Acid suppressants in Cardiac Patients: Sneak Peak of Clinical Guidelines
Cardiovascular diseases (CVD) encompass a range of congenital or acquired pathological conditions that affect the structure or function of the heart, commonly, coronary artery disease (CAD), arrhythmia, myocardial infarction, cardiomyopathy, and peripheral artery disease.
In most patients, thrombus formation due to platelet activation and aggregation is the initial mechanism that ultimately leads to coronary artery thrombosis and further CV complications. This forms the basis for the use of dual antiplatelet therapy (DAPT) with aspirin and an oral P2Y12 inhibitor (Clopidogrel, Prasugrel), which is regarded to be the mainstay of antithrombotic therapy after MI and/or PCI. (1)
However, Antiplatelet agents increase the risk of bleeding associated with mucosal breaks in the upper and lower gastrointestinal (GI) tract. (2) To reduce the upper GI bleeding by suppressing gastric acid production, thereby promoting healing of peptic ulcers and mucosal erosions and stabilizing thrombi,(3) concomitant use of a proton pump inhibitor is recommended in patients receiving aspirin monotherapy, DAPT, or oral anticoagulant (OAC) monotherapy. (4)
Patients receiving clopidogrel, particularly as part of DAPT, are often prescribed proton pump inhibitors (PPIs) for gastroprotection or acid suppression. (5)
At present, a growing body of evidence suggests the strong possibility of potential adverse drug interactions between PPIs and antiplatelet drugs, specifically the P2Y12 inhibitors. Addressing the basics of drug metabolism, recent studies have shown that the commonly prescribed PPIs including omeprazole, esomeprazole, pantoprazole, rabeprazole, lansoprazole, and dexlansoprazole are metabolized by the hepatic cytochrome P-450 system, pre-dominantly CYP2C19, and, to a lesser extent, CYP3A4. (6) This competitively inhibits activation of clopidogrel by CYP2C19, thereby attenuating its antiplatelet effect. The reported interaction of. clopidogrel and PPIs is consistent with a set of clinical pharmacokinetic findings referred to as 'high-risk' pharmaco-kinetics. (7)
This reduced biological action of clopidogrel due to competitive metabolic effects of CYP2C19 has been proven in clinical trials like PRINCIPLE–TIMI (Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis In MyocardialInfarction ) and SPICE (Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effect) Trials (8,9). The results of both revealed that PPI use in cardiac patients led to significantly reduced platelet inhibition than the placebo group, indicating a high risk for further CV complications, despite being on standard antiplatelet therapy.
Long-term proton pump inhibitor use has also been associated with hypomagnesemia (10), limiting the co-administration of omeprazole or esomeprazole with clopidogrel.
Acknowledging such evidence-based drug interactions and focusing on the patient customized risk-benefit ratios, there has been a paradigm shift in current recommendations that support only selective and not regular use of PPI in cardiac patients.
As many recent investigations of this potential adverse interaction have been performed, using a variety of research designs, it has been difficult for practitioners to assimilate this flood of information and to develop an optimal and standard treatment protocol for managing patients who might benefit from antiplatelet therapy, yet who might suffer from GI bleeding.
The present review is focused on highlighting the updated guidelines and recommendations on the rational use of PPIs in cardiac patients. (1,4,11)
1. Clinical decisions regarding concomitant use of PPIs and thienopyridines must balance overall risks and benefits, considering both CV and GI complications.
2. AHA Guidelines have clearly mentioned that routine use of a PPI is not recommended for patients at lower risk of upper GI bleeding(Class III: No Benefit), who have much less potential to benefit from prophylactic therapy. (1)
PPIs are recommended to reduce GI bleeding only among patients with a history of upper GI bleeding (Class I). (Strong Recommendation, Moderate-Quality Evidence) PPIs are appropriate in patients with multiple risk factors for GI bleeding who require antiplatelet therapy. (11)
This recommendation recognizes the risk and consequences of gastrointestinal bleeding and the benefit demonstrated to prevent these events in this population. It recognizes that CYP2C19 inhibition significantly reduces the pharmacologic action of clopidogrel on platelet inhibition. Although the physiological effect has not been demonstrated to have a clinical effect on thrombotic events, it has also not been eliminated. Because PPIs with minimal effect on CYP2C19 are available, the use of such agents might be most prudent. Specific PPIs that inhibit CYP2C19 can interact with clopidogrel, resulting in reduced efficacy and consequently, increased risk of cardiovascular events; this might be particularly undesirable in patients deemed at "high risk" of thrombosis.
