Aspirin resistance and ischemic heart disease on Iranian experience
Masoumeh Sadeghi1, Afsoon Emami2, Naghmeh Ziyaei3, Majid Yaran2, Allahyar Golabchi3, Azam Sadeghi4
1 Cardiac Rehabilitation Research Center, Isfahan Cardiovascular Research Institute, Isfahan, Iran
2 Isfahan University of Medical Sciences, Isfahan, Iran
3 Department of Cardiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
4 Cardiovascular Research Center, Isfahan Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
|Date of Submission||10-Dec-2011|
|Date of Acceptance||12-Mar-2012|
|Date of Web Publication||03-Aug-2012|
Cardiac Rehabilitation Research Center, Isfahan Cardiovascular Research Institute WHO Collaborating Center. (http://crc.mui.ac.ir), Isfahan University of Medical Sciences (http://mui.ac.ir), Isfahan, PO BOX: 81465 1148
Source of Support: None, Conflict of Interest: None
Background: Coronary artery disease (CAD) and myocardial infarction are the most common causes of mortality and morbidity all over the world. Aspirin resistance is an important part of therapeutic failure in patients who experience several atherosclerotic events despite aspirin therapy. Different studies have reported aspirin resistance between 5% and 45% all over the world.
According to different responses to aspirin therapy in countries and lack of adequate studies on aspirin resistance in Iran, this study was designed for evaluation of aspirin resistance in ischemic patients.
Materials and Methods: Total 170 patients with documented coronary artery stenosis with were enrolled in this cross-sectional prospective study. Two cc urine samples were obtained from all the subjects. Then a questionnaire including questions about major risk factors (hypertension, diabetes, hyperlipidemia, obesity and smoking) was completed for each patient. Thromboxane B2 level in urine was measured two times for each patient by one kit of via ELISA method. Gensini modified was usedfor assessment of severity of coronary arteries involvement. Data were analyzed via SPSS 16. with general linear model (univariate).
Results: 75.3% of studied patients were aspirin resistant. There was significant relationship between angiography score and aspirin resistance (P<0.001).Our results also showed that aspirin resistance is more common in studied women than men (P=0.003).Significant correlation was observed between diabetes and aspirin resistance in studied subjects (P=0.023).
Conclusion: Our study showed aspirin resistance in a sample of Iranian ischemic patients is so prevalent which is higher than other studies in another communities and also aspirin resistance is more common in patients with severe CAD.
Keywords: Aspirin resistance, coronary artery disease, thromboxane B2 level
|How to cite this article:|
Sadeghi M, Emami A, Ziyaei N, Yaran M, Golabchi A, Sadeghi A. Aspirin resistance and ischemic heart disease on Iranian experience. Adv Biomed Res 2012;1:33
|How to cite this URL:|
Sadeghi M, Emami A, Ziyaei N, Yaran M, Golabchi A, Sadeghi A. Aspirin resistance and ischemic heart disease on Iranian experience. Adv Biomed Res [serial online] 2012 [cited 2015 Jul 5];1:33. Available from: http://www.advbiores.net/text.asp?2012/1/1/33/99345
| Introduction|| |
Coronary artery disease (CAD) is the most common causes of mortality and morbidity all over the world. Aspirin is a very important and inexpensive medication for secondary prevention from atherosclerotic events. Many studies have shown that aspirin can prevent from 25% of atherosclerotic events. ,
Arachidonic acid is converted into thromboxane A2 via cyclo-oxygenase (COX) enzyme within the platelets. Thromboxane A2 prevents from platelet aggravation via fibrin receptor inhibition on the platelet surface. Aspirin acetylise catalytic region of cox enzyme and prevents from conversion of arachidonic acid to thromboxane A2. ,
Biochemical aspirin resistance is defined as stable platelet activity which is calculated via activity measurement tests and occurs despite correct use of aspirin in common therapeutic dose.  Aspirin resistance is an important part of therapeutic failure in patients who experience several atherosclerotic events despite its use. , Studies showed different factors which are effective on aspirin resistance like correct use of drug, dosage, drug interactions and genetic and racial polymorphism. ,,,
A growing body of evidences show that up to 70% of aspirin-takers are at risk of atherothrombotic complications because of aspirin resistance.  Kim et al. study showed 14% aspirin resistance in patients with CAD and ischemic cerebrovascular disease.  Shen et al. study showed 21% aspirin resistance in asymptomatic subjects (30% in women and 16% in men).  Pinto Slottow et al. reported 23% aspirin resistance in patients with stent thrombosis (ST).  Sanioglu et al. showed 60% resistance in postoperative patients who underwent elective coronary artery bypass graft (CABG).  Acikel et al. reported 29.9% laboratory-defined aspirin resistance in patients with unstable angina.  Akhtar et al. study showed 12% aspirin resistance in patients with stable CAD. 
