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Thrombosis Research (2005) 116, 465 — 470 Effect of increasing doses of aspirin on plateletfunction as measured by PFA-100 in patients withdiabetes Adnan Abacia,T, Yucel Yilmazb, Mustafa Caliskanb, Fahri Bayramc,Mustafa Cetind, Ali Unald, Servet Cetinb aDepartment of Cardiology, Gazi University School of Medicine, Ankara 06550, TurkeybDepartment of Cardiology, Erciyes University School of Medicine, Kayseri, TurkeycDepartment of Endocrinology, Erciyes University School of Medicine, Kayseri, TurkeydDepartment of Hematology, Erciyes University School of Medicine, Kayseri, Turkey Received 18 October 2004; received in revised form 7 February 2005; accepted 7 February 2005Available online 11 March 2005 Introduction: Platelets of diabetic patients have been reported to be less sensitive to aspirin. The aim of this study is to compare a medium (300 mg) and low (100 mg) dose of aspirin on platelet function in diabetic patients.
Methods: We have included one hundred and two patients with type 2 diabetesmellitus. Platelet function was measured as closure time (CT) with the PlateletFunction Analyzer (PFA)-100k before the administration of aspirin. Initially thepatients were given 100 mg aspirin once daily for seven days, and then themeasurements were repeated. If the CT exceeded the upper limit of 300 s, the studywas terminated. If not, the patients continued the aspirin therapy with a dose of 300mg daily for another seven days, and the CTs were measured again.
Results: After taking 100 mg aspirin, the CT significantly increased from 126 F 29 s to256 F 66 s ( p b 0.001). In 68 of 102 (67%) patients, the CT increased to 300 s. In theremaining 34 patients, the baseline CT was 113 F 29, and increased to 170 F 45 safter 100 mg aspirin ( p b 0.001). In these patients, there was a further increase inthe CT from 170 F 45 to 229 F 75 s following 300 mg aspirin ( p b 0.001). On average,the CT was increased by 60% and 39% following ingestion of 100 and 300 mg aspirin,respectively. CT N 300 s were obtained in 15 (44%) of 34 patients after 300 mg aspirin.
T Corresponding author. Gazi Universitesi Tip Fakultesi, Kardiyoloji Anabilim Dali, BesSevler/Ankara 06550, Turkey. Tel.: +90 312 318 E-mail address: (A. Abaci).
0049-3848/$ - see front matter D 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.thromres.2005.02.005 Conclusions: Although, a daily dose of 100 mg aspirin effectively inhibited plateletfunction in a majority of diabetics, a considerable proportion of patients showed agreater platelet inhibition with the use of 300 mg aspirin. The PFA-100k closuretime may be used to separate those patients who require a higher dose of aspirin toachieve desired antiplatelet effect.
D 2005 Elsevier Ltd. All rights reserved.
Aspirin reduces the risk of cardiovascular events in previous upper gastrointestinal hemorrhage, a all patients with coronary artery disease .
