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. Author manuscript; available in PMC: 2020 Dec 1.
Published in final edited form as: Cardiovasc Revasc Med. 2019 Feb 10;20(12):1125–1133. doi: 10.1016/j.carrev.2019.02.002

Meta-Analysis of Efficacy and Safety of Proton Pump Inhibitors with Dual Antiplatelet Therapy for Coronary Artery Disease

Safi U Khan a,*, Ahmad N Lone a, Zain Ul Abideen Asad b, Hammad Rahman c, Muhammad Shahzeb Khan d, Muhammad A Saleem e, Adeel Arshad f, Najma Nawaz g, Sudhakar Sattur c, Edo Kaluski c
PMCID: PMC7489463  NIHMSID: NIHMS1620969  PMID: 30773427

Abstract

Background:

There is inconsistency in the literature regarding the clinical effects of proton pump inhibitors (PPI) when added to dual antiplatelet therapy (DAPT) in subjects with coronary artery disease (CAD). We performed meta-analysis stratified by study design to explore these differences.

Methods and results:

39 studies [4 randomized controlled trials (RCTs) and 35 observational studies) were selected using MEDLINE, EMBASE and CENTRAL (Inception-January 2018). In 221,204 patients (PPI = 77,731 patients, no PPI = 143,473 patients), RCTs restricted analysis showed that PPI did not increase the risk of all-cause mortality (Risk Ratio (RR): 1.35, 95% Confidence Interval (CI), 0.56–3.23, P = 0.50, I2 = 0), cardiovascular mortality (RR: 0.94, 95% CI, 0.25–3.54, P = 0.92, I2 = 56), myocardial infarction (MI) (RR: 0.97, 95% CI, 0.62–1.51, P = 0.88, I2 = 0) or stroke (RR: 1.11, 95% CI, 0.25–5.04, P = 0.89, I2 = 26). However, PPI significantly reduced the risk of gastrointestinal (GI) bleeding (RR: 0.32, 95% CI, 0.20–0.52, P < 0.001, I2 = 0). Conversely, analysis of observational studies showed that PPI significantly increased the risk of all-cause mortality (RR: 1.25, 95% CI, 1.11–1.41, P < 0.001, I2 = 82), cardiovascular mortality (RR: 1.25,95% CI, 1.03–1.52, P = 0.02, I2 = 71), MI (RR: 1.30, 95% CI, 1.16–1.47, P < 0.001, I2 = 82) and stroke (RR: 1.60, 95% CI, 1.43–1.78, P < 0.001, I2 = 0), without reducing GI bleeding (RR: 0.74, 95% CI, 0.45–1.22, P = 0.24, I2 = 79).

Conclusion:

Meta-analysis of RCTs endorsed the use of PPI with DAPT for reducing GI bleeding without worsening cardiovascular outcomes. These findings oppose the negative observational data regarding effects of PPI with DAPT.

Keywords: Proton pump inhibitors, Dual antiplatelet therapy, Coronary artery disease, Meta- analysis

1. Introduction

Dual antiplatelet therapy (DAPT) reduces the risk of adverse cardiovascular events in patients with coronary artery disease (CAD) [1,2]. However, the addition of P2Y12 inhibitor to aspirin is associated with increased risk of significant bleeding [3,4]. The European Society of Cardiology (ESC) guidelines endorse PPI prescription (class I, Level: B) with DAPT for all CAD patients [5], whereas, the 2016 American College of Cardiology/American Heart Association focused update recommend the concomitant use of proton pump inhibitors (PPI) with DAPT in the following patients: (a) prior history of GI bleeding (Class I) and (b) higher risk of GI bleeding (i.e. advanced age, concomitant use of warfarin, steroids or non-steroidal inflammatory drugs (Class II a). The routine use of PPIs is not recommended for patients at low risk of GI bleeding (Class III: No Benefit) [6]. While there is paucity of randomized controlled trials (RCTs) on this subject, various meta-analyses and observational studies showed drug interaction and adverse cardiovascular outcomes with co-administration of PPI and DAPT [7-9]. Furthermore, these studies were also inconsistent regarding the protective effects of PPI on GI bleeding. We performed meta-analysis stratified according to study design to explore these clinical differences among RCTs and observational studies regarding use of PPI with DAPT in CAD.