A probable reason for different responses to aspirin in different races may be due to polymorphism in cyclooxygenase 1 and 2 genes and other metabolites of arachidonic acid. 
Diagnosis of aspirin resistance is important in different communities because its impact on therapeutic costs and therapeutic response. Thromboxane B2 is a metabolite of thromboxane A2 in urine which shows the in vitro response to aspirin and is a simple, non-invasive, and inexpensive. ,
According to different responses to aspirin therapy in different countries and lack of adequate studies on aspirin resistance in Iran, this study was designed for evaluation of aspirin resistance in Iranian ischemic patients .We also assessed the correlation between its resistance with severity of coronary artery involvement which hasn't report in previous studies.
| Materials and Methods|| |
This study was a cross-sectional prospective study on patients with documented coronary artery stenosis via angiography which were admitted in University hospitals in Isfahan.
Inclusion criteria were: Age between 40 and 70 years, 75-100 mg daily aspirin use, significant stenosis in at least one coronary artery (more than 75% of intravessel diameter). Exclusion criteria were: Hb <8 g/dl, platelets <150000/dl, non-steroid anti-inflammatory medications, plavix and ticlopidin use, surgery during last 2 weeks, malignancy or acute inflammatory disease, heparin and warfarin use, emergency angiography. One hundred and seventy participants were selected via a simple sampling method among hospitalized patients with inclusion criteria. Written consents were obtained from all of the participants.
Subjects were divided to three groups (stable angina, unstable angina, and myocardial infarction (MI)) by history and medical record. Significant severity of coronary artery stenosis has been confirmed by three cardiologists after angiography and showed as quantitative numbers with the Gensini method. 
Two milliliters urine samples were obtained from all the subjects. Then a questionnaire was filled about risk factors (hypertension, diabetes, hyperlipidemia, and smoking) for each patient. Hypertension was defined according to WHO definition as systolic blood pressure ≥140 mmHg and diastolic blood pressure ≥90 mmHg or anti-hypertensive medications use.  Diabetes was defined as fasting blood sugar ≥126 mg/dl or 2 h post prandial blood sugar >200 or use of hypoglycemic agents.  Hyperlipidemia was defined as total cholesterol >200 mg/dl or use of anti-cholesterol agents or triglyceride >200 mg/dl or use of anti-triglyceride agent.  Cigarette smokers were defined as individuals who smoked more than 10 packets in last year and were between 20 and 60 year old and non-smokers were defined as individuals who never smoked any cigarettes. 
Thromboxane B2 level in urine was measured via the ELISA method. A diluted sample of subjects urine, a control sample and a solution of purified thromboxan attached to alkaline phosphatase and monoclonal antibody of mouse were put in one container and a chromogen agent was added to the container for assay.  For more accuracy of the results, ELISA was done two times, with two separated same kits for each participant. Intensity of produced color in the container had reverse correlation with concentration of thromboxan in the urine sample. 
