National Institute for Clinical Excellence by HC12073004473


									                                                  National Institute for Health and Clinical Excellence

                                                    Clinical guideline: Acute coronary syndromes

                                                      PRE-PUBLICATION CHECK ERROR TABLE

   Organisation     Order     Section number in        Page
                   number      FULL guideline         number            ERROR REPORT                             Response from developers

Department of        1      General                  General   Just to confirm that my policy colleagues     Thank you.
Health                                                         in the department have no comments to
                                                               make regarding NICE's pre-publication
                                                               check of factual errors
Royal                1      General                  General   We are not responding on this occasion        Thank you.
Society of Great
Royal College of     1      General                  General   Thank you for the opportunity to carry out    Thank you.
Nursing                                                        a pre-publication check on this guideline.

                                                               There are no further comments to make
                                                               on this on behalf of the Royal College of
DISN UK Group        1      General                  General   I sent this to a few selected members as it   None of these comments pertain to
                                                               is not my main field of expertise. Nobody     factual accuracy. The management of
                                                               highlighted any factual errors from what I    hypoglycaemia was not included in
                                                               could see, but the following comments         the scope of the guidance. This scope
                                                               were made:                                    was put to public consultation in
                                                               The authors of the NICE document,             accordance with the NICE Technical
                                                               “Unstable Angina and NSTEMI: The early        Manual 2009.
                                                               management of unstable angina and non-
                                                               ST-segment elevation myocardial
                                                               infarction update for the management of
                                                               patients with ST-elevation myocardial
                                                               infarction” deal with several key issues
                                                               related to this group of individuals.
However, in a similar fashion to the recent
ACC/AHA consensus document, they fail
to address the big white elephant in the
room – the management of
hyperglycaemia (1). This may, of course
be due to the lack of consensus on this
issue due to the conflicting results from
large outcome trials. (2-4)
Despite these disagreements, as the
discussions in these studies highlight, the
current treatments available to patients
who have a myocardial infarction or acute
coronary syndrome with concurrent
hyperglycaemia result in poorer outcomes
than in people with normal blood glucose
levels on admission and throughout their
hospital stay.(5) It is a pity that the writing
committee did not take the opportunity to
address this issue at all – if only to
acknowledge recently issued guidance.(6)
Until then, practicing clinicians are at risk
of remaining in limbo about how this
increasingly prevalent group of patients
should be optimally managed.
(1) Antman EM, Hand M, Armstrong PW,
Bates ER, Green LA, Halasyamani LK,
Hochman JS, Krumholz HM, Lamas GA,
Mullany CJ, Pearle DL, Sloan MA, Smith
SC. 2007 focused update of the
ACC/AHA 2004 guidelines for the
management of patients with ST-elevation
myocardial infarction: A report of the
American College of Cardiology/American
Heart Association Task Force on practice
guidelines: Developed in collaboration
with the Canadian Cardiovascular Society
endorsed by the American Academy of
Family Physicians: 2007 writing group to
review new evidence and update the
ACC/AHA 2004 guidelines for the
management of patients with ST-elevation
myocardial infarction, writing on behalf of
the 2004 writing committee. Circulation
2008; 117(2):296-329.
(2) The CREATE-ECLA Trial Group.
Effect of glucose-insulin-potassium
infusion on mortality in patients with acute
ST-segment elevation myocardial
infarction: The CREATE-ECLA
randomized controlled trial. JAMA 2005;
(3) Malmberg K. Prospective randomised
study of intensive insulin treatment on
long term survival after acute myocardial
infarction in patients with diabetes
mellitus. DIGAMI (Diabetes Mellitus,
Insulin Glucose Infusion in Acute
Myocardial Infarction) Study Group. Br
Med J 1997; 314(7093):1512-1515.
(4) Malmberg K, Ryden L, Wedel H,
Birkeland K, Bootsma A, Dickstein K,
Efendic S, Fisher M, Hamsten A, Herlitz J,
Hildebrandt P, MacLeod K, Laakso M,
Torp-Pedersen C, Waldenstrom A, for the
DIGAMI. Intense metabolic control by
means of insulin in patients with diabetes
mellitus and acute myocardial infarction
(DIGAMI 2): effects on mortality and
morbidity. Eur Heart J 2005; 26(7):650-
(5) Norhammar A, Lindback J, Ryden L,
Wallentin L, Stenestrand U, on behalf of
the Register of Information and
Knowledge about Swedish Heart
Intensive Care Admission (RIKS-HIA).
Improved but still high short- and long-
term mortality rates after myocardial

