The Clinical Efficiency and the Cost-Effectiveness of Clopidogrel - Report Example

Most of death in animals associated with non-ST-segment advancement acute coronary syndromes (ACS) arises from a disturbance to athermanous plaques, followed by platelet combination and thrombus creation. Aspirin is the most frequently recommended antiplatelet agent, known to diminish the risk of deadly and non-fatal myocardial infarction in animals with unbalanced angina. Clopidogrel, a dissimilar antiplatelet agent, prevents platelet aggregation prompted by adenosine diphosphate, thereby decreasing ischemic happenings. Mixing clopidogrel with aspirin may therefore, have an additive consequence as each act via a diverse inhibitory pathway. To evaluate systematically evaluate the clinical efficiency and the cost-effectiveness of clopidogrel used in the mixture with standard treatment including aspirin, related to the standard treatment alone for the cure of non-ST-segment elevation acute coronary syndromes (ACS). The review evaluated clopidogrel used in combination with ordinary treatment for both the short and long term cure of ACS. Introduction Atherothrombosis, a disorder of the blood vessels widely acknowledged as the root course of occlusive vascular events. The objectives of antiplatelet therapy are, therefore, two-fold, firstly to prevent the occurrence of ischemic happenings through prevention of platelet thrombus formation and secondly to safeguard distal tissues through inhibition of microembolisation. It obtains information on the possible different precautionary profiles from those seen in old animals. Young animals studies were used to examine findings that cannot sufficiently, ethically, and carefully evaluated in pediatric clinical trials. Serious adverse reactions that may be permanent are of particular importance when test is carried out. The plan of non-clinical studies in juvenile animals will vary subject to the findings observed in adult animal trail studies and previous animal studies. If adversative reactions on growing organs projected from animal data, research in immature animals might be warranted. This enables addressing the particular interest or studying the reversibility or likely worsening of the required findings, as well as to inaugurate safety factors. The guidance also makes endorsements on the timing and usefulness of the young animal research in relation to phases of clinical development. According to the study, the care and effectiveness profile of clopidogrel has verified in several clinical trial details of which can be found in the EPAR for Plavix. In addition, there is long-term post marketing information contributing to the understanding of the clinical use of this product. Clopidogrel bisulfate is a film-coated tablet, which comprises of clopidogrel biciliate. Since this application is a variety application referring to the mention of the curative product Plavix, summary of the veterinary information of clopidogrel hydrogen sulphate is available and no new veterinary research concerning pharmacology, pharmacokinetics and effectiveness and safety has been carried out with clopidogrel biciliate. The indication for Clopidogrel bisulfate turned out to be different from the reference therapeutic product. It is part of the idea accepted for the reference medicinal product. Clopidogrel bisulfate indicated in animals for the prevention of atheroma-thrombotic occasions where animal suffering from myocardial infarction, ischemic stroke or recognized peripheral arterial disease. The therapeutic suggestion of Plavix is also indicated in mature animals for the prevention of atherothrombotic events where animals suffering from myocardial infarction, ischemic stroke or recognized outlying arterial illness. Animals suffering from acute coronary syndrome: Non-ST segment advancement to acute coronary disease (unsteady angina or non-Q-wave myocardial infarction), including patients enduring a stent placement due to percutaneous coronary interference, in combination with acetylsalicylic acid (ASA). ST segment advancement sharp myocardial infarction, in a mixture with ASA in medically treated patients eligible for thrombolytic therapy. Thrombotic Thrombocytopenic Purpura (TTP) has been stated very rarely following the use of Clopidogrel bisulfate, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic hemolytic anaemia related to either neurological results, renal dysfunction or fever. TTP is a possibly deadly condition requiring prompt treatment including plasmapheresis. In the case of the lack of data, Clopidogrel bisulfate cannot be recommended during the first seven days after acute ischaemic stroke. In patients who are poor CYP2C19 metabolizers, Aropes at prescribed doses forms less of the active metabolite Clopidogrel bisulfate and has a smaller effect on platelet function. Tests are available for identifying a patients CYP2C19 genotype. Since Clopidogrel bisulfate is metabolized to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of Clopidogrel bisulfate. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged. Therapeutic experience with Clopidogrel bisulfate is limited in patients with renal impairment. Therefore, should be Clopidogrel bisulfate used with caution in these patients. Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel bisulfate can, therefore, be used with caution in this population. This product contains hydrogenated castor oil which may cause stomach upset and diarrhea. For animals that had non-ST-segment advancement ACS, as well as animals to be managed therapeutically and those that are to be managed with coronary revascularization, Plavix was shown to decrease the frequency of a collective endpoint of cardiovascular death, myocardial infarction (MI), also known as stroke, as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or an intractable ischemia. For animals that had ST-elevation myocardial infarction (STEMI), Plavix showed to lessen the rate of demise from any cause and the rate of a collective endpoint of death, reinfection, or stroke. The benefit for animals that undergo primary percutaneous coronary intermediation is unknown. The optimum duration of Plavix therapy in ACS is unknown. Animals that had a history of having a recent myocardial infarction (MI), recent stroke, or recognized peripheral arterial disease, Plavix showed to diminish the rate of a combined endpoint of fresh ischemic stroke (deadly or not), new MI (deadly or not), and other vascular deaths. Plavix was administered with or without food. For animals with non-ST-elevation ACS (UA/NSTEMI), Plavix with a single 300 mg oral loading dose was administered. The administration of the Plavix was continued at 75 mg once daily. Aspirin of the amount 75–325 mg was also administered at least once daily once daily in combination with Plavix. Some animals with STEMI, the recommended dose of Plavix were 75 mg once daily orally, which was administered in combination with aspirin 75–325 mg once daily. Thrombolytic was also included in the combination. Plavix was initiated without a loading dose. The dose of Plavix recommended daily was 75 mg once daily orally, without food. CYP2C19 Poor metabolizer status was related to reducing antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response according to Clinical Pharmacology, a suitable dose procedure for this animal population had not been found. Omeprazole 80mg once daily administered either at the same time as Clopidogrel bisulfate or with 12 hours between the administrations of the two drugs decreased the exposure of the active metabolite by 45% (loading dose) and 40% (maintenance dose). The decrease was associated with a 39% (loading dose) and 21% (maintenance dose) reduction inhibition of platelet aggregation. Esomeprazole is required to give a similar interaction with Clopidogrel bisulfate. Inconsistent data on clinical implications of this pharmacokinetic (PK)/pharmacodynamic (PD) interaction in terms of major cardiovascular events have been reported from both observational and clinical studies. As a precaution, concomitant use of omeprazole or esomeprazole should be discouraged. Less pronounced reductions of metabolite exposure have been observed with pantoprazole or lansoprazole. The plasma concentrations of the active metabolite were 20% reduced (loading dose) and 14% reduced (maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was associated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%, respectively. These results indicate that Aropes can be administered with pantoprazole. There is no evidence that other medicinal products that reduce stomach acid such as H2 blockers except cimetidine which is a CYP2C19 inhibitor, or antacids interfere with the antiplatelet activity of Clopidogrel bisulfate. A number of other clinical studies have been conducted with Aropes and other concomitant medicinal products to investigate the potential for pharmacodynamics and pharmacokinetic interactions. However, clinically significant pharmacodynamics interactions were observed when Clopidogrel bisulfate was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamics activity of Aropes was not significantly influenced by the Coad ministration of phenobarbital, cimetidine, or estrogen. The co-administration of Aropes did not modify the pharmacokinetics of digoxin or theophylline. Antacids did not modify the extent of Clopidogrel bisulfate) absorption. Data from the CAPRIE study indicates that phenytoin and tolbutamide which are metabolized, by CYP2C9, can be safely co-administered with Clopidogrel bisulfate. Apart from the specific medicinal product interaction information described above, communication studies with Clopidogrel bisulfate) and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed. However, according to reports patients entered into clinical trials with Clopidogrel bisulfate received a variety of associated medicinal products including diuretics, beta blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiuretic agents (including insulin), antiepileptic agents, and antagonists without evidence of clinically significant adverse interactions. It was found that using omeprazole or esomeprazole in combination with Plavix was to be avoided. This is because Omeprazole and esomeprazole reduce the antiplatelet action of Plavix. When simultaneous administration of a PPI was required, the use