Efficacy of aspirin (325 mg) + omeprazole (40 mg) in treating coronary artery disease

Introduction: Aspirin is indicated for primary and secondary prevention of cardiovascular diseases (CVD) by major guidelines. However, its use may be associated with gastrointestinal (GI) toxicities, including, but not limited to, GI bleeding. This may lead to increased morbidity and mortality, as well as diminished compliance, which again leads to increased risk of major cardiovascular events. Modified formulations of aspirin often have comparable risks of GI toxicity despite their dose or formulation and have had limited success to prevent GI toxicities. Simultaneous treatment with Proton pump inhibitors (PPIs) has been used successfully to prevent GI toxicities from aspirin. However, addition of an extra medication may lead to lower compliance and hence ineffective or less than optimal treatment.

Areas covered: After a selective literature search, a brief review of the available evidence regarding GI toxicity of aspirin and the protective effects of PPIs was conducted. The concept of combination tablets, and the available data about Aralez Pharmaceuticals’ YOSPRALA (aspirin (81 mg or 325 mg) and omeprazole (40 mg) fixed dose combination tablet being evaluated for secondary prevention of cardiovascular and cerebrovascular events in patients at risk for GI complications of aspirin therapy) is also presented.

Expert opinion: The available evidence suggests that PPIs are the best option to prevent aspirin-related GI toxicities, but compliance is low in people who are prescribed both aspirin and PPI. Combination tablets containing both aspirin and a PPI may be a good option for providing protection against GI toxicities in people who require aspirin for secondary prevention of cardiovascular diseases.     

Cardioprotective effects and gastrointestinal risks of aspirin: Maintaining the delicate balance

Aspirin is a very useful medication for the prevention of cardiovascular thrombotic events in patients with or those at risk for cardiovascular disease (CVD). Aspirin, however, carries an increased risk for gastrointestinal (GI) injury (e.g., ulceration) and its complications (e.g., hemorrhage), which may be caused by its antiplatelet and gastric mucosal effects. In those with established CVD, aspirin use has been documented to decrease the risk of a first myocardial infarction (MI). Its effects on stroke and vascular death are less conclusive. The use of aspirin in these individuals is recommended only for those whose risk for cardiovascular events (based on coronary risk assessment tools) is sufficiently high that it outweighs the risk for GI complications. Secondary prevention refers to the use of aspirin to prevent cardiovascular events in patients with established CVD such as an MI, stroke, or angina. The use of aspirin in these individuals is recommended based on a documented decrease in future cardiovascular events and mortality. The risk for GI events with aspirin is at least additive to the risk for these events in those who also are receiving therapy with a nonsteroidal anti-inflammatory drug. Patients being treated with aspirin, even at 81 mg/day for cardioprotection, should be assessed for factors that increase the risk for GI injury. Studies have confirmed that co-therapy with a proton pump inhibitor (PPI) or misoprostol decreases the risk for GI injury and complications. Although both classes of such gastroprotective agents are effective, treatment with a PPI is tolerated better, with fewer patients discontinuing the drug because of side effects such as diarrhea.     

质子泵抑制剂与氯吡格雷药物相互作用研究进展

对2010年Mdeline收载的关于质子泵抑制剂(PPIs)与氯吡格雷相互作用的研究文献进行综述分析,PPIs对氯吡格雷抗血小板聚集活性的影响与多个因素相关:氯吡格雷和阿司匹林合用时,PPIs与氯吡格雷之间无临床意义的药物相互作用;当单用氯吡格雷抗血小板聚集时,PPIs对其药效的影响显著,而且不同的PPIs之间的作用强度有差异;以微观指标(如ADP或花生四烯酸诱导的血小板聚集度)为标准,则氯吡格雷和PPIs之间存在不良药物相互作用,但以宏观指标(如一级事件发生率)为标准则无临床意义的不良药物相互作用;PPIs对氯吡格雷的影响与CYP2C19基因多态性有关:快代谢型患者PPIs对氯吡格雷的抗血小板聚集作用影响显著,慢代谢型无明显影响;与单用氯吡格雷相比,PPI+阿司匹林可以显著降低胃肠道出血事件,对心血管系统没有不良影响。因此,对于PCI术后短期内行氯吡格雷和阿司匹林双抗血小板聚集患者,临床可以根据情况选择任何一个PPIs;对于单用氯吡格雷抗血小板聚集的患者,应该首选与泮托拉唑合用;PPIs合用阿司匹林能有效抗血小板聚集,而且显著减少胃肠道出血事件,因此在必须应用PPIs的情况下,阿司匹林是氯吡格雷的一个有效替代药物。     

