Clopidogrel is a second-generation thienopyridine, which became available in its generic form in 2012. Clopidogrel is a prodrug, which is well absorbed from the gut, but remains pharmacologically inert until activated in the liver through the CYP system (Fig. 1). The majority of administered clopidogrel is metabolized by an esterase pathway not resulting in active drug metabolites, and only 15 % reaches the liver for active metabolite transformation [14]. This is mediated by a two-step oxidative process regulated by the CYP system. Ultimately, as little as 2 % ends up irreversibly inhibiting the P2Y₁₂ receptor [21]. Among the different CYP variants involved in the hepatic conversion of clopidogrel, CYP2C19 is the major variant responsible for approximately 45 % [21].

Prasugrel is activated in a one-step oxidative process and, unlike clopidogrel, none of the drug is shunted to an inactive pathway (Fig. 1). Compared to clopidogrel, the hepatic conversion of prasugel is less dependent on CYP2C19 [22]. Ticagrelor is an adenosine triphosphate analogue not belonging to the thienopyridine family. Ticagrelor inhibits the P2Y₁₂ receptor reversibly and does not require hepatic bioactivation (Table 1 and Fig. 1). Prasugrel and ticagrelor are more potent platelet function inhibitors than clopidogrel and are now being widely used in combination with aspirin in the setting of ACS.

The CURE trial from 2001 documented the benefit of clopidogrel in addition to aspirin in patients with non-ST elevation MI [23]. The relative risk for the primary end point (cardiovascular death, non-fatal MI, or stroke) with aspirin and clopidogrel was 0.80 (95 % confidence interval [CI] 0.72–0.90) compared to aspirin alone. Since then, clopidogrel has been used in combination with aspirin in the setting of percutaneous coronary intervention (PCI), especially in the treatment of ACS. In 2005, a similar benefit was documented in patients with ST elevation MI [24, 25]. Overall, dual antiplatelet therapy with aspirin and clopidogrel in patients with ACS reduced cardiovascular risk by approximately 10 % compared to aspirin alone [23–25]. Documenting its widespread use, clopidogrel was the second most prescribed drug worldwide in 2010 (atorvastatin was the most prescribed) [26].

From 2009 to 2011 ticagrelor and prasugrel received authorization from European and American authorities for use in combination with aspirin for prevention of atherothrombotic events in patients with ACS undergoing PCI. Approvals were based on two phase III trials, TRITON-TIMI 38 (prasugrel) [27] and PLATO (ticagrelor) [28], documenting significant reductions in cardiovascular death, non-fatal MI, or stroke when using prasugrel or ticagrelor instead of clopidogrel. In TRITON-TIMI 38 the hazard ratio with prasugrel was 0.81 (95 % CI 0.73–0.90), and in PLATO the hazard ratio with ticagrelor was 0.84 (95 % CI 0.77–0.92). Although prasugrel and ticagrelor increased the risk of non-coronary artery bypass grafting-related major bleeding according to the Thrombolysis in Myocardial Infarction criteria (by 32 % and 25 %, respectively), both drugs are now widely used as treatment and short-term prevention of atherothrombotic events in patients with ACS [4].

Cardiovascular protection by aspirin and ADP receptor antagonists accrue at the expense of an increased risk of upper gastrointestinal bleeding [29, 30]. Gastrointestinal bleeding is life-threatening, especially in patients presenting with ACS [31] and documenting this, aspirin remains the dominant contributor to gastrointestinal bleeding-related mortality [32].

The gastrotoxic effects of aspirin that cause ulceration and bleeding have been attributed to (1) topical mucosal injury caused by inhibition of prostaglandin and (2) systemic antiplatelet effects driven by inhibition of thromboxane A₂ generation [33, 34]. Prostaglandins are essential in protecting the gastric mucosa. They increase mucosal blood flow, promote proliferation of gastric epithelial cells, and stimulate mucus and bicarbonate secretion. Therefore, inhibition of prostaglandin synthesis by aspirin makes the gastric mucosa susceptible to ulcer formation and bleeding in the highly acidic environment. Furthermore, platelet inhibition with aspirin impairs healing of the vulnerable gastric mucosa [33, 34].

Unlike aspirin, ADP receptor antagonists do not cause injury of the gastric mucosa, but their inhibition of platelet aggregation are likely to impair healing and aggravate already existing gastric injuries caused by acidic drugs such as aspirin [33, 34].

