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Penulis Topik: Antikoagulan, Antitrombotik, Trombolitik, Hemostatik  (Dibaca 36722 kali)

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Re: Antikoagulan, Antitrombotik, Trombolitik, Hemostatik
« Jawab #45 pada: Maret 11, 2010, 11:21:34 PM »
3. Impact of Combined Clopidogrel and PPI Therapy on Cardiovascular Outcomes

In response to reports of this potential drug interaction, several investigators have sought to determine the potential impact of combined clopidogrel and PPI therapy on cardiovascular outcomes. Pezalla et al.[17] evaluated medical and pharmacy databases to determine rates of AMI during 1 year of follow-up for patients taking clopidogrel with or without a concurrent PPI. The final analysis included over 5000 patients <65 years of age, who were determined as being adherent to clopidogrel therapy. Based on PPI adherence, patients were classified into low or high exposure or no exposure (control) groups. One-year crude rates of AMI were 1.38% for control patients, 3.08% for those with low PPI exposure, and 5.03% for those with high PPI exposure. Compared with control patients, the observed differences in AMI rates were significantly greater for those with high PPI exposure (p < 0.05), a difference that remained after adjustment for differences in co-morbidities among a subset of 1010 patients (11.38% vs 2.60%, p< 0.05). Although these findings further suggest a potential interaction, the study was published only as a letter. No details on the methods used were provided, including definitions for patient adherence and low versus high exposure to PPIs, and the possibility of unknown confounding was not addressed.

Two studies presented at the 2008 American Heart Association (AHA) meeting examined the impact of combined clopidogrel-PPI therapy on cardiovascular outcomes, and produced conflicting results. Dunn et al.[18] conducted analyses on data from the CREDO (Clopidogrel for the Reduction of events During Observation) study, which demonstrated the benefit of clopidogrel therapy for 1 year versus 1 month after coronary stenting. The subgroup analyses of data from this randomized clinical trial evaluated the risk of death, AMI, or stroke in 2116 patients who received clopidogrel or placebo with or without a PPI. While patients who received PPIs had higher baseline risk and worse overall outcomes, clopidogrel reduced adverse cardiovascular outcomes at 1 year to a similar degree irrespective of PPI use.

Conversely, the second study presented at the meeting once again demonstrated a negative impact of PPI therapy on the antiplatelet effects of clopidogrel. The Clopidogrel Medco Outcomes Study[19] was a retrospective cohort study using the National Medco Integrated Database file, which covers approximately 19 million individuals. The investigators studied patients who were prescribed clopidogrel for coronary stent placement and were at least 80% compliant with their medication over the following year. Patients taking clopidogrel alone (n = 9862) were compared with those taking clopidogrel plus PPIs (4521) for 1 year to determine the following major cardiovascular events: hospitalization for stroke, AMI, angina, or coronary artery bypass graft surgery. Adjustments were made for baseline differences in age, gender, and co-morbidities. Among stent patients with no preceding cardiovascular event, major cardiac events occurred in 32.5% of those receiving combined therapy versus 21.2% of those receiving clopidogrel alone (adjusted odds ratio [OR] 1.79; CI 1.62, 1.97). The effect was even more pronounced among patients with a preceding cardiovascular event (39.8% vs 26.2%, respectively; adjusted OR 1.86; CI 1.63, 2.12). These findings led the researchers to conclude that the interaction between clopidogrel and PPIs may lead to serious cardiovascular consequences.