Efficacy and safety of concomitant use of rabeprazole during dual-antiplatelet therapy with clopidogrel and aspirin after drug-eluting stent implantation: a retrospective cohort study

After coronary stent implantation, dual-antiplatelet therapy (DAT), such as aspirin and clopidogrel, is essential to prevent stent thrombosis. Proton-pump inhibitors (PPIs) may be used to prevent gastrointestinal (GI) bleeding during DAT, but there is no evidence for the efficacy of PPIs in this setting. Because both clopidogrel and PPIs are metabolized by cytochrome P450 (CYP) 2C19, there is a possibility that, through drug interaction, PPIs diminish the antiplatelet effect of clopidogrel. In this retrospective cohort study, we evaluated the efficacy and safety of rabeprazole in patients receiving DAT of clopidogrel and aspirin after drug-eluting stent implantation. In 199 patients treated with DAT alone (control group) and 103 patients treated with rabeprazole plus DAT (rabeprazole group), we examined the incidences of GI bleeding and major adverse cardiac events (MACE) including stent thrombosis. The incidence of GI bleeding was not significantly different between the groups (hazard ratio 0.47 [95% confidence interval 0.15-1.42], P=0.18; P=0.17 in log-rank test), although no patient with severe bleeding was observed in the rabeprazole group. The use of rabeprazole did not increase the incidence of MACE (hazard ratio 1.28 [95% confidence interval 0.54-3.00], P=0.56; P=0.56 in log-rank test). One patient who developed subacute stent thrombosis under DAT was genetically proven to be a CYP2C19 poor metabolizer. The effect of rabeprazole to prevent GI bleeding is limited in patients receiving DAT. It remains to be confirmed whether these results may depend on CYP2C19 polymorphisms or a class of PPIs.     

Pharmacokinetic and clinical evaluation of esomeprazole and ASA for the prevention of gastroduodenal ulcers in cardiovascular patients

Introduction: Low-dose aspirin (ASA, 75 - 325 mg/day) is widely used for the primary and secondary prevention of cardiovascular (CV) diseases. However, the value of primary prevention ASA is uncertain as the reduction in occlusive events needs to be weighed against the significant increase in major bleedings. Prevention with antisecretory drugs has been proposed to reduce the incidence of ASA-induced gastrointestinal (GI) bleedings, but non-adherence to gastro-protection is of concern, as it significantly increases the risk of upper GI adverse events. Beside patients and physicians education, one approach to overcome non-adherence is the development of fixed-dose combination. Area covered: This review explores the results of clinical studies on the influence of the combination esomeprazole (ESA) and ASA on pharmacokinetic (PK) parameters, and the role for such combination in prevention of CV events in patients at risk of gastric ulcers. Expert opinion: Patients at risk of ASA-induced gastroduodenal ulcer might benefit from a fixed ASA and proton pump inhibitor (PPI) combination. PK and PD parameters suggest there is no significant interaction between these drugs. Nevertheless, attention must be paid on the appropriate use of such combination, that is, still balancing the risk:benefit ratio in a real-life setting, and any increase in the proportion of patients receiving ASA and PPI should be considered as a warning signal.     

