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| Journal of the New Zealand Medical Association,
07-October-2005, Vol 118 No 1223
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Non ST-elevation acute coronary syndromes: New Zealand
management guidelines
Non ST-Elevation Acute Coronary Syndrome Guidelines Group
and the New Zealand Branch of the Cardiac Society of Australia and New Zealand
Glossary
PurposeThese guidelines apply to the management of patients with
non-ST elevation acute coronary syndromes (NSTEACS). The purpose of these
guidelines is to provide a summary of the most up to date New Zealand and
overseas evidence and to make recommendations based on the evidence that will
lead to the best practice for patients with NSTEACS in New Zealand. The
guideline is aimed at all health providers who care for patients with NSTEACS.
These guidelines are based on the Cardiac Society of
Australia and New Zealand (2000) Guidelines on the Management of Unstable
Angina1 as well as a meeting held in Queenstown in May 2001, to which doctors
from every major New Zealand hospital, recommended by the Head of Department,
were invited to attend. The aim of this meeting was to discuss the management of
patients with NSTEACS, to define guidelines and to develop a New Zealand Audit.
The meeting was initiated by the Cardiac Society of New Zealand with a Grant
from Roche Pharmaceuticals. The choice of content of the meeting and the
organisation was completely independent.
For a detailed description of the levels of evidence cited
in this guideline please see Appendix 2. These guidelines are intended for best
clinical practice. Where physicians or hospitals are not able to meet the
guidelines it is important that there is documentation that there have been
communications between clinicians and managers clearly defining the clinical
implications of any resource shortages.
Early risk stratificationIntroductionRisk assessment of patients with NSTEACS plays an important
role in predicting patient prognosis. This also enhances the cost-effectiveness
of patient care by enabling evidence-based treatments including antiplatelet,
antithrombotic, and revascularisation therapies to be targeted at the patients
who are most likely to benefit from their use. The clinical history, examination
findings, electrocardiographic changes, and blood levels of cardiac marker and
troponins are all critical factors in determining risk.2-9
Risk assessment should be considered a dynamic process and
patients should be assessed when first seen, after several hours, 6–8
hours, 24 hours and prior to discharge. The presence of continuing symptoms and
response to therapy are important in risk assessment. Refractory ischaemia or
evidence of ongoing (including silent) ischaemia on electrocardiogram (ECG)
monitoring should mandate early angiography. Risk assessment may be enhanced by
determining the number and severity of flow-limiting coronary artery stenoses
and the presence or absence of left ventricular impairment. Risk assessment in
patients with NSTEACS allows prediction of the low, intermediate or high risk of
death or nonfatal myocardial infarction (MI) and particularly the risk of events
occurring in the short term.
The important features contributing to risk assessment are
shown in Table 1. Various risk scores can also be used—e.g. The
Thrombolysis In Myocardial Infarction TIMI risk score (Table 2).10
Measurement of markers of myocardial necrosis, inflammation, and natriuretic peptidesCardiac markersIn patients presenting with symptoms within the last 24
hours suggestive of acute myocardial ischaemia cardiac troponins T or I have the
best sensitivity and specificity for the diagnosis of MI and these are the
markers of choice.11,12 In both short- and long-term follow-up studies, the
magnitude of troponin elevations has correlated consistently with the risk of
death and the composite risk of death or nonfatal MI2,8,1314 and troponin levels
have been shown to be more powerful prognostic indicators than CKMB levels
(Table 3).13,15(Click here to view Table 1, Table 2, and
Table 3)
Troponins may be the only markers required if utilised in a
chest pain pathway with patients undergoing a 6-8 hour observation period.16
Point of care testing is recommended when hospital logistics cannot consistently
deliver laboratory-assayed results within 1 hour.17
Troponins are very sensitive markers of myocyte necrosis,
and elevated levels can occur in settings other than spontaneous myocardial
ischaemia or percutaneous coronary intervention (PCI) (Table 4).5 Apart from
acute coronary syndromes (ACS), the most frequent causes of elevated troponin
levels are atrial or ventricular tachycardia (often with hypotension and an
increased myocardial oxygen demand), pulmonary emboli with right ventricular
infarction, and cardiac failure18 with myocardial necrosis due to neurohumoral
changes and elevated left ventricular end-diastolic pressure. Other causes of
elevated troponin levels include cardiac surgery, myocarditis, and renal
failure.
