Heart doi:10.1136/heartjnl-2012-302034
  • Education in Heart
  • Acute coronary syndromes

Timing of angiography in non-ST elevation myocardial infarction

  1. Freek W A Verheugt
  1. Department of Cardiology, Heart Center, Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam, The Netherlands
  1. Correspondence to Dr Robert Klaas Riezebos, Department of Cardiology, Heart Center, Onze Lieve Vrouwe Gasthuis, PO Box 95500, Amsterdam 1090 HM, The Netherlands; R.K.Riezebos{at}

Acute coronary syndromes

Acute chest pain remains one of the most difficult challenges for the clinician. Nowadays, chest pain and its related complaints account for up to 10% of the adult emergency admissions and around 25% of all hospital admissions.w1 Notably, the number of patients presenting with complaints of chest pain is rising.w2 In a typical population of patients presented for the evaluation of acute chest pain in emergency departments, about 20% will have an acute coronary syndrome (ACS).w3 w4 The principal pathophysiological mechanism of an ACS is one of myocardial underperfusion resulting from either atherosclerotic plaque rupture or from erosion with different degrees of superimposed thrombus.1 ,2 A minority of patients, estimated to be around 10% of those who presented with chest pain, will not have an ACS but another life threatening problem such as a pulmonary embolism or an acute aortic dissection.w1 Most patients are discharged with the diagnosis of a non-cardiac condition. These non-cardiac conditions include musculoskeletal syndromes, gastrointestinal syndromes, and psychological disorders.

When evaluating cardiac chest pain, an ECG provides the initial classification. Patients are subdivided into those with a persistent ST segment elevation and those without a persistent ST segment elevation. The latter is called a non-ST elevation ACS (NSTE-ACS). The concentration of the biomarkers of necrosis above a certain prespecified threshold differentiates NSTE-ACS patients into those with a non-ST elevation myocardial infarction (NSTEMI) as opposed to those with unstable angina (Ofigure 1). This article focuses on the timing of invasive evaluation in those patients with a suspected NSTE-ACS.

Figure 1

Diagnostic approach to the patient with chest pain. NSTE-ACS, non-ST elevation acute coronary syndrome; NSTEMI, non-ST elevation myocardial infarction; STEMI, ST elevation acute myocardial infarction; UAP, unstable angina pectoris.

Evaluate the probability of an ACS

In patients presenting with a suspected NSTE-ACS, the first hurdle is to confirm the diagnosis. Guidelines recommend the use of elementary tools—such as the patient's symptoms, the risk profile for coronary artery disease (CAD), the ECG, and biomarkers—to estimate the likelihood of the disease. Echocardiography in the acute phase is also used to confirm a diagnosis.1 ,2 w5 However, should the diagnosis remain uncertain, the clinical probability of an ACS should be assessed.w6 In the case of a low clinical probability, patients could be discharged safely following application of a diagnostic test using a high sensitivity and high negative predictive value. Recent focus has mainly been on biomarker analysis, with high sensitive troponin assays currently being the preferred biomarkers for ruling out ACS.1 ,3 However, lowering the detection limit by the use of an increased sensitivity assay results in identifying more patients with a cardiac injury which is not caused by ACS. OFigure 2 shows that with a decreasing detection level for troponin, both the absolute number of patients with ACS as well as the proportion of patients with an alternative pathology will increase. Obviously, the need for additional testing still remains.

Figure 2

The influence of the troponin detection limit in relation to its diagnostic performance in detecting acute coronary syndrome (ACS) and non-ACS pathology. Decrease of the troponin detection limit results in an absolute increase in patients with ACS and a higher proportion of alternate pathology identification.

