The value of clopidogrel in addition to standard therapy in reducing atherothrombotic events

The recent multinational, randomised, prospective studies Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), Percutaneous Coronary Intervention substudy of CURE (PCI-CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO) have demonstrated the clinical efficacy and safety of clopidogrel for the treatment of patients with non-ST-segment elevation acute coronary syndromes (ACS), including those undergoing percutaneous coronary intervention. In these settings, clopidogrel significantly reduces the risk of atherothrombotic events, with relative risk reductions of 20-30% (absolute risk reduction 1.9-3.0%). Health economic evaluations based on data from these studies conducted in Europe and the United States have clearly demonstrated the cost-effectiveness of clopidogrel in combination with aspirin compared with aspirin alone for the management of ACS. Within-trial evaluations based on CURE and PCI-CURE data showed that treatment with clopidogrel on top of standard therapy reduced the cost of initial hospitalisation as well as the total cost associated with hospitalisations. Long-term economic analyses based on the CURE study demonstrate that clopidogrel is cost saving in the Netherlands and that the cost per life-year gained (LYG) in other European countries is between Euros 549 and Euros 5048. In the United States, the cost per LYG for clopidogrel has been assessed at US dollars 6173 on the basis of CURE, US dollars 5910 for PCI-CURE and US dollars 3685 for CREDO, all of which are considerably lower than that associated with common cardiovascular benchmarks. The results are robust and consistent across different countries using varying costing strategies and estimates of survival. In conclusion, these data demonstrate that clopidogrel in combination with aspirin for the management of ACS is both clinically effective and cost-effective in this setting.     

Long-term clopidogrel therapy in patients receiving percutaneous coronary intervention

BACKGROUND: The PCI-CURE (Percutaneous Coronary Intervention-Clopidogrel in Unstable Angina to Prevent Recurrent Events) and CREDO (Clopidogrel for the Reduction of Events During Observation) studies have demonstrated that, in addition to aspirin, pre-treatment with clopidogrel followed by long-term (i.e. 9-12 months) therapy significantly reduces the risk of atherothrombotic events in patients undergoing percutaneous coronary intervention (PCI). OBJECTIVE: To examine the economic implications, from the Dutch healthcare perspective, of the use of clopidogrel in patients undergoing PCI (elective procedures or in patients with acute coronary syndrome), comparing pre-treatment followed by long-term therapy with only 4 weeks of treatment. METHODS: A lifetime Markov model was used to combine data from the PCI-CURE and CREDO trials with data from the literature concerning epidemiology, costs and quality of life. The model was run separately for each trial. Only direct healthcare costs (euro, year 2004 values) were considered. Costs and outcomes were discounted at 4% per anum. For each trial, the cost effectiveness is expressed as costs per life-year and QALY gained. Uncertainties are addressed by uni- and probabilistic multivariate sensitivity analysis. RESULTS: When starting with the data from the PCI-CURE trial, pre-treatment plus 9-month clopidogrel therapy was predicted to save 1119 euros and gain 0.03 life-years and 0.07 QALYs per patient compared with short-term treatment. When starting with the data from the CREDO trial, the combination of pre-treatment and prolonged clopidogrel therapy (1 year) was estimated to save 497 euros and gain 0.10 life-years and 0.14 QALYs per patient. Univariate and probabilistic multivariate sensitivity analyses suggested that the conclusions were generally robust, but that the expected gain in survival for the PCI-CURE population was very sensitive to the effects on mortality within the combined endpoint of myocardial infarction/stroke-free survival. CONCLUSIONS: In The Netherlands, pre-treatment plus long-term (9-12 months) therapy with clopidogrel is estimated to save costs and increase (quality-adjusted) survival in the prevention of ischaemic events among patients undergoing elective PCI (CREDO) and in patients with acute coronary syndrome (PCI-CURE) compared with short-term treatment with clopidogrel without pre-treatment.     