The diagnostic criteria for MI for troponin T is a
discrimination level of 0.03μg/L, there are different cutpoints for
troponin I.19 The levels of troponins predict the benefits of therapy with low
molecular weight heparins (LMWH),20 glycoprotein IIb/IIIa antagonists,21 and of
an early invasive/revascularisation strategy.22 The use of troponins to diagnose
reinfarction is problematic in the 2 weeks after an initial MI as these markers
have a long half-life (up to 14 days) and CKMB or CK should be measured in these
circumstances.D4
Inflammatory markersThere has been extensive research into the roles of
inflammation and inflammatory markers in NSTEACS. The levels of high sensitivity
C-reactive protein (hsCRP), interleukin-6 and more recently CD-40 ligand (which
has prothrombotic effects) have been shown to have independent prognostic
information.23 Elevated levels of other inflammatory markers such as adhesion
molecules,24 interleukin-725 and matrix-metalloproteinases (including pregnancy
associated plasma protein A)26 also have been observed in patients with NSTEACS.
Conversely, levels of the anti-inflammatory cytokine, interleukin-10 have been
shown to be reduced and patients with higher levels of interleukin-10 suffer
fewer events during follow-up.27 There have been no prospective trials of
therapies aimed at modulating the levels of these markers. Neither the current
ACC/AHA,3 ESC treatment guidelines for NSTEACS28 or the guidelines of The
Australian and New Zealand Cardiac Society1 recommend the measurement of
inflammatory marker levels. Nor does this guideline recommend measurement, but
recognises that in the near future with further evidence inflammatory markers
may have an important role in risk assessment and choice of therapy.
Natriuretic peptidesIn observational studies of patients with NSTEACS, brain
natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide
(NT-proBNP) levels have been shown to be independent prognostic factors for
mortality and myocardial infarction. Elevation of BNP levels may be related to
ischaemia causing myocardial stretch.29-31
In the FRISC-II substudy NT-proBNP levels measured at admission predicted
the benefit of revascularisation and added prognostic information to that
obtained from clinical and ECG information and from markers of myocyte necrosis
and inflammation.30 However in the TACTICS trial revascularisation did not
provide more benefit for patients with elevated BNP levels (>80 ng/L) at
admission.32 The results may relate to the enrolment of higher risk patients in
FRISC-II and issues of statistical power. To enhance risk stratification and
targeting of therapies, measurement of BNP or NT-proBNP levels may be considered
but are not currently recommended.29
Initial medical managementThe recommended pathway of triage and indications for
hospitalisation in patients with NSTEACS is summarised in Figure 1. An ECG and bloods for troponins, full blood count
and lipids should be obtained within 10 minutes of presentation. If a chest pain
unit pathway is used patients should be observed and have repeat measurements of
troponins at 6–8 hours. Some patients will develop elevated troponins up
to 12 hours after symptom onset. Early discharge decisions can then be made
based on clinical features, including the presence or absence of recurrence of
ischaemia, troponin levels, electrocardiographic changes, and testing for
inducible ischaemia as appropriate, usually with exercise testing. Table 5
summarises the recommended dosage regimens for various antiplatelet and
antithrombotic therapies (for more details see Appendix 2). Where to manage
patients is an important consideration. It is recommended that all high risk
patients should be managed in a CCU or CCU step-down until further risk
stratification shows them to be at lower risk or revascularisation is
performed.
The very important role of nurses in the management of these
patients is acknowledged and highly valued.
