Guideline Development Groups (GDG) within the American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC) review the literature periodically, and using a rigid methodology, produce guidelines relevant to an area of clinical practice. The weight of evidence for each recommendation is carefully evaluated. In this context, they have developed guidelines for the management of acute coronary syndromes (ACS).1,2 As one of their aims, the British Cardiovascular Society and the Royal College of Physicians promote best practice and the implementation of the above clinical guidelines, but together with other professional bodies within the UK, they also agreed to participate in the development and implementation of a guideline on unstable angina and non-ST-segment-elevation myocardial infarction (NSTEMI), produced by the National Institute for Health and Care Excellence (NICE).
Why do we need NICE guidelines as well as internationally agreed clinical guidelines? International GDGs synthesise numerous studies that are derived from different healthcare systems and base their recommendations on clinical outcomes with no bearing on cost effectiveness. The NICE guidelines translate the findings from international studies into the UK setting and also perform cost-effectiveness analyses for key decisions within the guidance. Of course, since devolution, guidelines from NICE are only relevant to England and Wales; Scotland and Northern Ireland are both free to follow different systems. For example, in Scotland, most clinicians follow the relevant Scottish Intercollegiate Guidelines Network (SIGN) guideline.3
The recently published NICE guideline on The early management of unstable angina and non-ST-segment-elevation myocardial infarction (Clinical Guidance 94) concentrates on five major areas:4,5
- Risk assessment
- Antiplatelet therapy
- Anticoagulant therapy
- The early invasive strategy
- Long-term management.
After a patient has been diagnosed with unstable angina or NSTEMI, the individual risk of future cardiovascular events should be assessed. The likelihood of a patient either dying or having a major heart attack can be determined by integrating a number of key clinical, electrocardiographic, and biochemical markers. The NICE GDG compared a number of risk scores for this purpose. Arguably, the most useful of these is the 6-month risk score developed from the Global Registry of Acute Coronary Events (GRACE).6 An analysis showed that predicted mortality from the GRACE score correlated well with national mortality data from the Myocardial Ischaemia National Audit Project (MINAP) database.7 The score can be calculated online8 and can also be downloaded onto a palmtop or iPhone, making it easy to use in daily practice. Although some clinicians seem to think that risk stratification is based largely on troponin testing, this is clearly not the case. It is true that troponin testing has radically altered the management of patients in the hospital setting, but it is important to realise that troponin is one of many risk markers. Although troponin-positive patients are at higher risk than those who are troponin-negative, many individuals who are positive for this factor still remain at relatively low risk.9
The clinical indicators required to calculate the GRACE risk score are:8
- heart rate on admission
- systolic blood pressure on admission
- serum creatinine on admission
- Killip class (a classification of acute heart failure)
- cardiac arrest during presentation
- ST-segment deviation on presenting electrocardiogram
- positive initial cardiac biomarkers.
The GDG classified patients in the MINAP database into five risk groups (see Table 1).5 These groups were important in the various cost-effectiveness analyses that helped to inform the NICE recommendations.
|Table 1: Categorising risk in patients with unstable angina and NSTEMI4,5|
|Risk of future adverse cardiovascular events||Predicted 6-month mortality (%)|
|Low||1.5 to 3|
|Intermediate||>3.0 to 6.0|
|High||>6.0 to 9.0|
The aim of treating ACS is to minimise the risk of thrombotic and ischaemic complications (myocardial infarction, worsening ventricular function, and death). The therapeutic strategies include:
- the use of antiplatelet and antithrombotic therapy, and
- the use of coronary revascularisation by either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).
Although the effectiveness of treatment strategies is well recognised, they all carry a risk of bleeding. Bleeding may be minor (e.g. oozing from gums) or major (e.g. significant gastrointestinal, retro-peritoneal, or intra-cerebral bleeds). Significant bleeds are associated with a mortality risk of their own, countering the potential positive effects of the treatments chosen.10 The guideline highlights this fact and suggests that an evaluation of bleeding risk is also performed on all patients and taken into account when determining which treatment to apply. In other words, some treatments might not be chosen for some patients on the basis that the risks of the treatment outweigh the benefits.
The NICE guideline points to four markers associated with high bleeding risk:4,5
- Increasing age
- Low body weight
- Renal dysfunction
- Known propensity to bleeding (e.g. a recent cerebral event or active peptic ulcer disease).