2. Methods

Current meta-analysis was conducted and reported according to Cochrane Collaboration guidelines [10] and Preferred Reporting Item for Systematic Reviews and Meta-Analyses [11].

2.1. Data sources and searches

Electronic search was carried out by two authors (ANL and HR) using MEDLINE (Ovid SP, PubMed), EMBASE and CENTRAL data bases (Inception-January 2018). Following key search terms were used: “proton pump inhibitor” OR “omeprazole” OR “pantoprazole” OR “lansoprazole” OR “esomeprazole” OR “rabeprazole” OR “PPI” OR “dual antiplatelet therapy” OR “DAPT” OR “clopidogrel” AND “Acute coronary syndrome” OR “ACS” OR “percutaneous coronary intervention”. There was no restriction on article types, language, sample size, publication dates, co-morbidities or follow up duration. We also reviewed references contained in the relevant articles. All the citations were downloaded into End note X7 (Thompson ISI ResearchSoft, Philadelphia, Pennsylvania, USA) and duplicates were removed electronically and manually.

2.2. Study selection

Two authors (ANL and HR) screened the search results in a two steps process. Citations were screened at title and abstract level followed by full text screening based on prespecified inclusion criteria: [1] studies comparing PPI versus no PPI in patients with CAD receiving DAPT, [2] studies reporting at least one event for outcomes of interest in adult population (age ≥ 18 years) and [3] Full text articles. Studies were excluded if interaction of PPI was studied with single antiplatelet agent only or if DAPT was used for any other indication such as peripheral vascular disease or stroke.

2.3. Data extraction

Data abstraction was done by two authors (MSK and ANL) on study design, baseline characteristics of the participants, medical therapy, events, non-events, sample size and follow up duration on Microsoft Excel spreadsheets (Microsoft Corporation, Redmond, WA, USA). When available, data was extracted for intention to treat analysis. When possible, standard adjusted estimates were collected. Quality assessment of RCTs was appraised by Cochrane bias assessment tool [12](Supplement Table 1); while observational studies were evaluated using New-Castle Ottawa Scale [13]. We assessed eight domains in New-Castle Ottawa Scale and score of 6/8 was consistent with good quality data (Supplement Table 2).

2.4. Outcome measures

The primary outcome was all-cause mortality. The secondary outcomes were cardiovascular mortality, myocardial infarction(MI), stroke, and GI bleeding events. We used the definitions as reported in the included studies.

2.5. Statistical analysis

Meta-analysis was stratified according to study design (RCT and observational studies). Estimates were pooled using generic invariance weighted random effects model. Statistical heterogeneity was checked by Q statistics and quantified via I2 with value ≥75% was consistent with high degree of heterogeneity [14]. Outcomes were calculated as risk ratio (RR) and risk difference (RD) with 95% confidence interval (CI). Since both summary measures account for same data, forest plots are generated for RRs only. However, RDs are provided in Supplement Table 3. All analyses were conducted at 5% significance. Publication bias was assessed using Egger's regression test [15]. Comprehensive Meta-analysis software version 3.0 (Biostat, Englewood, NJ) was used for all the analyses.

3. Results

Initial search yielded 38,725 citations, 21,480 were duplicates and 15,830 were excluded at titles and abstract level screening and 1376 articles were removed based on prior inclusion/exclusion criteria. Ultimately, 39 studies (4 RCTs and 35 observational studies) were selected (Fig. 1). 15 studies recruited patients with acute coronary syndrome (ACS) while 24 studies had participants with mixed presentation (stable CAD and ACS). The pooled mean age was 65 ± 3 years, 72% were males, 25% had prior MI, 69% had hypertension and 33% had diabetes mellitus. Except for two studies [16,17], all studies used Clopidogrel as P2Y12 inhibitor. Whereas, different PPIs were used across all the studies. The pooled average follow-up duration was 15 months (Table 1).

Fig. 1.

Fig. 1.

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Search strategy according to preferred reporting items of systematic reviews and meta-analyses.

Table 1.

baseline characteristics of the studies and participants.

