Bivalirudin For The Treatment of ST

Bivalirudin for the treatment of ST
ST-segment-ele
segment-elevation
vation m
myyocardial infarction
Technology appraisal guidance
Published: 27 July 2011
nice.org.uk/guidance/ta230
NICE 2011. All rights reserved.
Myocardial infarction (persistent ST-segment elevation) - bivalirudin (TA230)
Contents
1 Guidance ..........................................................................................................................................................................
2 The technology .............................................................................................................................................................
3 The manufacturer's submission..............................................................................................................................
Clinical effectiveness....................................................................................................................................................................
Cost effectiveness .........................................................................................................................................................................
Evidence Review Group comments ........................................................................................................................................
4 Consideration of the evidence ................................................................................................................................ 12

Clinical effectiveness.................................................................................................................................................................... 12
Cost effectiveness ......................................................................................................................................................................... 14
Summary of Appraisal Committee's key conclusions ...................................................................................................... 17
5 Implementation............................................................................................................................................................. 21
6 Related NICE guidance............................................................................................................................................... 22
Published ........................................................................................................................................................................................... 22
Under development ...................................................................................................................................................................... 22
7 Review of guidance ...................................................................................................................................................... 23

Appendix A: Appraisal Committee members, and NICE project team ....................................................... 24
A Appraisal Committee members ........................................................................................................................................... 24
B NICE project team ..................................................................................................................................................................... 25
Appendix B: Sources of evidence considered by the Committee ................................................................. 26

About this guidance......................................................................................................................................................... 29
Page 2 of 30
Guidance
1.1
Bivalirudin in combination with aspirin and clopidogrel is recommended for the

treatment of adults with ST-segment-elevation myocardial infarction
undergoing primary percutaneous coronary intervention.
Page 3 of 30
The technology
2.1
Bivalirudin (Angiox, The Medicines Company) has a marketing authorisation 'as

an anticoagulant in adult patients undergoing percutaneous coronary
intervention (PCI), including patients with ST-segment-elevation myocardial
infarction (STEMI) undergoing primary PCI'. This indication is an extension of
the original indication and was approved in November 2009. The summary of
product characteristics (SPC) states that bivalirudin should be administered
with aspirin and clopidogrel.
2.2
According to the SPC, a very common adverse event associated with bivalirudin
treatment is bleeding, which can occur anywhere in the body. Common adverse
events are thrombosis (blood clots) and bleeding and bruising at the puncture
site (after PCI). Uncommon adverse events are allergic reactions such as hives
(nettle rash), itching all over the body and tightness of the chest. For full details
of side effects and contraindications, see the SPC.
2.3
Bivalirudin is administered by injection or infusion. It is available in vials

containing 250 mg powder for reconstitution and dilution before injection or
infusion. The recommended dose of bivalirudin for patients undergoing PCI is an
intravenous bolus of 0.75 mg/kg body weight followed immediately by an
intravenous infusion at a rate of 1.75 mg/kg body weight/hour for at least the
duration of the procedure. The infusion may be continued for up to 4 hours after
PCI according to clinical need. After cessation of the infusion at 1.75 mg/kg/
hour, a reduced dose infusion of 0.25 mg/kg/hour may be continued for
412 hours as clinically necessary. Assuming one 250 mg vial is used per patient,
the acquisition cost of treatment with bivalirudin is 310.00 (British national
formulary [BNF] edition 61]), excluding VAT. Costs may vary in different settings
because of negotiated procurement discounts.
Page 4 of 30
The manufacturer's submission
The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of

bivalirudin and a review of this submission by the Evidence Review Group (ERG; appendix B).
3.1
The manufacturer's decision problem compared bivalirudin in combination with

aspirin and clopidogrel against a strategy of heparin with glycoprotein inhibitor
in combination with aspirin and clopidogrel. The population was adults with STsegment-elevation myocardial infarction intended for primary PCI.
Clinical effectiveness
3.2
The main evidence for the clinical effectiveness of bivalirudin was from one
prospective, dual-arm, single-blind, randomised multicentre study. The
HORIZONS-AMI trial recruited 3602 patients with STEMI intended for a
primary PCI and compared a strategy of bivalirudin with one using heparin plus
glycoprotein IIb/IIIa inhibitors. Both treatment arms received aspirin and
clopidogrel. The trial is ongoing and has at least 3 years of follow-up data
available at this time.
3.3
Patients in the bivalirudin treatment group (n = 1800) received a 0.75 mg/kg

intravenous bolus of bivalirudin followed by a 1.75 mg/kg/hour infusion that
was continued uninterrupted until at least the end of the PCI. An optional postprocedural dose of 0.25 mg/kg/hour was recommended for up to 4 hours after
the procedure; 6% (105/1749) of patients received this. A median of one vial
(mean = 1.23 vials) of bivalirudin was used per patient (non-integer numbers of
bivalirudin and glycoprotein IIb/IIIa inhibitor vials were increased to the next
integer to cover wastage at patient level). Patients in the heparin with
glycoprotein IIb/IIIa inhibitor treatment group (n = 1802) received 60 IU/kg
heparin as recommended by the European Society of Cardiology guidelines for
the management of patients with STEMI undergoing primary PCI. A
glycoprotein IIb/IIIa inhibitor (either eptifibatide or abciximab) was given in
accordance with its summary of product characteristics.
3.4
The ages of the patients were similar across the treatment groups, with slightly
more older patients in the heparin with glycoprotein IIb/IIIa inhibitor group. The
mean patient age was 61 years in both treatment groups. Slightly more than
75% of patients were men and more than 90% were white. The study was
Page 5 of 30
conducted at 123 sites in 11 countries; 57% of patients were enrolled in Europe

and approximately 3% in the UK. Of the recruited population, 19 left the study
because they withdrew consent and 28 were lost to follow-up.
3.5
There were two primary outcomes: a composite of major adverse