                                       infarction in patients with diabetes
                                       mellitus: a time-trend report from the
                                       Swedish Register of Information and
                                       Knowledge about Swedish Heart
                                       Intensive Care Admission. Heart 2007;
                                       (6) Anonymous. Guidelines on diabetes,
                                       pre-diabetes, and cardiovascular
                                       diseases: executive summary: The Task
                                       Force on Diabetes and Cardiovascular
                                       Diseases of the European Society of
                                       Cardiology (ESC) and of the European
                                       Association for the Study of Diabetes
                                       (EASD). Eur Heart J 2007; 28(1):88-136.

The Medicines   1   1.3.1   Page 32    Key messages of the Guideline:             Please refer to section 9.4 of the
Company                     Line 12-   Omission of recommended                    NICE Technical Manual (2009) for
(MDCO)                         19      interventions                              details about key priorities for
                                                                                  implementation. This recommendation
                                       Currently the summary draft guideline only was not prioritised for inclusion in the
                                       includes discussion of eptifibatide or     list.
                                       tirofiban for the management of patients
                                       who have an intermediate or higher risk of
                                       adverse cardiovascular events (predicted
                                       6-month mortality above 3.0%).

                                       [MDCO]: There are no data in the key
                                       messages section, referencing the
                                       detailed recommendations in the body of
                                       the guideline for interventions and
                                       practice in early angiography and for the
                                       optimal timing of abciximab and
                                       Recommendations relating to bivalirudin
                                       can be found on Page 168:

                                       Draft Guideline: PAGE 168
                                       “R22:     Once     risk    of   adverse
                                       cardiovascular events is known, consider
                                      switching to bivalirudin, rather than adding
                                      a GPI to an alternative antithrombin, for
                                      patients who:
                                      • are at intermediate or higher risk of
                                      adverse cardiovascular events (predicted
                                      6-month mortality above 3%), and
                                      • are not already receiving a GPI or
                                      fondaparinux, and
                                      • are scheduled to undergo angiography
                                      (with follow-on PCI if indicated) within 24
                                      hours of admission. “

                                       “R23: Consider bivalirudin at the time of
                                      PCI as an alternative to the combination
                                      of another antithrombin plus a GPI for
                                      patients not already receiving a GPI or

The Medicines   2   3.3   Page        Updated Summary of Product                   As this summary of product
Company                   139, line   Characteristics for bivalirudin              characteristics does not pertain to the
(MDCO)                    28-34                                                    population considered by this
                                      [MDCO]: Please note that the labelled guideline, this amendment has not
                                      indication for bivalirudin has recently been been accepted.
                                      updated. At the end of November 2009,
                                      the EMEA fully approved an extended
                                      label for ANGIOX (bivalirudin). Section 4.1
                                      now states:

                                      [SmPC]:“Angiox is indicated as an
                                      anticoagulant     for     adult    patients
                                      undergoing      percutaneous      coronary
                                      intervention (PCI) including patients with
                                      ST-segment        elevation     myocardial
                                      infarction (STEMI) undergoing primary
                                      PCI. Angiox is also indicated for the
                                      treatment of adult patients with unstable
                                      angina / non-ST segment elevation
                                      myocardial     infarction    (UA/NSTEMI)
                                      planned for urgent or early intervention.