Ischaemia testing, such as exercise testing optionally combined with an imaging modality, is frequently used within the subacute setting. These tests are most useful in patients with an intermediate probability of an ACS. Poor performing tests, such as treadmill or bicycle exercise testing, should be used for prognostic purposes only. CT angiography (CTA) is at present the most accurate non-invasive test to rule out CAD.1 ,4 Nowadays, more sophisticated scan protocols using prospective ECG gated triggering have led to a substantial reduction in radiation exposure without loss of image quality.w7 Moreover, alternative pathologies such as pulmonary tumours, embolism, and aortic dissection can also be detected.w8 In selected patients with acute chest pain and a low to intermediate risk, the diagnostic accuracy of CTA is sound and reduces hospital admission rates and length of stay.w9–w12

Wherever there is a high probability of ACS, patients should be admitted to a hospital for clinical follow-up and treatment. When in doubt the diagnosis of ACS should only be waived if based on tests with both a high sensitivity and specificity—invasive coronary angiography is currently the gold standard.1 In this population, coronary angiography is able to exclude CAD reliably. This must be ascertained because, even in the presence of ECG changes and a rise in troponin, about a fifth of patients suspected of a high risk NSTE-ACS will show no significant lesions on coronary angiography.5 w13 These patients generally have a low risk and should be evaluated for alternative pathologies.

Invasive strategies in NSTE-ACS

Early angiographic observations in the 1970s showed that most cases of acute myocardial ischaemia are caused by coronary atherosclerosis. In a myocardial infarction (MI) showing ST segment elevation (STEMI) on a given ECG, an occlusion of a major epicardial coronary artery will also be observed in most cases.w14 Unlike STEMI, acute total coronary occlusion is not very common in NSTE-ACS. Therefore, reperfusion therapy with fibrinolysis is not appropriate and is reportedly harmful.w15 Even so, myocardial ischaemia is a key element in NSTE-ACS and anti-ischaemic and antithrombotic treatment should be initiated. An early coronary intervention regarding this syndrome is quite feasible, as was first discovered in the mid 1980s.w16 It relieves myocardial ischaemia and by visualising the coronary anatomy it becomes a good prognostic indicator.

Patients with NSTE-ACS have a diverse prognostic outcome. In general, the expected risk determines the extent of the pharmacologic and revascularisation treatment. Risk assessment is a continuous process that may modify the diagnostic and treatment strategy at any given time. Besides well known clinical markers such as age, sex, and comorbidities, the abnormalities and dynamics in both ECG and biomarkers play an important role in the determination of the prognosis.1 In general, extensive ECG changes such as ST segment depression, negative T waves or a rise and fall in troponin concentrations correspond to an increased risk. In order to quantify this risk more accurately, several (scoring) models have been developed, with the GRACE (Global Registry of Acute Coronary Events) and TIMI (Thrombolysis in Myocardial Infarction) risk scores being the most widely used. Both models show a strong relationship between indicators for the likelihood of an NSTE-ACS and the prognosis.6 w17 The clinical application of the TIMI and GRACE risk scores has been evaluated extensively and recently highlighted in Education in Heart.7

A revascularisation procedure will be considered when NSTE-ACS patients are thought to have an intermediate to high risk of recurrent events.1 ,2 During NSTE-ACS, applying an early coronary intervention may prevent a myocardial (re)infarction. However, long term mortality is not effectively altered.8–,10 w18 This benefit is most pronounced in patients with the highest risk. There are two revascularisation methods: percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG).1 ,2 Coronary bypass surgery was first applied in the early 1960s by René Favoloro in Cleveland and has significantly contributed to the quality of life and lifespan of patients with symptomatic ischaemic heart disease. In 1977 Andreas Grüntzig introduced percutaneous transluminal coronary angioplasty, a technique that postponed or even prevented coronary surgery in many symptomatic patients. Nowadays, the number of PCIs undertaken largely outnumbers CABG in the western world. Both methods have their own particular benefits and shortcomings. Choosing a revascularisation method therefore depends mainly on the clinical characteristics, coronary anatomy, and the patient's preference. On the whole, when both options are considered equally feasible, PCI seems to relate to more repeat revascularisation procedures whereas CABG relates to a higher rate of perioperative cerebral vascular accidents.11

