Original Contribution

Cerebrovascular Outcomes With Proton Pump

Inhibitors and Thienopyridines
A Systematic Review and Meta-Analysis
Konark Malhotra, MD; Aristeidis H. Katsanos, MD; Mohammad Bilal, MD;
Muhammad Fawad Ishfaq, MD; Nitin Goyal, MD; Georgios Tsivgoulis, MD

Background and Purpose—Pharmacokinetic and prior studies on thienopyridine and proton pump inhibitors (PPI)
coadministration provide conflicting data for cardiovascular outcomes, whereas there is no established evidence on the
association of concomitant use of PPI and thienopyridines with adverse cerebrovascular outcomes.
Methods—We conducted a systematic review and meta-analysis of randomized controlled trials and cohort studies from
inception to July 2017, reporting following outcomes among patients treated with thienopyridine and PPI versus
thienopyridine alone (1) ischemic stroke, (2) combined ischemic or hemorrhagic stroke, (3) composite outcome of stroke,
myocardial infarction (MI), and cardiovascular death, (4) MI, (5) all-cause mortality, and (6) major or minor bleeding
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events. After the unadjusted analyses of risk ratios, we performed additional analyses of studies reporting hazard ratios
adjusted for potential confounders.
Results—We identified 22 studies (12 randomized controlled trials and 10 cohort studies) comprising 131 714 patients.
Concomitant use of PPI with thienopyridines was associated with increased risk of ischemic stroke (risk ratio, 1.74;
95% confidence interval [CI], 1.41–2.16; P<0.001), composite stroke/MI/cardiovascular death (risk ratio, 1.14; 95% CI,
1.01–1.29; P=0.04), and MI (risk ratio, 1.19; 95% CI, 1.00–1.40; P=0.05). Likewise, in adjusted analyses concomitant
use of PPI with thienopyridines was again associated with increased risk of stroke (hazard ratios adjusted, 1.30; 95%
CI, 1.04–1.61; P=0.02), composite stroke/MI/cardiovascular death (hazard ratios adjusted, 1.23; 95% CI, 1.03–1.47;
P=0.02), but not with MI (hazard ratios adjusted, 1.19; 95% CI, 0.93–1.52; P=0.16).
Conclusions—Co-prescription of PPI and thienopyridines increases the risk of incident ischemic strokes and composite stroke/
MI/cardiovascular death. Our findings corroborate the current guidelines for PPI deprescription and pharmacovigilance,
especially in patients treated with thienopyridines.   (Stroke. 2018;49:00-00. DOI: 10.1161/STROKEAHA.117.019166.)
Key Words: ischemic stroke ◼ myocardial infarction ◼ pharmacovigilance ◼ proton pump inhibitors
◼  thienopyridines

T hienopyridines including clopidogrel, prasugrel, and

ticlopidine are antiplatelet medications that inhibit
P2Y12 adenosine phosphate receptor on platelets and impair
its activation.1 These are prodrugs that require conversion
to active forms with cytochrome P450 isoenzymes, mainly
CYP2C19 and CYP3A4.2 Because of their favorable profile
(especially clopidogrel and prasugrel) and efficacy for plate-
let inhibition, thienopyridines have been increasingly used
for secondary prevention of cardiovascular,3 peripheral vas-
cular,4 and cerebrovascular diseases.1 Proton pump inhibi-
tors (PPI) are often used concomitantly with thienopyridines
in these patients as gastroprotective agents to prevent gas-
trointestinal bleeding.5,6 However, as PPIs are competitive
inhibitors of cytochrome P450 pathway, pharmacodynamic
data suggests significant interaction between PPIs and thi-
enopyridines,1 predisposing to major adverse cardiovascular
events including stroke.
Majority of the studies on PPI and thienopyridine inter-
action have focused over cardiovascular outcomes, whereas
only few studies have reported adverse cerebrovascular out-
comes.7–14 Individual studies have been unable to ascertain the
risk of ischemic stroke (IS) in patients with concomitant use
of clopidogrel and PPIs.15 Furthermore, absence of evidence-
based guidelines and lack of clear consensus poses a clini-
cal conundrum for PPI used along with thienopyridines.8,16,17
Because of insufficient data, we aimed to synthesize the

Received August 21, 2017; final revision received October 27, 2017; accepted November 21, 2017.
From the Department of Neurology, West Virginia University-Charleston Division (K.M.); Second Department of Neurology, National and Kapodistrian
University of Athens, “Attikon” University Hospital, Greece (A.H.K., G.T.); Department of Neurology, University of Ioannina School of Medicine,
Greece (A.H.K.); Department of Gastroenterology & Hepatology, University of Texas Medical Branch, Galveston (M.B.); and Department of Neurology,
University of Tennessee Health Science Center, Memphis (M.F.I., N.G., G.T.).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
117.019166/-/DC1.
Correspondence to Konark Malhotra, MD, Department of Neurology, West Virginia University-Charleston Division, 415 Morris St, Suite 300, Charleston,
WV 25301. E-mail konark.malhotra@yahoo.com
© 2018 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.117.019166