Studies (year/design) Setting Groups N Age (years) Men (%) Type of P2Y12
inhibitors		 Type of PPI Prior MI (%) DM (%) HTN (%) Smoking (%) Follow up
(months)
Brada [30] (2008/OS) ACS PPI 705 64.3 ± 13.0 75 Clopidogrel NR 59 31 53 58 In-hospital
No PPI 318 62.6 ± 11.4 79 27 34 61 62
Gao [25] (2009/RCT) ACS PPI 114 58.2 ± 8.7 NR NR Omeprazole NR NR NR NR 0.5
No PPI 123 57.5 ± 9.2 NR NR NR NR NR
Ho [19](2009/OS) ACS PPI 5244 67.7 ± 11.4 98.4 Clopidogrel Omeprazole, Rabeprazole 26.4 45.5 NR NR 17.3
No PPI 2961 65.7 ± 11.7 98.9 20.1 38 NR NR
O'Donoghue (PRINCIPLE-TIMI 44/TRITON-TIMI 38) [17](2009/OS) Mixed PPI 28/2257 63.1/62 67.9/70.3 Clopidogrel Pantoprazole, Omeprazole, Esomeprazole, Lansoprazole, Rabeprazole 39.3/17.2 39.3/24.2 78.6/65.9 32.1/36.7 6
No PPI 71/4538 64.1/60 71.3/74.7 23.9/18.1 23.9/22.5 77.5/63.5 9.9/38.7
PPI 25/2272 61.8/61 72.0/73.0 Prasugrel 52.0/17.6 52.0/23.5 92.0/64.6 24.0/38.5
No PPI 77/4541 64.7/60 71.4/76.0 23.4/18.2 23.4/23.0 83.1/63.9 15.6/38.3
Bhatt [27] (2010/RCT) Mixed PPI 1876 68.5 66.9 Clopidogrel Omeprazole 30.5 31.7 80.1 12.5 3.5
No PPI 1885 68.7 69.5 28.5 28.6 81.4 14.1
Charlot [31](2010/OS) ACS PPI 6753 67.5 ± 12.5 61.8 Clopidogrel Pantoprazole, Lansoprazole, Omeprazole, Esomeprazole, Rabeprazole NR 5.8 NR NR 12
No PPI 17,949 64.1 ± 12.5 71.3 NR 3.7 NR NR
Evanchan [32] (2010/OS) ACS PPI 1369 63.5 NR Clopidogrel Esomeprazole, Pantoprazole, Omeprazole, Lansoprazole - 46 61 NR 12
No PPI 4425 62.9 NR - 36 64 NR
Gaglia [33 ] (2010/OS) Mixed PPI 318 63.8 ± 11.6 61.9 Clopidogrel Esomeprazole, Omeprazole, Lansoprazole, Rabeprazole 28.1 36.3 78.5 13.8 12
No PPI 502 63.7 ± 11.6 64.1 23.7 33.1 74.8 18.9
Gaspar [34] (2010/OS) ACS PPI 274 65 ± 13 73.7 Clopidogrel Lansoprazole Omeprazole, Rabeprazole 20.1 25.5 67.5 34.7 6
No PPI 528 61 ± 13 76.7 20.1 27.1 61.4 43
Gupta [18] (2010/OS) Mixed PPI 72 61.7 ± 1.2 NR Clopidogrel Rabeprazole, Omeprazole, Lansoprazole NR 36 76 25 50
No PPI 243 62.0 ± 0.7 NR NR 30 68 33
Huzdik [35] (2010/OS) Mixed PPI 18 62.8 ± 9.4 83.3 Clopidogrel Omeprazole 76.5 44.4 72.2 NR 12
No PPI 20 60.5 ± 11.8 65 70 30 70 NR
Kreutz [36] (2010/OS) Mixed PPI 6828 67.5 ± 10.4 62 Clopidgrel Esomeprazole, Omeprazole, Pantoprazole, Lansoprazole NR 25.9 50.6 NR 12
No PPI 9862 65.2 ± 10.6 73.9 NR 22.7 46.5 NR
Ray [37] (2010/OS) Mixed PPI 7593 60.8 ± 11.3 45.6 Clopidogrel Pantoprazole, Lansoprazole Omeprazole, Esomeprazole, Rabeprazole NR NR NR NR 12
No PPI 13,003 60.4 ± 11.2 53.1 NR NR NR NR
Sarasoff [38] (2010/OS) Mixed PPI 698 68.7 ± 11.1 62.9 Clopidogrel Pantoprazole, Lansoprazole Omeprazole, Esomeprazole, Rabeprazole 36.1 28.8 62.9 16.5 1
No PPI 2640 66.3 ± 10.8 66.1 29.5 25 66.1 17.2
Tentzeris [39] (2010/OS) Mixed PPI 691 64.1 ± 12.4 65.4 Clopidogrel Pantoprazole, Lansoprazole Omeprazole, Esomeprazole, Rabeprazole 18.7 18.7 73.7 27.9 7.8
No PPI 519 64.4 ± 11.9 72.6 19.7 26 78.2 23.1
Yasu [40] (2010/OS) Mixed PPI 103 69.0 ± 9.6 67 Clopidogrel Rabeprazole 32 35 64.1 24.3 13
No PPI 188 67.4 ± 10.1 72.4 17.6 39.7 64.8 27.1
Ziaris [41] (2010/OS) Mixed PPI 340 62.1 ± 10.5 82.4 Clopidogrel Omeprazole 17.1 30 50.9 49.7 12
No PPI 248 61.7 ± 10.8 81.9 17.7 26.2 46.4 50.8
Banerjee [42] (2011/OS) ACS PPI 867 64.5 ± 10.3 98.2 Clopidogrel NR 24.9 51.4 92.4 40 72
No PPI 3678 63.8 ± 9.9 98.3 17.6 45.1 88.9 39.5
Yi-hong [43] (2011/RCT) ACS PPI 86 62.1 ± 10.6 72.1 Clopidogrel Omeprazole NR NR NR NR 1
No PPI 86 61.8 ± 11.2 73.3 NR NR NR NR