Timing of angiography in NSTEMI

A subset of patients with NSTE-ACS are considered to have such an increased mortality risk that immediate revascularisation is indicated.1 ,2 These include patients with cardiogenic shock, severe left ventricular dysfunction, suspected left main stem disease, recurrent or refractory ischaemia at rest despite intensive pharmacological treatment, mechanical complications such as acute mitral regurgitation, and sustained ventricular tachycardias. However, most patients can be medically stabilised. Intermediate to high risk patients should be evaluated for an invasive approach. In this patient group, the correct timing of percutaneous intervention in a patient with NSTEMI has been a matter of much debate.

Early intervention may prevent further infarcts, but it can also be more harmful as it may lead to an increased incidence of periprocedural complications related to the thrombotic state of the culprit lesion. First line medical treatment of the culprit coronary plaque may be beneficial, but it takes time to have an effect, during which recurrent infarction may occur. Several recent randomised trials compared an urgent (<2 h after admission) or early (6–24 h) invasive strategy with a delayed (24 h) or a longer delayed (72 h or more) intervention (table 1).

Table 1

Methodological differences between trials evaluating the timing of the invasive approach in non-ST elevation acute coronary syndromes

The first published study which evaluated the timing of the routine invasive approach is the ISAR-COOL (Intracoronary Stenting With Antithrombotic Regimen Cooling-Off) trial.12 This trial randomised patients with a suspected NSTE-ACS to an early (within 24 h after anginal complaints) or a 3–5 day deferred invasive diagnostic strategy. Although there was no difference between the groups regarding the individual end points, the combined end point of death and MI occurred significantly less in the early arm when compared to the deferred strategy.12 Recently, both TIMACS (Timing of Intervention in Patients with Acute Coronary Syndromes) and ABOARD (Angioplasty to Blunt the Rise of Troponin in Acute Coronary Syndromes Randomized for an Immediate or Delayed Intervention) trials assessed the feasibility of a very early invasive diagnostic routine.13 ,14 The TIMACS trial is clearly the largest study performed to date, with about 1500 patients in both arms. The study resulted in negative primary end points. However, a sub-analysis of the high risk population, defined as a GRACE risk score of >140, suggested a benefit in the early arm.14 The ABOARD trial evaluated the primary PCI approach for NSTE-ACS and compared this to elective angiography on the following day.13 The trial failed to show any benefit when using this approach. In addition, a trend towards more MI in the early group was suggested.

Based on the TIMACS,14 ABOARD,13 and ISAR-COOL12 trials, the recently updated European guidelines advise that high risk patients (GRACE risk score >140) should be evaluated by an early invasive strategy within 24 h. Furthermore, it states that in intermediate risk patients, the invasive evaluation can be safely delayed but should be performed during the same hospital stay, preferably within 72 h of admission.1

The recently published LIPSIA-NSTEMI (Leipzig Immediate versus Early and Late Percutaneous Coronary Intervention trial in NSTEMI) trial randomised patients with NSTEMI to an immediate (within 2 h after randomisation), an early (10–48 h after randomisation), and a selective invasive approach. There was no difference in mortality. The trial did show a more prevalent MI in patients receiving the immediate approach, but it was also associated with less refractory ischaemia as compared to a deferred or selective invasive approach.15

Timing of PCI in NSTEMI

The influence of timing on PCI remains inconclusive because the aforementioned trials chose to randomise the timing of coronary angiography and not all of the patients were treated with PCI (table 1). It is likely that the influence of timing of coronary angiography is less pronounced in patients who are treated conservatively or who eventually undergo CABG. It is clear that a fast, invasive diagnostic approach has diagnostic benefits and facilitates the logistics of further treatment planning. However, the question remains: should an early angiography always be followed by prompt intervention? To assess this question, the OPTIMA trial randomised patients with a suspected NSTEMI to immediate or delayed PCI after eligibility was determined by acute coronary angiography.5 Although the trial was terminated prematurely, due to slow patient recruitment, it seemed to suggest more periprocedural MI in the immediately treated group (table 1).5

