Patient Comorbidities

The demographics of patients in need of revascularization who present to tertiary care services are changing. This has largely been the consequence of increased longevity of the general population, a lower threshold to investigate patients presenting with symptoms suggestive of obstructive coronary disease, and increased resources, making revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) more accessible. Owing to their generally older age, patients in need of revascularization are now more likely to have comorbidities, such as diabetes, hypertension, and hyperlipidemia.^2,3 These factors are all implicated in accelerating the progression of CAD; consequently patients are more likely to present with more extensive disease. The Arterial Revascularization Therapies Studies (ARTS) Parts I and II were separated by a period of 5 years and, although both studies had the same inclusion criteria, patients in ARTS II had a significantly greater incidence of risk factors and overall increased disease complexity (Table 1-1).⁴

TABLE 1-1 The Changing Baseline Demographics of Patients Enrolled in Trials of Drug-Eluting Stents

Comorbidities must be taken into consideration in assessing patients for revascularization, as these have the potential to significantly influence outcomes; moreover, the impact of treatment may depend on the underlying revascularization strategy selected. Of note, Legrand et al.⁵ demonstrated that patient age was a significant independent predictor of major adverse cardiovascular and cerebrovascular events (MACCE) in patients enrolled in the ARTS I and II studies who were treated with CABG but not in those who received PCI. In a collaborative patient-level analysis of 10 randomized trials of patients with multivessel disease (MVD) treated with PCI using bare metal stents (BMS) and CABG, Hlatky et al.⁶ demonstrated comparable 5-year mortality rates among both the PCI and CABG treatment groups in patients without diabetes. Importantly, among those with diabetes, mortality was significantly higher in patients treated with PCI even after multivariate adjustment (Figure 1-1). The clear importance of patient comorbidities is highlighted by their central presence in the risk models now used to assist in decision making. This topic is discussed at greater length further on in this chapter.

Figure 1-1 Cumulative survival curve of long-term mortality stratified according to diabetic status among patients with multivessel disease who were randomized to treatment with either percutaneous coronary intervention or coronary artery bypass graft surgery. The influence of diabetic status on outcome is highlighted not only by the higher mortality among diabetics versus nondiabetic patients but also by the greater impact diabetic status had on patients treated with PCI compared with CABG.

(Reprinted with permission from Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet. 2009;373(9670):1190–1197.)

Technological Advances

The introduction in 2002 of the drug-eluting stent (DES) revolutionized the practice of interventional cardiology, primarily owing to the dramatic reduction in rates of repeat revascularization resulting from its use.⁷ The impressive results seen with the use of the DES promptly led to an expansion in the indications for PCI, such that bifurcation lesions, chronic total occlusions, and MVD were increasingly treated with PCI. Previously, these lesion subsets had been deemed more appropriate for surgical revascularization. Evidence of this expansion can be seen in the changing baseline lesion characteristics of patients enrolled in “all comers” PCI studies such as SIRTAX (sirolimus-eluting and paclitaxel-eluting stents for coronary revascularization trial),⁸ LEADERS (Limus Eluted from A Durable versus ERodable Stent coating study)⁹ and studies of complex (triple-vessel disease [3VD], and/or left main [LM]) CAD such as ARTS I,¹⁰ ARTS II,¹¹ and the SYNTAX study (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) (Table 1-1).¹² Further evidence in support of this change come, from assessments of “real world” clinical practice, which indicate that approximately one-third of patients with complex disease are now treated with PCI.¹³ Coupled with this expanding use of PCI, driven largely through the beneficial effects of DES, the new lower-profile balloons and guidewires are among other advances; these also include new adjunctive pharmacological therapies and the increasing availability of percutaneous extracorporeal circulatory support (Figure 1-2).^14,15 From a technical point of view, therefore, the majority of coronary lesions can now be addressed with PCI; however, this approach may not always be appropriate, necessitating the careful selection of individual patients.

Figure 1-2 Devices that are increasingly available to provide assistance during high-risk PCI include those providing percutaneous extracorporeal circulatory support, such as the TandemHeart (A, B) and the Impella device (C). The TandemHeart (A) removes oxygenated blood from the left atrium and returns it to the peripheral arterial circulation with the aid of a centrifugal pump (B). (Reprinted with permission from Vranckx P, Meliga E, De Jaegere PP, et al: The TandemHeart, percutaneous transseptal left ventricular assist device: a safeguard in high-risk percutaneous coronary interventions. The six-year-Rotterdam experience. EuroIntervention 2008;4(3):331–337.) The Impella left ventricular assist device (C) is a miniaturized rotary blood pump, which is placed retrograde across the aortic valve and aspirates (inlet area) up to 2.5 L/min of blood from the left ventricular cavity and subsequently expels (outlet area) this blood into the ascending aorta.

(Reprinted with permission from Valgimigli M, Steendijk P, Serruys PW, et al: Use of Impella Recover LP 2.5 left ventricular assist device during high-risk percutaneous coronary interventions: clinical, haemodynamic and biochemical findings. EuroIntervention. 2006;2(1):91–100.)