1
 2  Stroke  February 2018
evidence of co-prescription of PPIs with thienopyridines on
adverse cerebrovascular outcomes.
Methods
The authors declare that all supporting data are available within the
article (and its online supplementary files). Our meta-analysis adopted
Preferred Reporting Items for Systematic reviews and Meta-Analyses
guidelines18 and is reported in accordance with the meta-analysis of
observational studies in epidemiology proposal.19 We used publicly
available published studies, and our study was exempt for approval
from Institutional Review Board.
Data Sources and Database Searches
We identified all eligible randomized controlled trials (RCTs) and
cohort studies that investigated the association of PPI with thi-
enopyridines. Systematic search was performed in PubMed, Ovid
MEDLINE, and Ovid Embase databases from the inception to July
20, 2017. Our literature was restricted to involve human participants
and articles in English language. Keywords used to query all the
databases included stroke, PPI, clopidogrel, prasugrel hydrochloride,
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and ticlopidine. The complete search algorithm used in MEDLINE
is available in the online-only Data Supplement. Additional manual
search included conference abstracts and bibliographies of candidate
studies and recent systematic reviews for a comprehensive literature
search.
Study Selection
We identified studies that investigated cerebrovascular outcomes in
patients on thienopyridines treated with or without PPIs. The inclu-
sion criteria for our study were (1) studies including patients treated
with thienopyridine and PPI versus thienopyridine alone as the pri-
mary inclusion criteria; (2) studies with documented adverse cere-
brovascular outcomes as either primary or secondary end points; (3)
studies with a minimum follow-up duration of 6 months; and (4) adult
patients (>18 years old).
Data Extraction and Quality Assessment
Two authors (Drs Malhotra and Bilal) independently screened all the
titles or abstracts, and later evaluated all the relevant articles based
on the full-text reviews. From the articles meeting our selection cri-
teria, all unadjusted and adjusted data for potential confounders was
extracted and disagreements, if any, were resolved with mutual con-
sensus. Studies published as post hoc analysis of RCTs that compared
different class of thienopyridines were considered as separate studies.
Following data were extracted author, publication year, trial name,
total number and type of study participants, prevalence of cerebro-
vascular risk factors such as hypertension, hyperlipidemia, diabetes
mellitus, alcohol intake, smoking, prior histories of stroke or transient
ischemic attack and myocardial infarction (MI), primary and second-
ary end points, and follow-up duration.
Cochrane risk of bias assessment was used to evaluate the potential
sources of bias in the included RCTs,20 whereas the quality of cohort
studies was assessed using the Newcastle–Ottawa scale.21 Quality
control and bias identification were performed independently by 2
reviewers, and disagreements if any, were resolved by a third tie-
breaking evaluator.
Data Synthesis and Statistical Analysis
We calculated corresponding relative risk ratios (RR) and 95% con-
fidence intervals (CIs) to measure the effect size while comparing
the thienopyridines use with and without PPIs. We additionally per-
formed adjusted analyses on the effect of coadministration of thieno-
pyridines with PPIs by including only those studies reporting hazard
ratios (HRs). We also performed subgroup analyses according to the
thienopyridine type for the outcomes of all stroke and the composite
outcome of stroke, MI, and cardiovascular death (CVD). Finally, we
conducted additional analyses of studies on the subgroup of patients
with history of acute ischemic stroke or transient ischemic attack. As
per the Cochrane Handbook for Systematic Reviews of Interventions,22
we assessed for heterogeneity using Cochran Q and I2 statistics. For
the qualitative interpretation of heterogeneity, I2>50% and I2>75%
indicated substantial and considerable heterogeneity, respectively.
Publication bias across individual studies was graphically evaluated
using a funnel plot,23 whereas funnel plot asymmetry was assessed
using Egger linear regression test with P<0.10 significance level. A
random-effects model (DerSimonian Laird) was used to calculate the
pooled RRs and HRs in both the overall and subgroup analyses. We
performed equivalent z test for each pooled RR or HR, and a 2-tailed
P values of <0.05 was considered statistically significant.24
Statistical analyses were conducted using Review Manager
(RevMan; computer program; version 5.3). Copenhagen: The
Nordic Cochrane Center, The Cochrane Collaboration, 2014 and
Comprehensive Meta-Analysis (version 2; computer software),
Englewood, NJ: Biostat, 2014.
Results
Study Selection and Study Characteristics
We screened 5584 titles and abstracts from which 47 eligi-
ble studies were retained for full-text evaluation. After care-
ful evaluation and no disagreements among the 2 reviewers,
25 studies were excluded (Table I in the online-only Data
Supplement) and 22 studies were selected that met the inclu-
sion criteria (Figure I in the online-only Data Supplement).
One study by Kimura et al25 was excluded as 90% of patients
were treated with ticlopidine, whereas neither of the included
studies evaluated ticlopidine likely because of its unfavorable
adverse effect profile.
We included 22 studies (131  714 participants; median
follow-up of 12 months) with 12 RCTs (n=68 296 partici-
pants)8,26–32 and 10 observational studies (n=63 418; Table 1).7,9–
14,33–35
The baseline characteristics of the included patients are
presented in Table II in the online-only Data Supplement.
Sixteen trials included patients with acute coronary syndrome,
2 trials involved high cardiovascular risk patients with previ-
ous history of stroke, MI, or peripheral artery disease, 2 stud-
ies involved patients with peptic ulcer disease, and 2 studies
involved patients with IS. Five cohort studies were prospec-
tively and 7 studies were retrospectively conducted, whereas
remaining 10 studies were post hoc analysis of major RCTs.
Seven studies were conducted in North America, 6 studies
in Europe, 4 studies in Asia, whereas remaining were mul-
tinational studies. Cerebrovascular outcomes were reported
as IS,8–10,12,26,33 stroke,7,11,13,14,31,33,34 and composite stroke/MI/
CVD.8,11,26–32
Study Quality and Publication Bias
The majority of RCTs had high risk of selection, performance
and detection bias, as the majority of the studies were post hoc
or subgroup analysis of RCTs. All or majority of the included
RCTs had low risk of reporting bias, attrition bias, and other
biases (Table III in the online-only Data Supplement).
Risk of bias among the cohort studies was assessed using
Newcastle–Ottawa scale (Table IV in the online-only Data
Supplement). The risk of selection and comparability bias
was considered low in all the studies except one,34 as the study
did not adjust for potential confounders. Outcome bias was
counted as moderate for studies that did not report the data on
patients lost to follow-up,11,12,14,35 or the follow-up period was
 Malhotra et al   Stroke With PPI-Thienopyridine Coadministration   3

