmark, Hamar, N-2315, Norway Send response to journal: Re: Non-compliance does not explain "aspirin resistance", which may (just) be a marker of increased risk.	In our study (1), we measured the levels of thromboxane B2. In both aspirin groups, in responders as well as in non-responders, the levels were extremely low compared to the group not taking aspirin, indicating good compliance of aspirin intake, and inhibition of the cyclooxygenase pathway. Only very few patients on aspirin had thromboxane B2-levels as those not on aspirin, these may represent the true non-compliers. Reduced levels of thromboxane B2 in patients taking aspirin, irrespective of their classification as aspirin responders or not, has been described years ago by others (2). The platelets in "aspirin resistant" patients as a group are obviously not totally resistant to aspirin, even though in these patients as a group their activity and behaviour in various tests of platelet function are not influenced as expected with aspirin therapy. The phenomenon termed "aspirin resistance", and what now seems to be a link to increased risk of cardiovascular morbidity, is probably the result of several mechanisms, of which lack of compliance may be a minor one. My favorite theory as a major contributor, is that "aspirin resistance" identifies a subgroup of patients which are more severly diseased, and hence at increased risk. They have more intense activation of their platelets and various cascade systems involved in platelet activation and other aspects of cardiovacular disease. Thus, aspirin is not enough to inhibit their platelets, as it can do in patients with less stimulated platelets. Addition of other platelet inhibiting drugs as Clopidogrel will not abolish the difference in risk between aspirin responders and non-responders, but may reduce it. As a consequence, patients identified as aspirin non-responders should: A - not discontinue their aspirin, which seems to inhibit the cyclooxygenase pathway and thus make the platelets less reactive than what they would have been without aspirin. B - However, they may benefit from addition of other platelet inhibiting drugs, not to eliminate their increased risk, but to reduce it. C - And, as aspirin non-response is a marker of increased risk, focus on other means of secondary prevention should be strengthened even further. (1) Andersen K, Hurlen M, Arnesen H, Seljetflot I. Aspirin nonresponsiveness as measured by PFA-100 in patients with coronary artery disease. Thromb Res 2003; 108: 37-42. (2) Buchanan MR, Brister SJ. Individual variation in the effects of ASA on platelet function: implications for the use of ASA clinically. Can J Cardiol. 1995;11(3):221–7. Competing interests: None declared
Management of aspirin resistance 11 February 2008
Burak Pamukcu, Medical doctor, researcher Istanbul University Istanbul Faculty of Medicine Department of Cardiology, 34093 Capa / Istanbul / Turkey Send response to journal: Re: Management of aspirin resistance	In the last decade the wonderful drug of the 20th century, aspirin, is studied again in clinical studies but this time for its failure in the prevention of vascular thrombotic events called as aspirin resistance. Researchers defined aspirin resistance clinically and/or with the aid of laboratory techniques. Possible mechanisms of aspirin resistance are also well described previously. The hallmark of aspirin resistance studies is its implication on clinical outcomes in patients with cardiovascular diseases. Recent studies established that patients who developed a new acute coronary syndrome under aspirin therapy are at higher risk (1, 2). Prior aspirin use is also a component of TIMI risk score which guides us in the management of acute coronary syndromes (3). Aspirin resistance’s impact on clinical outcomes are established previosuly in different patient groups (1, 4, 5). The major limitations of studies on aspirin resistance are; use of different methods which makes difficult to compare the results, insufficient monitorization of compliance and differences in diagnostic criteria of aspirin resistance. We need also to make a concensus on the definition of aspirin resistance. Development or determination of an optimal platelet function analyzer or method is also necessary to standardize the results. This method should be cheap, accurate, available and applicable in every hospital. We need to discuss also the monitorization of aspirin compliance in patients with cardiovascular diseases. A fast diagnostic tool consisted of a platelet function test, blood an/or urine salycilate and/or thromboxane level may serve us in daily clinical practise. I think that a such diagnostic tool should be used at least in patients with higher risk of aspirin resistance (eg elder patients, patients with an acute coronary syndrome or diabetes or intracoronary stent restenosis). None of the recent studies advised the cessation of aspirin in case of aspirin resistance. Aspririn therapy should be continued in aspirin resistant subjects and management of aspirin resistant subjects should be based on clinical evidence. We have aditional antiplatelet agents which may be used in aspirin resistant subjects. Prasugrel is one of these hopeful molecules and its effectiveness is proven in aspirin-treated subjects with coronary artery disease. Prasugrel 60/10 mg provided faster onset and greater inhibition of P2Y(12) receptor-mediated platelet aggregation than clopidogrel 600/75 mg, because of greater and more efficient generation of the active metabolite (6). 