Oh..begitu...pantes mahal harganya...Tapi makasih mas,..atas diskusinya...link jurnalnya saya kopi yah mas...Makasih...

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.

New Oral Anticoagulants on the Horizon

Background

Warfarin, a vitamin K antagonist, has been the essential key in deep venous thromboembolism treatment for more than 60 years. Warfarin is a coumarin derivative and acts as a vitamin K antagonist to antagonize the effect of vitamin K required for the synthesis of active clotting factors II, VII, IX, and anticoagulant proteins C and S. Antagonism of vitamin K reduces the amount of these clotting factors, thereby producing anticoagulation. However, warfarin is a relatively dangerous drug, with serious and significant limitations in relation to titrating a safe and therapeutic anticoagulation level. It requires adjusted and variable doses dependent upon the prothrombin time, reported as the International Normalized Ratio. Its narrow therapeutic dose range is 2.0-2.5. To achieve the desired therapeutic level, warfarin requires frequent monitoring and takes about 5 days for a stable antithrombotic effect to be achieved. Warfarin is influenced by several factors such as age, genetic status, medications, diet, and some medical conditions that contribute to variability of patient response. Although the safe use of warfarin is a challenge, there has not been a market competitor for oral long-term anticoagulation in the management of venous thromboembolism (VTE) until recently, with the development of 2 new oral anticoagulants: dabigatran, a direct thrombin inhibitor and rivaroxaban, a direct factor Xa inhibitor.
Article Summary

This article examines the potential of these new oral anticoagulants to offer a safer therapeutic alternative to warfarin, as well as their clinical efficacy, specifically in relation to the prevention of venous thromboembolism in patients undergoing hip and knee replacement surgery. This article reviews the mechanism of action, bioavailability, and safety profile of these new drugs.

An improved understanding of how the blood clotting cascade works has led to the evolution of new oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. The new class of oral anticoagulants has been developed to pinpoint a specific target for controlling the clotting cascade with maximum efficacy and minimum inconvenience. Oral direct thrombin inhibitor binds directly to thrombin, blocking interaction with its substrates, thereby preventing the conversion of fibrinogen to fibrin and forming a crosslinked blood clot or preventing thrombin generation, and thus producing a state of anticoagulation.

The authors summarized the results of 7 randomized clinical trials, in which dabigatran has demonstrated noninferior efficacy to enoxaparin, with a similar safety profile. Following a single technology appraisal of dabigatran, the United Kingdom's National Institute of Clinical Excellence (NICE) has now endorsed dabigatran's clinical efficacy as a serious alternative to low-molecular-weight heparin and fondaparinux. Three randomized clinical trials have also concluded that rivaroxaban is as efficacious and safe as enoxaparin in the prevention of venous thromboembolism for patients undergoing major orthopedic surgery of the lower limbs. In a single technology appraisal, rivaroxaban was recommended by NICE in April 2009, as an option for the prevention of venous thromboembolism in adults having elective hip or knee replacement surgery.

The results of clinical trials (RE-VOLUTION for dabigatran etexilate and RECORDS for rivaroxaban) substantiate, at this time, the clinical efficacy of these drugs, without harmful effects. In the near future these new oral anticoagulants look poised to replace warfarin to some extent. Two more ongoing clinical trials (RE-MEDY and RESONATE), in addition to the RE-VOLUTION program undertaken by the manufacturer, are comparing the efficacy and safety of dabigatran with that of warfarin in the secondary prevention of VTE. These new oral thrombin and factor Xa inhibitors have demonstrated rapid onset of action and predictable pharmacokinetics. They offer the advantages of fixed dosing and preclude the need for routine blood monitoring, making them very attractive alternatives to warfarin. These anticoagulants also have a low propensity to clinically relevant drug-drug interactions. They potentially eliminate the need to provide additional follow up services to those on extended prophylaxis who are either unable or reluctant to self inject their low molecular weight heparin prophylaxis. Evidence is overwhelmingly supportive of the efficacy and safety of rivaroxaban and clinicians are eagerly anticipating that NICE will endorse the clinical and cost effectiveness data and deliver similar recommendations for dabigatran etexilate. US Food and Drug Administration approval of dabigatran is also pending.
Viewpoint

The debate on whether to treat certain types of patients with anticoagulant drugs has raged for years and around many different clinical conditions. Part of the controversy has to do with whether anticoagulation is really effective in preventing complications, and part of the controversy has to do with the risk-benefit ratio to patients. The risk of causing more problems with the use of warfarin has always weighed heavily in the treatment decision. The new anticoagulants discussed here have demonstrated their potential to revolutionize VTE management. When available, these drugs may enable clinicians and patients alike to make better treatment decisions. Although there are no reported adverse hepatic effects of these drugs, sufficient long-term data are unavailable to rule out this potential problem, seen in another drug previously introduced in the market. However, adverse hepatic effects will continue to be the focus of scrutiny as clinicians gain experience with these drugs.

cc gunain indo ja fromnya

ingris aku lemah....

lagi males nerjemahin... jari isa kriting. sekalian belajar bahasa inggris aja. kan ntar di kuliahan banyak text book yang pake bahasa inggris. kalo ga dimulai sekarang kapan lagi?

okok....