Table 1.  Study Design and Characteristics of Included Studies in Our Meta-Analysis
No. of Patients, Follow-Up, Outcomes of
Study Country Design TNP Studied TNP+PPI, TNP Month Interest
Aihara et al14 Japan Retrospective cohort Clopidogrel 1068, 819 12 2, 5, 7
Bhatt et al (COGENT) 8
United States Randomized Clopidogrel 1876, 1885 6 1, 4, 5, 6, 7
Chitose et al 10
Japan Prospective cohort Clopidogrel* 187, 443 18 1, 5, 6
Dunn et al (CAPRIE)29 United States Randomized, post hoc Clopidogrel 218, 18967 12 4
Dunn et al (CREDO)29 United States Randomized, post hoc Clopidogrel 374, 1742 12 4
Gargiulo et al (PRODIGY) 32
Europe Randomized, post hoc Clopidogrel 375, 612 24 4, 6, 7
Goodman et al (PLATO) 27
Canada Randomized, post hoc Clopidogrel 3255, 6021 12 4, 5, 6, 7
Hudzik et al34 Poland Retrospective cohort Clopidogrel 18, 20 12 2, 5, 7
Hsu et al 26
Taiwan Randomized Clopidogrel 83, 82 6 1, 4, 5
Jackson et al (TRANSLATE-ACS) 30
United States Randomized, post hoc Clopidogrel 1636, 7196 12 4
Jackson et al (TRANSLATE-ACS) 30
United States Randomized, post hoc Prasugrel 531, 2592 12 4
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Kreutz et al12 United States Retrospective cohort Clopidogrel 6828, 9862 12 1, 5, 6

Munoz-Torrero et al9 Spain Retrospective cohort Clopidogrel 519, 703 12 1, 5, 7
Nicolau et al (TRILOGY ACS) 31
Multiple Randomized, post hoc Clopidogrel 836, 2787 30 2, 4, 5, 6
Nicolau et al (TRILOGY ACS)31 Multiple Randomized, post hoc Prasugrel 830, 2790 30 2, 4, 5, 6
O’Donoghue et al (TRITON-TIMI 38)28 Multiple Randomized, post hoc Clopidogrel 2257, 4538 6 4, 5, 6, 7
O’Donoghue et al (TRITON-TIMI 38) 28
Multiple Randomized, post hoc Prasugrel 2272, 4541 6 4, 5, 6, 7
Ray et al 13
United States Retrospective cohort Clopidogrel 7593, 13003 12 2, 5, 6
Rossini et al35 Italy Retrospective cohort Clopidogrel 1158, 170 12 4, 7
Simon et al 11
France Prospective cohort Clopidogrel 1453, 900 12 4, 7
van Boxel et al 7
Netherlands Retrospective cohort Clopidogrel 5734, 12405 24 2, 5, 7
Yi et al33
China Prospective cohort Clopidogrel 166, 369 6 1, 2
(1) Ischemic stroke, (2) combined ischemic and hemorrhagic stroke, (3) intracerebral hemorrhage, (4) composite of stroke, myocardial infarction, or
cardiovascular death, (5) myocardial infarction, (6) cardiovascular death, and (7) all-cause mortality. TNP indicates thienopyridine; and PPI, proton pump
inhibitor.
*The study used either clopidogrel or ticlopidine as thienopyridines, however, clinical outcomes were available only for clopidogrel subgroup.