1. Pamukcu B, Oflaz H, Oncul A, et al. The role of aspirin resistance on outcome in patients with acute coronary syndrome and the effect of clopidogrel therapy in the prevention of major cardiovascular events. J Thromb Thrombolysis. 2006 Oct;22(2):103-10. 2. Hobikoglu GF, Norgaz T, Aksu H, et al. High frequency of aspirin resistance in patients with acute coronary syndrome. Tohoku J Exp Med. 2005 Sep;207(1):59-64. 3. Antman EM, Cohen M, Bernink PJLM, et al. The TIMI Risk Score for Unstable Angina/Non–ST Elevation MI. A Method for Prognostication and Therapeutic Decision Making. JAMA. 2000;284:835-842. 4. Pamukcu B, Oflaz H, Onur I, et al. Clinical relevance of aspirin resistance in patients with stable coronary artery disease: a prospective follow-up study (PROSPECTAR). Blood Coagul Fibrinolysis. 2007 Mar;18(2):187-92. 5. Sztriha LK, Sas K, Vecsei L. Aspirin resistance in stroke: 2004. J Neurol Sci. 2005 Mar 15;229-230:163-9. Epub 2004 Dec 23. Review. 6. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008 Jan;29(1):21-30. Epub 2007 Nov 30. Competing interests: None declared
Aspirin "resistance" - still a misnomer? 20 February 2008
Doson Chua, Clinical Pharmacy Specialist St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC Canada V6Z 1Y6, Chris Lo, Anita Lo Send response to journal: Re: Aspirin "resistance" - still a misnomer?	The systematic review by Krasopoulos et al is one of the first attempts to correlate aspirin resistance and cardiovascular morbidity (1). However, the term “aspirin resistance” is still a misnomer despite several excellent overviews of this clinical entity (2,3). Krasopoulos et al commented that the Antiplatelet Trialist’s Collaboration demonstrated a 25% risk reduction in cardiovascular morbidity with aspirin therapy (4). This impressive risk reduction was derived from an absolute risk reduction of 2.4% of antiplatelet therapy over control. If one calculates the number needed to treat (NNT), this would translate to 42. One would need to treat 42 patients with aspirin to prevent one cardiovascular event. Therefore, 41 patients treated with aspirin would suffer a cardiovascular event despite being on aspirin. Such patients may be inappropriately labelled as aspirin resistant, as based on the calculations above, 41 patients are expected to experience an event. Thus, aspirin resistance is a misnomer since a certain percentage of patients are expected to have a cardiovascular event while on aspirin. The term aspirin resistance implies that every patient on aspirin should not experience a cardiovascular event, thus suggesting that the NNT for aspirin therapy is 1. This is clearly not the case based on the evidence based calculation of treatment effect of aspirin. Future research is needed to clarify if patients whom experience a cardiovascular event while on aspirin therapy are truly “aspirin resistant” or are just statistically unlucky not to have derived benefit. 1. Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin “resistance”and cardiovascular morbidity: systematic review and meta- analysis. BMJ 2008;336:195-198 2. Hankey GJ, Eikelboom JW. Aspirin resistance. Lancet 2006;367:606- 617 3. Sanderson S, Emery J, Baglin T, Kinmonth AL. Narrative review: aspirin resistance and its clinical implications. Ann Intern Med 2005;142:370-380 4. Antiplatelet Trialist’s 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 1993;308:81-106 Competing interests: None declared
Aspirin “resistance” and risk of cardiovascular morbidity 1 March 2008
