Early risk assessment is emphasised in guidelines for the management of acute coronary syndromes (ACS) from the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA). They recommend angiography and any subsequent revascularisation should be performed in high-risk patients.

The trials these recommendations are based upon utilised an early invasive strategy. In FRISC II1 (FRagmin and Fast Revascularisation during InStability in Coronary artery disease) mean delay-to-angiography was four days. In TACTICS TIMI-182 (Treat Angina With Aggrastat (tirofiban)) and Determine Cost of Therapy with Invasive or Conservative Strategy Thrombolysis In Myocardial Ischemia/Infarction) median delay was 22 hours and in RITA-33 (Randomized Intervention Trial of unstable Angina) the median time-to-angiography was two days. Meta-analysis4 showed no early or intermediate mortality benefit from an early invasive strategy, but found a difference in late mortality in favour of early invasive treatment.

In real-world practice, this rapid access may not be achieved. Few data are available on the effects of an invasive approach after 72 hours in high-risk NSTE-ACS (non-ST-elevation acute coronary syndromes).

GRACE (Global Registry of Acute Coronary Events) is a multinational, prospective observational cohort study of patients hospitalised for suspected ACS.5 The study presents an opportunity to investigate whether time delays influence clinical outcomes in a large real-world population.

METHODS

The methods used in GRACE are described elsewhere.5 In all, 113 hospitals in 14 countries have enrolled patients. Patients were admitted for ACS, with at least one of the following: electrocardiographic changes, serial increases in cardiac markers and/or documentation of significant coronary disease. Patients were admitted between 1999–2006, when many landmark studies in the field were being published. Patient demographics, clinical characteristics, clinical outcomes and treatments were recorded.

Data from patients with high-risk NSTE-ACS, defined as dynamic ST changes and/or positive troponin, were analysed according to delay from admission to angiography (<72 vs ⩾72 hours). Further analyses were performed subclassifying patients into five groups: <24 hours, 24–72 hours, 72 hours–7 days, >7 days to initial angiography from admission or no angiography.

Data collection/analysis was in keeping with the World Medical Association’s Helsinki declaration.

The primary study endpoint was stroke, death or myocardial infarction within six months of admission (MACE). The individual endpoints were analysed, in-hospital, six months after discharge and from admission to six-month follow-up.

Statistical methods

Statistical analysis was performed with SAS v9.1. Categorical variables were analysed using the χ² test or Fisher’s exact test. Continuous variables were analysed using the Wilcoxon rank-sum test for two comparison groups and the Kruskal-Wallis test for more than two comparison groups.

Multiple logistic regression analysis and propensity score analysis were used to assess the impact of catheterisation, as well as timing. For cumulative outcomes rate from admission to six months post-discharge, it was adjusted for differences in baseline variables (age, sex and comorbidities (diabetes, hypertension and transient ischaemic attack (TIA)/stroke) and previous coronary disease (prior angina, myocardial infarction, heart failure percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)), GRACE risk scores and propensity score. GRACE risk scores are derived from clinical factors on admission—age, heart rate, systolic blood pressure, creatinine, Killip class, cardiac arrest, ST deviation or elevated biomarkers (http://www.outcomes-umassmed.org/GRACE/index.cfm). Outcomes rates at six months post-discharge were adjusted for differences in baseline variables (age, sex and comorbidities (diabetes, hypertension and TIA/stroke) and previous coronary disease (prior angina, myocardial infarction, heart failure PCI or CABG), in-hospital events (recurrent ischaemic symptoms, congestive heart failure (CHF)/pulmonary oedema, cardiogenic shock, cardiac arrest/ventricular fibrillation (VF), atrial fibrillation/flutter, sustained ventricular tachycardia (VT), thrombocytopenia, heparin-induced thrombocytopenia (HIT), acute renal failure, myocardial infarction (MI) >24 hours after hospital presentation/re-infarction, stroke, major bleeding), GRACE risk score and propensity score.

Because patients who died shortly after admission could not undergo catheterisation, we performed a sensitivity analysis excluding patients dying within 72 hours of admission when comparing very delayed angiography (>7 days) to no angiography.

RESULTS

Baseline characteristics

In 23 396 patients with high-risk NSTE-ACS, 10 089 (43.1%) had no catheterisation: 4818 (47.8%) of these 10 089 were from hospitals without catheter laboratoriess.

Of 13 307 patients undergoing angiography, full admission and six-month follow-up data were available in 10 882 (82%) and 8736 (66%), respectively.

Patients waiting longest were more frequently older, diabetic, female and had a history of heart failure, previous MI, or hypertension (table 1). Those with cardiogenic shock at presentation were likely to have very early angiography. GRACE risk scores were higher with no angiography than with angiography (mean scores 145.3 vs 124.9, p<0.0001 respectively). These patients were older (71.0 vs 65.2 years, respectively, p<0.0001), less likely to be male (59.1% vs 71.0%) and more often had a history of heart failure (20.4% vs 8.0%, p<0.0001), renal failure (12.4% vs 7.5%, p<0.0001), previous MI (38.0% vs 29.1%, p<0.0001) or diabetes (29.1% vs 26.5%, p<0.0001).