Harjai [44] (2011/OS) Mixed PPI 751 66 ± 11 62 Clopidogrel Omeprazole, Esomeprazole 22 30 73 21 6
No PPI 1902 64 ± 12 72 21 27 65 26
Nakayama [45] (2011/OS) Mixed PPI 280 68.4 ± 9.9 79 Clopidogrel Lansoprazole Omeprazole, Rabeprazole 16 37 89 65 30
No PPI 284 66.9 ± 9.9 75 21 45 89 61
Rossini [46] (2011/OS) Mixed PPI 1158 64 ± 11 75.6 Clopidogrel Lansoprazole Omeprazole, Pantoprazole 24.9 27.1 63.6 49.3 12
No PPI 170 63 ± 11 81.2 29 28 65.2 49.7
Simon [47] (2011/OS) ACS PPI 1453 64 ± 13 73 Clopidogrel Pantoprazole, Lansoprazole Omeprazole, Esomeprazole 10 30 52 35 12
No PPI 900 65 ± 14 72 14 35 53 33
Aihara [48] (2012/OS) Mixed PPI 500 68 ± 11 72.6 Clopidogrel Lansoprazole Omeprazole, Rabeprazole 15.8 40.8 71.2 44.6 12
No PPI 500 69 ± 10 75.8 16.8 39.4 69 43.2
Bhurke [49] (2012/OS) ACS PPI 2674 61.3 ± 11.7 70 Clopidogrel Pantoprazole, Lansoprazole, Omeprazole, Esomeprazole, Rabeprazole NR 29.1 NR NR 9
No PPI 2674 61.3 ± 11.7 70.1 NR 28.6 NR NR
Burkard [50] (2012/OS) Mixed PPI 109 66.5 ± 10.5 68.8 Clopidogrel Pantoprazole, Lansoprazole Omeprazole, Esomeprazole 22 29.6 72.5 24.8 36
No PPI 692 63.3 ± 11.3 79.9 27.9 17.2 65 29.8
Chitose [51] (2012/OS) Mixed PPI 331 70.3 ± 11.0 71.6 Clopidogrel, Ticlopidine NR 25.4 35.3 77.9 23.9 18
No PPI 939 68.9 ± 10.9 72.2 22.9 33.7 79 26.2
Douglas [52] (2012/OS) ACS PPI 9111 71 58 Clopidogrel Lansoprazole Omeprazole, Esomeprazole NR 34 NR 69 10
No PPI 15,360 68 65 NR 29 NR 69
Goodman [16] (Clopidogrel/Ticagrelor) (2012/OS) ACS PPI 6539 63 72.4 Clopidogrel/Ticagrelor Pantoprazole, Lansoprazole, Omeprazole, Esomeprazole, Rabeprazole 20.8 25.8 65.6 36.2 12
No PPI 12,062 62 71.2 20.5 24.7 65.4 35.7
Ng [26] (2012/RCT) ACS PPI 163 64.3 ± 13.8 77.3 Clopidogrel Esomeprazole NR NR NR 19.6 6
No PPI 148 63.1 ± 13.2 72.3 NR NR NR 18.9
Hauptle [53] (2012/OS) ACS PPI 87 68 ± 9 70.1 Clopidogrel NR NR 12.6 79.3 29.9 12
No PPI 631 64 ± 11 74.3 NR 15.8 62.1 34.5
Lin [54] (2012/OS) ACS PPI 5173 68.3 ± 11.4 66.2 Clopidogrel Pantoprazole, Lansoprazole Omeprazole, Esomeprazole, Rabeprazole NR 35.1 54.1 NR 12
No PPI 31,926 65.4 ± 12.4 71.6 NR 33 55.7 NR
Macaione [55] (2012/OS) ACS PPI 121 63.7 ± 10.6 80.2 Clopidogrel Pantoprazole, Lansoprazole Omeprazole, Esomeprazole 16.5 41.3 70.2 37.2 36
No PPI 55 65.8 ± 8.8 87.3 14.5 49.1 81.8 27.3
Ortolani [56] (2012/OS) ACS PPI 3519 69 ± 12 69 Clopidogrel Pantoprazole, Lansoprazole Omeprazole, Rabeprazole 20 24 63 NR 12
No PPI 377 63 ± 12 77 15 20 57 NR
Jiang [57] (2013/OS) Mixed PPI 1570 72.4 ± 12.3 66 Clopidogrel Lansoprazole Omeprazole, Esomeprazole NR NR NR 19.2 12
No PPI 1110 69.5 ± 13.8 65 NR NR NR 15.6
Zou [58] (2014/OS) ACS PPI 6188 66.2 ± 10.2 73.5 Clopidogrel Pantoprazole, Omeprazole, Esomeprazole 17.3 25.8 71.3 32.2 12
No PPI 1465 65.7 ± 10.6 73.9 19.8 23.6 70.4 31
Hsieh [59] (2015/OS) Mixed PPI 670 68.3 ± 10.7 63.6 Clopidogrel NR 31.8 100 NR NR 12
No PPI 5933 66.5 ± 10.5 66.4 31.3 100 NR NR
Weisz [60] (2015/OS) Mixed PPI 2697 64.4 ± 10.5 70.1 Clopidogrel NR 28.6 34.8 83.7 22.7 24
No PPI 5885 63.2 ± 11.0 75.9 23.7 31.4 77.8 22.6
Gargiulo [61 ] (2016/OS) Mixed PPI 738 71.2 72.5 Clopidogrel Pantoprazole, Lansoprazole 27 23.3 72.5 22.6 24
No PPI 1232 68.1 79.2 26.1 24.8 71.3 24.4
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ACS = Acute Coronary Syndrome, DM = Diabetes Mellitus, HTN = Hypertension, MI = Myocardial Infarction, NR = Not Reported, OS = Observational Studies, PPI = Proton Pump Inhibitors, RCT = Randomized Controlled Trial, Mixed = Both ACS and non-ACS presentations.