platelet count less than 150 Â 109/L, hemoglobin However, the optimal dosage of aspirin is subject b 12 g/dL, or known intolerance to aspirin were not to great debate. Meta-analysis of the randomized included in the study. Diabetes was defined if the trials failed to reveal greater benefit from doses patients were taking insulin or oral hypoglycemic z 350 mg compared with lower doses The ACC/ drugs on the basis of elevated (N7.0 mmol/L) levels AHA guidelines for the treatment of acute myocar- of fasting blood glucose on at least two separate dial infarction recommend an initial dose of 162— assessments. The study was approved by the local 325 mg to achieve full antiplatelet effect rapidly ethics committee of our institution, and written Although, comparison of the two lower doses of informed consent was obtained in all patients aspirin with one another has not been performed, 75—325 mg of aspirin daily is recommended inpatients with chronic stable angina for long-term Diabetes is associated with an increased risk of Blood samples for the determination of platelet cardiovascular events, even in the absence of function was obtained from the antecubital vein diagnosed cardiovascular disease The American using a 19-gauge needle and collected in Vacutainer Diabetes Association recommended low-dose (75— tubes (Becton Dickinson, Franklin Lakes, NJ) anti- 150 mg daily) aspirin as a primary prevention coagulated with 3.8% sodium citrate. Throughout strategy not only in high-risk diabetic patients but the study, same type of Vacutainer tubes were for anyone with diabetes who is N30 years of age used. One additional tube of blood anticoagulated and has no known contraindications Platelets of with ethylenediaminetetraacetic acid was col- patients with diabetes exist in a relatively acti- lected for the hematocrit and platelet count vated state, and synthesize significantly higher analysis. The blood was drawn 2 h after the last amounts of thromboxane than those from non- dose of aspirin. Daily variation of platelet aggrega- diabetic controls Consequently, diabetics tion has been reported in healthy subjects have increased platelet aggregation and thrombus Therefore, platelet function studies were per- formed at the same time of day in all patients in platelet thromboxane synthesis is lower in diabetic patients compared to nondiabetic individuals and a higher incidence of aspirin resistance in diabetics has been reported . Therefore, low-dose aspirin might be inadequate for inhibition of Platelet function was measured by the Platelet platelet function, and relatively higher doses of Function Analyzer (PFA)-100k assay which is a aspirin may be needed in diabetic patients. The aim simple and easy to use system that can provide a of the study was to compare the medium (300 mg) quantitative measure of platelet function in vitro and low (100 mg) dose of aspirin on platelet using anticoagulated whole blood The test cartridge simulates an injured blood vessel andmeasures the time required to form a platelet plug(defined as CT) that occludes a microscopic aper- ture cut into a collagen/epinephrine or collagen/ADP coated membrane under high shear flow We included the patients with type 2 diabetes mellitus who did not use aspirin or other drugs tridge is the primary cartridge for detection of known to modify platelet function for at least two aspirin effect on platelet function. Previous studies weeks prior to beginning of the study. Patients with have shown that effect of aspirin treatment on an active duodenal or gastric ulcer, a history of platelet function can be measured with the PFA-100 Effect of increasing doses of aspirin on platelet function in patients with diabetes The baseline characteristics of the study repeated. If the CT exceeded the upper limit of 300 s, the study was terminated. If not, the patients continued the aspirin therapy at a doseof 300 mg daily for seven days, and the CT was again Continuous variables were given as mean val- ues F SD, and categorical variables as percentages.
A chi-square test was used for comparison of categorical variables. Comparison of continuous variables were performed by means of Student’s t test. The relations between the variables and the baseline CT were evaluated using the Spearman’s correlation coefficient or the Pearson’s correlation coefficient. Statistical analysis was performed by use of the SPSS statistical software package (ver- sion 10.0). A p value of b0.05 was considered Values are given as mean F SD (range) or number (%).
CT = closure time, ACEI = angiotensin converting enzymeinhibitor, ARB = angiotensin receptor blocker, CCB = calcium canal blocker, NS = non-significant.
One hundred and two patients with type 2 diabetesmellitus were included in the study. The baseline characteristics of the study subjects are given in using collagen/epinephrine cartridges according to Of the patients, 46 (45.1%) were insulin- the manufacturer’s instruction not earlier than 30 treated and 56 (54.9%) were treated by oral agents.
min after and within 2 h of blood sampling. The The duration of diabetes ranged from 1 month to 25 maximal CT for collagen/epinephrine cartridges is years, averaging 6.4 F 6.1 years. The mean level of 300 s and values greater than 300 s are reported as HbA1c was 8.1 F 2.4%. There were no hemorrhagic non-closure. Platelet function was determined before the administration of aspirin. Initially the Before aspirin administration, the CT ranged 71— patients were given 100 mg aspirin once daily for 182 s, (mean 126 F 29, median 129.5 s). Patients receiving insulin had a similar baseline CT as Closure times before (A), after 100 mg (B) and 300 mg (C) doses of aspirin in 34 patients in which the closure times did not exceeded the upper limit of 300 s. *p b 0.05 (100 mg vs. before treatment and 300 mg vs. 100 mg).
compared to patients receiving oral hypoglycemic doses of aspirin, there may be no bidealQ dose of agents (124 F 27 vs 128 F 31 s, respectively). There aspirin for all patients. If optimal dose of aspirin for is no relation between the baseline CT and age, a particular patient can be known, a greater gender, hypertension, smoking, serum cholesterol proportion of patients may benefit from aspirin level, hematocrit, platelet count, and HbA1c.
