INTRODUCTION
The pathological condition of many coronary artery diseases (CADs) or difficulties of coronary surgical interfering is related to the thrombi formation in the artery because of higher agglomeration of platelets. Thereby, many drugs were introduced for the treatment of these problems such as clopidogrel, prasugrel, and ticagrelor.[1,2]
After coronary surgical interfering and attachment of stents, thrombi may form and called stent thrombosis. To avert this problem, two types of antiplatelets drugs are used, clopidogrel and aspirin, but this combination may lead to elevate the incidence of digestive tract bleeding.[3] Thus, one of the oral proton-pump inhibitors (PPIs) drugs is used with the above drugs to minimize the incidence of bleeding.[4]
After conversion of clopidogrel to its active structure, it connects to P2Y12-ADP receptor of platelet by disulfide link thereby prohibits the phosphorylation of vasodilator-stimulated phosphoprotein and then platelet activation.[5]
The shifting of clopidogrel to its active structure is done by a group of enzymes called cytochrome P-450 such as CYP3A4 and CYP2C19. Other drugs like atorvastatin also need CYP3A4 for its conversion, so this drug may influence on the level of active form of clopidogrel and thereby on its adequacy.[6,7]
PPIs are a group of drugs that used CYP2C19 enzyme for its processing inside the body and it per se acts as a CYP2C19 enzyme suppressor. Consequently, the dual use of PPI and clopidogrel may cause drug interference that reduces the activated level of clopidogrel and lessens its efficacy as platelets aggregation inhibitor thereby could intensify the incidence of blood vessel obstruction/or stent occlusion,[8] whereas other studies reported that unimportant inference might occur with dual use of PPIs and clopidogrel.[9,10]
Diverse forms of PPIs generate diverse effects on clopidogrel activity. Inferior level of activated clopidogrel testified with esomeprazole neither with pantoprazole.[11,12] Omeprazole has a high affinity to CYP2C19; thereby, it made interferences with the activity of many drugs other than clopidogrel such as warfarin, phenytoin, and diazepam. Whereas Pantoprazole has feeble affinity to CYP2C19 and therefore has feeble interferences with other drugs.[13]
The objective of this study is to appraise the effects of three different types of PPIs, pantoprazole, esomeprazole, or rabeprazole on clopidogrel activity by measuring the maximal platelet aggregation percent (MPA%) before and after the period of treatment that lasted for 10 days.
METHODS
Study design and location
The study was a prospective clinical study performed at Ibn Al-Nafees Hospital in Iraq. Primarily, one hundred patients (30 females and 70 males) ranging from 45 to 60 years of any sex with CAD consecutively joined in this study.
Patients' selection
The choosing of the patients was made based on their medical background, clinical symptoms, and tests such as electrocardiogram and echocardiogram stress test. Subsequently, the patients with unsuitable criteria will be omitted such as history of acute coronary disease, bleeding, impaired pulmonary function, thrombocytopenia, hepatic disease, ulcer of gastrointestinal tract, and concurrent therapy with CYP3A suppressors or activators.
Written informed consent was acquired from each patient before his or her participation in this study. Patients' selection and study protocol conformed to the Helsinki ethical guidelines and were approved by the Institutional Ethics Committee.
Depending on the type of treatment, the patients randomly parted into four groups: one group treated with clopidogrel (Plavix, France) 75mg daily alone and other groups associated with PPI drugs either pantoprazole (T and D Pharma) 20 mg daily or esomeprazole (AstraZeneca) 20 mg daily or rabeprazole (Jamjoom Pharma) 20mg daily for 10 days of treatment.
The percentage of inhibition of platelet aggregation (IPA%) was computed using this formula:
IPA% = ([baseline MPA% – with treatment MPA%]/baseline MPA%) ×100%
Data collection and laboratory measurements
In the morning and after 12 h fasting, the blood specimens were drawn from each patient and put in a test tube coated with sodium citrate 3.2% on day 0 before the treatment (baseline) and on day 10 after 3 h of drug received to quantify the MPA%.
The assay of MPA% (with the presence of clopidogrel in the blood of the patients) reliance on deactivation of ADP (20 μmol/L) added, that lead to decline in the aggregation of platelet-rich plasma (PRP) and increase in the light transmittance which quantified by light transmission aggregometry. The use of platelet-poor plasma as blank is to set 100% transmission.[14]
Statistical analyses
All numerical data were arranged as mean ± standard deviation with a 95% confidence interval. Comparisons of continuous variables were evaluated using Student's t-test, P < 0.05 was regarded to be statistically significant. All statistical analyses were achieved using SPSS version 18.0 (Wiley; 1st edition, Hoboken, New Jersey, United States) for Windows and Microsoft Excel.