cardiovascular events and major bleeding. Secondary outcomes were the
components of major adverse cardiovascular events: death (all-cause mortality
and cardiac mortality), reinfarction, target vessel revascularisation for
ischaemia, and stroke. The rate of stent thrombosis was also assessed. Analyses
were conducted on the intention-to-treat population and outcomes were
presented for 30 days and for 1 year after PCI.
3.6
For the primary outcome of major adverse cardiovascular events, bivalirudin

was not inferior to heparin plus glycoprotein IIb/IIIa inhibitor at 30 days and 1
year. In both treatment groups around 5.5% of patients had a major adverse
cardiovascular event after 30 days and about 12% after 1 year. For the primary
outcome of major bleeding, there was a statistically significant difference
(p 0.0001) between the treatment groups at 30 days and at 1 year. At 30 days,
major bleeding occurred in 5.1% of patients in the bivalirudin group and 8.8% of
patients in the heparin plus glycoprotein IIb/IIIa inhibitor (comparator) group
(p < 0.0001). At 1 year, major bleeding occurred in 5.8% of patients in the
bivalirudin group and 9.2% of patients in the comparator group (p < 0.0001).
3.7
For the secondary outcomes of all-cause mortality and cardiac mortality, there
were statistically significant differences between treatment with bivalirudin
and treatment with heparin plus glycoprotein IIb/IIIa inhibitor. After 1 year of
follow-up, all-cause mortality was 3.5% in the bivalirudin group and 4.8% in the
comparator group (p = 0.037). The 1-year results for cardiac mortality were
2.1% for bivalirudin and 3.8% for comparator (p = 0.005). For the intention-totreat population, 3-year all-cause mortality was significantly lower (p = 0.03) for
bivalirudin (5.9%) than for the comparator (7.7%).
3.8
The proportion of patients who experienced a reinfarction was similar between

the treatment groups, as was the proportion experiencing a stroke, and the
differences were non-significant. A slightly higher percentage of patients in the
bivalirudin group had a target vessel revascularisation than in the heparin plus
glycoprotein IIb/IIIa inhibitor group (7.2% compared with 5.9% at 1 year), but
this difference was not statistically significant.
Page 6 of 30
3.9
The overall rate of any stent thrombosis at 30 days and at 1 year was identical in
the bivalirudin and the heparin plus glycoprotein IIb/IIIa inhibitor groups.
However, more stent thrombosis events occurred in the bivalirudin group
within the first 24 hours of PCI.
3.10
Investigators reported comparable rates of adverse events between the

treatment groups, with a trend towards fewer events in the bivalirudin group
and significantly reduced rates of drug-related adverse events (p < 0.0001).
Significantly fewer thrombocytopenia events occurred in the bivalirudin group
(1.4%) than in the heparin plus glycoprotein IIb/IIIa inhibitor group (3.9%;
p < 0.0001).
3.11
Subgroup analyses were presented for all-cause mortality and for major
bleeding. For all-cause mortality, the results for bivalirudin were more
favourable for most subgroups that were analysed, but differences were not
statistically significant. Treatment with bivalirudin was associated with fewer
incidents of major bleeding than treatment with heparin plus glycoprotein IIb/
IIIa inhibitor.
3.12
In the HORIZONS-AMI trial, radial arterial access was used for 5.9% (214/3597)
of patients overall, whereas brachial or femoral access was used for most
patients. In clinical practice in England and Wales a higher level of radial access
is expected. Because of the small numbers of patients undergoing a primary PCI
with radial arterial access, the manufacturer was not able to carry out a
statistically meaningful direct comparison of radial arterial access and other
routes of access. Bivalirudin was associated with a statistically significant
reduction in non-access site (organ) bleeding, with a relative risk of 0.684 (95%
confidence interval 0.507 to 0.922) compared with heparin plus glycoprotein
IIb/IIIa inhibitor.
Cost effectiveness
3.13
The manufacturer submitted an economic analysis that employed an economic

model based primarily on the analysis of patient-level data from the
HORIZONS-AMI trial. The model has two parts. The first part is a decision-tree
structure that covers the initial reperfusion to the end of a specified follow-up
period (1 year in the base case). The tree splits into branches to allow for
different events to occur: no relevant complications; minor bleed; major bleed;
Page 7 of 30
ischaemic stroke; myocardial infarction; repeat revascularisation; or death. The

tree is coupled with a two-state (alive/dead) Markov model to account for
subsequent survival over a 39-year horizon using an annual cycle length.
3.14
The model is primarily affected by the differences in all-cause mortality

between the two treatments observed in the HORIZONS-AMI trial.
3.15
Absolute and relative clinical event risks and most resource use parameters
were derived from the raw data of the HORIZONS-AMI intention-to-treat
population. The relative risks of treatment with bivalirudin compared with
heparin plus a glycoprotein IIb/IIIa inhibitor for major bleed, minor bleed,
ischaemic stroke, repeat myocardial infarction, repeat revascularisation and
death were 0.643, 0.536, 1.057, 0.817, 1.124 and 0.710, respectively. Average
life expectancy assumed in the model was 11.26 years. Radial access use of
42.5% was assumed.
3.16
Costs of bivalirudin treatment were based on the costs of initial angiography,