Clinical Trial Results

Randomized trials comparing CABG and PCI have centered on two major patient groups: those with isolated lesions of the proximal left anterior descending artery and those with complex disease, namely 3VD and/or LM disease. Taking the results of these studies at face value and irrespective of which patient group has been assessed, results at short- and long-term follow-up suggest that there are no differences in the hard clinical outcomes of death and myocardial infarction (MI) between patients treated with PCI or CABG (Table 1-2).^6,16–20 Undisputedly CABG has been associated with a clear, consistent, and significant reduction in rates of repeat revascularization. Importantly, all of these studies have several notable limitations that restrict the ability to extrapolate their results to routine clinical practice. This, consequently, reinforces the need to assess patients individually before a revascularization therapy is selected.

TABLE 1-2 A Summary of Metanalyses Reporting Long-Term Outcomes in Patients with Isolated Proximal LAD Disease or Multi-Vessel Disease Randomized to Percutaneous or Surgical Revascularization

The SYNTAX Trial

The SYNTAX trial, which to date has been the largest assessment of treatment with PCI or CABG in patients with complex disease, represents an important study that clearly indicates the importance and potential benefits of evaluating patients at an individual level.

This study aimed to supply evidence to support the already established, but not evidence-based practice of performing PCI in patients with complex disease¹³; it also sought to identify which patients should be treated only with CABG. The study design attempted to address the limitations of the earlier trials described above; in doing so, it was anticipated that the results would be more relevant to clinicians’ everyday practice. Specifically, it was intended to do the following:

• To ensure that the results would be applicable to routine practice, the study was designed as “an all comers” trial such that there were no specific inclusion criteria other than the need to have 3VD or LM disease (in isolation or with CAD). Exclusion criteria were minimal and limited to prior revascularization, recent MI, or the requirement for concomitant cardiac surgery.²³ In contrast to the earlier studies, 70.9% of eligible patients were enrolled.

• The previously indicated problem of reporting outcomes from all patients with complex CAD together, irrespective of disease severity, was addressed in the SYNTAX study through the utilization of the newly developed SYNTAX score (SXscore) (Table 1-3), which enabled CAD complexity to be quantified.

• To ensure the assessment of patients on an individual level, all patients eligible for enrollment were discussed at a “Heart Team” conference at which an interventional cardiologist and cardiac surgeon carried out a careful, through review of each patient in terms of his or her anginal status, comorbidities, and coronary anatomy using the respective Braunwald score, euroSCORE, and SXscore (discussed later in this chapter). The consensus reached from this meeting was then used to allocate the patient to one of the three arms of the trial. In total, 3,075 patients were enrolled into the following groups:

1 Randomized group (1,800 patients [58.5%]: 897 CABG, 903 PCI): these patients had CAD suitable for treatment with PCI or CABG. The mean SXscores in this group were 26.1 and 28.8, respectively, in patients treated with CABG and PCI.

2 CABG registry (1,077 patients [35.0%]): these patients had CAD unsuitable for PCI, as clearly reflected in the high mean SXscore for this group of 37.8.

3 PCI registry (198 patients [6.4%]): these patients were deemed unsuitable for CABG. The most common reason for this decision was the presence of multiple comorbidities²⁴ as reflected in the mean euroSCORE of patients in this group, which was 2 points higher than the mean in the randomized group (5.8 vs. 3.8).

TABLE 1-3 The SYNTAX Score Algorithm³⁸*

1. Arterial dominance 2. Arterial segments involved per lesion 3. Diameter of stenosis i Total occlusion ii Significant lesions (50–99%)

Adverse lesion characteristics

4. Total occlusion i Number of segments involved ii.Age of the total occlusion (>3 months) iii Blunt stump iv Bridging collaterals v First segment beyond the occlusion visible by antegrade or retrograde filling vi Side branch involvement 5. Trifurcation i Number of segments diseased 6. Bifurcation i Medina type ii Angulation between the distal main vessel and the side branch < 70 degrees 7. Aorto-ostial lesion 8. Severe tortuosity 9. Length > 20 mm 10. Heavy calcification 11. Thrombus 12. Diffuse disease/small vessels i Number of segments with diffuse disease/small vessels

* The angiographic components of the SYNTAX score. Each component is assigned a specific weight according to its contribution to procedural risk. The characteristics above are scored for each lesion with a greater than 50% diameter stenosis; these are added together to provide the total SYNTAX score. Full definitions of all variables are published^38,39 and available online (www.syntaxscore.com).