CLARITY about the use of clopidogrel in patients with acute coronary syndromes and myocardial infarction

Clopidogrel was shown to have added benefits to aspirin in patients with acute coronary syndromes without ST-segment elevation in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial. The cost in CURE was estimated to be US$442 greater in the clopidogrel group and the incremental cost-effectiveness ratio (incremental cost/life-year gained) was US$6318. Clopidogrel has also recently been shown to have added benefits to aspirin in patients with myocardial infarction with ST-segment elevation in the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) – Thrombolysis in Myocardial Infarction (TIMI) 28 study. The primary efficacy composite end point in CLARITY was an occluded infarct-related artery, death from any cause prior to angiography, or recurrent myocardial infarction, and this end point occurred less in the clopidogrel group (15%, 262 of 1752 patients) than placebo group (21.7%, 377 of 1739 patients). This difference was predominantly due to a reduction in the occluded infarct-related artery, which occurred in less of the clopidogrel (11.7%) than placebo group (18.4%). There was also a reduction in urgent revascularisations in the clopidogrel group of CLARITY. Thus, clopidogrel is effective and cost effective in acute coronary syndromes, and is also beneficial in patients with myocardial infarction with ST-segment elevation.     

CLARITY about the use of clopidogrel in patients with acute coronary syndromes and myocardial infarction

Clopidogrel was shown to have added benefits to aspirin in patients with acute coronary syndromes without ST-segment elevation in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial. The cost in CURE was estimated to be US442 dollars greater in the clopidogrel group and the incremental cost-effectiveness ratio (incremental cost/life-year gained) was US6318 dollars. Clopidogrel has also recently been shown to have added benefits to aspirin in patients with myocardial infarction with ST-segment elevation in the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)--Thrombolysis in Myocardial Infarction (TIMI) 28 study. The primary efficacy composite end point in CLARITY was an occluded infarct-related artery, death from any cause prior to angiography, or recurrent myocardial infarction, and this end point occurred less in the clopidogrel group (15%, 262 of 1752 patients) than placebo group (21.7%, 377 of 1739 patients). This difference was predominantly due to a reduction in the occluded infarct-related artery, which occurred in less of the clopidogrel (11.7%) than placebo group (18.4%). There was also a reduction in urgent revascularisations in the clopidogrel group of CLARITY. Thus, clopidogrel is effective and cost effective in acute coronary syndromes, and is also beneficial in patients with myocardial infarction with ST-segment elevation.     

Cost-effectiveness of clopidogrel treatment in percutaneous coronary intervention: a European model based on a meta-analysis of the PCI-CURE,CREDO and PCI-CLARITY trials*

ABSTRACT

Objective: Our objective was to conduct a comprehensive cost-effectiveness analysis of pre-treatment and long-term treatment with clopidogrel in percutaneous coronary intervention (PCI) in three European countries based on a meta-analysis of the PCI-Clopidogrel in Unstable angina to prevent Recurrent Events (CURE), Clopidogrel for the Reduction of Events During Observation (CREDO) and PCI-Clopidogrel as Adjunctive Therapy (CLARITY) trials. This analysis adds to existing knowledge by providing further data on the cost-effectiveness of clopidogrel in PCI across a wide spectrum of patients.

Methods: A combined decision tree and Markov model was created. The relative risks of myocardial infarction, cardiovascular death and of major bleedings with clopidogrel were based on a fixed-effects meta-analysis. The risk of ischaemic events in untreated patients and long-term survival were taken from the Swedish hospital and death registers. A societal perspective was used in Sweden and a payer perspective in Germany and France. Costs are stated in €2006 and effectiveness measured in quality-adjusted life-years (QALYs).

Results: The pooled effects of clopidogrel on the combined endpoint showed a relative risk of 0.711 (p = 0.003) at 30 days and 0.745 (p = 0.002) at end of follow-up (up to 1 year). Pre-treatment with clopidogrel compared with aspirin alone is a dominant strategy. Long-term treatment with clopidogrel compared with 1-month treatment leads to approximately 0.09 QALYs at an incremental cost of €393 in Sweden, €709 in Germany and €494 in France. The corresponding incremental cost-effectiveness ratios range from €4225/QALY to €7871/QALY.

Conclusion: The results of this modelling analysis suggest that pre-treatment and long-term treatment in PCI with clopidogrel for up to 1 year are cost-effective in a range of patient groups and settings given commonly accepted thresholds.     