because the sensitivity of platelets to aspirin At the end of one week of 100 mg per day aspirin differs between patients. However, there is no administration, the CT significantly increased to study to detect the difference between individu- 256 F 66 s (range 91—300) ( p b 0.001). The CT was alized aspirin dosage and the fix low dose aspirin.
the same in both genders after the administration Whether individualized aspirin dosage is superior of aspirin. In 68 of 102 (67%) patients, the CT remains an open question. Platelet function tests increased to 300 s, which is the upper limit for the may be used to differentiate those patients most collagen/epinephrine cartridges. In these patients likely to benefit from a higher aspirin dosage. The PFA-100k appears to be a simple test for the In the remaining 34 patients, the baseline CT was assessment of antiplatelet effect of aspirin that 113 F 29 s (range 71—167), and increased to could be easily employed as a routine test in the 170 F 45 s (range 91—232) after 100 mg aspirin clinical practice. However, studies relating to fail- daily ( p b 0.001) (With these patients, there ure of prolonged CT with aspirin and the clinical was a further increase in CT from 170 F 45 s to 229 F 75 s (range 95—300) following 300 mg aspirin Bedside testing of aspirin by the PFA-100k may daily ( p b 0.001). On average, the CT was increased allow us to measure the antiplatelet effect of by 60% and 39% following ingestion of 100, and 300 aspirin and the ideal dose of aspirin for a particular mg aspirin, respectively. In fifteen (44%) of the 34 patient may be determined. In our study, although patients, the CT increased to the upper limit of 300 100 mg aspirin was effective for the majority of diabetic patients, some patients showed a greaterplatelet inhibition with the use of 300 mg aspirin. Inaccordance with the results of our study, Watala etal. have recently shown that the inhibitory effect of 150 mg aspirin a day on platelet function is lessprofound in diabetic patients compared to non- Our results showed that aspirin at 100 mg daily was diabetic individuals and have suggested that at effective in the inhibition of platelet function as least some patients with diabetes might require assessed by PFA-100 in majority of patients. How- higher aspirin doses Indeed, the results of the ever, there was a further increase in platelet primary prevention project trial suggested inhibition with higher aspirin doses in patients that low-dose aspirin might be less effective in who have not achieved the desired level of anti- primary prevention of cardiovascular disease in platelet effects from 100 mg aspirin daily. The diabetic patients as compared to nondiabetics.
discussion on the correct dosage of aspirin in There are small-sized studies investigating the platelet inhibition seems to be never ending.
effect of different doses of aspirin on platelet Meta-analysis of randomized trials of antiplatelet function in various diseases or health subjects therapy failed to reveal greater benefit from doses 27]. A majority of these studies showed that aspirin z 350 mg compared with lower doses . There- inhibited platelet function in a dose dependent fore, it is now accepted that high doses of 500— 1500 mg aspirin daily are no more effective than bleeding time has been demonstrated in healthy medium doses of 160—325 mg/day or low doses of 75—150 mg/day However, there is no large inhibition of platelet function is dose dependent in scale, randomized clinical study comparing the patients taking aspirin for stroke prevention and medium (160—325) and low dose (75—150) aspirin increase of aspirin dose resulted in complete inhibition of platelet function in more patients.
Preference of a low dose of aspirin is due to Tohgi et al. showed that with higher doses, fewer gastrointestinal side effects and undesired platelet aggregability and thromboxane A2 produc- cyclooxygenase inhibition of the vascular wall tion were inhibited more conspicuously and in a greater proportion of stroke patients. Two recent mended in the use of the lowest dose of aspirin studies have also shown that aspirin inhibited shown effective in the prevention of events.
platelet function in a dose dependent manner in Although the results of the previous studies dem- patients with stable coronary artery disease or onstrated preventive effects of low or medium stroke To our knowledge, there is no study Effect of increasing doses of aspirin on platelet function in patients with diabetes comparing two different doses of aspirin on plate- patients with ST-elevation myocardial infarction: executive summary: a report of the ACC/AHA Task Force on PracticeGuidelines. Circulation 2004;110:588 – 636.
