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Table 1 Study detailsa

From: The potential interaction between clopidogrel and proton pump inhibitors: a systematic review

Study Population
(special conditions)
PPIs studied Propensity for bias* Procedures to minimize bias** Study quality*** Primary outcome/Results
(all PPIs combined)
Secondary analyses according to specific PPIs Authors' conclusions about clopidogrel-PPI interaction
Ho et al. [11] 8,205 ACS
(VA patients)
L, O, P, R Moderate Yes Low 3-year mortality or ACS
OR: 1.25; 95% CI: 1.11-1.41
O = OR: 1.24; 95% CI: 1.08-1.41
R = OR, 2.83; 95% CI: 1.96-4.09
"Concomitant use after hospital discharge for ACS was associated with increased risk of adverse outcomes."
Juurlink et al. [12] 13,636 ACS
(age ≥66)
L, O, P, R Moderate Yes Low 90-day nonfatal MI
OR: 1.27; 95% CI: 1.03-1.57
P = OR 1.02, 95% CI 0.70-1.47
Non P = OR 1.40 (1.10-1.77)
"Concomitant therapy with PPIs other than pantoprazole was associated with loss of beneficial effects of clopidogrel."
Aubert et al. [23] 14,383 PCI NR Uncertain Uncertain Low 1-year combined stroke, MI, angina or CABG
OR:1.79; 95% CI 1.62-1.97
NR "The drug interaction between PPIs and clopidogrel may result in serious adverse outcomes within one year of therapy initiation."
Banerjee et al. [24] 534 PCI NR Uncertain Uncertain Low Mortality, MI, repeat revascularization and stroke
OR 1.54 no CI P < 0.006
(557-615 days)
NR "PPI(s) with clopidogrel is associated with an increased risk."
Bhatt et al. [25] 3,267 ACS PCI O Low Yes High 130-day CD, nonfatal MI, revascularization or ischemic stroke
HR: 1.02; 95% CI = 0.70-1.51
Only O studied "No apparent cardiovascular interaction between clopidogrel and omeprazole"
Dunn et al. [26] 1,053 PCI NR Uncertain No Low 1-year death, MI or stroke
OR: 1.63; 95% CI, 1.02-2.62
NR "PPI use was associated with an increased cardiovascular risk."
Gaspar et al. [27] 922 ACS O, L, R Uncertain Uncertain Low 6-month death, MI or UA
8.8% vs. 8.4%, P = NS
NR "Was not associated with a worse prognosis in patients with ACS"
Gupta et al. [28] 315 PCI
(VA patients)
L, O, R Moderate No Low 4-year death, MI or TVF
OR: 1.95; 95% CI: 1.09-3.49
NR "PPIs may attenuate clopidogrel's beneficial antiplatelet effect."
Huang et al. [29] 3,278 PCI
NR Moderate No Low 5-year all-cause mortality
HR: 1.65; 95% CI, 1.35-2.01
NR "Concomitant use should be done with care to avoid adverse outcomes."
O'Donoghue et al. [30] 6,795 ACS
(age ≥60)
E, L, O, P, R Low Yes Moderate 1-year CD, MI or stroke
OR: 0.94; 95% CI: 0.80-1.11
No specific data reported "Regardless of PPI type (including omeprazole alone or the exclusion of pantoprazole), no independent association existed" "No clinically relevant adverse cardiovascular interaction between clopidogrel and PPIs."
Pezalla et al. [31] 1,010 ACS
(age <65)
NR Uncertain No Low 1-year adjusted MI
OR 4.3; 95% CI 2.2-8.4#
NR "Evidence is pointing toward a potentially significant interaction."
Ramirez et al. [32] 534 PCI NR Uncertain Uncertain Low 1-year mortality/MI
P = 0.32
NR "Concomitant use of PPI's did not result in adverse cardiovascular outcomes at one year."
Rassen et al. [33] 18,565 ACS PCI
(age ≥65)
E, L, O, P, R Low Yes Moderate 180-day death or MI
OR: 1.22; 95% CI: 0.99-1.51
O = RR 1.17; 95% CI: 0.68-2.01
P = RR 1.26; 95% CI: 0.93-1.71
"We did not observe conclusive evidence of a clopidogrel/PPI interaction."
Ray et al. [34] 20,596 ACS PCI
(age ≥30)
E, L, O, P, R Low Yes Moderate 1-year MI, CD or stroke
HR: 0.99; 95% CI, 0.82-1.19
E = HR 0.71; 95% CI 0.48-1.06
L = HR 1.06; 95% CI 0.77-1.45
O = HR 0.79;95% CI 0.54-1.15
P = HR 1.08; 95% CI 0.88-1.32
R = HR 0.54; 95% CI 0.30-0.97
"Concurrent use of a PPI was not associated with a statistically significant increased risk for serious cardiovascular disease."
Sarafoff et al. [35] 2,025 PCI NR Uncertain Uncertain Low 30-day stent thrombosis
OR NR, P = 0.002
death OR NR, P = 0.04
NR "A PPI is associated with higher rates of stent thrombosis and an increased mortality."
Stockl et al. [36] 2,066 ACS PCI
(age 18-84)
E, L, O, P, R Moderate Yes Low 1-year nonfatal MI
HR: 1.93; 95% CI: 1.05-3.54
P = HR 2.18; 95% CI 0.88-5.39 "Patients who received clopidogrel plus a PPI had a significantly higher risk."
Tsiaousis et al. [37] 612 PCI NR Uncertain Uncertain Low 1-year death HR: 1.1; 95% CI: 0.7-1.4
1-year MI HR: 1.0; 95% CI: 0.8-1.3
NR "PPIs drug therapy does not have any impact on the effectiveness."
Charlot et al. [38] 56,408 AMI E, L, O, P Low Yes Moderate 1-year death, MI, stroke
HR: 0.98; 95% CI, 0.88-1.10
"No difference in risk associated with the type of PPI" "No statistically significant interaction occurred between a PPI and clopidogrel."
  1. aACS, acute coronary syndrome; AMI, acute myocardial infarction; AR, absolute risk; C, clopidogrel; CABG, coronary artery bypass graft; CD, cardiovascular death; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; OHIP, Ontario health insurance program; OR, odds ratio; PCI, percutaneous coronary intervention; PPI, proton pump inhibitor; TIA, transient ischemic attack; TVF, target vessel failure; TVR, target vessel revascularization; VA, Veterans Administration; UA, unstable angina; NR, not reported; E, esomeprazole; L, lansoprazole; O, omeprazole; P, pantaprazole; R, rabeprazole.
  2. *Biases considered are selection, confounding and misclassification; the probability of bias in the studies available as abstracts was deemed uncertain.
  3. **Procedures to minimize bias include multiple sensitivity analyses for varying drug exposures, multiple methods for control of confounding and time-varying analysis for misclassification.
  4. ***High study quality was reserved for RCTs. For observational studies, moderate study quality required low propensity for bias and specific efforts to minimize bias. Otherwise, quality was assessed as low.
  5. #Calculated by combining high- and low-dose PPI groups.