American College of Cardiology Foundation/American Heart Association
A Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention (PCI) Or as Pre-treatment at the Time of Diagnosis in Patients With Non-ST-Elevation Myocardial Infarction (NSTEMI)
age, creatinine, ejection fraction
acute coronary syndromes
Acute Catheterization and Urgent Intervention Triage strategy
Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents
Apixaban for Prevention of Acute Ischemic and Safety Events
activated partial thromboplastin time
Assessment by a double Randomization of a Conventional antiplatelet strategy vs. a monitoring-guided strategy for drug-eluting stent implantation and, of Treatment Interruption vs. Continuation one year after stenting
Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty
Arterial Revascularization Therapies Study
American College of Cardiology Foundation–Society of Thoracic Surgeons Database Collaboration
ATLAS ACS 2–TIMI 51
Anti-Xa Therapy to Lower cardiovascular events in Addition to Standard therapy in subjects with Acute Coronary Syndrome–Thrombolysis In Myocardial Infarction 51
Acute STEMI Treated with primary PCI and intravenous enoxaparin Or UFH to Lower ischaemic and bleeding events at short- and Long-term follow-up
aortic valve replacement
Angina With Extremely Serious Operative Mortality Evaluation
Continuing TIrofiban in Myocardial infarction Evaluation
Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice
per os (by mouth)
Paclitaxel-Coated Balloon Catheter
peripheral artery disease
Patterns of Non-Adherence to Anti-Platelet Regimens In Stented Patients
Primary Coronary Angioplasty vs. Thrombolysis
percutaneous coronary intervention
Paclitaxel-Eluting PTCA–Catheter In Coronary Disease
positron emission tomography
Study of Platelet Inhibition and Patient Outcomes
Preventive Angioplasty in Acute Myocardial Infarction
Premier of Randomized Comparison of Bypass Surgery vs. Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease
Parisian Region Out of Hospital Cardiac Arrest
PROlonging Dual Antiplatelet Treatment In Patients With Coronary Artery Disease After Graded Stent-induced Intimal Hyperplasia studY
Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation
randomized clinical trial
Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events
Real Safety and Efficacy of a 3-month Dual Antiplatelet Therapy Following Zotarolimus-eluting Stents Implantation
RadIal Vs. femorAL access for coronary intervention
relative risk reduction
Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus
stable coronary artery disease
Swedish Coronary Angiography and Angioplasty Registry
Sudden Cardiac Death in Heart Failure Trial
Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock
Studies of Left Ventricular Dysfunction
single photon emission computed tomography
ST-segment elevation acute coronary syndrome
Safety and Efficacy of Intravenous Enoxaparin in Elective Percutaneous Coronary Intervention Randomized Evaluation
ST-segment elevation myocardial infarction
Surgical Treatment for Ischemic Heart Failure
STrategic Reperfusion Early After Myocardial infarction
Society of Thoracic Surgeons
saphenous vein graft
surgical ventricular reconstruction
Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery.
Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction
Do Tirofiban and Reo-Pro Give Similar Efficacy Outcome Trial
Thrombus Aspiration during PCI in Acute Myocardial Infarction
transcatheter aortic valve implantation
transient ischaemic attack
Timing of Intervention in Patients with Acute Coronary Syndromes
Trial of Invasive Medical therapy in the Elderly
Thrombolysis in Myocardial Infarction
Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel
TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel–Thrombolysis In Myocardial Infarction 38
target vessel revascularization
ventricular assist device
vitamin K antagonist
ventricular septal defect
What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing
Zotarolimus-Eluting Stent, Sirolimus-Eluting Stent, or PacliTaxel-Eluting Stent Implantation for Coronary Lesions - Late Coronary Arterial Thrombotic Events/REAL-world Patients Treated with Drug-Eluting Stent Implantation and Late Coronary Arterial Thrombotic Events
Guidelines summarize and evaluate all available evidence, at the time of the writing process, on a particular issue with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help health professionals to make decisions in their daily practice; however, the final decisions concerning an individual patient must be made by the responsible health professional(s), in consultation with the patient and caregiver as appropriate.
A great number of guidelines have been issued in recent years by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS), as well as by other societies and organisations. Because of their impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC/EACTS Guidelines can be found on the ESC web site (http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx). These ESC/EACTS guidelines represent the official position of these two societies on this given topic and are regularly updated.
Members of this Task Force were selected by the ESC and EACTS to represent professionals involved with the medical care of patients with this pathology. Selected experts in the field undertook a comprehensive review of the published evidence for management (including diagnosis, treatment, prevention and rehabilitation) of a given condition, according to the ESC Committee for Practice Guidelines (CPG) and EACTS Guidelines Committee policy. A critical evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger populations were included, where data exist. The level of evidence and the strength of recommendation of particular management options were weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2.
The experts of the writing and reviewing panels completed ‘declarations of interest’ forms which might be perceived as real or potential sources of conflicts of interest. These forms were compiled into one file and can be found on the ESC web site (http://www.escardio.org/guidelines). Any changes in declarations of interest that arise during the writing period must be notified to the ESC/EACTS and updated. The Task Force received its entire financial support from the ESC and EACTS, without any involvement from the healthcare industry.
The ESC CPG supervises and co-ordinates the preparation of new guidelines produced by Task Forces, expert groups or consensus panels. The Committee is also responsible for the endorsement process of these guidelines. The ESC and Joint Guidelines undergo extensive review by the CPG and partner Guidelines Committee and external experts. After appropriate revisions it is approved by all the experts involved in the Task Force. The finalized document is approved by the CPG/EACTS for simultaneous publication in the European Heart Journal and joint partner journal, in this instance the European Journal of Cardio-Thoracic Surgery. It was developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating.
The task of developing ESC/EACTS Guidelines covers not only the integration of the most recent research, but also the creation of educational tools and implementation programmes for the recommendations. To implement the guidelines, condensed pocket versions, summary slides, booklets with essential messages, summary cards for non-specialists, electronic versions for digital applications (smart phones etc.) are produced. These versions are abridged and thus, if needed, one should always refer to the full-text version, which is freely available on the ESC and EACTS web sites. The national societies of the ESC and of the EACTS are encouraged to endorse, translate and implement the ESC Guidelines. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations.
Surveys and registries are needed to verify that real-life daily practice is in keeping with what is recommended in the guidelines, thus completing the loop between clinical research, writing of guidelines, disseminating them and implementing them into clinical practice.
Health professionals are encouraged to take the ESC/EACTS Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC/EACTS Guidelines do not, in any way whatsoever, override the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of the condition of each patient’s health and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. It is also the health professional’s responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.
In 2014, coronary artery bypass grafting (CABG) celebrates the 50th anniversary of the first procedures performed in 1964.1 Thirteen years later, the first percutaneous coronary intervention (PCI) was performed.2 Since then both revascularization techniques have undergone continued advances, in particular the systematic use of arterial conduits in the case of CABG, and the advent of stents. In the meantime, PCI has become one of the most frequently performed therapeutic interventions in medicine,3 and progress has resulted in a steady decline of periprocedural adverse events, resulting in excellent outcomes with both revascularization techniques. Notwithstanding, the differences between the two revascularization strategies should be recognized. In CABG, bypass grafts are placed to the mid-coronary vessel beyond the culprit lesion(s), providing extra sources of bloodflow to the myocardium and offering protection against the consequences of further proximal obstructive disease. In contrast, coronary stents aim at restoring normal bloodflow of the native coronary vasculature by local treatment of obstructive lesions without offering protection against new disease proximal to the stent.
Myocardial revascularization has been subject to more randomized clinical trials (RCTs) than almost any other intervention (Figure 1). In order to inform the current Guidelines, this Task Force performed a systematic review of all RCTs performed since 1980, comparing head-to-head the different revascularization strategies—including CABG, balloon angioplasty, and PCI with bare-metal stents (BMS) or with various US Food and Drug Administration-approved drug-eluting stents (DES)—against medical treatment as well as different revascularization strategies, and retrieved 100 RCTs involving 93 553 patients with 262 090 patient-years of follow-up.4
Randomized trials in myocardial revascularization therapy over the past five decades.
Formulation of the best possible revascularization approach, also taking into consideration the social and cultural context, will often require interaction between cardiologists and cardiac surgeons, referring physicians, or other specialists as appropriate. Patients need help with taking informed decisions about their treatment and the most valuable advice will probably be provided to them by the ‘Heart Team’.5 Recognizing the importance of the interaction between cardiologists and cardiac surgeons, the leadership of both the ESC and the EACTS has given this Joint Task Force, along with their respective Guideline Committees, and the reviewers of this document the mission to draft balanced, patient-centred, evidence-driven practice guidelines on myocardial revascularization. The respective Chairpersons of these two associations and CPG Chairperson were also given the task to adapt to the declaration of interest policy and to ensure that their Task Force members followed it throughout the development process of the Guidelines. In the event that any of the Task Force members had a potential conflict of interest to declare, he/she did not participate in the final decision of the Task Force on the given subject.
3. Scores and risk stratification
Myocardial revascularization in the elective setting is appropriate when the expected benefits, in terms of survival or health outcomes (symptoms, functional status, and/or quality of life), exceed the expected negative consequences of the procedure. Whether medical therapy, PCI, or CABG is preferred should depend on the risk–benefit ratios of these treatment strategies, weighting the risks of periprocedural death, myocardial infarction and stroke against improvements in health-related quality of life, as well as long-term freedom from death, myocardial infarction or repeat revascularization. The Heart Team should take into consideration the coronary anatomy, disease, age and comorbidities, patient preference, and hospital/operator experience.
Numerous models have been developed for risk stratification, focussing on anatomical complexity or clinical risk, and have demonstrated their value during decision-making.6 Those models most frequently used in a clinical setting are summarized in the Tables of recommendation [risk models to assess short-term (in-hospital or 30-day) and medium-to-long-term (≥1 year) outcomes].
The EuroSCORE predicts surgical mortality.7,8 It is based on an old data set and has been shown to overestimate the risk of mortality, and should therefore no longer be used.9,10
The EuroSCORE II is an update of the logistic EuroSCORE model and is derived from a more contemporary data set better reflecting current cardiac surgical practice.11 Its value has been demonstrated in specific cohorts of patients undergoing CABG.12 Compared with its original version, the EuroSCORE II may have a better ability to predict mortality.12–14
The Society of Thoracic Surgeons (STS) score is a risk-prediction model, validated in patients undergoing cardiac surgery, with a specific model for CABG surgery and combined CABG and valve surgery.15,16 It can be used to predict in-hospital or 30-day mortality (whichever occurs last) and in-hospital morbidity.
The SYNTAX score (Table 3) was developed to grade the anatomical complexity of coronary lesions in patients with left main or three-vessel disease, and was found to be an independent predictor of long-term major adverse cardiac and cerebrovascular event (MACCE) in patients treated with PCI but not CABG.17,18 It facilitates the selection of optimal treatment by identifying patients at highest risk of adverse events following PCI. The interobserver variability of the Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) score is significant,19 although development of non-invasive assessments may simplify calculation of the SYNTAX score.20
The National Cardiovascular Database Registry (NCDR CathPCI) risk score has been developed to predict risk in PCI patients and should only be used in this context.21
The age, creatinine, ejection fraction (ACEF) model is a simple score as it contains only three variables, and was developed using data from a cohort of surgical patients.22 ACEF has also been validated to predict mortality in patients undergoing PCI.23
The clinical SYNTAX score is a combination of the ACEF and SYNTAX scores. Originally established as an additive model, the subsequent development of a logistic model has provided more tailored risk assessment.24
The SYNTAX II score is a combination of anatomical and clinical factors [age, creatinine clearance, left ventricular (LV) function, gender, chronic obstructive pulmonary disease, and peripheral vascular disease] and predicts long-term mortality in patients with complex three-vessel or left main (LM) coronary artery disease (CAD).25 It was found to be superior to the conventional SYNTAX score in guiding decision-making between CABG and PCI in the SYNTAX trial, and subsequently validated in the drug-eluting stent for left main coronary artery disease DELTA registry.
For the American College of Cardiology Foundation–Society of Thoracic Surgeons Database Collaboration (ASCERT) study,26 two large datasets from the National Cardiovascular Data Registry (NCDR) and STS were used to develop several models to predict mortality at different time points following CABG and PCI.27,28
Comparative analyses of these models are limited because available studies have largely evaluated individual risk models in different patient populations, with different outcome measures being reported at various time points, and most models are restricted to one type of revascularization. In addition, several important variables, such as frailty, physical independence and porcelain aorta, are not incorporated in current risk scores. An ideal risk–benefit model enables comparison of the short-term benefits of PCI to the long-term benefits of CABG; however, even though risk models may provide useful information for predicting mortality and major adverse events, prediction of which patients will receive benefit in terms of quality of life is so far unavailable.
These limitations restrict the ability to recommend one specific risk model. It is also important to acknowledge that no risk score can accurately predict events in an individual patient. Moreover, limitations exist in all databases used to build risk models, and differences in definitions and variable content can affect the performance of risk scores when they are applied across differing populations. Ultimately, risk stratification should be used as a guide, while clinical judgement and multidisciplinary dialogue (The Heart Team) remain essential.25
Risk models to assess medium- to long-term (≥1 year) outcomes
ASCERT = American College of Cardiology Foundation–Society of Thoracic Surgeons Database Collaboration (ACCF–STS) on the comparative effectiveness of revascularization strategies; (i) CABG = (isolated) coronary artery bypass grafting; MACCE = major adverse cardiac and cerebrovascular events; PCI = percutaneous coronary intervention; SYNTAX = synergy between percutaneous coronary intervention with TAXUS and cardiac surgery.
4. Process for decision-making and patient information
4.1 Patient information and informed consent
The process of medical decision-making and patient information is guided by the ‘four principles’ approach to healthcare ethics: autonomy, beneficence, non-maleficence, and justice.31 The informed consent process should not be regarded as a necessary legal requirement but as an opportunity to optimize decision-making. Patient-related factors, institutional factors and referral patterns may impact the decision-making process.
Informed consent requires transparency, especially if there is controversy over various treatment options. Collaborative care requires the pre-conditions of communication, comprehension, and trust. Treatment decisions should not be based solely on research results and the physician’s appraisal of the patient’s circumstances, since active patient participation in the decision-making process may yield better outcomes. Patients are subject to bias by labels when considering coronary revascularization,32 and patient preference may sometimes contradict evidentiary best practice. Patients may have limited understanding of their disease and sometimes unreasonable expectations with regard to the outcomes of a proposed intervention. As many as 68% of patients are not aware of an alternative revascularization strategy.33 Short-term procedure-related and long-term risks and benefits—such as survival, relief of angina, quality of life, potential need for late re-intervention, and uncertainties associated with different treatment strategies—should be thoroughly discussed. Patients can only weigh this information in the light of their personal values and cultural background and must therefore have the time to reflect on the trade-offs imposed by the outcome estimates.
In order to seek a second opinion or to discuss the findings and consequences with referring physicians, enough time should be allowed—up to several days, as required—between diagnostic catheterization and intervention. Patient information needs to be unbiased, evidence-based, up-to-date, reliable, accessible, relevant, and consistent with legal requirements. Consistent use of terminology, that the patient understands, is essential. A written patient information document is needed. These recommendations pertain to patients in stable condition, for whom various treatment options exist and who can make a decision without the constraints of an urgent or emergency situation (Table 4).
Anonymous treatment should be avoided. The patient has the right to obtain information on the level of expertise of the operator, the workload of the centre and whether all treatment options including surgery are available on site. Patients considered for revascularization should also be clearly informed of the continuing need for medical therapy, as well as lifestyle modification and other secondary prevention strategies (section 20).
The Heart Team, made up of clinical or non-invasive cardiologists, cardiac surgeons and interventional cardiologists, provides a balanced, multidisciplinary decision-making process.5 Additional input may be needed from other specialties involved in the care of the patient. The Heart Team should meet on a regular basis to analyse and interpret the available diagnostic evidence, put into context the clinical condition of the patient, determine the need—or otherwise—for an intervention and the likelihood of safe and effective revascularization with either PCI or CABG. Ad hoc meetings of the Heart Team should facilitate and support efficient clinical workflows.