Aspirin resistance has been reported in 5.5% and [3] Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania 60% of patients using different techniques and PC, Douglas JS, et al. ACC/AHA 2002 guidelines update for different definitions . Patients with diabetes the management of patients with chronic stable angina: a have been reported to have a higher rate of aspirin report of the American College of Cardiology/American resistance in comparison to nondiabetic control Heart Association Task Force on Practice Guidelines.
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We did not measure the von Willebrand factor [7] Davi G, Rini GB, Averna M, Novo S, Di Fede G, Pinto A, et al.
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on vWF levels, the measured CT negatively corre- [8] Aronson D, Rayfield EJ, Chesebro JH. Mechanisms deter- mining course and outcome of diabetic patients who have vWF may provide an explanation for the poor had acute myocardial infarction. Ann Intern Med 1997; aspirin response to aspirin in some individuals.
[9] Bell DSH. Diabetes mellitus and coronary disease. Coron Although we did not measure serum salicylate levels, compliance was ascertained by pill count [10] Mori TA, Vandongen R, Douglas AJ, McCulloch RK, Burke V.
at the time of blood sampling. Since we only Differential effect of aspirin on platelet aggregation in included diabetic patients, our results cannot be generalized to all patients in which aspirin therapy [11] Watala C, Golanski J, Pluta J, Boncler M, Rozalski M, Luzak B, et al. Reduced sensitivity of platelets from type 2 is indicated. Although there was a further inhibition diabetic patients to acetylsalicylic acid (aspirin)—its rela- of platelet function with higher aspirin doses in tion to metabolic control. Thromb Res 2004;113:101 – 13.
patients who have not achieved the desired level of [12] Fujimura A, Ohashi K, Ebihara A. Daily variations in platelet antiplatelet effects from 100 mg aspirin daily, we aggregation and adhesion in healthy subjects. Life Sci did not follow the patients for the clinical con- [13] Mammen EF, Comp PC, Gosselin R, Greenberg C, Hoots WK, sequences of dose escalation. Clinical trials are Kessler CM, et al. PFA-100 system: a new method for needed to evaluate the efficacy of different doses assessment of platelet dysfunction. Semin Thromb Hemost of aspirin with regard to the incidences of cardio- vascular complications of type 2 diabetes. Although [14] Kundu SK, Heilman EJ, Sio R, Garcia C, Ostgaard RA.
the results of our study cannot be used as a basis for Characterization of an in vitro platelet function analyzer,PFA-100k. Clin Appl Thromb/Hemost 1996;2:241 – 9.
recommending individualized aspirin dosing, it may [15] Homoncik M, Jilma B, Hergovich N, Stohlawetz P, Panzer S, stimulate such a study in this field.
Spelser W. Monitoring of aspirin (ASA) pharmacodynamics In conclusion, although a daily dose of 100 mg with the platelet function analyzer PFA-100. Thromb Hae- aspirin effectively inhibited platelet function in majority of diabetics, a considerable proportion of [16] Weksler BB, Pett SB, Alonso D, Richter RC, Stelzer P, Subramanian V, et al. Differential inhibition by aspirin of patients showed a greater platelet inhibition with vascular and platelet prostaglandin synthesis in athero- the use of higher doses. The PFA-100 closure time sclerotic patients. N Engl J Med 1983;308:800 – 5.
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[18] Sacco M, et al, on behalf of the PPP Collaborative Group.
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[28] Wong S, Appleberg M, Ward CM, Lewis DR. Aspirin [23] Tohgi H, Konno S, Tamura K, Kimura B, Kawano K. Effect of resistance in cardiovascular disease: a review. Eur J Vasc low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin. Stroke [29] Chakroun T, Gerotziafas G, Robert F, Lecrubier C, Samama MM, Hatmi M, et al. In vitro aspirin resistance detected by [24] Malhotra S, Sharma YP, Grover A, Majumdar S, Hanif SM, PFA-100k closure time: pivotal role of plasma von Wille- Bhargava VK, et al. Effect of different aspirin doses on brand factor. Br J Haematol 2004;124:80 – 5.
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