The COURAGE and SYNTAX trials: will they impact how we manage patients?

Zulfiquar Adam, MBChB, MRCP; Mark de Belder, MA, MD, FRCP James Cook University Hospital, Middlesbrough, UK
Address for correspondence:
Dr Mark de Belder
Cardiothoracic Unit
James Cook University Hospital
Marton Road
Middlesbrough TS4 3BW, UK
Tel: 44 (0)1642 854620
Fax: 44 (0)1642 282408
E-mail:mark.debelder@stees.nhs.uk

Abstract

The main focus of managing patients with coronary artery disease centres on improving symptoms and/or prognosis. All patients should get advice on lifestyle and risk factor modification and be offered optimal medical therapy. A decision on revascularisation and whether this is achieved by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) also needs to be made.

Numerous studies have been performed to help address this issue. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) and Synergy between Percutaneous Coronary Intervention with Taxus® and Cardiac Surgery (SYNTAX) are two such trials. COURAGE supports the use of optimal medical therapy as an initial strategy compared to PCI in patients with stable coronary disease but also reinforces the need for risk stratification. The danger currently is that the baseline results from COURAGE will be applied to higher risk patients than were enrolled in this trial and such patients will then be denied the prognostic benefits of revascularisation. For patients with extensive multivessel disease and left main stem disease, CABG remains the mainstay of treatment and SYNTAX reinforces this. Further results may help determine which patients, if any, get a distinct survival advantage with CABG in the longer term, and for how long any such benefit lasts.

Introduction

Over recent decades, there have been key advances in the treatment of coronary artery disease (CAD). On the one hand, there has been an increased understanding of the pathophysiology of atherosclerosis and with that a focus on lifestyle and risk factor modification, whilst on the other hand there have been advances in pharmacotherapy and the evolution of revascularisation therapies in the form of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). The focus of treatment remains centred on two key strategies: 1) improving symptoms at the lowest possible risk, and,2) improving prognosis. A key clinical decision to be made for each patient is whether revascularisation is warranted and, if so, how this should be achieved.

The case for revascularisation by PCI as a means of improving prognosis is strongest in the setting of the acute coronary syndromes (ACS). Primary angioplasty is emerging as the dominant form of reperfusion therapy for ST elevation myocardial infarction (MI) and current guidelines advocate an early invasive strategy for suitable patients with the non-STEMI acute coronary syndromes[1, 2 ].

Previous guidelines for chronic stable angina have highlighted the need for risk stratification and the use of angiography and revascularisation where there is evidence for improving prognosis[3]. For patients where angina cannot be controlled with medical therapy (MT), successful revascularisation clearly improves symptoms, but for patients who have few symptoms the decision to consider revascularisation is harder. The case for considering revascularisation came from studies that demonstrated prognostic benefit from this approach in subgroups of patients where significant inducible ischaemia could be shown and/or with certain angiographic patterns of disease. Having made a decision to consider revascularisation, the advantages and disadvantages of PCI and CABG should be considered. Previous trials in the elective setting (of patients where both treatments were technically feasible) showed that the risk of death or MI in the short-to-medium term was equivalent between these two forms of treatment, but that repeat revascularisation was needed more often with PCI (whether with balloon angioplasty alone or stenting)[4, 5]. Patients could then choose which of these treatments they preferred.

These trials have been interpreted in different ways. Some interventionists have suggested that as prognostic benefit is achieved with surgery and that PCI is associated with equivalent hard end points of death and MI in the comparative trials with surgery, then PCI appears to provide prognostic advantage in some patients. Some surgeons and others have commented that angioplasty has never directly been shown to have a prognostic benefit when compared to MT, a view that has been reinforced by the results of the relatively small MASS-II trial[6].