A total of 221,204 patients (PPI = 77,731 patients and no PPI = 143,473 patients) participated in meta-analysis. In the RCTs restricted analysis, PPI did not increase all-cause mortality (RR: 1.35, 95% CI, 0.56–3.23, P = 0.50, I2 = 0; Fig. 2), cardiovascular mortality (RR: 0.94, 95% CI, 0.25–3.54, P = 0.92, I2 = 56; Fig. 3), MI (RR: 0.97, 95% CI, 0.62–1.51, P = 0.88, I2 = 0; Fig. 4) or stroke (RR: 1.11, 95% CI, 0.25–5.4, P = 0.89, I2 = 26; Fig. 5). While, PPI significantly reduced the risk of GI bleeding (RR: 0.32, 95% CI, 0.20–0.52, P < 0.001, I2 = 0; Fig. 6). Conversely, analysis of the observational studies showed that PPI was associated with significant increase in risk of all-cause mortality (RR: 1.25, 95% CI, 1.11–1.41, P < 0.001, I2 = 82; Fig. 2), cardiovascular mortality (RR: 1.25, 95% CI, 1.03–1.52, P = 0.02, i2 = 71; Fig. 3), MI (RR: 1.30, 95% CI, 1.16–1.47, P < 0.001, I2 = 82; Fig. 4) and stroke (RR: 1.60,95% CI, 1.43–1.78, P < 0.001, I2 = 0; Fig. 5), without providing meaningful protection against GI bleeding (RR: 0.74, 95% CI, 0.45–1.22, P = 0.24, I2 = 79; Fig. 6). Egger's regression test did not detect publication bias [Intercept: −0.56, 95% CI, −1.89, 0.76, P (2-tailed) =0.39].