The value of clopidogrel versus aspirin in reducing atherothrombotic events: the CAPRIE study

Atherothrombotic disease is a growing health problem, and is increasingly more costly to manage. Clopidogrel is an advanced, specific adenosine diphosphate receptor antagonist, which has been shown to be a highly potent antiplatelet agent. Data from the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study have demonstrated the significantly superior clinical benefit of clopidogrel over aspirin for secondary prevention of atherothrombotic disease, with a relative risk reduction in myocardial infarction, stroke or vascular death of 8.7% (95% confidence interval 0.3, 16.5; P = 0.043). Moreover, clopidogrel demonstrated an amplified clinical benefit versus aspirin in patients at high risk of atherothrombotic events, such as those with a previous history of symptomatic atherothrombotic disease or with major risk factors such as diabetes mellitus or hypercholesterolaemia. On the basis of commonly accepted threshold criteria (Euros 20000 per life-year gained; LYG), clopidogrel in comparison with aspirin is cost-effective for the secondary prevention of atherothrombotic disease (cost per LYG ranging from Euros 19462 to Euros 3256). Economic analyses have demonstrated consistent cost-effectiveness results with clopidogrel in different countries. Moreover, in high-risk patient subgroups the cost-effectiveness of clopidogrel in comparison with aspirin was evenbetter (cost per LYG ranging from Euros 5900 to Euros 6310). Compared with other treatment strategies used for the prevention of ischaemic or atherothrombotic events, the cost-effectiveness of clopidogrel in comparison with aspirin based on CAPRIE is favourable, with most analyses in the intermediate range of cost-effectiveness. The available data thus support the use of clopidogrel as a clinically efficient and cost-effective option for secondary prevention of atherothrombotic disease, particularly in high-risk patients.     

Clopidogrel: a CURE in acute coronary syndromes?

The standard approach to preventing acute coronary syndromes (ACSs)has been to inhibit platelet aggregation with aspirin and to inhibit blood coagulation with low molecular-weight heparin (LMWH). Even with this combination there is still a substantial short and long-term cardiovascular risk. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial [1] compared clopidogrel plus aspirin against aspirin alone in patients with ACSs. The clopidogrel regimen was a loading dose of 300 mg p.o. followed by 75 mg/day and the recommended dose of aspirin was 75 - 325 mg/day. The first primary outcome was a composite of death from cardiovascular causes, non-fatal myocardial infarction (MI) or stroke and this occurred significantly less often in the clopidogrel than the placebo group (9.3 vs. 11.4%). Although there were more clopidogrel patients with life-threatening bleeding (clopidogrel 2.2%, placebo 1.8%), this represented GI haemorrhages and bleeding at sites of arterial puncture rather than fatal bleeding. This trial suggests a role for clopidogrel in the long-term treatment of ACSs.     

Cost effectiveness of adding folinic acid to fluorouracil plus levamisole as adjuvant chemotherapy in patients with colon cancer in Germany

OBJECTIVE: To assess the cost effectiveness of the addition of folinic acid to fluorouracil plus levamisole in patients with colon cancer from the perspective of the German Social Health Insurance. STUDY DESIGN AND METHODS: Patients with International Union Against Cancer (Union International Contre Cancer; UICC) II/T(4) or UICC III colon cancer enrolled in an open-label randomised clinical trial in Germany (Forschungsgruppe Onkologie Gastrointestinaler Tumoren-1 [FOGT-1]) received either fluorouracil plus levamisole (A, standard) or fluorouracil plus levamisole and folinic acid (B) for 12 months as adjuvant chemotherapy after curative intended surgery. Outcome measures for economic evaluation were disease-free life-years gained (df-LYG) and overall life-years gained (LYG) derived from the respective Kaplan-Meier survival curves. Direct medical costs from the perspective of the German Social Health Insurance were estimated retrospectively (2000 values) and incremental cost-effectiveness ratios (ICERs) were calculated. A Markov model was used to project the trial results beyond 5 years for the patients' remaining life expectancy. RESULTS: Adding folinic acid to the fluorouracil/levamisole regimen results in an increase in time to progression and survival in patients with locally advanced colon cancer. Within the trial period of 5 years ICERs (B versus A) were 33,008 Euro per df-LYG and 51,225 Euro per LYG (costs and effects discounted at 5%). The Markov model yielded ICERs of 11,176 Euro per df-LYG and 11,020 Euro per LYG (costs and effects discounted at 5%). The model was robust for variations of key variables in the sensitivity analysis. CONCLUSIONS: Results of this cost-effectiveness analysis suggest that the addition of folinic acid offers clinical benefits at additional costs which are likely to be acceptable for decision makers in the long term. Cost-effectiveness ratios calculated within the clinical trial period were just above 50,000 Euro/LYG. Because treatment benefits, i.e. prolonged survival, are sustained beyond 5 years whereas incremental costs are mainly incurred in the first year, results of the Markov model yielded cost-effectiveness ratios that compare more favourably with other published ICERs.     