The demand for an interdisciplinary approach is underlined by reports on (i) underuse of revascularization procedures in 18–40% of patients with CAD,34 and (ii) inappropriate use of revascularization strategies and a lack of case discussions.35 The large variability between European countries in PCI-to-CABG ratios (ranging from 2.0 to 8.6 in 2007) has raised concerns regarding the appropriate selection of revascularization in Europe.36 Rates for the inappropriate use of PCI (11–15%) or doubt over the appropriateness of PCI (40–50%)5,37 and, to a lesser degree for CABG (1–2% and 0–9%, respectively) are reported.5,38 The increasing underuse of CABG is in part explained by PCI treatment in patients with indications for surgery.39,40 Multidisciplinary decision-making in a Heart Team can minimize specialty bias and prevent self-referral from interfering with optimal patient care.32,41
Standard evidence-based, interdisciplinary, institutional protocols may be used for common case scenarios, to avoid the need for the systematic case-by-case review of all diagnostic angiograms, but complex cases should be discussed individually. In these cases, revascularization should not be performed at the time of diagnostic angiography, to allow sufficient time to assess all available information, and clearly explain and discuss the findings with the patient.41 The rationale for a decision and consensus on the optimal revascularization treatment should be documented on the patient’s chart. In hospitals without a cardiac surgical unit or in an ambulatory setting, protocols should be designed in collaboration with an expert interventional cardiologist and a cardiac surgeon. Decisions made by a Heart Team seem to be reproducible.42
4.3 Timing of revascularization and ad hoc percutaneous coronary intervention
Studies of patients scheduled for revascularization have revealed that considerable morbidity and mortality are associated with extended delay of treatment.43,44 The waiting period for diagnostic catheterization should therefore be minimal. Once the decision for revascularization has been reached after diagnostic coronary angiography, the Task Force recommends that patients with severe symptoms Canadian Cardiovascular Society (CCS) Class 3 and those with high-risk anatomy [left main disease or equivalent; three-vessel disease or proximal left anterior descending (LAD) or depressed ventricular function] preferably undergo revascularization (PCI or CABG) within 2 weeks. For all other patients with stable coronary artery disease (SCAD) and an indication for revascularization, it is desirable to perform revascularization (PCI or CABG) within 6 weeks (Table 4).44
Ad hoc PCI is defined as a therapeutic intervention performed within the same procedure as the diagnostic coronary angiography. Ad hoc PCI is convenient, associated with fewer access site complications, and often cost-effective and safe.45 In the USA, however, up to 30% of patients undergoing ad hoc PCI are potential candidates for CABG.45 Although this number may be lower in Europe,35 ad hoc PCI should not be applied as a default approach.45,46Ad hoc PCI in stable patients is only justified after adequate information given to the patient (see section 4.1) and if a full diagnostic work-up, including functional testing (section 5) is available. Institutional protocols developed by the Heart Team in accordance with current guidelines should define specific anatomical criteria and clinical subsets that may be—or should not be—treated ad hoc. Complex pathologies in stable patients, including lesions of the LM or proximal LAD and three-vessel disease, should in general not be treated ad hoc, but discussed by the Heart Team.
Recommendations for decision-making and patient information in the elective setting
PCI = percutaneous coronary intervention.
aClass of recommendation.
bLevel of evidence.
5. Strategies for diagnosis: functional testing and imaging
Exercise testing and cardiac imaging are used to confirm the diagnosis of CAD, to document ischaemia in patients with stable symptoms, to risk-stratify patients, and to help choose treatment options and evaluate their efficacy as explained in detail in the ESC Guidelines on the management of stable coronary artery disease.47
Another indication for non-invasive imaging before revascularization is the detection of myocardial viability in patients with poor LV function.
5.1 Non-invasive tests
The documentation of ischaemia using functional testing is recommended in patients with suspected SCAD before elective invasive procedures, preferably using non-invasive testing before invasive angiography. Although several tests can be used, it is important to avoid unnecessary diagnostic steps. The current evidence supporting the use of various tests for the detection of CAD is based on meta-analyses and multicentre studies, and using only anatomical evaluation of invasive coronary angiography as the reference standard.47 The risks of exercise, pharmacological stressors, contrast agents, invasive procedures, and cumulative ionizing radiation must be weighed against the risk of disease or delayed diagnosis.48
Multi-detector computed tomography (MDCT) can detect coronary atherosclerosis and stenoses and is reliable for ruling out significant CAD in patients with low-to-moderate probability of CAD.49 The tests for detection of ischaemia are based on either reduction of perfusion or induction of ischaemic wall motion abnormalities during exercise or pharmacological stress. The best-established stress imaging techniques are echocardiography and perfusion scintigraphy. Both may be used in combination with exercise stress or pharmacological stress. Newer stress imaging techniques also include stress magnetic resonance imaging (MRI), positron emission tomography (PET), and combined approaches. The term ‘hybrid imaging' refers to imaging systems in which two modalities [MDCT and PET; MDCT and single photon emission computed tomography (SPECT)] are combined in the same scanner, allowing both studies to be performed in a single imaging session. Ischaemia imaging has been regarded the most appropriate in patients with intermediate pre-test probability (15–85%) of significant CAD,47 while in asymptomatic patients or in those with low or high pre-test probability, the tests are generally not recommended. More detailed information about the imaging tests in the detection of CAD are available in the ESC Guidelines on the management of SCAD47 and in the Web addenda.
5.2 Invasive tests
Invasive coronary angiography has been regarded as the reference standard for the detection and the assessment of the severity of CAD but, as an invasive procedure, it is associated with specific procedure-related adverse events. Even experienced interventional cardiologists cannot, without functional information, accurately predict the significance of many intermediate stenoses on the basis of visual assessment or quantitative coronary angiography. When non-invasive stress imaging is contraindicated, non-diagnostic, or unavailable, the measurement of fractional flow reserve (FFR) or coronary flow reserve is helpful during diagnostic coronary angiography.50 Deferral of PCI or CABG in patients with FFR >0.80 appears safe.51–53 Fractional flow reserve measurement is indicated for the assessment of the functional consequences of moderate coronary stenoses. FFR-guided PCI with medical therapy has been shown to decrease the need for urgent revascularization compared with the best available medical therapy alone.54
5.3 Detection of myocardial viability
Non-invasive assessment of myocardial viability has been used to guide the management of patients with chronic ischaemic systolic LV dysfunction. Multiple imaging techniques, including PET, SPECT, and dobutamine stress echocardiography, have been evaluated for assessment of viability and prediction of clinical outcome after myocardial revascularization.55 In general, nuclear imaging techniques have a high sensitivity, whereas techniques evaluating contractile reserve have a somewhat lower sensitivity but higher specificity. MRI has a high diagnostic accuracy for assessing the transmural extent of myocardial scar tissue and can also assess contractile reserve, but its ability to detect viability and predict recovery of wall motion is no better than other imaging techniques. The differences in performance between the various imaging techniques are small, and experience and availability commonly determine which technique is used. The evidence is mostly based on observational studies or meta-analyses. One RCT, relating to PET imaging, showed that patients with a substantial amount of dysfunctional but viable myocardium are likely to benefit from myocardial revascularization.56
Indications for diagnostic testing in patients with suspected CAD and stable symptoms
CAD = coronary artery disease; CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography.
aScreening for silent (asymptomatic) myocardial ischaemia may be considered in selected high-risk patients, such as those with diabetes mellitus.84
bPre-test probability of CAD. Low 0—15%; intermediate 15—85%; high >85% as assessed using the criteria based on ESC Guidelines of SCAD.47
cClass of recommendation.
dLevel of evidence.
fThis refers to CT angiography, not calcium scoring.
gCT is considered to perform best in the lower range of pre-test probability (15—50%).47
6. Revascularization for stable coronary artery disease
6.1 Rationale for revascularization
Prior to revascularization, patients with SCAD must receive guideline-recommended medical treatment, due to its established benefits in terms of prognosis and symptom relief.47 Revascularization, by either PCI or CABG, may be indicated in flow-limiting coronary stenoses to reduce myocardial ischaemia and its adverse clinical manifestations.85–87 The indications for revascularization in patients with SCAD are persistence of symptoms despite medical treatment and/or improvement of prognosis.47 Consequently, revascularization and medical therapy should be seen as complementary, rather than competitive treatment strategies. Specific evidence and recommendations for diabetic patients are addressed in section 10.
Angina is associated with impaired quality of life, reduced physical endurance, mental depression, and recurrent hospitalizations and outpatient visits.88 Revascularization by PCI or CABG more effectively relieves angina, reduces the use of anti-angina drugs, and improves exercise capacity and quality of life, compared with a strategy of medical therapy alone (Table 2 Web addenda).54,89–96
Ischaemia is of prognostic importance in patients with SCAD, particularly when occurring at low workload.97,98 Revascularization relieves myocardial ischaemia more effectively than medical treatment alone.92,97,99,100 The extent, location, and severity of coronary artery obstruction as assessed by coronary angiography or coronary computed tomography (CT) angiography are important prognostic factors in addition to ischaemia and left ventricular function.101–103
6.2 Evidence basis for revascularization
The evidence basis for revascularization with PCI and/or CABG, compared with medical treatment, is derived from several RCTs that are summarized in Table 5. It is important to consider that the best current revascularization results achieved with PCI are with new-generation drug-eluting stents (DES) and for CABG with maximal use of arterial grafts. Although revascularization procedures are associated with the risk of biomarker-defined periprocedural myocardial infarction, several studies indicate that pre-PCI—but not post-PCI—biomarker elevations impact adversely on prognosis.104 While spontaneous myocardial infarction has a well established adverse impact on prognosis and notably mortality, recent studies suggest that, compared with medical treatment, PCI is associated with a lower risk of spontaneous myocardial infarction.105
Although individual RCTs and subsequent meta-analyses constitute the highest hierarchical form of evidence-based medicine,106–108 extrapolation of their results to routine clinical practice has its limitations. The majority of RCTs included mainly male patients who were relatively young [with the exception of Trial of Invasive Medical therapy in the Elderly (TIME)], had preserved LV function, and had not previously undergone revascularization. Patients were highly selected, as randomization was usually performed following delineation of coronary anatomy by angiography without routine assessment of ischaemia. By design, all the RCTs compared treatment strategies that allowed subsequent revascularization when patients deteriorated on medical therapy. As a result, the proportion of patients who did not undergo revascularization progressively declined during follow-up, camouflaging differences between the two strategies and making analysis according to the intention-to-treat principle more problematic. Finally, limited duration of follow-up (usually <5 years) incompletely depicts the advantages of CABG related to arterial grafts, which accrue with time but which may also eventually be eroded by progressive vein graft failure.
Only trials with at least 100 patients per treatment arm were included. Age and ejection fraction are reported as means.
6.2.1 Revascularization with the use of percutaneous coronary intervention
The efficacy of PCI in addition to medical therapy in patients with SCAD has been addressed in several RCTs,54,91,94 meta-analyses,106,107,117–120 and large-scale registries.121 The most important recent studies and their data are summarized in Table 5.
The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE)91 trial included 2287 patients with SCAD, who showed objective evidence of ischaemia and significant CAD, randomizing them to medical therapy alone or medical therapy plus PCI with BMS. At a median follow-up of 4.6 years, there were no significant differences between the PCI and medical therapy groups in the composite of death, myocardial infarction and stroke. Freedom from angina was significantly greater in the PCI group at 1 year and 3 years but the advantage was eroded by 5 years, by which time 21% of the PCI group and 33% of the medical therapy group had received additional revascularization (P <0.001). The severity of CAD in COURAGE was moderate and the majority of patients (70%) had no or mild ischaemia at baseline and most patients had normal LV function.122 Patients with LM disease were excluded.
The Medical, Angioplasty or Surgery Study II (MASS II) trial, covering 611 patients with multivessel disease, all recruited at a single institution, is the only RCT comparing medical therapy with PCI (72% with BMS; 28% with balloon angioplasty only) and with CABG. Over 10 years, comparing medical therapy with PCI, the respective rates for all-cause mortality were 31% and 24.1% (P =0.09), for myocardial infarction 20.7% and 13.3% PCI (P =0.01), and for freedom from angina 43% and 59% (P <0.001).94
In the Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME-2) trial,54 patients with SCAD and at least one functionally significant stenosis (invasive FFR ≤0.80) were randomly assigned to medical therapy alone or to medical therapy plus FFR-guided PCI. The trial was planned to include 1632 patients but the data safety monitoring board stopped the study prematurely after enrolment of 888 patients, due to a highly significant difference in the incidence of the primary endpoint (a composite of death, myocardial infarction, and urgent revascularization) in favour of FFR-guided PCI that was unlikely to be neutralized with recruitment of more patients. Final analysis showed an incidence of the primary endpoint of 4.3% in the PCI group and 12.7% in the medical therapy group (P <0.001) but without a difference in rates of death or myocardial infarction between the two groups. Interpretation of FAME-2 is complicated, in that the decision for urgent revascularization may have been influenced by the open nature of the trial. The definition of 'urgent revascularization' met the criteria for the clinical presentation of an acute coronary syndrome (ACS) and 50% of the patients undergoing urgent revascularization displayed objective evidence of continuing ischaemia.
Most meta-analyses comparing a strategy of PCI against initial medical therapy found no evidence in favour of an invasive strategy, in terms of survival or myocardial infarction.117,118,123,125 Two reported a small survival benefit for PCI over medical therapy, although this might have been influenced by the inclusion of a subset of patients who had had a recent (<4 weeks) myocardial infarction.107,119One meta-analysis, updated for more recent RCTs, showed that, compared with an initial strategy of medical therapy, PCI was not associated with significant improvement in all-cause mortality [risk ratio (RR) 0.85; 95% confidence interval (CI) 0.71–1.01], cardiac death (RR 0.71; 95% CI 0.47–1.06), myocardial infarction (RR 0.93; 95% CI 0.70–1.24), or repeat revascularization (RR 0.93; 95% CI 0.76–1.14) during short- or long-term follow-up.96 In a meta-analysis of five RCTs covering 5286 patients and site-reported ischaemia at baseline, there were no differences between PCI and medical treatment in terms of death, myocardial infarction, unplanned revascularization or angina during a median follow-up of 5 years.100
In the New York State’s Cardiac Diagnostic Catheterization Database, 9586 patients were identified between 2003 and 2008, who had either PCI (n = 8486; 89%) or medical therapy (n = 1100; 11%). A comparison of 933 propensity-score matched patients in each group showed, with PCI over 4 years, a lower incidence of the composite of mortality and myocardial infarction (16.5% vs. 21.2%, respectively; P =0.003) as well as the individual components: death (10.2% vs. 14.5%, respectively; P =0.02) and myocardial infarction (8.0% vs. 11.3%, respectively; P =0.007).121 The authors caution that part of the difference in outcomes might be explained by the differences between the groups in their use of routine medical therapy.
6.2.2 Percutaneous coronary intervention with drug-eluting stents vs. bare-metal stents
The major limitation of most of the previous comparisons is the lack of use of DES. Several meta-analyses of RCTs comparing early-generation DES with bare-metal stents (BMS) reported similar rates of death, cardiac death, and non-fatal myocardial infarction, but a 50−70% relative risk reduction (RRR) in the need for subsequent or repeat target vessel revascularization (TVR) with DES.124,125
New-generation DES, with thin strut stent platforms, biocompatible durable or biodegradable polymers and limus-based antiproliferative agents, have further advanced efficacy and safety compared with early-generation DES and BMS (see section 17 for more information). Compared with early-generation DES, repeat revascularization was reduced by 10–20%.126–129 Compared with bare-metal stents and early-generation DES, new-generation DES have also improved safety outcomes including death, myocardial infarction and stent thrombosis. Several studies have reported an approximately 50% lower risk of definite or probable stent thrombosis, than with early-generation DES, particularly during the late phase,128–131 and some studies reported a lower risk of stent thrombosis than with BMS.125,131 A mixed-treatment comparison of DES and BMS, embracing 76 RCTs and 117 762 patient-years of follow-up, did not report a lower risk of death but a lower risk (20–35%) of myocardial infarction with DES (except paclitaxel-eluting stents) than with BMS.132 The randomized Basel Stent Kosten Effektivitäts Trial–Prospective Validation Examination (BASKET–PROVE) trial, comparing DES with BMS among patients with large vessels (>3 mm) showed no significant differences between sirolimus-eluting, everolimus-eluting, and bare-metal stents in terms of the rate of death or myocardial infarction; however, there was a lower risk of cardiac death or myocardial infarction with DES (pooled DES vs. BMS: RR 0.60; 95% CI 0.39–0.93; P =0.02) at 2 years of follow-up.133 An individual patient-data meta-analysis of three RCTs including 4989 patients, which compared new-generation everolimus-eluting stents with early-generation paclitaxel-eluting stents, reported a lower risk of death (3.2% vs. 5.1%; hazard ratio (HR) 0.65; 95% CI 0.49–0.86; P = 0.003), cardiac death or myocardial infarction (4.4% vs. 6.3%; HR 0.70; 95% CI 0.54–0.90; P = 0.005), and stent thrombosis (0.7% vs. 1.7%; HR 0.45; 95% CI 0.26–0.78; P = 0.003) after 3 years of follow-up.126 A patient-level pooled analysis of 26 RCTs in 11 557 women, reported a lower incidence of the composite of death or myocardial infarction in female patients treated with new-generation DES (9.2%) compared with both early-generation DES (10.9%) and BMS (12.8%; P =0.001) at 3 years.129 Similarly, the incidence of definite or probable stent thrombosis was lowest with new-generation DES (1.1%) followed by BMS (1.3%), and early-generation DES (2.1%; P =0.01).