Mau tanya...
Kenapa pemakaian aspirin pada pasien paska ganti-katup jantung dan paska coronary bypass meningkatkan resiko stroke dan MI?
Bukannya aspirin tuh anti-platelet? Dan aspirin digunakan sebagai profilaksis untuk MCI kan?

@ 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...

Itu kudapat ketika pembahasan tentang sakit kepala di kampus.. Kan ada obatnya aspirin. Trus dibilangin kawanku (dikasih liat printoutnya; tapi gak tau darimana), kalo aspirin itu gak boleh diberikan untuk pasien gitu....

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

Hmm..nanti coba saya cari tahu deh....

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

aspirin emang menghambat stroke iskemik tapi bisa bikin stroke hemoragi.

Kutip dari: r.a.n pada Februari 04, 2010, 09:24:21 PM
@ 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...

musti baca-baca dulu... saya blom pernah utak-atik obat tersebut.

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.

2. Impact of PPI Therapy on Clopidogrel Antiplatelet Activity

Gilard et al.[14] performed one of the earliest studies demonstrating an association between PPI use and diminished antiplatelet activity with clopidogrel. The study was based on the fact that platelet inhibition by clopidogrel is mediated by blockade of the P2Y12 platelet receptor. Activation of this receptor is associated with dephosphorylation of intraplatelet vasodilator-stimulated phosphoprotein (VASP). As VASP phosphorylation increases, the risk of thrombosis also increases. The VASP test was performed in 105 patients receiving aspirin and clopidogrel for high-risk coronary angioplasty. Patients were predominantly male (61%) with a mean age of 63.7 years. The study found that patients using concomitant PPIs (n = 24) had significantly higher VASP values (61.4 ±23.2 vs 49.5±16.3, respectively, p = 0.007) compared with nonusers (n = 81).

In a follow-up study, Gilard et al.[15] conducted a doubleblind trial involving 124 patients undergoing coronary stent implantation, who received aspirin 75 mg daily and a loading dose of clopidogrel followed by 75 mg daily. Patients were randomized to receive omeprazole 20mg daily or placebo for 7 days. The antiplatelet activity of clopidogrel, measured by the VASP test for both groups on days 1 and 7, was reported as a platelet reactivity index (PRI). On day 1, there was no significant difference in PRIs between placebo and omeprazole recipients (83.2%±SD 5.6% vs 83.9%±4.6%). Conversely, at day 7, the PRI was significantly higher in patients receiving omeprazole (51.4%±16.4% vs 39.8%±15.4%; p< 0.0001), indicating an increased risk of thrombosis.

Because all PPIs are metabolized to some extent by CYP2C19, other investigators[16] conducted a study to determine if the reported interaction between clopidogrel and omeprazole was a drug-class effect. Responsiveness to the antiplatelet effect of clopidogrel was assessed using the VASP assay and ADP-induced platelet aggregometry in 300 patients undergoing PCI who received pantoprazole, esomeprazole, or no PPI. As assessed by the VASP assay, no significant differences were found for the mean PRI between patients with or without PPI treatment (51% vs 49%; p = 0.724). Similarly, platelet aggregation did not differ significantly between patients with or without PPI therapy (45U vs 41U; p = 0.619). Overall, there were no significant differences in PRI or platelet aggregation across the groups of patients (p = 0.382) taking pantoprazole (PRI 50%, aggregation 47 U), esomeprazole (PRI 54%, aggregation 42U), or no PPI (PRI 49% aggregation 41U). The findings of this study suggest that the reported interaction between clopidogrel and PPIs is not a class effect. The investigators theorize that this finding might be explained by the stereoselective metabolism of omeprazole by CYP2C19, which may not occur with pantoprazole or esomeprazole. The study's findings are strengthened by the use of two methods to evaluate the drug interaction, but are limited by the nonrandomized design, the potential for confounding, and the failure to include omeprazole as a comparator.