Clopidogrel and acute coronary syndrome

Clopidogrel (Plavix-Sanofi-Synthelabo & Bristol-Myers Squibb) blocks platelet aggregation through an action distinct from that of aspirin. In the UK, it is licensed for the secondary prevention of atherosclerotic events and for this, we concluded 3 years ago that clopidogrel "appears to offer no worthwhile advantage over aspirin". After publication of the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial, which assessed adjunctive use of clopidogrel with aspirin in patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q wave infarction), clopidogrel was hailed in the lay media as "the biggest breakthrough in 20 years". Do the CURE study results warrant the use of clopidogrel in patients with acute coronary syndrome without ST elevation (currently an unlicensed indication)?     

Prevention of coronary heart disease with aspirin and clopidogrel: efficacy, safety, costs and cost-effectiveness

Atherothrombotic coronary artery disease is the single most common cause of death worldwide and a growing public health problem. Platelets play a central role in the pathogenesis of atherothrombosis and are therefore commonly targeted by one or more antiplatelet drugs as part of primary and secondary atherothrombosis prevention strategies. Aspirin reduces the risk of serious vascular events (myocardial infarction, stroke or cardiovascular death) by approximately 20% in a broad range of high-risk patients and remains the first-line antiplatelet drug because of its relative safety, low cost and cost-effectiveness. Compared with aspirin alone, clopidogrel reduces the risk of serious vascular events by approximately 10% and the combination of aspirin and clopidogrel reduces the risk by approximately 20% in patients with non-ST-segment elevation acute coronary syndrome. Clopidogrel has a similar safety profile to aspirin but clopidogrel tablets are substantially more expensive. However, the incremental cost-effectiveness ratio of clopidogrel compared with aspirin is favourable, particularly in high-risk patients and is intermediate compared with a range of other effective therapeutic strategies for the treatment of coronary heart disease. Clopidogrel should be considered as a replacement for aspirin in patients who are allergic to aspirin, cannot tolerate aspirin, have experienced a recurrent atherothrombotic vascular event whilst taking aspirin and are at very high absolute risk of a serious vascular event (e.g., > 20%/year). The combination of clopidogrel and aspirin should be considered in patients with non-ST-segment elevation acute coronary syndrome or undergoing percutaneous coronary intervention.     

Aspirin and Platelet Adenosine Diphosphate Receptor Antagonists in Acute Coronary Syndromes and Percutaneous Coronary Intervention

Platelet activation and aggregation are key components in the cascade of events causing thrombosis following plaque rupture. Antiplatelet therapy is essential in the treatment of patients with acute coronary syndromes (ACS) and for those requiring percutaneous coronary intervention (PCI). Aspirin (acetylsalicylic acid) is a well established antiplatelet therapy and is mandated for secondary prevention of cardiovascular events following ACS. In patients with ACS, the addition of clopidogrel to aspirin is more effective than aspirin alone. For patients undergoing PCI, dual antiplatelet therapy with aspirin and clopidogrel is warranted. Aspirin should be continued indefinitely after PCI. Pretreatment of patients with clopidogrel prior to PCI lowers the incidence of cardiovascular events, yet the optimum timing of drug administration and dose are still being investigated, as is the duration of therapy following PCI. Late-stent thrombosis with drug-eluting stents has pushed the recommendation for duration of clopidogrel therapy up to 1 year and perhaps beyond, in patients without risks for bleeding. The concepts of aspirin and clopidogrel resistance are important clinical questions. No uniform definition exists for aspirin or clopidogrel resistance. Measurements of resistance are often highly variable and do not necessarily correlate with clinical resistance. Noncompliance remains the most prominent mode of resistance. Screening of selected patient populations for resistance or pharmacologic intervention of those patients termed 'resistant' warrants further study.     