6.2.3 Revascularization with the use of coronary artery bypass grafting
The superiority of CABG to a strategy of initial medical therapy for specific subsets of SCAD was established in a meta-analysis of seven RCTs.108 It demonstrated a survival benefit from CABG in patients with LM or three-vessel SCAD, particularly when the proximal LAD coronary artery was involved. Benefits were greater in those with severe symptoms, early positive exercise tests, and impaired LV function. Notably, in these early studies only 10% of CABG patients received an internal mammary artery (IMA), which is an important prognostic component of CABG. Furthermore, 40% of patients in the medical group crossed over to CABG during follow-up. A more recent meta-analysis has reported a reduction in the risk of death with CABG vs. medical therapy (HR 0.62; 95% CI 0.50–0.77).107
The MASS II trial randomly compared medical therapy with PCI and CABG. At 10 years, compared with medical therapy, CABG was associated with reduced rates of cardiac mortality, myocardial infarction and angina.94 In the Surgical Treatment IsChemic Heart failure (STICH) trial, 1212 patients with CAD and a left ventricular ejection fraction (LVEF) of ≤35% were randomized to medical therapy or CABG. Patients with LM disease were excluded, and 17% of patients on medical therapy underwent CABG and 6% of patients underwent PCI by the end of the follow-up period. In the intention-to-treat analysis, all-cause mortality was not significantly lower with CABG than with medical therapy (36% vs. 41%; HR 0.86; 95% CI 0.72–1.04; P =0.12); however, all-cause mortality or hospitalization for cardiovascular causes occurred less frequently among patients undergoing CABG (58% vs. 68%; HR 0.74; 95% CI 0.64–0.85; P <0.001). The results with respect to all other secondary clinical outcomes also favoured CABG. In addition, CABG was associated with a reduced risk for the primary outcome, death, in the ‘as treated’ analysis (HR 0.70; 95% CI 0.58–0.84; P <0.001).112
aWith documented ischaemia or FFR ≤ 0.80 for diameter stenosis <90%.
bClass of recommendation.
cLevel of evidence.
6.3 Percutaneous coronary intervention vs. coronary artery bypass grafting
The multitude of studies comparing these two revascularization strategies has shown that neither PCI nor CABG alone can provide a solution for the entire spectrum of SCAD patients who need revascularization; however, CABG results in more complete revascularization than PCI, and the placement of bypass grafts on the mid-coronary vessel makes the complexity of proximal lesions less relevant for the procedure, especially when there are chronic proximal occlusions. The evidence derived from RCTs comparing CABG with PCI is summarized in Table 6.
BMS = bare-metal stents; CABG = coronary artery bypass grafting; EF = ejection fraction; MI = myocardial infarction; MV = multivessel; MVD = multivessel disease; PES = paclitaxel-eluting stents; Revasc = revascularization; SES = sirolimus-eluting stents; TVR = target-vessel revascularization; y = years.
cNon-inferiority failed only trials with at least 100 patients per treatment arm were included.
Age and ejection fraction are reported as means.
6.3.1 Proximal left anterior descending coronary artery disease
Two meta-analyses—one including nine RCTs involving 1210 patients with isolated proximal LAD lesions followed for up to 5 years,160 and the other including six RCTs and two non-randomized studies with a total of 1952 patients with isolated proximal LAD lesions, who were followed for up to 4 years161—reported no significant difference in mortality, myocardial infarction, or stroke, but a three-fold increase in recurrent angina and a five-fold increase in repeat revascularization with PCI compared with CABG. Most of the above-mentioned studies have used BMS in the PCI arm, while DES have markedly reduced the risk of repeat revascularization. Similarly, only few trials in patients with isolated proximal LAD lesions have reported long-term outcomes, although the angiographic patency of the IMA has been documented to be >90% at two decades of follow-up. Furthermore, the survival benefit of a single IMA in patients with multivessel CAD, initially reported after a decade of follow-up, has now been extended into the second and third decades, especially with bilateral IMAs.162–165
6.3.2 Left main coronary artery disease
For several decades, CABG was regarded as the standard of care for significant LM disease in patients eligible for surgery, largely based on the Coronary Artery Surgery Study (CASS) registry.108 It has been suggested that two important pathophysiological features mitigate against the success of PCI in LM lesions (i) up to 80% of LM disease involves the bifurcation, which is known to be at higher risk of restenosis and (ii) up to 80% of LM patients also have multivessel SCAD, where CABG offers a survival advantage independent of the presence of LM disease.159,166,167 More recent evidence suggests, however, that PCI provides at least equivalent results to CABG for lower-severity LM lesions at up to 5 years of follow-up.
The SYNTAX trial included a pre-specified subgroup analysis of limited power in 705 patients with predominant distal LM disease, who were randomly assigned to CABG or PCI. The primary endpoint of 1-year MACCE—the composite of death, myocardial infarction, stroke, and repeat revascularization—was comparable for both revascularization strategies (CABG 13.7% vs. PCI 15.8%; P =0.44).168 At 5 years' follow-up, rates of death (CABG = 14.6% vs. PCI = 12.8%; P =0.53) and myocardial infarction (CABG = 4.8% vs. PCI = 8.2%; P =0.10) were not significantly different, whereas CABG was associated with a higher rate of stroke (4.3% vs. 1.5%; P =0.03) and a lower risk of repeat revascularization (15.5% vs. 26.7%; P <0.001) with no significant difference in the overall MACCE rates (31.0% vs. 36.9%; P =0.12).17,169 MACCE outcomes were comparable for PCI and CABG in the lower (0–22: 30.4% vs. 31.5%; P =0.74) and intermediate (23–32: 32.7% vs. 32.3%; P =0.88) SYNTAX score tertiles. In patients with SYNTAX scores >32, CABG was associated with numerically lower mortality (14.1% vs. 20.9%; P =0.11) and a significantly reduced need for repeat revascularization (11.6% vs. 34.1%; P <0.001) albeit at a numerically higher risk of stroke (4.9% vs. 1.6%; P =0.13).
The Premier of Randomized Comparison of Bypass Surgery vs. Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease (PRECOMBAT) trial randomized 600 patients with LM disease to PCI or CABG.159 The primary endpoint—the 1-year composite rate of death, myocardial infarction, stroke, or repeat revascularization—was 6.7% in the CABG group and 8.7% in the PCI group (P =0.37). The 1-year composite rate of death, myocardial infarction or stroke was 4.0% for CABG and 3.3% for PCI (P =0.66). The lack of significant differences between the two groups was maintained over 2 years from randomization and was also valid for mortality (3.4% in the CABG group and 2.4% in the PCI group; P =0.45) and for the composite rate of death, myocardial infarction, or stroke (4.4% in the CABG group and 4.7% in the PCI group; P =0.83). In contrast to the findings in SYNTAX, the incidence of stroke was similar for PCI (0.4%) and CABG (0.7%).
A meta-analysis170 pooled the results of three dedicated RCTs on PCI vs. CABG for LM disease158,159,171 and one pre-specified LM lesion subset from the largest RCT.168 In total, this meta-analysis assessed the 1-year outcomes of 1611 patients. The composite of death, myocardial infarction, stroke, or TVR was observed in 11.8% of the CABG group and 14.5% of the PCI group (P =0.11); the composite of death, myocardial infarction, or stroke was 6.8% in the CABG group and 5.3% in the PCI group (P =0.26). Whilst there was no significant difference in mortality (4.1% in the CABG group and 3.0% in the PCI group; P =0.29) or myocardial infarction (2.8% in the CABG group and 2.9% in the PCI group; P =0.95), the CABG group showed a higher rate of stroke (1.7% vs. 0.1%; P =0.01) but a lower rate of TVR (5.4% vs. 11.4%; P <0.001).
The ASAN Medical Centre-Left Main Revascularization Registry compared the outcomes of patients with LM disease who were treated by either PCI or CABG within the same period. In two analyses—one of 10-year outcomes among 100 patients treated with BMS and 250 patients with CABG, and the other of 5-year outcomes among 176 patients with DES and 219 patients with CABG—neither mortality nor the composite of death, myocardial infarction, or stroke was significantly different between the two treatment approaches. CABG was associated with a decreased risk of revascularization in both comparisons.172 In a registry of 810 patients with LM disease treated by CABG (335 patients) or PCI (475 patients), which ran in parallel with the RCT, no significant difference was observed between the two treatment options in terms of the composite of death, myocardial infarction, or stroke over 2 years, whereas the risk of re-intervention was significantly lower with CABG.159
6.3.3 Three-vessel coronary artery disease
A meta-analysis, based on individual patient data from RCTs that were performed before the introduction of DES, reported no difference in mortality between PCI and CABG, although mortality was reduced by CABG in diabetic patients and those aged 65 years or more.106 A meta-analysis of six randomized trials involving 6055 patients, which compared CABG with arterial grafts and PCI (balloon angioplasty, BMS and DES), reported a significant reduction in mortality (RR 0.73; 95% CI 0.62–0.86), myocardial infarction (RR 0.58; 95% CI 0.48–0.72) and repeat revascularization (RR 0.29; 95% CI 0.21–0.41) in favour of CABG.173 There was a trend toward excess strokes with CABG (RR 1.36; 95% CI 0.99–1.86; P =0.06). Several RCTs and meta-analyses indicate that CABG is associated with a greater risk of stroke than PCI, which diminishes during long-term follow-up.174,175
SYNTAX randomly assigned 1800 patients with LM and/or three-vessel CAD to either an early-generation paclitaxel-eluting stent or CABG.157 At 1 year, 12.4% of CABG and 17.8% of PCI patients (P =0.002) reached the primary composite endpoint of MACCE. At 5 years, CABG, as compared with PCI, significantly reduced overall MACCE with respective rates of 26.9% vs. 37.3% (P <0.001), 11.4% vs. 13.9% had died (P =0.10), 3.8% vs. 9.7% (P <0.0001) had a myocardial infarction, 3.7% vs. 2.4% (P =0.09) incurred a cerebrovascular accident, and 13.7% vs. 25.9% (P <0.0001) of the patients required repeat revascularization.17 In the 1095 patients with three-vessel CAD, in comparison with PCI, CABG resulted in lower total death (9.2% vs.14.6%; P =0.006), cardiac death (5.3% vs. 9.0%; P =0.003), myocardial infarction (3.3% vs. 10.6%; P< 0.001) and repeat revascularization (12.6% vs. 25.4%; P <0.001).176 In these patients with low SYNTAX score (0–22), rates of MACCE were similar (26.8% vs. 33.3%; P =0.21) for CABG and PCI, respectively. Conversely, when compared with PCI in patients with intermediate and high SYNTAX scores, CABG showed lower rates of MACCE (22.6% vs. 37.9%; P =0.0008 and 24.1% vs. 41.9%; P =0.0005, respectively), including its mortality, myocardial infarction and repeat revascularization components.176 Notably, patients who were included in the CABG registry of the SYNTAX trial because of ineligibility for PCI had lower MACCE rates than the randomized CABG cohort (23.3% vs. 26.9%, respectively), this being potentially related to more complete revascularization (76% vs. 63%, respectively).17
An observational study based on the New York State registry assessed patients with CAD who had been treated with either isolated bypass surgery (13 212 patients) or DES (20 161 patients) between 2003 and 2005, with focus on 5-year survival.177 The difference in absolute survival in the overall population was small (CABG 78.5% vs. PCI 76%). The main analysis was performed after propensity matching of 8121 pairs of patients, with survival at 5 years of 80.4% for CABG and 73.6% for PCI with DES (HR 0.71; 95% CI 0.67–0.77; P <0.001). A lower risk of death was noted in all subgroups, except for those with two-vessel CAD without proximal LAD lesions. Two main findings can be highlighted from this study: (i) the presence of LAD disease conferred a survival benefit to CABG and (ii) the survival benefit with CABG became evident only during the second half of the 5-year follow-up. In the ASCERT registry of elective patients >65 years of age with two- or three-vessel CAD, 86 244 patients underwent CABG and 103 549 patients underwent PCI (78% with early-generation DES). Using propensity scores and inverse probability adjustment, mortality at 4 years—but not at 1 year—was lower for CABG than for PCI (16.4% vs. 20.8%; RR 0.79; 95% CI 0.76–0.82).26 The observational nature of the studies does not permit assessment of how each patient was selected for each kind of treatment and, despite statistical adjustments, residual confounders cannot be excluded. Early-generation DES were used, which are devoid of the advantages of the newer generation.125–131,133 There is notable consistency in the findings on the survival advantage of CABG over PCI for more severe three-vessel CAD.
7. Revascularization in non-ST-segment elevation acute coronary syndromes
Non-ST-segment elevation acute coronary syndrome (NSTE-ACS) is the most frequent manifestation of ACS, and mortality and morbidity remain high and equivalent to those of patients with ST-segment elevation myocardial infarction (STEMI) during long-term follow-up. The key objectives of coronary angiography and subsequent revascularization are symptom relief and improvement of prognosis. Overall quality of life, length of hospital stay, and potential risks associated with invasive and pharmacological treatments must also be considered when deciding on a treatment strategy.
Early risk stratification is important, in order to identify patients at high immediate- and long-term risk for death and cardiovascular events, in whom an early invasive strategy with adjunctive medical therapy may reduce that risk. Patients in cardiogenic shock, or after resuscitation, should undergo immediate angiography (within 2 hours) because of the high likelihood of critical CAD, but it is equally important to identify patients at low risk, in whom invasive and medical treatments provide little benefit or may even cause harm. Details on risk stratification, particularly with respect to the interpretation of troponins, are found in the ESC Guidelines on NSTE-ACS.180
7.1 Early invasive vs. conservative strategy
A meta-analysis of seven RCTs that compared routine angiography followed by revascularization against a selective invasive strategy, showed reduced rates of combined death and myocardial infarction [odds ratio (OR) 0.82; 95% CI 0.72–0.93; P =0.001].181 The routine revascularization strategy was associated with a risk of early death and myocardial infarction during the initial hospitalization; however, four of the seven trials included in this meta-analysis were not contemporary, due to marginal use of stents and glycoprotein (GP) IIb/IIIa receptor inhibitors. Another meta-analysis, covering seven trials with more up-to-date adjunctive medication, showed a significant reduction in risk for all-cause mortality (RR = 0.75; 95% CI 0.63–0.90; P <0.001) and myocardial infarction (RR = 0.83; 95% CI 0.72–0.96; P =0.012), for an early invasive vs. conservative approach at 2 years without excess of death and myocardial infarction at 1 month.182 A further meta-analysis of eight RCTs showed a significant lower incidence of death, myocardial infarction, or rehospitalization for ACS (OR = 0.78; 95% CI 0.61–0.98) for the invasive strategy at 1 year.183 The benefit was carried mainly by improved outcomes in biomarker-positive (high-risk) patients. In a gender-specific analysis, a similar benefit was found in biomarker-positive women, compared with biomarker-positive men. Importantly, biomarker-negative women tended to have a higher event rate with an early invasive strategy, suggesting that early invasive procedures should be avoided in low-risk, troponin-negative, female patients. A more recent meta-analysis, based on individual patient data from three studies that compared a routine invasive against a selective invasive strategy, revealed lower rates of death and myocardial infarction at 5-year follow-up (HR = 0.81; 95% CI 0.71–0.93; P =0.002), with the most pronounced difference in high-risk patients.184 Age, diabetes, previous myocardial infarction, ST-segment depression, hypertension, body mass index (<25 kg/m2 or >35 kg/m2), and treatment strategy were found to be independent predictors of death and myocardial infarction during follow-up. All results supported a routine invasive strategy but highlight the importance of risk stratification in the decision-making process management.
