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On the horizon

Concise evaluated information to alert NHS Managers and Budget Holders to future drug technologies.
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Prasugrel for Acute Coronary Syndrome
managed with Percutaneous Coronary
Clinical and Patient Impact
• Prasugrel is an antiplatelet agent with a similar mode of action to clopidogrel. The manufacturer has submitted an application for licensing for the proposedindication of prevention of atherothrombotic events in patients with acute coronarysyndrome (ACS) managed with percutaneous coronary intervention (PCI). • In carefully defined patient groups, prasugrel has demonstrated improved efficacy when compared to clopidogrel in reducing atherothrombotic events in patientswith moderate to high risk ACS undergoing PCI. However, balancing the potentialrisks and benefits for individual patients will be vital as, compared with clopidogrelplus aspirin, prasugrel plus aspirin was associated with an increased major, andin some cases fatal, bleeding risk.
• In the double-blind, randomised trial, TRITON-TIMI 38 (13,608 patients), the primary end-point, a composite of cardiovascular death, non-fatal myocardialinfarction or non-fatal stroke, occurred in 9.9% of the prasugrel plus aspirinpatients and 12.1% of the clopidogrel plus aspirin group. However, major bleedingoccurred in 2.4% of the prasugrel patients compared with 1.8% for clopidogrel.
These were statistically significant results. • Based on this trial, for every 1,000 patients treated with prasugrel plus aspirin rather than clopidogrel plus aspirin for 14.5 months, 23 will have a primarycardiovascular end-point prevented but 6 will have a major bleed.
• Prasugrel may be suitable for patients who are at high risk of ischaemic events but at low risk of bleeding. Clopidogrel may be a safer choice in patients at a lowerrisk of ischaemic events but higher risk of bleeding. Differentiating between thesegroups in clinical practice may be difficult. • Prasugrel plus aspirin has not shown an overall mortality benefit over clopidogrel plus aspirin. However, TRITON-TIMI 38 was not powered to show such adifference.
NHS and Financial Impact
• The possible impact of prasugrel may depend not only on the acquisition cost, but also on identification of those patients for whom prasugrel may be appropriate,bearing in mind the possibility of increased efficacy but at the expense of anincreased risk of bleeding.
Action Required
• Area Prescribing Committees are advised to engage with local clinicians and • NICE are due to review prasugrel plus aspirin for the treatment of ACS with PCI as part of their 17th wave of technology appraisals.
Produced by a collaboration between the National Prescribing Centre and Wessex Drug and Medicines Information Centre.
cause of death in the UK [1]. Acute coronary syndrome (ACS) relates to a spectrum ofdisorders including acute myocardial infarction(MI) and unstable angina (UA). Despite Efficacy
A phase III randomised, double-blind trial of admission rates for patients with ACS remain prasugrel has been published [8]. TRITON-TIMI high [2]. For example, hospital mortality in 38 assessed 13,608 patients with moderate to high risk ACS who were to undergo scheduled (STEMI) is about 7% and for those with non- A licence
ST-segment-elevation ACS (NSTE-ACS) it is application for
randomised to either prasugrel (60mg loading prasugrel was
disruption lead to the local thrombosis and dose then 10mg daily) or clopidogrel (300mg submitted to the
ischaemic symptoms of ACS by triggering the loading dose then 75mg daily) for 6 to 15 EMEA in February
activation and aggregation of platelets [3].
Therefore, drugs which inhibit platelet function dose was given anytime between randomisation 2008 for the
are widely used in the management of patients prevention of
with ACS and those undergoing percutaneous catheterisation laboratory. Additionally, patients atherothrombotic
were treated with standard therapy, such as events in patients
with ACS managed
information on the pathogenesis of ACS and with PCI. Prasugrel
the medical management with drugs such as should be statins can be found on the cardiovascular
diagnosis. Patients with UA or NSTEMI were co-prescribed with
enrolled within 72 hours of symptoms starting.