initial revascularisation and hospital care, anticoagulant medications,
management of treatment-related adverse events and long-term follow-up.
Unit costs for interventional procedures and associated treatment costs were
based on NHS reference costs. Medication usage was based on usage in the
HORIZONS-AMI trial. Treatment with the most expensive glycoprotein IIb/IIIa
inhibitor (abciximab) was assumed in more than 70% of cases in which
glycoprotein IIb/IIIa inhibitor was administered. The cost of heparin treatment
was considered insignificant and was omitted from the model. The treatment
cost per patient with bivalirudin was 412 compared with 573 for heparin plus
glycoprotein IIb/IIIa inhibitor.
3.17
Two utility values were used in the model for the period after the initial STEMI
event: a value of 0.683 was applied in the first year only and 0.718 was applied
for each subsequent year of life. The utility values were obtained from a review
of the literature. Costs and health outcomes were discounted at 3.5%.
3.18
In the base-case analysis the bivalirudin strategy dominated the heparin plus
glycoprotein IIb/IIIa inhibitor strategy because it was cheaper and more
effective, with total costs of 12,843 and 13,110, and total QALYs of 6.256 and
6.166, respectively. The manufacturer's deterministic sensitivity analysis
showed that the results of the model were robust to a number of parameters,
Page 8 of 30
including changes in the relative risks of death and major bleed in the bivalirudin
strategy, life expectancy, and type of glycoprotein IIb/IIIa inhibitor used.
3.19
Probabilistic sensitivity analysis presented for the base-case 1-year analysis

showed that the bivalirudin strategy was dominant (that is, it was cost-saving
and showed a QALY gain) in 9924 (99.2%) of 10,000 ICER results at the 20,000
per QALY threshold.
3.20
When the manufacturer presented an 'extreme case scenario' combining several

unfavourable assumptions (only eptifibatide but no abciximab use; 100% radial
arterial access; no difference in length of initial hospital stay), the ICER was
4106 per QALY gained (with a difference in cost of 367 and a difference in
QALYs of 0.089). In all other scenarios, the bivalirudin strategy remained
dominant.
Evidence Review Group comments

3.21
The ERG noted that there is a lack of comparison of bivalirudin with heparin
alone, but the use of heparin alone is not common UK practice. The ERG
considered that the manufacturer's submission provided a thorough account of
the only available RCT.
3.22
The ERG noted that the RCT reported data on the licensed dose of bivalirudin in
patients undergoing PCI for STEMI. The RCT differed from standard UK
practice in that pre-procedural heparin was used for most patients. Within the
bivalirudin group, patients treated with pre-procedural heparin had a lower rate
of major adverse cardiovascular events than those who did not receive
pre-procedural heparin. This pattern was not seen in the comparator group.
However, there was no significant interaction between treatment group and
pre-procedural heparin (p = 0.1060). The ERG noted that it is unclear how the
RCT results would be reflected in practice, given the lack of pre-procedural
heparin in standard UK practice. The RCT also differed from standard UK
practice in using predominantly femoral rather than radial arterial access. The
ERG thought that because access site bleeding is less common with radial than
femoral arterial access, the benefit seen in reduced bleeding from bivalirudin is
likely to be lower in practice than in the RCT.
Page 9 of 30
3.23
Overall the ERG considered that the model structure employed by the
manufacturer addresses the scope of the decision problem. The choice of
intervention and comparator was appropriate. The ERG noted that the model
applies the same relative risk of events with bivalirudin treatment to all patients
in the bivalirudin group, regardless of whether they had undergone a primary
PCI. However, this assumption did not alter the conclusions from the model.
3.24
The ERG noted that the decision tree part of the model treats clinical events as
being mutually exclusive, although in reality they are not. For example, some
patients could experience both a bleed and a stroke during the initial period
after STEMI. The ERG noted that the same utility values are applied to both
treatment strategies, such that any difference in health-related quality of life in
the model is driven by differences in survival between the treatment groups.
Utility decrements arising from complications following reperfusion were not
included in the base-case analysis. However, the ERG noted that only negative
health effects associated with repeat revascularisation would have an
unfavourable impact on the cost effectiveness of bivalirudin.
3.25
The ERG identified some minor issues and discrepancies on costs in the model,
but none of these had any significant impact on the results of the model.
3.26
The ERG was satisfied that the results of the manufacturer's model, which
suggest that a bivalirudin-based intervention dominates heparin plus
glycoprotein IIb/IIIa inhibitor, were robust to sensitivity analyses. Bivalirudin
remained dominant across most sensitivity analyses and in cases in which it was
more effective and more expensive than heparin plus glycoprotein IIb/IIIa
inhibitor, the ICER for bivalirudin remained below 5000 per QALY gained.
3.27
The ERG conducted exploratory analyses to check that the manufacturer's

model was robust. This included sensitivity analysis concerning the long-term
Markov model to assess the impact of uncertainty around longer-term
outcomes for patients after reperfusion. In this analysis the ERG found that the
structure of the manufacturer's model and the use of a Markov component
means that provided use of bivalirudin is associated with an improved survival
rate and lower cost at 1 year, it will always dominate heparin plus glycoprotein
IIb/IIIa inhibitor over longer time horizons.
3.28
The ERG investigated the following two issues:
Page 10 of 30
the impact of assuming 2 vials of bivalirudin per patient instead of 1.23