                                     Angiox should be administered with
                                     aspirin and clopidogrel “
                                     Draft Guideline: “In current UK practice
                                     bivalirudin is used as an anticoagulant
                                     during percutaneous coronary intervention
                                     (PCI), as an alternative to the combination
                                     of heparin and a GPI, (initiated at the time
                                     of PCI). It is also approved for use in
                                     UA/NSTEMI patients planned for urgent
                                     or early invasive intervention (coronary
                                     angiography      with PCI/CABG/medical
                                     management as indicated), and is initiated
                                     prior to angiography in combination with
                                     aspirin and clopidogrel and continued
                                     through PCI in those who undergo this
                                     procedure. ..”

                                     [MDCO]: For factual accuracy, the
                                     underlined sentence above should read:

                                     “It is also approved for use in STEMI
                                     patient undergoing Primary PCI, and in
                                     UA/NSTEMI patients planned for urgent
                                     or early invasive intervention....”

                                     This extended indication for Angiox was
                                     granted on the basis of a statistically
                                     significant reduction in mortality and
                                     bleeding events at 30 days and one year
                                     in STEMI patients when compared
                                     against a heparin plus GPI strategy.

                                     We attach the latest SmPC for your

The Medicines   3   3.3.2   Page     Minor typographical error                      Thank you. This has been amended.
Company                     140
(MDCO)                      Line 1   Draft Guideline: “For patients who do are
                                     managed medically or go on to CABG

                                            following angiography... “

                                            [MDCO]: Removal of “do”

The Medicines        4   3.3.7   Page       Factual error                                  Thank you. This sentence has been
Company                          162                                                       amended to aid clarity of intention.
(MDCO)                           Line 18-   Draft Guideline: The ACUITY trial reflects
                                 21         practice in the USA and the time from
                                            hospital admission to angiography
                                            (around 19.5 hours), and the duration of
                                            treatment prior to angiography (median 4
                                            hours), were short compared to UK

                                            [MDCO]: The ACUITY trial was a
                                            multinational trial reflecting international
                                            practice. It is of note that 35% of patients
                                            were enrolled from European centres.

                                            It is therefore factually incorrect that the
                                            trial reflects USA practice, and the above
                                            statement should read:

                                            “..The ACUITY trial reflects international
                                            practice, with 35% of patient contribution
                                            from European centres.....”

The Medicines        5   2.5.5   Page       Clarification                                  Thank you. This has been added to
Company                          112                                                       the glossary of terms.
(MDCO)                           Line 29    [MDCO]: For clarity to the reviewer, the
                                            “Incremental Net Benefit” (INB) could be
                                            stated in full on first use and in the
                                            glossary of terms (page 13) with a
                                            reference to page 292 for definition /
British Society of   1   Full    General    We are grateful to the committee for the Thank you.
Cardiovascular                              opportunity to check the final
Magnetic                                    recommendations and have no further
Resonance                                   comments on the issues that we have
(BSCMR)                                   raised.

                                          We maintain that the assessment of
                                          ischaemia and myocardial viability is of
                                          paramount importance in patients
                                          presenting with ACS in order to guide
                                          appropriate, individual revascularisation
                                          decisions. We hope that NICE take
                                          onboard your recommendation for specific
                                          guidance on this issue in relation to the
                                          different cardiovascular imaging
                                          modalities available.

