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Δ. Κουναλάκης:
Cytochrome P-450 Polymorphisms and Response to Clopidogrel

ABSTRACT

Background Clopidogrel requires transformation into an active metabolite by cytochrome P-450 (CYP) enzymes for its antiplatelet effect. The genes encoding CYP enzymes are polymorphic, with common alleles conferring reduced function.

Methods We tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. We then examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1477 subjects with acute coronary syndromes who were treated with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38.

Results In healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (P<0.001). Carriers also had an absolute reduction in maximal platelet aggregation in response to clopidogrel that was 9 percentage points less than that seen in noncarriers (P<0.001). Among clopidogrel-treated subjects in TRITON–TIMI 38, carriers had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs. 8.0%; hazard ratio for carriers, 1.53; 95% confidence interval [CI], 1.07 to 2.19; P=0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; hazard ratio, 3.09; 95% CI, 1.19 to 8.00; P=0.02).

Conclusions Among persons treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse cardiovascular events, including stent thrombosis, than did noncarriers.

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Genetic Determinants of Response to Clopidogrel and Cardiovascular Events

ABSTRACT

Background Pharmacogenetic determinants of the response of patients to clopidogrel contribute to variability in the biologic antiplatelet activity of the drug. The effect of these determinants on clinical outcomes after an acute myocardial infarction is unknown.

Methods We consecutively enrolled 2208 patients presenting with an acute myocardial infarction in a nationwide French registry and receiving clopidogrel therapy. We then assessed the relation of allelic variants of genes modulating clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19), and biologic activity (P2RY12 and ITGB3) to the risk of death from any cause, nonfatal stroke, or myocardial infarction during 1 year of follow-up.

Results Death occurred in 225 patients, and nonfatal myocardial infarction or stroke in 94 patients, during the follow-up period. None of the selected single-nucleotide polymorphisms (SNPs) in CYP3A5, P2RY12, or ITGB3 were associated with a risk of an adverse outcome. Patients with two variant alleles of ABCB1 (TT at nucleotide 3435) had a higher rate of cardiovascular events at 1 year than those with the ABCB1 wild-type genotype (CC at nucleotide 3435) (15.5% vs. 10.7%; adjusted hazard ratio, 1.72; 95% confidence interval [CI], 1.20 to 2.47). Patients carrying any two CYP2C19 loss-of-function alleles (*2, *3, *4, or *5), had a higher event rate than patients with none (21.5% vs. 13.3%; adjusted hazard ratio, 1.98; 95% CI, 1.10 to 3.58). Among the 1535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with two CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none (95% CI, 1.71 to 7.51).

Conclusions Among patients with an acute myocardial infarction who were receiving clopidogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not. This effect was particularly marked among the patients undergoing percutaneous coronary intervention. (ClinicalTrials.gov number, NCT00673036 [ClinicalTrials.gov] .)

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Δ. Κουναλάκης:
Dangerous Interaction Between Heartburn Drugs and Clopidogrel (PLAVIX)
Worst Pills Best Pills Newsletter article March, 2009

A new study, published online in Canadian Medical Association Journal January 28th, has found that people taking both clopidogrel (PLAVIX — a drug to prevent heart attacks in people who have just had a heart attack) and certain heartburn drugs, such as esomeprazole (NEXIUM — a PPI or proton pump inhibitor that inhibits stomach acid formation) had a 27 percent increased risk of subsequent heart attacks, compared with people who used only clopidogrel.

In the study, this dangerous interaction was only present in people who had used PPI drugs along with clopidogrel within the 30 days prior to their hospitalization with the recurrent heart attack. People who had used a PPI drug but stopped using it more than 30 days before the second heart attack did not have an increased risk of heart attacks compared to those who had never used PPI drugs with their clopidogrel.

The reason for this serious adverse interaction between these commonly used drugs is that clopidogrel is not effective until it has been converted to its active form by a drug-metabolizing enzyme in the liver. PPI drugs (such as esomeprazole) are often used by people who are taking clopidogrel because they are frequently taking aspirin as well and because clopidogrel can be irritating to the stomach.

When both drugs—clopidogrel and a PPI drug—are being used, the liver is stopped from converting clopidogrel into its active metabolic product. Much of the effectiveness of clopidogrel is therefore lost and its ability to prevent heart attacks is seriously impaired.

Recent guidelines published by the American Heart Association, the American College of Gastroenterology and the American College of Cardiology advocate proton pump inhibitor therapy for the majority of patients receiving ASA after myocardial infarction, including all patients aged 60 years or older. Our findings suggest that indiscriminate treatment with a proton pump inhibitor could result in thousands of additional cases of recurrent myocardial infarction each year, all of which could potentially be avoided by preferentially using pantoprazole in patients taking clopidogrel who require treatment with a proton pump inhibitor.

Of the two drugs involved in this interaction, clopidogrel is clearly the more important one in terms of its heart attack prevention effects.