AnalgesiaSub-lingual nitroglycerine is recommended for symptoms of
ischaemia.D4 Morphine
or omnopon together with an antiemetic should be used to relieve severe
pain.D4 Intravenous
nitroglycerine can also achieve symptomatic relief and be used for blood
pressure
lowering.D3
Antiplatelet agentsAspirin—Aspirin
reduces progression to MI and cardiac mortality by about 50%33 and all patients
without contraindication should immediately receive aspirin 150-300mg,1++A which
should be chewed if enteric coated. Long-term, lower doses of 75-100mg in
enteric coated formulations to maintain efficacy and to minimise bleeding risk
should be given indefinitely.33,34
Clopidogrel—The
CURE trial35 and the separately reported PCI-CURE36 results provide important
evidence for the use of clopidogrel in patients with NSTEACS regardless of
whether they are managed conservatively or invasively. In the CURE trial which
randomised 12,562 patients (77% managed conservatively), clopidogrel reduced the
incidence of death, non-fatal MI and stroke by 20% over an average 9-month
follow-up period (9.3% with clopidogrel vs 11.5% with placebo, P<0.001).
There were also reductions in the rates of revascularisation, as well as need
for thrombolytic therapy and intravenous glycoprotein IIb/IIIa inhibitors in the
clopidogrel group. (Click here to view Table 4 and Table
5)
Table 4. Causes of elevated
troponin levels in clinical settings other than ACS or PCI5
Table 5. Clinical use of
antithrombotic therapies
*
Different dose regimens were tested in recent clinical trials before
percutaneous interventions
‡
Adjustment required for age ≥75 years and renal dysfunction – see
pharmacy guidelines.
There was an excess of major bleeding with clopidogrel (3.7%
vs 2.7%, P=0.003) but life-threatening bleeding was not increased. In patients
undergoing CABG within 5 days of receiving clopidogrel, there was an increase in
major bleeding from 6.3% to 9.6%, p=0.05. This compares with 7 major events per
1 000 patients (cardiovascular death, MI or stroke) prevented within the first
24 hours with clopidogrel.
In the PCI-CURE trial with 2658 patients, pre-treatment with
clopidogrel for 10 days prior to PCI reduced 30-day composite of death,
non-fatal MI and urgent target vessel revascularisation by 30% after PCI (4.5%
vs 6.4%, P=0.03).36 Long-term administration of clopidogrel after PCI for 12
months was associated with a lower rate of cardiovascular death, MI, or any
revascularisation (p=0.03), and of cardiovascular death or MI (p=0.047). Overall
(including events before and after PCI) there was a 31% reduction cardiovascular
death or MI (p=0.002). Long-term benefit of clopidogrel plus aspirin after PCI
in patients with chronic stable angina was also shown in the CREDO trial.37 At 1
year, the composite endpoint of death, myocardial infarction or stroke was
reduced by 27% in the clopidogrel group. Greater benefit was achieved in
patients receiving clopidogrel >6 hours prior to PCI.
In the CAPRIE trial38 in patients with previous MI, stroke
or peripheral vascular disease clopidogrel had an 8.7% greater benefit than
aspirin on reducing vascular death, MI and ischaemic stroke. Clopidogrel is
therefore a useful alternative to aspirin when there is intolerance to
aspirin.1++A
Clopidogrel (300-600mg orally and then 75 mg daily) should
be considered in all patients at intermediate or high risk in addition to
aspirin or as an alternative to aspirin and continued for 9 months according to
appropriate funding.1+A
There are two approaches, one is to give clopidogrel at the time of stenting
after the coronary anatomy is known and the other is to give it to all patients
prior to angiography, except those in whom urgent coronary artery bypass
grafting (CABG) is likely as there is increased bleeding if clopidogrel has been
given within 5 days of surgery.35 These patients include those with ECG changes
suggestive of ≥50% left main stenosis (i.e. ST deviation in ≥2
coronary artery territories), known coronary anatomy from a previous angiogram
which is inappropriate for PCI, the presence of multiple regional wall motion
abnormalities on echocardiography, haemodynamic instability or heart failure.