Fig. 2.

Fig. 2.

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Forest plot showing comparison between proton pump inhibitors (PPI) versus no PPI for all-cause mortality. C = Clopidogrel, T = Ticagrelor, P = Prasugrel.

Fig. 3.

Fig. 3.

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Forest plot showing comparison between proton pump inhibitors (PPI) versus no PPI for cardiovascular mortality. C = Clopidogrel, T = Ticagrelor, P = Prasugrel.

Fig. 4.

Fig. 4.

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Forest plot showing comparison between proton pump inhibitors (PPI) versus no PPI for myocardial infarction. C = Clopidogrel, T = Ticagrelor, P = Prasugrel.

Fig. 5.

Fig. 5.

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Forest plot showing comparison between proton pump inhibitors (PPI) versus no PPI for stroke.

Fig. 6.

Fig. 6.

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Forest plot showing comparison between proton pump inhibitors (PPI) versus no PPI for gastrointestinal bleeding. C = Clopidogrel, T = Ticagrelor.

4. Discussion

In this review of 39 studies enrolling 221,204 subjects with CAD requiring DAPT, meta-analysis of RCTs suggested that over an average follow up duration of one year, PPI prevented 36 GI bleeding events per 1000 patients compared with no PPI. This benefit was achieved without increasing the risk cardiovascular events or mortality. Conversely, analysis of observational studies suggested that the use of PPI was associated with significant risk of mortality and cardiovascular outcomes without providing protection against GI bleeding.

Several observational studies have shown that PPIs interfere with the efficacy of DAPT and subsequently may cause adverse cardiovascular outcomes [8,16,18,19]. The interaction between omeprazole and clopidogrel is considered vigorous due to the inhibitory effect of PPI on CYP2C19 isoenzyme [20,21]. Clopidogrel is a prodrug and requires conversion to its active metabolite for inhibition of platelet aggregation. While the conversion from prodrug to active metabolite requires CYP2C19 enzymes, there are genetic variations in CYP2C19 enzymes leading to poor metabolism of the drug in certain patients. Subsequently these patients have reduced efficacy of Clopidogrel. Similarly, Omeprazole and Esomeprazole are inhibitors of CYP2C19 and they can significantly reduce the efficacy of Clopidogrel by preventing conversion to its active metabolite. Therefore, FDA precautions against use of Omeprazole and Esomeprazole use in patients taking Clopidogrel [22].

There is observational data suggesting that the blunting effect of PPI could be expanded to ticagrelor and prasugrel. In a post hoc analysis of PRINCIPLE (Prasugrel In Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation)-TIMI 44 and TRITON (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel)-TIMI 38 trials, there was modest attenuation of the in vitro antiplatelet effects of prasugrel and clopidogrel in the setting of PPI therapy. Another hypothesis for PPI related enhanced cardiovascular risk is that PPI use is a marker for high risk of cardiovascular complications rather than a cause of cardiovascular complications [16,23]. In post hoc analysis of the PLATO (Platelet Inhibition and Patient Outcomes) trial the use of PPI was independently associated with higher risk of cardiovascular events for both clopidogrel and ticagrelor [16]. Similar observation was made in the post-hoc analysis of CREDO (Clopidogrel for Reduction of Events During Observation) and CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) where PPI use was associated with worse cardiovascular outcomes in both clopidogrel (Estimated hazard ratio (EHR): 1.67, 95% CI 1.06 to 2.64) and placebo arms (HER: 1.56, 95% CI 1.06 to 2.30) [24].