Rationale for a trial of low-dose aspirin for the primary prevention of major adverse cardiovascular events and vascular dementia in the elderly: Aspirin in Reducing Events in the Elderly (ASPREE)

Low-dose aspirin (acetylsalicylic acid) therapy has been shown to reduce the risk of vascular events and there is increasing evidence of its potential to reduce the rate of cognitive decline in the elderly. Adverse effects including gastrointestinal and intracranial haemorrhage may offset these benefits. The balance of risks versus benefits of aspirin for the primary prevention of cardiovascular disease and vascular dementia has not been established in the elderly. There is clearly a need to conduct a study in family practice to investigate whether routine use of low-dose aspirin for the primary prevention of cardiovascular disease and vascular dementia in the elderly is beneficial or harmful. Aspirin in reducing events in the elderly (ASPREE) is a placebo-controlled trial of low-dose aspirin for the primary prevention of major adverse cardiovascular events and vascular dementia. It will follow 15,000 subjects aged 70 years or more for an average of 5 years. This sample size has a power of 87% to detect a 15% reduction in primary events in the aspirin group, with an anticipated combined primary event rate of 20 per 1000 patient years.     

NSAID-associated adverse effects and acid control aids to prevent them: a review of current treatment options.

NSAIDs are central to the clinical management of a wide range of conditions. However, NSAIDs in combination with gastric acid, which has been shown to play a central role in upper gastrointestinal (GI) events, can damage the gastroduodenal mucosa and result in dyspeptic symptoms and peptic lesions such as ulceration.NSAID-associated GI mucosal injury is an important clinical problem. Gastroduodenal ulcers or ulcer complications occur in up to 25% of patients receiving NSAIDs. However, these toxicities are often not preceded by indicative symptoms. Data obtained from the Arthritis, Rheumatism, and Aging Medical Information System have shown that 50-60% of NSAID-associated peptic ulcer cases can remain clinically silent and do not present until complications occur. Therefore, prophylactic treatment to prevent GI complications may be necessary in a substantial proportion of NSAID users, especially those in groups associated with a high risk of developing these complications.Use of cyclo-oxygenase (COX)-2 selective NSAIDs, also known as 'coxibs', substantially reduces the incidence of upper GI toxicities seen with non-selective NSAIDs. However, there are concerns regarding the cardiovascular safety of coxibs. For this reason, the US FDA recommends minimal use of coxibs and only when strictly necessary. Additionally, rofecoxib has been removed from the US market and sales of valdecoxib have been suspended. Furthermore, upper GI toxicities still occur in patients receiving coxibs. Therefore, cotherapies are required to prevent and/or heal upper GI effects associated with NSAID use. Effective prophylactic and treatment strategies include misoprostol, histamine H(2) receptor antagonists and proton pump inhibitors (PPIs). The key role that gastric acid plays in upper GI adverse events among NSAID users suggests that it is important to choose the most effective agent for acid control to alleviate symptoms, heal mucosal erosions and improve the reduced quality of life in this patient population. PPIs provide effective acid suppression, which is essential to avoid GI mucosal injury, and they are, therefore, capable of dramatically decreasing the morbidity and mortality associated with this disorder.Since many serious GI complications are not heralded by any previous symptoms, physicians need to be aware of risk factor profiles that predispose patients to serious GI problems. Physicians also need to initiate the appropriate preventative acid suppressive therapy to minimise the burden of NSAID-associated GI adverse effects.     

Adherence to statin or aspirin or both in patients with established cardiovascular disease: exploring healthy behaviour vs. drug effects and 10-year follow-up of outcome

Aims

To characterize adherence in patients with established cardiovascular disease taking statins and aspirin and to estimate the effects of adherence due to health behaviour, a lack of beneficial drug effect, or both on recurrence of cardiovascular disease or all-cause mortality over 10 years.

Methods

A population-based cohort study using a record-linkage database in Tayside, Scotland. Subjects with cardiovascular disease (n = 7657; 4185 aspirin-alone cohort, 671 statin-alone cohort and 2801 combination use cohort) were studied between 1993 and 2003. The effects of adherence on recurrence of cardiovascular disease or mortality were assessed using Poisson regression model.