The modified Gensini method was used for assessment of severity of coronary arteries involvement (coronary angiography score).  Aspirin resistance was described by quantitative numbers and based on the definition in the laboratory kit, numbers≥ 1700 ng/dl were considered as aspirin resistance. Data were analyzed via SPSS 16; general linear model (univariate) was used for assessment of correlation between aspirin resistance with CAD risk factors and coronary artery involvement. A P value less than 0.05 was considered as significant.
| Results|| |
Total 170 subjects were enrolled in this study. [Table 1] shows characteristics of study participants. Most of the studied subjects were male (53.5%) and more than half of them (55.9%) had chronic stable angina.
Results of this study showed that 128 of 170 participants (75.3%) had aspirin resistance.
Correlation between aspirin resistance with CAD risk factors was assessed too [Table 2]. Our results showed, aspirin resistance is significantly higher in studied women (P=0.003, B=768.697). Also, aspirin resistance was significantly higher in diabetic subjects (P=0.023, B=604.353). There wasn't any significant relationship between aspirin resistance and other CAD risk factors in this study.
|Table 2: Correlation between aspirin resistance and mean of baseline characteristics in study participants|
Click here to view
Results of our study showed that patients with more sever CAD (according to Gensini score), had more resistance to aspirin (P<0.001, CI=±3.712, B=7.485, CI=±3.712) [Figure 1].
| Discussion|| |
In this study, we estimated aspirin resistance in patients with coronary artery stenosis about 75.3%. This percentage is higher than the results of previous studies.
Several studies have reported aspirin resistance in different communities between 5.5% and 60% according to definition and measured parameters. 
Christiaens et al. study showed 29% aspirin resistance in patients with stable angina under treatment with aspirin.  Akay et al. reported 27% aspirin resistance in healthy subjects. 
Recently, a growing body of evidences show that about 70% of aspirin-takers are at risk of atherothrombotic complications. 
Shen et al. study showed 21% aspirin resistance in asymptomatic subjects (30% in women and 16% in men). 
Sanioglu et al. showed 60% aspirin resistance in postoperative patients who underwent elective CABG. 
Singla et al. assessed laboratory aspirin resistance in patients with type II diabetes and reported 7.2% aspirin resistance and 39.1% semi-aspirin resistance. 
Zimmermann et al. study reported Laboratory aspirin resistance up to 60% in patients after stroke or peripheral arterial disease, up to 70% in stable coronary heart disease, and even up to 80% in acute MI. 
Aspirin-resistance percent (75.3%) in our study is close to results of Zimmermann et al. study (70% in stable CAD and 80% in MI)  , may be because of similar sample group disease the subjects have of both studies.
These differences between our results and other studies may have several reasons like: Racial differences and genetic polymorphism between different communities; we didn't separate aspirin-resistant and semi-aspirin resistant patients from each other like some studies.
Another probable reasons for different percent of aspirin resistance in our study is more non-smokers (80%) in our participants. Studies have reported that biochemical aspirin resistance is more common in non-smokers. 
The prevalence of aspirin resistance depends on the method of testing  and this may be another reason for different reported prevalence of aspirin resistance between different studies.
Another study in Iran showed that approximately 49.2% patients were resistant to ASA, 15.3% borderline response, and 35.5% were sensitive to ASA. Acetyl salicylic acid resistance same as our study was present in a high number of patients with chronic stable angina. Moreover, advanced age and smoking had a direct influence on the aspirin resistance. 
The top point of this study was that aspirin resistance was measured with the ELSIA method which is the most accurate method for measurement of aspirin resistance and to get more accurate results, in each patient aspirin resistance was checked twice with two separate same kits.
Also in this study, we assessed the correlation between aspirin resistance with severity of CAD which hasn't been assessed in the previous studies.
| Conclusion|| |
Our results showed that in patients with coronary artery stenosis, aspirin resistance has significant correlation with diabetes, female sex, and severity of coronary artery stenosis.