The findings regarding the effects of periprocedural MI risk observed in OPTIMA, ABOARD, and LIPSIA-NSTEMI seem to contradict data from a post-hoc analysis of the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial which suggested a better outcome with urgent revascularisation.16 Although this study included a large patient sample, the design of the ACUITY trail was not suited to detect the influence of timing of PCI. These observational studies are extremely liable to indication bias and should therefore be interpreted with the utmost caution.

Influence between timing of intervention and MI

Are there any clues regarding the optimal timing of intervention which can be distilled from the data provided by the five trials on this topic? It is reasonable to presume that the influence of the timing of an invasive therapy is most pronounced just after an acute event. Therefore, it is likely that the timing of the initiation of therapy in the early invasive group will be the most important variable. In this case, a time–event relationship can be estimated using the relative risk for MI for each trial and plotted against the time of admittance to diagnostic catheterisation—the latter being at least slightly related to the timing of intervention. OFigure 3 shows the results for MI and major bleeding, respectively, according to time of angiography for the different trials on the subject. Although the combined data show no significant hazard for the early invasive approach, there appears to be an inverse relationship between time to angiography and the occurrence of (mostly) periprocedural MI (relative risk (RR) 1.3, 95% confidence interval (CI) 0.77 to 2.25) (figure 3A). OFigure 4 shows this interpretation and suggests a ‘U’ shaped curve time–event relationship for high risk patients, whereas the beneficial effect of PCI on recurrent ischaemia is less pronounced for low risk patients. According to this scheme the optimal timing of angiography in patients with NSTE-ACS might well prove to be between 12–24 h after admittance.

Figure 3

The risk of clinical events with an early versus a more deferred invasive strategy in non-ST elevation acute coronary syndrome in five randomised trials comparing the (very) early with the later invasive treatment: ABOARD,13 OPTIMA,5 ISAR-COOL,12 LIPSIA-NSTEMI15 and TIMACS.14 (A) Myocardial infarction. (B) Major bleeding. See text for explanation of trial names.

Figure 4

The relationship between timing of intervention and myocardial infarction according to risk stratification in the setting of a non-ST elevation acute coronary syndrome: a trade-off between periprocedural and spontaneous events.

Influence between timing of intervention and major bleeding

The influence of timing of intervention on bleeding risks has not been critically assessed in the literature. Nevertheless, major bleeding could be another important clinical event which is likely to be associated with the timing of intervention. Once more, the combined data of the five trials show no significant benefit for the early invasive approach (RR 0.82, 95% CI 0.60 to 1.13) (figure 3B). However, although the number of bleeding events was limited, major bleeding was less prevalent in the earliest treated groups in almost all the aforementioned trials. This might reflect the increasing effect of anticoagulant and antiplatelet treatment over time, whereby the increased risk of periprocedural MI could be counterbalanced by a decreased risk of major bleeding. Similar to the relationship of timing and MI risk, the influence between time to angiography and major bleeding seems to be the most pronounced in the very early treated patient groups. This could imply that patients at high risk of bleeding may benefit from an early angiography.14

Trade-off between periprocedural and spontaneous MI

Several trials show that a very early invasive strategy is associated with an increase in periprocedural myocardial damage.5 ,13 ,15 Intervention delay, on the other hand, appears to be associated with the risk of new, spontaneous ischaemic events.14 ,15 The higher the risk for recurrent ischaemic events, as estimated by the GRACE risk score, the more benefit one may expect from an early invasive approach (figure 4). Nonetheless, neither approach results in a mortality benefit.17 w19 An important question to address is whether periprocedural myocardial necrosis should be considered reciprocal to the adverse consequences of spontaneous myocardial necrosis.