GlaxoSmithKline   1   General   General   Further to your email below,                  Thank you.
                                          GlaxoSmithKline have reviewed the
                                          updated Acute coronary syndromes
                                          clinical guideline and have no further
Iroko             1   General   General   Iroko would like to congratulate NICE and     Thank you.
Pharmaceuticals                           the guidelines committee for an excellent
                                          job on updating the ACS clinical guidance.
Sanofi-aventis    1   2.4.7     88        Lines 6-9 Please remove the inaccurate        Thank you. This has been removed.      Formatted: No underline
                                          sentence regarding plan to submit for a
                                          clopidogrel hydrogen sulphate 600mg
                                          licence We do not currently anticipate any
                                          extensions to the current marketing
                                          authorisation (commercial in
                                          confidence). (Commercial in confidence
                                          information removed by NICE).The results
                                          of CURRENT OASIS 7 were presented at
                                          the ESC conference in August 2009.
Sanofi-aventis    2   3.1       119       Lines 14-16 In line with previous footnotes   Thank you but this is already          Formatted: No underline
                                          regarding the licensed indications for        discussed in the introduction to the
                                          other therapy classes (e.g. GPIs), a          chapter.
                                          footnote should be added to state that the
                                          LMWHs with licensed indications for the
                                          treatment of UA and NSTEMI are
                                          enoxaparin and dalteparin.

Sanofi-aventis   3   3.2.6                137   Line 19 the incorrect drug name has           Thank you. This has been amended.         Formatted: No underline
                                                been inserted, this arm was in fact for
                                                enoxaparin, as such the text should be
                                                amended as shown here:
                                                “It 17 is possible that this difference in
                                                administration of additional heparin
                                                contributed to the 18 observation of higher
                                                bleeding in the enoxaparin arm of the
Eli Lilly and    1                              We are very concerned at the extensive        Thank you. The developers agree that
Company                                         changes made to the ACS (UA &                 there is no head to head data to
Limited                                         NSTEMI) guideline since the draft for         support the use of bivalirudin ahead of
                                                consultation, without the opportunity         abciximab and this was not the
                                                to comment on them.                           intention of the recommendation. The
                                                                                              wording of the recommendation has
                                                The amended relative place of therapy of      now been changed to more accurately
                                                bivalirudin compared to abciximab is not      reflect this.
                                                clearly supported by the evidence base
                                                and may lead to confusing advice to
                                                clinicians. It is very important to have a
                                                full consultation on the proposed clinical
                                                guidance, particularly when clear head to
                                                head data is not available to establish the
                                                most appropriate position of a therapy.
                                                We therefore trust our comments below
                                                are given detailed consideration.
Eli Lilly and    2   R15, section 2.5.8   118   We supported the recommendation in the        Thank you. The developers agree with
Company                                         draft for consultation which stated:          your comments, as stated above and
Limited                                                                                       agree with the limitations of the
                                                ‘Consider offering abciximab as an            ACUITY and REPLACE2 trials.
                                                adjunct to PCI to patients at intermediate
                                                or higher risk of adverse cardiovascular
                                                events who are not already receiving a

                                                However, the recommendation R15 in the
                                                prepublication check version now states
                                                that abciximab should be considered as
                                                an adjunct to PCI for patients at

intermediate or higher risk of adverse
cardiovascular events who are not already
receiving a GPI or bivalirudin.

The inclusion of bivalirudin in this
recommendation is not supported by the
literature and no justification is provided in
the ‘evidence to recommendations’

There is no head to head data to support
the use of bivalirudin ahead of abciximab.

There are various limitations with
ACUITY, the registration trial for
Angiomax (bivalirudin), which compared
heparin + GPI vs. bivalirudin + GPI vs.
bivalirudin alone in medium to high-risk
patients undergoing an early invasive
     The study was open-label and
        designed as a non-inferiority trial,
        with a generous non-inferiority
        margin of 25%
     The trial was not restricted to
        patients undergoing PCI - only
        56% of patients underwent PCI
     The study was not in a truly high
        risk cohort as troponin levels were
        only elevated in 58% of patients.
     The study was not a direct
        comparison with abciximab, the
        choice of GPI was at the operators
        discretion. Abciximab was used in
        only 17.8% and 16.3% of cases in
        the GPI arms only. {A published
        substudy of ACUITY (presented by
        Kirtane AJ et al., at AHA 2007
        (Circulation. 2007;116:II_629-
       II_630.) showed significant
       differences in ischaemic event
       rates between eptifibatide and
       abciximab, favouring abciximab.
       Whilst there are limitations with the
       ACUITY study, the benefit seen
       with abciximab in the ACUITY
       substudy was consistent with the
       benefit seen in the head-to-head
       TARGET ACS-PCI subgroup
       analysis from TARGET (Stone
       GW, Circulation 2002;105:2347-
      9.1% of patients in the bivalirudin
       arm required a GPI (“bail-out” use)
       as well

