Invasive versus medically managed acute coronary syndromes with prior bypass (CABG-ACS): insights into the registry versus randomised trial populations

Background Coronary artery bypass graft (CABG) patients are under-represented in acute coronary syndrome (ACS) trials. We compared characteristics and outcomes for patients who did and did not participate in a randomised trial of invasive versus non-invasive management (CABG-ACS). Methods ACS patients with prior CABG in four hospitals were randomised to invasive or non-invasive management. Non-randomised patients entered a registry. Primary efficacy (composite of all-cause mortality, rehospitalisation for refractory ischaemia/angina, myocardial infarction (MI), heart failure) and safety outcomes (composite of bleeding, stroke, procedure-related MI, worsening renal function) were independently adjudicated. Results Of 217 patients screened, 84 (39%) screenfailed, of whom 24 (29%) did not consent and 60 (71%) were ineligible. Of 133 (61%) eligible, 60 (mean±SD age, 71±9 years, 72% male) entered the trial and 73 (age, 72±10 years, 73% male) entered a registry (preferences: physician (79%), patient (38%), both (21%)). Compared with trial participants, registry patients had more valve disease, lower haemoglobin, worse New York Heart Association class and higher frailty. At baseline, invasive management was performed in 52% and 49% trial and registry patients, respectively, of whom 32% and 36% had percutaneous coronary intervention at baseline, respectively (p=0.800). After 2 years follow-up (694 (median, IQR 558–841) days), primary efficacy (43% trial vs 49% registry (HR 1.14, 95% CI 0.69 to 1.89)) and safety outcomes (28% trial vs 22% registry (HR 0.74, 95% CI 0.37 to 1.46)) were similar. EuroQol was lower in registry patients at 1 year. Conclusions Compared with trial participants, registry participants had excess morbidity, but longer-term outcomes were similar. Trial registration number NCT01895751.


INTRODUCTION
Coronary artery bypass graft (CABG) surgery is standard of care for patients with obstructive coronary artery disease.However, occlusive disease of saphenous vein grafts is common within 10 years of surgery, [1][2][3] meaning patients with prior CABG have a progressive longerterm risk of recurrent ischaemia, including angina and myocardial infarction (MI), heart failure (HF) and death.Given the large number of CABG recipients living globally, and their health complexities, including increasing age and multimorbidity, this represents an increasing healthcare challenge globally,

Key questions
What is already known about this subject?
► Pivotal clinical trials of invasive management versus non-invasive medical management in acute coronary syndromes (ACS) excluded patients with prior coronary artery bypass graft (CABG).
What does this study add?
► The CABG-ACS trial and registry provides novel, contemporary insights into an understudied subgroup of ACS patients with a substantial health burden.
How might this impact on clinical practice?
► The CABG-ACS pilot trial and registry fills in an evidence gap on the natural history and optimal treatment strategy for this comparatively large subgroup of patients.Furthermore, the CABG-ACS trial and registry may be helpful in the design of clinical trials in this patient group.on September 14, 2023 by guest.Protected by copyright.not least because of rehospitalisation due to recurrent ischaemia. 4 5Chest pain is the most common reason for hospital admission in the UK and about 1 in 10-15 patients admitted to hospital with an acute non-ST segment elevation acute coronary syndrome (NSTE-ACS) have a prior CABG. 6ivotal clinical trials comparing routine invasive management vs conservative non-invasive management in unstable coronary syndromes excluded patients with prior CABG (online supplemental table 1).1][12] Furthermore, when invasive management is performed, percutaneous coronary intervention (PCI) is less likely in prior CABG patients, [11][12][13] implying a lower likelihood of benefit with a routine invasive strategy.Real-world evidence implies clinical practice departs from the results of systematic reviews and guidelines, 14 15 indicating physician and patient preferences for treatment options may be relevant.Overall, evidence is lacking to inform the validity of current guideline recommendations, [7][8][9] in NSTE-ACS patients with prior CABG.This important subgroup of ACS patients remains comparatively understudied.Enrolment into randomised trials can be challenging, 16 particularly when the intervention disrupts standard care.][19] We hypothesised that the clinical characteristics, treatment and health outcomes would differ between participants enrolled in a randomised controlled trial of routine invasive versus routine non-invasive management in NSTE-ACS patients with prior CABG, and participants enrolled in the registry due to physician and/or patient preference.We aimed to prospectively gather information on the trial and registry participants in order to gain contemporary information on the natural history and reasons for trial participation or not.

