The Scottish Medicines Consortium issued on 7th December, 2008 an advice on bivalirudin (Angiox):

Bivalirudin  (Angiox)  is accepted  for  restricted use within NHS Scotland  for  the  treatment of adult patients with acute coronary syndromes (unstable angina/non-ST segment elevation myocardial  infarction)  planned  for  urgent  or  early  intervention. It  is  restricted  to  use  in patients  who  would  otherwise  have  been  considered  for  heparin  in  combination  with  a glycoprotein  IIb/IIIa  antagonist.  In  these  patients  bivalirudin  monotherapy  may  be  a suitable alternative. It should not be used as an alternative to heparin alone.

Bivalirudin should be administered with aspirin and clopidogrel.

Bivalirudin  showed  a  reduced  risk of bleeding  compared  to  a  heparin-based  anticoagulant strategy in patients with moderate and high risk acute coronary syndromes undergoing early invasive management.

This is an excerpt of the detailed advice on bivalirudin:

Treatment  of  adult  patients with  acute  coronary  syndromes  (ACS: unstable  angina/non-ST segment  evaluation  myocardial  infarction  (UA/NSTEMI))  planned  for  urgent  or  early intervention.  Bivalirudin should be administered with aspirin and clopidogrel.

Dosing information
Start  with  an  intravenous  bolus  of  0.1mg/kg  followed  by  an  infusion  of  0.25mg/kg/hour.
Subsequent dosing varies according  to  the  intervention  (medical, percutaneous or surgical) undertaken for ACS.

Product availability date
January 2008

Summary of evidence on comparative efficacy

Bivalirudin  is direct  inhibitor of  thrombin.    It was originally  licensed as an anticoagulant  for use  in  patients  undergoing  percutaneous  coronary  intervention  (PCI)  and  the  licence  has been extended to include the treatment of ACS planned for urgent or early intervention.

The pivotal evidence  for  this  indication comes  from a multicentre, prospective  randomised, open-label, parallel-group  trial and  the most  relevant comparison  is between 4,603 patients randomised  to  heparin  (unfractionated  heparin  (UFH)  or  enoxaparin)  plus  a  glycoprotein IIb/IIIa  inhibitor  (GPI)  and  4,612  randomised  to  bivalirudin  alone  (without  GPI).    Eligible patients were adults with moderate and high  risk ACS.   Angiography was performed  in all patients within 72 hours of randomisation,  followed by  triage at  the physician’s discretion  to further  treatment  (percutaneous, surgical, or medical).   A  third arm received bivalirudin and GPI  but  the  results  are  not  presented  because  the  addition  of  GPI  conferred  no  clinical advantage.  All patients were recommended to receive clopidogrel or ticlopidine, though this, and the regimen used, was at the discretion of the investigator.

At  30-days’  follow-up  (±  5  days)  three  primary  endpoints  were  tested  sequentially  in  the following order  for the comparison between bivalirudin alone and heparin/GPI: 1) superiority of the bleeding endpoint (major bleeding according to a trial-specific scale); 2) non-inferiority then  superiority  of  a  composite  net  clinical  outcome  endpoint;  3)  non-inferiority  then superiority  of  a  composite  ischaemic  outcome  endpoint.    The  non-inferiority  margin  was
25%.   The  ischaemic endpoint was a composite of death  from any cause, MI or unplanned revascularisation  for  ischaemia.   The net clinical outcome endpoint was a composite of  the ischaemic  and  major  bleeding  outcomes.    All  analyses  were  on  the  intention  to  treat population  and  adjustment  was  made  for multiple  comparisons.    One-year  data  are  also available for the ischaemic and major bleeding outcomes.

The European Medicines Agency  (EMEA) considered bleeding  to be a safety outcome and questioned  the  validity  of  the  net  clinical  outcome  therefore  results  are  presented  for  the composite ischaemic endpoint only in this section.  At 30-days, bivalirudin was non-inferior to heparin plus GPI for the incidence of this endpoint but there was a non-significant numerical advantage for heparin/GPI for the composite and all of its individual components (Table 1).

At one year  the  rates of composite  ischaemia were 15.4% and 16.2%  for heparin/GPI and bivalirudin  alone  respectively,  representing  a  relative  risk  of  1.06  (95%  CI  0.95  to  1.17).
Heparin/GPI was also numerically superior to bivalirudin for MI and revascularisation but not for death from any cause.  None of these differences were significant.

Summary of evidence on comparative safety

Although defined as an efficacy variable, major bleeding was considered by the EMEA to be a  safety  outcome.    It  was  reported  both  as  a  trial-specific  scale  and  according  to  the Thrombolysis in Myocardial Infarction (TIMI) definition.