Jean-Luc Reny, MD, PhD Beziers hospital, 34500 Béziers and EA 2992 Montpellier I University, Nîmes., Philippe de Moerloose, Jean-Christophe Gris, Pierre Fontana Send response to journal: Re: Aspirin “resistance” and risk of cardiovascular morbidity	P. Fontana‡, P de Moerloose‡, J-C Gris† and J.-L. Reny*† ‡ Division of Angiology and Haemostasis, Department of Internal Medicine, Faculty of Medicine and University Hospitals of Geneva, Geneva, Switzerland. † EA 2992, Montpellier 1 University, Nîmes, France. *Department of Internal Medicine, Béziers Hospital, Béziers, France. Correspondence: Jean-Luc Reny Department of Internal Medicine Centre Hospitalier de Béziers 2 rue Valentin Hauÿ F-34525 Béziers Cedex France Phone: 33-4-67-35-73-48 Fax: 33-4-67-33-77-54 Email: jean-luc.reny@ch-beziers.fr and Pierre Fontana Division of Angiology and Haemostasis University Medical Centre 1 rue Michel-Servet CH-1211 Geneva 14 Switzerland Phone: 41-22-379-59-38 Fax: 41-22-372-92-99 E-mail: pierre.fontana@medecine.unige.ch In their interesting meta-analysis, Krasopoulos et al1 found that aspirin “resistance” (AR) was associated with increased cardiovascular morbidity in aspirin-treated patients. This, however, deserves some comments. As in the meta-analysis by Snoep et al2, the pooled analysis of odds ratios is undermined by a highly significant heterogeneity test3, partly owing to the use of different biological definitions of AR, as acknowledged by the authors themselves. Indeed, the biological tests used in these studies had highly variable specificity for aspirin inhibition of thromboxane (Tx) A2 generation, and the prevalence of AR was consequently very heterogeneous4. Using a global platelet function test like the PFA- 100 may help to identify patients with high residual platelet reactivity but do not necessarily identify patients who are pharmacodynamically “resistant” to aspirin,5 as TxA2 is similarly inhibited by aspirin in “aspirin resistant” subjects and “aspirin responders” on the basis of PFA- 100 values6. One of the most specific tests for evaluating the capacity of aspirin to inhibit platelet TxA2 production is the quantification of serum TxB2, a stable TxA2 metabolite5. Surprisingly, Krasopoulos et al chose not to include any studies that used this test, “because inhibition of thromboxane B2 synthesis could simply reflect a measure of patient compliance”1. On the contrary, we think this is one of the few appropriate tests for identifying true pharmacodynamic AR, reflecting both compliance and specific aspirin potency; the non-specific tests used in the other studies evaluate both compliance and undetermined factors that induce high residual platelet reactivity despite aspirin-mediated inhibition of TxA2 generation. Interestingly, Krasopoulos et al report that “most of the heterogeneity was contributed to by the eight studies that used the PFA- 100”. Only seven studies of PFA-100 are available, however, and all were included in the meta-analysis, even though three were not truly prospective (Grundmann et al 2003, Hobikoglu et al 2005 and Yilmaz et al. 2005) and one compared acute coronary syndrome patients to patients with chest pain of non-cardiac origin (Borna et al 2005). Finally, the study by McCabe et al. (Platelets 2005) compared ischemic stroke patients in the acute phase and during the recovery period. These differences in study design may well account for the observed statistical heterogeneity. Indeed, in our meta-analysis of prospective studies using the PFA-100, we observed a low and non significant level of heterogeneity (I2=9.4%; Q Cochran, P=0.36)7. The main issue raised by this meta-analysis is obviously the need for a consensus definition of aspirin resistance. It seems too early to propose “strategies” for the management of AR patients,8 and, according to the Working Group on Aspirin Resistance, patients should only be tested within research protocols9. To address the clinical implications of AR, tests that specifically evaluate TxA2 production should be used for the laboratory definition of AR, whereas non-specific tests should be reserved for studies addressing “high residual platelet reactivity” in aspirin- treated patients. Meta-analyses of the clinical impact of AR or of “high residual platelet reactivity” should take into account the type of laboratory test used to define AR, in order to avoid a major cause of heterogeneity and to allow practical conclusions to be drawn7. References 1. 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. 2. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Huisman MV. Association of laboratory-defined aspirin resistance with a higer risk of recurrent cardiovascular events. A systematic review and meta-analysis. Arch Intern Med 2007;167(15):1593-1599. 3. Fontana P, Reny JL. Laboratory-defined aspirin resistance and recurrent cardiovascular events. Arch Intern Med 2008:in press. 4. Lordkipanidze M, Pharand C, Schampaert E, Turgeon J, Palisaitis DA, Diodati JG. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J 2007;28(14):1702-8. 5. Cattaneo M. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection. J Thromb Haemost 2007;5 Suppl 1:230-7. 6. Fontana P, Nolli S, Reber G, de Moerloose P. Biological effects of aspirin and clopidogrel in a randomized cross-over study in 96 healthy volunteers. J Thromb Haemost 2006;4(4):813-9. 7. Reny JL, de Moerloose P, Dauzat M, Fontana P. Use of the PFA-100 closure time to predict cardiovascular events in aspirin-treated cardiovascular patients: a systematic review and meta-analysis. J Thromb Haemost 2008; 6:444-50. 8. Biondi-Zoccai G, Lotrionte M. Aspirin resistance in cardiovascular disease. BMJ 2008;336(7637):166-7. 9. Michelson AD, Cattaneo M, Eikelboom JW, Gurbel P, Kottke-Marchant K, Kunicki TJ, et al. Aspirin resistance: position paper of the Working Group on Aspirin Resistance. J Thromb Haemost 2005;3(6):1309-11. Competing interests: None declared
