Antiplatelet agents and proton pump inhibitors – personalizing treatment

Figures & data

Table 1 Pharmacodynamic Studies involving clopidogrel

Authors	Study type and population	Outcome	N	Significance	Results
Gilard et al^Citation31	Double-blind placebo-controlled randomized trial Elective coronary stent implantation	Platelet Reactivity Index	Omeprazole = 64 Placebo = 60	P < 0.0001	Poor responders in: Omeprazole: 60.9% (39) Placebo: 26.7% (16) OR for poor reactivity = 4.31(2.0–9.2)
Cuissett et al^Citation35	Prospective randomized trial Planned coronary stenting after ACS	Platelet Reactivity Index	Omeprazole = 52 Pantoprazole = 52	P = 0.04	Poor responders in: Omeprazole: 44% Pantoprazole: 22% OR for poor reactivity = 2.6(1.2–6.2)
Small et al^Citation32	Randomized open label crossover Healthy volunteers	Inhibition of ADP-induced platelet aggregation	Clopidogrel = 24 Clopidogrel and Lansoprazole = 24	P = 0.046	Statistically similar for clopidogrel alone and with lansoprazole Except with 5 micrometer ADPat 24 hrs (reduced to 39% from 49%)
O’Donoghue et al^Citation37	Retrospective cohort within Principle TIMI and TRITON Timi Planned percutaneous coronary intervention	ADP-induced platelet aggregation at 6 hours	PPI = 28 No PPI = 71	P = 0.50,0.051,0.11 (respectively) P = 0.009	Lower mean inhibition in those taking PPI at 2, 6 and 18–24 h Nonresponders at 6 h 50.0% on PPI compared to 18.2% without PPI
Collet et al^Citation23	Prospective cohort	CV death, nonfatal MI, urgent revascularization	Any PPI = 83 No PPI = 176	P = 0.40	No significant differences according to CYP2C19^*2 genotype with PPI
Gilard et al^Citation30	Prospective cohort High risk coronary angioplasty	Platelet Reactivity Index	PPI = 24 No PPI = 81	P = 0.007	VASP = 61.4% No PPI VASP = 4.95%
Siller-Matula et al^Citation33	Prospective cohort Undergoing percutaneous coronary intervention	Platelet Reactivity Index ADP-induced aggregation	PPI = 226 (Pantoprazole = 152 Esomeprazole = 74) No PPI = 74	P = 0.724	Platelet Reactivity Index pantoprazole = 50% Esomeprazole =54% No PPI = 49%
Sibbing et al^Citation34	Prospective cohort Prior coronary stent placement	ADP-induced platelet aggregation	Pantoprazole = 162 Omeprazole = 64 Esomeprazole = 42 No PPI = 732	P = 0.001 P = 0.69 P = 0.88	Pantoprazole 226.0 AU^*min Omeprazole 295.5 AU^*min Esomepraozle 209.0 AU^*min No PPI = 220.0 AU^*min

Abbreviations: ADP, adenosine diphosphate; ACS, acute coronary syndrome; CV, cardiovascular; MI, myocardial infarction; PPI, proton pump inhibitor; N, total number.