There were significant advantages  for bivalirudin alone versus heparin/GPI  for both scales, but the incidence rates and absolute difference were smaller in the TIMI analysis.

Other than for bleeding, the analysis of adverse events combined results from the bivalirudin alone and bivalirudin plus GPI arms.   Up  to  the Day 30  visit, 416  (8.9%) heparin and 772 (8.6%) bivalirudin patients experienced one or more serious adverse events (SAEs, including SAEs  with  an  outcome  of  death).  The  system  order  classes  (SOCs)  most  commonly associated with SAEs up  to  the Day 30 visit were cardiac disorders, general disorders and administration  site  conditions,  and  infections  and  infestations  (in  ≥1.0%  of  all  heparin  and bivalirudin patients). The overall  incidence of SOCs associated with SAEs up  to  the Day 30 visit was  comparable  for  the heparin and bivalirudin  treatment groups.   More heparin  than bivalirudin  patients  experienced  cardiac  disorder  (3.4%  versus  3.2%),  respiratory,  thoracic and  mediastinal  disorder  (1.1%  versus  0.9%),  and  vascular  disorder  (1.0%  versus  0.8%) SAEs  (≥0.2% difference between  treatment groups), but  the  incidence of  these events was low.

Summary of clinical effectiveness issues

The  key  efficacy  outcome  for  registration was  considered  to  be  the  composite  ischaemic events  for  which  bivalirudin  alone  was  shown  to  be  non-inferior  but  not  superior  to heparin/GPI at 30-days’ follow-up.  Efficacy was also similar between groups after one year.
The EMEA considered the non-inferiority margin of 25% to be rather wide but noted that the one-year results were ‘reassuringly tight’ – effectively within a 15% margin.

The  primary  outcome  of  major  bleeding  was  considered  by  the  EMEA  to  be  a  safety outcome  and  significantly  favoured  bivalirudin  alone  over  heparin/GPI.    This  advantage disappeared when bivalirudin was combined with GPI such that addition of GPI to bivalirudin was not considered to offer any clinical advantage.

Feedback and data obtained during expert consultation  indicate  that  the  trial design differs substantially  from  Scottish  practice.    For  example,  GPI  are  used  more  conservatively  in Scottish  practice  (in  about  44%  of  patients  overall  and  less  than  7%  as  an  early intervention).  Radial access is the default route for PCI in Scotland and is associated with a lower risk of bleeding  than  the  femoral  route used  in 87% of patients  in  the  trial.   The  trial-specific  definition  of major  bleeding was  argued  to  be more  specific  to ACS/PCI  than  the Thrombolysis in MI scale, but it was strongly influenced by access site bleeding, particularly haematoma,  and  the  EMEA  had  reservations  about  its  validity  to  reflect  major  bleeding.

Major bleeding rates continued to favour bivalirudin using the TIMI scale and after exclusion of access site haematoma, but the incidence rates, and hence the absolute difference, were smaller than with the specific trial scale.

The pivotal  trial  incorporated a  further randomisation  in  the heparin/GPI and bivalirudin/GPI arms.  This was between routine ‘up-stream’ introduction of GPI and selective deferred use – only  in  patients  undergoing  PCI.    The  primary  hypothesis  of  this  analysis  did  not  involve bivalirudin,  however  in  the  light  of  expert  comment  it  is  notable  that  deferred  GPI  was associated  with  a  significantly  reduced  rate  of  major  bleeding  at  30  days.    Over-representation of GPI use, particularly upstream, may have  inflated  the  incidence of major bleeding in the heparin/GPI arm compared with Scottish practice.

About 64% of patients received heparin pre-randomisation, and the incidence was similar in all treatment arms, including those in which patients received bivalirudin.

Additional analyses showed that the results of the composite ischaemic endpoint were more favourable to bivalirudin, especially bivalirudin alone, in patients who also receive aspirin and clopidogrel and  the bleeding advantage was retained  in  those patients. Thus the indication for bivalirudin specifies co-administration with those agents.

Bivalirudin  was  associated  with  a  significant  advantage  over  heparin  and GPI  for  the  net clinical benefit outcome.  The EMEA did not consider this for registration purposes as it was of  the  strong  opinion  that  efficacy  and  safety  variables  should  not  be  mixed  in  a  single outcome.  Nevertheless, with similar efficacy between bivalirudin alone and heparin/GPI and significantly reduced rates of bleeding, it reflects a net clinical advantage for bivalirudin when
combined with aspirin and clopidogrel as licensed (but not when combined with GPI).

The  trial was  open-label  but  hard  endpoints,  including  death  and MI, were  adjudicated  by blinded assessors to minimise bias.

Source: Scottish Medicines Consortium Drug Advice: bivalirudin (Angiox). Full text PDF

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