Chinese Herbs: A Probable Succedaneum of Aspirin 2 March 2008
Hongcai Shang, Post-doctoral West China Hospital Sichuan University, Youping Li,Boli Zhang Send response to journal: Re: Chinese Herbs: A Probable Succedaneum of Aspirin	We read with interest the review written by Krasopoulos and Colleagues (1). We consider everyone should not dispute whether aspirin resistance is a misnomer or not. Occurrence of a question should have it¡¯s reason, meanwhile, could be solved. Aspirin resistance is indeed an important and formidable problem. In our practice we realized some Chinese herbs could substitute aspirin for their anti-aggregation of platelet (2)(3). Six kinds of constituents, Flavonoids, Terpene, Alkaloids, organic acid, lignans and oleoresia, can all possess this activity. This prospect is worth expectation. 1. Krasopoulos G, Brister SJ, Beattle WS, Buchanan MR. Aspirin "resistance" and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ 2008;336:195-198 2. Zhao L, Gaudry L, Dunkley SS, et al. Modulation of platelet and leucocyte function by a Chinese herbal formulation as compared with conventional antiplatelet agents. Platelets. 2008;19(1):24-31 3.Chen CC, Huang YL, Teng CM. Antiplatelet aggregation principles from Ephemerantha lonchophylla. Planta Med. 2000 May;66(4):372-4 Competing interests: None declared
Hypothesis influences outcome 6 March 2008
Yaozu Xiang, MD Tianjin University of Traditional Chinese Medicine, 300193, Tianjin, China Send response to journal: Re: Hypothesis influences outcome	In the systematic review by Krasopoulos et al, it concluded that 28% patients (810/2930) were classified as aspirin resistant and considered to be at a greater risk of clinically important cardiovascular morbidity long term.It is an interested and controversial topic indeed. From Table I (Characteristics of included studies),I found out a big problem that the data are origined from a variety of platelet function assays. However, prevalences widely differ between studies reporting on aspirin resistance. Both aspirin dosage and the method of defining aspirin resistance strongly influence estimated prevalence [1].Moreover,the use of various agonists in those platelet function assays directly influence the accuracy ofplatelet reactivity assessment [2].In fact, the platelet aggregation should be a normal ditribution among populations [3],and Aspirin responsiveness seem to be the same as well. To define aspirin resistance based on such circumstance should be more reasonable. Krasopoulos et al. found that aspirin resistant patients did not benefit from other antiplatelet treatment.It is also a controversial issue which have been disscussed in my recent paper on Drugs Journal. REFERENCE: 1.Hovens MM, Snoep JD, Eikenboom JC, van der Bom JG, Mertens BJ, Huisman MV.Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review.Am Heart J. 2007;153:175-81. 2.Yee DL, Sun CW, Bergeron AL, Dong JF, Bray PF.Aggregometry detects platelet hyperreactivity in healthy individuals.Blood. 2005;106:2723-9. 3.Gurbel PA, Bliden KP, Etherington A, Tantry US.Assessment of clopidogrel responsiveness: measurements of maximum platelet aggregation, final platelet aggregation and their correlation with vasodilator-stimulated phosphoprotein in resistant patients.Thromb Res. 2007;121:107-15. Competing interests: None declared
Aspirin resistance: should we test it or not? 20 March 2008
Gergely Feher, MD Department of Neurology, University of Pecs School of Medicine, Pecs, Hungary, Ret utca 2, Pecs, Bar, Andrea Feher, Gabriella Pusch Send response to journal: Re: Aspirin resistance: should we test it or not?	We have read with great enthusiasm the recently published article by Krasopoulos and coworkers. Platelets have a central role in the development of arterial thrombosis and subsequent cardiovascular events. An appreciation of this complex process has made antiplatelet therapy the cornerstone of cardiovascular disease management. On the other hand, patients on antiplatelet medication continue to suffer atherothrombotic complications. Their meta-analysis showed the associatuion between laboratory and clinical aspirin resistance based on different methods. This is in concordance with the statement of Wang et al who suggested that a new era of individualized antiplatelet therapy may arise with routine measurements of platelet activity in the same way that cholesterol, blood pressure, and blood sugar are followed, thus improving the care for millions of people (2). On the other hand, no clear and generally accepted definition of aspirin