Delay-to-angiography

Median delay-to-angiography was 46 hours (P25 = 19.5, P75 = 94.5); 31.1% had angiography <24 hours after admission, 35.1% waited 24–72 hours, 24.5% waited 72 hours–7 days and 9.3% waited >7 days before angiography; 3680 (33.8%) patients waited >72 hours. In all, 5789 patients had in-patient PCI. Median delay was 42 hours (P25 = 15.8, P75 = 94); 35.5% had PCI <24 hours after admission, 32% waited 24–72 hours, 21.9% waited 72 hours–7 days and 10.6% waited >7 days in hospital before PCI was performed. Some 16.3% of patients in <72 hours group and 16.4% in >72 hours group (p = 0.837) were transferred from another hospital.

In-hospital events

Revascularisation, whether by PCI or CABG, was progressively less likely as angiography was delayed. A total of 2665 of patients had revascularisation if angiography was performed within 24 hours (78.8% of this group), 2472 (64.8%) of those waiting 24–72 hours, 1444 (54.2%) of those waiting 3–7 days and 473 (46.9%) of those waiting >7 days for angiography (p<0.0001 for trend across groups).

Recurrent in-hospital ischaemia (33% vs 22%, p<0.0001), reinfarction (8.4% vs 5.0%, p<0.0001) and heart failure (14% vs 9.1%, p<0.0001) were more common in the late (>72 hours) than in the early (<72 hours) angiography group (table 2).

Patients having no angiography were more likely to experience heart failure during admission compared to those undergoing angiography (18.7% vs 10.7%, respectively, p<0.0001) but less likely to experience recurrent ischaemia (21.8% vs 25.7%, respectively, p<0.0001). Reinfarction rates were similar (6.2% vs 6.6% respectively, p = 0.162).

In-hospital mortality was high in the first 24 hours. Once patients with cardiogenic shock are excluded (table 2), mortality falls in all groups, with less pronounced difference between time points.

Outcomes from admission to six months

MACE from admission to six months was higher in patients waiting longest for angiography (<24 hours = 12.1%, 24–72 hours = 11.6%, 72 hours–7 days = 14.7%, >7 days = 18.9%, p<0.0001).

MACE rates were highest with no catheterisation (after excluding patients dying within 72 hours of admission). When this group was compared to those waiting >7 days for angiography, death rates were lower in the group having a delayed angiogram. MACE rates at six months were not statistically worse, but MACE rates post-discharge were higher in the follow-up period with no angiogram (table 3).

Post-discharge outcomes

In the post-discharge period (and removing patients dying before they could have had an angiogram), delayed (>72 hours) angiography was associated with both higher death rates (4.6% vs 2.8% in <72 hour group, p<0.001) and MACE rates (7.5% vs 5.9%, p = 0.005). When adjusted for other variables, death rate (but not MACE) was higher in the delayed group (odds ratio 1.49 (95% confidence interval 1.08 to 2.07), p = 0.02).

Multivariate analysis

Baseline characteristics (age, sex, comorbidities, previous ischaemic heart disease and GRACE risk score) were adjusted for by multivariate analysis and using quintiles based on propensity score. Increased rates of myocardial infarction (OR 1.37 (95% CI 1.16 to 1.61), p<0.001) and MACE (OR 1.19 (95% CI 1.04 to 1.37), p = 0.011) were identified within six months of admission in those delaying >72 hours compared to those undergoing angiography within 72 hours. Death and stroke rates were not significantly different.

Reductions in MACE (OR 0.85 (95% CI 0.77 to 0.94), p = 0.002) and mortality (OR 0.83 (95% CI 0.74 to 0.95), p = 0.006) in the six months following discharge remained in high-risk patients undergoing angiography as opposed to no angiography.

DISCUSSION

European Society of Cardiology guidelines6 recommend angiography-guided treatment within 72 hours for patients at intermediate/high risk and urgently in patients with haemodynamic instability. We found that one in three high-risk patients had no angiography. When angiography was undertaken it was within 72 hours in two-thirds of cases. We noted a correlation between higher-risk patients (the elderly, women, those with heart failure or renal impairment) and a higher likelihood of delayed angiography (or no angiography). A similar, apparently risk-averse, approach to angiography in the GRACE population has been previously reported.7 Researchers found an inverse relation between GRACE risk scores and likelihood of PCI. This further paper finds that high-risk patients also face greater delay to angiography than lower-risk patients, as well as being less likely to undergo angiography overall.