Table 2 Clinical studies involving clopidogrel

Authors	Study type and population	Outcome	N	Significance	Results
Bhatt et al^Citation39	Double-blind randomized incomplete (COGENT) ACS and coronary stent placement	Stroke, MI, CABG, PCI and CV death	PPI = 1878 Placebo = 1895	P = 0.007	HR 0.55(0.36–0.85)
Dunn et al^Citation40	Retrospective cohort within CREDO trial (RCT) High likelihood of PCI or undergoing PCI	Death, MI, stroke at 1 year	PPI = 366 No PPI = 1750	P = 0.043 P = 0.035	Clopidogrel and PPI OR = 1.633(1.015–2.627) Placebo and PPI OR = 1.554(1.031–2.341)
Ho et al^Citation43	Retrospective cohort Discharged after MI or unstable angina	Mortality or rehospitalization for ACS	PPI = 5244 Omeprazole = 3132(59.7%) Rabeprazole = 22(0.4%) No PPI = 2961	P = 0.46	Adjusted OR = 1.25(1.11–1.41) OR = 1.24(1.08–1.41) OR = 2.83(1.96–4.09)
O’Donoghue et al^Citation37	Retrospective cohort Principle-TIMI 44 and TRITON-TIMI 38 RCT ACS undergoing PCI	CV death, MI or stroke	No PPI = 4538 PPI = 2257		Pantoprazole 1844 0.94 (0.74–1.18) Omeprazole 1675 0.91 (0.72–1.15) Esomeprazole 613 1.07 (0.75–1.52) Lansoprazole 441 1.00 (0.63–1.59) Rabeprazole 66 no calculations Overall 0.94 (0.80–1.11)
Pezalla et al^Citation41	Retrospective cohort Younger than 65 years and taking clopidogrel	MI within 1 year	Low PPI = 712 No PPI = 4800 Subset of all risk factors = 1010	P < 0.05 P < 0.05	Unadjusted comorbidities MI Rates low PPI = 3.08%, no PPI = 1.38%, high PPI = 5.03% MI Rates low PPI = 10.0%, no PPI = 2.60%, high PPI = 11.38%
Ramirez et al^Citation38	Retrospective cohort PCI	MI, death, CABG or repeat PCI	PPI = 138 No PPI = 397	P = 0.32	Death/MI for PPI = 6.7% vs no PPI 9.6% Repeat vascularization PPI = 15.8% vs no PPI 14.2%
Rassen et al^Citation3	Retrospective cohort Older than 65 years old with PCI or ACS and had started clopidogrel	MI, death	PPI = 3996 No PPI = 14659		Pooled RR = 1.22 (0.99–1.51)
Ray et al^Citation36	Retrospective cohort Hospitalized for MI, revascularization or unstable angina	Gastroduodenal bleeding or serious CV disease	PPI = 7593 (Omeprazole 9%) (Pantoprazole 62%)		HR = 0.99 (95% CI, 0.82–1.19)
Stanek et al^Citation44	Retrospective cohort Consistent use of clopidogrel after coronary stent	Stroke, TIA, MI, coronary revascularization, Death (adjusted risk for age/sex/comorbidity)	PPI = 6826 (25.1%) Omeprazole = 2307 Esomeprazole = 3257 Pantoprazole = 1653 Lansoprazole = 785 No PPI = 9862 (17.9%) No PPI = 602	P < 0.0001 P < 0.0001 P < 0.0001 P < 0.0004	Adjusted HR = 1.51 (1.39–1.64) HR = 1.39(1.22–1.57) HR = 1.57(1.40–1.76) HR = 1.61(1.41–1.88) HR = 1.39(1.16–1.67)
Juurlink et al^Citation42	Population-based nested case-control study Older than 65 years old with discharge after MI	Died or readmitted for MI within 90 days after initial hospital discharge Controls matched for age, PCI, date of discharge, comorbidities, medications	Cases on PPI = (26.4%) Controls on PPI = (20.6%)		OR = 1.25 (1.03–1.57) Pantoprazole = 1.02 (0.70–1.47) All other PPI = 1.40 (1.10–1.77)

Abbreviations: CV, cardiovascular, MI, myocardial infarction; TIA, transient ischemic attack; PCI, percutaneous intervention; PPI, proton pump inhibitor; N, total number.

Table 3 Odds and hazard ratio for increased risk of adverse outcome when on concurrent proton pump inhibitors and clopidogrel

Proton pump inhibitor	O’Donoghue et al^Citation37	Ho et al^Citation43	Stanek et al^Citation44 PPI = 6826	Juurlink et al^Citation42
Pantoprazole	1844 OR = 0.94 (0.74–1.18)		24.2% HR = 1.61(1.41–1.88)	OR = 1.02 (0.70–1.47)
Omeprazole	1675 OR = 0.91 (0.72–1.15)	59.7% OR = 1.24(1.08–1.41)	33.8% HR = 1.39(1.22–1.57)
Esomeprazole	613 OR = 1.07 (0.75–1.52)		47.7% HR = 1.57(1.40–1.76)
Lansoprazole	441 OR = 1.00 (0.63–1.59)		11.5% HR = 1.39(1.16–1.67)
Rabeprazole	66 no calculations	0.4% OR = 2.83(1.96–4.09)

Abbreviations: OR, odds ratio; HR, hazard ratio.

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