In the future, specific risk models for bleeding in this patient group may become used on a routine basis. One such model is the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) risk score, which also has the benefit of being available online.11
Aspirin and thienopyridine treatment
Aspirin is well established in the management of ACS and there has been no new information that changes this. Once a diagnosis of unstable angina or NSTEMI has been made (the latter requires the use of biomarker evidence of myocardial necrosis, usually troponin), patients should be offered a single loading dose of 300 mg aspirin and then receive 75–150 mg daily thereafter. The NICE GDG did not address the question of whether this should be 75 mg or 150 mg as there were no new studies that informed this issue; most clinicians use 75 mg. Aspirin therapy should be continued indefinitely.4,5
Patients who have aspirin hypersensitivity should be offered clopidogrel monotherapy.12 Since the NICE guideline on unstable angina and NSTEMI was published, the results of the CURRENT-OASIS 7 (Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTS/Optimal Antiplatelet Strategy for Interventions) trial have been reported (although not yet published).13 This used a 2 x 2 factorial randomised trial to investigate both a higher loading and early dosing regimen for both clopidogrel and aspirin. The results did not provide compelling evidence for the use of higher doses of aspirin following the initial loading dose.
The GDG evaluated new evidence that had emerged following the previous recommendations on the use of thienopyridine antiplatelet drugs and confirmed that clopidogrel should be prescribed to all but the lowest risk (predicted 6-month mortality <1.5%) patients. A 300 mg loading dose of clopidogrel was recommended.4,5
The GDG was not able to evaluate some of the emerging data on a 600 mg loading dose of clopidogrel because of the timelines of the NICE process, but this dosage was discussed in the full guideline.5 There is emerging evidence for the clinical benefit of a 600 mg load, especially for individuals undergoing early PCI,4,5 but the guideline could not make this recommendation, partly because there is no marketing authorisation for this dose in the UK. Nevertheless, many centres have started to use this dose for patients undergoing an early invasive strategy (see below).
Following the loading dose, patients should receive clopidogrel 75 mg daily, and so the vast majority of patients will be discharged from hospital on dual antiplatelet therapy (aspirin and clopidogrel), which should be continued for 1 year. Thereafter, the patients should continue with aspirin alone.4,5
Timing of antiplatelet therapy
When weighing up the timing of starting treatment, one has to consider the desire to avoid early adverse events, and balance it with bleeding risks in the individual patient. This is particularly important for patients who undergo coronary angiography and for whom revascularisation with CABG is deemed appropriate.
If the healthcare professional postpones giving clopidogrel when the diagnosis is first made, some patients may have an adverse event while waiting for angiography and then, if immediate PCI is required, this procedure would be carried out without the benefits of clopidogrel pre-treatment. On the other hand, delaying clopidogrel therapy until after coronary angiography is performed in patients undergoing CABG, removes the concern over the increased potential for bleeding that occurs if the patient is on dual antiplatelet therapy; hence early surgery can be planned.
However, as the majority of patients undergoing angiography are treated either by medical therapy alone or by PCI, most units prescribe clopidogrel immediately following diagnosis to reduce the risks of early events and to minimise the risks of PCI. In these circumstances, clopidogrel should be withdrawn following angiography if CABG is deemed appropriate, and surgery delayed until the effect of clopidogrel wears off (at least 5 days). If the patient is very unstable, then clinicians need to weigh up the ischaemic and bleeding risks when deciding on the most appropriate time for surgery.
New antiplatelet therapies
A new antiplatelet drug, prasugrel, has now been licensed. In some patients there is a genetically determined reduction in the efficacy of clopidogrel as an antiplatelet agent, but most of these patients will respond to prasugrel. By using prasugrel for all individuals, the doctor would be more confident that the majority of patients receive the desired effect of the drug. This additional efficacy has been shown to provide better outcomes in some circumstances, but it is also associated with a slightly higher risk of bleeding. It should, therefore, not be prescribed to patients:14
- with evidence of a previous cerebrovascular accident or transient ischaemic attack
- aged 75 years or more,
- with a low body weight (<60 kg).
The use of prasugrel was not covered within the unstable angina/NSTEMI guideline because NICE had already produced separate guidance on its use.14 It has not been recommended for all patients presenting with unstable angina or NSTEMI, but can be considered for patients:14
- undergoing PCI in the setting of ST-segment-elevation myocardial infarction (STEMI)
- with diabetes mellitus
- who have suffered a stent thrombosis while already taking clopidogrel.
Other drugs are under evaluation, some of which are already undergoing appraisal by NICE and so recommendations can be expected to change in due course. One such drug, ticagrelor, has been shown to provide better clinical outcomes than clopidogrel,15 but it is not yet available in the UK and has not been fully appraised.