Results

In subjects taking both aspirin and statins, those adherent to statins but not aspirin had a lower risk of recurrence [adjusted risk ratio (RR) 0.64; 95% confidence interval 0.49, 0.82], but those adherent to aspirin but not statins has no such effect (adjusted RR 0.91; 0.72, 1.15), suggesting that adherence behaviour alone was not responsible for the beneficial effect. Within the group adherent to aspirin, ≥80% adherence to statins was associated with reduced recurrence compared with those poorly adherent (adjusted RR 0.76; 0.62, 0.94), but no such effect of aspirin was seen in those adherent to statins. Similar results were found for all-cause mortality.

Conclusions

Poor health behaviour is not a sufficient explanation of adverse outcome in poorly adherent patients. Adverse outcome is more likely to be driven by foregone drug benefits.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Aspirin and statins are widely-used drugs in patients with cardiovascular disease.
• There is less information on healthy behaviour vs. drug effects.

WHAT THIS STUDY ADDS

• Long-term adherence to aspirin and statin treatments in patients with established cardiovascular disease has been investigated.
• Poor health behaviour is not a sufficient explanation of adverse outcome in poorly adherent patients.

     

An evaluation of the impact of NICE guidelines regarding COX‐2 selective inhibitors on GP prescribing

The recent introduction of cyclo‐oxygenase 2(COX‐2) selective inhibitors for the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA) provides an important means of reducing gastrointestinal (GI) adverse effects The National Institute for Clinical Excellence recommends that COX‐2 inhibitors should only be used in high GI risk patients with OA or RA. NICE does not recommend COX‐2 selective inhibitors in cardiovascular patients or patients who are co‐prescribed aspirin Seventy‐seven per cent of patients were not prescribed a COX‐2 inhibitor according to the guidelines set out by NICE The nature of these non‐adherences included the 24 per cent of patients with cardiovascular disease, of whom 16 per cent were co‐prescribed aspirin Other areas of concern include patients receiving a COX‐2 inhibitor who have not been diagnosed as having OA or RA and patients not at high GI risk This study highlights a need for education relating to the effective and appropriate prescribing of COX‐2 inhibitors, with guidance on the correct place of simple analgesics and non‐drug therapy     

Interactions between clopidogrel and proton pump inhibitors: a review of evidence

Clopidogrel is a thienopyridine, which inhibits the platelet P2Y adenosine diphosphate (ADP) receptor termed P2Y(12). It is taken as a prodrug that requires biotransformation to an active metabolite by cytochrome P450 (CYP) isoenzymes. In addition, esterases shunt the majority of clopidogrel to an inactive pathway, whilst the remaining prodrug requires two separate CYP-dependent oxidative steps. PPIs might diminish the antiplatelet effects and the clinical effectiveness of clopidogrel possibly through inhibition of CYP2C19 and CYP3A4 isoenzymes. Treatment with clopidogrel and aspirin decreases recurrent cardiovascular events after an acute coronary syndrome. However, an inherent increment of major bleeding is also associated with antiplatelet therapy, as well as dyspepsia with aspirin. Also, major bleeding has been associated with high risk for ischemic events and mortality. For this reason, a proton pump inhibitor (PPI) is often co-prescribed to reduce the risk of gastrointestinal tract bleeding, but its concomitant use might reduce the inhibitory effect of clopidogrel on platelet aggregation. Nevertheless, doubts exist about the possible interaction of concomitant PPI use that may reduce the inhibitory effect of clopidogrel on platelet aggregation. Indeed, there is some controversy with regard to the true risk of cardiovascular adverse events arising from a potential drug-drug interaction between clopidogrel and PPI. In this article, we will review the current status and controversies in relation to a possible interaction between clopidogrel and PPIs.     

Aspirin resistance: disparities and clinical implications

Abstract Aspirin is one of the most widely prescribed drugs for the prevention of thrombosis in patients with vascular disease. Yet, aspirin is unable to prevent thrombosis in all patients. The term "aspirin resistance" has been used to broadly define the failure of aspirin to prevent a thrombotic event. Whether this is directly related to aspirin itself through biochemical aspirin resistance or treatment failure, or if it is because of aspirin's inability to overcome the thrombogenic aspects of the disease process itself, has not been elucidated. This can have dramatic clinical implications for a variety of vascular disease subsets and is cause for concern, considering the high prevalence of aspirin use for both primary and secondary prevention. Disparities exist in the rates of aspirin resistance among certain patient populations, such as women, patients with diabetes mellitus, and those with heart failure, and across clinical conditions, such as cardiovascular and cerebrovascular disease. Clinical trial data from studies observing resistance have revealed that regardless of study size, dose of aspirin, control for drug interactions and adherence, or assay used to measure platelet function, aspirin resistance is associated with an increased risk for adverse events. Although the evidence is mounting, there has yet to be a consensus on the appropriate clinical response to aspirin resistance.     