METHODS
We undertook a randomised controlled trial of routine invasive management vs routine conservative management in NSTE-ACS patients with prior CABG.Concurrently, patients who were ineligible for randomisation and who gave informed consent were entered into an observational registry.The study design, 20 and results of the main trial have been published. 21

Study population
Inclusion criteria were: (1) unstable angina or non-ST segment elevation MI; (2) stabilised symptoms without recurrent chest pain or intravenous therapy for 12 hours and (3) prior CABG.
Exclusion criteria were: (1) refractory ischaemia (ie, recurrent angina with minimal exertion or at rest (ie, Canadian Cardiovascular Society (CCS) class III or IV) not controlled by medical therapy); (2) cardiogenic shock; (3) lack of informed consent and (4) unsuitable for invasive management.

Randomisation
Patients fulfilling inclusion criteria without any exclusion criteria who consented to participate in the randomised trial were enrolled (figure 1).Randomisation was performed by the Trials Unit interactive voice recognition system to one of two groups: initial medical management or initial invasive management (online supplemental methods).

Registry
Information was prospectively recorded in a registry for acute NSTE-ACS and prior CABG patients who were not randomised but consented to participate in the registry.Reasons for non-participation in the randomised trial were prospectively recorded: exclusion criteria present, unsuitability for either invasive or non-invasive management, physician preference, patient preference or a combination of these factors.Baseline and follow-up clinical information were obtained similarly to the trial patients.Follow-Up Follow-up (via telephone contact, clinic visits, letter) with completion of quality of life assessments (EuroQol Visual Analogue Scale (EQ-VAS) and EuroQol 5 Dimensions 5 Levels (EQ-5D-5L)) was maintained 6 monthly until ≥18 months follow-up was reached for the final recruited patient (online supplemental methods).

Clinical event committee
An independent clinical event committee reviewed the primary efficacy and safety endpoints (online supplemental methods).

Definitions of adverse events
Refractory ischaemia, death, procedure-related MI, stroke, major bleeding and worsening renal function are defined in online supplemental methods.
In-hospital clinical course and invasive management More than twice as many patients in the registry versus the trial had a medication change for recurrent angina.Approximately three-quarters of registry patients had medication changes for standard optimisation of secondary prevention therapy compared with trial patients (table 2).

Health outcomes
During a median of 694 (IQR 558-841) days follow-up, the primary efficacy outcome occurred in 26 (43%) and 36 (49%) trial and registry participants, respectively (HR 1.14, 95% CI 0.69 to 1.89) (table 4).The primary safety outcome occurred in 17 (28%) and 16 (22%) trial and registry participants, respectively (HR 0.74, 95% CI 0.37 to 1.46).The observed proportion of registry patients experiencing the efficacy outcome was slightly higher than in the trial group, whereas the opposite occurred for the safety  outcome.When considered together (efficacy or safety), the rates were very similar between the groups.There was a lower proportion in the registry group experiencing both outcomes, but these events were very small in number.Kaplan-Meier survival curves (figure 2) reveal that health outcomes in the trial and registry groups were similar during follow-up.Compared with the trial group, all-cause mortality and cardiovascular death occurred more often in the registry group, but non-fatal MI and worsening renal function during the index hospitalisation occurred less often (table 4).Two-thirds of patients in both groups experienced a serious adverse event (table 4).Redo CABG occurred in only one registry patient and in none of the trial participants (table 4).

Health status
Compared to the trial group, the median EQ-VAS health status in the registry group was 25 points lower (worse) at 6 months, and 12 points lower at 12 months (table 4).

DISCUSSION
The main findings of our study are, compared with the trial group, in the registry group: (1) multimorbidity, functional limitation, frailty and impaired health status were more pronounced; (2) changes to medication were more often made because of recurrent angina but less often made for standard optimisation of secondary prevention; (3) in invasively managed patients, the extent of jeopardised myocardium was similarly high and the culprit lesion was identified in half, and revascularisation by PCI was performed on one third; (4) health-related quality of life was lower at baseline, 6 and 12 months and ( 5) there was a fourfold increased risk of cardiovascular death, although power was limited.Overall, our study provides novel, contemporary insights into an understudied subgroup of ACS patients with a substantial health burden.
Our registry-based trial provided a framework for information to be prospectively gathered on patients who may have been eligible for randomisation but were not, including the reasons for not being randomised.Registry participation reflected physician and/or patient preferences for one form of treatment over another. 16hese beliefs substantially limited enrolment into the randomised trial.This finding has implications for the design and funding of future trials in this population.Moreover, the finding in the comparison of the Coronary artery disease randomised trial groups that health outcomes were not different with invasive management versus conservative management supports the notion that enrolment rates could be increased by education of physicians and patients. 21Our trial results broadly reflect equipoise between the randomised strategies which should enhance confidence to support enrolment into a future randomised trial.
Compared with trial participation, registry participation was associated with a fourfold higher likelihood of cardiovascular death, with the caveat that event rates were very low for this outcome.This prognostic association may be partly explained by the greater burden of cardiovascular health problems at baseline, including HF and valve disease.Compared with trial patients, registry patients had more medication changes for recurrent angina-this may be partly explained by some registry patients having symptoms which were not stabilised and/ or refractory ischaemia (both reasons for exclusion from the randomised trial) (figure 1).However, up-titration of medical therapy for secondary prevention occurred less often in the registry group, implying less intensive management, less scope for therapy improvements or both.The results highlight the substantial levels of morbidity, polypharmacy and adverse health outcomes in this group.The clinical course of two participants is illustrated (online supplemental figures 1 and 2).