Further analyses of data from the Clopidogrel Medco Outcomes Study was presented subsequently, at the 2009 Scientific Sessions of the Society of Cardiovascular Angiography and Interventions (SCAI).[20] This analysis, which included a larger cohort of 16 690 patients and a 1-year follow-up, showed a 50% increase in major cardiovascular events for patients taking clopidogrel with a PPI compared with patients not taking a PPI (25.1%vs 17.9%;HR1.51; 95%CI 1.39, 1.64; p < 0.0001).When analyzed separately, significant increases were seen in all components of the combined endpoint including AMI or unstable angina (70%), stroke (48%), and the need for repeat coronary procedures (35%). Increased risk was observed for all PPIs with sufficient numbers to analyze, including omeprazole, esomeprazole, lansoprazole, and pantoprazole, with considerable overlap between agents. Finally, the authors reported no increased cardiovascular events in patients taking a PPI without clopidogrel compared with a control group of patients taking neither clopidogrel nor a PPI.

Additional evidence for a potential clopidogrel-PPI interaction has come from two recent and more methodologically rigorous observational trials. Canadian researchers conducted a population-based study using a nested case-control design. In this study, Juurlink et al.[21] evaluated patients aged ≥66 years who were prescribed clopidogrel after an AMI and were readmitted to hospital within 90 days due to reinfarction. Cardiac event-free controls at a 3 : 1 ratio were matched for age, receipt of PCI, date of hospital discharge, and risk of short-term mortality using a previously validated cardiac risk prediction model. Exposure to PPIs was categorized as current (within 30 days before the index event), previous (31–90 days after the index event), or remote (91–180 days after the index event). Multivariable analysis was used to control for numerous potential confounders, including age, Charlson co-morbidity index, length of hospital stay, nine medical co-morbidities known to correlate with short-term mortality after AMI, and other medications including cardiovascular agents and known inhibitors or inducers of CYP2C19 or CYP3A4.

The final analysis included 734 cases and 2057 controls. Current use of PPIs was associated with an increased risk of reinfarction (adjusted OR 1.27; 95% CI 1.03, 1.57). There was no association with more distant use of PPIs. In a stratified analysis of the individual PPIs used, omeprazole, lansoprazole, and rabeprazole were associated with an increased risk of AMI, whereas pantoprazole was not. This finding would be consistent with the fact that pantoprazole is a weak inhibitor of CYP2C19 compared with the other PPIs studied.[13] Important limitations of this study included lack of data on coronary risk factors, such as smoking, BP, and lipids and the inability to identify nonprescription use. In discussing their findings, the investigators estimated that 5–15% of early readmissions for AMI among patients taking clopidogrel could have resulted from the interaction with PPIs. Moreover, they note that the increase in absolute risk of AMI in patients receiving PPIs and clopidogrel approximated the absolute risk reduction with clopidogrel in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events) study, a finding consistent with the hypothesis that some PPIs blunt the cardioprotective effects of clopidogrel.[3]