Clopidogrel

Dual antiplatelet therapy with acetylsalicylic acid (aspirin) and clopidogrel is a guideline-recommended standard of care for patients with acute coronary syndromes (ACS) and those who undergo percutaneous coronary intervention (PCI). Despite a large body of clinical evidence obtained from randomized clinical trials and patient registries supporting the efficacy and safety of aspirin plus clopidogrel therapy in these patients, questions concerning the optimal use of dual antiplatelet therapy remain. Widely debated topics pertaining to dual antiplatelet therapy in patients with ACS or undergoing PCI include (i) the appropriate clopidogrel loading dose; (ii) the optimal time to initiate the clopidogrel loading dose; (iii) the optimal duration of dual antiplatelet therapy following ACS or PCI; (iv) impact of variability of platelet response on patient outcomes; and (v) the role of other recommended and emerging P2Y₁₂ antagonists. This review discusses these ongoing controversies regarding the optimal use of dual antiplatelet therapy with aspirin and clopidogrel in patients with ACS or those undergoing PCI.     

Paclitaxel: a pharmacoeconomic review of its use in the treatment of ovarian cancer.

Paclitaxel belongs to the group of antitumour agents called the taxanes. Its efficacy in advanced ovarian cancer has been established in large, randomised phase III clinical trials. When used in combination with cisplatin for first-line treatment of advanced ovarian cancer, it is superior to cyclophosphamide/cisplatin, with gains in median survival of around 1 year. Paclitaxel plus carboplatin has similar efficacy to paclitaxel plus cisplatin. There is now consensus that paclitaxel plus either carboplatin or cisplatin is the recommended first-line therapy for patients with advanced ovarian cancer. The particular combination employed may vary between institutions and geographical regions, although paclitaxel plus carboplatin is generally better tolerated (i.e. lower incidence of non-haematological adverse events) than paclitaxel plus cisplatin and is widely used in many countries. Paclitaxel is also used as monotherapy in second-line (salvage) treatment of ovarian cancer. Pharmacoeconomic analyses performed to date have primarily focused on first-line therapy comparing the combination of paclitaxel/cisplatin with cyclophosphamide/cisplatin. All studies incorporated clinical outcomes data, most commonly from the Gynecologic Oncology Group (GOG) 111 trial, showing a survival advantage for paclitaxel/cisplatin. These studies report incremental cost-effectiveness ratios (ICERs) ranging from $US 6395 per additional life-year gained (LYG) in Spain (1995/96 values) to $US 44,690 per additional progression-free LYG in France (year of costs not reported). Five studies were based in the US and Canada and these reported very similar ICERs of $US 13,135 (year of costs not reported) to $US 25,131 (1993 costs) per additional LYG. In all of these studies the incremental costs of paclitaxel/cisplatin therapy fall well within the commonly cited threshold limit of $US 50,000 for new therapies and compare well with incremental costs reported for other oncological and life-saving therapies. Patient preferences and quality of life are important issues due to the short survival of patients with advanced ovarian cancer. Two cost-utility studies reported similar incremental cost-utility ratios (ICURs). In the study based on US costs, the ICUR of paclitaxel/cisplatin treatment was US $18,200 per additional quality-adjusted life-year (QALY) [1995 drug costs]. In a Canadian study the ICUR ranged from 11,600 Canadian dollars ($Can) to $Can 24,200 (1996 costs) per additional progression-free QALY depending on the choice of second-line treatment. CONCLUSIONS: Paclitaxel used in combination with cisplatin offers survival and utility gains versus cyclophosphamide plus cisplatin, when used as first-line treatment in patients with stage III or IV ovarian cancer. The incremental cost for these gains is within the accepted range for healthcare interventions. However, pharmacoeconomic analyses of paclitaxel plus carboplatin--a combination widely accepted for use in women with advanced ovarian cancer and with clinical advantages over paclitaxel plus cisplatin in terms of ease of administration and tolerability profile--are currently lacking. Nevertheless, results of available pharmacoeconomic data support the clinical use of paclitaxel/platinum combinations, particularly paclitaxel plus cisplatin, as a first-line chemotherapy treatment option in patients with advanced ovarian cancer.     