In 2006, national audit data showed that over within 12 hours of onset of symptoms with a 73,000 PCI procedures were undertaken in the PCI planned, or within 14 days of receiving UK [4]. It is estimated that approximately half management of ACS [4]. Aspirin, clopidogrel discretion of the doctor. Exclusion criteria and glycoprotein IIb/IIIa inhibitors are the main included any thienopyridine (e.g. clopidogrel) within 5 days of randomisation, increased risk of bleeding and a history of pathological serious adverse effects of antiplatelet therapy [5]. Therefore, selecting patients suitable fortreatment with various antiplatelet agents is a major challenge, and the potential benefits cardiovascular (CV) death, non-fatal MI, or prasugrel patients and 12.1% of the clopidogrelgroup (intention-to-treat analysis, HR 0.81, Prasugrel is an oral pro-drug. Its active 95% CI 0.73–0.90, P<0.001, NNT=45). The metabolite, an adenosine diphosphate (ADP) difference was mainly due to a statistically receptor antagonist, works at the same site of significant decrease in non-fatal MI. The trial action as clopidogrel, binding irreversibly to platelets, inhibiting their activation and significant difference in CV or all-cause prasugrel plus aspirin for the treatment of ACS efficacy over clopidogrel was seen within the first three days. Stent thrombosis, a secondary end-point, was also significantly reduced with
prasugrel. See table on page 3 for detailed
Proposed indication and marketing
The manufacturer of prasugrel (Daiichi-
Sankyo/Lilly) submitted an application for
licensing to the European Medicines Agency The results of TRITON-TIMI 38 suggest that prasugrel is associated with an increase in indication of prevention of atherothrombotic major bleeding compared with clopidogrel [8].
Major bleeding not related to coronary-artery elevation MI (NSTEMI) managed with PCI, or STEMI managed with primary or delayed PCI.
(1.8%) of those on clopidogrel (HR 1.32, 95% aspirin. It is likely to be available as 10mg threatening bleeding occurred in 1.4% of the tablets, with a proposed loading dose of 60mg, clopidogrel (P=0.01). Five clopidogrel patients Prasugrel
Table. Results from TRITON-TIMI 38 [8]
Hazard ratio (95%
Number of patients (%)
Primary end-point: composite of CV
Non-fatal MI
All-cause mortality
Probable or definite stent
and 21 prasugrel recipients had fatal bleeding (P=0.002).
those without (1.4%, HR 0.86, 95% CI 0.76–0.98, P=0.02).
2.5% of the prasugrel group stopped treatment due to Post-hoc analyses indicate that there were sub-groups of bleeding vs. 1.4% of the clopidogrel patients (P<0.001).
patients who had a less favourable clinical benefit* from Serious adverse events not related to bleeding were similar prasugrel (*defined as the rate of death from any cause, in the prasugrel and clopidogrel patients (22.5% vs. 22.8%, non-fatal MI, non-fatal stroke or non-fatal major bleeding not related to CABG) [8]. Patients with a history of stroke ortransient ischaemic attack suffered net harm; whereas for Other efficacy and safety results from TRITON-TIMI 38
patients with a body weight of less than 60kg or aged 75 There are a number of further results from TRITON-TIMI 38 and over, there was no net clinical benefit. which could be described as hypothesis-generating. Someof these have come from sub-group analyses, which weknow should be treated with caution, as they can be Proposed cost/course and treatment alternatives
Approx. annual
A pre-specified sub-group analysis of patients with at least one coronary stent has been undertaken (n=12,844, 94% ofthe TRITON-TIMI 38 patients; 50.3% bare-metal stents Prasugrel
only, 44.7% drug-eluting stents only) [9]. 9.7% of theprasugrel patients reached the primary end-point vs. 11.9% Clopidogrel
of clopidogrel patients (HR 0.81, 95% CI 0.72–0.90, P=0.0001). Major bleeding (not related to CABG) was seenin more of the prasugrel patients but did not reach statistical * Personal communication, Daiichi-Sankyo/Lilly, May 2008 significance (2.4% vs. 1.9%, HR 1.27, 95% CI 0.99–1.63, A further pre-specified analysis has broken down ischaemicevents that are probably attributable to the loading dose Current drug usage
(from randomisation to day 3) and events related to In England in 2007, there were approximately 3.5 million maintenance dosing (from day 3 to the end of the trial) [10].
items of clopidogrel dispensed in primary care, at a cost of This suggested that both the prasugrel loading and about £148 million [11]. A proportion of this use will have maintenance doses were superior to loading and been for the management of ACS with PCI, but it is not maintenance doses of clopidogrel in reducing ischaemic known what proportion this represents.
events. With regard to the timing of major bleeding events,although there was no significant difference in major non- In 2006, approximately 36,000 PCI procedures were CABG-related bleeding during the first three days, from this carried out in the UK for the management of ACS [4]. If we point onwards until the end of the trial, prasugrel was assume that clopidogrel was used in all these procedures, associated with a significantly greater rate of bleeding the cost of one years use (assuming a loading dose of events than clopidogrel (HR 1.39, 95% CI 1.02–1.89, 300mg followed by 75mg/day for one year) would be over Patients with diabetes are known to be at higher baseline riskof having an atherothrombotic event. The groups in TRITON- Estimated NHS impact
TIMI 38 included 23% of patients with diabetes (n=3,146) [8].