7.2 Timing of angiography and intervention
Patients at highest risk (i.e. those with refractory angina, severe heart failure or cardiogenic shock, life-threatening ventricular arrhythmias, or haemodynamic instability) were generally not included in RCTs, in order not to withhold potentially life-saving treatments. It has been generally accepted that such patients should be taken for an immediate (<2 hours) invasive evaluation, regardless of electrocardiogram (ECG) or biomarker findings.180
An early invasive strategy (0.5–14 hours of diagnosis), as opposed to a delayed invasive strategy (within 21–86 hours), was tested in several RCTs. In a meta-analysis of three recent trials, early catheterization, followed by coronary intervention on the first day of hospitalization, was shown to be safe and superior in terms of lower risk of recurrent ACS (–41%) and shorter hospital stay (–28%).185 Similar findings were reported in a more recent meta-analysis.186
There is growing evidence to suggest benefit from an invasive strategy within 24 hours in patients with a high-risk profile. The Timing of Intervention in Patients with Acute Coronary Syndromes (TIMACS) trial revealed a significant 38% lower incidence of death, myocardial infarction, or stroke at 6 months in high-risk patients (Global Registry of Acute Coronary Events (GRACE) score >140), with an early (≤24 hours), as compared with a delayed (≥36 hours) strategy.187 No significant difference was observed in patients with a low- to intermediate-risk profile (GRACE score ≤140). Notably, there was no safety issue relating to an early invasive strategy. In the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) data analysis, a delay of more than 24 hours before PCI was an independent predictor of 30-day and 1-year mortality.188 This increased ischaemic event rate was most evident among moderate- and high-risk patients [according to the Thrombolysis in Myocardial Infarction (TIMI) risk score].
In summary, the timing of angiography and revascularization should be based on patient risk profile. Patients at very high risk (as defined above) should be considered for urgent coronary angiography (in less than 2 hours). In patients at high risk, with at least one primary high-risk criterion, an early invasive strategy within 24 hours appears to be the reasonable timescale. In lower-risk subsets, with a GRACE risk score of <140 but with at least one secondary high-risk criterion (Table 7), the invasive evaluation can be delayed without increased risk but should be performed during the same hospital stay, preferably within 72 hours of admission. In other low-risk patients without recurrent symptoms, a non-invasive assessment of inducible ischaemia should be performed before hospital discharge.
Criteria for high risk with indication for invasive management
CABG = coronary artery bypass grafting; eGFR = estimated glomerular filtration rate; GRACE = Global Registry of Acute Coronary Events; LV = left ventricular; PCI = percutaneous coronary intervention.
7.3 Type of revascularization
There are no specific RCTs comparing PCI with CABG in patients with NSTE-ACS. In all trials comparing an early invasive with a late strategy, or an invasive with a medical management strategy, the decision on whether to perform CABG or PCI was left to the investigator’s discretion.
In stabilized patients, the choice of revascularization modality can be made in analogy to patients with SCAD. In approximately one-third of patients, angiography will reveal single-vessel disease, allowing ad hoc PCI in most cases. Multivessel disease will be present in another 50%. Here the decision is more complex and the choice has to be made between culprit-lesion PCI, multivessel PCI, CABG, or a combined (hybrid) revascularization. The distribution of PCI vs. CABG in patients with multivessel disease suitable for revascularization is approximately 80% vs. 20%.189 The revascularization strategy in patients with multivessel CAD should be determined early by the Heart Team and based on the patient’s clinical status, as well as the severity and distribution of the CAD and the characteristics of the lesion. The SYNTAX score has proved to be strongly predictive of death, myocardial infarction and TVR.190
Culprit-lesion PCI is usually the first choice in most patients with NSTE-ACS and multivessel disease; however, there are no prospective studies comparing culprit-lesion PCI with early CABG. In stabilized patients with multivessel disease and a high SYNTAX score (>22), particularly when there is no clearly identified culprit lesion, a strategy of urgent CABG should be preferred. The strategy of multivessel PCI for suitable significant stenoses—rather than PCI limited to the culprit lesion—has not been evaluated in an appropriate, randomized fashion. In a large database including 105 866 multivessel CAD patients with NSTE-ACS, multivessel PCI was compared with single-vessel PCI and was associated with lower procedural success but similar in-hospital mortality and morbidity.191 Complete revascularization at the time of the index procedure did not result in lower mortality rates over 3 years, as compared with a staged procedure strategy.192 However, incomplete revascularization appears to be associated with more 1-year adverse event rates.193
CABG was compared with PCI in a propensity-matched analysis among patients with multivessel disease from the ACUITY trial.189 PCI-treated patients had lower rates of stroke, myocardial infarction, bleeding, and renal injury, similar 1-month and 1-year mortality, but significantly higher rates of unplanned revascularization at both 1 month and 1 year. However, only 43% of CABG patients could be matched and there was a strong trend for a higher rate of major adverse cardiac events (MACE) at 1 year with PCI, compared with CABG (25.0% vs. 19.5%, respectively; P =0.05). These results are consistent with the 1-year and 5-year outcomes of the multivessel SYNTAX trial, which included 28.5% of patients with a recent ACS, in both the PCI and the CABG arms.17,157 However, a subanalysis of these patients has not been reported.
Culprit-lesion PCI does not necessarily require a case-by-case review by the Heart Team when, on clinical or angiographic grounds, the procedure needs to be performed ad hoc after angiography. This is the case when there is continuing or recurrent ischaemia, haemodynamic instability, pulmonary oedema, recurrent ventricular arrhythmias, or total occlusion of the culprit coronary artery requiring urgent revascularization. For all other scenarios, revascularization should be discussed in a multidisciplinary setting, with protocols based on the SYNTAX score at each institution, defining specific anatomical criteria and clinical subsets that can be treated ad hoc or transferred to CABG. After culprit-lesion PCI, patients with scores in the two higher terciles of the SYNTAX score should be discussed by the Heart Team, in the context of functional evaluation of the remaining lesions. This also includes the assessment of patients' comorbidities and individual characteristics.
7.3.1 Coronary artery bypass surgery
As there is no randomized study comparing an early with a delayed CABG strategy, the general consensus is to wait 48–72 hours in patients who had culprit-lesion PCI and have residual severe CAD. In a large database analysis of unselected patients admitted for ACS, performance of early CABG, even in higher-risk patients, was associated with low in-hospital mortality.194 In registries, unadjusted and adjusted analyses showed no difference in outcomes between patients undergoing early (≤48 hours) or in-hospital late (>48 hours) surgery, although CABG was delayed more often in higher-risk patients, suggesting that timing might be appropriately determined by multidisciplinary clinical judgement.195 Therefore, in patients assigned for CABG, timing of the procedure should be decided on an individual basis, according to symptoms, haemodynamic stability, coronary anatomy, and signs of ischaemia. When there is continuing or recurrent ischaemia, ventricular arrhythmias, or haemodynamic instability, CABG should be performed immediately. Patients with LM or three-vessel CAD involving the proximal LAD should undergo surgery during the same hospital stay. In this decision process, it is important to consider the risk of bleeding complications when initially applying aggressive antiplatelet treatment; however, pre-treatment with a dual antiplatelet regimen should be considered only as a relative contraindication to early CABG and does require specific surgical measures to minimize bleeding.
7.3.2 Percutaneous coronary intervention
The safety and efficacy of DES have not been prospectively tested in a specific population of patients with NSTE-ACS, but this subset comprises up to 50% of patients included in most stent trials particularly those with an all-comer design. There is no particular safety concern in NSTE-ACS as new-generation DES have shown superior safety and efficacy in both SCAD and STEMI patients. Accordingly, new-generation DES are preferred over BMS as the default option.196 Dual antiplatelet therapy (DAPT) should be maintained for 12 months, irrespective of stent type.
8. Revascularization in ST-segment elevation myocardial infarction
8.1 Time delays
Delays in the timely implementation of reperfusion therapy are key issues in the management of STEMI, since the greatest benefit gained from reperfusion therapy occurs within the first 2–3 hours of symptom onset.201,202 The total ischaemic time, between symptom onset and provision of reperfusion therapy (either starting fibrinolysis or mechanical reperfusion by primary PCI), is probably the most important factor. The aim is to provide optimal care while minimizing delays, in order to improve clinical outcomes (Figure 2).201 The reduction of first-medical-contact-to-balloon (FMCTB) time—defined as the time from the (first) medical/hospital door to the time of primary PCI—relies on efficient coordination of care between first medical contact or referral hospitals, the emergency medical service (EMS), and the receiving hospitals. It is currently estimated that about 66% of patients achieve a guideline-recommended overall first-hospital-door-to-balloon time of <120 minutes.203 The door-to-balloon (DTB) time refers to patients presenting in PCI-capable centres and should be less than 60 minutes. Door-in to door-out (DI–DO) time is a performance measure that assesses the timeliness and quality of initial reperfusion care. It is defined as the duration from arrival to discharge at the first or STEMI-referral hospital. A DI–DO time ≤30 minutes is associated with shorter reperfusion delays (i.e. a first-hospital DTB time <120 minutes) and lower in-hospital mortality, and should be implemented in non-PCI-capable hospitals as a quality metric.204,205
Organization of STEMI patient disposal describing pre- and in-hospital management and reperfusion strategies within 12 hours of first medical contact with ideal time interval for interventions.
8.2 Selection of reperfusion strategy
Primary PCI is defined as percutaneous catheter intervention in the setting of STEMI, without previous fibrinolysis. It has replaced fibrinolysis as the preferred reperfusion strategy in patients with STEMI, provided it can be performed in a timely manner in high-volume PCI centres with experienced operators and 24-hour, 7-day catheterization laboratory activation.201,206–209 In settings where primary PCI cannot be performed in a timely fashion, fibrinolysis should be considered, particularly if it can be administered pre-hospital (e.g. in the ambulance)210–212 and within the first 120 minutes after symptom onset (Figure 2).213–215 It should be followed by transfer to PCI-capable centres for routine coronary angiography in all patients and for rescue PCI in case of unsuccessful fibrinolysis.
During the past decade, primary PCI has become established as the dominant reperfusion therapy in Europe, irrespective of whether patients present early or the journey to the primary PCI-capable hospital is long.202,203,216,217 Four European Union countries have documented full implementation of primary PCI as the preferred reperfusion strategy, including countries in which travelling can be difficult.218 In most other European countries, fibrinolysis for STEMI is becoming a rare therapy; for example 6% of cases in the UK, 7% in Poland, and 8% in France.218 It is interesting to note that, even in countries with a large catchment area, such as Denmark—with one primary PCI centre per 1.4 million inhabitants and correspondingly long transportion distances—the STEMI case–fatality rate is among the lowest recorded in Europe, with an in-hospital mortality of only 3%. The initial diagnosis of STEMI is operational and based on ECG findings with a predictive value of 85%.205 False activation of the catheterization laboratory may therefore occur in 15–30% of cases,216 in which PCI can be deferred but where fibrinolysis is a hazard. In either case, there are costs and some inherent risks associated with the procedure or treatment.
Key points for optimizing and guiding primary PCI are summarized below:
The infarct-related artery should be systematically treated during the initial intervention. Evidence supporting immediate (preventive) intervention in non-infarct-related lesions is a matter of debate.233 On the one hand, patients with extensive CAD in vessels remote from the infarct-related artery have reduced success in reperfusion and an adverse prognosis following primary PCI.188 Staged PCI in patients with multivessel disease and no haemodynamic compromise is an independent predictor of survival, and more frequent ischaemic events have been reported in direct vs. staged revascularization of STEMI patients with multivessel disease.234–236 In the recent, randomized Preventive Angioplasty in Acute Myocardial Infarction (PRAMI) trial (n = 465), preventive PCI in non-infarct-related coronary arteries with stenosis ≥50%, when compared with PCI limited to the infarct artery, was associated with a reduced risk of the composite of death, myocardial infarction, or refractory angina (HR in the preventive-PCI group 0.35; 95% CI 0.21–0.58; P <0.001). The HR for non-fatal myocardial infarction was 0.32 (95% CI 0.13–0.75). It remains to be determined how clinicians can identify lesions that should be revascularized beyond the culprit lesion and whether complete revascularization should be performed in single- or multi-stage procedures. At present, multivessel PCI during STEMI should be considered in patients with cardiogenic shock in the presence of multiple, critical stenoses or highly unstable lesions (angiographic signs of possible thrombus or lesion disruption), and if there is persistent ischaemia after PCI on the supposed culprit lesion.
The radial approach should be the preferred method of access, as it has been shown to reduce the incidence of acute bleeding events—especially in ACS—and was associated with lower mortality in the subset of STEMI patients that were enrolled in the RadIal Vs. femorAL access for coronary intervention (RIVAL) trial.237–239 However, the benefit of radial over femoral access depends upon the operators' expertise in the radial technique.240
Stenting should be preferred over balloon angioplasty in the setting of primary PCI,241,242 as it reduces the risk of abrupt closure, re-infarction, and repeat revascularization. Although early-generation DES have not been associated with an increased risk of death, myocardial infarction, or stent thrombosis during long-term follow-up,243 there have been concerns over an increased risk of very late stent thrombosis, owing to delayed arterial healing of stents implanted into lesions with a large necrotic core.244,245 More recent evidence has, however, demonstrated the superiority of new-generation everolimus-eluting stents in reducing major acute vascular events in STEMI patients, as compared with early-generation sirolimus-eluting stents.246 Two dedicated trials directly compared new-generation DES with BMS among STEMI patients undergoing primary PCI. The everolimus-eluting stent vs. BMS in ST-segment elevation myocardial infarction (EXAMINATION) trial in 1504 STEMI patients reported no significant differences for the primary endpoint of all-cause death, re-infarction and any revascularization, in patients assigned to everolimus-eluting stents, compared with those assigned to BMS, (11.9% vs. 14.2%, respectively, difference -2.3%; 95% CI -5.8–1.1%; P =0.19) at 1 year.247 However, everolimus-eluting stents were associated with a lower risk of revascularization of the target lesion (2.1% vs. 5.0%; P =0.003) and definite stent thrombosis (0.5% vs. 1.9%; P =0.02). The Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare-Metal Stents in Acute ST-Elevation Myocardial Infarction (COMFORTABLE AMI) trial, examining patients assigned to either BMS or to biolimus-eluting stents with a biodegradable polymer, reported that the latter showed a lower risk of the composite primary endpoint of cardiac death, target-vessel myocardial infarction, and target-lesion revascularization (4.3% vs. 8.7%; HR 0.49; 95% CI 0.30–0.80; P =0.004) as well as a lower risk of target-vessel myocardial infarction (0.5% vs. 2.7%; HR 0.20; 95% CI 0.06–0.69; P =0.01) and a trend towards a lower risk of definite stent thrombosis (0.9% vs. 2.1%; HR 0.42; 95% CI 0.15–1.19; P =0.10).248 Results were maintained throughout 2 years of follow-up and a pooled analysis of both trials confirmed a lower risk of stent thrombosis and re-infarction with DES than with BMS.249 Overall, these findings suggest that new-generation DES are more effective and potentially safer than BMS during primary PCI in STEMI.