The evidence base for such guidance has moved on. In particular, we now have more evidence of the potential to stabilise atheromatous plaque and to reduce the risk of future cardiovascular events[7, 8]. Statins and angiotensin-converting enzyme (ACE)-inhibitors were not used in the original trials looking at the prognostic benefits of CABG. Given the benefits of these drugs (albeit they would influence both sides of a trial randomising patients between revascularisation or continued medical therapy), it has been necessary to design trials to look again at the prognostic potential of revascularisation. In addition, techniques in PCI have improved with the development of drug-eluting stents and effective antiplatelet drugs, and there are potential advances in CABG with the increased usage of arterial grafting. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE)[9] and Synergy between Percutaneous Coronary Intervention with Taxus® and Cardiac Surgery (SYNTAX) trials[10] are two contemporary studies that were designed to address some of the issues, and their potential impact on current practice is addressed here.

Need for Revascularisation

In the context of chronic stable angina, revascularisation (with either CABG or PCI) has been shown to be superior to MT with regards to improving symptoms and probably also improves quality of life[11]. This is reflected in current guidelines suggesting it would be reasonable to offer an invasive approach to patients who fail MT or are intolerant of medication[3]. The impact on prognosis, however, warrants further discussion.

CABG was first performed in the 1960s, whereas the first balloon angioplasty was performed in 1977. It is therefore not surprising that most of the early data relating to identifying which patients derived benefit from revascularisation was obtained from trials comparing MT with CABG. Yusuf and colleagues conducted a patient-level meta-analysis utilising data from three large studies (the Veterans’ Administration [VA] Trial, European Cardiac Society Study [ECSS] and Coronary Artery Surgery Study [CASS]) as well as four other smaller studies[12]. There are several key observations from this analysis. First, there was a small early hazard of surgery compared to a medium-term prognostic benefit which, however, was lost by 12 years’ follow-up. Secondly, the annual mortality rate of the medically treated patients was just over 3% per year (i.e. these were not the highest-risk patients). Overall, among the 1324 patients allocated surgery and the 1325 allocated medical treatment, those that had CABG had lower mortality at 5 years (39% relative risk reduction (RRR) (95% CI 23-52), 7 years (32% RRR (95% CI 17-44) and 10 years (17% RRR (95% CI 2-30). This is despite the fact that 41% of patients in the MT arm had received CABG after 10 years. The survival advantage was greatest for left main stem (LMS) disease, three-vessel disease (VD), especially if patients had impaired LV function, and 2VD with involvement of the proximal left anterior descending artery (LAD). The advantage with CABG was greatest for those with additional factors:

• increased severity of angina
• hypertension
• prior MI
• ST depression at rest
• positive exercise tolerance test.

It is worth pointing out that there was a trend towards greater mortality with CABG with low-risk cases. This meta-analysis helped to define so-called “prognostic disease”, i.e. LMS, 3VD or 2VD with proximal LAD pattern of CAD, and influenced decision-making for individual patients (Figures 1 and 2).

If CABG improves prognosis, it is relevant to consider how this is achieved. Is it because of a reduction in ischaemia? Or is it because potentially unstable plaque is bypassed, or both? Is there a placebo effect or some other reason? If it relates to bypassing of unstable plaque, then plaque stabilising drugs would be expected to impact the prognostic potential of surgery. If it relates more to a reduction in ischaemia, then plaque stabilising drugs might be expected to have less effect, and therefore the reduction of ischaemia would remain a justifiable goal. Do the trials comparing PCI and CABG help answer these questions?

PCI vs. CABG

The early surgical trials helped identify which groups of patients derived most benefit from revascularisation. With the development of percutaneous transluminal coronary angioplasty (PTCA, an expression that most now use with reference to balloon angioplasty without stenting) trials were designed to establish its role compared with both CABG as well as a strategy of continuing MT. Clearly, these different trials enrolled different subsets of patients. The randomised controlled trials (RCTs) against MT included patients where clinicians felt it justified for patients to continue with MT (i.e. predominantly low risk patients). The RCTs against CABG examined the utility of balloon angioplasty in patients for whom it was felt that surgery was justified and where angioplasty was felt to be technically feasible (i.e. higher risk patients) (Table 1). For the RCTs versus CABG, meta-analysis showed no mortality difference at 1 and 3 years, no significant difference in MI rate, but further treatment was required in the first year in 33% of PTCA vs. 3% of CABG and angina was worse at 1 year in PTCA group but equivalent at 3 years[4].