another acid-reducing agent with minimal or no CYP2C19 inhibitory effect was considered on the formation of clopidogrel active metabolite In a clinical study conducted in healthy subjects, Clopidogrel bisulfate did not necessitate modification of the heparin dose or altered the effect of heparin on coagulation. Coadministration of heparin had no effect on the inhibition of platelet aggregation induced by Clopidogrel bisulfate. A pharmacodynamic interaction between Aropes and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. The safety of the concomitant administration of Clopidogrel bisulfate, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-administered with ASA. In a clinical study conducted in healthy volunteers, the concomitant administration of Clopidogrel bisulfate and naproxen increased occult gastrointestinal blood loss. However, due to the lack of information research with other NSAIDs it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and Clopidogrel bisulfate should be co-administered with caution. Since Clopidogrel bisulfate is metabolized to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of Clopidogrel bisulfate. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged. Medicinal products that inhibit CYP2C19 include omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine and chloramphenicol. Clopidogrel bisulfate has been evaluated for safety in more than 42,000 animals, who have participated in clinical research, including over 9,000 patients treated for one year or more. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY and COMMIT studies are discussed below. Overall, Clopidogrel bisulfate 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. In addition to clinical research experience, adverse reactions have been spontaneously reported. Bleeding is the most common reaction reported both in clinical research as well as in postmarketing experience where it was mostly reported during the first month of treatment. In CAPRIE, in patients treated with either Clopidogrel bisulfate or ASA, the overall rate of any bleeding was 9.3%. The rate of severe cases was similar for Clopidogrel bisulfate and ASA. In CURE, there was no excess in major bleeds with Aropes plus ASA within seven days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery. In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% Clopidogrel bisulfate plus ASAand 6.3% for placebo plus ASA. In CLARITY, there was an overall increase in bleeding in the Clopidogrel bisulfate plus ASA group vs. the placebo plus ASA group. The occurrence of major bleeding was similar between groups. This was consistent across subgroups of patients defined by baseline characteristics, and fibrin lytic or heparin therapy. Including Plavix increases the risk of excessive bleeding. If an animal has to experience surgical treatment and an antiplatelet effect is not wanted, terminate the administration Plavix five days prior to surgery. In animals that stopped treatment more than five days prior to CABG the rates of major bleeding were similar (at event rate of 4.4% Plavix + aspirin; 5.3% placebo + aspirin). In animals that remained on treatment within five days of CABG, the major bleeding rate was 9.6% for Plavix + aspirin, and 6.3% for placebo + aspirin. Thienopyridines prevent platelet coagulation for the lifetime of the platelet (7–10 days), so suppression a dose was not useful in handling a bleeding event or the chances of bleeding related with an invasive process. Because the half-life of clopidogrels active metabolite is short, it was possible to reinstate hemostasis by administering exogenous platelets; however, platelet transfusions within four hours of the filing dose or two hours of the preservation dose may be less operational. Avoid lapses in rehabilitation, and if Plavix must be briefly discontinued, resume as soon as possible. Early discontinuation of Plavix may surge the risk of cardiovascular occurrences. For animals diagnosed with recent TIA or stroke which are at high risk for recurrent ischemic events, a mixture of aspirin and Plavix has not been shown to be more operative than Plavix alone, but the combination has been shown to increase major bleeding. TTP, sometimes deadly, has been reported following use of Plavix, sometimes after a short contact (of about 2 weeks). TTP is a serious disorder that requires urgent treatment including plasma exchange. It is categorized by thrombocytopenia, microangiopathic hemolytic anemia seen commonly on peripheral smear, neurological findings, renal dysfunction, and fever according to Adverse Reactions. Patients ought to be evaluated for the history allergic a reaction to another thienopyridine, since allergic cross-reactivity among thienopyridines has been reported. Because clinical attempts are conducted under widely fluctuating conditions and periods of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Plavix has been assessed for safety in more than 45000 patients, including over 21,000 patients treated for one year or more. The clinically significant adverse reactions observed in trials comparing Plavix plus aspirin to placebo plus aspirin and trials comparing Plavix alone to aspirin alone