Thrombus aspiration has been proposed as an adjunct during primary PCI, to further improve epicardial and myocardial reperfusion by prevention of distal embolization of thrombotic material and plaque debris. Individual RCTs and meta-analyses have suggested that the use of manual aspiration thrombectomy during primary PCI may be beneficial to improve epicardial and myocardial reperfusion and reduce the rate of MACE including mortality.250–255 In the largest randomized trial to date, the Thrombus Aspiration during PCI in Acute Myocardial Infarction (TASTE) study (7244 patients), the primary endpoint of all-cause mortality occurred in 2.8% of patients in the thrombus aspiration group and in 3.0% in the PCI-only group (HR 0.94; 95% CI 0.72–1.22; P =0.63) at 30 days.256 However, events were evaluated at short-term follow-up, and there was a trend towards a reduction of non-adjudicated events including stent thrombosis (0.2% vs. 0.5%, respectively; HR 0.47; 95% CI 0.20–1.02; P =0.06) and re-infarction (0.5% vs. 0.9%, respectively; HR 0.61; 95% CI 0.34–1.07; P =0.06) in favour of thrombus aspiration. Taken together, these results suggest that routine use of thrombus aspiration is not necessary but selected use may be useful to improve Thrombolysis in Myocardial Infarction (TIMI) 3 flow or prevent stent thrombosis. No clinical benefit of routine rheolytic thrombectomy has been demonstrated in primary PCI.255,257–259
Pre- and post-conditioning warrant randomized trials before these procedures can be recommended in routine clinical practice. Remote ischaemic pre-conditioning has engendered little enthusiasm.260 Early administration of metoprolol before PCI in STEMI patients presenting with Killip Class II or less has been shown to reduce infarct size, with a trend toward fewer ischaemic events.261 Trials evaluating the use of antithrombotic and vasodilator agents have been disappointing.
Incomplete stent deployment and undersizing should be avoided.262 Massive thrombotic burden and low-pressure delivery, to avoid distal embolization, are the two major contributing factors in stent malapposition in STEMI patients. Self-expanding stents and stents covered with ultra-thin micronets have shown favourable preliminary results in terms of surrogate endpoints.263 However, large-scale clinical outcome studies are required before these devices can be recommended.
Despite its frequent contraindications, limited effectiveness in inducing reperfusion, and greater associated risk of bleeding, fibrinolytic therapy—preferably administered as a pre-hospital treatment—remains an adjunct to mechanical revascularization if the latter cannot be performed in time.207,208 The incremental benefit of primary PCI over timely fibrinolysis is diminished when PCI-related delay exceeds 120 minutes, depending on patient age, duration of symptoms, and infarct location. Fibrinolysis is discussed in detail in the ESC Guidelines on STEMI.201
Pre-hospital fibrinolysis has been compared with primary PCI in early-presenting patients in the STrategic Reperfusion Early After Myocardial infarction (STREAM) study.215 In patients with early STEMI (onset <3 hours previously) who could not undergo primary PCI within 60 minutes after first medical contact, pre-hospital fibrinolysis (amended to half dose in patients >75 years of age) with timely coronary angiography (6–24 hours in stable patients) and rescue PCI for failed fibrinolysis was as effective as primary PCI in reducing the primary endpoint, a composite of death, shock, congestive heart failure, or re-infarction up to 30 days (12.4% vs. 14.3%, respectively; RR 0.86; 95% CI 0.68–1.09; P =0.21). However, there was a significant increase in intracranial bleeding (1.0% vs. 0.2%; P =0.04) particularly in patients >75 years of age with fibrinolysis. The median times until reperfusion were 100 minutes in the fibrinolysis group and 178 minutes in the primary PCI group, which are an hour shorter on average than the delays in the DANish trial in Acute Myocardial Infarction (DANAMI) trial, which established the superiority of transfer PCI over in-hospital fibrinolysis.219 In view of the lack of superior efficacy and increased rate of intracranial haemorrhage, emphasis should remain on timely PCI within STEMI networks as the preferred treatment for STEMI. Facilitated PCI, defined as routine use of reduced or normal dose fibrinolysis combined with GP IIb/IIIa inhibitors or other antiplatelet agents followed by coronary angiography, has shown no significant advantages over primary PCI alone.271
8.5 Secondary percutaneous coronary intervention
Several randomized trials and meta-analyses have shown that early, routine, post-thrombolysis angiography with subsequent PCI (if required) reduced the rates of re-infarction and recurrent ischaemia, compared with a strategy of ‘watchful waiting’, in which angiography and revascularization were indicated only in patients with spontaneous or induced severe ischaemia or LV dysfunction.272–281 The benefits of early, routine PCI after thrombolysis were seen in the absence of an increased risk of adverse events (stroke or major bleeding). Based on data from the four most recent trials, all of which had a median delay between start of thrombolysis and angiography of 2–6 hours, a time-frame of 3–24 hours after successful lysis is recommended.215,272–274 In cases of failed fibrinolysis, or if there is evidence of re-occlusion or re-infarction with recurrence of ST-segment elevation, the patient should undergo immediate coronary angiography and rescue PCI.282
Patients presenting between 12 and 48 hours after onset of symptoms, even if pain-free and with stable haemodynamics, may still benefit from early coronary angiography and possibly PCI.223,224 In patients presenting days after the acute event with a completed myocardial infarction, only those with recurrent angina or documented residual ischaemia—and proven viability on non-invasive imaging in a large myocardial territory—may be considered for revascularization when the infarct artery is occluded. Systematic late PCI of an occluded infarct-related artery after myocardial infarction in stable patients has no incremental benefit over medical therapy.115
Management and revascularization after fibrinolysis
PCI = percutaneous coronary intervention.
aClass of recommendation.
bLevel of evidence.
8.6 Coronary artery bypass surgery
CABG may be indicated in STEMI patients with unsuitable anatomy for PCI, but who have a patent infarct-related artery, since patency of this artery provides time for transfer to the surgical team and a large myocardial area in jeopardy. It should be considered in patients in cardiogenic shock if the coronary anatomy is not amenable to PCI,221 or at the time of repair for patients with mechanical complications.285
CABG is infrequently used and its benefits are uncertain in STEMI patients with failed PCI, coronary occlusion not amenable to PCI, and in the presence of refractory symptoms after PCI since, in most of these cases, time for implementation of surgical reperfusion will be long and the risks associated with surgery are increased in this setting.286
When possible, in the absence of persistent pain or haemodynamic deterioration, a waiting period of 3–7 days appears the best compromise.286 Patients with multivessel disease, who are receiving primary PCI or secondary (post-fibrinolysis) PCI on the culprit artery, will need risk stratification and further, staged revascularization with PCI or surgery following a Heart Team discussion.
9. Revascularization in patients with heart failure and cardiogenic shock
9.1 Chronic heart failure
Coronary artery disease remains the most common cause of chronic heart failure; patients with depressed LV function remain at risk of sudden cardiac death with or without revascularization, and the indication for prophylactic implantable cardioverter defibrillator (ICD) therapy should always be examined.287
Revascularization with CABG or PCI is indicated for symptomatic relief of angina pectoris in patients with heart failure. The prognostic importance of surgical revascularization in patients with chronic heart failure has recently been studied in the STICH trial,112 with the aim of comparing the efficacy of initial medical therapy with that of revascularization by CABG plus medical therapy in a sample of 1212 patients with CAD and LV dysfunction (EF ≤35%). Patients with significant LM disease or CCS Classes III and IV were excluded. Most patients had two-vessel (31%) or three-vessel (60%) CAD, and 68% had a proximal LAD stenosis. Although the primary outcome of all-cause mortality was not significantly reduced by CABG (HR with CABG 0.86; 95% CI 0.72–1.04; P =0.12) in the intention-to-treat analysis, it offered superior pre-specified secondary outcomes, including cardiovascular mortality (HR 0.81; 95% CI 0.66–1.00; P =0.05) and all-cause mortality or hospitalization for heart failure (HR 0.84; 95% CI 0.71–0.98; P =0.03). Among patients allocated to medical therapy, 17% crossed over to CABG and 6% to PCI. The ‘as-treated’ analysis compared the outcomes of 592 patients treated with medical therapy throughout the first year after randomization with those of 620 patients who underwent CABG—either as a consequence of randomization or crossover—and reported significantly lower all-cause mortality in favour of CABG (HR 0.70; 95% CI 0.58–0.84; P <0.001).112 These findings have been confirmed in a recent propensity-matched observational cohort of similar patients during long-term follow-up over 10 years.288 The choice between CABG and PCI should be made by the Heart Team after careful evaluation of the patient’s clinical status and coronary anatomy, including SYNTAX score, comorbidities, and expected completeness of revascularization. A specialist in heart failure should be consulted.
9.1.2 Myocardial viability and revascularization
The risk–benefit balance for revascularization in patients without angina/ischaemia or viable myocardium remains uncertain. In an observational study using cardiac imaging techniques (stress–rest Rb-82/F-18 fluorodeoxyglucose PET) in 648 patients with an LVEF of 31% ± 12%, hibernating myocardium, ischaemic myocardium, and scarred myocardium were associated with all-cause death (P =0.0015; P =0.0038, and P =0.0010, respectively). An interaction between treatment and hibernating myocardium was present, such that early revascularization in the setting of hibernating myocardium, when compared with medical therapy, was associated with improved survival, especially when the extent of viability exceeded 10% of the myocardium.289,290The viability substudy of the STICH trial found viable myocardium in 487 of 601 patients (81%) and no viable myocardium in 114 (19%).289 Among patients without viability, 60 were allocated to CABG and 54 to medical therapy and, among the 487 patients with myocardial viability, 244 were assigned to CABG and 243 to medical therapy. The differences in baseline characteristics, between patients who underwent myocardial viability testing and those who did not, indicate some selection bias driven by clinical factors. Viability was arbitrarily defined using different cut-off values for the different tests used. By univariate analysis, there was a significant association between myocardial viability and outcome; however, this association was not significant on multivariable analysis that included other prognostic variables. It is likely that other variables, such as LV volumes and ejection fraction, are causally determined by the extent of viable myocardium. The lack of correlation between myocardial viability status and benefit from CABG in this study indicates that assessment of myocardial viability should not be the sole factor in selecting the best therapy for these patients.
9.1.3 Ventricular reconstruction
The aim of surgical ventricular reconstruction (SVR) is to remove scar tissue from the LV wall by an endoventricular patch plasty, thereby restoring physiological volume, and to restore an elliptical rather than spherical shape. The decision to add SVR to CABG should be based on a careful evaluation of symptoms (heart failure symptoms should take priority over angina), measurement of LV volumes, and assessment of the transmural extent of myocardial scar tissue, and should be performed only in centres with a high level of surgical expertise. The STICH trial failed to show a difference in the primary outcome (death from any cause or hospitalization for cardiac causes) between CABG and the combined procedure (CABG and SVR). The reduction in end-systolic volume index in STICH—smaller than in previously reported observational studies treating larger aneurysms—might explain the inconsistent finding and, thus, the value of reasonable SVR might be underestimated.291,292 Subgroup analyses of the STICH trial suggest that patients with less-dilated LV and better LVEF may benefit from SVR, while those with larger LV and poorer LVEF may do worse.293 In the STICH trial, a post-operative left ventricular end-systolic volume index (LVESVI) of 70 mL/m2 or lower, after CABG plus SVR, resulted in improved survival compared with CABG alone. In another study, in patients treated with CABG and SVR, a post-operative LVESVI of less than 60 mL/m2 was associated with improved survival compared with a post-operative LVESVI of 60 mL/m2 or more.294 In some patients with large aneurysms, who would have been excluded from STICH (due to acute heart failure, inotropic support or violation of other inclusion criteria), surgical ventricular restoration has shown favourable outcomes although in the absence of a comparator.295
Recommendations on revascularizations in patients with chronic heart failure and systolic LV dysfunction (ejection fraction ≤35%)
CABG = coronary artery bypass grafting; LAD = left anterior descending; LCx = left circumflex; LM = left main; LVESV = left ventricular end-systolic volume; PCI = percutaneous coronary intervention; SVR = surgical ventricular reconstruction.
aClass of recommendation.
bLevel of evidence.
9.2 Cardiogenic shock
Acute myocardial infarction accounts for approximately 75% of all patients with cardiogenic shock, and the incidence has remained somewhat constant for many years at 6–8%.296–298 Cardiogenic shock complicating acute myocardial infarction is caused by LV failure in about 80% of cases. Mechanical complications, such as papillary muscle rupture with severe mitral valve incompetence (6.9%), ventricular septal defect (3.9%), or free wall rupture (1.4%), are other precipitating causes. Because revascularization is the cornerstone of the treatment in patients with cardiogenic shock complicating ACS, emergency coronary angiography is indicated. The general triage and treatment of these complex patients is presented in Figure 3.
The Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) trial demonstrated that, in patients with cardiogenic shock due to acute myocardial infarction, emergency revascularization with PCI or CABG improved long-term survival when compared with initial intensive medical therapy. All-cause mortality at 6 months was lower in the group assigned to revascularization than in the group assigned to medical therapy (50.3% vs. 63.1%, respectively; RR 0.80; 95% CI 0.65–0.98; P =0.03).221 Subgroup analysis revealed that the only variable that correlated significantly with treatment both at 30 days and at 6 months was age, with little or no effect of invasive treatment on mortality in elderly patients (>75 years); however, these findings were not corroborated in the SHOCK trial registry, in which a covariate-adjusted model also suggested a lower mortality among elderly patients (>75 years) undergoing revascularization, as compared with initial intensive medical therapy (RR 0.46; 95% CI 0.28–0.75; P =0.002).299
9.2.2 Mechanical circulatory support
Intra-aortic balloon pump (IABP) counterpulsation has been widely used as mechanical support in cardiogenic shock.300 The efficacy of IABP in cardiogenic shock has recently been challenged in the large, randomized Intraaortic Balloon Pump in Cardiogenic Shock IABP-SHOCK II trial, which included 600 patients with cardiogenic shock complicating acute myocardial infarction, who were assigned to IABP or no IABP. The primary endpoint of 30-day mortality was not reduced with the use of IABP (39.7% IABP vs. 41.3% control; RR 0.96; 95% CI 0.79–1.17; P =0.69) and there was no long-term benefit.301,302 As a result, the use of IABP for this indication is not routinely recommended but remains an adjunct for patients with mechanical complications as a bridge to surgery.
Three randomized trials and a large registry have demonstrated superior haemodynamic support with percutaneous mechanical circulatory assist systems than with IABP, without differences in mortality but with an increased risk of adverse events.303–306 A meta-analysis, comparing the safety and efficacy of percutaneous left ventricular assist devices (LVAD) in IABP in patients with cardiogenic shock, found LVAD-treated patients to have a similar mortality and incidence of lower extremity ischaemia, but more bleeding than those treated with IABP.307
In younger patients with no contraindication for cardiac transplantation, LVAD therapy can be implemented as a bridge to transplantation. In patients not eligible for transplant, LVADs may be inserted as a bridge to recovery or with the goal of destination therapy.308–310
9.2.3 Right ventricular failure
Almost 50% of patients with inferior acute myocardial infarction show echocardiographic evidence of right ventricular dysfunction, with haemodynamic compromise developing in <25% of cases.311–315 Isolated right ventricular failure accounts for 2.8% of cases of cardiogenic shock complicating acute myocardial infarction.316,317 Successful primary PCI leads to a haemodynamic improvement, recovery of right ventricular free wall and global function and, hence, improved survival compared with unsuccessful reperfusion.317–319
9.2.4 Mechanical complications
Mechanical complications of acute myocardial infarction comprise myocardial rupture, resulting in either mitral regurgitation due to papillary muscle rupture, ventricular septal defect (VSD), or free wall rupture with tamponade.320–322
Ventricular septal defect, characterized by haemodynamic compromise, is treated by IABP followed by early surgical repair.323 Percutaneous closure devices for patients' post-infarct VSDs have been reported in case series and, in centres with appropriate experience, may be considered in selected cases as alternatives to surgery.324–326
Rupture of the free wall, resulting in tamponade, should be salvaged by prompt pericardial drainage and surgical intervention. Left ventricular free wall rupture accounts for approximately 15% of in-hospital mortality from myocardial infarction.327 Data from the SHOCK trial registry, on patients with and without LV free wall rupture who underwent surgery, showed similar mortality rates.327,328
Acute mitral regurgitation due to rupture of the papillary muscle should be treated by immediate surgery and revascularization.317,329,330
Data from randomized trials on revascularization in diabetic patients are summarized in Table 8. For additional information on diabetes, we refer to the ESC Guidelines on diabetes.84 Diabetic patients undergoing revascularization, either with CABG or PCI, are at greater risk for kidney injury than patients without diabetes.
