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On the horizon
Concise evaluated information to alert NHS Managers and Budget Holders to future drug technologies.
Confidential for planning purposes only.
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.
• 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 . Acute coronary
syndrome (ACS) relates to a spectrum ofdisorders including acute myocardial infarction(MI) and unstable angina (UA). Despite
A phase III randomised, double-blind trial of
admission rates for patients with ACS remain
prasugrel has been published . TRITON-TIMI
high . 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-
ST-segment-elevation ACS (NSTE-ACS) it is
randomised to either prasugrel (60mg loading
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 .
Therefore, drugs which inhibit platelet function
dose was given anytime between randomisation
2008 for the
are widely used in the management of patients
with ACS and those undergoing percutaneous
catheterisation laboratory. Additionally, patients
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
statins can be found on the cardiovascular
diagnosis. Patients with UA or NSTEMI were
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 . It is estimated that approximately half
management of ACS . 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
. 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 .
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
Table. Results from TRITON-TIMI 38 
Number of patients
composite of CV
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) . 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
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
only, 44.7% drug-eluting stents only) . 9.7% of theprasugrel patients reached the primary end-point vs. 11.9%
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) .
items of clopidogrel dispensed in primary care, at a cost of
This suggested that both the prasugrel loading and
about £148 million . 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 . 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) .
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
to high risk of MI or death . The licence application for
necessary . 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 . 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) . 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 . It has been postulated that
analyses, have found an increase in fatal bleeding . 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 .
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 ; aspirin plus clopidogrel is the
clinical practice may be greater, especially in those at
standard antiplatelet regimen that is used . 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
). 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 . 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
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
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
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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