Since there are many limitations to this
trial, the results should be treated with
caution and any recommendations made
on the basis of this study should be
carefully considered.

There are also limitations with the
REPLACE 2 trial which enrolled unstable
and stable patients undergoing PCI
    Three-quarters of the patients in
       this study were stable patients.
    only 42.9% of patients in
       REPLACE 2 received abciximab
       as a GPI
    Unfractionated heparin plus
       planned abciximab treated patients
       trended to better ischemic
       outcomes compared to bivalirudin
       + provisional abciximab. There
       was no difference seen between
       eptifibatide vs. bivalirudin plus
       provisional eptifibatide which
                                                       suggests that abciximab may be
                                                       more effective than a small
                                                       molecule. {These findings are
                                                       consistent with the TARGET trial,
                                                       that showed the superiority of
                                                       abciximab over a small molecule
                                                       GPI (tirofiban) in the overall PCI
                                                       study population and more
                                                       profound in the ACS-PCI subgroup
                                                       (Stone GW, Circulation

                                               To date, no trial has compared bivalirudin
                                               to abciximab in NSTEMI patients
                                               undergoing PCI. The ISAR REACT 4 trial
                                               is still ongoing ( Identifier
                                               NCT00373451). Due to the lack of data,
                                               we think it would be inappropriate, to
                                               prefer one or the other. Furthermore, the
                                               most current SPC for Angiomax
                                               (bivalirudin)1 doesn’t exclude Angiomax
                                               (bivalirudin) from being used together with
                                               a glycoprotein IIb/IIIa receptor antagonist.

Eli Lilly and   3   R22, section 3.3.8   168   As discussed above, the evidence base             Thank you. The developers agree with
Company                                        does not support the prepublication               your comments and the
Limited                                        guideline’s preference for bivalirudin over       recommendations have been
                                               GPI + heparin and contradicts the ESC             amended to reflect this. It was never
                                               guidelines for the Diagnosis and                  the intended that bivalirudin should be
                                               Treatment of Non-ST-Segment Elevation             recommended in preference to a
                                               Acute Coronary Syndromes (Bassand et              heparin plus GPI.
                                               al. European Heart Journal 2007; 28,
                                               1598–1660) which recommend bivalirudin
                                               [only] as an alternative to GPIs (see
                                               Recommendations for GPIs [page 1621])

                                               The ISAR-REACT 3 trial showed that
                                               bivalirudin is not better than heparin.
                                               Bivalirudin and unfractionated heparin had
                                               opposite effects on the individual
                                               components of the composite endpoint.
                                               Patients treated with bivalirudin had
                                               significantly less bleeding, and those
                                               treated with heparin tended to have fewer
                                               myocardial infarctions than with bivalirudin
                                               (Kastrati et al N Engl J Med 2008;
                                               359:688–696). There is an interesting
                                               substudy (Iijama, EHJ 2009, 30, 290-296)
                                               which concludes, that "Compared with
                                               heparin, bivalirudin was associated with a
                                               reduction in major bleeding, but mostly in
                                               low-risk patients. A reduction in the
                                               bleeding risk inversely correlated with an
                                               increase in the risk of myocardial
                                               infarction with bivalirudin."

Eli Lilly and   4   R23, section 3.3.8   168   Again the preference for bivalirudin over      Thank you. The developers agree.
Company                                        GPIs is not supported by the literature.
Limited                                        See above.


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