The main difference between the two strategies was a higher recurrence rate of angina with PTCA and a greater need for repeat revascularisation. The introduction of coronary stenting sparked the next major group of trials (Table 2).

A meta-analysis aggregating some of these trials and the previous PTCA vs. CABG trials with follow-up to 8 years also showed no significant differences in mortality between the strategies at 1 and 3 years; there was a statistically significant difference at 5 years (in favour of CABG) but this was lost by 8 years except in multivessel disease[5]. However, the advantage of CABG was only evident against balloon angioplasty, and not with stenting (at least out to 5 years), a finding confirmed in other studies[13]. Moreover, stenting was associated with less non-fatal MI compared to CABG out to 3 years. When subgroup analyses were performed, the rate of revascularisation had been halved with the introduction of stenting compared to PTCA[5].

A recurring theme throughout this period was also the superiority of CABG compared to PCI in patients with diabetes. The reason for this may be related to the findings that diabetic patients have a higher frequency of left ventricular dysfunction, three-vessel disease and diffuse coronary artery disease[14] However, the duration of this prognostic benefit may be limited to just over 6 years[5].

These trials helped evaluate the outcomes of patients treated with different strategies. The future of patients undergoing PCI reflects the acute risk of treatment, the potential for restenosis and stent thrombosis and the natural history of the coronary circulation in the untreated segments. The outcomes following CABG reflect the acute risk of surgery, the short- and longer-term graft attrition rate and the natural history of the coronary circulation, especially the disease downstream of those grafts that remain patent.

Since these earlier trials, percutaneous intervention has undergone an advance with the introduction of drug-eluting stents (DES) and more effective antiplatelet drugs. When compared to bare metal stents (BMS), DES have been shown to have superior outcomes with regards to restenosis and need for repeat revascularisation[15]. The ARTS II registry compared sirolimus-eluting DES with historical data from the ARTS I CABG and BMS cohorts. At 3 years, although the need for revascularisation was lower than with BMS, it was still higher than with CABG (14.5% for DES vs. 6.6% for CABG, p < 0.001). In keeping with previous analyses, there were no significant differences in mortality or MI[16].

In comparison with some of the RCT results, some registry data suggest there is survival advantage with CABG over PCI in multivessel disease, even in the medium term. For example, data from the New York state registry showed that, at a mean follow-up of 18 months, CABG was associated with a significantly higher adjusted survival rate compared to DES in patients with either 3VD (94.0% vs. 92.7%, p = 0.03) or 2VD (96.0% vs. 94.6%, p = 0.003) respectively[17]. The difficulty with interpreting data from registries is that although they include all comers (i.e. higher risk patients), they are less well monitored than in trials, there is often a lack of validation, data collection is often incomplete and the databases use fewer variables. Multivariate analyses used to correct for differences can only include the variables included. In comparison, randomised trials are tightly monitored, administration is comprehensive and databases are usually more comprehensive. However, in general, the RCTs usually recruit lower risk patients and the results only apply to a subset of patients treated in daily practice.

Although the ARTS II study suggested improved outcomes of PCI with DES, it was clearly desirable to perform further RCTs against CABG and the first year results of the SYNTAX trial are now available[10]. In this “all comers” design trial there was consecutive enrolment of all patients with multivessel or LMS disease. A team consisting of cardiologist and cardiac surgeon would decide whether the coronary anatomy was suitable for either PCI or CABG. Consenting patients who could be treated by either strategy were then randomised. Patients who were deemed suitable for treatment by only one strategy were not included but rather entered into registries. At 1 year, CABG was associated with a lower occurrence of the primary end point, a combination of death from any cause, stroke, myocardial infarction, or repeat revascularisation compared to PCI (12.4% vs. 17.8 % respectively, p = 0.002). When the need for repeat revascularisation was excluded, there was a higher incidence of stroke in the CABG group whereas the incidence of death and MI was not statistically significant (Figure 3). The timing of the stroke in relation to the surgery was not provided by the authors so it is difficult to know whether this was due to operative or other factors. There was a greater use of secondary prevention therapy such as antiplatelet, statin and ACE-inhibitor treatment in the PCI group, all of which reduce the risk of stroke.