According to high prevalence of aspirin resistance in our community based on the current study and considering potential cardiovascular complications and their mortality and morbidity due to aspirin resistance, it is important to assess the aspirin sensitivity as a screening method for evaluation of patients participated to aspirin therapy. In this way, we can increase anti-platelet effect with an alternative or adjuvant medication and benefit from the effects of this medication in treatment of patients with CAD.
Our study was some limitations. Aspirin use in this study was based on response to a questionnaire and wasn't confirmed by pill count or salicylate level, we didn't separate aspirin-resistant and semi-aspirin resistant patients from each other.
| Acknowledgment|| |
Authors have special thanks from Miss Safoura yazdekhasti and staffs of Yaran laboratory for their sincerely helping in this study. Persian language of this article has been published in Journal of Isfahan Medical School.
| References|| |
|1.||Collaborative overview of randomized trials of antiplatelet therapy-I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ1994;308:81-106. |
|2.||Collaborative meta-analysis of randomized trials of antiplateler therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86. |
|3.||Vane JR, Bakhlle YS, Botting RM. Cyclooxygenaz 1 and 2. Annu Rev Pharmacol Toxicol 1998;38:97-120. |
|4.||Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl I Med 2001;345:1809-17. |
|5.||Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol1998;38:97-120. |
|6.||Hankey GJ, Eikelboom JW. Aspirin resistance BMJ 2004;328:477-9. |
|7.||Weber AA, Przytulski B, Schanz A, Hohlfeld T, Schror K. Towards a definition of aspirin resistance: A typological approach. Platelets2002;13:37-40. |
|8.||Smout J, Stansby G. Aspirin resistance. Br J Surg 2002;89:4-5. |
|9.||Tarjan J, Salamon A, Jager R, Poor F, Barczi V, Dinnyes J, et al. [The rate of acetylsalicylic acid non-respondents among patients hospitalized for acute coronary disease, previously undergoing secondary salicylic acid prophylaxis]. Orv Hetil 1999;140:2339-43. |
|10.||Patrono C, Coller B, Dalen JE, FitzGerald GA, Fuster V, Gent M, et al. platelet-active drugs: The relationships among dose, effectiveness, and side effects. Chest2001;119:39S-63S. |
|11.||Halushka MK, Walker LP, Halushka PV. Genetic variation in cyclooxygenase 1: Effects on response to aspirin. Clin Pharmacol Ther 2003;73:122-30. |
|12.||Kasotakis G, Pipinos II, Lynch TG. Current evidence and clinical implications of aspirin resistance. J Vasc Surg 2009;50:1500-10. |
|13.||Kim H, Lee HK, Han K, Jeon HK. Prevalence and risk factors for aspirin and clopidogrel resistance in patients with coronary artery disease or ischemic cerebrovascular disease. Ann Clin Lab Sci 2009;39:289-94. |
|14.||Shen H, Herzog W, Drolet M, Pakyz R, Newcomer S, Sack P,et al. Aspirin Resistance in healthy drug-naive men versus women (from the Heredity and Phenotype Intervention Heart Study). Am J Cardiol 2009;104:606-12. |
|15.||Pinto Slottow TL, Bonello L, Gavini R, Beauzile P, Sushinsky SJ, Scheinowitz M,et al. Prevalence of aspirin and clopidogrel resistance among patients with and without drug-eluting stent thrombosis. Am J Cardiol 2009;104:525-30. |
|16.||Sanioglu S, Tetik S, Sokullu O, Deniz H, Aydemir N, Yilmaz M,et al. Aspirin resistance after CABG. Thorac Cardiovasc Surg 2009;57:281-5. |
