Download Data were recorded in case record forms from Life Care Hospital

EFFECT OF PROTON PUMP INHIBITORS ON EFFICACY OF
CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY
SYNDROMES
Introduction
Clopidogrel is an antiplatelet prodrug, mainly indicated in acute coronary syndromes for
prevention of further major adverse cardiac events like progression of Myocardial Infarction
(MI), restenosis, stroke and death.[1, 2] GI bleeding is the major adverse effect of clopidogrel and
observed more often. So, Proton Pump Inhibitors are used widely in co administration with
clopidogrel.[3] Some recent studies suggest that concomitant use of PPI and Clopidogrel results in
decreased efficacy of clopidogrel due to common enzyme (CYP2C19) involvement in their
metabolic pathways.[4-9] Our aim was to establish the relation between efficacy of clopidogrel
and concomitant PPI use.
Background
Metabolism of Clopidogrel:
Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by
esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating
metabolites) and one mediated by multiple cytochrome P450 enzymes.[10]
During this cytochrome P450 enzyme pathway, Clopidogrel is activated in a 2-step process
mediated by oxidative biotransformation in the liver, in which CYP2C19, CYP3A, CYP2B6 and
CYP1A2 have particularly important roles Cytochromes first oxidize clopidogrel to a 2-oxoclopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxoclopidogrel
intermediate metabolite results in formation of the active metabolite. The active thiol metabolite
binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the
lifespan of the platelet.[11]
Metabolism of PPI
All
PPIs
(omeprazole,
esomeprazole,
pantoprazole,
rabeprazole,
lansoprazole,
and
dexlansoprazole) are metabolized by the hepatic cytochrome P-450 system, predominantly
CYP2C19, and, to a lesser extent, CYP3A4. The degree to which different PPIs interact with
CYP2C19 is responsible for Interaction with other agent metabolized through CYP2C19. [4]
Concomitant use of clopidogrel with medications that inhibit the CYP2C19 pathway can
potentially reduce its efficacy; agents with a high affinity for CYP2C19 can prevent other
CYP2C19 substrates, like clopidogrel, from binding to it.[12]
Genetic variants of other CYP450 enzymes may also affect the formation of clopidogrel's active
metabolite. The CYP2C19*1 allele corresponds to fully functional metabolism while the
CYP2C19*2, *3 and *4 alleles are nonfunctional and decrease active metabolite production
compared with the most common CYP2C19 genotype. Individuals who are heterozygous for
nonfunctional alleles are “intermediate metabolizers,” and those who are homozygous are “poor
metabolizers”.[4]
Studies have shown 51% to 55% of asians, 33% to 40% of african americans, 24% to 30% of
caucasians, and 18% of mexican americans have CYP2C19*2 allele. Therefore when clopidogrel
is given along with PPI there are chances for competitive drug interaction during metabolism by
CYP2C19, and even more in Poor metabolizres which may result in reduced antiplatelet effect
and higher rate of cardiovascular events.[13]
Pharmacokinetic and pharmacodynamic studies, using platelet assays as surrogate endpoints,
suggest that concomitant use of clopidogrel and a PPI reduces the antiplatelet effects of
clopidogrel. The strongest evidence for an interaction is between omeprazole and clopidogrel. It
is not established that changes in these surrogate endpoints translate into clinically meaningful
differences.[14]
Observational studies have shown inconsistent effects on Cardio vascular outcomes of
concomitant use of clopidogrel and PPIs.[15]
Study Methodology:
A prospective as well as retrospective analysis of patients with Clinical diagnosis of ACS was
carried out. Patients with Unstable Angina (UA), Non ST Elevation Myocardial Infarction
(NSTEMI) or ST Elevation Myocardial Infarction (STEMI) who underwent surgical
revascularization and took treatment at Life Care hospital, Ahmadabad were observed in two
groups. (1) Patients receiving clopidogrel alone (n = 36) and (2) Patients receiving clopidogrel
and PPI (n=39). Patients of age > 18 year with any of Index event (UA or STEMI/NSTEMI)
with or without Percutaneous Coronary Intervention (PCI) or Coronary Artery Bypass Grafting
(CABG) after Jan 2010, managed with clopidogrel were enrolled. Patients having any history of
GI bleeding, ulceration, impaired renal function or taking NSAIDs other than aspirin were
excluded from study
Study protocol, Case Record Form and Informed consent Form were approved by ethics
committee of Life Care institute of medical sciences and research with protocol number RGR -1.
Before enrolling patients, Informed consent process was carried out in presence of study
investigator and signed informed consent forms were collected from the patients. Their follow up
and maintenance therapy were observed for occurrence Major Adverse cardiac Events (MACE)
including progression of MI, stroke, rehospitalization, revascularization or restenosis and death.
Clopidogrel activity was measured in total 26 patients of which 14 patients had taken PPI (4
Patients received Omeprazole, 5 received Pantoprazole and 5 received Rabeprazole) against 12
patients had not taken any PPI during study period. Efficacy of clopidogrel was carried out by