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Re: Antikoagulan, Antitrombotik, Trombolitik, Hemostatik
« Jawab #46 pada: Maret 11, 2010, 11:23:38 PM »
Another large epidemiologic study exploring the potential clopidogrel-PPI interaction was conducted by Ho et al.[22] using a national Veterans Affairs (VA) cohort discharged after ACS. The primary outcome was the combined endpoint of all-cause mortality or rehospitalization for ACS, including AMI and unstable angina, for patients taking clopidogrel with and without PPIs. Data for the study were obtained from the Cardiac Care Follow-up Clinical Study abstracted for an external peer review quality-monitoring program. For this retrospective study, all ACS patients discharged between 1 October 2003 and 31 January 2006 were eligible. During this period, 8205 patients filled prescriptions for clopidogrel through the outpatient VA pharmacy. Among these patients, 5244 (63.9%) were prescribed a PPI at discharge, at follow-up, or both, whereas 2961 (36.1%) were not. The median follow-up after hospital discharge was 521 days. The study used a nested case control design to confirm the findings of the primary cohort analysis and various sensitivity analyses to test for robustness of the data. The primary endpoint occurred in 20.8%(n = 615) of patients receiving clopidogrel without a PPI compared with 29.8%(1561) of those receiving clopidogrel and a PPI. Based on multivariable analysis, use of clopidogrel with a PPI at any timepoint was associated with an increased risk of death or rehospitalization for ACS compared with clopidogrel without a PPI (adjusted OR 1.25; 95% CI 1.11, 1.41). Multivariable analyses of secondary outcomes found that the use of clopidogrel plus a PPI, compared with clopidogrel without a PPI, was associated with an increased risk of recurrent ACS (adjusted OR 1.86; 95% CI 1.57, 2.20) and revascularization (adjusted OR 1.49; 95% CI 1.30, 1.71), but not all-cause mortality (adjusted OR 0.91; 95% CI 0.80, 1.05). The finding that the largest risk was associated with rehospitalization for recurrent ACS would be consistent with a drug-interaction mechanism that reduced the anti-platelet effect of clopidogrel. Within this cohort, 59.7% of patients who were prescribed a PPI received omeprazole, 2.9% rabeprazole, 0.4%lansoprazole, 0.2%pantoprazole, and 36.7% more than one PPI during the follow-up period. When evaluating the individual PPIs, a consistent adverse association was seen with omeprazole and rabeprazole. The small numbers of patients taking other PPIs precluded analysis of these drugs. No obvious dose-response relationship could be demonstrated for any PPI. However, each 10%increase in time of exposure to the clopidogrel-PPI combination was associated with an increase in risk for the primary endpoint (OR 1.07; 95%CI 1.05, 1.09). The increase in risk for an adverse outcome remained significant after exclusion of patients with a history of GI bleeding prior to or during hospitalization for ACS and those prescribed a histamine H2-receptor antagonist. Finally, the investigators examined the impact of PPI therapy itself on outcomes after ACS and found no increased risk for patients prescribed a PPI in the absence of clopidogrel. This well designed observational study provides the strongest evidence to date of a potential adverse effect of PPIs on cardiovascular outcomes in patients receiving clopidogrel. Nonetheless, it cannot prove causality and is limited, like all observational studies, by several design factors including the inability to exclude possible confounders.

The latest development in this ongoing debate has been the recent presentation of data from the COGENT (Clopidogrel and the Optimization of Gastrointestinal Events) study[23] at the 2009 Transcatheter Cardiovascular Therapeutics (TCT) meeting.[24] This phase III clinical trial was designed to investigate the impact of an investigational combination product (clopidogrel 75 mg plus omeprazole 20 mg) versus clopidogrel in patients who were also receiving aspirin following an ACS or stent implantation. The study was prematurely terminated by the sponsor (as a result of bankruptcy filing) after only 3627 of the planned 5000 patients were enrolled. Data were analyzed and presented for these patients with a mean follow-up of 133 days. The analysis included 136 adjudicated cardiovascular events and 105 adjudicated GI events.

Overall, the study found no differences in the risk of cardiovascular events (3.8% vs 3.7%; HR 1.0; 95% CI 0.70, 1.51), risk of MI (HR 0.96; 95% CI 0.59, 1.56) or need for revascularization (HR 0.95; 95% CI 0.59, 1.55) for patients taking clopidogrel with or without omeprazole. Moreover, omeprazole was associated with a significant benefit in terms of reduced adverse GI events compared with placebo (2.0%vs 3.5%;HR 0.55; 95% CI 0.36, 0.85; p = 0.007). The study investigators suggested that these findings once again point out the limitations and dangers of evidence-based clinical decisions based solely on observational data. They also indicated that these clinical trial findings provide definitive proof that concomitant PPI therapy is not harmful and, in fact, is beneficial for patients receiving dual antiplatelet therapy. While the preliminary report of the COGENT findings is certainly reassuring, final interpretation of this study should await full publication, when the study limitations and impact of early termination can be more accurately assessed.