3. As per ESC guidelines, Co-administration of PPIs like omeprazole or esomeprazole, which have repeatedly shown to interfere with the action of P2Y12 inhibitors, is generally not recommended. (4)
The guidelines (1, 4) have further addressed some controversial viewpoints that exist on the role of PPIs in cardiac patients.
Do PPIs Decrease Clinical Efficacy of antiplatelet drugs?
Observational studies of different populations, sizes, and degrees of the methodologic range have examined whether patients prescribed a PPI plus clopidogrel have an increased risk of CV events compared with patients prescribed clopidogrel alone. (12) In the CREDO (Clopi-dogrel for Reduction of Events During Observation) trial, PPI use was associated with an increased rate of CV events whether or not the patient was treated with clopidogrel. (13)
1. Does the Choice of PPI Matter?
Pharmacodynamic studies using ADP-stimulated plate-let aggregation in patients treated with clopidogrel suggest a variable inhibitory effect of different PPIs. (14) A nested case-control study of patients receiving clopidogrel after MI suggested pantoprazole may increase the risk of rehospitalization for MI or PCI compared with other PPIs. (15)
2. Timing of Dosing to Minimize Interactions
Because the plasma half-lives of both clopidogrel and all available PPIs are less than 2 hours,interactions between these drugs might be minimized by separating the timing of drug administration, even among poor CYP2C19 metabolizers.
In a crossover study examining 72 healthy subjects who were administered standard-dose clopidogrel (300 mg followed by 75 mg daily) and a supratherapeutic dose of omeprazole (80 mg daily), mean inhibition of platelet aggregation was greater when the drugs were given 12 hours apart. (16) Until data from further studies are available, there is no solid evidence to recommend that the dosing of PPIs be altered.
3. Are H2RAs a Reasonable Alternative and in Which Population?
Available data suggest PPIs are superior to H2RAs, but H2RAs pose a very strong reasonable alternative in patients at lower risk for GI bleeding, and in those who do not require PPI for refractory gastroesophageal reflux disease. (17)
From Epidemiologic Evidence Supporting concomitant use of PPIs and thienopyridines, the experts draw the following conclusions:
• The magnitude of association in positive observational studies reviewed is small to moderate (HR or OR: 2).
A significant association between PPI use and increased CV events has been inconsistently demonstrated in observational studies, with experimental pharmacodynamic data consistently indicating that omeprazole diminishes the effect of clopidogrel on platelets.
• PPIs are co-prescribed with antiplatelet drugs for one reason—to reduce the increased risk of GI complications caused by antiplatelet drugs. The need for GI protection increases with the number of risk factors for severe bleeding. Use of PPIs is rational in the following 'high risk' groups.
1. Patients with ACS and prior upper GI bleeding are at substantial CV risk, so dual antiplatelet therapy with concomitant use of a PPI may provide the optimal balance of risk and benefit.
2. Advanced age; concomitant use of warfarin, steroids, or NSAIDs; or H. pylori infection all raise the risk of GI bleeding with antiplatelet therapy.
3. The reduction of GI symptoms by PPIs (ie, treatment of dyspepsia) may also prevent patients from discontinuing their antiplatelet treatment. The discontinuation of antiplatelet therapy in patients with GI bleeding may increase the risk of CV events.
The challenge for healthcare providers is to determine the risk/benefit balance for individual patients or subsets of the target population. Prior evaluation of patient history, including the details of anginal symptoms, and evaluation of risk factors including co-morbidities and manifestations of CVD, are crucial for the management of such patients and determining whether or not to co- prescribe PPIs along with standard therapy.
References
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