Strategies to prevent gastrointestinal discomfort, ulceration, and bleeding during antiplatelet treatment include the identification and modification of associated risk factors as well as concomitant treatment with gastroprotective agents, mainly histamine H₂ receptor antagonists and PPIs [33, 35]. For more than two decades, PPIs have been used extensively for the treatment of gastric acid-related disorders. Even though H₂ receptor antagonist are effective in preventing gastrointestinal complications [36], PPIs produce a higher degree and longer duration of gastric acid suppression than H₂ receptor antagonists leading to higher healing rates [8]. Although PPIs have widely been considered harmless, there are studies associating these drugs with serious adverse effects such as pneumonia, interstitial nephritis, osteoporotic fractures, and intestinal Clostridium difficile infections [37].

Under acidic conditions, PPIs are protonated and converted to cyclic sulphenamides. These active PPI metabolites reduce gastric acid production by irreversibly inhibiting the enzyme responsible for gastric acid secretion: the H⁺/K⁺-exchanging adenosine triphosphatase, often referred to as “the proton pump” [8]. The proton pump, which is located on gastric parietal cells, is directly responsible for H⁺ secretion into the gastric lumen. It follows that PPIs, as opposed to H₂ receptor antagonists, target the terminal step in gastric acid secretion making the gastric acid suppression particularly strong. PPIs have a short plasma half-life of 30–120 min depending on pH level, yet the antacid effect is sustained for days due to the irreversible inhibition as well as accumulation of the drug in parietal cells [8].

Under physiological conditions, aspirin is absorbed in its non-ionized lipid state across the gastric mucosal barrier. A pH-dependent mechanism has been suggested to explain a drug interaction between aspirin and PPIs. PPI reduce gastric acid production by inhibiting the enzyme responsible for gastric acid secretion from gastric parietal cells: the H⁺/K⁺-exchanging adenosine triphosphatase (Fig. 2) [103]. According to the pH partition hypothesis [38], modifying the intragastric milieu by raising pH potentially reduces the bioavailability of drugs, in particular those being absorbed across the gastric mucosal membrane, such as aspirin [39]. During PPI treatment, intragastric pH does indeed rise above the pK _a (3.5) of aspirin potentially reducing its lipophilicity and gastric absorption [39, 40].

The activity of CYP2C19 is altered by PPIs, which are CYP2C19 substrates and thus may interact with clopidogrel and prasugrel metabolism through competitive antagonism. It follows that the interaction between PPIs and thienopyridines depends on the capacity of each PPI subtype to inhibit CYP2C19. Omeprazole, esomeprazole, and lansoprazole have a relatively high potency towards CYP2C19, while rabeprazole and pantoprazole have less potency. Accordingly, PPIs with low inhibitory effect on CYP219 are recommended if combined treatment with a thienopyridine and a PPI is required [35].

The number of studies addressing a drug interaction between PPIs and aspirin remains relatively sparse (Table 2). Evidence is gathered from statistical modeling [41], pharmacokinetic measurements [42–44], large observational studies with clinical end points [45, 46], post–hoc analyses of large clinical trials [47], smaller interventional studies with clinical end points [48], or derived from studies utilizing ex vivo platelet function tests as a marker for the clinical effect of aspirin [49–53].

In previous animal studies, omeprazole reduced the analgesic and antipyretic effects of aspirin, which was measured by means of reduced gastric aspirin absorption [40, 54]. Similar findings were reported from a study of humans [55]. On the other hand, Iñarrea et al. measured the antiplatelet effect of aspirin in 14 healthy individuals before and after 4 days of 20 mg/day omeprazole treatment. Bleeding time and platelet aggregation levels were both unaffected by omeprazole [49]. In a randomized cross-over study of 24 healthy individuals, 100 mg of enteric-coated aspirin was given for 4 weeks with or without concomitant 30 mg/day lansoprazole. Thereafter, participants were switched to the other treatment regimen for another 4 weeks. Platelet function assessed by light transmittance aggregometry (APACT 4) and shear stress-stimulated closure time (Platelet Function Analyzer-100) suggested no difference in antiplatelet potency between aspirin with lansoprazole and aspirin alone [51]. Another study showed no pharmacokinetic interaction based on measurements of acetylsalicylic acid plasma concentrations in 55 healthy volunteers subjected to three treatment periods comprising esomeprazole, aspirin, and both [42]. Subsequently, the authors evaluated the bioequivalence between 40 mg esomeprazole and 325 mg aspirin given separately and as a single-tablet formulation including both agents. Analyzing the same end point of acetylsalicylic acid maximal plasma concentration, the two treatment schemes remained bioequivalent [43]. In a randomized cross-over study, 29 healthy individuals received low-dose aspirin with or without esomeprazole 20 mg once daily for 5 days followed by 14-day washout and subsequent treatment cross-over. Platelet aggregation evaluated with the VerifyNow® Aspirin test did not differ between the two treatment regimens, neither did levels of serum thromboxane B₂ [53].