Overall the study failed to meet the prespecified primary endpoint of noninferiority in terms of 12-month major adverse cardio- and cerebrovascular events (MACCE), a composite of death, stroke, MI, and repeat revascularization (17.8% vs. 12.4%, P = 0.002). This was driven by significantly lower rates of repeat revascularization with CABG (13.5% vs. 5.9%, P < 0.0001). Moreover, consistent with prior studies of MVD, there were no significant differences in the overall safety endpoints of death, MI, or death/stroke/MI out to 12 months of follow-up. Results at the 2-year follow-up, which are considered hypothesis-generating in view of the failure to reach the primary endpoint, are somewhat similar to earlier results, with comparable rates of death (PCI 6.2% vs. CABG 4.9%, P = 0.24) and the composite of death/stroke and MI (10.8% vs. 9.6%, P = 0.44), while significantly higher rates of repeat revascularization (17.4% vs. 8.6%, P < 0.001) and overall MACCE (23.4% vs. 16.3%, P < 0.001) were seen with PCI.²⁵ As indicated earlier, the analysis of all patients irrespective of disease severity does not provide adequate information for clinicians, who daily see patients with wide variations in CAD complexity. To address this limitation of earlier studies, patient outcomes in the SYNTAX study were stratified according to terciles of the SXscore. As shown in Figure 1-3, clinical outcomes between patients treated with PCI and CABG were similar in those with low SXscores, trended in favor of CABG in the intermediate group, and were significantly lower in the CABG group among patients with high SXscores. The intermediate group was further subdivided into a 3VD cohort, where outcomes were lower with CABG, and into an LM cohort, where outcomes were comparable between PCI and CABG (Figure 1-4).^26,27 These results reiterate the importance of assessing patients when a revascularization strategy is being selected. The SYNTAX study was able to identify those patients in whom either PCI or CABG was appropriate and, perhaps more importantly, the group of patients in whom CABG was the optimal treatment. Considering the distribution of CAD in the SYNTAX study, overall one-third of patients with 3VD/LM disease were deemed to have CAD that could be treated safely and effectively with PCI or CABG; in the remaining two-thirds, CABG remained the standard of care. Although these results were consistent with what was already practiced,¹³ validation of the SXscore importantly facilitates a more objective assessment of patients, as discussed in the following pages.

Figure 1-3 Two-year rates of major adverse cardiovascular and cerebrovascular events (a composite of death, stroke, myocardial infarction, and repeat revascularization) among the 1,800 patients randomized to PCI or CABG in the SYNTAX study, stratified according to SYNTAX score. Of note, clinical outcomes were comparable between PCI and CABG in those with an SXscore of 0 to 22, trended in favor of CABG in those with an SXscore of 23 to 32, and were significantly lower with CABG in those with an SXscore ≥ 33.²⁵

Figure 1-4 The evidence supporting the use of the SYNTAX score as a tool to assist in revascularization decisions. A. In patients with three-vessel disease, the rate of major adverse cardiovascular and cerebrovascular events (MACCE, a composite of death, stroke, myocardial infarction, and repeat revascularization) at 2-year follow-up was comparable only between patients treated with PCI and CABG for SYNTAX scores of 0 to 22; for all other SYNTAX scores, outcomes were significantly better following CABG.²⁶ B. In patients with left main disease, clinical outcomes were comparable between patients treated by PCI or CABG for all SYNTAX scores, apart from those above 32, when outcomes were significantly better with CABG (CABG: purple line; PCI: green line).²⁷

Qualitative Versus Quantitative Risk Assessment

Qualitative risk stratification is subjective and relies on the clinician’s experience. This assessment is advantageous from an individual’s perspective because it possesses the greatest sensitivity. In qualitative risk stratification, all factors relevant to assessing risk in a particular individual are considered; in the risk model, only the select list of variables involved are considered. Moreover, this subjective qualitative assessment also allows risk to be calculated and tailored to the expertise of the physician performing the procedure, as opposed to a clinician in another region who may use different techniques and have different equipment available. Finally, this assessment does not require a calculator or computer and can be “computed” subconsciously very quickly. The major disadvantages of this method of risk assessment are its dependence on an operator’s prior experience and its high interobserver variability.

Quantitative risk stratification can be performed using a variety of risk models that incorporate clinical variables sourced from large patient databases.^29–36 These risk models largely incorporate objective variables, thus ensuring adequate reproducibility of the score. However, models such as the American College of Cardiology/American Heart Association (ACC/AHA) lesion score³⁷ or the SYNTAX score,³⁸ which include angiographic variables, continue to have documented intra- and interobserver variability.^39,40 In addition to their role in the risk stratification of individual patients, these quantitative risk models have increasing use in the wider context of overall healthcare. They can provide a vital measure of overall patient care and can help to identify future directions to further improve outcomes. Clinical governance and the increasing requirement to report clinical performance (and complications) publicly have also propelled the need to risk stratify patients, thereby allowing useful comparisons of performance to be made between clinicians (and institutions) and the standards dictated by regulatory authorities.⁴¹ In addition, the calculation of risk using accepted risk models can aid clinicians who are faced with an increasing need to justify their clinical decisions to peers, regulatory bodies, and patients. In comparison to the qualitative risk models, the use of a finite number of variables makes these model less sensitive and therefore less able to accurately predict risk in an individual, such that they are more effective in predicting risk for a population of patients with similar comorbidities. The number of variables included in the model must strike a balance between sufficient numbers to enable the calculation of a meaningful prediction of risk; however, the number must not be so excessive as to prevent the use of the model in routine practice. In addition, a minimal number of variables reduces the chances of colinearity between independent variables, which can result in the collection of redundant information³⁴

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