Prevention of Aspirin-Related Gastric Ulcers

The use of low-dose aspirin in the prevention of cardiovascular disease is frequently associated with a development of dyspeptic symptoms and erosions or ulcerations in the upper GI tract. Eradication of Helicobacter pylori and maintenance therapy with proton pump inhibitors (PPIs) are effective in the prevention of aspirin-induced GI lesions. The potential role of H2-receptor antagonists after the healing of aspirin-induced ulcers or erosions is unclear.

Ng and colleagues (2010) have reported the results of a randomized, double-blind, controlled study comparing the efficacy of high-dose famotidine with that of pantoprazole in the prevention of recurrent dyspeptic/complicated ulcer or erosions in patients taking low-dose aspirin. Consecutive patients at a center in Hong Kong with a history of aspirin-related peptic disease with or without a history of bleeding were randomized to receive 80 mg of aspirin, with either 40 mg of famotidine or 20 mg of pantoprazole daily for 48 weeks. The endpoints were the presence of ulcer complications and the severity of ulcer complications. Those patients with peptic ulcerations received a healing dose of PPI for 8 weeks while those who were H. pylori positive received an initial 7-day standard PPI-based triple therapy followed by 7 weeks of PPI therapy alone.

Of a total of 161 patients who were randomized, 65 in each arm completed the study. The prevalence of significant dyspepsia or peptic ulceration was significantly higher in the famotidine group compared with the pantoprazole group (20% vs. 0%; p < .0001).

These findings demonstrate that high-dose famotidine therapy is inferior to PPI therapy in preventing recurrence of aspirin-related peptic ulcers or erosions. Thus, PPIs rather than H2-receptor antagonists are recommended in the prevention of recurrent low-dose aspirin–induced upper GI injury.

cc gunain indo ja fromnya

ingris aku lemah....

okok....

@ Huria...
Info dari mana minta linknya donk...

@ syx
Itu serius..mas..dabigatran..sama rivaroxaban....margin of safety..oke nggak mas...trus...replacement..sama obat lain  untuk berikatan sama albumin lebih baik nggak dibanding warfarin...

tapi mas...sepeti yang sudah dibahas di antikoagulan...PPI + klopi..itu efektivitas klopi jadi turun sampai 50%..Makanya lebih sering dipakai ranitidin...

Loh mas...
Knapa PPI menghambat klopidogrel?
Karna menghambat kerja sitokrom?
Tapi bukannya itu cimetidine mas?

Potential Interaction between Clopidogrel and Proton Pump Inhibitors
Patricia A. Howard; James L. Vacek

Abstract
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.

Introduction
Clopidogrel is a potent antiplatelet drug with actions mediated through irreversible inhibition of the platelet ADP receptor, P2Y12.[1] Clopidogrel is widely used to prevent thrombotic complications in patients with acute coronary syndromes (ACS), with or without percutaneous coronary intervention (PCI), and is particularly effective for patients with drug-eluting devices. Clopidogrel monotherapy has been associated with an increased risk of bleeding.[2] Several clinical trials have shown that the risk of bleeding, especially gastrointestinal (GI) bleeding, is further increased in high-risk coronary patients who often require dual antiplatelet therapy with both clopidogrel and aspirin (acetylsalicylic acid).[3–5] Guidelines for the prevention or treatment of antiplatelet drug-associated GI injury recommend proton pump inhibitors (PPIs) as first-line agents.[6]

Recently, concerns have been raised over a potential drug interaction between clopidogrel and PPIs that may diminish the antiplatelet activity of clopidogrel. Because of the serious clinical implications of a decreased antiplatelet response in high-risk coronary patients, reports of this potential interaction with PPIs must be further explored.

1. Proposed Mechanism for an Interaction between Clopidogrel and Proton Pump Inhibitors (PPIs)
Clopidogrel is a prodrug that requires activation in the liver by cytochrome P450 (CYP) isoenzymes, particularly CYP2C19.[7] The important role of CYP2C19 in the conversion of clopidogrel to a therapeutically active form has been well documented. The CYP2C19 isoenzyme has associated polymorphisms, and in vitro studies have shown that individuals with specific alleles of CYP2C19 have a decreased antiplatelet response to clopidogrel.[7,8] Specifically, individuals with the CYP2C19*2 allele have been shown to have resistance to clopidogrel after coronary stent placement and following ST-segment elevation myocardial infarction.[9,10]

Two additional studies add to our understanding of the important relationship between the antiplatelet activity of clopidogrel and CYP isoenzyme function. Simon et al.[11] evaluated a cohort of 2208 patients treated with clopidogrel following acute myocardial infarction (AMI). Clinical events including death from any cause, nonfatal stroke, or AMI during a 1-year period were increased in individualswith any two loss-of-function alleles for CYP2C19 (*2, *3, *4, or *5) compared with noncarriers (21.5% vs 13.3%, adjusted hazard ratio [ HR ] 1.9; 95% CI 1.10, 3.58). Among the 1535 patients who underwent PCI, cardiovascular events were 3.58 times higher for those with two CYP2C19 loss-of-function alleles than for those with none. Carriers of the ABCB1 variant, which alters drug absorption, also had modest increases in event rates. Conversely, no adverse associations were seen with polymorphisms of P2Y12 or glycoprotein IIb/IIIa and, interestingly, none with the coadminstration of omeprazole.

In a second study, Mega et al.[12] investigated the association between CYP genetic variants, plasma concentrations of active clopidogrel metabolite, and platelet function in healthy volunteers. They found that carriers of at least one CYP2C19 loss-of-function allele had decreased levels of active clopidogrel metabolite and less reduction in platelet aggregation compared with noncarriers. The investigators then looked at the association between CYP genetic variants and cardiovascular outcomes in a separate cohort of 1477 ACS patients treated with clopidogrel in TRITON-TIMI (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel –Thrombolysis inMyocardial Infarction) 38. An increased risk of death from cardiovascular causes, AMI, or stroke was seen in carriers of the loss-of-function alleles compared with noncarriers. Moreover, subjects with the CYP2C19*2 allele had a 3-fold increased risk of stent thrombosis compared with noncarriers. Differences between groups were observed early after starting clopidogrel, suggesting an immediate loss of platelet-inhibitory effect.

These findings, demonstrating the important role of CYP enzyme function in the pharmacologic properties of clopidogrel, have led investigators to suggest that drug interactions that alter CYP function, particularly CYP2C19, may also impact on the antiplatelet activity of clopidogrel. A comparative in vitro study using human liver microsomal preparations demonstrated varying degrees of CYP2C19 inhibition among different PPIs.[13] In this study, omeprazole, esomeprazole, and lansoprazole were shown to be the strongest CYP2C19 inhibitors, followed by pantoprazole and, lastly, rabeprazole. These findings provide a plausible explanation for the hypothesis that there are probable differences in the extents to which different PPIs diminish the antiplatelet effects of clopidogrel. However, the investigators caution that in vitro studies of enzyme inhibition do not always correlate with in vivo studies. For example, although lansoprazole was shown in vitro to be at least equivalent to omeprazole in the degree of CYP2C19 inhibition, omeprazole has been associated with many more reports of clinically significant drug interactions involving CYP2C19 inhibition. The authors further speculate that other factors are likely to play an important role, such as drug potency, usual dosage range, serum drug concentrations, and rate of drug elimination, all of which impact the extent and duration of drug exposure.