measuring maximum platelet aggregation before clopidogrel dosing (Baseline) and 2 hour after
dosing Platelet aggregation was measured using VarifyNow analyzer in P2Y12 Reaction Unit
(PRU) Efficacy of clopidogrel was represented as % Inhibition of Platelet aggregation (% IPA).
% IPA was defined as following equation [7]
(Maximum PRU at baseline− Maximum PRU at 2 Hr after dosing )
Maximum PRU at baseline
X 100
Data were recorded in case record forms from Life Care Hospital, Ahmedabad and converted
into Excel sheets. The data were compiled and analyzed as per ICH GCP guideline followed by
Life Care Hospital. Results of % IPA were compared using one way ANOVA with 95%
confidence level. Incidence of Major Adverse Cardiac Events (MACE) of both groups were
compared and tested for their significances using chi square analysis using SPSS 17.
Results
A total of 75 patients diagnosed with ACS with or without revascularization (PCI or CABG) and
had received clopidogrel were enrolled. Out of these 75 patients, 39 patients ( 74.36 % male)
taking concomitant PPI had mean age of 59.95 ± 6.22 and mean BMI value of 25.84 ± 2.24 and
in other group 36 patients (77.78% male) without concomitant PPI had mean age of 57.86 ± 5.39
and Mean BMI value of 26.10 ± 1.75 as shown in Table -1. Previous history and current comorbid conditions were recorded in both groups as mentioned in Table 1. Furthermore
Concomitant medicines other than PPI taken by all patients during study period for management
of cardiac condition were recorded as mentioned in Table 1
Inhibition of platelet aggregation was measure in total 26 out of these 75 patients. Of which 14
patients were taking concomitant PPI (4 Patients received Omeprazole, 5 received Pantoprazole
and 5 received Rabeprazole) and 12 who had not taken any PPI.
Inhibition of platelet aggregation was found significantly reduced in patients taking concomitant
PPI administration against patients taking clopidogrel alone (Mean % IPA 16.04 ± 1.99 % Vs
23.79 ± 1.83 %, p value < 0.05) as mentioned in Table 2 & Figure 1
In addition, Inhibition of Platelet aggregation was found significantly reduced in patients taking
Omeprazole (13.68 %) as compared to Pantoprazole (16.78 %) and Rabeprazole (17.18 %) as
shown in Figure 2
At the end of study period, Efficacy endpoints of Major Adverse Cardiac Events (MACE) were
measured and evaluated. Total incidence of rehospitalisation, reinfarction and restenosis was
found greater in patients taking concomitant PPI as compared to patients not taking PPI as shown
in Table 3 and Figure 3
Discussion
Major finding of this study was that concomitant PPI use caused reduction in antiplatelet effect
of clopidogrel. Though our finding suggested that concomitant use of PPI was associated with
increased risk of major adverse cardiac events (MACE), it could not be proved statistically
significant because of the limitation of smaller population size.
Our results indicated that omeprazole interacted with clopidogrel resulting reduced efficacy,
other PPIs also interact though to somewhat lesser extent resulting in reduced clopidogel
efficacy.
Effect of this reduced efficacy on rate of MACE is controversial and different studies have
suggested confounding results about this scenario. Juurlink et al concluded that concomitant use
of PPI with clopidogrel was associated with 40% increased risk of recurrent MI which is relevant
to our study data.[16] In TIMI-TRITON 38 trial, Michelle L. O’Donoghue, found that use of PPI
was not associated with increased cardio vascular events.[7] Regulatory authorities like UFFDA
and EMEA also have given statements regarding PPI use. EMEA said “The product information
for all clopidogrel‐containing medicines should be amended to discourage concomitant use of
PPIs unless absolutely necessary."[17] And USFDA also supports this by “Healthcare providers
should re‐evaluate the need for starting or continuing treatment with a PPI, including Prilosec
(omeprazole) OTC, in patients taking clopidogrel."[18]
Patients on dual anti-platelet therapy of aspirin clopidogrel often require gestroprotecction. The
beneficial effect of PPI in preventing upper GI bleeding in patients taking antiplatelet therapy
than H2 receptor antagonist has been proved.[19] Hence pantoprazole and rabeprazole should be
preferred, which found inhibiting efficacy of clopidogrel in lesser amount than omeprazole as
found in present study.
Restriction of PPI use is very difficult because of their major part in ACS patients on
clopidogrel, but separation of administration of clopidogrel and PPI including omeprazole
decreases the risk of potential clinical interaction.[20] Andrzej Surdacki et al suggest that ADP
induced platelet aggregation was found lower in subjects receiving clopidogrel dose after 15
hour of omeprazole administration as compared to both drug given at same time. It could be
beneficial to adjust the dosing interval to administer one drug in the morning and the other one in
the evening.[21]
The overall risk balance between GI bleeding Vs MACE must be measured. Further studies on
large population should be conducted using platelet assay as surrogate end point for entire
pharmacokinetic profile or using more sophisticated analytical techniques like HPLC or LC-MS
to determine effect of interaction on plasma clopidogrel level.
Conclusion