10.1.1 Stable coronary artery disease
The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) trial specifically addressed the question of myocardial revascularization in diabetic patients with SCAD.334 A total of 2368 patients with diabetes and evidence of ischaemia, or symptoms of angina in the presence of angiographically defined SCAD, were randomized to medical therapy or to myocardial revascularization in addition to medical therapy. Before randomization, patients were placed in either the PCI or CABG stratum of revascularization as deemed appropriate by the responsible physician. The enrolment target of 2800 patients was not met and follow-up had to be extended by 1.5 years to 5.3 years. Patients with LM disease, those who were unstable, requiring immediate revascularization, and patients with creatinine values >2.0 mg/dL or moderate-to-severe heart failure were excluded. The primary endpoint was all-cause mortality and the principal secondary endpoint was a composite of death, myocardial infarction, or stroke (MACCE). The use of DES (35%) was low and restricted to early-generation devices. A total of 42% of patients in the medical therapy group underwent clinically indicated revascularization during follow-up.
At 5 years, survival did not differ between the medical therapy and revascularization groups, and there were no differences in MACCE (Table 8). In the PCI group, there was no outcome difference between PCI and medical therapy. In the CABG stratum, where patients had more extensive CAD, freedom from MACCE was significantly higher with revascularization than with medical treatment.334 Survival, however, was not significantly different, which may reflect a power issue or the fact that patients with more extensive myocardial perfusion abnormalities or LV function impairment were more likely to receive revascularization over time in the medical therapy group.335 Compared with medical therapy, the revascularization strategy at the 3-year follow-up had a lower rate of worsening angina (8% vs. 13%, respectively; P <0.001), new angina (37% vs. 51%, respectively; P <0.001), and subsequent coronary revascularizations (18% vs. 33%, respectively; P <0.001), and a higher rate of angina-free status (66% vs. 58%, respectively; P <0.003).
The investigators speculated that the benefit of CABG over medical therapy emerged due to a preference for CABG rather than PCI among patients with more advanced CAD. This was further substantiated in a study of the impact of angiographic (BARI-2D score) risk stratification on outcomes. Among the CABG stratum patients with high-risk angiographic scores, the 5-year risk of death, myocardial infarction or stroke was significantly lower and amplified for those assigned to revascularization, when compared with medical therapy (24.8% vs. 36.8%, respectively; P =0.005).336
10.1.2 Acute coronary syndromes
Approximately 20–30% of patients with NSTE-ACS have known diabetes, and at least as many have undiagnosed diabetes or impaired glucose tolerance.337 Mortality in patients with ACS is two- to three-time increased in diabetic patients, compared with non-diabetic.338 Despite the higher risk, revascularization and thienopyridines are less frequently prescribed among diabetics than non-diabetics, with an impact on in-hospital and long-term mortality.339–341
In NSTE-ACS patients, there is no clear correlation between the treatment effect of myocardial revascularization and diabetic status.342,343,364 In both the Fragmin during Instability in Coronary Artery Disease-2 (FRISC-2) and Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction 18 (TACTICS-TIMI 18) trials,342,343,364 an early invasive strategy in ACS patients was associated with better outcomes than with a conservative strategy; in TACTICS-TIMI 18,364 the magnitude of the benefit to diabetic patients was greater than that to non-diabetic patients. In a recent meta-analysis of nine RCTs with 9904 ACS patients, diabetic patients (n= 1789) had a higher rate of death (9.3% vs. 3.2%; P <0.001), non-fatal myocardial infarction (11.3% vs. 7.1%; P <0.001), and rehospitalization with ACS (18.1% vs. 13.0%; P <0.001) than non-diabetic patients at 1 year post-procedure. An early invasive strategy was associated with a similar risk reduction in death, myocardial infarction, or rehospitalization for ACS in diabetic and non-diabetic patients (RR 0.87; 95% CI 0.70–1.03 vs. 0.86; 95% CI 0.70–1.06; P for interaction 0.83).338 Accordingly, diabetes presents a secondary indication for high risk and for invasive management, and further efforts need to be made to give diabetic patients with ACS better access to revascularization therapy.180
Compared with non-diabetic patients, diabetics with STEMI present later, are more likely to experience haemodynamic instability and end-organ damage, and have delayed revascularization. In STEMI patients, the Primary Coronary Angioplasty vs. Thrombolysis (PCAT)-2 collaborative analysis of 19 RCTs with individual patient data from 6315 patients (14% with diabetes mellitus) showed a similar benefit of primary PCI over fibrinolytic treatment in diabetic and non-diabetic patients.363 The OR for mortality in favour of primary PCI was 0.49 for diabetic patients (95% CI 0.31–0.79). Recurrent myocardial infarction and stroke were also significantly lower in favour of primary PCI. Patients with diabetes had significantly delayed initiation of reperfusion treatments and longer ischaemic times, probably related to atypical symptoms causing significant delays in initiating reperfusion therapy. Owing to a higher absolute risk, the number needed to treat to save one life at 30 days was significantly lower for diabetic patients (number needed to treat = 17; 95% CI 11–28) than for non-diabetic patients (number needed to treat = 48; 95% CI 37–60).
10.2 Type of myocardial revascularization
The presence of diabetes mellitus defines the treatment strategy for an important subset of patients with multivessel CAD.
10.2.1. Randomized clinical trials
The Future Revascularization Evaluation in Patients with Diabetes Mellitus (FREEDOM) trial is the only adequately powered, randomized study comparing CABG against PCI with use of early-generation DES (94%) in diabetic patients undergoing elective revascularization for multivessel disease without LM coronary stenosis.175 Between 2005 and 2010, 33 966 patients were screened, of whom 3309 were considered eligible and 1900 (6%) enrolled. Their mean SYNTAX score was 26 ± 9. The primary outcome of death from any cause, non-fatal myocardial infarction, or stroke was lower in the CABG than the PCI group, with divergence of the curves starting at 2 years. This difference was driven by a borderline reduction of all-cause mortality (P =0.049) and by a markedly lower rate of myocardial infarction favouring the CABG group (P <0.001). Conversely, rates of stroke were doubled in the CABG group (P =0.03). The superiority of CABG over PCI was consistent across all pre-specified subgroups, including SYNTAX score, the only exception being that patients recruited outside the USA (n = 1130) had a less-pronounced relative benefit from CABG than those enrolled in the USA (n = 770) (P =0.05 for interaction).175 Detailed assessment of quality of life revealed substantial and durable improvements in cardiovascular-specific health status with both PCI and CABG groups. During the first month after treatment, PCI resulted in more rapid improvement in health status and quality of life, this changing between 6 months and 2 years in favour of CABG and differences disappearing beyond 2 years.344
It is unclear, however, whether the SYNTAX score was analysed by a blinded 'core' laboratory, which is essential for reproducibility. It should be noted that the SYNTAX score became operational during the FREEDOM trial and is not mentioned in the FREEDOM trial study protocol.345 Therefore, the validity of the observation that CABG led to better outcomes than PCI, irrespective of the SYNTAX score, remains unclear, and it is not consistent with the findings related to the diabetic subgroup of the SYNTAX trial. The increased risk of stroke raises the question of treatment selection, particularly among elderly patients. In addition, the median follow-up was 3.8 years but only 23% of patients were at risk at 5 years.
In the subset of 452 diabetic patients with multivessel CAD who were enrolled in the SYNTAX trial, there were no significant differences at 5 years in the composite of all-cause death, myocardial infarction, or stroke (CABG 19.1% vs. PCI 23.9%; P =0.26) or in the individual components such as all-cause death (P =0.07), stroke (P =0.34), or myocardial infarction (P =0.20).346 However, repeat revascularization was less frequently required in the CABG group (P < 0.001). Among patients with low SYNTAX score (≤ 22), rates of MACCE were similar for CABG and PCI (33.7% vs. 42.5%, respectively; P =0.38) but repeat revascularization remained more frequent in the PCI group (18.5% vs. 38.5%, respectively; P =0.01). Interestingly, in the SYNTAX trial, diabetes was not an independent predictor of outcomes once the SYNTAX score was entered into the multivariable model.25
In the Coronary Artery Revascularization in Diabetes (CARDia) trial, 510 diabetic patients with multivessel or complex single-vessel CAD, enrolled at 24 sites, were randomly assigned to either CABG or PCI with use of either BMS or DES and routine use of abciximab. There were no differences between CABG and PCI for the primary endpoint, the 1-year composite of death, myocardial infarction, or stroke.347 Comparing the subset of patients treated with DES, the primary outcome rates were 12.4% in the CABG and 11.6% in the PCI group (HR 0.93; 95% CI 0.51–1.71; P =0.82). Repeat revascularization was more common among patients assigned to PCI (P <0.001), whereas stroke tended to be less common among patients assigned to PCI (P =0.07).
Hence, taking currently available evidence into consideration, CABG is the revascularization modality of choice among diabetic patients with multivessel CAD; however, PCI can be considered as a treatment alternative among diabetic patients with multivessel disease and low SYNTAX score (≤ 22).
Randomized trials on revascularization in diabetic patients
BMS = bare-metal stent; CABG = coronary artery bypass grafting; CV = cardiovascular; DES = drug-eluting stent; EF = ejection fraction; MI = myocardial infarction; MT = medical therapy; MVD = multivessel disease; PCI = percutaneous coronary intervention; PES = paclitaxel-eluting stent; Revasc = revascularization; SES = sirolimus-eluting stent; Sx-Score = SYNTAX score; y = years.
bRandomization stratified by revascularization modality.
Age and ejection fraction are reported as means.
A meta-analysis of individual data from 10 RCTs of elective myocardial revascularization106 confirms a survival advantage for CABG over PCI in diabetic patients, whereas no difference was found for non-diabetic patients; the interaction between diabetic status and type of revascularization was significant. In this pooled analysis, PCI patients were treated with either balloon angioplasty or BMS. A more recent meta-analysis—dedicated to diabetic patients treated with either CABG or PCI, with at least 80% of arterial conduit(s) or stents (BMS and early-generation DES)—showed significantly lower mortality with CABG at 5 years or the longest follow-up (RR 0.67; 95% CI 0.52–0.86; P =0.002).349 On the other hand, this pooled analysis showed increased rates of stroke using CABG vs. PCI at 5-year follow-up (RR 1.72; 95% CI 1.18–2.53; P =0.005). Similarly, a meta-analysis—restricted to four RCTs covering 3052 patients, which compared PCI with use of early-generation DES vs. CABG in diabetic patients with multivessel CAD—reported a higher risk of death and myocardial infarction with revascularization by early-generation DES (RR 1.51; 95% CI 1.09–2.10; P =0.01) but a lower risk of stroke (2.3% vs. 3.8%; RR 0.59; 95% CI 0.39–0.90; P =0.01).350 A sensitivity analysis revealed that the superiority of CABG over early-generation DES for the endpoint MACCE was most pronounced among patients with high SYNTAX score, but not significant in those with low SYNTAX score. All RCTs have shown higher rates of repeat revascularization procedures after PCI compared with CABG, in diabetic patients.106,346
10.3 Revascularization with the use of percutaneous coronary intervention
A collaborative network meta-analysis has compared DES with BMS in 3852 diabetic patients.351 The need for target-lesion revascularization was considerably lower with DES than with BMS [OR 0.29 for sirolimus-eluting stent; 0.38 for paclitaxel-eluting stent]. A more recent mixed-treatment comparison of 42 trials with 22 844 patient-years of follow-up assessed the efficacy and safety of several early and new-generation DES and BMS in patients with diabetes. Compared with BMS, all DES showed a rate of TVR that was lower by 37–69%. Compared with BMS, there were no differences in rates of death, myocardial infarction, or stent thrombosis for any DES in diabetic patients.352 There are no robust data to support the use of any one DES over another in patients with diabetes.
10.4 Revascularization with the use of coronary artery bypass grafting
There is no direct, randomized evidence for or against the use of one vs. two IMA conduits in diabetic patients. Whether use of bilateral IMA increases the risk of deep sternal wound complications is still a matter of debate, although diabetic patients are particularly prone to sternal infections in bilateral IMA operations. However, observational evidence, with follow-up periods up to 30 years, suggests that bilateral IMA use improves long-term outcomes.23,24 Pending the long-term results of the randomized Arterial Revascularisation Trial (ART) trial,353 it is still not clear whether bilateral IMA grafting produces better outcomes, but the superior survival observed with bilateral IMA grafting has been seen not to depend on diabetic status.354 In a recent analysis, there was no significant correlation with diabetic status over 15-year follow-up when using multiple arterial grafts.355 Indeed, alternative strategies—including use of the radial artery in patients with an excessively high risk for sternal complications (e.g. obese patients)—have been shown to be safe during follow-up, and to prolong survival compared with using vein grafts.356
10.5 Antithrombotic pharmacotherapy
There is no indication that antithrombotic pharmacotherapy should differ between diabetic and non-diabetic patients undergoing revascularization. Although a correlation between diabetic status and efficacy of GP IIb/IIIa inhibitors was noted in earlier trials without concomitant use of thienopyridines, this was not confirmed in the more recent Early glycoprotein IIb/IIIa inhibition in non-ST-segment elevation acute coronary syndrome (EARLY-ACS) trial.357 In the current context of use of oral P2Y12 inhibitors, diabetic patients do not specifically benefit from the addition of GP IIb/IIIa inhibitors.
10.6 Anti-diabetic medications
Only a few specific trials of anti-diabetic medications have been conducted in patients undergoing myocardial revascularization.
Because of the risk of lactic acidosis in patients receiving iodinated contrast media, it is generally stated that administration of metformin should be suspended before angiography or PCI, and resumed 48 hours later, subject to adequate renal function. The plasma half-life of metformin is 6.2 hours; however, there is no convincing evidence for such a recommendation. Checking renal function after angiography in patients on metformin and witholding the drug when renal function deteriorates might be an acceptable alternative to automatic suspension of metformin. In patients with renal failure, metformin should preferably be stopped before the procedure. Accepted indicators for metformin-induced lactic acidosis are arterial pH <7.35, blood lactate >5 mmol/L (45 mg/dL), and detectable plasma metformin concentration. Accurate recognition of metformin-associated lactic acidosis and prompt initiation of haemodialysis are important steps towards rapid recovery.
Observational data have raised concern over the use of sulphonylureas in patients treated with primary PCI for acute myocardial infarction. Such concern has not been backed up by a post hoc analysis of the Diabetes, Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI)-2 trial, although the number of patients undergoing primary PCI in this trial was low.358 Arrhythmias and ischaemic complications were also less frequent in patients receiving gliclazide or glimepiride.359 Thiazolidinediones may be associated with lower rates of restenosis after PCI with BMS,360 but carry an increased risk of heart failure resulting from water retention in the kidney.
No trial has demonstrated that the administration of insulin or glucose–insulin–potassium improves PCI outcome after STEMI. Observational data in patients undergoing CABG suggest that use of a continuous intravenous (i.v.) insulin infusion to achieve moderately tight glycaemic control (6.6–9.9 mmol/L or 120–180 mg/dL) is independently associated with lower rates of mortality and major complications than those observed after tighter (6.6 mmol/L or 120 mg/dL) or more lenient (9.9 mmol/L or 180 mg/dL) glycaemic control.361 In the BARI-2D trial, outcomes were similar in patients receiving insulin sensitization vs. insulin provision to control blood glucose. In the CABG group, administration of insulin was associated with more cardiovascular events than the insulin-sensitization medications.139
In the Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus SAVOR-TIMI 53 trial, dipeptidyl peptidase 4 (DPP-4) inhibition with saxagliptin neither increased nor decreased the incidence of ischaemic events, although the rate of hospitalization for heart failure was increased.362
11. Revascularization in patients with chronic kidney disease
11.1 Evidence-base for revascularization
Myocardial revascularization is underused in patients with chronic kidney disease (CKD).369–371 In all categories of kidney function (defined in the web addenda), observational studies suggest that CKD patients with multivessel disease who undergo revascularization have better survival than those who receive medical therapy.372,373 Particularly among patients with ACS, large-scale registries indicate better short- and long-term survival with early revascularization than with medical therapy across all CKD stages.371,374 When there is an indication for PCI, DES should be preferred over BMS, because of its lower risk of revascularization and the absence of safety concerns.375,376 Notwithstanding, the use of contrast media during diagnostic and interventional vascular procedures represents the most common cause of acute kidney injury in hospitalized patients. In addition, patients with CKD have frequent comorbidities that increase the risk of periprocedural ischaemic and bleeding events. Notably, there is little evidence from RCTs, as most therapeutic RCTs on revascularization have excluded CKD patients. Current treatment strategies are therefore based on retrospective analyses of RCTs and data from large registries.