inadequate.33 The overall score of Newcastle–Ottawa scale
was 80/90 (88.8%), which is considered to represent an over-
all high quality.
Funnel plot inspection and Egger statistical test revealed
no evidence of asymmetry in both studies reporting the out-
come of stroke (6 studies; P=0.43; Figure II in the online-only
Data Supplement) and composite stroke/MI/CVD (P=0.873;
Figure III in the online-only Data Supplement). We also did
not observe evidence of publication bias among studies report-
ing all strokes (Egger test P value=0.25), MI (P=0.69), cardio-
vascular mortality (P=0.94), and all-cause mortality (P=0.39).
Association Between PPI and Thienopyridines
Table 2 presents an overview on the overall unadjusted and
adjusted for potential confounders analyses on the association
of the concomitant administration of PPIs and thienopyridines
with cerebrovascular, cardiovascular, and safety outcomes.
Primary Outcomes
Concomitant use of PPI with thienopyridine was associated with
increased risk of IS (6 studies; RR, 1.74; 95% confidence inter-
val [CI], 1.41–2.16; P<0.001; Figure 1) and composite stroke/
MI/CVD (14 studies; RR, 1.14; 95% CI, 1.01–1.29; P=0.04;
Figure 2A). No evidence of heterogeneity was observed for
IS (I2=0%, P for Cochran Q statistic=0.46), whereas substan-
tial heterogeneity was evident for composite stroke/MI/CVD
(I2=75%, P for Cochran Q statistic<0.001). Use of PPI was not
associated with the risk of stroke (7 studies; RR, 1.12; 95%
CI, 0.94–1.35; P=0.22) with no evidence of heterogeneity
(I2=42%, P for Cochran Q statistic=0.11; Figure 3A).
Cardiovascular Outcomes
Use of PPI with thienopyridine was associated with increased
risk of MI (15 studies; RR, 1.19; 95% CI, 1.00–1.40;
P=0.050), however, considerable heterogeneity (I2=80%, P
for Cochran Q statistic<0.001; Figure IV in the online-only
Data Supplement) was observed. Concomitant use of PPI was
not associated with the risk of CVD (10 studies; RR, 1.04;
95% CI, 0.93–1.17; P=0.49). No evidence of heterogeneity
was observed (I2=18%, P for Cochran Q statistic=0.28; Figure
V in the online-only Data Supplement).
Safety Outcomes
Concomitant use of PPI was not associated with the all-cause
mortality (10 studies; RR, 1.21; 95% CI, 0.89–1.64; P=0.23)
 4  Stroke  February 2018

Table 2.  Overview of the Primary and Secondary Analyses on Different End Points
Unadjusted Analyses Adjusted Analyses
No. of
End Point No. of Studies RR (95% CI) P Value Heterogeneity Studies HR (95% CI) P Value Heterogeneity
Ischemic stroke I =0%, P for Cochran
2
6 1.74 (1.41–2.16) <0.001 … … … …
Q=0.46
Stroke I2=42%, P for I2=0%, P for Cochran
7 1.12 (0.94–1.35) 0.22 4 1.30 (1.04–1.61) 0.020
Cochran Q=0.25 Q=0.53
Myocardial infarction I2=80%, P for I2=83%, P for Cochran
15 1.19 (1.00–1.40) 0.050 7 1.19 (0.93–1.52) 0.16
Cochran Q<0.001 Q<0.001
Cardiovascular death I2=18%, P for I2=47%, P for Cochran Q
10 1.04 (0.93–1.17) 0.49 6 1.07 (0.82–1.39) 0.64
Cochran Q=0.28 statistic=0.09
Stroke/myocardial
I2=75%, P for I2=82%, P for Cochran Q
infarction / 14 1.14 (1.01–1.29) 0.040 8 1.23 (1.03–1.47) 0.02
Cochran Q=<0.001 statistic<0.001
cardiovascular death
Major or minor bleeding I2=59%, P for
3 1.19 (0.88–1.61) 0.27 … … … …
Cochran Q=0.57
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All-cause mortality I2=87%, P for I2=82%, P for Cochran Q

10 1.21 (0.89–1.64) 0.23 8 1.11 (0.81–1.53) 0.51
Cochran Q=0.39 statistic<0.001
CI indicates confidence interval; HR, hazard ratio; and RR, risk ratio.

and major or minor bleeding (3 studies; RR, 1.19; 95% CI,
0.88–1.61; P=0.27). Both the analyses demonstrated consid-
erable (all-cause mortality, I2=87%, P for Cochran Q statis-
tic<0.001; Figure VI in the online-only Data Supplement)
and substantial (major or minor bleeding, I2=59%, P for
Cochran Q statistic=0.09; Figure VII in the online-only Data
Supplement) heterogeneity.
Sensitivity Analyses
We conducted additional analyses of trials reporting incidence
of stroke and composite stroke/MI/CVD among patients with
prior history of acute ischemic stroke. Concomitant use of thi-
enopyridine and PPIs was not associated with increased risk
of recurrent strokes (2 studies; RR, 1.24; 95% CI, 0.75–2.05;
P=0.39; P for Cochran Q statistic=0.52, I2=0%; Figure VIII
in the online-only Data Supplement) and composite stroke/
MI/CVD among patients with prior history of acute ischemic
stroke/ transient ischemic attack (2 studies; RR, 1.33; 95% CI,
0.81–2.19; P=0.26; P for Cochran Q statistic=0.21, I2=37%;
Figure IX in the online-only Data Supplement).
Adjusted Analyses
After adjusting for potential confounders, the association
of concomitant use of PPIs and thienopyridines showed
increased risk of composite stroke/MI/CVD (8 studies; HR,
1.23; 95% CI, 1.03–1.47; P=0.02; P for Cochran Q statis-
tic<0.001, I2=82%; Figure 2B) and all strokes retained the sta-
tistical significance (4 studies; HR, 1.30; 95% CI, 1.04–1.61;
P=0.02; P for Cochran Q statistic=0.53, I2=0%; Figure 3B).
No evidence of increased risk was observed for MI (7 stud-
ies; HR, 1.19; 95% CI, 0.93–1.52; P=0.16; P for Cochran
Q statistic<0.001, I2=83%; Figure X in the online-only Data
Supplement), CVD (6 studies; HR, 1.07; 95% CI, 0.82–1.39;
P=0.64; P for Cochran Q statistic=0.09, I2=47%; Figure XI in
the online-only Data Supplement), and all-cause mortality (8
studies; HR, 1.11; 95% CI, 0.81–1.53; P=0.51; P for Cochran
Q statistic<0.001, I2=82%; Figure XII in the online-only Data
Supplement).
Subgroup Analyses
To confirm the robustness of our study findings, individual
subtypes of thienopyridines were assessed for clinical out-
comes. No significant differences were found (P=0.21) on
the concomitant use of clopidogrel with PPIs (11 studies;
RR, 1.18; 95% CI, 1.01–1.38) or prasugrel with PPIs (3 stud-
ies; RR, 1.04, 95% CI, 0.93–1.17) with the composite stroke/
MI/CVD (Figure XIII in the online-only Data Supplement).
Considerable heterogeneity was documented in the subgroup
of patients receiving clopidogrel (I2=79%, P for Cochran Q