The safety of lumiracoxib when used in the treatment of arthritis

The gastrointestinal (GI) adverse effects of NSAIDs are generally considered to be partly due to the inhibition of COX-1 in the GI tract. Therefore, it was anticipated that there would be fewer such events with the selective COX-2 inhibitors. However, selective COX-2 inhibitors will probably lack the cardioprotective effects associated with COX-1 inhibition. The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) evaluated the ulcer complications and cardiovascular outcomes with the use of the selective COX-2 inhibitor, lumiracoxib, versus naproxen/ibuprofen in the treatment of osteoarthritis. Patients (～ 18,000) received either lumiracoxib 400mg/day, naproxen 500mg b.i.d. or ibuprofen 800mg t.i.d. for 52weeks. The primary end point was difference in time-to-event distribution of definite or probable upper GI ulcer complications, and these were lower in the lumiracoxib (29 of 9117) than in the ibuprofen (33 of 4397) or naproxen (50 of 4730) groups. The benefit with lumiracoxib was mainly due to a reduced risk of faeces containing blood and of the laboratory evidence of bleeding, and occurred in the population not taking aspirin, but not in the patients taking aspirin. The primary cardiovascular end point was the composite of non-fatal and silent myocardial infarction, stroke or cardiovascular death, and this did not differ between lumiracoxib and naproxen/ibuprofen. However, there were slightly more end points with lumiracoxib (85) than with naproxen/ibuprofen (75), and this nonsignificant difference was due to fewer end points in the naproxen group. Although TARGET establishes the GI safety of lumiracoxib, questions about the cardiovascular outcomes with COX-2 inhibitors, including lumiracoxib, especially in the absence of low-dose aspirin, remain.     

Combining aspirin and proton pump inhibitors: for whom the warning bell tolls?

Aspirin and clopidogrel are well-known antiplatelet agents that are widely used across the spectrum of cardio- and cerebrovascular disease. Upper gastrointestinal complications, including ulcer and bleeding, are relatively common during antiplatelet treatment and, therefore, many patients are also treated with a proton pump inhibitor (PPI). PPIs exert gastroprotection by raising intragastric pH. In recent years, it has been heavily discussed whether PPIs may reduce the cardiovascular protection by aspirin and, even more so, clopidogrel. Initially, pharmacodynamic and pharmacokinetic studies suggested a considerable drug interaction between PPIs and clopidogrel, and subsequent clinical studies were conducted to evaluate the clinical impact of this interaction. More recently, it has been reported that PPIs may also attenuate the antiplatelet effect of aspirin. This is particularly interesting, because a fixed combination of aspirin and a PPI (esomeprazole) has been developed and is currently under approval. Given the large number of patients taking aspirin and PPIs, even a small attenuation of the antiplatelet effect of aspirin may have substantial clinical impact. The present editorial summarizes current evidence on this drug interaction and discusses potential clinical implications.     