4. Advisory Statements
The US FDA announced in January 2009 that it is conducting an ongoing safety review of clopidogrel.[25] Specifically, the manufacturers of Plavix® (Sanofi-Aventis and Bristol-Myers Squibb) have agreed to work with the FDA to conduct additional studies that will better characterize the effects of genetic factors and other drugs (especially the PPIs) on the effectiveness of clopidogrel. The FDA acknowledges that current studies are inconsistent. Until more data are available, the FDA has issued the following general recommendations: (i) healthcare providers should continue to prescribe and patients should continue to take clopidogrel as directed because clopidogrel has demonstrated benefits in preventing blood clots that could lead to a heart attack or stroke; (ii) healthcare providers should re-evaluate the need for starting or continuing treatment with a PPI, including prilosec OTC (over-the-counter) in patients taking clopidogrel; and (iii) patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking a PPI, including prilosec OTC. It should be noted that this FDA announcement was released prior to the publication of the study by Ho et al.[22] and the presentation of the COGENT results,[24] and therefore, it is not known to what extent, if any, these studies may alter the FDA's future recommendations.

In response to the presentation of findings from the Clopidogrel Medco Outcomes study at the 2009 SCAI Scientific Sessions plus those of earlier studies, the SCAI has also issued an advisory statement.[26] SCAI acknowledges that more research is needed, but urges cardiologists to consider using an H2-receptor antagonist or antacids instead of a PPI for poststent implantation patients on dual antiplatelet therapy. For patients who require treatment for other GI disorders, cardiologists are urged to discuss treatment alternatives with the patient's primary care physician or gastroenterologist.

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Re: Antikoagulan, Antitrombotik, Trombolitik, Hemostatik
« Jawab #47 pada: Maret 11, 2010, 11:26:37 PM »
5. Discussion
A growing body of evidence has raised legitimate concerns over a potential decrease in the antiplatelet activity of clopidogrel, when prescribed concurrently with PPIs, which could adversely affect cardiovascular outcomes. However, many issues remain that require further study. None of the studies to date have taken into account genetic variants in the studied populations that could also impact on clopidogrel response. If, in fact, an adverse interaction exists, there are many questions about the possible time course. For example, it is not known if patients receiving clopidogrel would be at risk for this interaction throughout their lifetime or if the interaction is more likely in periods following coronary events or procedures, when there is upregulation of platelet activation pathways and increased platelet turnover. Findings from the study by Ho et al.[22] suggest an ongoing interaction risk; however, data are insufficient to draw definitive conclusions. The role of CYP3A4, which plays a lesser role in the metabolism of clopidogrel, should also be explored, given the large numbers of medications that may impact on the activity of this isoenzyme. Well designed comparative studies are needed to fully determine if the interaction is a class effect or is limited to certain PPIs. Finally, studies are also needed to more fully determine the optimal prophylactic regimens for GI protection in coronary and post-stent implantation patients with varying levels of baseline risk. Indeed, some researchers have suggested that the current evidence for routine use of a PPI in coronary patients on dual antiplatelet therapy is not strong and requires further study before exposing millions of individuals to this potentially harmful combination.[27]

Until these issues are resolved, the critical importance of maintaining clopidogrel after coronary artery stent implantation, particularly for those with drug-eluting devices, cannot be overemphasized. Acute stent occlusion is usually a dramatic and catastrophic event, to be avoided if at all possible. Consideration of the use of other agents and interventions to protect the gastric mucosa and reduce GI hemorrhagic risk should be considered as alternatives to PPIs. Given the fact that clopidogrel and PPIs are among the most widely prescribed drugs worldwide, ongoing attention to this drug interaction should remain at the forefront of concern for physicians and pharmacotherapy specialists alike.

