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FREQUENCY OF ASPIRIN RESISTANCE IN PATIENTS WITH CARDIOVASCULAR DISEASES.

Byline: Mohammad Faheem, Jabar Ali, Ibrahim Shah, Samiullah, Hameedullah, Mohammad Asghar, Farhat Abbas, Adnan Gul and Mohammad Hafizullah

ABSTRACT

Objectives: To find out the frequency of aspirin resistance, as measured by the inhibition of platelet aggregation, using Whole Blood Aggregometery, in patients with cardiovascular diseases presenting to out patient department of a tertiary care hospital.

Methodology: This study was conducted in the outpatient department of Cardiology, Lady Reading Hospital Peshawar, from October 2007 to January 2008. A total of 105 normal individuals not taking aspirin and 136 patients taking aspirin for cardiovascular diseases were randomly included. Blood was taken for measuring platelet aggregation using whole blood aggregometer. Result of each individual was noted on a proforma . Patients who were on any other ante-platelet like clopidogrel; or on warfarin and heparin were excluded from the study. Chi -square and independent t-test were used to find significant differences between different groups and variables.

Results: Platelet aggregability in 105 normal subjects, not taking aspirin was 9.28+-3.23ohms. So cutoff for aspirin non responsiveness was taken as 9.28-3.23=6.0 ohms. Mean aggregability of 136 cardiovascular patient, taking aspirin was 5.81+- 5.47 ohms. Mean age was 52.66+- 10 years.Male were 80(58.8%).

Patients having aggregability (greater then =)6 ohms were 47.1%(n=64). Mean aggregability of male patients was 5.66+- 5.45 ohms. Mean aggregability of female patients was 6.03 +- 5.54 ohms(p=0.69). When age was correlated with aggregability, both have a weak negative correlation (Pearson correlation coefficient= - .109 (p=0.205). Mean age of patients having aggregability [?] 5 was 53.73+- 9.73 and aggregability (greater then =) 6 was 51.46 +- 10.36 (p=0.19).

Conclusion: Aspirin resistance as defined by inhibition of platelet aggregation measured with Whole Blood Aggregometry, is a common problem. Gender and age has no significant affect on platelet aggregability.

Key Words: Aspirin resistance, Whole Blood Aggregometery, Platelet aggregability

INTRODUCTION

Plate let adhesion, activation and aggregation is the main underlying mechanism of thromboembolic vascular events; like myocardial infarction and stroke. Inhibiting platelets is the primary strategy for preventing vascular events.

Aspirin is the most widely used anti platelet drug world wide1.

Its use reduces the risk of major vascular events by approximately 25% in high risk cardiovascular patiens2.

Aspirin inhibits platelet aggregation by acetylation of platelet cyclo-oxygenase (COX) enzyme, thus blocking the transformation of 3 arachidonic acid (AA) into thormboxane (TX)A2 .

Aspirin's antiplatelet effect may not be uniform in all patients because many patients taking aspirin still suffer from vascular events. The term aspirin resistance is used to describe clinical and laboratory (biochemical) phenomena.

Clinical aspirin resistance include patients who, despite aspirin use, experience vascular events4,5.

Biochemical aspirin resistance can be defined as incomplete suppression of platelet aggregation, as assessed by various platelet function tests6-8.

Previous studies have estimated that 0.4-83.3% of patients were aspirin resistant7.

In our country very limited work has been done on this subject so far9.

This study was initiated to evaluate frequency of aspirin resistance in our local patients with cardiovascular disease.

METHODOLOGY

This study was conducted in the outpatients department (OPD) of Cardiology, Post-Graduate Medical Institute, Lady Reading Hospital (PGMI/LRH) Peshawar, from October 2007 to January 2008. A total of 105 normal individuals not taking aspirin and 136 patients, taking aspirin for cardiovascular diseases, were randomly included in the study. Patients who were included were aged 18 years or above and taking aspirin in doses 75 to 325 mg for atleast 10 days duration.

Patients who were on any other ante-platelet like clopidogrel; or on warfarin and heparin were excluded from the study.

We measured the inhibition of platelet aggregation (using WBA aggregometer) in these patients. Result of each individual along with age,gender and diagnosis were noted on a specially designed proforma prepared in accordance with the objective of the study.

The machine used for platelet aggregation was chronolog whole-blood platelet aggregometer (WBA). Other supplies needed for performing whole-blood aggregation were reagents, cuvettes, stir bars, micropipettes, tips etc.

Whole blood (0.5 ml) was diluted with an equivalent volume of isotonic saline and incubated for 5 minutes. The impedance of each sample was monitored at sequential 1-minute intervals until a stable baseline established. The agonist ADP (20 umol/L) was then added to the sample and aggregation was monitored for 6 minutes. With time platelets aggregated over electrodes and impedance increases . The final increase in impedance (in ohms) over this period was displayed as a numeric readout.

In addition, a graphical printout (i.e. chart tracing) of each electrical impedance aggregometry was also obtained. Each reading was noted on the patient's proforma. Normal individuals were used as control group. Mean aggregability (in ohms) of the normal individuals minus 1 standard deviation was taken as Cutoff value for aspirin resistance in cardiovascular patients.

All the information collected was analyzed using SPSS version 11. Categorical variables were presented as frequencies and percentages. Continuous variables were presented as mean+- SD. Categorical variables were compared using chi square test. Continuous variables were compared using independent sample t-test. Pvalue less than 0.05 was considered significant.

RESULTS

When Platelet aggregabllity was performed in the control group (105 normal subjects, not taking aspirin)it was found to be 9.28+-3.23ohms (Figure 1).