Figure 1. Forest plot comparing the unadjusted risk of ischemic stroke between patients on thienopyridine (TNP) treated with and without
proton pump inhibitors (PPI). CI indicates confidence interval.
 Malhotra et al   Stroke With PPI-Thienopyridine Coadministration   5

B
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Figure 2. Forest plot comparing the (A) unadjusted and (B) adjusted for potential confounders risk of composite stroke/myocardial infarc-
tion (MI)/cardiovascular death between patients on thienopyridine (TNP) treated with and without proton pump inhibitors (PPI). CI indi-
cates confidence interval.

statistic<0.001), but not in the subgroup of patients treated
with prasugrel (I2=0%, P for Cochran Q statistic=0.98; Figure
XIV in the online-only Data Supplement).
Discussion
In our systematic review and meta-analysis involving 131 714
patients on thienopyridine treatment with or without PPI, we
documented that concomitant use of PPI was associated with
increased risk of IS, composite stroke/MI/CVD, and MI in
crude analyses. This association persisted for stroke and com-
posite stroke/MI/CVD in adjusted analyses. In addition, the
subgroup analysis demonstrated increased risk of both cere-
brovascular and cardiovascular outcomes among patients on
thienopyridines treated with PPIs.
Previous studies have been unable to demonstrate clini-
cal significance with concomitant use of PPI and thienopyri-
dines on adverse cerebrovascular outcomes. Recent analyses
suggests positive association of PPI and thienopyridine with
increased stroke risk, however, the association was not con-
sistent in sensitivity analyses.16,36 Leonard et al15 performed
a propensity score-matched analysis using Medicaid claims
database and demonstrated no additional increased IS risk

Figure 3. Forest plot comparing the (A) unadjusted and (B) adjusted for potential confounders risk of stroke between patients on thieno-
pyridine (TNP) treated with and without proton pump inhibitors (PPI). CI indicates confidence interval.
 6  Stroke  February 2018
with concomitant use of clopidogrel and PPIs. Similarly, no
association was observed for stroke recurrence or mortality
from large case–control study involving stroke patients on
concomitant clopidogrel and PPI use.17 Our study highlights
an increased association of concomitant use of PPI and thi-
enopyridines for incident IS, even after adjustment for poten-
tial confounders. Although only 2 studies were included in
the subgroup analysis to assess for secondary prevention of
stroke and composite stroke/MI/CVD, our findings corrobo-
rates previously published findings of PPI and thienopyridine
coadministration on stroke recurrence.17 These considerations
underscore the need for future RCTs to assess the safety of
PPIs in patients with IS.
The interaction between PPI and thienopyridines has sev-
eral public health implications. Thienopyridines are similar
in efficacy to aspirin in preventing serious vascular events,
including fatal and nonfatal IS.1 However, several patients
are frequently coprescribed PPIs for stress ulcer prophy-
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laxis and prevention of gastrointestinal bleeding. Over
decades, PPIs have transformed from benign acid suppres-
sants and have been associated with adverse cardiovascular
outcomes,37 all-cause mortality,38 and adverse cerebrovas-
cular outcomes including IS.39 To reduce inadvertent PPI
usage, recent guidelines provide evidence-based recom-
mendations for PPI deprescription, that is, dose reduction
and stoppage after the minimum intended duration of use.40
Despite these practice updates, the real-world medicine and
decision-making continues to ignore the PPI deprescrip-
tion because of scarcity of data and conflicting results. Our
results underscore the need for pharmacovigilance with
PPIs and restrict their use to appropriate indications to curb
the healthcare costs.
Our study has certain limitations. First, the majority of
included patients comprised of acute coronary syndrome.
Second, the majority of the studies did not clearly define their
end points, especially stroke subtype, composite stroke/MI/
CVD and cardiovascular outcomes. We selected studies that
reported composite of fatal or nonfatal stroke/MI/CVD as
either primary or secondary end points. Although limiting the
eligibility criteria could inhere the risk of missing or exclud-
ing data from studies not reporting the aforementioned out-
comes of interest as their primary or secondary end points,
this decision was made a priori during the meta-analysis pro-
tocol to include only studies succinctly reporting outcomes of
interest as per protocol predefined end points and not as post
hoc analyses to avoid the possibility of reporting bias (selec-
tive outcome reporting).41
Third, majority of the included RCTs comprised of post hoc
analysis with prespecified study protocols, whereas cohort
studies could have introduced additional biases. However, we
additionally performed adjusted analyses using correspond-
ing HRs to ascertain any disparities existent between quality
assessment and analysis presentation. Fourth, potential inher-
ent limitations among included studies were differences in fol-
low-up times, varied study cohorts, use of different PPIs, and
the lack of data on stroke subtypes; that could have led to the
observed heterogeneity. Fifth, we acknowledge that many of
the reported secondary analyses could have been underpow-
ered to detect significant differences among groups, and thus
these nonsignificant findings do not necessarily signify lack of
association. Finally, the evaluation of publication bias using
funnel plot inspection and Egger test was weak because of the
small number of studies.
In conclusion, our systematic review and meta-analysis
suggests an increased risk of IS, stroke, composite stroke/MI/
CVD and cardiovascular outcomes with concomitant use of
PPIs and thienopyridines. Our findings corroborate the cur-
rent guidelines for PPI deprescription, and further underscore
the need for pharmacovigilance, especially in patients treated
with thienopyridines.
Disclosures
None.
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 Cerebrovascular Outcomes With Proton Pump Inhibitors and Thienopyridines: A
Systematic Review and Meta-Analysis
Konark Malhotra, Aristeidis H. Katsanos, Mohammad Bilal, Muhammad Fawad Ishfaq, Nitin
Goyal and Georgios Tsivgoulis
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 ONLINE SUPPLEMENT