the impact of using prasugrel in the comparator group rather than clopidogrel.
3.29
The ERG found that when the assumption of mean vial use was changed from
1.23 vials to 2 vials per patient, bivalirudin remained the dominant strategy.
3.30
The ERG stated that for investigating the impact of using prasugrel in the
comparator arm rather than clopidogrel, there are no data directly comparing
bivalirudin plus clopidogrel, with heparin plus glycoprotein IIb/IIIa inhibitor plus
prasugrel. The ERG also found that there is a lack of data for treatment with
heparin plus glycoprotein IIb/IIIa inhibitor plus prasugrel. There are two
ongoing trials of bivalirudin plus prasugrel. The first is comparing bivalirudin
plus prasugrel with clopidogrel plus heparin plus abciximab. The second trial is
comparing bivalirudin plus prasugrel with clopidogrel plus heparin.
3.31
The ERG referred to details contained within the manufacturer's submission for
NICE technology appraisal 182 on prasugrel for the treatment of acute
coronary syndromes with PCI, which showed that prasugrel results in an
additional per patient drug cost of 162 compared with clopidogrel. Costs of
hospitalisation in each group were estimated to be similar. The ERG found that if
this cost difference was applied to the heparin plus glycoprotein IIb/IIIa
inhibitor group in the model, bivalirudin (given with clopidogrel) would remain
cost-saving. However, evidence relating to the relative impact of bivalirudin plus
clopidogrel versus prasugrel plus heparin and glycoprotein IIb/IIIa inhibitor is
not available.
3.32
Full details of all the evidence are in the manufacturer's submission and the ERG
report, which are available from www.nice.org.uk/guidance/TA230
Page 11 of 30
Consider
Consideration
ation of the e
evidence
vidence
4.1
The Appraisal Committee reviewed the data available on the clinical and cost
effectiveness of bivalirudin, having considered evidence on the nature of STsegment-elevation myocardial infarction (STEMI) and primary percutaneous
coronary intervention (PCI) and the value placed on the benefits of bivalirudin
by people with the condition, those who represent them, and clinical specialists.
It also took into account the effective use of NHS resources.
4.2
The Committee considered the nature of the condition, and noted evidence
submitted and presented by the patient experts and clinical specialists on the
clinical signs and symptoms associated with STEMI. The Committee heard that
bivalirudin is already in use in the UK and that both patients and clinicians are in
favour of its continued use. It was noted that bivalirudin is easier to use than
abciximab because the solution is easier to prepare and administer. The patient
expert stressed the importance of reducing major bleeding, which was thought
to be an important benefit of bivalirudin. Compared with anticoagulants,
bivalirudin may require less monitoring and therefore be more convenient for
patients.
Clinical effectiveness
4.3
The Committee discussed the evidence for the clinical effectiveness of

bivalirudin in combination with aspirin and clopidogrel. It agreed that the results
of the single but large HORIZONS-AMI trial (both the primary outcome of major
bleeding, and the secondary outcomes of all-cause mortality and cardiac
mortality) showed statistically significant advantages for treatment with
bivalirudin over treatment with heparin plus glycoprotein IIb/IIIa inhibitor. In
particular it noted that all-cause mortality was 1.3% and 1.8% lower in the
bivalirudin group than in the comparator group after 1 and 3 years of follow-up,
respectively.
4.4
The Committee discussed whether similar outcomes to those in the

HORIZONS-AMI trial can be expected for patients seen in UK clinical practice.
The Committee heard from the clinical specialists that the trial had some
limitations: it only compared bivalirudin with heparin and glycoprotein IIb/IIIa
inhibitors, not with heparin alone; in the UK, more people have PCI via the radial
Page 12 of 30
access site than in the trial; and a substantial proportion of the trial population
received pre-procedural heparin, which is not standard UK practice.
4.5
The Committee heard how the use of the radial access site rather than femoral
access reduces the incidence of access site bleeding. Radial access is more
common in UK practice than in the trial, and hence this could reduce the benefit
of reduced access site bleeding with bivalirudin shown in the trial. However, in
the trial bivalirudin was also shown to reduce bleeding not related to the access
site
in comparison with glycoprotein IIb/IIIa inhibitor plus heparin. The Committee
accepted that similar outcomes for bleeding not
related to access site could be expected in UK clinical practice as in the trial.
4.6
The Committee discussed the omission of a comparison against heparin alone in

the manufacturer's submission. The clinical specialists stated that there is a
question around the necessity to include a glycoprotein IIb/IIIa inhibitor with
heparin, because there is some evidence to support the use of heparin alone
from the BRAVE-3 study. However, the clinical specialists stated that clinicians
still feel that this question is largely unanswered. Treatment with heparin alone
is not standard practice in the UK. The Committee was satisfied that it was not
necessary to compare bivalirudin against treatment with heparin alone.
4.7
The Committee discussed the use of bivalirudin in combination with aspirin and
prasugrel as opposed to aspirin and clopidogrel. The clinical experts stated a
prasugrel/bivalirudin combination was likely to be better than a clopidogrel/
bivalirudin combination because prasugrel reduces stent thrombosis. This was
considered particularly important because the bivalirudin group in the trial had
a higher incidence of stent thrombosis within the first 24 hours of PCI than the
comparator group. The manufacturer, however, explained that when the trials
for bivalirudin were designed, and at the time of the first licence application for
bivalirudin, prasugrel had not received a marketing authorisation. For this
reason, bivalirudin has only been studied with aspirin and clopidogrel, and
therefore the marketing authorisation is specifically in combination with these
two drugs. The Committee was satisfied that treatment with bivalirudin in
combination with aspirin and prasugrel is outside the marketing authorisation
for bivalirudin and therefore beyond the remit of this appraisal.
Page 13 of 30
4.8
The Committee explored the reasons why in the bivalirudin group, the rates of
major adverse cardiovascular events and stent thrombosis were lower in
patients treated with pre-procedural heparin. The clinical specialists explained
that it is hard to understand clinically why taking pre-procedural heparin would
reduce the rate of major adverse cardiovascular events. They suggested that the
population who received pre-procedural heparin may be different from those
who did not, and it is this difference that may have affected the rate of major
adverse cardiovascular events. The Committee heard from the ERG that there
was no interaction between pre-procedural heparin and the major adverse
cardiovascular events outcome. The clinical specialists also explained that it is
not common practice in the UK to administer pre-procedural heparin, and
anecdotally this has not reduced the effectiveness of bivalirudin in clinical
practice. The Committee was satisfied that differences in the use of preprocedural heparin between the trial and UK clinical practice would not
significantly alter the favourable outcomes for bivalirudin.
4.9
The Committee considered whether there were any subgroups of patients who
would be expected to benefit from treatment with bivalirudin more than other
groups. It heard from the clinical specialists that theoretically it might be
possible to reserve bivalirudin for those who are at the greatest risk of bleeding,
but that in reality the same patients would be at a high risk of other symptoms
and may not be a discrete subgroup for the purposes of targeting treatment.
The Committee was persuaded that no subgroups could be selected on the basis
of the greatest potential to benefit from bivalirudin.
4.10
The Committee also considered other limitations of the trial. It noted that there
was only a single trial and that it was an open-label design with some risk of bias,
but agreed that the results suggested an advantage for bivalirudin. The
Committee concluded that there was sufficient evidence to demonstrate that
bivalirudin was more clinically effective than glycoprotein IIb/IIIa inhibitor plus
heparin, leading to lower rates of major bleeds and mortality.
Cost effectiveness
4.11
The Committee discussed the manufacturer's economic model in which the