Our study concluded that concomitant use of PPI led to inhibition of antiplatelet effect of
clopidogrel (measured by % IPA)

This is expected to be due to inhibition of clopidogrel metabolism pathway by PPIs
resulting in decreased prodrug formation and efficacy.

Besides, the study also substantiated the reported data that omeprazole is more prone to
interact with clopidogrel compared to other PPIs like pantoprazole and rabeprazole.

Eventhough rate and risk of MACE was found greater in ACS patients taking
concomitant PPI than patients taking clopidogrel alone, this could not be established
statistically due to limited study population.

Cohorts including large population are necessary to confirm the correlation between this
drug interaction and to determine its fallout on frequency MACE like rehospitalization,
reinfarction stroke, restenosis, revascularization and death.
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8. Hulot JS, Collet JP, Silvain J, Pena A, Cayla G, Beygui F et al. Cardiovascular Risk in
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13. Mega JL, Close SL, Wiviott SD, Hockett RD, Brandt JT, Walker JR et al. Cytochrome p450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360:354–362
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Tables and Figures
Table 1: Demographic, history, co-morbod condition and Concomitant medication data
Patients receiving clopidogrel Patients receiving clopidogrel and
alone (n = 36)
PPI (n=39)
Male
28 (77.78%)
29 (74.36%)
female
8 (22.22%)
10 (25.64%)
Age
57.86 ± 5.39
59.95 ± 6.22
BMI
26.10 ± 1.75
25.84 ± 2.24
Demography
History and Co-morbid condition
UA
11(30.56 %)
12(30.77 %)
NSTEMI
15 (41.67 %)
17 (43.59 %)
STEMI
10 (27.78 %)
10 (25.64 %)
Diabetes
18 (50.00 %)
19 (48.72 %)
Hypertension
33 (91.68 %)
35 (89.74 %)
PCI
25 (69.44 %)
24 (61.54 %)
CABG
5 (13.89% )
8 (20.51 %)
Hyperlipidemia
25 (69.44 %)
26 (66.67 %)
Smoking
0
5 (12.82 %)
Concomitant Medication
Aspirin
31 (86.11 %)
38 (97.44 %)
β-blocker
30 (83.33 %)
28 (71.79 %)
Ca blocker
14 (38.89 %)
16(41.03 %)
ACEI/ARB
12 (33.33 %)
12 (30.77 %)
Statins
25 (69.44 %)
26 (66.67 %)
Table 2: Mean% inhibition of platelet aggregation
Patients
Mean % IPA
receiving Patients receiving clopidogrel P Value
clopidogrel alone (n = 12)
and PPI (n=14)
23.79 ± 1.83
16.04 ± 1.99
p Value obtained by One way ANOVA
<0.05
Table 3: Incidence of various MACE
Patients
receiving Patients receiving clopidogrel p
clopidogrel alone (n = 36)
and PPI (n=39)
Value
Hospitalizations
7 (19.44%)
10 (25.64 %)
NS
Reinfarction
4 (11.11 %)
7 (17.95 %)
NS
Restenosis
3 (8.33 %)
5 (12.82 %)
NS
p value obtained by chi square analysis
Figure 1: Mean % Inhibition of Platelet Aggregation
25.00
Mean % IPA
20.00
15.00
10.00
5.00
0.00
Patients receiving Patients receiving
clopidogrel alone (n clopidogrel and PPI
= 12)
(n=14)
Figure 2: Mean % Inhibition of Platelet Aggregation for different PPI
20.00
18.00
Mean % IPA
16.00
14.00
12.00
10.00
8.00
6.00
4.00
2.00
0.00
Omeprazole
Pantoprazole
Rabeprazole
Figure 3: Incidence of various MACE
No of Patients
15
10
5
0
Hospitalizations
Reinfarction
MACE
Restenosis
Patients receiving clopidogrel alone (n = 36)
Patients receiving clopidogrel and PPI (n=39)