RESULTS
Table 1 illustrates the features of demographic characteristics, biochemical data, and statistical analyses of the selected variables in the studied groups. Of the 100 selected patients in this study, 25 patients were treated with clopidogrel alone and consider as control, 25 patients were treated with clopidogrel plus pantoprazole, 25 patients were treated with clopidogrel plus esomeprazole, and 25 patients were treated with clopidogrel plus rabeprazole. No patients were lost during the follow-up period.
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Table 1: Clinical data and demographic characteristics of the participants' patients
Notably, the baseline features of the studied groups were well adjusted between them. Likewise, the mean levels of the MPA% prior treatments for all groups seem to be approximately analogous.
Consequently, after 10 days of treatments, the mean levels of MPA% were nonsignificantly (P > 0.05) altered in patients on co-therapy of clopidogrel and pantoprazole and in patients on co-therapy of clopidogrel and esomeprazole as compared to patients on monotherapy of clopidogrel [Table 1]. Conversely, the mean levels of MPA% were significantly (P < 0.05) elevated in patients on co-therapy of clopidogrel and rabeprazole as compared to patients on monotherapy of clopidogrel [Table 1].
The bar graph that sketched in [Figure 1] elucidates the IPA% with the uses of clopidogrel alone or with the uses of other PPIs after 10 days of treatment. High inhibition (52.5%) was achieved in patients on clopidogrel alone and low inhibition (43.3%) was verified in the patients on clopidogrel and rabeprazole.
Figure 1: Bar graph clarified the percentage of inhibition of platelet aggregation with the uses of clopidogrel alone or with the other proton-pump inhibitors for 10 days of treatments
Figure 2 charts the considerable power analysis for the minimum detectable effect (MDC%) of esomeprazole, pantoprazole, or rabeprazole addition to clopidogrel on MPA% after 10 days of treatments.
Figure 2: Power analysis for the minimum detectable effect of esomeprazole, pantoprazole, or rabeprazole addition to clopidogrel on maximal platelet aggregation percent after 10 days of treatments. Assuming alpha = 0.05, beta = 0.2, power (1-beta) =0.8 (80%), and sample size = 25
Concerning the 80% probability of minimum detectable change (MDC) of MPA% and minimum detectable change percentage (MDC%) for the addition of Esomeprazole (20 mg daily) or Pantoprazole (20 mg daily) or rabeprazole (20 mg daily) to clopidogrel treatment (75 mg daily), the results were elevated by 8.93% (21.27%), 9.4% (22.46%), and 9.996% (23.8%), respectively.
DISCUSSION
Many reports stated that antiplatelet drugs such as clopidogrel were negatively interfere with drugs that inhibit proton pump. Therefore, in the current study, we clinically analyzed this interference between clopidogrel and many drugs that inhibit proton pumps such as pantoprazole, esomeprazole, and rabeprazole.
The implication of this study showed that the concurrent use of clopidogrel and pantoprazole or esomeprazole for 10 days of treatment was not importantly altered MPA%. Conversely, the simultaneous use of clopidogrel and rabeprazole for 10 days of treatment was importantly attenuate MPA% variation.
As the potency of PPIs drugs on many types of cytochrome enzymes elevated as their concomitant use with clopidogrel be unfavorable such as lansoprazole or rabeprazole. Likewise, when these potency of PPIs drugs decrease the concurrent use with clopidogrel be favorable such as pantoprazole or esomeprazole.[15,16]
Many studies confirm with the inferences of this study and reported that omeprazole, lansoprazole, and rabeprazole, but not pantoprazole or esomeprazole, have a diminishable impact on antiplatelet activity of clopidogrel in patients with coronary diseases.[17,18,19,20,21] Conversely, other research stated that concomitant use of clopidogrel and pantoprazole or esomeprazole attenuates the antiplatelet aggregation of clopidogrel.[22]
CONCLUSION
Of three types of PPIs drugs, pantoprazole, esomeprazole, ands rabeprazole, the use of pantoprazole or esomeprazole as cotreatment with clopidogrel to reduce the incidence of internal bleeding is more therapeutically satisfiable than the use of rabeprazole.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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