The evidence on this topic is conflicting. Although MI related to CABG is evidently associated with a worse prognosis, the association between prognosis and type 4a MI is less clear.18–,20 w20 In a recent evaluation of TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38), the occurrence of a type 4a MI more than doubled the mortality risk.18 However, patient pooling of three large ACS trials regarding the use of routine versus selective invasive procedures did not detect an adverse prognostic association regarding long term mortality.19 It might well be that type 4a MI has a lesser influence on future events than spontaneous or other procedural MIs, such as stent thrombosis and those related to CABG. However, there still appears to be an inverse relation between the amount of myocardial damage and the patient's prognosis, regardless of the type of MI.18 w20 Therefore, it seems reasonable to argue that one should attempt to minimise periprocedural myocardial injury.

Future research

There remain several issues to be resolved regarding the use of an immediate invasive strategy. First, does the observed increase in periprocedural myocardial enzyme lead to a diminished prognosis? The available studies were insufficiently powered to detect a difference in mortality and there is a lack of long term follow-up data. The IDEAL NSTEMI (Immediate versus Early Invasive Approach in NSTEMI) trial is currently recruiting patients with NSTE-ACS and randomly assigning them to immediate (<2 h) or a delayed (12–72 h) invasive approach according to guidelines with respect to 6 months death and mortality. This trial is sufficiently powered and expected to include more than 2000 patients.

The second issue to be addressed is whether modern pharmacological therapy, using novel quick acting antiplatelet agents, anticoagulants and statins, can prevent the excess of periprocedural MI observed during application of the immediate invasive strategy. Until now, all trials have used clopidogrel as an ADP antagonist, and because of its late and unreliable onset, this is no longer regarded as the standard of care.1 It is not unlikely that modern pharmacological treatment reduces the periprocedural risk while the protective effect regarding recurrent ischaemia remains. In order to address this question, the OPTIMA-2 trial will evaluate an immediate (<3 h) invasive strategy with a 12–24 h delayed invasive strategy using modern antiplatelet and anticoagulant treatment with infarct size as its primary end point.


In NSTE-ACS, a myocardial (re)infarction may be effectively diminished by applying an early coronary intervention, but long term mortality may not be diminished. This benefit is most pronounced in patients at the highest risk. These patients should be evaluated by early angiography during their hospitalisation. However, the available studies suggest a modest increase of periprocedural MI in the group treated very early. The time–event relationship of intervention within ACS takes the form of a ‘U’ shaped curve, with times to intervention that are either too short or too long posing a certain risk of infarction. However, there is evidence that periprocedurally inflicted MI has lesser influence on future events than a spontaneous MI. In addition, very early intervention seems to be associated with a diminished risk of major bleeding. Both observations suggest a crescendo effect of antiplatelet and coagulant treatment in time. Consequently, these associations are likely to change as newer, stronger and faster acting medications are introduced.

For now, the timing of intervention does influence the clinical course, and the optimal time to intervene could well be around 12–24 h after initiation of medical treatment. The patient at highest risk should be treated sooner, and those at lowest risk can wait longer, as is stated in the recent European NSTE-ACS guidelines.

Timing of angiography in non-ST elevation myocardial infarction: key points

  • Evaluation of non-ST elevation acute coronary syndrome (NSTE-ACS) and treatment strategies

  • In patients presenting for the evaluation of acute chest pain in emergency departments, about 20% will have an ACS.

  • Of these patients the first hurdle is to confirm the diagnosis by: differentiating the evaluation of the symptoms; the risk profile for coronary artery disease; the ECG; and by biomarker analysis.

  • Patients with NSTE-ACS have a diverse prognostic outcome whereby the expected risk determines the extent of revascularisation and pharmacotherapy.

  • A revasculariation procedure is to be considered when NSTE-ACS patients have an intermediate to high risk of recurrent events.

