Proton pump inhibitors and gastroprotection in patients treated with antithrombotic drugs: A cardiologic point of view

Table 1 Antiplatelet drugs and gastrointestinal bleeding in the real world

Ref.	Setting	Main results
Casado Arroyo et al[49], 2012	Spanish observational register with 1219 patients undergoing PTA, 96.7% of whom were in DAPT with LDA and clopidogrel, and 76.6% on PPI therapy	Eight patients developed GIB during hospitalization, and 27 during follow-up (1.52 bleeds per patient/year). Most GIB cases (81.4%) occurred during the first year. Overall, 84.6% of patients were on long-term PPI at the time of the bleed; lower GIB occurred more frequently than upper GIB (74% vs 26%)
Tsai et al[50], 2012	Observational study aiming to investigate the characteristics of endoscopic findings in clopidogrel or aspirin users undergoing endoscopy for upper gastrointestinal symptoms	Gastroduodenal haemorrhagic spots were more common in clopidogrel users than in aspirin users (10.1% vs 25.5%, P = 0.004). Gastroduodenal erosions were more common in aspirin users than clopidogrel users (53.2% vs 38.7%; P = 0.04), whilst gastroduodenal peptic ulcers were more common in clopidogrel users than in aspirin users (38.7% vs 23.9%; P = 0.027)
de Abajo et al[51], 2013	Case-control study involving 669115 patients assessed the incidence of GIB, evaluating the age of the patients and use of different treatments	The incidence of bleeding observed was 76 per 100000 people/year, with a prevalence higher in men than in women (109 vs 49 per 100000 people/year; OR: 2.23; 95%CI: 1.99-2.50), and with a progressive increase of incidence with age. The risk was significantly higher in patients with a previous episode of GIB (RR: 11.27, 95%CI: 8.35-15.20), in those using aspirin (medium-high doses: RR: 3.29; 95%CI: 1.42-7.62; low doses: RR: 1.74; 95%CI: 1.37-2.21), and other antiplatelet agents (RR: 1.73; 95%CI: 1.27-2.36)
Lanas et al[26], 2015	Case-control study	Non-aspirin antiplatelet agents (mostly clopidogrel) were associated with an increased risk of upper GIB that was similar to that observed with aspirin
Alexopoulos et al[52], 2016	Prospective, observational multicentre cohort trial (GRAPE), performed in patients with ACS undergoing PTA-48% of whom treated with clopidogrel, 18% with prasugrel, and 35% with ticagrelor in dual therapy with LDA	The rate of MACEs was lower in prasugrel treated patients (4.4%) than in clopidogrel treated patients (10.1%) (HR: 0.53; 95%CI: 0.30-0.91), although not significantly different between ticagrelor (6.8%) and clopidogrel groups (HR: 0.78; 95%CI: 0.54-1.12). Any type of bleeding was more frequent in prasugrel-treated patients (51.2%) than in clopidogrel-treated patients (37.6%) (HR: 1.61; 95%CI: 1.33-1.95), and more frequent in ticagrelor-treated patients (56.9%) than in clopidogrel-treated patients (HR: 1.81; 95%CI: 1.55-2.10), but there was no significant difference for fatal events
Sahlén et al[53], 2016	Swedish register SWEDEHEART, where 45073 patients with ACS were enrolled	At 24 mo, the risk of ischemic events, death, and MI was lower with ticagrelor than with clopidogrel (11.7% vs 22.3%, aHR 0.85, 95%CI: 0.78-0.93; 5.8% vs 12.9%, aHR 0.83, 95%CI:0.75-0.92; 6.1% vs 10.8%, Ahr aHR 0.89, 95%CI: 0.78-1.01; respectively). However, re-admission with bleeding was lower in patients taking ticagrelor as compared to those taking clopidogrel: 5.5% vs 5.2%; aHR: 1.20; 95%CI: 1.04-1.40. Furthermore, in a subset of patients undergoing PCI, the PCI-related in-hospital bleeding was higher in patients on ticagrelor compared to those on clopidogrel (7.0% vs 2.7%, aOR: 1.57, 95%CI: 1.30-1.90)
Sehested et al[54], 2019	Danish registry on 46301 patients hospitalized with a MI (35% of whom were at high risk of GIB) treated with clopidogrel (76.2%), ticagrelor (20.3%), or prasugrel (3.5%)	At 12 mo, an episode of digestive bleeding occurred in 1.0% (95%CI: 0.9-1.1) of patients with low risk of bleeding, and in 1.7% (95%CI: 1.5-2.0) of those at high risk. In patients receiving PPIs, the absolute risk of bleeding was overall reduced by 0.44% (95%CI: 0.39-0.48), and by 0.47% (95%CI: 0.43%-0.51%) in those at high risk
Nishtala et al[55], 2019	Study performed in New Zealand on 66500 patients aged ≥ 65 yr	No significant change in the incidence of GIB in patients using aspirin (Arr: 0.84; 95%CI: 0.79-0.89), or clopidogrel (Arr: 0.97; 95%CI: 0.87-1.08) in monotherapy, while DAPT resulted in an increased rate of bleeding (aRR: 1.34, 95%CI: 1.14-1.57). In addition, the incidence of bleeding was increased when an anticoagulant therapy was associated with aspirin (aRR: 1.79; 95%CI: 1.30-2.46), clopidogrel (aRR: 6.36; 95%CI: 2.24-18.03), or DAPT (aRR: 4.85; 95%CI: 1:51 to 15:57)
Vidyanti et al[56], 2019	Retrospective study on 1119 ischemic stroke patients	The HR for GIB was significantly in favour of clopidogrel (HR: 2.60; 95%CI: 2.82-3.70)
Zheng et al[57], 2019	Meta-analysis of 13 trials-with a median age of trial participants of 62 yr (range, 53-74)	Aspirin use was associated with an increased risk of bleeding events compared with no aspirin (23.1 per 10000 participant-years with aspirin and 16.4 per 10000 participant-years with no aspirin-HR: 1.43; absolute risk increases 0.47%)

ACS: Acute coronary syndromes; aHR: Adjusted hazard ratio; aOR: Adjusted odds ratio; aRR: Adjusted relative risk; CI: Confidence interval; DAPT: Double antiplatelet therapy; GIB: Gastrointestinal bleeding; HR: Hazard ratio; LDA: Low dose aspirin; MACEs: Major adverse cardiovascular events; MI: Myocardial infarction; OR: Odds ratio; PCI: Percutaneous coronary intervention; PPI: Proton pump inhibitor; PTA: Percutaneous transluminal angioplasty; RR: Relative risk.