Glycoprotein IIb/IIIa inhibitors
Glycoprotein IIb/IIIa inhibitors (GPIs) are powerful antiplatelet treatments that are given intravenously. Two of these treatments—the so-called ‘small-molecule’ GPIs eptifibatide and tirofiban—are licensed for use in the management of patients with ACS. The third agent, abciximab, is licensed for use during PCI. Previous NICE guidance on the use of GPIs was based on an early meta-analysis that demonstrated a reduction in the composite of death and myocardial infarction when used in the treatment of NSTEMI ACS, particularly in patients with a positive troponin test.16 However, these studies were performed prior to the widespread use of clopidogrel and other oral antiplatelet therapies.
The NICE GDG evaluated a number of more recent studies and concluded that GPIs remained clinically effective and cost effective if the predicted risk of mortality at 6 months was >6%, and are likely to be cost effective for those with a predicted 3–6% mortality.4,5 However, their efficacy in lower risk patients was questionable and the cost-effectiveness analyses did not support the use of these agents in this group of patients.
Unfractionated heparin, enoxaparin, and fondaparinux
In former years, patients with unstable angina or NSTEMI were routinely treated with unfractionated heparin (UFH). Although this reduces adverse events, it requires an intravenous infusion and also has to be carefully monitored as dose response in individual patients varies considerably. In a new meta-analysis, NICE confirmed that the use of the low molecular weight heparin (LMWH), enoxaparin, reduced the risk of myocardial infarction, albeit at a small increased risk in (mainly minor) bleeding. The increased drug cost of enoxaparin is offset by the administration costs of giving intravenous UFH, and cost-effectiveness analyses are in favour of using this agent.5 It is given subcutaneously twice daily and does not require blood tests for dose adjustments. However, it is very important to adjust the dose in some patients, especially those with renal dysfunction who are at increased bleeding risk.
International guidelines support the use of LMWH in the ACS setting, and also approve the use of the related pentasaccharide agent, fondaparinux. This drug was compared with enoxaparin in the large Fifth Organization to Assess Strategies in acute Ischemic Syndromes (OASIS 5) trial.5,17 This study demonstrated that fondaparinux had several benefits over enoxaparin, including:
- a lower bleeding risk
- it is given only once a day rather than twice a day
- it is less expensive
- a reduction in mortality at 6 months as well as a reduction in the 6-month composite endpoint of death, myocardial infarction, and stroke.
The NICE guideline therefore recommended that fondaparinux is offered to patients who do not have a high bleeding risk (unless coronary angiography is planned within 24 hours of admission). It should, however, not be used in patients with significant renal dysfunction (those with a creatinine >265 ?mol/l were excluded from the trial). It was recommended that UFH be used with appropriate dose monitoring, in this particular group of patients.4,5
Bivalirudin is a direct antithrombin agent that has been evaluated in a number of trials. It is relatively expensive compared with heparin but it (together with the restricted use of a GPI in a bail-out situation [when thrombotic complications occur in spite of bivalirudin] during PCI) can be considered as an alternative to the combination of heparin (UFH or LMWH) and routine use of GPI agents.4,5 NICE did not recommend its use as a routine upstream treatment. Analyses of the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial have shown that bivalirudin is more or less equivalent to heparin plus a GPI, but its effectiveness was dependent on the concomitant use of clopidogrel.18,19
A cost-effectiveness analysis led to the recommendation that bivalirudin could be used in patients who:4,5
- have a predicted 6-month mortality above 3% and
- are not already receiving a GPI or fondaparinux and
- are scheduled for early angiography within 24 hours of admission.