discussed below. Bleeding cure in cure, Plavix use with aspirin was associated with an increase in major bleeding (Primarily gastrointestinal and at puncture sites) Compared to placebo with aspirin. The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise. Clopidogrel bisulfate is broken down to its active metabolite in part by CYP2C19. Relative use of certain drugs that hinder the effect of this enzyme results in condensed plasma concentrations of the vigorous metabolite of Clopidogrel bisulfate a lessening in platelet inhibition. Avoid associated use of Plavix with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to diminish the antiplatelet activity of Plavix when given alongside or 12 hours apart. A higher dose schedule of clopidogrel concomitantly administered with omeprazole upturns antiplatelet response; a suitable dose regimen has not been found. A similar decrease in antiplatelet effect was observed with esomeprazole when given concomitantly with Plavix. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of Plavix than did omeprazole or esomeprazole according to Dosage and Administration Warnings and Precautions and Clinical Pharmacology Non-steroidal Anti-Inflammatory Drugs (NSAIDs) are Coad ministration of Plavix and NSAIDs upsurges the risk of gastrointestinal bleeding. Although the administration of clopidogrel 75 mg per day did not change the pharmacokinetics of S-warfarin, a CYP2C9 substrate or INR in patients receiving long-term warfarin therapy, coadministration of Plavix with warfarin growths the risk of bleeding because of autonomous effects on hemostasis. However, an extraordinary concentration in vitro, clopidogrel inhibits CYP2C9. Reproduction studies done in rats and rabbits at doses up to 400 and 200mg/kg/day, respectively- 65 and 78 times the endorsed daily human number, respectively, on a mg/m2 basis, discovered no proof of impaired fertility or toxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in expectant women. Because animal reproduction studies are not always analytical of human response, Plavix should be used during gestation only if clearly needed. Studies in rats have demonstrated that clopidogrel and/or its metabolites are removed in the form of waste in the milk. Because many drugs are excreted in animal milk and because of the likely for serious adversative reactions in nursing children from clopidogrel, a choice should be made whether to halt the nursing or to terminate the drug, taking into account the importance of the drug to the mother. Protection and efficiency in pediatric people has not been found. A randomized, Placebo controlled trial (CLARINET) did not establish a clinical benefit of Clopidogrel in neonates and newborns with cyanotic inherited heart malady palliated with a systemic-to pulmonary Arterial shove. Possible factors causative to this consequence were the number of Clopidogrel, the affiliated administration of aspirin and the late commencement of treatment following diversion palliation. It cannot be ruled out that a trial with a dissimilar design would prove a clinical benefit in this patient group.8.5 Geriatric. Use of the total number of subjects in the CAPRIE and cure organized clinical research, gives around 50% of patients treated with Plavix were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients suffering from with Plavix were 60 years and older, 26% of whom were 70 years and older. The observed risk of bleeding events with Plavix plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and respectively. No dosage adjustment is necessary for elderly patients. Experience is limited in patients with severe and moderate renal impairment According to research, the medicine can lead to severe bleeding and hence these precautions ought to be followed strictly. 1. Due to the risk of bleeding and hematological undesirable effects, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during treatment. 2. As with other antiplatelet agents, Clopidogrel should be used with caution in an animal that may be at risk of increased bleeding from trauma, surgery or other pathological conditions and in the animal receiving treatment with aspirin, nonsteroidal anti- inflammatory drugs, heparin, glycoprotein inhibitors or thrombolytic. Animals should be followed carefully for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery. 3. The simultaneous administration of Clopidogrel with warfarin is not advised since it may upsurge the intensity of bleeding. If the animal is to undergo elective surgery and an antiplatelet effect is not necessary, Clopidogrel should be discontinued seven days prior to surgery. 4. Clopidogrel prolongs bleeding time and should be used with caution in animals that have lesions with a propensity to bleed predominantly gastrointestinal and intraocular. 5. Animal owner ought to be told that it may take longer than normal to stop bleeding when they take Clopidogrel (alone or in combination with aspirin) and that they should report any unusual bleeding (site or duration) to their veterinary. 6. Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of Clopidogrel, sometimes after a short exposure. It is characterized by thrombocytopenia and Microangiopathic hemolytic anemia associated with neurological findings, renal dysfunction or fever. TTP is a condition requiring prompt treatment including Plasmapheresis. 7. In the opinion of the absence of data in animals with acute myocardial infarction with ST-segment advancement, Clopidogrel treatment should not be started within the first few days following myocardial infarction. 8. In the assessment of the lack of data, Clopidogrel cannot be recommended in acute ischemic stroke (less than seven days). 9. Healing experience with Clopidogrel is limited in patients with renal impairment. Therefore, Clopidogrel should be used with caution in these patients. 10. Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel, therefore, be used with caution in this population. The safety and efficacy of Clopidogrel bisulfate in children and adolescents under Due to the chances of bleeding and hematological adverse occurrences, blood cell count examination and other appropriate testing should be promptly put in consideration whenever clinical signs that are suggestive of bleeding arise during treatment. As with other antiplatelet agents, Clopidogrel bisulfate ought to be used with precaution in patients who may be have high chances of increased bleeding due to trauma, surgery or other pathological circumstances and in patients getting treatment with ASA, heparin, glycoprotein Ilia inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) including Cox-2 inhibitors. Those infected should be followed keenly for any indication of bleeding including occult bleeding, in particular during the first few weeks of medication and after invasive cardiac procedures or surgery. The concomitant administration of Clopidogrel bisulfate with oral anti-coagulants is not advocated since it may increase the intensity of bleedings. Research has proved that if a patient is to go through an elective operation and antiplatelet outcome becomes undesirable Clopidogrel bisulfate should be discontinued 7 days prior to surgery. Patients ought to inform those carrying out the operation that they are under medication prior to any surgery is arranged and before any new treatment product is taken. Clopidogrel bisulfate prolongs bleeding time and should be used with precaution measures in patients who have wounds with a probability of bleeding particularly gastrointestinal and intraocular). Patients ought to be told that it might take longer time than normal to halt bleeding when they take Aropes (alone or in mixture with ASA) and that they ought to report any abnormal bleeding to their physicians. In summation, no dosage adjustment is necessary for animals with hepatic impairment. Platelet prevention by Plavix is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting, prostration, difficult breathing, and gastrointestinal hemorrhage in animals. Based on biological plausibility, platelet transfusion may restore clotting ability. Clopidogrel is a similar particle to ticlopidine and rapidly binds to the platelet inhibition platelet combination. Clopidogrel is digested by the liver creating its main inactive metabolite, the carboxylic acid. Due its wide-ranging metabolization approaches were established for the quantifications in plasma of carboxylic acid. The quantification of different drugs by chromatography with cycle mass spectrometry is if becoming each more universal time due to enhancement in the sensitivity and the selectivity of this technique with the improvement of the chromatography the value in the determination of the concentrations is more accurate, getting a lower LOQ and better examination of outcomes. A few critical methods have been available for the determination of the sedentary metabolite of clopidogrel in the living matrix. A sensitive gas chromatography–mass spectrometric method with LOQ of 0.005μg/mL has been published. In this process, however, a complex two steps removal process using both liquid–liquid and solid phase extraction techniques as well as derivatization of the analytic are required. Two LC–MS methods for the determination inactive metabolite of clopidogrel have been Journal of Bioequivalence & Bioavailability Key words Atheroma Fat deposited in the wall of medium and larger-sized arteries, causing narrowing of the artery. Atherosclerosis A major illness of the arteries. Deposition of structured lipid and platelets on the arterial wall forming athermanous plaques. Atherothrombosis Atherothombosis classified by thrombosis superimposed on an atheromatous ST-elevation Elevation of the ST part in an ECG. Stent An artificial structure inserted into a coronary artery following PTCA to support the vessel wall and reduce the risk of CABG coronary artery bypass graft CAD coronary artery disease CHD coronary heart disease CHF congestive heart failure CI confidence interval CK-MB creatine kinase myocardial band fraction ACS- Acute Coronary Syndromes ST- ST-troponin Atheroma- this is a fat deposited in the walls of medium and larger sized arteries, causing narrowing of the artery. Work Cited Majerus PW, Tollefsen DM. Blood Coagulation and Anticoagulant, Thrombolytic, and Antiplatelet drugs. The Pharmacological Basis of Therapeutics (2006). Read More