6. Conclusions
The current studies exploring a possible interaction between clopidogrel and PPIs raise serious concerns, but provide no definitive data. However, because of the widespread use of combined therapy with clopidogrel and PPIs and the serious clinical consequences of failed antiplatelet therapy, further studies are urgently needed. The current advisory from the FDA has raised awareness, but provides little guidance to clinicians faced with a difficult therapeutic decision. Because of the proven efficacy of clopidogrel in patients with ACS, indications for its use remain unchanged. However, the need for PPI therapy should be assessed in individual patients. For lower-risk patients, serious consideration should be given to the use of H2-receptor antagonists or locally acting mucosal protective agents, which do not adversely interact with clopidogrel. Patients should be advised to avoid self-medication with nonprescription omeprazole, which could lead to unrecognized complications.When concomitant clopidogrel and PPI therapy is considered necessary, patients should be counseled regarding the risk of thrombosis and actions to take if symptoms occur. Among the currently available PPIs, some studies suggest that pantoprazole may offer the safest choice; however, data are far from conclusive and further study is needed.

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Re: Antikoagulan, Antitrombotik, Trombolitik, Hemostatik
« Jawab #48 pada: Maret 11, 2010, 11:27:49 PM »
Info dari FDA:

Follow-Up to the January 26, 2009, Early Communication about an Ongoing Safety Review of Clopidogrel Bisulfate (marketed as Plavix) and Omeprazole (marketed as Prilosec and Prilosec OTC)

[11/17/2009] – The U.S. Food and Drug Administration (FDA) is recommending that the co-administration of clopidogrel (Plavix), a drug used to prevent blood clot formation, and omeprazole (Prilosec/Prilosec OTC), a proton pump inhibitor (PPI) used to reduce stomach acid, be avoided because omeprazole reduces the effectiveness of clopidogrel. The new recommendations, updated from a January 2009 Early Communication, are based on study results from the manufacturers of clopidogrel.

Patients who are at risk for heart attacks or strokes may not get the full protective anti-clotting effect if they are using clopidogrel and omeprazole together.

The studies confirm that co-administration of omeprazole with clopidogrel results in decreased levels of clopidogrel's active metabolite (through inhibition of the CYP 2C19 enzyme, the enzyme that forms the active metabolite), reducing clopidogrel's anti-clotting effect.

Sanofi-Aventis and Bristol-Myers Squibb, the makers of Plavix (clopidogrel), are updating this drug's label with the details of the studies and are conducting follow-up studies to further explore drug interactions with clopidogrel.

FDA has provided more detailed information about this drug interaction in a Public Health Advisory1 and Information for Healthcare Professionals2 sheet.

Other stomach acid reducing drugs, such as Zantac (ranitidine), Pepcid (famotidine), Axid (nizatidine), or antacids, are not expected to interfere with the anti-clotting activity of clopidogrel because they do not inhibit CYP 2C19 activity. Tagamet and Tagamet HB (Cimetidine) does inhibit CYP 2C19 activity and should not be used. Ranitidine and famotidine are available by prescription and OTC and antacids are available OTC.

Until further information is available, FDA recommends the following:

    * Avoid using omeprazole and clopidogrel together and at any time of the day. Separating the dose of clopidogrel and omeprazole in time will not reduce this drug interaction.
    * Avoid using other potent CYP 2C19 inhibitors, including esomeprazole, with clopidogrel.
    * At this time, FDA does not have enough information about drug interactions between clopidogrel and PPIs other than omeprazole and esomeprazole to advise on their use together.
    * Patients who use clopidogrel and need a medication to reduce stomach acid can use antacids and most H2 blockers such as Zantac (ranitidine), Pepcid (famotidine), Axid (nizatidine), but not Tagamet and Tagamet HB (cimetidine).
    * Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking omeprazole, including Prilosec OTC.



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Re: Antikoagulan, Antitrombotik, Trombolitik, Hemostatik
« Jawab #49 pada: Mei 04, 2010, 10:02:52 PM »
Clopidogrel Receives Boxed Warning for Reduced Benefit in Poor Metabolizers

April 21, 2010 — On March 12, the US Food and Drug Administration (FDA) announced it is requiring a boxed warning for the anticoagulant clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership) to caution that poor metabolizers of the drug may not receive full protection from myocardial infarction, stroke, and cardiovascular death.