Another feature of this trial was the development of an angiographic scoring system, the SYNTAX score. It was designed to reflect the extent as well as complexity of the coronary anatomy more objectively with higher scores corresponding to more severe/complex disease. The investigators found that in patients with low or intermediate scores (defined as SYNTAX score less than 33), outcomes were similar between the groups but there was a clear reduction in major cardiac or cerebrovascular events (MACCE) with CABG in patients with high scores. Further subgroup analysis of diabetic patients showed that there was less MACCE in those who had undergone CABG, but there was no reduction in the hard end points of death, MI or stroke.

The aim of the SYNTAX trial was to show that PCI with DES was not inferior to CABG but based on the results of the combined end point used (which included repeat revascularisation), the authors concluded that CABG should remain the standard of care for multivessel or LMS CAD. However, analysis of the harder end points at 1 year suggests that most patients have an equivalent outcome at 1 year with less repeat revascularisation with CABG but with a slightly higher risk of stroke.

Overall, the results of SYNTAX are in keeping with previous comparisons between PCI and CABG. Further subgroup analyses have suggested slightly better outcomes with PCI for patients with isolated LM disease or LM in association with 1VD, at least at 1 year, but better overall outcomes with CABG with multivessel disease with or without LM disease. Such analyses however must be seen only as hypothesis-generating and do not provide definitive guidance. Longer term follow-up of SYNTAX will provide additional information to guide selection of treatment.

Does this trial and the other comparative trials between CABG and PCI help us determine the over-riding influences on improved outcomes? Unfortunately, no. It is a shame that the surgical cohort of the SYNTAX trial has received less optimal medical therapy (OMT) compared to the PCI cohort. If, on the other hand, the longer term results of SYNTAX show improved outcomes in some patients despite less comprehensive medical therapy, then this will suggest that either ischaemia reduction or bypassing of vulnerable plaque is an important goal. Analysis of comparative ischaemia reduction in the various SYNTAX score subsets might help us determine which. If on the other hand the outcomes are equivalent, we will not be certain about the relative influences but at least we will be able to tell that PCI with DES and OMT provides equivalent outcomes to CABG with a slightly more lax approach to secondary prevention.

Medical Therapy vs. PCI

The influence of PCI on prognosis in patients with stable angina has been addressed by trials involving relatively small numbers of patients over the past two decades but the results have been subject to meta-analysis (Table 3)[18].

Most of these trials were performed in an era prior to the routine use of dual/triple antiplatelet therapy and coronary stents and enrolled patients with predominantly single-vessel disease. A strategy of PCI for these patients failed to demonstrate a significant reduction in death (6.9% for MT vs. 6.4% for PCI, p = 0.68) or MI compared with MT. Statins and ACE-inhibitors were not routinely used in these studies.

COURAGE was a trial designed to compare OMT with or without PCI in patients with stable CAD[9]. Patients were randomised between OMT alone or OMT with PCI if they had ≥ 70 % coronary artery stenosis in at least one major epicardial territory and objective evidence of myocardial ischaemia (substantial changes in ST-segment depression or T-wave inversion on the resting electrocardiogram or inducible ischaemia with either exercise or pharmacologic vasodilator stress) or at least one coronary stenosis of at least 80% and classic angina without provocative testing. A total of 2287 patients were randomly assigned to OMT (n = 1138) or PCI with OMT (n = 1149). Most of the patients in the PCI group received at least one bare metal stent. The results were in keeping with the previous meta-analysis. PCI did not reduce the risk of death or MI over a median 4.6 years of follow-up (19.0% for PCI vs. 18.5% for MT; hazard ratio 1.05; 95% CI 0.87 to 1.27; p = 0.62). Furthermore, with regards to relief of symptoms, patients initially fared better with PCI but at 5 years the numbers of patients experiencing angina were not significantly different.

