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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 5  |  Issue : 3  |  Page : 327-330

Platelets prohibition with clopidogrel alone versus with proton-pump inhibitors


Department of Pharmaceutics, College of Pharmacy, Al-Nahrain University, Baghdad, Iraq

Date of Submission30-Jun-2021
Date of Acceptance20-Jul-2021
Date of Web Publication7-Sep-2021

Correspondence Address:
Feryal Hashim Rada
Department of Pharmaceutics, College of Pharmacy, Al-Nahrain University, Baghdad
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_134_21

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  Abstract 


Background: Clopidogrel and proton-pump inhibitors (PPIs) are inert drugs that need cytochrome P450 enzymes to switch chemically to their active forms. The aim of this research is to evaluate the influences of three different types of PPIs on platelet restraining effect of clopidogrel. Methods: This study consecutively enlisted 100 patients (30 females and 70 males), ranging from 45 to 60 years with coronary artery disease from Ibn Al-Nafees Hospital. The patients randomly divided into four groups and each group consists of 25 patients. One of them treated with clopidogrel tablet (75 mg daily) alone. Others treated with clopidogrel (75 mg daily) and pantoprazole (20 mg daily), or esomeprazole (20 mg daily), or rabeprazole (20 mg daily) for a period of 10 days. Light transmission aggregometry instrument was used for the estimation of maximal platelet aggregation percent (MPA%). Results: The statistical outcomes after 10 days of treatments demonstrated that high inhibition of platelet aggregation was achieved in patients on clopidogrel alone 52.5% and low inhibition of platelet aggregation was confirmed in patients on clopidogrel and rabeprazole 43.3%. Conclusions: Even each drug of PPIs that used in this study changed the MPA% as compared to clopidogrel alone, but rabeprazole had an appreciable impact on MPA% and thereby on clinical adequacy of clopidogrel as platelets aggregation preventer drug.

Keywords: Clopidogrel, esomeprazole, pantoprazole, rabeprazole


How to cite this article:
Rada FH. Platelets prohibition with clopidogrel alone versus with proton-pump inhibitors. Biomed Biotechnol Res J 2021;5:327-30

How to cite this URL:
Rada FH. Platelets prohibition with clopidogrel alone versus with proton-pump inhibitors. Biomed Biotechnol Res J [serial online] 2021 [cited 2021 Dec 6];5:327-30. Available from: https://www.bmbtrj.org/text.asp?2021/5/3/327/325612




  Introduction Top


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 Top


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 Top


[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.
Table 1: Clinical data and demographic characteristics of the participants' patients

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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

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[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

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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 Top


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 Top


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.



 
  References Top

1.
Rada FH. Platelet reactivity with a third generation thienopyridine drug versus with a second-generation thienopyridine drug. Int J Res Pharm Sci 2020;11:3704-9.  Back to cited text no. 1
    
2.
Rada FH. Antiplatelet adequacy of cyclopentyl triazolopyrimidine versus clopidogrel IN Patients with coronary heart disease. Asian J Pharm Clin Res 2018;11:536-9.  Back to cited text no. 2
    
3.
Nakayama M, Iwakiri R, Hara M, Ootani H, Shimoda R, Tsunada S, et al. Low-dose aspirin is a prominent cause of bleeding ulcers in patients who underwent emergency endoscopy. J Gastroenterol 2009;44:912-8.  Back to cited text no. 3
    
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Yasuda H, Yamada M, Sawada S, Endo Y, Inoue K, Asano F, et al. Upper gastrointestinal bleeding in patients receiving dual antiplatelet therapy after coronary stenting. Intern Med 2009;48:1725-30.  Back to cited text no. 4
    
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Barragan P, Bouvier JL, Roquebert PO, Macaluso G, Commeau P, Comet B, et al. Resistance to thienopyridines: Clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003;59:295-302.  Back to cited text no. 5
    
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Hasan NA, Al-Baghdadi MH, Rada FH. Assessment of adverse effect of atorvastatin with platelet p2y12-adp receptor antagonist on platelets aggregation and renal function in coronary heart disease treated patients. Inter J Res Pharma Chem 2014;4:274-82.  Back to cited text no. 6
    
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Rada FH, Hasan NA, Al-Baghdadi MH. Hepatotoxicity of combined therapy of atorvastatin with platelet P2Y12-ADP receptor antagonist in coronary heart disease treated patients. The Iraqi Postgraduate Med J 2015;14:108-13.  Back to cited text no. 7
    
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Ancrenaz V, Daali Y, Fontana P, Besson M, Samer C, Dayer P, et al. Impact of genetic polymorphisms and drug-drug interactions on clopidogrel and prasugrel response variability. Curr Drug Metab 2010;11:667-77.  Back to cited text no. 8
    
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O'Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: An analysis of two randomised trials. Lancet 2009;374:989-97.  Back to cited text no. 9
    
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Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 2009;120:2322-9.  Back to cited text no. 10
    
11.
Angiolillo DJ, Gibson CM, Cheng S, Ollier C, Nicolas O, Bergougnan L, et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: Randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther 2011;89:65-74.  Back to cited text no. 11
    
12.
Harmsze AM, vanWerkum JW, Taubert D, Hackeng CM, Deneer VH. Esomeprazole but not Pantoprazole is associated with lower plasma concentrations of clopidogrel's active metabolite. Ann Pharmacother 2011;45:542-3.  Back to cited text no. 12
    
13.
Umemura K, Furuta T, Kondo K. The common gene variants of CYP2C19 affect pharmacokinetics and pharmacodynamics in an active metabolite of clopidogrel in healthy subjects. J Thromb Haemost 2008;6:1439-41.  Back to cited text no. 13
    
14.
Gurbel PA, Bliden KP, Hiatt BL, O'Connor CM. Clopidogrel for coronary stenting: Response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908-13.  Back to cited text no. 14
    
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Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57.  Back to cited text no. 15
    
16.
US Food and Drug Administration. FDA Reminder to Avoid Concomitant use of Plavix (Clopidogrel) and Omeprazole; 2010. Available from: http://www.fda.gov/drugs/drug safety/ucm 231161. Htm. [Last acessed on 2010 Oct 27].  Back to cited text no. 16
    
17.
Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009;180:713-8.  Back to cited text no. 17
    
18.
Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301:937-44.  Back to cited text no. 18
    
19.
Sibbing D, Morath T, Stegherr J, Braun S, Vogt W, Hadamitzky M, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009;101:714-9.  Back to cited text no. 19
    
20.
Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009;157:5.e1-5.  Back to cited text no. 20
    
21.
Siriswangvat S, Sansanayudh N, Nathisuwan S, Panomvana D. Comparison between the effect of omeprazole and rabeprazole on the antiplatelet action of clopidogrel. Circ J 2010;74:2187-92.  Back to cited text no. 21
    
22.
Zuern CS, Geisler T, Lutilsky N, Winter S, Schwab M, Gawaz M. Effect of comedication with proton pump inhibitors (PPIs) on post-interventional residual platelet aggregation in patients undergoing coronary stenting treated by dual antiplatelet therapy. Thromb Res 2010;125:e51-4.  Back to cited text no. 22
    


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