The early invasive strategy
A number of trials have randomised patients to either undergo early (in-hospital) angiography with a view to coronary revascularisation, or to follow an initial conservative strategy in which patients are selected for revascularisation on the basis of clinical ischaemic events or inducible ischaemia as identified by exercise testing or a perfusion scan. The results of these trials appear to depend on the rate of revascularisation in the conservative arm.5 A meta-analysis of studies comparing an invasive strategy against a truly conservative approach demonstrated that invasive interventions resulted in a reduction in the composite endpoint of death and myocardial infarction, and other analyses have shown a reduction of readmissions for unstable angina in most trials.20
A new meta-analysis performed by NICE suggested that routine angiography for all patients could not be supported because this strategy has not been shown to be either effective or cost effective in low-risk patients. However, unless contraindicated, angiography with a view to follow-on PCI as appropriate is recommended for all patients with a predicted 6-month mortality of 3% or more. Angiography should be performed as soon as possible for patients who are clinically unstable or at very high ischaemic risk.4,5
Coronary angiography (with follow-on PCI if indicated) should be offered to patients initially assessed to be at low risk of adverse cardiovascular events (predicted 6-month mortality 3.0% or less) if ischaemia is subsequently experienced or is demonstrated by ischaemia testing.4,5
After coronary angiography, a choice has to be made as to whether the patient is best treated with continuing medical treatment, PCI, or CABG. For patients where this decision is not clear, it is recommended that advice is given to the patient after appropriate discussion with both a cardiologist and a cardiac surgeon.4,5
Following publication of the NICE guideline, the results of the Timing of Intervention in Acute Coronary Syndromes (TIMACS) study were reported.21 This demonstrated no benefit for angiography within the first 24 hours for low-risk patients, but there was a clear benefit in terms of reducing composite endpoint of death, myocardial infarction, and stroke over the first 6 months for patients with a GRACE score of >140. Systems of care will therefore be challenged to try and provide angiography earlier than has been the case to date, with much earlier angiography in the higher risk patients. This will have the added advantage of reducing length of stay in hospital, and is likely to be welcomed by patients.
All patients with NSTEMI should have an evaluation of left ventricular function prior to discharge and those presenting with unstable angina should also be considered for pre-discharge assessment. Patients should be treated with appropriate long-term secondary preventive therapies12 (unless contraindicated or not tolerated, this means aspirin, a beta blocker, statin therapy, and either an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker), and the majority of patients will be treated with clopidogrel or an equivalent for 1 year.12 Spironolactone or epleronone should be considered for individuals with poor ventricular function.
Rehabilitation and discharge planning
Key questions for general practice regarding discharged patients and communication between primary and secondary care are listed in Box 1.
Following discharge, patients with heart failure and the appropriate electrocardiographic and ventricular dysfunction criteria should be considered for treatment with either an implantable defibrillator or cardiac resynchronisation therapy (or both).22,23
Lifestyle advice should be offered by rehabilitation teams and this should be supported in community care after discharge. All patients should be advised about:4,5,12
- physical activity and exercise
- diet and weight management
- smoking cessation.
In essence, all patients should be offered cardiac rehabilitation, and active management of their risk factors and titration of secondary preventive medications is necessary.4,5 Hospital services need to work with colleagues in primary care to ensure all patients receive optimal care and are maintained on secondary preventive treatments in the long term. Effective and timely communication between all those involved with the management of these patients within a clinical network is therefore essential. Time and effort is necessary to educate patients about the importance of these treatment strategies.
Finally, the NICE guideline urges the use of audit both within primary and secondary care to ensure that patients receive the appropriate investigations and management, and where these are found to be sub-optimal, systematic changes will be necessary to ensure patients receive a high standard of care.
|Box 1: Key questions for general practice|
NSTEMI=non-ST-segment-elevation myocardial infarction; PCI=percutaneous coronary intervention; CABG=coronary artery bypass grafting
Primary care services should ensure that the doses of secondary prevention medications are uptitrated appropriately, patients are on local coronary heart disease monitor registers, and that weight, blood pressure, and cholesterol levels are continually monitored. Advice on lifestyle measures should be reinforced as necessary.
The recent NICE guideline reinforces the various clinical guidelines that have been previously published, but will influence practice in the UK in several key ways:
- Use of risk stratification to determine the appropriate clinical pathway
- Promotion of:
- an effective and cost-effective antiplatelet and antithrombotic drug regimen for individual patients
- an early invasive strategy in patients who are at intermediate to high risk
- cardiac rehabilitation and secondary preventive treatment strategies for all patients with ACS.
|NICE implementation tools|
NICE has developed the following tools to support implementation of Clinical Guideline 94 on Unstable angina and NSTEMI: the early management of unstable angina and non-ST-segment-elevation myocardial infarction. They are now available to download from the NICE website: www.nice.org.uk.
Baseline assessment tool
- The NICE guideline sets many standards for secondary care in the initial assessment and treatment of unstable angina and NSTEMI—commissioners should ensure contracts specify these interventions
- Key to these standards is the use of a risk assessment tool, such as GRACE, at presentation
- All patients should be offered cardiac rehabilitation on discharge and commissioners should ensure that this is available—a community based service can help reduce tariff costs
- Commissioners should agree audits to ensure patients are receiving the correct treatment, investigations, and secondary prevention across primary and secondary care
- Follow up for secondary prevention in primary care is vital and audit will be required to ensure this meets NICE guidance
- Clopidogrel is recommended for use for 1 year—its cost has recently decreased as it has become generic
- Actual or suspected MI = £1569 (code EB10Z)a
- Clopidogrel 75 mg daily = £10.90 per month (generic), £35.64 (branded)
NSTEMI=non-ST-segment-elevation myocardial infarction; GRACE=Global Registry of Acute Coronary Events; MI=myocardial infarction
- Anderson J, Adams C, Antman E et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction. J Am Coll Cardiol 2007; 50 (7): e1–e157.
- Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology, Bassand J, Hamm C, Ardissino D et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007; 28 (13): 1598–1660.
- Scottish Intercollegiate Guidelines Network. Acute coronary syndromes. A national clinical guideline. SIGN 93. Edinburgh: SIGN, 2003. Available at: www.sign.ac.uk/guidelines/fulltext/93/index.html
- National Institute for Health and Care Excellence. Unstable angina and NSTEMI: The early management of unstable angina and non-ST-segment-elevation myocardial infarction. Clinical Guideline 94. London: NICE, 2010. Available from: www.nice.org.uk/guidance/CG94
- National Clinical Guideline Centre. Unstable angina and NSTEMI: The early management of unstable angina and non-ST-segment-elevation myocardial infarction. London: NICE, 2010. Available at: www.nice.org.uk/guidance/CG94
- Fox K, Dabbous O, Goldberg R et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). Br Med J 2006; 333 (7578): 1091–1094.
- Royal College of Physicians website. Myocardial Ischaemia National Audit Project (MINAP). www.rcplondon.ac.uk/clinical-standards/organisation/partnership/Pages/MINAP-.aspx (accessed 19 July 2010).
- Global Registry of Acute Coronary Events—GRACE. www.outcomes-umassmed.org/grace (accessed 28 July 2010).
- Steg P, FitzGerald G, Fox K. Risk stratification in non-ST-segment elevation acute coronary syndromes: troponin alone is not enough. Am J Med 2009; 122 (2): 107–108.
- Subherwal S, Bach R, Chen A et al. Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score. Circulation 2009; 119 (14): 1873–1882.
- CRUSADE bleeding score. www.crusadebleedingscore.org (accessed 28 July 2010).
- National Institute for Health and Care Excellence. MI: secondary prevention. Secondary prevention in primary and secondary care for patients following a myocardial infarction. Clinical Guideline 48. London: NICE, 2007. Available at: www.nice.org.uk/guidance/CG48
- The Heart.org. CURRENT OASIS-7: Benefit to doubling clopidogrel dose in ACS patients undergoing PCI. www.theheart.org/article/995967.do (accessed 28 July 2010).
- National Institute for Health and Care Excellence. Prasugrel for the treatment of acute coronary syndromes with percutaneous coronary intervention. Technology Appraisal 182. London: NICE, 2009. Available at: www.nice.org.uk/guidance/TA182
- Wallentin L, Becker R, Budaj A at al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361 (11): 1045–1057.
- National Institute for Clinical Excellence. Guidance on the use of glycoprotein IIb/IIIa inhibitors in the treatment of acute coronary syndromes. Technology Appraisal 47. London, NICE: 2002. Available at: www.nice.org.uk/nicemedia/live/11470/32442/32442.pdf
- Yusuf S, Mehta S, Chrolavicius S et al; Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006; 354 (14): 1464–1476.
- Stone G, McLaurin B, Cox D et al; ACUITY Investigators. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355 (21): 2203–2216.
- Lincoff A, Steinhubl S, Manoukian S et al; ACUITY Investigators. Influence of timing of clopidogrel treatment on the efficacy and safety of bivalirudin in patients with non-ST-segment-elevation acute coronary syndromes undergoing percutaneous coronary intervention: an analysis of the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) Trial. JACC Cardiovasc Interv 2008; 1 (6): 639–648.
- Bavry A, Kumbhani D, Rassi A et al. Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials. J Am Coll Cardiol 2006; 48 (7): 1319–1325.
- Mehta S, Granger C, Boden W et al; TIMACS Investigators. Early versus delayed
invasive intervention in acute coronary syndromes. N Engl J Med 2009; 360 (21): 2165–2175.
- National Institute for Health and Care Excellence. Implantable cardioverter defibrillators for arrhythmias. Technology Appraisal 95. London: NICE, 2006. Available at: www.nice.org.uk/guidance/TA95
- National Institute for Health and Care Excellence. Cardiac resynchronisation therapy for the treatment of heart failure. Technology Appraisal 120. London: NICE, 2007. Available at: www.nice.org.uk/guidance/TA95G