Aspirin in Cardiovascular Disorders

Clinical trials of aspirin (acetylsalicylic acid) for cardiovascular disorders have employed doses defined for other pharmacological effects of the drug (such as analgesic effects). Antioxidant and anti-inflammatory mechanisms with different dose-response relationships may contribute to the clinical effect of aspirin in cardiovascular disease. The optimal aspirin dose remains uncertain. Although the difference between 325 mg/day and 81 mg/day of aspirin sounds trivial, finding an optimal aspirin dose has enormous potential to reduce ischemic events. Large aspirin doses have not been associated with proportionally greater benefit. For patients with ischemic heart disease, overall consensus defines a range between 75 and 160 mg/day for the secondary prevention of myocardial infarction, stroke, and vascular death. Any benefit of aspirin must be measured against its adverse effects, principally gastrointestinal hemorrhage. The potential for adverse bleeding events may be lower with a 81mg dose, while maintaining clinical benefit. Although current aggregate data is reassuring about aspirin administration, it is increasingly clear that existing aspirin studies are insufficient to conclusively determine an optimal aspirin dose. Platelets can be activated by pathways that are not blocked by aspirin, and the dose of aspirin needed to fully suppress platelet aggregation may be higher in some patients as a result. Higher doses of aspirin than are currently used (75-325 mg/day) may be required in these patients to achieve desired antithrombotic effects. Better understanding of aspirin-resistant populations will facilitate identification of patients who require higher aspirin doses or alternative forms of antiplatelet therapy.     

Interaction between clopidogrel and proton-pump inhibitors

The American Heart Association/American College of Cardiology guidelines recommend initiating a proton-pump inhibitor (PPI) to prevent gastrointestinal bleeding if patients are receiving concomitant therapy with clopidogrel and aspirin. Recently, concern has been raised regarding the ability of PPIs to decrease the antiplatelet activity of clopidogrel. To date, there are 16 studies that evaluated the outcomes of using clopidogrel with a PPI. One of the studies has shown that adding lansoprazole to clopidogrel has no effect on the concentration of clopidogrel's inactive metabolite. The eight clinical trials that studied the effect of using PPIs and clopidogrel together on platelet function testing have shown differing effects between PPIs. Concurrent omeprazole and clopidogrel use was shown to decrease the antiplatelet effects of clopidogrel in three studies; whereas pantoprazole, lansoprazole and esomeprazole have been shown to have no significant effect on the antiplatelet response to clopidogrel. Six other studies showed that using PPIs and clopidogrel together led to adverse clinical outcomes; however, one study that did a separate analysis on pantoprazole, showed that using pantoprazole with clopidogrel had no significant impact on clinical outcomes. Post hoc analysis from a large randomized trial comparing prasugrel with clopidogrel indicated no clinically significant effects of PPIs in patients treated with either prasugrel or clopidogrel. Preliminary results from a prospective, randomized trial comparing cardiovascular clinical outcomes between omeprazole and placebo in clopidogrel-treated patients have been reported and suggest no interaction. However, the study was stopped prematurely secondary to loss of funding and follow-up limited to a median of 133 days so no firm conclusions were drawn. The data currently available regarding concurrent clopidogrel and PPI use are limited, so further studies are needed to provide a definite conclusion. Until additional prospective studies are available, the use of clopidogrel with a PPI should be avoided, if possible, and a H(2)-receptor antagonist be selected instead. Prasugrel may be administered safely with a PPI as there is currently no evidence of a pharmacokinetic, pharmacodynamic or adverse clinical effects.     

Burden of Upper Gastrointestinal Symptoms in Patients Receiving Low-Dose Acetylsalicylic Acid for Cardiovascular Risk Management

Background

Continuous low-dose acetylsalicylic acid (aspirin; ASA) is a mainstay of cardiovascular (CV) risk management. It is well established, however, that troublesome upper gastrointestinal (GI) symptoms are commonly experienced among low-dose ASA users.

Objective

The objective of this study was to investigate the occurrence of upper GI symptoms, and their impact on well-being, among patients taking low-dose ASA for CV risk management.

Study Design

This was a multicenter, non-interventional, 12-week study carried out in primary-care, cardiology, and practice group centers in the USA, Canada, and France.

Patients

Eligible patients were adults (age ≥18 years) at risk of or with confirmed CV disease, with physician-prescribed/-recommended low-dose ASA (75–325 mg) use.

Main Outcome Measures

An electronic device (eDiary) was used to collect patient-reported outcome data three times per day (morning, afternoon, and evening; regular reports), including upper GI (gastroesophageal disease [GERD]-like or dyspepsia-like) symptoms and the impact of such symptoms on sleep quality, perceived stress, and emotions. In addition to regular reports, patients were able to self-initiate a report of upper GI symptoms (spontaneous reports).