Despite this negative interaction between PPI and antiplatelet therapy shown by observational data, this effect was not translated into any significant clinical impression in RCTs. Gao and colleagues [25] reported that early use of omeprazole in acute MI not only reduced the incidence of GI bleeding compared with control (5.3% versus 14.6%, P = 0.017) but also had protective effect on all-cause mortality (3.5% versus 10.6%, P = 0.035). In another trial by Ng et al. [26], omeprazole was superior to famotidine in reducing the risk of GI bleeding (HR: 0.212, P = 0.008) without increasing the risk of cardiovascular outcomes (P = 0.77). In the largest COGENT study (Clopidogrel and the Optimization of Gastrointestinal Events Trial) [27], the addition of omeprazole to DAPT significantly reduced the risk of major GI bleeding without increasing the risk of cardiovascular events, though with broader confidence interval around HRs and limited statistical power. Our meta-analysis is in consensus with these findings and highlights the importance of potential bias introduced by observational studies which results in conflicting outcomes.

We compare our results with prior meta-analyses. Cardoso et al. [28] (39 studies and 214,851 patients) reported 60% relative risk reduction in GI bleeding with PPI (odds ratio (OR): 0.40, 95% CI, 0.22–0.74) but at the cost of increased risk of cardiovascular events. However, Cardoso’s meta-analysis had certain limitations. First, authors combined RCTs and observational studies together in their pooled analysis. This strategy has the potential to generate higher risk of selection and attrition biases. Second, the analysis was primarily focused on interaction of PPI with single clopidogrel therapy and a subgroup analysis on DAPT was limited by various confounders due to mixing of RCTs and propensity matched score studies. Third, post hoc analyses of various RCTs were treated as RCTs which is issue of standardized and comprehensive reporting because post hoc analyses generally do not fill the criteria of a RCT [29]. Another systematic review by Melloni and colleagues (35 studies) was in consensus with our findings [9]. However, authors focused on observational studies only and lacked separate examination of RCTs. Hence, comparison of the effect sizes among RCTs and observational studies could not be performed. Furthermore, key endpoint of GI bleeding was not included. Similar issues related to study design [7,8] or lack of assessment of important endpoints [7] were noticed in other meta-analyses.

That said, the current meta-analysis has certain limitations. First, RCTs data is dominated by the COGENT study population which contributes ~ 84% of RCTs cohort [27]. The COGENT suffered from premature study termination, abbreviated follow up duration and had a high-risk population. Furthermore, due to low event rate and limited follow up duration, COGENT lacked statistical power to detect cardiovascular harm. Second, studies had heterogeneities with regards to clinical presentation, drugs and dosages, procedural techniques, definition of the endpoints and follow up duration which could not be compensated due to lack of access to individual patient data. Therefore, certain outcomes such as stent thrombosis or coronary revascularization could not be assessed. Finally, this review predominantly generates the evidence regarding clopidogrel based DAPT.

In conclusion, we report that meta-analysis of RCTs endorse the use of PPI with DAPT (predominantly clopidogrel based therapy) in CAD patients for prevention of GI bleeding without worsening cardiovascular outcomes. The findings of RCTs restricted analysis are in line with current professional guidelines [6] and oppose the negative observational data on the use of PPI with DAPT. Our review serves as refined summary of published literature on this issue and would allow the clinicians to compare the effects of PPI with concomitant clopidogrel based DAPT based on quality of evidence. This review also highlights the importance of conducting further well-designed RCTs comparing use of specific PPIs with different DAPT regimens (Ticagrelor and Prasugrel) to generate more durable evidence and compensate for relative scarcity of quality data on this subject.

Supplementary Material

Supplement

Acknowledgments

Funding

None.

Footnotes

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.carrev.2019.02.002.

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