In order to understand the possible place in therapy of Pre-specified sub-group analysis indicated that the absolute prasugrel, we need to consider the current place of benefit for prasugrel over clopidogrel was greater in patients clopidogrel. NICE recommends clopidogrel in combination with diabetes (absolute reduction in the primary end-point of with low-dose aspirin for up to 12 months in the 4.8%, HR 0.70, 95% CI 0.58–0.85, P<0.001) compared to management of NSTE-ACS in people who are at moderate Prasugrel
to high risk of MI or death [12]. The licence application for necessary [10]. The rapid onset of effect of prasugrel may prasugrel is for prevention of atherothrombotic events in enable clinicians to determine if the coronary anatomy is patients with ACS managed with PCI, so the results of suitable for PCI before committing to irreversible platelet currently published trials of prasugrel should not be extrapolated to other situations where clopidogrel is used.
The potential use of prasugrel in medically managed ACS TRITON-TIMI 38 used the standard, licensed dose of is only just starting to be investigated in the TRILOGY ACS clopidogrel. Although higher doses of clopidogrel have trial [Personal communication, Daiichi-Sankyo/Lilly, May been assessed, there is little outcome data from large studies [2,8]. Trials using new dosing regimens ofclopidogrel are currently recruiting or planned [16]. Other Theoretically, prasugrel may have some advantages over antiplatelet agents are also in development (e.g. IV clopidogrel. However, whether these translate into clinical cangrelor, oral ticagrelor) [17]. It remains to be seen if these benefits for patients is difficult to ascertain at the current will have a better risk:benefit ratio.
time. Preclinical studies indicate that prasugrel has a fasteronset of action than clopidogrel and leads to higher Although the absolute increased risk of fatal bleeding was inhibition of platelet aggregation [13,14]. Compared with small in TRITON-TIMI 38 (about 3 cases/1,000 patients), it standard doses of clopidogrel, prasugrel is said to be more is noteworthy because no previous trials of dual antiplatelet effectively metabolised to its active metabolite, leading to therapy in patients with coronary artery disease, or pooled less inter-patient variability [14]. It has been postulated that analyses, have found an increase in fatal bleeding [6]. It some patients have a variable response to clopidogrel due has been postulated that this finding may be due to the trial to genetic, metabolic or clinical factors [14]. including older patients and those with moderate renaldysfunction. However, patients at high risk of bleeding were PCI (with stenting where indicated) is generally excluded from the trial. Therefore, the potential risks may recommended in the management of moderate to high be greater in the real world. But, conversely, the benefits in risk patients with ACS [2]; aspirin plus clopidogrel is the clinical practice may be greater, especially in those at standard antiplatelet regimen that is used [15]. Based on higher baseline risk of ischaemic events (e.g. patients with the proposed licence indication, the manufacturer estimates that prasugrel may be suitable for use in up tohalf the PCIs performed in the UK i.e. the approximate In TRITON-TIMI 38, stent thrombosis was significantly 36,000 procedures a year performed for ACS [Personal reduced with prasugrel compared with clopidogrel. This is a communication, Daiichi-Sankyo/Lilly, May 2008]. The rare but recognised complication of PCI-with-stenting, acquisition cost could be about the same as clopidogrel, associated with high morbidity and mortality. In the TRITON- or up to 60% more (see Proposed Cost/Course and
TIMI 38 sub-group analysis of patients with at least one Treatment Alternatives). However, the possible impact
coronary stent, 89% of patients (186/210) with probable or of prasugrel may depend not only on the acquisition cost, definite stent thrombosis died or had an MI associated with but also on identification of those patients undergoing PCI for ACS for whom prasugrel may be appropriate,bearing in mind the possibility of increased efficacy but at From the data currently available, switching from the expense of an increased risk of bleeding.