All of these patients should be considered for expeditious angiography.
Clopidogrel is expensive but several studies have shown it
to be cost effective.39-41 It is not currently funded except for patients
undergoing stenting.
Glycoprotein IIb/IIIa
antagonists—Patients with ischaemic ST depression on an ECG
(≥0.5 mm), those with elevated troponin levels and those with diabetes
have a worse prognosis and have been shown to have better outcomes with
administration of intravenous glycoprotein IIb/IIIa antagonists. In a
meta-analysis of glycoprotein IIb/IIIa inhibitors involving a total of 31,402
patients not routinely scheduled for PCI a 9% reduction of death or non-fatal MI
was reported in the active treatment group (10.8% vs 11.8%, P=0.015).42 Patients
with elevated troponins had an 18% reduction in death and MI equating to 20
events reduced for 1000 patients treated.
Diabetics have been shown to have a reduction in mortality
with glycoprotein IIb/IIIa administration.43 It is recommended that
administration of either tirofiban or eptifibatide be considered in these high
risk groups of patients as well as in patients with recurrent ischaemic symptoms
and continued until the time of early coronary
angiography.1++A These
agents have been shown to be cost effective but are not available in some
hospitals.13,44-46
Combination of antiplatelet
therapy—The optimal antiplatelet therapy for patients with non
ST-elevation acute coronary syndromes is not defined. There are no randomised
clinical trial data comparing triple therapy (aspirin, clopidogrel and a
glycoprotein IIb/IIIa antagonist) with double therapy—i.e. with aspirin
plus clopidogrel or with aspirin plus a glycoprotein IIb/IIIa antagonist. There
is in-vitro evidence showing greater inhibition of platelet function with
combined therapy and there is non-randomised information47 in non-ACS48 and36 in
ACS showing improved efficacy with modest increases in bleeding.
Other antiplatelet agents—Dipyridamole does not confer any additional reduction in coronary events when added to aspirin and is not recommended.D4 Antithrombotic agentsAntithrombotic therapy is recommended in intermediate or
high risk patients with either unfractionated heparin (UFH) or
LMWH1++A with the
preferred therapy being enoxaparin because a meta-analysis of all enoxaparin
trials shows a 9% reduction in death and MI at 30 days compared to therapy with
UFH (see Table 5 for suggested doses noting that APTT ranges are reagent
specific and individual hospitals may have a different target range).49
The recent SYNERGY (Superior Yield of the New Strategy of
Enoxaparin, Revascularisation and glycoprotein IIb/IIIa Inhibitors) trial showed
similar outcomes with UFH compared with enoxaparin on a background of high usage
of clopidogrel and glycoprotein IIb/IIIa antagonists and an invasive strategy
with a modest increase in bleeding. There was no significant increase in
transfusions but there was an increase in TIMI major bleeding (See Appendix 3)
(non CABG related) in all patients 1.7% UFH, 2.4% enoxaparin; p=0.025. In
patients undergoing PCI there were similar TIMI major bleeding rates of 2.8% in
patients receiving UFH vs 2.7% in patients receiving enoxaparin on a background
of aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors. Either enoxaparin
or UFH should be continued until catheterisation or for 48 hours but in view of
increased bleeding and events if patients are switched from one antithrombotic
agent to another, patients should continue on the initial antithrombotic
agent.1++A
β-blockersAlthough there is no strong evidence base in NSTEACS
patients β-blockers may reduce progression to MI. IV β-blockers are
recommended for patients at high risk and for those with continuing ischaemia if
there are no contraindications (asthma, systolic BP <110 mmHg, heart rate
<50 min or AV block) and oral therapy should be continued
indefinitely.++B
Calcium channel blockersIf β-blockers are contraindicated, diltiazem should be
given.D4 Calcium
channel blockers that increase heart rate should not be used without concomitant
β-blockers
therapy.D4
Lipid modifying therapyInitiation of statin therapy