|17.||Acikel S, Yildirir A, Aydinalp A, Bal U, Kaynar G, Ozin B, et al. The clinical importance of laboratory-defined aspirin resistance in patients presenting with non-ST elevation acute coronary syndromes. Coagul Fibrinolysis 2009;20:427-32. |
|18.||Akhtar N, Junaid A, Khalid A, Ahmed W, Shah MA, Rahman H. Report: Frequency of aspirin resistance in patients with coronory artery disease in Pakistan. Pak J Pharm Sci 2009;22:230-3. |
|19.||Bruno A,McConnel JP,Mansbach HH,Cohen SN,Tietjen GE,Bang NU.Aspirin and urinary 11-dehydrothroboxaneB2 in African American stroke patients.Stroke 2002;33:57-60. |
|20.||Sanderson S,Emery J,Baglin T,Kinmonth AL.Narrtaive Review:Aspirin resistance and its clinical implications.Ann Intren Med 2005;142:370-80. |
|21.||Sullivan DR,Marwick TH,Freedman SB.A new method of scoring coronary angiogram to reflect extent of coronary atherosclerosis and improve correlation with major risk factors AmHeartJ 1990;119:1262-6. |
|22.||Sadeghi M, Roohafza HR, Kelishadi R. High Blood pressure and associated cardiovascular risk factors in Iran, IHHP. Med J Malaysia 2004; 59(4): 295-304. |
|23.||Sadeghi M, Roohafza HR, Shirani SH, Poormoghadas M, Kelishadi R, Baghaie A. Diabetes and associated cardiovascular risk factors in Iran: Isfahan Healthy Heart Programms. Annals Academy of Medicine, Singapore 2007; 36: 175-80. |
|24.||Sadeghi M, Roohafza HR. Serum lipid distribution and prevalence of dyslipidemia in urban and rural communities in Iran, IHHP. Pakistan Journal of Cardiology 2004; 14 (2):88-95. |
|25.||Roohafza H, Shahnam M, Zolfaghari B, Toloei HR, Tavassoli A, Sadeghi M, et al. Stress level and smoking status in central Iran: Isfahan Healthy Heart Program. ARYA Atherosclerosis Journal 2011, 6(4): 144-148. |
|26.||Peterson P. Aspirin resistance: Fact and Fiction. Medscape 2005; 12-20. |
|27.||Siavash M, Sadeghi M, Salarifar F, Amini M, Shojaee-Mporadie F. Comparison of body mass index and waist/height ratio in predicting definite coronary artery disease. Ann Nutr Metab 2008;53(3):162-6. |
|28.||Gasparyan AY, Watson T, Lip GY. The role of aspirin in cardiovascular prevention: Implications of aspirin resistance. J Am Coll Cardiol 2008;51:1829-43. |
|29.||Christiaens L, Ragot S, Mergy J, Allal J, Macchi L.Major clinical vascular events and aspirin-resistance status as determined by the PFA-100 method among patients with stable coronary artery disease: A prospective study.Blood Coagol Fibrinolysis2008;19:235-9. |
|30.||Akay OM, Canturk Z, Akin E, Bal C, Gulbas Z. Aspirin resistance frequency: A prospective study in 280 healthy Turkish volunteers. Clin Appl Thromb Hemost2009;15:98-102. |
|31.||Singla MK, Lahiri P, Mukhopadhyay P, Pandit K, Chaudhuri U, Chowdhury S. A study of aspirin resistance in type 2 diabetes. J Indian Med Assoc 2008;106:722-3. |
|32.||Zimmermann N, Hohlfeld T. Clinical implications of aspirin resistance. Thromb Haemost 2008;100:379-90. |
|33.||Sanderson S,Emery J,Baglin T,Kinmonth AL.Narrtaive Review:Aspirin resistance and its clinical implications.Ann Intren Med 2005;142:370-80. |
|34.||Durmaz T, Keles T, Ozdemir O, Bayram NA, Akcay M, Yeter E, et al. Heart rate variability in patients with stable coronary artery disease and aspirin resistance. Int Heart J 2008;49:413-22. |
|35.||Eskandarian R, Darabian M, Heshmatnia J, Ghorbani R. Acetyl salicylic acid resistance in patients with chronic stable angina and the correlation with coronary risk factors. Saudi Med J 2012;33:39-43.1 |
[Table 1], [Table 2]