TITLE: Cerebrovascular Outcomes with Proton Pump Inhibitors and Thienopyridines: A

Systematic Review and Meta-analysis

Supplemental Methods
Complete Search algorithm used in MEDLINE search
(("stroke"[All Fields] OR "stroke"[MeSH Terms]) OR "cerebrovascular"[All Fields]) OR
"cerebrovascular accident"[All Fields]) OR "cerebrum"[All Fields]) OR "cerebrum"[MeSH
Terms]) OR "brain"[All Fields]) OR "brain"[MeSH Terms]) OR "ischemia"[All Fields]) OR
"ischemia"[MeSH Terms]) OR "cerebral ischemia"[All Fields]) AND "thienopyridine"[All
Fields]) OR "thienopyridines"[MeSH Terms]) OR "clopidogrel"[All Fields]) OR "prasugrel"[All
Fields]) OR "prasugrel hydrochloride"[MeSH Terms]) OR "effient"[All Fields]) OR
"ticlopidine"[All Fields]) OR "ticlopidine"[MeSH Terms]) AND "proton pump inhibitors"[All
Fields]) OR "proton pump inhibitors"[MeSH Terms]) OR "proton pump"[All Fields]) OR
"omeprazole"[All Fields]) OR "omeprazole"[MeSH Terms]) OR "pantoprazole"[All Fields]) OR
"esomeprazole"[All Fields]) OR "esomeprazole"[MeSH Terms]) OR "lansoprazole"[All Fields])
OR "lansoprazole"[MeSH Terms]) OR "rabeprazole"[All Fields]) OR "rabeprazole"[MeSH
Terms]))

1
Supplemental Tables
Supplemental Table I: Excluded studies with reasons for exclusion

Study name Reason for exclusion

Tanaka et al1 Comparison of clopidogrel v/s ticlopidine

Kimura et al2 90% of cohort treated with ticlopidine
Charlot et al3 Comparison of PPI + clopidogrel v/s PPI
Juurlink et al4 No data stratified by concurrent PPI treatment
Vaduganathan et al5 Overlap with COGENT trial
Weisz et al6 Study not reporting stroke outcomes
Vardi et al7 Study not reporting stroke outcomes
Depta JP et al8 Study not reporting stroke outcomes
Burkard et al9 Study not reporting stroke outcomes
Pasquali et al10 Study not reporting stroke outcomes
Cai et al11 Outcomes reported < 6 months
Cuisset et al12 Study not reporting stroke outcomes
Leonard et al13 No control group involved
Wang et al14 Study not reporting stroke outcomes
Mahabaleshwar et al15 No outcome data available for controls
Chandrashekhar et al16 Study not reporting stroke outcomes
Feng et al17 Study not reporting stroke outcomes, Chinese
Park et al18 Study not reporting stroke outcomes
Biering-Sorensen et al19 Stroke outcome data not available, abstract
Bhurke et al20 Study not reporting stroke outcomes
Katoh et al21 Stroke outcome data not available, abstract
Tsai et al22 Study not reporting stroke outcomes
Burton et al23 Stroke outcome data not available, abstract

2
Huang et al24 Study not reporting stroke outcomes
Hsiao et al25 Study not reporting stroke outcomes

3
Supplemental Table II: Baseline characteristics of the included patients

Study Age Males HTN HLD DM Smoker Prior Prior MI PPIs

(years) (%) (%) (%) (%) (%) AIS/TIA (%) used
(%)
TNP + TNP + TNP + TNP + TNP + TNP + TNP +
PPI, PPI, PPI, PPI, PPI, PPI, TNP + PPI,
TNP TNP TNP TNP TNP TNP PPI, TNP
TNP

Aihara et al26 69, 68 73.8, 70.8, 82.1, 84 40.9, 43.6, 8.2, 7.9 15.7, O, L, R
75.9 67.7 37.8 41.3 17.4

Bhatt et al 27 68.5, 66.9, 80.1, 79.1, 31.7, 12.5, 7.3, 8.1 NR O

(COGENT) 68.7 69.5 81.4 77.1 28.6 14.1

Chitose et al28 69.7, 74.3, 77, 78.7 58.8, 58 34.2, 25.6, 15.5, 29.4, N/A
69.6 73.5 34.0 25.5 32.7 22.5