main factor affecting cost effectiveness is the reduced mortality risk with
bivalirudin treatment compared with treatment with glycoprotein IIb/IIIa
inhibitor plus heparin. It noted that in the base case, treatment with bivalirudin
Page 14 of 30
was both more effective and less expensive than treatment with a glycoprotein
IIb/IIIa inhibitor plus heparin. This finding appeared robust in the face of both
deterministic and probabilistic sensitivity analyses.
4.12
The Committee discussed the robustness of the manufacturer's model. First the
Committee discussed the two-stage structure of the model: an initial stage, in
which clinical events could occur, followed by a stage representing the rest of
the lifetime. The manufacturer presented one model in which the first stage is
1 year, and another model in which the first stage is 3 years. The Committee was
satisfied that the results from the 3-year model were consistent with those from
the 1-year model. Second, it questioned the appropriateness of mutually
exclusive events within the first stage of the model and suggested that this was
an oversimplification. The manufacturer explained that there were no common
combinations of events which could have been modelled. The Committee noted
that the ERG's rebuilding of the model found no discrepancies. The Committee
was satisfied with the approach taken by the manufacturer in its model design.
4.13
The Committee then discussed key input assumptions used in the model,
concerning firstly vial use and, secondly, choice of glycoprotein IIb/IIIa inhibitor
in the comparator group, and thirdly radial arterial access. With regards to vial
use, it heard from the clinical specialists that treatment with bivalirudin would
take place at the time of PCI, and that usually not more than one vial would be
used. The mean use of 1.23 vials from the trial was used for calculating cost of
treatment. The Committee questioned whether vials could be split and heard
from the clinical specialists that if more than 1 vial were needed, a second vial
would be used and any extra discarded. Sensitivity analysis was conducted by
the ERG on the effect of including 2 vials instead of 1.23 vials in the model, but
did not lead to any changes in the results. The Committee was satisfied with the
way that vial use was incorporated into the economic model.
4.14
The Committee considered the assumptions around the choice of glycoprotein

IIb/IIIa inhibitor used in the manufacturer's model. It noted that abciximab,
which is the most costly glycoprotein IIb/IIIa inhibitor, was assumed to be used
in 73% of people, tirofiban in 19% and eptifibatide, which is the least costly
glycoprotein IIb/IIIa inhibitor, in only 8.1%. The Committee heard from the
clinical specialists that this was largely because abciximab has been the
favoured glycoprotein IIb/IIIa inhibitor for many years, and some clinicians are
so familiar with its use that they are reluctant to change to eptifibatide or
Page 15 of 30
tirofiban. The Committee noted that 100% use of eptifibatide in the

manufacturer's sensitivity analysis had a small impact on the ICER, with the
ICER for bivalirudin rising to 1764 per QALY gained. The Committee accepted
that 100% eptifibatide use was an extreme position and was satisfied that the
high usage of abciximab in the model had a limited impact on the cost
effectiveness of bivalirudin.
4.15
The Committee considered the assumptions around radial arterial access site in
the model. In the base-case analysis, radial arterial access was assumed in 42.5%
of cases, in line with UK practice. A sensitivity analysis from the manufacturer
which increased the usage to 100% led to no changes in the results, with
bivalirudin remaining the dominant treatment option. The Committee was
satisfied that the model results were robust to changes in
access site.
4.16
The Committee discussed the results of the combined sensitivity analysis, in

which 100% eptifibatide use had been combined with the assumptions of 100%
radial arterial access and equal length of hospital stay in those treated with
bivalirudin and those treated with glycoprotein IIb/IIIa inhibitors. In this
analysis, which was considered by the manufacturer to be the most
unfavourable scenario for bivalirudin, the ICER increased to 4106 per QALY
gained. The Committee accepted that this unfavourable position was clinically
unrealistic, but noted that the ICER produced with this analysis was still well
within the range normally considered to be a cost-effective use of NHS
resources.
4.17
The Committee concluded the discussion by noting the robustness of the

manufacturer's base case, in which treatment with bivalirudin dominated
treatment with a glycoprotein IIb/IIIa inhibitor plus heparin (that is, was less
costly and more effective) and that the results of the model are robust to the
various sensitivity analyses. The Committee concluded that the model is
associated with a very low degree of decision uncertainty and that bivalirudin
should be recommended for the treatment of adults with STEMI undergoing
PCI.
4.18
No equalities issues were raised at any point in the appraisal.
Page 16 of 30
Summary of Appraisal Committee's key conclusions

TA230
Appraisal title: Bivalirudin for the treatment of ST-segmentelevation myocardial infarction
Section
Key conclusion
Bivalirudin in combination with aspirin and clopidogrel is recommended for the
treatment of adults with ST-segment-elevation myocardial infarction (STEMI)
undergoing primary percutaneous coronary intervention (PCI).
1.1
Current pr
practice
actice
Clinical need of
patients, including
the availability of
alternative
treatments
Bivalirudin is already in use in the UK and both patients and