Mesalazine for the treatment of inflammatory bowel disease

Clopidogrel has become a mainstay in the management of acute coronary syndrome patients over the past decade, as well as an essential component of percutaneous coronary intervention (PCI) pharmacotherapy. Until recently, no prospective study has evaluated the effectiveness of clopidogrel in the setting of an ST-segment elevation myocardial infarction (STEMI). The majority of patients presenting with STEMI receive thrombolytic therapy (aspirin, heparin and a fibrinolytic agent) although many do not achieve or maintain adequate reperfusion of the infarct-related artery. The CLARITY (Clopidogrel as Adjunctive Reperfusion Therapy) study and the PCI–CLARITY substudy were designed to address whether a beneficial effect of clopidogrel, including a loading dose, would be attained among STEMI patients who were being treated with thrombolytic therapy and undergoing coronary angiography during the index hospitalisation. A total of 3491 patients who presented within 12 h after the onset of STEMI were randomly assigned to receive clopidogrel (300-mg loading dose followed by 75 mg daily) or placebo. Patients were scheduled to undergo coronary angiography after 48 h, and those who underwent PCI during the index hospitalisation formed the basis of PCI–CLARITY. This PCI cohort was followed for the combined end point of cardiovascular death, recurrent myocardial infarction and stroke for 30 days.     

Clopidogrel: a review of its use in the prevention of thrombosis

Clopidogrel (Plavix), Iscover) selectively and irreversibly inhibits adenosine diphosphate (ADP)-induced platelet aggregation. Long-term administration of clopidogrel was associated with a modest but statistically significant advantage over aspirin in reducing adverse cardiovascular outcomes in patients with established cardiovascular disease in the CAPRIE trial. In other large well designed multicentre trials, such as CURE, COMMIT and CLARITY-TIMI 28, the addition of clopidogrel to aspirin therapy improved outcomes in patients with acute coronary syndromes. However, some issues regarding the use of clopidogrel remain unresolved, such as the optimal loading dose in patients undergoing percutaneous coronary interventions (PCI) and the optimal treatment duration following drug-eluting intracoronary stent placement. Results of several large randomised trials, therefore, have established clopidogrel as an effective and well tolerated antiplatelet agent for the secondary prevention of ischaemic events in patients with various cardiovascular conditions, including those with ischaemic stroke or acute coronary syndromes. In addition, treatment guidelines from the US and Europe acknowledge the importance of clopidogrel in contemporary cardiovascular medicine.     

Clopidogrel in ST-elevation myocardial infarction patients undergoing percutaneous coronary intervention

Clopidogrel has become a mainstay in the management of acute coronary syndrome patients over the past decade, as well as an essential component of percutaneous coronary intervention (PCI) pharmacotherapy. Until recently, no prospective study has evaluated the effectiveness of clopidogrel in the setting of an ST-segment elevation myocardial infarction (STEMI). The majority of patients presenting with STEMI receive thrombolytic therapy (aspirin, heparin and a fibrinolytic agent) although many do not achieve or maintain adequate reperfusion of the infarct-related artery. The CLARITY (Clopidogrel as Adjunctive Reperfusion Therapy) study and the PCI-CLARITY substudy were designed to address whether a beneficial effect of clopidogrel, including a loading dose, would be attained among STEMI patients who were being treated with thrombolytic therapy and undergoing coronary angiography during the index hospitalisation. A total of 3491 patients who presented within 12 h after the onset of STEMI were randomly assigned to receive clopidogrel (300-mg loading dose followed by 75 mg daily) or placebo. Patients were scheduled to undergo coronary angiography after 48 h, and those who underwent PCI during the index hospitalisation formed the basis of PCI-CLARITY. This PCI cohort was followed for the combined end point of cardiovascular death, recurrent myocardial infarction and stroke for 30 days.     

Ticagrelor for acute coronary syndrome?

Current guidelines from the National Institute for Clinical Excellence (NICE) recommend antiplatelet therapy comprising aspirin plus either clopidogrel or prasugrel for patients with acute coronary syndrome (ACS). However, such dual therapy increases the likelihood of bleeding compared to that with aspirin alone. Ticagrelor (Brilique - Astra-Zeneca) is a new oral antiplatelet drug recently licensed in the UK (since publication of the NICE guidelines) for use with aspirin in patients with ACS, including those managed medically or undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Here we review the place of ticagrelor in the management of people with ACS, and whether it offers advantages over standard therapy in terms of greater efficacy or lower likelihood of bleeding complications.     