Results

Overall, 81,282 eDiary reports (including 4,407 spontaneous reports of upper GI symptoms) were collected from 340 patients. Upper GI symptoms (most commonly GERD-like) were commonly blamed on food/drink (39 %), and around one-third of patients (37 %) used medication to relieve their symptoms. Analysis showed that upper GI symptoms had a negative impact on sleep quality, perceived stress, and emotions (all p < 0.01). Overall, GI medication use was infrequent, but was more common among low-dose ASA-experienced patients (41 % vs. 12 % of evening reports in patients naïve to low-dose ASA at baseline; p < 0.01); adherence to prescribed daily proton pump inhibitors (PPIs) was poor (47 %).

Conclusion

Upper GI symptoms impact negatively on well-being among low-dose ASA users, in terms of decreased quality of sleep, increases in perceived stress, and negative impact on emotions. Despite this, patients may not necessarily associate these symptoms with their low-dose ASA therapy and do not readily take steps to manage such symptoms, which extends to poor adherence to prescribed daily PPIs.     

Potential Interaction between Clopidogrel and Proton Pump Inhibitors

Clopidogrel is widely used in patients with acute coronary syndromes and following percutaneous coronary intervention with stent implantation. The antiplatelet action of clopidogrel is felt to be of critical importance for the reduction of abrupt thrombotic occlusion of stents, particularly with drug-eluting devices. When clopidogrel is used alone or in combination with aspirin (acetylsalicylic acid), the benefits of antiplatelet therapy must be weighed against the potential for serious bleeding, particularly gastrointestinal (GI) bleeds. To minimize the risk of GI injury, proton pump inhibitors (PPIs) are considered the drugs of choice. However, a growing body of evidence suggests that PPIs may adversely interact with clopidogrel, diminishing the antiplatelet effect. Although the current evidence remains controversial, the potential for increased risk of thrombotic complications warrants cautious use of this drug combination until further research can determine the extent of this interaction and whether it is a drug-class effect.     

Interaction between clopidogrel and proton-pump inhibitors

The American Heart Association/American College of Cardiology guidelines recommend initiating a proton-pump inhibitor (PPI) to prevent gastrointestinal bleeding if patients are receiving concomitant therapy with clopidogrel and aspirin. Recently, concern has been raised regarding the ability of PPIs to decrease the antiplatelet activity of clopidogrel. To date, there are 16 studies that evaluated the outcomes of using clopidogrel with a PPI. One of the studies has shown that adding lansoprazole to clopidogrel has no effect on the concentration of clopidogrel’s inactive metabolite. The eight clinical trials that studied the effect of using PPIs and clopidogrel together on platelet function testing have shown differing effects between PPIs. Concurrent omeprazole and clopidogrel use was shown to decrease the antiplatelet effects of clopidogrel in three studies; whereas pantoprazole, lansoprazole and esomeprazole have been shown to have no significant effect on the antiplatelet response to clopidogrel. Six other studies showed that using PPIs and clopidogrel together led to adverse clinical outcomes; however, one study that did a separate analysis on pantoprazole, showed that using pantoprazole with clopidogrel had no significant impact on clinical outcomes. Post hoc analysis from a large randomized trial comparing prasugrel with clopidogrel indicated no clinically significant effects of PPIs in patients treated with either prasugrel or clopidogrel. Preliminary results from a prospective, randomized trial comparing cardiovascular clinical outcomes between omeprazole and placebo in clopidogrel-treated patients have been reported and suggest no interaction. However, the study was stopped prematurely secondary to loss of funding and follow-up limited to a median of 133 days so no firm conclusions were drawn. The data currently available regarding concurrent clopidogrel and PPI use are limited, so further studies are needed to provide a definite conclusion. Until additional prospective studies are available, the use of clopidogrel with a PPI should be avoided, if possible, and a H₂-receptor antagonist be selected instead. Prasugrel may be administered safely with a PPI as there is currently no evidence of a pharmacokinetic, pharmacodynamic or adverse clinical effects.