4.2
clinicians are in favour of its continued use. Bivalirudin is easier
to use than abciximab (a glycoprotein IIb/IIIa inhibitor)
because the solution is easier to prepare and administer. The
patient expert stressed the importance of reducing major
bleeding, which was thought to be an important benefit of
bivalirudin. Compared with anticoagulants, bivalirudin may
require less monitoring and therefore be more convenient for
patients.
The technology
Proposed benefits of The primary outcome of major bleeding and the secondary
the technology
outcomes of all-cause mortality and cardiac mortality showed
statistically significant advantages for treatment with
How innovative is
the technology in its bivalirudin over treatment with heparin plus glycoprotein IIb/
potential to make a IIIa inhibitor. In particular, all-cause mortality was 1.3% and
1.8% lower in the bivalirudin group than in the comparator
significant and
substantial impact
on health-related
benefits?
group after 1 and 3 years of follow-up, respectively.
What is the position

of the treatment in
the pathway of care
for the condition?
Bivalirudin is used as an anticoagulant in adult patients with

STEMI undergoing primary PCI.
4.3
2.1
Page 17 of 30
Adverse effects
The bivalirudin group had a higher incidence of stent

thrombosis within the first 24 hours of PCI than the
comparator group
4.7
Evidence for clinical effectiv

effectiveness
eness
Availability, nature
and quality of
evidence
A single trial (HORIZONS-AMI) formed the evidence base. It

4.10
was an open-label trial with some risk of bias. However, the
Committee concluded that there was sufficient evidence to
demonstrate that bivalirudin was more clinically effective than
glycoprotein IIb/IIIa inhibitor plus heparin.
Relevance to
general clinical
practice in the NHS
In the UK, more people have PCI via the radial access site than
in the trial. The use of the radial access site, compared with
femoral access, reduces the incidence of access site bleeding.
Hence the reduced access site bleeding observed with
bivalirudin in the trial may be attenuated in UK practice. The
Committee accepted that similar rates of non-access site
bleeding could be expected in UK clinical practice as in the
trial.
4.4
4.5
4.8
In the trial a substantial number of patients were treated with

pre-procedural heparin but this is not common practice in the
UK. The Committee was satisfied that differences in the use of
pre-procedural heparin between the trial and UK clinical
practice would not significantly alter the favourable outcomes
for bivalirudin.
Uncertainties
generated by the
evidence
The Committee discussed the use of bivalirudin in combination 4.7

with aspirin and prasugrel as opposed to aspirin and
clopidogrel. It was satisfied that this treatment combination is
outside the marketing authorisation for bivalirudin and
therefore beyond the remit of this appraisal.
Are there any

The Committee was persuaded that no subgroups could be
clinically relevant
selected on the basis of the greatest potential to benefit from
subgroups for which bivalirudin.
there is evidence of
differential
effectiveness?
4.9
Page 18 of 30
Estimate of the size

of the clinical
effectiveness
including strength of
supporting evidence
The primary outcome of major bleeding and the secondary

outcomes of all-cause mortality and cardiac mortality showed
statistically significant advantages for treatment with
bivalirudin over treatment with heparin plus glycoprotein IIb/
IIIa inhibitor. In particular, all-cause mortality was 1.3% and
1.8% lower in the bivalirudin group than in the comparator
group after 1 and 3 years of follow-up, respectively.
4.3
Evidence for cost effectiv

effectiveness
eness
Availability and
nature of evidence
The manufacturer submitted an economic analysis that

employed an economic model based primarily on the analysis
of patient-level data from the HORIZONS-AMI trial.
3.13
Uncertainties
The Committee considered that the results from the model
4.17
around and
plausibility of
assumptions and
inputs in the
economic model
were associated with a very low degree of decision

uncertainty.
Incorporation of
health-related
quality-of-life
benefits and utility
values
There were no issues raised about health-related quality-oflife values that were thought to be relevant. No health-related
benefits were identified that were not included in the
economic model.
Have any potential

significant and
substantial healthrelated benefits
been identified that
were not included in
the economic model,
and how have they
been considered?
Page 19 of 30
Are there specific

groups of people for
whom the
technology is
particularly cost
effective?
The Committee was persuaded that no subgroups could be

selected on the basis of the greatest potential to benefit from
bivalirudin.
4.9
What are the key

drivers of cost
effectiveness?
The main factor affecting cost effectiveness in the model is the 4.11
reduced mortality risk with bivalirudin treatment compared
with treatment with glycoprotein IIb/IIIa inhibitor plus
heparin.
Most likely costeffectiveness

estimate (given as an
ICER)
In the base case, treatment with bivalirudin dominated the

comparator in that it was both more effective and less
expensive than treatment with a glycoprotein IIb/IIIa inhibitor
plus heparin.
4.17
Additional factors tak