should begin in hospital in all ACS patients in order to enhance compliance and
to reduce events.1++A
Use of a fixed dose of simvastatin (40 mg) has been shown to reduce events by
over 20% in HPS in non ACS patients.50 Achievement of an LDL level of 1.6mmol/L
with atorvastatin (80 mg) has been shown to reduce by 16% a composite endpoint
of death, MI, readmission with unstable angina, revascularisation and stroke
compared to an LDL level of 2.5mmol/L achieved with pravastatin therapy (40
mg).51
ACE inhibitorsAll patients with evidence of heart failure, should receive
oral ACE inhibitors beginning 2 hours after admission if the systolic BP is
>100 mmHg using (e.g. 6.25 mg tds, or equivalent medication) and then
increasing over several days to maximally tolerated
doses.1++A In patients
who are at high risk, ramipril and perindopril have been shown to reduce death
and MI.52,53 In patients at low risk because of low cholesterol levels, non
smoking, controlled blood pressure, previous revascularisation, and high usage
of aspirin, beta-blockers, and statins, trandolapril has been shown not to be
beneficial.53,54 ACE inhibitors should be commenced during hospitalisation and
continued
indefinitely.1++C
Early angiography and revascularisationThe FRISC-II trial demonstrated superiority in higher risk
patients of an invasive approach with PCI or CABG after initial medical
treatment with the low molecular weight heparin dalteparin and aspirin for 4-7
days with a reduction in mortality at 1 year from 3.9% to 2.2% p=0.01612. The
TACTICS trial4 randomised 2220 high risk patients with aspirin, unfractionated
heparin and tirofiban to an early invasive strategy with angiography within
4–48 hours followed by revascularisation if the anatomy was suitable, or
to a more conservative strategy with catheterisation only for recurrent
ischaemia or a positive stress test. Death, non-fatal MI and rehospitalisation
for ACS at 6 months occurred in 15.9% of patients in the invasive arm and 19.4%
in the conservative arm (P=0.025). The benefit of an invasive approach was
confined to medium and high-risk patients who had elevated troponins, ST segment
changes or diabetes.
RITA 355 also showed benefit of an invasive strategy in high
risk patients treated with enoxaparin for 3 days prior to intervention. The ISAR
Cool study56 showed that an immediate invasive approach in 410 patients with
either ST depression or elevated troponins (time to angiography of 2.4 hours)
together with aspirin, clopidogrel, UFH and tirofiban resulted in lower rates of
MI (5.9% vs 10.1%) compared with delaying PCI while on the same therapy for 72
hours. In the ICTUS (Invasive vs Conservative Treatment in Unstable Coronary
Syndromes) study (Hot Lines ESC Munich 2004) a very high rate of intervention
(73%) showed no advantage over a selective invasive strategy (47%).
An early invasive strategy within 48–72 hours together
with intensive antithrombotic therapy is strongly recommended for patients with
elevated troponin levels (or other cardiac markers of myocardial necrosis)
1++A,
patients with ST segment changes, diabetes, patients with recurrent or
continuing ischaemic symptoms at rest or on mild exertion despite medical
therapy (beta-blocker or calcium channel blockers) and patients with
interstitial or pulmonary
oedema.D4
Several comorbidities such as renal failure are relative
contraindications for angiography and revascularisation. Advanced age is not an
absolute contraindication for angiography and PCI. Because of data22 showing
reduced readmissions, PCI may be of particular value in the elderly.57
Increasing stroke rates with surgery makes surgery unattractive in the very
elderly.
In patients going to the catheterisation laboratory without
pre-treatment with glycoprotein IIb/IIIa antagonists, it is recommended that
administration of eptifibatide or abxicimab in the laboratory be considered,
especially in patients with diabetes or the presence of angiographic
thrombus.1++A
It is recommended that troponin positive patients waiting
for surgery should be on clopidogrel and have it stopped 5 days before
surgery.1++B
Secondary preventionAll patients should be referred to rehabilitation services.