11.1.1 Patients with moderate chronic kidney disease
Observational studies suggest an increased risk of perioperative and short-term (∼12 months) fatal events but lower medium-to-long-term mortality after CABG compared with PCI.377,378 The absolute risk for end-stage renal disease is smaller than that for fatal events in this patient population and the combined incidence of death or end-stage renal disease may remain lower after CABG at long-term follow-up. In the post hoc analysis of patients with CKD (25% of 1205 patients) in the randomized Arterial Revascularization Therapies Study (ARTS) trial, which compared CABG against multivessel PCI with the use of BMS, no difference was observed in the primary endpoint of death, myocardial infarction, or stroke (19% vs. 17%; HR 0.93; 95% CI 0.54–1.61; P =0.80) as well as mortality after 3 years of follow-up; however, the risk of repeat revascularization was reduced in favour of CABG (25% vs. 8%; HR 0.28; 95% CI 0.14–0.54; P =0.01).379 There is some evidence that suggests that the off-pump approach may reduce the risk of perioperative acute renal failure and/or progression to end-stage renal disease in these patients.380 Predictive tools have been proposed, which hold promise as a means of identifying CKD patients who are likely to derive the most benefit from one particular revascularization strategy, but these have not been systematically validated externally.381
11.1.2 Patients with severe chronic kidney disease and end-stage renal disease or in haemodialysis
In the absence of data from RCTs, results from a large cohort of 21 981 patients with end-stage renal disease (data from US Renal Data System) with poor 5-year survival (22–25%) suggest that CABG should be preferred over PCI for multivessel coronary revascularization in appropriately selected patients on maintenance dialysis.382 Compared with PCI, CABG was associated with significantly lower risks for both death and the composite of death or myocardial infarction.382 Selection of the most appropriate revascularization strategy must therefore account for the general condition and life expectancy of the patient, the least invasive approach being more appropriate in the most fragile and compromised patients.
Candidates for renal transplantation must be screened for myocardial ischaemia, and those with significant CAD should not be denied the potential benefit of myocardial revascularization. Renal transplant recipients have been reported to have similar long-term survival after CABG and PCI.383
11.2 Prevention of contrast-induced nephropathy
Especially if glomerular filtration rate (GFR) is <40mL/min/1.73 m2, all patients with CKD who undergo diagnostic catheterization should receive preventive hydration with isotonic saline, to be started approximately 12 hours before angiography and continued for at least 24 hours afterwards to reduce the risk of contrast-induced nephropathy (CIN).384,385 The implementation of high-dose statin before diagnostic catheterization has been shown to reduce the incidence of CIN and should be considered as an additional preventive measure in patients without contraindications.386 The antioxidant ascorbic acid has been explored in oral and intravenous preparations, for protection against CIN. A recent meta-analysis of nine RCTs in 1536 patients suggested a somewhat lower risk of CIN among pre-existing CKD patients who received ascorbic acid, than in patients who received placebo or an alternate treatment (9.6% vs. 16.8%, respectively; RR = 0.67; 95% CI 0.47 to 0.97; P =0.034)387 but more evidence is required to make definite recommendations. Although performing diagnostic and interventional procedures separately reduces the total volume exposure to contrast media, the risk of renal atheroembolic disease increases with multiple catheterizations. Therefore, in CKD patients with diffuse atherosclerosis, a single invasive approach (diagnostic angiography followed by ad hoc PCI) may be considered, but only if the contrast volume can be maintained <4 mL/kg. The risk of CIN increases significantly when the ratio of total contrast volume to GFR exceeds 3.7:1.388,389 For patients undergoing CABG, the effectiveness of the implementation of pharmacological preventive measures—such as clonidine, fenoldopam, natriuretic peptides, N-acetylcysteine or elective pre-operative haemodialysis—remains unproven.
dEspecially in patients with eGFR <40 mL/min/1.73 m2.
12. Revascularization in patients requiring valve interventions
12.1 Primary indication for valve interventions
Overall, 40% of patients with valvular heart disease will have concomitant CAD. Coronary angiography is recommended in all patients with valvular heart disease requiring valve surgery, apart from young patients (men <40 years and pre-menopausal women) without risk factors for CAD or when the risks of angiography outweigh the benefits (e.g. in cases of aortic dissection, a large aortic vegetation in front of the coronary ostia, or occlusive prosthetic thrombosis leading to an unstable haemodynamic condition).411 In patients undergoing aortic valve replacement (AVR) who also have significant CAD, the combination of CABG and aortic valve surgery reduces the rates of perioperative myocardial infarction, perioperative mortality, late mortality, and morbidity, when compared with patients not undergoing simultaneous CABG.412–415 This combined operation, however, carries an increased risk of mortality over isolated AVR.11,416–418 In a contemporary analysis of a large cohort, the greater risk of the combined operation than with isolated AVR was associated with effects of pre-existing ischaemic myocardial damage and comorbidities.419
In patients with severe comorbidities, the Heart Team may opt for transcatheter valve interventions. Although a systematic review of observational studies has shown no significant impact of CAD on mortality in patients undergoing transcatheter aortic valve implantation (TAVI),420 a recent single-centre investigation found an increased risk of cardiovascular adverse events among patients with advanced CAD (SYNTAX score >22).421 PCI, among patients with CAD undergoing TAVI, does not appear to increase the short-term risks of death, myocardial infarction, or stroke, compared with patients undergoing isolated TAVI; however, its impact on long-term prognosis is not well established.422–425 The selection of lesions treated by PCI is usually based on clinical presentation and angiography, as functional methods of detecting ischaemia have not been validated among patients with severe aortic stenosis.422,423,426–428 Currently, there is no conclusive evidence as to whether PCI should be performed as a staged intervention or during the same procedure, and the decision may be made on an individual basis according to the leading clinical problem, renal failure, and complexity of the underlying CAD.422,424,425,428,429 Published experience with PCI and percutaneous mitral valve repair is currently limited to case reports.
Alternative treatments for high-risk patients also include ‘hybrid’ procedures, which involve a combination of scheduled surgery for valve replacement and planned PCI for myocardial revascularization. At present, however, the data on hybrid valve/PCI procedures are very limited, being confined to case reports and small case series.430 Individual treatment decisions in these complex patients are best formulated by the Heart Team.
12.2 Primary indication for coronary revascularization
Many patients with CAD and reduced LV function have concomitant secondary mitral regurgitation. Observational data from the STICH trial suggest that adding mitral valve repair to CABG in patients with LV dysfunction (LVEF ≤35%) and moderate-to-severe mitral regurgitation offers better survival than CABG alone.431 Likewise, in patients undergoing CABG for the clinically leading problem of CAD, aortic valves with moderate stenosis should be replaced.411 Case-by-case decisions by the Heart Team are needed for patients with an indication for PCI and moderate-to-severe valve disease.
13.1 Associated coronary and carotid artery disease
The prevalence of severe carotid artery stenosis increases with the severity of CAD and is an indicator of impaired prognosis.433 Although the association between carotid artery stenosis and CAD is evident, the prevalence of significant carotid artery stenosis in the entire cohort remains relatively low. Conversely, up to 40% of patients undergoing carotid endarterectomy (CEA) have significant CAD and may benefit from pre-operative cardiac risk assessment.
13.1.1 Risk factors for stroke associated with myocardial revascularization
The incidence of stroke after CABG varies depending on age, comorbidities and surgical technique. The FREEDOM trial, which compared PCI with CABG in diabetic patients with multivessel CAD, showed a 30-day rate of stroke of 1.8% after CABG and 0.3% after PCI (P =0.002).175 Similarly, a greater risk of stroke was reported in the SYNTAX trial, which diminished during long-term follow-up and was no longer significant at 5 years (CABG 3.7% vs. PCI 2.4%; P =0.09).17 In a meta-analysis of 19 randomized trials with 10 944 patients, the risk of stroke was lower among patients assigned to PCI than in those assigned to CABG after 30 days and at 1 year.131 These findings indicate that CABG carries a greater periprocedural risk of stroke but that the long-term risk of cerebrovascular events persists with both treatments.17 The most common cause of CABG-related stroke is embolization of atherothrombotic debris from the ascending aorta, particularly during aortic cannulation. The risk of periprocedural stroke after CABG in patients with carotid artery stenosis is associated with the severity of stenosis but even more with a history of stroke or transient ischaemic attack (TIA) (within 6 months).434 There is a lack of strong evidence that CAD is a significant cause of perioperative stroke.435 The extension of atherosclerotic disease to intracerebral and extracerebral territories, radiographic demonstration of previous stroke and aortic atheromatous disease, are the most important factors for predicting an increased risk of perioperative stroke.435
Although symptomatic carotid artery stenosis is associated with a greater risk of stroke, 50% of patients suffering strokes after CABG do not have significant carotid artery disease and 60% of territorial infarctions on CT scan/autopsy cannot be attributed to carotid disease alone. Furthermore, only around 40% of strokes following CABG are identified within the first day after surgery, while 60% of strokes occur after uneventful recovery from anaesthesia. In a recent study including 45 432 patients undergoing CABG, 1.6% experienced a stroke and risk factors for all strokes were age, smaller body surface area, emergency surgery, previous stroke, pre-operative atrial fibrillation (AF), and on-pump CABG with hypothermic circulatory arrest. For intraoperative strokes, additional risk factors were peripheral and carotid artery disease, previous cardiac surgery, worse clinical condition, LV dysfunction, left circumflex (LCx) coronary artery stenosis >70%, and on-pump CABG with arrested heart or hypothermic circulatory arrest.436
Although the risk of stroke is low among patients with carotid artery disease undergoing PCI, ACS, heart failure, and extensive atherosclerosis are independent risk factors for this adverse event. In a large registry of 348 092 PCI patients, the rates of stroke and TIA amounted to only 0.11% and did not differ between transfemoral and radial access.437
13.1.2 Preventive measures to reduce the risk of stroke after coronary artery bypass grafting
Detection of severe carotid artery bifurcation disease may lead to concomitant carotid revascularization in selected cases. Identification of an atherosclerotic aorta is believed to be an important step in reducing the risk of stroke after CABG. Pre-operative CT scan or intraoperative ultrasound epiaortic scanning—better than aortic palpation—can lead to modifications in the operative management that may reduce the risk of stroke associated with CABG.438,439 There is conflicting evidence regarding the influence of off-pump CABG on the incidence of stroke.440 A recent randomized trial showed no difference in the incidence of stroke between off-pump CABG and on-pump CABG at 30 days.441 However, studies employing a 'minimal touch' technique for the aorta reported a lower risk of stroke and MACCE with off-pump CABG.442,443
Perioperative medical therapy plays a fundamental role in the prevention of neurological complications following CABG. Statins in combination with beta-blockers have shown a protective effect on the risk of stroke after CABG.444
CABG = coronary artery bypass grafting; CAD = coronary artery disease; CT = computed tomography; MRI = magnetic resonance imaging; PAD = peripheral artery disease; TIA = transient ischaemic attack.
aClass of recommendation.
bLevel of evidence.
13.1.3 Carotid revascularization in patients scheduled for myocardial revascularization
In patients with previous TIA or stroke and the presence of carotid artery stenosis (50–99% in men; 70–99% in women), CEA performed by experienced teams may reduce the risk of perioperative stroke or death.434 Conversely, isolated myocardial revascularization should be performed among patients with asymptomatic unilateral carotid artery stenosis because of the small risk reduction in stroke and death achieved by concomitant carotid revascularization (1% per year).434 Carotid revascularization may be considered in asymptomatic men with bilateral severe carotid artery stenosis or contralateral occlusion, provided that the risk of stroke or death within 30 days can be reliably documented to be <3% in the presence of a life expectancy >5 years. In women with asymptomatic carotid disease or patients with a life expectancy of <5 years, the benefit of carotid revascularization remains unclear.434 In the absence of clear proof that staged or synchronous CEA or carotid artery stenting (CAS) is beneficial in patients undergoing CABG, patients should be assessed on an individual basis by a multidisciplinary team including a neurologist. This strategy is also valid for patients scheduled for PCI. The strategy of combining PCI with CAS in the same procedure in elective patients is not routinely recommended, except in the infrequent circumstance of concomitant acute severe carotid and coronary syndromes.
13.1.4 Type of revascularization in patients with associated carotid and coronary artery disease
Few patients scheduled for CABG require synchronous or staged carotid revascularization.445–448 In the absence of randomized trials comparing management strategies in patients with concomitant CAD and carotid disease, the choice of carotid revascularization modality (CEA vs. CAS) should be based on patient comorbidities, supra-aortic vessel anatomy, degree of urgency for CABG and local expertise.449 Operator proficiency impacts on results of both carotid revascularization methods but even more in CAS, with higher mortality rates in patients treated by low-volume operators or early in their experience.450 If CAS is performed before elective CABG, the need for dual antiplatelet therapy (DAPT) usually delays cardiac surgery for 4–5 weeks.451,452
Carotid artery revascularization in patients scheduled for CABG
CABG = coronary artery bypass grafting; CAS = carotid artery stenting; CEA = carotid endarterectomy; TIA = transient ischaemic attack.
aClass of recommendation.
bLevel of evidence.
The term carotid artery stenosis refers to a stenosis of the extracranial portion of the internal carotid artery, and the degree of stenosis is according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria.451
ASA = acetylsalicylic acid; CABG = coronary artery bypass grafting; CAS = carotid artery stenting; CEA = carotid endarterectomy.
aClass of recommendation.
bLevel of evidence.
13.2 Associated coronary and peripheral arterial disease
Peripheral artery disease (PAD) is an important predictor of adverse outcome after myocardial revascularization, and portends a poor long-term outcome.457,458 Patients with clinical evidence of PAD are at increased risk for procedural complications after either PCI or CABG. When comparing the outcomes of CABG vs. PCI in patients with PAD and multivessel disease, CABG is associated with a trend for better survival. Risk-adjusted registry data have shown that patients with multivessel disease and PAD undergoing CABG have better survival at 3 years than similar patients undergoing PCI, in spite of higher in-hospital mortality. In the case of CABG, surgeons should avoid harvesting veins from legs that are affected by significant clinical symptoms of PAD; however, with no solid data available in this population, the two myocardial revascularization approaches are probably as complementary in patients with PAD as they are in other CAD patients.
Non-cardiac vascular surgery in patients with associated coronary artery disease
Patients scheduled for non-cardiac vascular surgery are at greater risk of cardiovascular morbidity and mortality due to a high incidence of underlying symptomatic or asymptomatic CAD.451,459 Results of the largest RCT have demonstrated that, among 510 patients randomized to prophylactic myocardial revascularization (by either PCI or CABG) or to medical therapy alone, there is no advantage in terms of incidence of perioperative myocardial infarction, early or long-term mortality before major vascular surgery.460 Patients included in this study had preserved LV function and SCAD. A RCT with 208 patients at moderate or high cardiac risk, who were scheduled for major vascular surgery, reported similar results: patients undergoing systematic pre-operative coronary angiography and revascularization had similar in-hospital outcomes but greater freedom from cardiovascular events at 4 years than with a selective strategy.461 In summary, selected high-risk patients may benefit from staged or concomitant myocardial revascularization, with options varying from a one-stage surgical approach to combined PCI and peripheral endovascular repair or hybrid procedures.