taken
en into account
Patient access
schemes (PPRS)
No patient access schemes were submitted.
End-of-life
considerations
End-of-life considerations were not discussed.
Equalities
considerations and
social value
judgements
No equalities issues were raised at any point in the appraisal.
4.18
Page 20 of 30
Implementation
5.1
The Secretary of State and the Welsh Assembly Minister for Health and Social
Services have issued directions to the NHS in England and Wales on
implementing NICE technology appraisal guidance. When a NICE technology
appraisal recommends use of a drug or treatment, or other technology, the NHS
must usually provide funding and resources for it within 3 months of the
guidance being published. If the Department of Health issues a variation to the
3-month funding direction, details will be available on the NICE website. When
there is no NICE technology appraisal guidance on a drug, treatment or other
technology, decisions on funding should be made locally.
5.2
NICE has developed tools to help organisations put this guidance into practice
(listed below). These are available on our website (www.nice.org.uk/guidance/
TA230).
Costing template and report to estimate the national and local savings and costs
associated with implementation.
Audit support for monitoring local practice.
Page 21 of 30
Related NICE guidance
Published
Off-pump coronary artery bypass. NICE interventional procedure guidance 377 (2011).
Available from www.nice.org.uk/guidance/IPG377
Unstable angina and NSTEMI. NICE clinical guideline 94 (2010). Available from
www.nice.org.uk/guidance/CG94
Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary
intervention. NICE technology appraisal guidance 182 (2009). Available from
www.nice.org.uk/guidance/TA182
Drug-eluting stents for the treatment of coronary artery disease. NICE technology appraisal
guidance 152 (2008). Available from www.nice.org.uk/guidance/TA152
MI: secondary prevention. NICE clinical guideline 48 (2007). Available from www.nice.org.uk/
guidance/CG48
Balloon angioplasty with or without stenting for coarctation or recoarctation of aorta in adults
and children. NICE interventional procedure guidance 74 (2004). Available from
www.nice.org.uk/guidance/IPG74
Coronary imaging: myocardial perfusion scintigraphy for the diagnosis and management of
angina and myocardial infarction. NICE technology appraisal guidance 73 (2003). Available
from www.nice.org.uk/guidance/TA73
Guidance on the use of coronary artery stents. NICE technology appraisal guidance 71 (2003).
Available from www.nice.org.uk/guidance/TA71
Under development
NICE is developing the following guidance (details available from www.nice.org.uk):
Ticagrelor for the treatment of acute coronary syndromes (ACS). NICE technology appraisal.
Publication date to be confirmed.
Page 22 of 30
Re
Review
view of guidance
7.1
The guidance on this technology will be considered for review in July 2014. The
Guidance Executive will decide whether the technology should be reviewed
based on information gathered by NICE, and in consultation with consultees and
commentators.
Andrew Dillon
Chief Executive
July 2011
Page 23 of 30
Appendix A: Appr
Appraisal
aisal Committee members, and NICE project team
A Appraisal Committee members
The Appraisal Committees are standing advisory committees of NICE. Members are appointed for
a 3-year term. A list of the Committee members who took part in the discussions for this appraisal
appears below. There are four Appraisal Committees, each with a chair and vice chair. Each
Appraisal Committee meets once a month, except in December when there are no meetings. Each
Committee considers its own list of technologies, and ongoing topics are not moved between
Committees.
Committee members are asked to declare any interests in the technology to be appraised. If it is
considered there is a conflict of interest, the member is excluded from participating further in that
appraisal.
The minutes of each Appraisal Committee meeting, which include the names of the members who
attended and their declarations of interests, are posted on the NICE website.
Dr Kathryn Abel Reader and Consultant Psychiatrist/Director of Centre for Women's Mental
Health, University of Manchester
Dr Daniele Bry
Bryden
den Consultant in Intensive Care Medicine and Anaesthesia, Sheffield Teaching
Hospitals NHS Trust
Da
David
vid Chandler Lay member
Dr Mary Cook
Cooke
e Lecturer, School of Nursing, Midwifery and Social Work, University of Manchester
Richard De
Devvereaux-Phillips Director, Public Policy and Advocacy NW Europe, BD, Oxford
Professor Rachel A Elliott Lord Trent Professor of Medicines and Health, University of Nottingham
Dr Alan Ha
Hayyco
coxx Reader in Health Economics, University of Liverpool Management School
Professor Cath
Cathyy Jackson Professor of Primary Care Medicine, University of St Andrews
Professor Gary McV
McVeigh
eigh Professor of Cardiovascular Medicine, Queens University Belfast and
Consultant Physician, Belfast City Hospital
Page 24 of 30
Dr Eugene Milne Deputy Regional Director of Public Health, North East Strategic Health Authority,
Newcastle upon Tyne
Ruth Oliv
Oliver-Williams
er-Williams Head of Nursing/Quality Improvement Lead Surgical Services, Royal Derby
Hospital
Professor Katherine P
Paayne Professor of Health Economics, University of Manchester
Dr Danielle Preedy Lay member
Ellen Rule Programme Director, NHS Bristol
Dr P
Peter
eter Selb
Selbyy Consultant Physician, Central Manchester University Hospitals NHS Foundation
Trust
Dr Surinder Sethi Consultant in Public Health Medicine, North West Specialised Services
Commissioning Team, Warrington
Professor Andrew Ste
Stevvens Chair of Appraisal Committee C, Professor of Public Health, University
of Birmingham
Professor P
Paul
aul T
Trueman
rueman Professor of Health Economics, Brunel University, London
Dr Judith W
Wardle
ardle Lay member
B NICE project team

Each technology appraisal is assigned to a team consisting of one or more health technology
analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.
Dr Helen Starkie Technical Lead
Joanne Holden Technical Adviser
Lori Farr
Farrar
ar Project Manager
Page 25 of 30
Appendix B: Sources of e
evidence
vidence considered b
byy the Committee
A The Evidence Review Group (ERG) report for this appraisal was prepared by School of Health and
Related Research (ScHARR):
Simpson EL, Fitzgerald P, Evans P, et al. Bivalirudin for the treatment of ST-segment elevation
myocardial infarction. March 2011
B The following organisations accepted the invitation to participate in this appraisal as consultees
and commentators. They were invited to comment on the draft scope. Organisations listed in I were
also invited to make written submissions. Organisations listed in II gave their expert views on
bivalirudin for the treatment of adults with ST-segment elevation myocardial infarction undergoing
percutaneous coronary intervention by providing a written statement to the Committee.
Organisations listed in I, II and III have the opportunity to appeal against the final appraisal
determination.
I Manufacturer/sponsor
The Medicines Company
II Professional/specialist and patient/carer groups:
Heart Care Partnership UK
HEART UK
British Association for Nursing in Cardiac Care
British Cardiovascular Intervention Society (BCIS)
British Cardiovascular Society
British Heart Foundation
Primary Care Cardiovascular Society Royal College of Nursing
Royal College of Physicians
III Other consultees:
Department of Health
Page 26 of 30
Welsh Assembly Government