clopidogrel to prasugrel use in PCI could have benefits interms of reduced ischaemic events and stent thrombosis, In TRITON-TIMI 38, coronary artery anatomy was defined but at the expense of an increased risk of bleeding. One before treatment, which is unlikely to happen in clinical way to reduce the risks associated with prasugrel use may practice. European guidelines recommend antiplatelet be to reserve it for patients at highest risk of ischaemic therapy immediately after the diagnosis has been made, events and/or those with documented stent thrombosis or a rather than waiting for the results of angiography, due to the previously poor response to clopidogrel. Clopidogrel may high risk of events in the early stages [2]. However, pre- be a safer choice in patients at a lower risk of ischaemic treating all patients with clopidogrel increases the risk of events but higher risk of bleeding [6,18,19].
perioperative bleeding if later CABG surgery proves Prasugrel
Points to consider in determining the place of prasugrel in the management of ACS with PCI
• TRITON-TIMI 38 demonstrated that, compared to clopidogrel plus aspirin, prasugrel plus aspirin was associated with an absolute reduction of 2.2% in a composite of CV death, non-fatal MI or non-fatal stroke (NNT 45). Thisdifference was magnified in patients with diabetes.
• The trial also suggests that prasugrel plus aspirin was associated with major, and in some cases fatal, bleeding, which continued to the end of the trial (NNH 167 for non-CABG-related major bleeding compared with clopidogrelplus aspirin).
• Based on TRITON-TIMI 38, for every 1,000 patients treated with prasugrel plus aspirin rather than clopidogrel plus aspirin for 14.5 months, 23 will have a primary cardiovascular end-point prevented but 6 will have a major bleed.
• In all patients with ACS, the risk of bleeding complications must be weighed against the potential benefit to be • Some risk factors for increased bleeding have been postulated, including previous cerebrovascular event. Currently we do not have enough information to indicate whether the drug may be contraindicated or its dosage modified incertain groups.
• Prasugrel plus aspirin did not demonstrate an overall mortality benefit over clopidogrel plus aspirin in TRITON-TIMI 38. However, the trial was not powered to show such a difference.
• The results of published trials of prasugrel should not be extrapolated to other situations where clopidogrel is References
England 2007. Available from URL: www.ic.nhs.uk/statistics-and-data- British Heart Foundation. Mortality statistics, updated 11/3/2008. Available from URL: collections/primary-care/prescriptions/prescription-cost-analysis-2007. Accessed on www.heartstats.org/topic.asp?id=17. Accessed on 28/5/2008 Bassand J-P on behalf of the Task Force for the diagnosis and treatment of non-ST- 12. NICE. Technology Appraisal 80. July 2004. Available from URL: segment elevation acute coronary syndromes of the European Society of Cardiology.
http://www.nice.org.uk/guidance/index.jsp?action=byID&o=11536. Accessed on Wiviott SD and Antman EM. Circulation 2004;109:3064–7 13. Brandt JT, Payne CD, Wiviott SD et al. Am Heart J 2007;153:66.e9–66.e16 Ludman PF. British Cardiovascular Intervention Society Audit Returns 2006.
14. Wallentin L, Varenhorst C, James S et al. Eur Heart J 2008;29:21–30 Available from URL: www.bcis.org.uk/resources/audit/audit_2006. Accessed on 15. Silber S on behalf of the Task Force for percutaneous coronary interventions of the European Society of Cardiology. Eur Heart J 2005;26:804–47 Bode C and Huber K. Eur Heart J 2008;10 (Suppl. A):A13–A20 16. US National Institutes of Health. Clopidogrel trials. Available from URL: Bhatt DL. N Engl J Med 2007;357:2078–81 http://clinicaltrials.gov/ct2/results?term=clopidogrel&recr=Open.
NICE. Acute coronary artery syndrome — prasugrel. Details available from URL: www.nice.org.uk/guidance/index.jsp?action=byID&o=12028. Accessed on 6/08/2008 17. Jakubowski JA, Winters KJ, Naganuma H et al. Cardiovascular Drug Reviews Wiviott SD, Braunwald E, McCabe CH et al. N Engl J Med 2007;357:2001–15 Wiviott SD, Braunwald E, McCabe CH et al. Lancet 2008;371:1353–63 18. Ajani AE and Lefkovits J. Lancet 2008;371:1315–6 10. Antman EM, Wiviott SD, Murphy SA et al. J Am Coll Cardiol 2008;51:2028–33 19. Hankey GJ, Eikelboom JW, Langton PE. MJA 2008;188:381–2 11. The Information Centre for health and social care. Prescription Cost Analysis: Monographs for unlicensed medicines / indications must not be circulated to prescribers. Not to be used for commercial purposes.
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