RCTs involving high-risk patients, cohort studies, and meta-analyses provide consistent evidence, in patients undergoing high-risk non-cardiac vascular surgery or endovascular procedures, of lower incidences of cardiac mortality and myocardial infarction related to medical therapy including statins.458 In summary, perioperative cardiovascular complications are common in PAD patients with associated CAD and result in significant morbidity following non-cardiac vascular surgery. All patients require pre-operative screening to identify and minimize immediate and future risk, with a careful focus on known CAD, risk factors for CAD, and functional capacity.451,462
dHigh cardiac risk (reported cardiac risk often >5%): 1) aortic and other major vascular surgery; 2) peripheral vascular surgery.462
14. Repeat revascularization and hybrid procedures
14.1 Early graft failure
Early graft failure after CABG is reported in up to 12% of grafts (left IMA 7%; saphenous vein graft 8%) as evaluated by intraoperative angiographic control,463 but only a minority, around 3%, are clinically apparent.464 Graft failure can be due to conduit defects, anastomotic technical errors, poor native vessel run-off, or competitive flow with the native vessel. When clinically relevant, acute graft failure may result in myocardial infarction with consequently increased mortality and major cardiac events. The suspicion of graft failure should arise in the presence of ECG signs of ischaemia, ventricular arrhythmias, important biomarker modifications, new wall motion abnormalities, or haemodynamic instability.465 Owing to the low specificity of ECG modifications and echocardiographic wall motion abnormalities during the post-operative course and the delay in appearance of biomarker changes, a careful assessment of all variables will influence the decision-making for angiographic evaluation.
Perioperative angiography is recommended in cases of suspected myocardial ischaemia to detect its cause and help decide on appropriate treatment.463,465,466 In symptomatic patients, early graft failure can be identified as the cause of ischaemia in about 82% of cases.467 In early post-operative graft failure, emergency PCI may limit the extent of myocardial infarction compared with re-do surgery.467 The target for PCI is the body of the native vessel or the IMA graft, while the acutely occluded saphenous vein graft (SVG) and the anastomosis should be avoided due to concerns over embolization or perforation. Re-do surgery should be favoured if anatomy is unsuitable for PCI, or if several important grafts are occluded. Early mortality in the range of 9–15% has been reported in this group of patients, without any difference between the two revascularization strategies.467 In asymptomatic patients, repeat revascularization should be considered if the artery is of appropriate size and supplies a large territory of myocardium. The optimal treatment strategy in patients with acute graft failure should be decided by ad hoc consultation between cardiovascular surgeon and interventional cardiologist, on the basis of the patient’s clinical condition and extent of myocardium at risk.
14.2 Disease progression and late graft failure
Ischaemia after CABG may be due to progression of disease in native vessels or disease of bypass grafts (Table 9). Repeat revascularization in these patients is indicated in the presence of significant symptoms despite medical treatment, and in asymptomatic patients with objective evidence of myocardial ischaemia (>10% LV).54,143 The survival of patients with patent left IMA to LAD and ischaemia in the territories of the right- and circumflex arteries does not appear to be influenced by mechanical revascularization when compared with medical therapy alone.468
Re-do coronary artery bypass grafting or percutaneous coronary intervention
Percutaneous coronary intervention in patients with previous CABG has worse acute and long-term outcomes than in patients without prior CABG. Re-do CABG has a two- to four-fold increased mortality compared with first-time CABG.477,478 There are limited data comparing the efficacy of PCI vs. re-do CABG in patients with previous CABG. In the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) RCT and registry, overall in-hospital mortality was higher with re-do CABG than with PCI.151,479 More recent observational data have shown similar long-term results in patients treated by re-do CABG and PCI, with a higher revascularization rate for the PCI group.479,480 In view of the higher risk of procedural mortality with re-do CABG and the similar long-term outcome, PCI is the preferred revascularization strategy in patients with patent left internal mammary artery (LIMA) and amenable anatomy. CABG is preferred for patients with extensively diseased or occluded bypass grafts, reduced systolic LV function, several total occlusions of native arteries and absence of patent arterial grafts. The IMA is the conduit of choice for revascularization during re-do CABG.481
Percutaneous coronary intervention via the by-passed native artery should be the preferred approach provided the native vessel is not chronically occluded. Percutaneous coronary intervention for a chronic total occlusion (CTO) may be indicated when ischaemic symptoms are present with evidence of significant ischaemia and viable myocardium in the territory supplied. If PCI in the native vessel fails, PCI in the diseased SVG remains an option.
Percutaneous coronary intervention for saphenous vein graft lesions
Percutaneous coronary intervention for SVGs is associated with an increased risk of distal coronary embolization, resulting in periprocedural myocardial infarction.482 Percutaneous coronary intervention of de-novo SVG stenosis is considered a high-risk intervention because SVG atheroma is friable and more prone to distal embolization. A pooled analysis of five RCTs reported that GP IIb/IIIa inhibitors are less effective for interventions in SVGs than in native vessels.483 Several different approaches have been evaluated to prevent distal embolization of particulate debris, including distal occlusion/aspiration, proximal occlusion, suction, filter devices or mesh-covered stents.484 Unlike occlusive devices, distal protection using filters offers the inherent advantage of maintaining antegrade perfusion and the opportunity for contrast injections. Combined data, mostly from comparative studies between devices and surrogate endpoints, support the use of distal embolic protection during SVG PCI.485,486 In an RCT comparing different distal-protection devices in SVG PCI, the only independent predictor of 30-day MACE was plaque volume, and not the type of protection device used.487 Experience with other devices used for SVG PCI, such as mesh-based stents, is limited.488
Implantation of DES in SVG lesions is associated with a lower risk of repeat revascularization than with BMS.489–497 In the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) of 3063 procedures with 4576 stents—including BMS and DES in SVG lesions—the incidence of death was lower among patients who received DES.489 However, no differences in terms of death, myocardial infarction, or stent thrombosis were observed in the randomized Is Drug-Eluting-Stenting Associated with Improved Results in Coronary Artery Bypass Grafts (ISAR-CABG) trial.495
Long-term results (up to 7 years post-procedure) of early-generation DES in SVG lesions are satisfactory, with no excess risk of stent thrombosis and maintained lower rate of restenosis than with BMS.494,496 Compared with PCI of native coronary vessels, patients undergoing PCI of SVGs have impaired long-term clinical outcomes.498
Most PCI-related complications (including dissections, vessel occlusion, intracoronary thrombosis, and coronary perforation) are successfully treated in the catheterization laboratory;499,500 on-site or stand-by surgery is therefore not required during these procedures. The need for urgent surgery to manage PCI-related complications is uncommon and only required in patients with major complications that cannot be adequately resolved by percutaneous techniques.499,500 This is mainly confined to patients with a large, evolving myocardial infarction due to iatrogenic vessel occlusion that cannot be salvaged percutaneously, and to those with iatrogenic cardiac tamponade with failed pericardiocentesis or recurrent tamponade.499,500 When severe haemodynamic instability is present, IABP or mechanical circulatory assistance may be desirable before emergency surgery.
14.4 Repeat percutaneous coronary intervention
Recurrence of symptoms or ischaemia after PCI is the result of restenosis, incomplete initial revascularization, or disease progression. Infrequently, patients may require repeat PCI due to late and very late stent thrombosis.
Restenosis associated with angina or ischaemia should be treated by repeat revascularization and repeat PCI remains the strategy of choice for these patients if technically feasible. Originally, balloon angioplasty was frequently used in this setting, with good initial results but high rates of recurrence.501,502 Bare-metal stents provided superior early results in patients with in-stent restenosis but produced unfavourable late outcomes and were therefore reserved for patients with suboptimal initial results after balloon angioplasty or for those with large vessels.501,502 Ablative techniques (including rotational atherectomy and laser) have failed to improve results in such patients. Although brachytherapy was effective for in-stent restenosis, it never achieved widespread use, mainly due to logistical issues. Currently DES implantation is recommended in patients with BMS or DES in-stent restenosis. In this setting, the results from DES are superior to those obtained with balloon angioplasty, BMS implantation or brachytherapy.501–505 Drug-coated balloons are also effective in these patients and are particularly attractive when more than two stent layers are already present in the vessel. Drug-coated balloons are superior to balloon angioplasty and give results similar to early-generation DES in patients with BMS or DES in-stent restenosis.506–512 The use of intracoronary imaging may provide insights into the underlying mechanisms of in-stent restenosis. The presence of an underexpanded stent should, if possible, be corrected during the repeat procedure. In patients with recurrent episodes of diffuse in-stent restenosis—and in those with associated multivessel disease, especially in the presence of other complex lesions such as chronic total occlusions—CABG should be considered before a new PCI attempt.
Patients with symptomatic disease progression after PCI account for up to 50% of re-interventions.513,514 They should be managed using criteria similar to patients without previous revascularization if angiographic and functional results of previous interventions remain satisfactory. Percutaneous coronary intervention is an excellent therapy for these patients but care should be taken to identify the sites of prior patent stents as, occasionally, these may complicate re-interventions in the same vessel. Preventive pharmacological strategies should be maximized in this population.
Although stent thrombosis is very rare it may have devastating clinical consequences. Stent thrombosis usually presents as a large myocardial infarction and patients should undergo emergency primary PCI.515 Owing to the rarity of this complication, the interventional strategy of choice remains unsettled but the use of thromboaspiration and intracoronary IIb/IIIa platelet inhibitors is frequently advocated. Aggressive, high-pressure balloon dilation should be used to correct underlying, stent-related, predisposing, mechanical problems.516 In this challenging setting, it has been suggested that intracoronary diagnostic techniques be used to correct mechanical problems and optimize final results.516,517 While optical coherence tomography (OCT) provides superior near-field resolution to intravascular ultrasound imaging (IVUS) and is able to identify red thrombus, thrombus shadowing may interfere with imaging of the underlying structures.516 Some patients with very late stent thrombosis actually have neoatherosclerosis as the underlying pathological substrate, and this can be recognized with intracoronary imaging.516 Although the value of repeat stenting in patients with stent thrombosis is under debate and should be avoided when satisfactory results are obtained with balloon dilation, a new stent may be required to overcome edge-related dissections and adjacent lesions or to optimize final results.517 Detection and correction of any predisposing thrombogenic milieu remains important during these interventions.516
Adequate inhibition of platelet aggregation is of great importance in minimizing the risk of stent thrombosis, as well as its recurrence. Hence, in patients presenting with stent thrombosis, particular care should be taken to select the most appropriate P2Y12 inhibitor and ensure the importance of compliance by adequate patient information. There is no evidence to suggest that platelet function testing is effective in guiding the decision-making process with respect to type of P2Y12 inhibitor in this specific setting. Since prasugrel and ticagrelor lower the risk of primary ST,341,518 these agents should be preferred over clopidogrel, if clinically indicated. Duration of treatment should be at least 12 months after the acute event and potentially longer if well tolerated. In cases where these new agents are not available or contra-indicated, doubling the dose of clopidogrel may be reasonable.519
14.5 Hybrid procedures
Hybrid myocardial revascularization is a planned intervention combining cardiac surgery with a catheter-based intervention performed within a predefined time.520–523 Procedures can be performed consecutively in a hybrid operating room, or sequentially on separate occasions in the conventional surgical and PCI environments. The Heart Team discussion and the design of a joint strategy are critical for these patients. Hybrid procedures consisting of IMA to LAD and PCI of other territories appear reasonable when PCI of the LAD is not an option or is unlikely to portend good long-term results or when achieving a complete revascularization during CABG might be associated with an increased surgical risk.520,521 Although in most centres the number of hybrid procedures is relatively small, it remains important to consider when they may be clinically indicated. Options include:
Selected patients with single-vessel disease of the LAD, or in multivessel disease but with poor surgical targets except for the LAD territory, in whom minimally invasive direct coronary artery bypass grafting (MIDCAB) can be performed to graft the LAD using the LIMA. The remaining lesions in other vessels are subsequently treated by PCI.
Patients who had previous CABG and now require valve surgery, and who have at least one important patent graft (e.g. IMA to LAD) and one or two occluded grafts with a native vessel suitable for PCI.
Combination of revascularization with non-sternotomy valve intervention (e.g. PCI and minimally invasive mitral valve repair, or PCI and transapical aortic valve implantation).
In addition, some patients with complex multivessel disease presenting with STEMI initially require primary PCI of the culprit vessel, but subsequently may require complete surgical revascularization. A similar situation occurs when patients with combined valvular and CAD require urgent revascularization with PCI. Finally, when a heavily calcified aorta is found in the operating room the surgeon may elect not to attempt complete revascularization and to offer delayed PCI.
15.1.1 Revascularization for prevention of sudden cardiac death in patients with stable coronary artery disease and reduced left ventricular function
Revascularization plays an important role in reducing the frequency of ventricular arrhythmias in normal and mildly reduced LV function (CASS study,525 European Coronary Surgery Study).109 Thus, revascularization significantly decreased the risk for sudden cardiac death in patients with CAD and LVEF <35% [Studies of Left Ventricular Dysfunction (SOLVD)].526 Likewise, simultaneous ICD implantation during CABG did not improve survival in patients with reduced LV function (CABG Patch).527 Conversely, an adjusted increased risk of ventricular tachycardia (VT) or ventricular fibrillation (VF) of 5% or 8%, respectively, was observed with every 1-year increment of time elapsed from revascularization, irrespective of the mode of revascularization, potentially related to a gradual progression of CAD (Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy (MADIT-CRT).528 Indirect evidence for a protective effect of coronary revascularization in terms of sudden cardiac death is provided by retrospective analysis of data from the Multicentre Automatic Defibrillator Implantation Trial II (MADIT II) and Sudden Cardiac Death in Heart Failure Trial (SCD-HEFT) studies, in which ICD implantation was performed for primary prophylaxis of sudden cardiac death in patients with CAD and an ejection fraction <30–35%, respectively. In these studies, ICD implantation did not reduce sudden death if revascularization had been performed within 6 months (MADIT II)608 or 2 years (SCD-HEFT)529 prior to ICD implantation. Finally, the STICH trial, which investigated the effect of revascularization (CABG) in patients with reduced LV function (<35%) revealed a non-significant trend towards lower overall mortality in the CABG group but a significant benefit in cardiovascular endpoints (e.g. death from cardiac causes including sudden death).112 Because of the protective effect of revascularization of ventricular arrhythmias, patients with ischaemic LV dysfunction (LVEF <35%) who are considered for primary preventive ICD implantation should be evaluated for residual ischaemia and for potential revascularization targets.
Since revascularization by CABG led to a 46% risk reduction of sudden cardiac death in the SOLVD study, and in view of the low risk for sudden cardiac death within 2 years after revascularization in MADIT-II, reassessment of LV function up to 6 months after revascularization may be considered before primary preventive ICD implantation in patients with CAD and LVEF <35%. This is based on the observation that reverse LV remodelling and improvement of LV function may occur up to 6 months after revascularization procedures.530,531
15.1.2 Revascularization for treatment of electrical storm
Electrical storm is a life-threatening syndrome related to incessant ventricular arrhythmias, which is most frequently observed in patients with ischaemic heart disease, advanced systolic heart failure, valve disease, corrected congenital heart disease, and genetic disorders such as Brugada syndrome, early repolarisation and long-QT syndromes. In the MADIT-II study, the occurrence of interim post-enrolment ischaemic events (angina or myocardial infarction) was independently predictive of the electrical storm, although there was no close correlation between the timing of the two.532 Urgent coronary angiography and revascularization should be part of the management of patients with electrical storm, as well as antiarrhythmic drug therapy and/or ablation of ventricular tachycardia.
15.1.3 Revascularization after out-of-hospital cardiac arrest
Approximately 70% of survivors of out-of-hospital cardiac arrest have CAD, with acute vessel occlusion observed in 50%.533 Multiple non-randomized studies suggest that emergency coronary angiography and PCI after out-of-hospital cardiac arrest yields a favourable survival rate of up to 60% at 1 year, which is considerably higher than the 25% overall survival rate in patients with aborted cardiac arrest.534,535 More recent data suggest that almost one-quarter of patients, resuscitated from cardiac arrest but without ST-segment elevation, show a culprit lesion (either vessel occlusion or irregular lesion).536,537 Notably, in the prospective Parisian Region Out of Hospital Cardiac Arrest (PROCAT) registry, 96% of patients with STEMI and 58% without STEMI after out-of-hospital cardiac arrest revealed at least one significant coronary artery lesion, and hospital survival rates were significantly higher if immediate PCI was performed successfully.538,539 Thus, in survivors of out-of-hospital cardiac arrest, early coronary angiography and PCI—if appropriate—should be performed irrespective of the ECG pattern if no obvious non-cardiac cause of the arrhythmia is present.540