The annual mortality of the OMT cohort in COURAGE was only about 2% suggesting that this was a relatively low-risk group of patients (cf about 4% per annum in SYNTAX). Criticisms of COURAGE have included the fact that it was vastly under-powered to show a mortality advantage and, indeed, with this level of risk, it would be extremely unlikely that a survival advantage could be obtained with any form of revascularisation. Moreover, there was no CABG arm, only 2.7% received DES, there was a concern about incomplete revascularisation (only 41% received more than one stent whereas 69% had multivessel disease), many patients underwent balloon angioplasty rather than stenting, and a concern has been expressed that the level of secondary prevention achieved may not be feasible in real life.

Of the patients recruited into COURAGE, 314 patients also took part in a nuclear substudy looking at the effect and amount of ischaemia reduction between PCI/OMT and OMT alone[19]. More patients with PCI/OMT had significant ischaemia reduction (defined as ≥5% reduction in ischaemic myocardium at follow-up) compared to patients treated with OMT alone (33% vs. 19% respectively, p = 0.0004), especially in those patients with moderate/severe pre-treatment ischaemia (i.e. ≥10% myocardium at risk). They also had lower unadjusted rates of mortality and MI. This result suggests that ischaemia reduction should still be an aim of treatment, even in the presence of OMT, and gives some guidance as to what level of ischaemia might be important.

Further recent meta-analyses comparing a PCI based strategy with MT in the non-acute setting have been performed by Schomig et al.and Jeremias et al.(Figure 4) including the results of COURAGE and other recent trials not included in the previous meta-analysis. Both of these analyses suggest a reduction in mortality in the region of 20% with a PCI based strategy[20, 21].

COURAGE is the largest randomised trial comparing PCI with MT in the context of stable angina, and the results did not show an advantage of PCI over MT as an initial therapy. However, the low-risk cohort studied and the other criticisms of the study leave many questions unanswered. The nuclear substudy suggests that ischaemia reduction should still be a goal in itself, even in the presence of OMT. Further trials are needed however to tell us at what level of ischaemia revascularisation still has a prognostic impact and whether PCI can match CABG with long-term outcomes. To this end a US-led trial, the WISDOM trial, has been proposed, whereby 5000 patients with ≥10% myocardial ischaemia on quantitative SPECT are randomised between a strategy of OMT or OMT with angiography with a view to revascularisation (by whatever technique is deemed appropriate).

Conclusion

In many respects, COURAGE and SYNTAX merely reinforce our previously acquired knowledge. PCI with DES has produced overall outcomes better than previous trials with BMS or balloon angioplasty, mainly by a reduction in the need for repeat revascularisation. The debates about the position of CABG and PCI in the various sub-groups seen in daily practice will continue, but both treatments have advantages and disadvantages. Previously, PCI has been used in single and selected multivessel and LM disease (usually those with low or intermediate SYNTAX scores) and it is likely that this practice will continue with an evidence base to support it. Most patients with LM disease and extensive multivessel disease have been treated conventionally with CABG, and the results of SYNTAX reinforce this practice. Further results may help determine which patients, if any, get a distinct survival advantage with CABG in the longer term, and for how long any such benefit lasts.

COURAGE supports the use of OMT as an initial strategy compared to PCI in patients with stable coronary disease but also reinforces the need for risk stratification. It also provides support for guidelines that suggest that where significant stress-related ischaemia can be demonstrated, patients should undergo angiography with a view to revascularisation. New trials may help to clarify at what level of ischaemia this clinical pathway should be activated. The current danger is that the baseline results from COURAGE will be applied to higher risk patients than were enrolled in this trial and such patients will then be denied the prognostic benefits of revascularisation.

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