Clopidogrel Bisulfate

Clopidogrel bisulfate (hereafter, clopidogrel), a selective inhibitor of ADP-induced platelet aggregation, is approved for the reduction of atherothrombotic events in patients with ST-segment elevation myocardial infarction (STEMI). In COMMIT/CCS-2, a well designed trial in 45,852 adult patients with STEMI, relative to aspirin alone, clopidogrel 75 mg/day plus aspirin treatment significantly reduced the risk of both coprimary endpoints: the composite endpoint of reinfarction, stroke, or death from any cause and the risk of death from any cause. Based on the findings of this trial, treating 1000 patients for approximately 2 weeks with clopidogrel is associated with nine fewer patient deaths, reinfarctions, or strokes during treatment. In CLARITY-TIMI 28, a well designed supportive study in 3491 adult patients with STEMI, clopidogrel plus aspirin reduced the odds that a composite primary endpoint event of an occluded infarct-related artery, recurrent myocardial infarction, or death from any cause would occur versus aspirin plus placebo. Clopidogrel treatment was generally well tolerated in these clinical trials, with no significant between-group difference in the rate of major bleeding in either trial. Experience in other patient populations (e.g. those with recent myocardial infarction, recent ischemic stroke, or established peripheral arterial disease) has shown that longer-term (< or =3 years) clopidogrel monotherapy is generally well tolerated.     

Clopidogrel

? Clopidogrel is a selective inhibitor of ADP-induced platelet aggregation.

? A large, multicenter, randomized study in 12562 patients with acute coronary syndromes without ST-segment elevation demonstrated that treatment with clopidogrel (loading dose of 300mg followed by once daily treatment with 75mg) in addition to standard therapy including aspirin (75 to 325 mg/day) significantly reduced the risk of the combined endpoint of cardiovascular death, myocardial infarction or stroke compared with treatment with standard therapy. Furthermore, the composite risk of these outcomes or refractory ischemia was also significantly reduced in patients treated with clopidogrel plus aspirin. The effects of clopidogrel were independent of background treatment with cardiovascular medications and/or interventions.

? The risk of severe ischemia, recurrent angina or heart failure was also significantly reduced in patients receiving clopidogrel plus aspirin. There was also a significant reduction in the need for coronary revascularization during the initial period of hospitalization.

? In patients undergoing percutaneous coronary intervention (PCI), the relative risk of the combined endpoint of cardiovascular death, myocardial infarction or urgent target-vessel revascularization within 30 days of the intervention was significantly reduced. Moreover, the relative risk of the single endpoint of myocardial infarction within 30 days of PCI was significantly in favor of clopidogrel-treated patients.

? Hemorrhagic events (both major and minor) were significantly more frequent in patients with acute coronary syndromes receiving treatment with clopidogrel plus aspirin than in patients treated with aspirin alone. This was largely attributable to an increased incidence in the rate of gastrointestinal hemorrhage and bleeding at the site of arterial puncture. However, there was no difference between the two groups in the incidence of bleeding episodes that were considered to be life-threatening.

     

Prasugrel: A Guide to Its Use in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention in the US

Oral prasugrel (Effient®; Efient®) provides rapid, potent inhibition of platelet aggregation. It is indicated (in combination with aspirin) for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). In the pivotal clinical trial in this patient population, prasugrel-based therapy was associated with a significantly lower incidence of ischemic events than clopidogrel-based therapy. However, the efficacy of prasugrel was offset by a higher risk of bleeding than clopidogrel, with patients aged ≥75 years, those weighing <60 kg and those with a history of stroke or transient ischemic attack at the greatest risk. Prasugrel appears to have an overall favorable risk: benefit ratio in ACS patients undergoing PCI who do not have these three easily identifiable clinical characteristics. Limited pharmacoeconomic analyses suggest that prasugrel-based therapy is an economically attractive treatment strategy relative to clopidogrel-based therapy from a US healthcare payer perspective.