Separate from the findings relating delay to angiography to risk levels at presentation, is the finding that delayed angiography (>72 hours), after adjustment for confounding variables, appeared to be associated with increased likelihood of further infarction and increased MACE. Nevertheless, delayed angiography was associated with reduced mortality and MACE compared to no angiography. This result should be considered hypothesis-generating since this was not a randomised controlled trial.

This study is the first large-scale analysis of the relation between delay-to-angiography and outcomes.

We cannot determine why angiography was delayed, or not performed. Some delays were probably caused by resource constraints—patients were often admitted to hospitals without catheter laboratories and so required inter-hospital transfer. An early invasive strategy requires coordination of extensive resources, within and between hospitals. Bellenger et al8 illustrate the difficulties encountered in the United Kingdom. Delays of 20 (SD 15) days between referral to tertiary hospital and angiography were seen before reorganisation of service. This improved to 8 (SD 3) days after service reconfiguration. Such delay occurs elsewhere, although data are limited.

Delay may occur for clinical reasons. Patients may have had contraindications to angiography such as previously documented anatomy unsuitable for revascularisation, non-cardiac severe or terminal diagnoses or no patient consent. Those having no or delayed angiography more commonly had renal insufficiency or heart failure. Clinicians may have delayed to improve renal failure or heart failure before angiography.

Delay (or avoidance) of angiography may relate to clinician preference for an ischaemia-driven strategy—as in the ICTUS9 (Invasive versus Conservative Treatment in Unstable Coronary Syndromes) trial.

Patients undergoing angiography in hospital more frequently experienced recurrent ischaemia during their admission than those where no angiography was performed. We have no data on the timing of these events, but some patients initially managed conservatively may have had angiography later, prompted by recurrent ischaemia.

Prompt angiography may be a surrogate for generally higher-quality care—patients undergoing angiography were more often prescribed aspirin, angiotensin-converting enzyme inhibitors and statins than those treated conservatively. This association between early angiography and evidence-based pharmacology was also observed in CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines).7

What is the optimal time for angiography? There are few data to support a strategy of “expedited” angiography (<6 hours). Previous analysis of >8000 GRACE patients found expedited angiography was associated with worse outcomes, largely related to more haemodynamic instability at presentation.10

Within 48 hours of presentation, there is no clear correlation with increased adverse outcomes as delay increases. Analysis of the CRUSADE registry of >56 000 patients compared weekend with weekday presentation. Delay-to-angiography was longer after weekend admission (46.3 vs 23.4 hours, p<0.0001), without worse in-hospital outcomes.11 A separate analysis of 17 926 patients in CRUSADE showed that less than half had angiography early (<48 hours). As with our GRACE analysis, early angiography in CRUSADE tended to be performed on younger, male patients without heart or renal failure and was associated with lower in-hospital mortality, after adjusting for different clinical characteristics.7

The Early or Late Intervention in unStable Angina (ELISA) pilot study12 randomised 220 patients to early angiography versus a delayed strategy after 24-48 hours of tirofiban. No difference in clinical outcome was observed, although delayed angiography was associated with improved angiographic outcomes.

One single-centre (836 patient) study13 analysed outcomes according to time-to-angiography: same day, 1–2-day delay or >2-day delay. Those waiting >2 days had increased three-year mortality (OR 2.12, 95% CI 1.03 to 4.35, p = 0.04). Analysis of TACTICS TIMI1814 compared outcomes in patients in the invasive arm having angiography before or after 48 hours. A trend to increased MI was seen (2.9 vs 6.5%, respectively, p = 0.08), but no difference in six-month MACE. ISAR-COOL (Intracoronary Stenting with Antithrombotic Regimen Cooling-Off)15 examined prospectively a deliberate delay to angiography, with aggressive anti-thrombotic therapy. Approximately two-thirds of the 410 ISAR-COOL patients had high-risk markers. Delay (median 2.6 vs 86 hours) led to worse outcomes in the “cooling-off” group (11.6% (three deaths, 21 infarctions) vs 5.9% (no deaths, 12 infarctions), relative risk (RR) 1.96 (95% CI 1.01 to 3.82) p = 0.04). Excess events in the late invasive arm occurred before angiography.

Our analysis suggests an early invasive approach is associated with better outcomes, with diminishing benefit of angiography over time. Even late angiography appeared associated with better outcomes than no angiography.

Limitations

The GRACE registry does not provide randomised controlled data. Some patients entered into the study were lost to follow-up before six months and so data are incomplete.

Conclusions

High-risk NSTE-ACS patients are suboptimally managed, with 43% not undergoing angiography during the index admission. One-third of patients undergoing angiography were delayed for >72 hours. Longer delays were more likely in higher-risk, sicker patients. These delays, probably multifactorial, are associated with adverse outcomes within six months. Delay >7 days, when adjusted for other variables, was still associated with lower rates of MACE post-discharge compared to conservative management.