resistance has been achieved up to now. Furthermore, previous studies found no association between the widely used platelet function tests (3,4) and thereby these test may are not comperable with each other. The broad use of statins, angiotensin receptor blockers and selective serotonin reuptake inhibitors may be in part responsible for the lack of agreement among the laboratory tests because each of these drug classes per se inhibits platelets by different pathways (5). Our previous results showed the effect of different cardiovascular drugs on the laboratory efficacy of aspirin (6). Based on these results the term aspirin resistance should be based on the difference of platelet aggregation between the pre-treated and the aspirin treated stage, not using any other medications. Krasopoulos and his coworkers also showed that aspirin resistant patients did not benefit from other antiplatelet treatment. This result should be interpreted carefully. A previous in vitro study showed the association between increased platelet response to ADP and aspirin resistance (7). Eikelboom et al raised the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin (8). In another study, the addition of clopidogrel to aspirin provided greater inhibition of platelets and could overcome aspirin resistance (9). Pamukcu et al. found associatin between aspirin resistance and poor clinical otucome in AICS patients and also showed that the prevalence of major acute cardiac events in patients who were on clopidogrel treatment for 12 months were significantly lower compared to those who were on a clopidogrel treatment for the first six months. In another study, aspirin resistance was also associated with clinical outcome, but the poor outcome increased just after cessation of clopidogrel therapy (11). In conclusion, platelet function tests seem to be important techniques which are frequently used by hemostaseologists and researchers. Their widespread clinical use is substantially limited due to complex preanalytic factors, reduced specificity and reproducibility. The results of these tests may become more comparable after the standardization of the different methods. The definition and clinical importance of aspirin resistance should be based on the results of randomized, prospective studies. There is also no clear evidence in the treatment of aspirin resistance. (1) Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR.Aspirin "resistance" and risk of cardiovascular morbidity: systematic review and meta-analysis.BMJ. 2008 Jan 26;336(7637):195-8. (2) Wang TH, Bhatt DL, Topol EJ.Aspirin and clopidogrel resistance: an emerging clinical entity.Eur Heart J. 2006 Mar;27(6):647-54. (3) Harrison P, Segal H, Silver L, Syed A, Cuthbertson FC, Rothwell PM.Lack of reproducibility of assessment of aspirin responsiveness by optical aggregometry and two platelet function tests.Platelets. 2008 Mar;19(2):119-24. (4) Lordkipanidzé M, Pharand C, Schampaert E, Turgeon J, Palisaitis DA, Diodati JG.A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease.Eur Heart J. 2007 Jul;28(14):1702-8. (5) Malinin AI, Ong S, Makarov LM, Petukhova EY, Serebruany VL.Platelet inhibition beyond conventional antiplatelet agents: expanding role of angiotensin receptor blockers, statins and selective serotonin reuptake inhibitors.Int J Clin Pract. 2006 Aug;60(8):993-1002. (6) Feher G, Koltai K, Papp E, Alkonyi B, Solyom A, Kenyeres P, Kesmarky G, Czopf L, Toth K. Aspirin resistance: possible roles of cardiovascular risk factors, previous disease history, concomitant medications and haemorrheological variables. Drugs Aging. 2006;23(7):559- 67. (7) Macchi L, Christiaens L, Brabant S, Sorel N, Allal J, Mauco G, Brizard A. Resistance to aspirin in vitro is associated with increased platelet sensitivity to adenosine diphosphate. Thromb Res. 2002 Jul 15;107(1-2):45-9. (8) Eikelboom JW, Hankey GJ, Thom J, Claxton A, Yi Q, Gilmore G, Staton J, Barden A, Norman PE. Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial. J Thromb Haemost. 2005 Dec;3(12):2649-55. (9) Dropinski J, Jakiela B, Sanak M, Wegrzyn W, Biernat M, Dziedzina S, Plutecka H, Szczeklik A.The additive antiplatelet action of clopidogrel in patients with coronary artery disease treated with aspirin.Thromb Haemost. 2007 Jul;98(1):201-9. (10) Pamukcu B, Oflaz H, Oncul A, Umman B, Mercanoglu F, Ozcan M, Meric M, Nisanci Y. The role of aspirin resistance on outcome in patients with acute coronary syndrome and the effect of clopidogrel therapy in the prevention of major cardiovascular events. J Thromb Thrombolysis. 2006 Oct;22(2):103-10. (11) Pamukcu B, Oflaz H, Onur I, Oncul A, Ozcan M, Umman B, Mercanoglu F, Meric M, Nisanci Y.Clinical relevance of aspirin resistance in patients with stable coronary artery disease: a prospective follow-up study (PROSPECTAR).Blood Coagul Fibrinolysis. 2007 Mar;18(2):187-92. Competing interests: None declared