Dunn et al29 63.9, 69.3, 49.5, 39.4, 16.5, 23.9, 26.6, 39.4, O, L
62.5 72.3 51.5 41.2 20.3 29.6 33.6 32.8
(CAPRIE)

Dunn et al29 61.8, 70.3, 69, 68.4 79.1, 27.3, 28.9, 6.1, 6.8 37.2, O, P, L,
(CREDO) 61.6 71.6 73.4 26.3 30.9 33.2 R

4
 Gargiulo et al30 71.8, 72.2, 75.7, 55.2/56. 24.8, 46.9, NR 25.8, O, P, E,
(PRODIGY) 67.9 80.5 71.4 5 24.6 23.8 28.2 L, R

Goodman et al31 63, 62 72.4, 65.6, 49.8, 45 25.8, 36.2, 5.9, 6.3 20.8, O, P, E,
(PLATO) 71.2 65.4 24.7 35.7 20.5 L, R

Hudzik et al32 62.8, 83.3, 65 72.2, 70 72.2, 75 44.4, 30 NR NR 72.2, 70 O

60.5

Hsu et al33 70.6, 78.3, 72 67.5, 57 NR 42.2, 28 12.0, 6.1 33.9, NR E

73.3 32.9

Jackson et al34 64, 60 63.3, 77.8, 74.5, 34.5, NR 9.5, 6.0 26.7, N/A
(TRANSLATE- 71.3 66.7 65.1 25.5 20.0
ACS)

Jackson et al34 60, 56 74, 79.4 71, 59.5 68.7, 26, 24.3 NR 2.3, 1.8 17.7, N/A
(TRANSLATE- 60.6 13.9
ACS)

Kreutz et al35 67.5, 61.9, 50.5, 67.8, 25.8, NR NR NR O, P, E,

65.2 73.9 46.4 63.4 22.6 L, R

Munoz-Torrero et 68, 64 75.3, 67.8, NR 40.4, 16.9, 27.3, 47.5, O, P, L

5
 al36 77.3 65.1 39.5 18.2 26.6 49.5

Nicolau et al37 63, 62 65.1, 79.5, 58.3, 42.0, 24.8/23. NR 44.8, O, P

(TRILOGY ACS) 64.2 80.7 60.1 38.5 3 44.8

Nicolau et al37 64, 62 61.9, 81.6, 80 59.2/57. 38.7, 25.5, NR 41.0, O, P

(TRILOGY ACS) 64.4 9 38.5 22.6 44.0

O'Donoghue et 62, 60 70.3, 65.9, 56.5, 24.2, 36.7, NR 17.2, O, P, E,

al38 (TRITON- 74.7 63.5 55.4 22.5 38.7 18.1 L, R
TIMI 38)

O'Donoghue et 61, 60 73, 76 64.6, 57.2, 23.5, 38.5, NR 17.6, O, P, E,

al38 (TRITON- 63.9 54.9 23.0 38.3 18.2 L, R
TIMI 38)

Ray et al39 60.8, 45.6, NR NR NR NR 20.8, NR O, P, E,

60.4 53.1 18.9 L, R

Rossini et al40 64, 63 75.6, 63.6, 65.8, 27.1, 28 NR 3.5, 4.9 24.9, 29 O, P, L
81.2 65.2 72.5

Simon et al41 64, 65 73, 72 52, 53 42, 48 30, 35 35, 33 3, 4 10, 14 O, P, E,

L

6
 Van Boxel et al42 68.6, 58.5, NR NR 6.1, 3.9 NR NR 34.8, O, P, E,
66.1 66.8 33.5 R

Yi et al43 68.78, 67.4, 80.5, NR 45.7, 40.9, NR 1.8, 1.6 O, P, L

68.35 62.8 82.6 44.1 39.0

TNP indicates Thienopyridine, PPI: Proton pump inhibitor, HTN: hypertension, HLD: hyperlipidemia, DM: diabetes mellitus, MI:
myocardial infarction, AIS: acute ischemic stroke, TIA: transient ischemic attack; NR: not reported

7
Supplemental Table III: Risk of bias assessment of randomized controlled trials.

Study Random Allocation Blinding of Incomplete Selective Other

sequence concealment participants outcome data reporting potential bias
generation (selection bias) and personnel (attrition bias) (reporting
(selection bias) (performance bias)
bias)

Bhatt et al, 2010 Low risk Low risk Low risk Unclear risk Low risk Low risk
(COGENT) Quote: random Quote: random Quote: Both comment: Comment: Comment: No
allocation using allocation using participants and insufficient other apparent
interactive interactive personnel were information All outcomes bias
voice response voice response blinded appear to be
system system reported

Dunn et al, 2013 High risk Unclear risk High risk Unclear risk High risk High risk
Quote: pre- Comment: comment: comment: Comment: Comment:
(CAPRIE) specified, insufficient Patients were insufficient Post-hoc Post-hoc
nonrandomized information not blinded. information analysis analysis
subgroup Unclear risk
analysis comment:
Insufficient
information
about personnel

Dunn et al, 2013 High risk Unclear risk High risk Unclear risk High risk High risk
Quote: pre- Comment: comment: comment: Comment: Comment:
(CREDO) specified, insufficient Patients were insufficient Post-hoc Post-hoc
nonrandomized information not blinded. information analysis analysis
subgroup Unclear risk
comment:

8
 analysis Insufficient
information
about personnel

Gargiulo et al, 2016 High risk Unclear risk High risk Unclear risk High risk High risk
(PRODIGY) Quote: pre- Comment: comment: comment: Comment: Comment:
specified, insufficient Patients were insufficient Post-hoc Post-hoc
nonrandomized information not blinded. information analysis analysis
subgroup Unclear risk
analysis comment:
Insufficient
information
about personnel

Goodman et al, High risk Unclear risk High risk Unclear risk High risk High risk
2012 (PLATO) Quote: pre- Comment: comment: comment: Comment: Comment:
specified, insufficient Patients were insufficient Post-hoc Post-hoc
nonrandomized information not blinded. information analysis analysis
subgroup Unclear risk
analysis comment:
Insufficient
information
about personnel

Hsu et al, 2011 Low risk Low risk High risk Low risk Low risk Low risk
(NCT01138969) Quote: Quote: comment: Comment: Comment: Comment: No
computer- manually by Open label. other apparent
generated the Sponsor, Unclear risk 4.8% vs 5.1% All outcomes bias
randomization based on a comment: patients lost to appear to be
computer- Insufficient follow-up reported
generated information
allocation about personnel
schedule

9
Jackson et al, 2016 High risk Unclear risk High risk Unclear risk High risk High risk
(TRANSLATE- Quote: pre- Comment: comment: comment: Comment: Comment:
ACS) specified, insufficient Patients were insufficient Post-hoc Post-hoc
nonrandomized information not blinded. information analysis analysis
subgroup Unclear risk
analysis comment:
Insufficient
information
about personnel

Nicolau et al, 2015 High risk Unclear risk High risk Unclear risk High risk High risk
(TRILOGY-ACS) Quote: pre- Comment: comment: comment: Comment: Comment:
specified, insufficient Patients were insufficient Post-hoc Post-hoc
nonrandomized information not blinded. information analysis analysis
subgroup Unclear risk
analysis comment:
Insufficient
information
about personnel

O’Donoghue et al,High risk Unclear risk High risk Unclear risk High risk High risk
2009 Quote: pre- Comment: comment: comment: Comment: Comment:
specified, insufficient Patients were insufficient Post-hoc Post-hoc
(TRITON-TIMI 38) nonrandomized information not blinded. information analysis analysis
subgroup Unclear risk
analysis comment:
Insufficient
information
about personnel

10
Supplemental Table IV: Quality assessment of included studies with the Newcastle–Ottawa Scale

11
Supplemental Figures

Supplemental Figure I: Flow-Chart Diagram Presenting the Selection of Eligible Studies

Identification

Records identified through Records identified through

PubMed (N=4589) EMBASE/MEDLINE (N=1062)

Records after duplicates removed

(N=5584)
Screening

Records screened
Records excluded
(N=5584) (N=5537)

Full text articles excluded,

Full-text articles Stroke outcomes not provided or
unavailable (N=18), no intended
Eligibility

assessed for eligibility

(n=47) stratification by PPI or thienopyridine
(N=5), overlapping data (N=1),
shorter follow-up duration (N=1)

Studies included in
qualitative synthesis
(N=22)
Included

Studies included in
quantitative synthesis
(meta-analysis) 12
(N=22)
Supplemental Figure II: Funnel plot of the included studies for the outcome of ischemic stroke

13
Supplemental Figure III: Funnel plot of the included studies for the combined outcome of stroke, myocardial infarction or
cardiovascular death

14
Supplemental Figure IV: Pooled risk ratios of myocardial infarction for patients on thienopyridine (TNP) and Proton Pump
Inhibitors (PPI) vs. TNP alone

15
Supplemental Figure V: Pooled risk ratios of cardiovascular mortality for patients on thienopyridine (TNP) and Proton Pump
Inhibitors (PPI) vs. TNP alone

16
Supplemental Figure VI: Pooled risk ratios of all-cause mortality for patients on thienopyridine (TNP) and Proton Pump Inhibitors
(PPI) vs. TNP alone

17
Supplemental Figure VII: Pooled risk ratios of major or minor bleeding for patients on thienopyridine (TNP) and Proton Pump
Inhibitors (PPI) vs. TNP alone

18
Supplemental Figure VIII: Subgroup analysis on the risk of Ischemic stroke recurrence amongst IS patients on thienopyridine (TNP)
and Proton Pump Inhibitors (PPI) vs. TNP alone

Supplemental Figure IX: Subgroup analysis comparing the risk of stroke/myocardial infarction and cardiovascular death in
thienopyridine (TNP) and Proton Pump Inhibitors (PPI) vs. TNP alone among patients with history of ischemic stroke/ transient
ischemic attack

19
Supplemental Figure X: Subgroup analysis after adjustment of potential confounders comparing the risk of myocardial
infarction in thienopyridine (TNP) and Proton Pump Inhibitors (PPI) vs. TNP alone

20
Supplemental Figure XI: Subgroup analysis after adjustment of potential confounders comparing the risk of cardiovascular
death in thienopyridine (TNP) and Proton Pump Inhibitors (PPI) vs. TNP alone

21
Supplemental Figure XII: Subgroup analysis after adjustment of potential confounders comparing the risk of all-cause
mortality in thienopyridine (TNP) and Proton Pump Inhibitors (PPI) vs. TNP alone

22
Supplemental Figure XIII: Subgroup analysis on the Risk of Composite of Stroke/MI/Cardiovascular Death Between Patients
on Clopidogrel or Prasugrel Treated With and Without Proton Pump Inhibitors

23
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