In a pharmacodynamic study by Würtz et al., we included 418 aspirin-treated patients with stable coronary artery disease, of whom 54 were PPI users. In multivariable adjusted analyses, platelet aggregation (median 180 [interquartile range 119–312] vs. 152 [84–226] aggregation units*minute, p = 0.013) and platelet activation measured by soluble serum P-selectin (88.5 [65.2–105.8] vs 75.4 [60.0–91.5] ng/ml, p = 0.013) were significantly higher in patients treated with a PPI. In contrast to many other pharmacodynamic studies, a non-enteric coated formulation of aspirin was used in this study, which may be important given that gastric absorption of enteric-coated aspirin has been shown to increase during omeprazole-treatment [56]. The findings by Würtz et al. were supported by a large Danish register-based study of 19,925 patients suffering a first-time MI. All patients were treated with aspirin, while almost 30,000 patients treated with clopidogrel were excluded. The risk of cardiovascular death, recurrent MI, or stroke was increased in patients receiving a PPI (adjusted hazard ratio 1.46, 95 % CI 1.33–1.61), but not in patients receiving a gastroprotective H₂ receptor antagonist [45].

Whellan et al. tested the hypothesis that a single-tablet formulation (PA32540) [57] of enteric-coated aspirin (325 mg) and immediate-release omeprazole (40 mg) would reduce gastrointestinal complications without promoting thrombotic complications compared to aspirin alone. A coordinated-delivery tablet was used, in which omeprazole is embedded within a film coat enabling instantaneous dissolution, whereas aspirin release occurs only when gastrointestinal pH reaches a level of 5.5 [48]. The primary end point of endoscopically verified gastric ulcer at 6 months occurred less frequently among users of the combined formulation (3.2 % vs. 8.6 %, p < 0.001), while the rate of major adverse cardiovascular events did not differ between treatment arms (1.7 % vs. 2.5 %, p > 0.05). Importantly, the study had a low rate of cardiovascular events, for which the study was underpowered [48].

Most recently, the combined analysis of coronary event rates in two large cohorts of first-time users of aspirin for secondary prevention was published [46]. The first cohort included first-time users of aspirin for any secondary prevention indication, while the second cohort consisted of patients who initiated aspirin treatment following an acute coronary event. Looking at the cohorts separately or combined, PPI treatment was not associated with an increase in the risk of non-fatal MI or coronary death [46], and the results thus contrast those of the above mentioned large registry-based study [45].

A recent analysis showed that co-prescription of low-dose aspirin and a PPI turned out to be cost-effective by reducing gastrointestinal as well as cardiovascular events [41]. This cost-effectiveness analysis was based on previously published clinical studies, and the cardiovascular benefit appeared to be partly driven by increased adherence to aspirin in PPI users. Furthermore, even in patients with cardiovascular disease who continue aspirin treatment after suffering a gastrointestinal bleeding event, aspirin seems to confer a net clinical benefit because the risk of bleeding is outbalanced by improved cardiovascular outcome [58]. This was shown in a small randomized study, in which aspirin users who suffered a peptic ulcer bleeding were given either aspirin or placebo on top of pantoprazole. While increasing the risk for recurrent gastrointestinal bleeding, continued aspirin treatment reduced mortality [58]. Although these interesting results should be confirmed in larger studies, they stress that discontinuing aspirin upon gastrointestinal events should be carefully considered in patients with increased risk of cardiovascular events.

Altogether, studies exploring whether PPIs reduce the effect of aspirin are sparse. Studies are small and relatively heterogeneous and this, coupled with the fact that only one randomized, yet underpowered, study has been performed makes it premature to change clinical recommendations at present as reflected in current guidelines [4, 5, 35].