Advances in interventional management
In our trial, invasive management was selected in 36 (49%) of registry participants at baseline, but PCI was performed in only 13 (36%) of these patients.The lower PCI rate in our population may be explained by the complex nature of native vessel and graft disease, lack of a clear culprit (in almost half), and, arguably, lack of definitive evidence in support of the benefits of PCI in this population.
PCI continues to evolve with technical advances potentially leading to improvements in safety and procedural success (online supplemental discussion).
Feasibility of a future substantive trial in patients with an NSTE-ACS and prior CABG About one in 10-15 NSTE-ACS patients have a prior CABG (online supplemental table 1). 6This proportion is likely to remain stable in the coming years reflecting revascularisation practices in the past decade and increasing longevity.Many participants in this study were elderly, frail and multimorbid.Screening and obtaining informed consent were time-consuming for research staff.Medical decisions during urgent care may happen out-with office hours when research staff availability was limited.Medical information was commonly lacking at the time of hospitalisation, for example, graft history, limited recall by patients.These considerations present logistical barriers to enrolling patients into a randomised trial.
High event rates in patients with an NSTE-ACS and prior CABG Almost half of the participants in both groups experienced a primary efficacy outcome event (table 4).In contemporary trials involving NSTE-ACS patients, the 12-month major adverse cardiac event (MACE) rate is usually 8%-10%, which is very much lower than observed in this study's patients.The proportion of affected patients increased substantially during longerterm follow-up beyond 12 months.Again, this progressive accrual of adverse cardiac events over time contrasts with other trials in NSTE-ACS patients in which cardiac events may plateau over time.The older age and universal presence of multi-morbidity probably explain the differences in prognosis between NSTE-ACS patients with versus without prior CABG.Considering future trials in NSTE-ACS patients with prior CABG, there are considerable logistical challenges to enrolment but, however, the event rate implies that the sample size may be lower than for other populations in which primary outcome event rates are expectedly lower.

Limitations
Our pilot trial was not powered to assess for betweengroup differences in the rates of the serious adverse events contributing to the prespecified efficacy and safety outcomes.The sample size was small, with resultant wide confidence intervals.Both groups included patients that were managed differently (PCI vs medical therapy), thereby confounding between-group comparisons.

CONCLUSION AND POTENTIAL VALUE OF RESULTS
Since clinical trials usually excluded patients with prior CABG, practice guidelines are not evidence based with respect to this group.In real-world practice, clinicians lack relevant information to inform decision making.Our trial and registry may be helpful in the design of clinical trials in this patient group.
Note that where there are missing values, the percentages are calculated out of the number of patients with data.Cardiac arrhythmia (2 missing from registry).New ischaemic ECG changes (1 missing from registry).Canadian Cardiovascular Society angina class (1 missing from trial, 1 missing from registry).Saphenous vein graft (2 missing from trial, 5 missing from registry).Mean ± SD or median (IQR) for normal and non-normally distributed data, respectively.*During the index hospitalisation, all patients in the randomised trial group had a type 1 MI, while seven patients in the registry group did not have a type 1 MI but had a type 2 MI (2 AF, 1 AF+HF, 1 severe aortic stenosis+HF, 1 anaemia, 1 AF+acute kidney injury, 1 HF+respiratory tract infection).http://openheart.bmj.com/Open Heart: first published as 10.1136/openhrt-2020-001453 on 26 February 2021.Downloaded from Lee MMY, et al.Open Heart 2021;8:e001453.doi:10.1136/openhrt-2020-001453