We therefore agree with the FDA’s recommendation that "healthcare providers […] continue prescribing clopidogrel and […] re-evaluate the need for starting or continuing treatment with a PPI in clopidogrel recipients. Clopidogrel recipients are advised to consult their healthcare providers if they are receiving or considering taking a PPI."

Unlike the other PPI drugs, the Canadian study found no increase in repeat heart attacks in people using the PPI drug pantoprazole (PROTONIX) with clopidogrel.

This may be attributed to the fact that, unlike the other PPI drugs, pantoprazole does not inhibit the liver enzyme that converts clopidogrel into its active form. Thus, clopidogrel may be metabolized properly and the drug may prevent subsequent heart attacks.

Για τους μη αγγλομαθείς, μια πραζόλη σε έναν ασθενή που λαμβάνει Plavix-Iscover φροντίζει απλά να μην δρα το Plavix-Iscover του και εάν πραγματικά το χρειάζεται είναι σε κίνδυνο χωρίς να έχει τίποτα να κερδίσει από την πραζόλη σε σχέση με κάποιο άλλο φάρμακο πχ Ζαντακ.

Gatekeeper:
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Unlike the other PPI drugs, the Canadian study found no increase in repeat heart attacks in people using the PPI drug pantoprazole (PROTONIX) with clopidogrel.

This may be attributed to the fact that, unlike the other PPI drugs, pantoprazole does not inhibit the liver enzyme that converts clopidogrel into its active form. Thus, clopidogrel may be metabolized properly and the drug may prevent subsequent heart attacks.

Για τους μη αγγλομαθείς, μια πραζόλη σε έναν ασθενή που λαμβάνει Plavix-Iscover φροντίζει απλά να μην δρα το Plavix-Iscover του και εάν πραγματικά το χρειάζεται είναι σε κίνδυνο χωρίς να έχει τίποτα να κερδίσει από την πραζόλη σε σχέση με κάποιο άλλο φάρμακο πχ Ζαντακ.



--- Τέλος παράθεσης ---

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Μαρία Χόρτη:
Προτείνεται η χρήση εναλλακτικών φαρμάκων των PPIs (πχ Zantac) σε ασθενείς υπο αντιθρομβωτική αγωγή

Providers Should Consider PPI Alternatives in Patients on Dual Antiplatelet Therapy, Group Advises

For patients receiving dual antiplatelet therapy who need heartburn treatment, healthcare providers should consider alternatives to proton pump inhibitors, the Society for Cardiovascular Angiography and Interventions (SCAI) has advised.
The group issued the recommendation after a large study showed adverse cardiac effects when clopodigrel was mixed with PPIs.
The study examined nearly 16,700 patients who took clopidogrel for a year after coronary stenting. Patients who were also using PPIs had significantly greater risk for the composite of MI, stroke, unstable angina, or repeat vascularization. Event rates ranged from 24% to 29% with lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), and pantoprazole (Protonix), compared with 18% without PPI use.
The SCAI calls for more research, but in the meantime, it advises providers to consider using histaminergic blockers (e.g., Zantac or Tagamet) or antacids instead of PPIs in this patient population.

SCAI statement
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ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use
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Δ. Κουναλάκης:
Οι υπάρχουσες μελέτες είναι αναδρομικές και στηρίζονται σε στατιστικά συμπεράσματα, τα σίγουρα θα τα έχουμε σε 2-3 χρόνια τουλάχιστον και το FDA δεν εξαίρεσε καμιά από τον πιθανό κίνδυνο. Επίσης, δεν εξαιρούν όλες οι μελέτες την παντοπραζόλη από αυτό το πρόβλημα. Υπάρχει πάντα η υποψία ότι επειδή είναι έτοιμος για κυκλοφορία ο "αντικαταστάτης" της κλοπιδογρέλης όλη η υπόθεση έχει στόχο να προετοιμάσει την επέλαση του.

Επειδή ζω τον αστερισμό των πραζολών όπου μετά την κυκλοφορία των φασόν ομεπραζόλης έχει γίνει το απίστευτο φαγοπότι θα έλεγα να σκεφτόμαστε διπλά το εάν μια πραζόλη είναι απαραίτητη στον ασθενή μας καθώς δεν είναι μόνο η κλοπιδογρέλη που έχει πρόβλημα αλλά και άλλες φαρμακευτικές ουσίες.

Επίσης, ίσως θα πρέπει να σκεφτούμε ξανά ότι εάν η πραζόλη είναι απαραίτητη ίσως ο συνδυασμός ασπιρίνη+πραζόλη είναι απίστευτα πιο προστατευτικός για τον ασθενή μας σε σχέση με κλοπιδογρέλη+πραζόλη, με καλύτερη λύση για κάποιες νοσολογικές οντότητες την κλοπιδογρέλη μόνη της χωρίς πραζόλη. Ας σκεφτούμε διπλά όταν δίνουμε ή συνεχίζουμε αγωγή σε κάποιον ασθενή μας.

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