  • In order to quantify this risk more accurately, several scoring models have been developed with the GRACE score being preferred by the European Society of Cardiology guidelines.

  • During NSTE-ACS, applying an early coronary intervention may prevent myocardial (re)infarction; however, long term mortality is not altered.

  • When percutaneous coronary intervention and coronary bypass surgery are considered, the former is associated with more repeat revascularisation procedures, whereas the latter is associated with a higher rate of perioperative cerebral vascular accidents.

  • Timing of invasive strategies in NSTE-ACS

  • A subset of patients with NSTE-ACS has such an increased mortality risk that immediate revascularisation is indicated, but most patients can be stabilised medically.

  • An early invasive diagnostic approach has diagnostic benefits and facilitates the logistics of further treatment planning.

  • Several trials show that a very early invasive strategy is associated with an increase in (mostly limited) periprocedural myocardial damage.

  • Delay of intervention is associated with the risk of new, spontaneous ischaemic events.

  • In high risk NSTE-ACS patients, the optimal timing of angiography is between 12–24 h after admittance.

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  • Contributors Both authors participated in the literature search and the writing of the article. Both authors gave approval to the final version to be published.

  • Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflict of interest that might cause a bias in the article. The authors have no competing interests.

  • Provenance and peer review Commissioned; externally peer reviewed.


  1. Contemporary registry evaluating the implementation of a novel high sensitive troponin essay in patients with suspected ACS. High sensitive troponin increased the diagnosis of MI and identified patients at high risk of recurrent MI and death. Lowering the diagnostic threshold of plasma troponin reduced morbidity and mortality.
  2. Meta-analysis evaluating the diagnostic accuracy of CT and MR. For ruling out CAD, CT proved more accurate than MRI. Scanners with more than 16 rows improved sensitivity, as did slowed heart rates.
  3. A randomised controlled trial in patients with NSTE-ACS evaluating immediate versus delayed (24–48 h) PCI. Patients were only randomised when they were deemed eligible for PCI after immediate angiography. Immediate PCI was associated with an increased rate of MI in comparison with a 24–48 h deferred strategy.
  4. Pooled analysis of the long term results of three randomised trials shows that a routine invasive strategy reduces long term rates of cardiovascular death or MI and the largest absolute effect is seen in higher risk patients.
  5. Large randomised controlled trial evaluating revascularisation using CABG or PCI in patients with three vessel or left main coronary artery disease. PCI showed an increased rate of repeat revascularisation, whereas stroke was significantly more likely to occur with CABG.
  6. The first randomised controlled trial that evaluated the influence of timing of angiography and subsequent intervention in NSTE-ACS. The results suggested that prolonged antithrombotic treatment poses a risk for the reoccurrence of new spontaneous ischaemic events.
  7. A randomised controlled trial that evaluated an immediate invasive approach in patients with NSTE-ACS as opposed to a next day approach. No difference was found in the primary end point which was a rise in troponin.
  8. The largest randomised controlled trial to date (n=3031) which evaluated the influence of timing of the early invasive approach in NSTE-ACS. Although there was no difference in mortality, the results suggested that an early intervention reduces the occurrence of refractory ischaemia in high risk patients.
  9. A randomised trial which evaluated the immediate (<2 h), an early (10–48 h), or a selective invasive approach in patients with NSTEMI. The routinely immediate invasive approach showed more non-fatal MI, whereas the delayed and selective approach showed more recurrent ischaemia. There was no mortality difference among the groups.
  10. A post-hoc analysis of 6 months results of the large TRITON-TIMI 38 trial (n=13 608), evaluating the prognostic influence of spontaneous versus procedure related MI. The results suggested that MI was associated with an increased risk of cardiovascular death irrespective of its cause.
  11. A pooled analysis whereby long term (5 year) results of three randomised trials in NSTE-ACS suggest that spontaneous MI will, but procedure related MI will not, be related to an increase in long term mortality.

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