Mean age of the 136 cardiovascular patients, taking aspirin was 52.66+-10.00 years. Male were 80(58.8%). Female were 56(41.2%). Most (82.4%) were suffering from IHD. Mean aggregability of all these patients was found to be 5.81+-5.47 ohms (Figure 2).

Patients having aggregability (greater then)6 ohms (aspirin resistance) were 47.1 %(n=64). Patients having aggregability,(less then) 6 ohms (aspirin sensitive) were 52.9 %( n=72) {Figure 3}.

Mean aggregability of all the male patients was 5.66+-5.45 ohms. Mean aggregability of all the female patients was 6.03+-5.54 ohms (p=0.69) {Figure 4}.

Sub group analysis of aspirin sensitive and resistant patients, on the basis of gender showed that among total 72 patients having aggregability (less then)6 ohms, male were 43 (59.7%) female were 29 (40.3%).

Among total 64 patients having aggregability (greater then)6 ohms male were 37 (57.8%) female were 27 (42.2%) (p=0.821) {Figure 5}.

When age was correlated with aggregability, both have aweak negative correlation. Pearson correlation coefficient= -.109 (p=0.205) {Figure 6}. Mean age of patients having aggregability (less then) 6 ohms was 53.73+-9.73 years. Mean age of Patients having aggregability (greater then)6 ohms was 51.46 +- 10.36 years (p=0.19).

As the cut off value for aspirin resistance was taken as the mean aggregability of normal individuals minus one standard deviation, so it was calculated as 9.28-3.23=6.05 ohms.

DISCUSSION

The issue of aspirin resistance has been emphasized in medical literature for more than a decade10-13.

Very limited work has been done in Pakistan to test platelet aggregability in patientstaking aspirin .

Prevalence of aspirin resistance reported 7 by previous studies ranged from 0.3 to 80% . Our study showed 47.8% of patients with cardiovascular disease to be aspirin resistant. Marielorkipandze et al reported 18% prevalence of aspirin resistance. They used whole blood aggregometry and took 3 ohms as cutoff 14 value for defining aspirin resistance .

Harrison P et al, using PFA 100 device, reported 22% prevalence of aspirin resistance patients taking aspirin after TIA or stroke Sane DC et al found that 57% of with congestive Heart failure were 16 resistance .

Anderson K at al found 35% resistance in post MI patients, using PFA 17 of service assay . With the ultra point of care rapid function assay ASA, the prevalence of 18,19 resistance was 19% to 23% .

The reason for this high range of prevalence among different studies, may be differences in studied populations, lack of formal definition of aspirin resistance, selecting different cutoff values for defining aspirin responders and non- responders and use of different diagnostic 7 methodologies by different researches .

Light transmission aggregometry has been in use for last 40years and is considered the historical gold standard for testing platelet 20 function .

Its use is very time consuming as it involves preparation of platelet rich plasma, needs manipulation by a skilled technician and its standardization is often poor limiting its use to 20-25 dedicated laboratories .

We used whole blood aggregometry (WBA) using chronolog aggregometer, because it is easy to use, gives faster results, does not require centrifugation and evaluates platelets in a physiologic milieu in presence of red and white blood cells, which are known to modulate platelet 26 functions .

WBA measures the electrical impedance, in ohms, between two electrodes immersed in whole blood as the platelets are aggregated on 21,22,27 them .

Previous studies, which used WBA for platelet function, used different cutoff values ranging from 3ohms to 18ohms for defining aspirin 16,28 resistance .

We evaluated 105 normal subjects, not taking aspirin and used their mean minus 1 SD agregability as cutoff value for aspirin resistance. This principle has been used previously by other 28,29 researchers .

Literature review shows that which ever test is used and whatever criteria is applied , still a good percentage of patients will turn out to be aspirin resistant.

Considering the common use of aspirin, this prevalence is of particular importance. On the other hand studies like ours, in which platelet functions are tested in vitro, can find only biochemical resistance.

To see whether this biochemical resistance translates in to clinical resistance the patients need to be followed up in prospective studies for occurrence of any clinical events. Work has been done in this regard and studies have suggested that risk of major cardiovascular events increases in patients who are 30,31 non responder to aspirin .

Our study did not show any significant difference between the platelet aggregabililty of male and female patients (5.66+5.45 ohms vs 6.03+5.54 ohms) with p=0.69. Previous studies showed female patients to have high platelet aggregability despite aspirin 29,32 use .

In our study there is a trend towards lower platelet aggregability as the age increases, but this negative correlation is weak (r=-.109) and insignificant (p= 0.205).

Previous studies reported contradicting results about the association of age and platelet aggregability.

Ivandic BTet al showed that age has no 29 association with platelet aggregability . Gum PA at al reported that aspirin semi responders 32 were significantly older. Different mechanisms have been implicated to cause aspirin resistance including poor compliance, in adequate dosing, interindividual variability in response to aspirin, genetic polymorphism in platelet receptors, extra 3 3 platelet sources of thromboxane A2 (e.g. monocytes/macrophages) and concomitant NSAIDs 34 use .

In addition platelet aggregability responses can vary with mental stress, age , gender , race, diet and hematocrit level and a person may have 35 different responses on repeated determinations .

CONCLUSION

Aspirin resistance as defined by inhibition of platelet aggregation measured with Whole Blood Aggregometry, is a common problem. Gender and age has no significant affect on platelet aggregability.

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Publication:Journal of Postgraduate Medical Institute
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Date:Dec 31, 2012
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