The boxed warning also states that tests are available to determine the genetic profile of a key liver enzyme and predict whether a patient will ineffectively convert clopidogrel to its active form. It advises clinicians to consider other antiplatelet medications or alternative dosing strategies for clopidogrel in patients who are poor metabolizers.

However, the FDA noted that although higher doses of clopidogrel increase antiplatelet response in poor metabolizers, an appropriate dose regimen for these patients has not been established in a clinical outcome trial.

The liver enzyme CYP2C19 is primarily responsible for converting clopidogrel into an active metabolite that will protect patients from blood clots. Some patients, however, have alleles, or variations, of this enzyme and cannot fully metabolize the drug to its active form.

Roughly 3% of the population are poor clopidogrel metabolizers, according to a press release issued by Sanofi-Aventis and Bristol-Myers Squibb. However, this metabolism inefficiency varies by race, from 2% to 14%.

Boxed Warning Follows Earlier Yellow Flags About Poor Metabolism of Clopidogrel

The requirement for the boxed warning comes after the FDA added information about poor metabolizers to the clopidogrel label in May 2009. The impetus for the boxed warning came from a cross-over study requested by the FDA and sponsored by the 2 drug manufacturers evaluating pharmacokinetic and antiplatelet response in 40 healthy individuals. Ten participants from each of 4 metabolizer groups (ultrarapid, extensive, intermediate, and poor) were randomly assigned to 2 treatment regimens: a 300-mg loading dose followed by 75 mg/day and a 600-mg loading dose followed by 150 mg/day.

The group of poor metabolizers in the study had a worse antiplatelet response than the others when the loading dose was 300 mg followed by 75 mg/day. Their antiplatelet response improved, however, when both the loading dose and the daily dose were doubled.

Last November, the FDA issued a similar warning about poor metabolism of clopidogrel when the drug was taken together with the heartburn medicine omeprazole (Prilosec, Proctor & Gamble). The FDA said at the time that omeprazole inhibited the CYP2C19 enzyme.

Roche Diagnostics Test of Key Liver Enzyme Would Be an Off-Label Use

At an FDA press conference, Courtney Harper, PhD, director of the Division of Chemistry and Toxicology Devices at the FDA's Center for Devices and Radiological Health, said that genetic tests to determine a patient's CYP2C19 status are widely available, and usually cost less than $500. Depending on the particular test, said Dr. Harper, the results may come back in a few hours or a few weeks.

Dr. Harper noted that Roche Diagnostics sells a test that can identify the most common alleles of the CYP2C1P enzyme that cannot metabolize clopidogrel. Because the FDA has not yet cleared the test for clopidogrel dosing, physicians would need to employ it on an off-label basis, she said. "At this point, we would leave it up to the physician's discretion."

Additional Safety Warnings and Precautions

The FDA also warned that thienopyridines such as clopidogrel are linked to an increased risk of bleeding and should be discontinued 5 days before surgical procedures in which an antiplatelet effect is not desired.

Clinical study data have shown that discontinuation of clopidogrel 5 days before coronary artery bypass graft surgery decreases the risk of major bleeding to that associated with use of aspirin alone (clopidogrel plus aspirin, 4.4% vs placebo plus aspirin, 5.3%). In contrast, patients who continued clopidogrel therapy are exposed to an increased risk vs aspirin alone (clopidogrel plus aspirin, 9.6% vs placebo plus aspirin, 6.3%).

Because thienopyridines (including clopidogrel) inhibit platelet aggregation for the lifetime of the platelet (7 - 10 days), withholding a single dose is not useful for managing a bleeding event or decreasing the risk of bleeding associated with surgery. However, the half-life of the clopidogrel active metabolite is short, and administration of exogenous platelets may restore hemostasis. This option is less effective when the infusion is given within 4 hours of a clopidogrel loading dose or within 2 hours of a maintenance dose.