All patients without contraindication should be on aspirin, a β-blocker, a
statin and an ACE inhibitor indefinitely and if funding allows clopidogrel for 9
months. Patients should also stop smoking, achieve ideal weight, and exercise 30
minutes/day.
Resource availabilityIt is recognised that in New Zealand that providing
expensive pharmaceuticals and equitable provision of an invasive strategy for
Maori and in rural populations will be challenging.58 However, it is recognised
that an invasive approach has been shown to be cost effective44,46 and it is
expensive to keep patients in hospital for long periods awaiting diagnostic
testing or to have these patients discharged with a high risk of reinfarction or
readmission to hospital. Extensive cost effective analyses are planned to
determine appropriate levels of funding in the New Zealand setting for patients
with NSTEACS.
ConclusionIn New Zealand cheap and readily available therapies such as
aspirin, beta blockers and ACE inhibitors are under prescribed.59 It is
important that these treatments are used is as many patients as possible and
treatment such as PCI in patients at high risk should also be equitably
available to all New Zealanders.
Author information:
Non ST-Elevation Acute Coronary Syndrome Guidelines Group (refer to Appendix 1
below), nationwide; The New Zealand Branch of The Cardiac Society of Australia
and New Zealand, Wellington
Appendix 1. Non ST-Elevation Acute Coronary Syndromes
Guidelines Group
Albert
Ko Middlemore Hospital, Auckland
Andrew
Hamer Nelson Marlborough Health Service, Nelson
Andrew
Kerr Middlemore Hospital, Auckland
Brandon
Wong Whangarei Hospital, Whangarei
Charles
Renner Kew Hospital, Invercargill
Cherian
Sebastian Taranaki Base Hospital
Cheuk-Kit
Wong Dunedin School of Medicine, Dunedin
Chris
Ellis Green Lane Cardiovascular Service, Auckland City Hospital
Chris
Nunn Waikato Hospital, Hamilton
Clyde
Wade Waikato Hospital, Hamilton
Elana
Curtis Auckland (Maori Advisory Group)
Euan
G. Grigor The Old Cottage Hospital (Lay Representative)
Gerry
Wilkins Dunedin Hospital, Dunedin (Cardiac Society Representative)
Guy
Armstrong North Shore Hospital, Auckland
Hamid
Ikram Christchurch Hospital, Christchurch
Hamish
Hart North Shore Hospital, Auckland
Harvey
White Green Lane Cardiovascular Service, Auckland City Hospital
Helen
Williams Ministry of Health Representative
Hitesh
Patel North Shore Hospital, Auckland
Ian
Crozier Christchurch Hospital, Christchurch
John
Elliott Christchurch Hospital, Christchurch (Heart Foundation
Representative)
John
French Green Lane Cardiovascular Service, Auckland City Hospital
Laura
Lambie Ministry of Health, Wellington
Malcolm
Abernathy Wakefield Hospital, Wellington (Private Hospital
Representative)
Mark
Simmonds Wellington Hospital, Wellington
Mark
Webster Green Lane Cardiovascular Service, Auckland City Hospital
Paul
Tansor Midcentral, Palmerston North
Penny
Astridge Nelson Marlborough Health Service, Nelson
Phil
Matsis Wellington Hospital, Wellington
Richard
Luke Napier Hospital, Napier
Stewart
Mann Wellington Hospital, Wellington
Younis
Al-Khairulla Greymouth
Gerry Devlin Waikato
Hospital, Hamilton
Acknowledgement:
We are extremely grateful to Charlene Nell for secretarial assistance.
Correspondence:
Professor Harvey White, Greenlane Cardiovascular Service, Auckland City
Hospital, Private Bag 92024, Auckland 1030. Fax: (09) 630 9915; email HarveyW@adhb.govt.nz
References:
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