IV Commentator organisations (did not provide written evidence and without the right of appeal):
British National Formulary
Commissioning Support Appraisals Service
Department of Health, Social Services and Public Safety for Northern Ireland
Healthcare Improvement Scotland
Eli Lilly
GlaxoSmithKline
Merck Sharp & Dohme
Sanofi Aventis
National Institute for Health Research Health Technology Assessment Programme
School of Health & Related Research Sheffield (ScHARR)
C The following individuals were selected from clinical specialist and patient expert nominations
from the non-manufacturer/sponsor consultees and commentators. They gave their expert
personal view on Bivalirudin for the treatment of ST-segment elevation myocardial infarction by
providing oral evidence to the Committee.
Dr Daniel Blackman, Consultant cardiologist, nominated by British Cardiovascular
Intervention Society clinical specialist
Dr Tim Kinnaird, Consultant Interventional Cardiologist, nominated by Welsh Assembly
Government clinical specialist
Valentino Oriolo, Acute Coronary Syndromes Advanced Nurse Practitioner, nominated by
British Association for Nursing in Cardiovascular Care - clinical specialist
John Miller, nominated by Heart Care Partnership UK patient expert
D Representatives from the following manufacturer/sponsor attended Committee meetings. They
contributed only when asked by the Committee chair to clarify specific issues and comment on
factual accuracy.
Page 27 of 30
The Medicines Company
Page 28 of 30
About this guidance

NICE technology appraisal guidance is about the use of new and existing medicines and treatments
in the NHS in England and Wales.
This guidance was developed using the NICE single technology appraisal process.
We have produced a summary of this guidance for patients and carers. Tools to help you put the
guidance into practice and information about the evidence it is based on are also available.
Your
ourresponsibility
responsibility
This guidance represents the views of NICE and was arrived at after careful consideration of the
evidence available. Healthcare professionals are expected to take it fully into account when
exercising their clinical judgement. However, the guidance does not override the individual
responsibility of healthcare professionals to make decisions appropriate to the circumstances of
the individual patient, in consultation with the patient and/or guardian or carer.
Implementation of this guidance is the responsibility of local commissioners and/or providers.
Commissioners and providers are reminded that it is their responsibility to implement the
guidance, in their local context, in light of their duties to avoid unlawful discrimination and to have
regard to promoting equality of opportunity. Nothing in this guidance should be interpreted in a
way which would be inconsistent with compliance with those duties.
Cop
Copyright
yright
National Institute for Health and Clinical Excellence 2012. All rights reserved. NICE copyright
material can be downloaded for private research and study, and may be reproduced for educational
and not-for-profit purposes. No reproduction by or for commercial organisations, or for
commercial purposes, is allowed without the written permission of NICE.
Page 29 of 30
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NICE 2011. All rights reserved.

Myocardial infarction (persistent ST-segment elevation) - bivalirudin (TA230)

2 The technology .............................................................................................................................................................

3 The manufacturer's submission..............................................................................................................................

Cost effectiveness .........................................................................................................................................................................

Evidence Review Group comments ........................................................................................................................................

4 Consideration of the evidence ................................................................................................................................ 12

7 Review of guidance ...................................................................................................................................................... 23

Appendix B: Sources of evidence considered by the Committee ................................................................. 26

NICE 2011. All rights reserved.

Myocardial infarction (persistent ST-segment elevation) - bivalirudin (TA230)

Bivalirudin in combination with aspirin and clopidogrel is recommended for the

NICE 2011. All rights reserved.

Myocardial infarction (persistent ST-segment elevation) - bivalirudin (TA230)

Bivalirudin (Angiox, The Medicines Company) has a marketing authorisation 'as

Bivalirudin is administered by injection or infusion. It is available in vials

NICE 2011. All rights reserved.

Myocardial infarction (persistent ST-segment elevation) - bivalirudin (TA230)

The manufacturer's submission

The Appraisal Committee (appendix A) considered evidence submitted by the manufacturer of

The manufacturer's decision problem compared bivalirudin in combination with

Patients in the bivalirudin treatment group (n = 1800) received a 0.75 mg/kg

NICE 2011. All rights reserved.

Myocardial infarction (persistent ST-segment elevation) - bivalirudin (TA230)

conducted at 123 sites in 11 countries; 57% of patients were enrolled in Europe

There were two primary outcomes: a composite of major adverse

For the primary outcome of major adverse cardiovascular events, bivalirudin

The proportion of patients who experienced a reinfarction was similar between

NICE 2011. All rights reserved.

Myocardial infarction (persistent ST-segment elevation) - bivalirudin (TA230)

Investigators reported comparable rates of adverse events between the

The manufacturer submitted an economic analysis that employed an economic

NICE 2011. All rights reserved.

Myocardial infarction (persistent ST-segment elevation) - bivalirudin (TA230)

ischaemic stroke; myocardial infarction; repeat revascularisation; or death. The

The model is primarily affected by the differences in all-cause mortality

Costs of bivalirudin treatment were based on the costs of initial angiography,

NICE 2011. All rights reserved.

Myocardial infarction (persistent ST-segment elevation) - bivalirudin (TA230)

Probabilistic sensitivity analysis presented for the base-case 1-year analysis

When the manufacturer presented an 'extreme case scenario' combining several

Evidence Review Group comments

NICE 2011. All rights reserved.

Myocardial infarction (persistent ST-segment elevation) - bivalirudin (TA230)

The ERG conducted exploratory analyses to check that the manufacturer's

The ERG investigated the following two issues:

NICE 2011. All rights reserved.

Myocardial infarction (persistent ST-segment elevation) - bivalirudin (TA230)

the impact of assuming 2 vials of bivalirudin per patient instead of 1.23

NICE 2011. All rights reserved.

Myocardial infarction (persistent ST-segment elevation) - bivalirudin (TA230)

The Committee discussed the evidence for the clinical effectiveness of

The Committee discussed whether similar outcomes to those in the

NICE 2011. All rights reserved.

Myocardial infarction (persistent ST-segment elevation) - bivalirudin (TA230)

The Committee discussed the omission of a comparison against heparin alone in