The agency notes that clopidogrel therapy should be restarted as soon as possible; lapses should be avoided in general, and premature discontinuation of treatment may increase the risk for cardiovascular events.

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Re: Antikoagulan, Antitrombotik, Trombolitik, Hemostatik
« Jawab #50 pada: Mei 04, 2010, 10:03:54 PM »
FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug

[03-12-2010] The U.S. Food and Drug Administration (FDA) has added a Boxed Warning to the label for Plavix, the anti-blood clotting medication. The Boxed Warning is about patients who do not effectively metabolize the drug (i.e. "poor metabolizers") and therefore may not receive the full benefits of the drug.

The Boxed Warning in the drug label will include information to:

    * Warn about reduced effectiveness in patients who are poor metabolizers of Plavix. Poor metabolizers do not effectively convert Plavix to its active form in the body.
    * Inform healthcare professionals that tests are available to identify genetic differences in CYP2C19 function.
    * Advise healthcare professionals to consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients identified as poor metabolizers.

Plavix is given to reduce the risk of heart attack, unstable angina, stroke, and cardiovascular death in patients with cardiovascular disease. Plavix works by decreasing the activity of blood cells called platelets, making platelets less likely to form blood clots.

For Plavix to work, enzymes in the liver (particularly CYP2C19) must convert (metabolize) the drug to its active form. Patients who are poor metabolizers of the drug, do not effectively convert Plavix to its active form. In these patients, Plavix has less effect on platelets, and therefore less ability to prevent heart attack, stroke, and cardiovascular death. It is estimated that 2 to 14% of the population are poor metabolizers; the rate varies based on racial background.

Healthcare professionals should be aware that a subgroup of patients are poor metabolizers and do not metabolize Plavix effectively; this can result in reduced effectiveness of Plavix. Healthcare professionals should consider use of other anti-platelet medications or alternative dosing strategies for Plavix in these patients.

Patients should not stop taking Plavix unless told to do so by their healthcare professional. They should talk with their healthcare professional if they have any concerns about Plavix, or to find out if they should be tested for being a poor metabolizer.

In May 2009, FDA added information about poor metabolizers of Plavix to the drug label. However, based on additional data reviewed by the agency (see Data Summary below) the Boxed Warning is now being added to highlight the reduced effectiveness of Plavix in these patients and to recommend that healthcare professionals consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients identified as poor metabolizers.

Additional Information for Patients

Patients currently taking Plavix should:

    * Be aware that some patients do not convert Plavix to its active form as well as other patients. These patients may not get the same benefit from Plavix and are known as poor metabolizers.
    * Not stop taking Plavix unless told to do so by their healthcare professional.
    * Talk with their healthcare professional if they have any concerns about Plavix.
    * Talk with their healthcare professional to see if testing to determine their metabolizer status is appropriate.

Additional Information for Healthcare Professionals

FDA recommends that healthcare professionals should:

    * Be aware that some patients may be poor metabolizers of Plavix. They do not effectively convert Plavix to its active form because of low CYP 2C19 activity.The effectiveness of Plavix as a preventive therapy is reduced in these patients.
    * Be aware that tests are available to determine patients' CYP2C19 status.
    * Consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients who have been identified as poor metabolizers.
    * Be aware that although a higher dose regimen (600 mg loading dose followed by 150 mg once daily) in poor metabolizers increases antiplatelet response, an appropriate dose regimen for poor metabolizers has not been established in a clinical outcome trial.
    * Review the newly approved Plavix drug label for complete information on the use of Plavix

Data Summary

The liver enzyme CYP2C19 is primarily responsible for the formation of the active metabolite of Plavix. Pharmacokinetic and antiplatelet tests of the active metabolite of Plavix show that the drug levels and antiplatelet effects differ depending on the genotype of the CYP2C19 enzyme. The following represent the different alleles of CYP2C19 that make up a patient's genotype:

    * The CYP2C19*1 allele has fully functional metabolism of Plavix.
    * The CYP2C19*2 and *3 alleles have no functional metabolism of Plavix. These two alleles account for most of the reduced function alleles in patients of Caucasian (85%) and Asian (99%) descent classified as poor metabolizers.
    * The CYP2C19*4, *5, *6, *7, and *8 and other alleles may be associated with absent or reduced metabolism of Plavix, but are less frequent than the CYP2C19*2 and *3 alleles.
    * A patient with two loss-of-function alleles (as defined above) will have poor metabolizer status.

The pharmacokinetic and antiplatelet responses to Plavix were evaluated in a crossover trial in 40 healthy subjects. Ten subjects in each of the four CYP2C19 metabolizer groups (ultrarapid, extensive, intermediate and poor) were randomized to two treatment regimens: a 300 mg loading dose followed by 75 mg per day, or a 600 mg loading dose followed by 150 mg per day, each for a total of 5 days. After a washout period, subjects were crossed over to the alternate treatment. Decreased active metabolite exposure and increased platelet aggregation were observed in the poor metabolizers compared to the other groups. When poor metabolizers received the 600 mg loading dose followed by 150 mg daily, active metabolite exposure and antiplatelet response were greater than with the 300 mg/75 mg regimen. Healthcare professionals should note that an appropriate dose regimen for patients who are poor metabolizers has not been established in clinical outcome trials.

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Re: Antikoagulan, Antitrombotik, Trombolitik, Hemostatik
« Jawab #51 pada: Agustus 11, 2011, 10:34:39 PM »
hasil penelitian terbaru dari The Health Improvement Network di UK menunjukkan bahwa individu dng sejarah kejadian kardiovaskuler yang menghentikan pemakaian aspirin dosis rendah mengalami peningkatan resiko non-fatal myocardial infarction dibandingkan yang tetap melanjutkan pengobatan dng aspirin.

obat terbaru antikoagulan produksi AstraZeneca, Brilinta (ticagrelor), dijual dengan harga lebih tinggi dari Plavix di US. alasan mereka adalah keamanan dan khasiat yang lebih tinggi ketimbang clopidogrel. padahal satu tablet Plavix harganya luar biasa sekarang...
« Edit Terakhir: Agustus 11, 2011, 10:38:01 PM oleh syx »

Offline Astrawinata G

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Re: Antikoagulan, Antitrombotik, Trombolitik, Hemostatik
« Jawab #52 pada: Agustus 24, 2011, 03:12:08 PM »
ticagrelor cara kerjanya gimana Om? ???
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Astrawinata G

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Re: Antikoagulan, Antitrombotik, Trombolitik, Hemostatik
« Jawab #53 pada: Agustus 26, 2011, 12:32:34 AM »
Ticagrelor (AZD6140) is the first drug of a new chemical class called cyclopentyltriazolopyrimidine, which is administered orally and has a reversible P2Y(12) receptor inhibitory effect. http://www.ncbi.nlm.nih.gov/pubmed/20136601

However, there are two "potential bugbears": one is that ticagrelor has to be dosed twice daily, as opposed to once daily for either clopidogrel or prasugrel; the second is that there have been some reports of dyspnea as a side effect with ticagrelor in phase 2 studies. http://www.theheart.org/article/969721.do

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Re: Antikoagulan, Antitrombotik, Trombolitik, Hemostatik
« Jawab #54 pada: Agustus 26, 2011, 05:24:28 AM »
August 15, 2011 — One in 20 ischemic strokes occurs soon after withdrawal of antithrombotic agents, warn researchers. They report that 5.2% of all stroke patients in a single year had an antithrombotic or antiplatelet agent withdrawn within the previous 60 days. Many went on to have strokes within 7 days of withdrawal.

 

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