Editor's Note: Commentary based on 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014;64:1929-49..

Background

The ACC/AHA/AATS/PCNA/SCAI/STS guidelines of stable ischemic heart disease (SIHD) were published in 2012.¹ This focused update adds some new recommendations and modifies some previous recommendations.

Methods

The guideline writers have reviewed medical literature concerning four main points of SIHD:

1. Coronary angiography (CA) for diagnosis of IHD,
2. Chelation therapy to prevent myocardial infarction (MI) and death,
3. Enhanced external counterpulsation (EECP) for the treatment of refractory angina, and
4. Coronary revascularization to improve survival.

Results

Four new recommendations are provided for CA in the diagnosis of SIHD, all with level of evidence (LoE) C: 

1. CA is useful in patients with symptoms despite optimal medical therapy (OMT) (Class I);
2. CA is reasonable when clinical and stress test data suggest high-risk IHD (Class IIa);
3. CA is reasonable in patients with suspected IHD when stress tests cannot be performed or gave inconclusive results, but CA findings might result in important changes in therapy (Class IIa); and
4. CA might be considered when, despite negative non-invasive work-up, the suspicion of coronary artery disease (CAD) remains high and CA might result in important changes in therapy (Class IIb).

Chelation therapy is now promoted from Class III to Class IIb recommendation (LoE B) with the following comment: the usefulness of chelation therapy is uncertain for reducing cardiovascular events in patients with SIHD. EECP is proposed again as Class IIb recommendation (LoE B) with the following comment: it may be considered for relief of refractory angina in patients with SIHD. Finally, a new Class I recommendation (LoE C) is given for a heart team approach to revascularization in patients with diabetes mellitus and complex multivessel CAD while the Class IIa recommendation that coronary artery bypass grafting (CABG) should be preferred to a percutaneous coronary intervention (PCI) for improving survival in diabetic patients with multivessel CAD has been promoted to Class I recommendation (LoE B), in particular if a left internal mammary artery graft can be anastomized on the left anterior descending (LAD) coronary artery.

Commentary

1) Coronary Angiography for Diagnosis of SIHD: A major observation about the new recommendations for coronary angiography (CA) in the diagnosis of SIHD is that the LoE for all of them is C. Indeed, no controlled trial has hitherto assessed the utility of CA in this setting. Recommendations supported by LoE C frequently raise controversies among clinicians. On the one hand, it is obvious that CA should be performed in patients with persistent symptoms in spite of optimal medical therapy (OMT) or when no- invasive tests suggest high risk conditions and coronary revascularization is judged to be feasible; on the other hand, the probability that no stress test can be performed is rather remote and the notion that patients should undergo CA in case of negative non-invasive testing if the suspicion of CAD remains high is difficult to accept as, for instance, the negative predictive value of computed tomography coronary angiography is very high.²

2) Chelation Therapy to Reduce Risk of MI and Death: Compared to the main document, the focused update advanced the recommendation for chelation therapy with disodium ethylene diamine tetraacetic acid (EDTA) to improve prognosis in patients with SIHD from class III to class IIb (LoE B). This recommendation is based on the results of a single randomized trial with several limitations.³ This trial randomized 1,708 patients with SIHD and a history of recent or old myocardial infarction (MI) to receive 40 intravenous infusions of disodium EDTA or placebo over a period of about 12 months. At a mean follow-up of 55 months, the primary endpoint (a combination of death, re-infarction, stroke, coronary revascularization or hospitalization for angina) occurred in 26% of EDTA and 30% of placebo groups (hazard ratio 0.82; p = 0.035). The hard secondary endpoint of cardiovascular death, re-infarction and stroke rate, however, did not differ between the two groups (11% vs. 13%, p = 0.22), as well as rate of single hard endpoints. Furthermore, the study was initially designed to enroll 2,372 patients, but the authors were subsequently obliged to review the sample size due to a low rate of enrollment, and about one third of patients discontinued the study treatment in both groups. Thus, although some benefit seems to derive from EDTA therapy, the complexity of the data do not seem to encourage the inclusion of this therapy among treatments to prevent MI and death in SIH patients.

3) Enhanced External Counterpulsation for Relief of Symptoms in Patients With Refractory Angina: After re-examining medical literature, the authors confirm the Class IIb indication (LoE B) for EECP in the treatment of refractory angina. This indication is supported by the large number of patients included in clinical registries, which reported a striking improvement in symptom severity.⁴ Yet, controversial results were reported in the two small randomized trials hitherto published. In one study, indeed, Braith et al. showed a significant reduction in angina functional class, number of angina episodes and nitrate consumption with EECP, compared to sham treatment.⁵ In contrast, the Multicenter Study of Enhanced External Counterpulsation (MUST-EECP) failed to find statistically significant differences between EECP and sham treatment with regard to number of angina episodes and nitroglycerin consumption, despite an improvement of exercise tolerance with the active treatment.⁶ Thus, although the recommendation is appropriate, it should be taken into account that the quality of the evidence is weak and that side effects of EECP are bothersome and not infrequent.

4) Coronary Revascularization to Improve Survival: Two relevant changes in this focused update concern recommendations about coronary revascularization for improving survival. First, a new Class I recommendation is that a heart team approach to revascularization in patients with diabetes mellitus and complex multivessel CAD (LoE C) should be followed. There is no evidence at present time that a heart team approach is superior to the judgment of an expert clinician in guiding management in patients with IHD, and recent data, in fact, do not suggest that this approach offers substantial benefits.⁷ Nevertheless, a heart team approach seems important due to the increasing number of therapeutic options (not always directly compared in clinical trials) and to the increasing number of old complex patients who are not enrolled in trials; thus, a thorough discussion among experts is mandatory in order to identify the most appropriate form of treatment in the individual patient. Of note, the heart team should be composed not only by an interventional cardiologist and a cardiac surgeon, as this focused update seems to suggest, but also by a clinical cardiologist and, when required, by other experts in specific medical fields.

Second, the Class IIa recommendation that coronary artery bypass grafting (CABG) should be preferred to a percutaneous coronary intervention (PCI) for improving survival in diabetic patients with multivessel CAD has been promoted to Class I recommendation (LoE B). This upgrade is mainly based on the results of the SYNTAX trial, that compared drug eluting stent (DES)-PCI with CABG in stable patients with multivessel CAD or left main (LM) coronary disease,^8,9 and of the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial, that compared DES-PCI with CABG in diabetic patients with stable multivessel CAD.¹⁰ While the choice to prefer CABG over PCI-DES is, indeed, supported by current evidence, it is worth noting that no study has hitherto demonstrated any additional benefit on survival of DES-PCI vs OMT in patients with SIHD. Indeed, although recent network meta-analyses suggested a survival benefit with third generation DES-PCI vs. OMT,¹¹ this statistical approach of indirect comparisons of treatments presents several limitations,¹² while standard high-quality meta-analyses of randomized controlled trials (RCTs) have consistently confirmed the lack of survival benefit by PCI, independently of the type of stent.¹³ It is also worth mentioning that while old CABG studies have shown some benefits over medical therapy in specific subgroups of patients, including those with left main disease, with three-vessel disease and depressed left ventricular function or with multivessel disease involving proximal LAD artery,¹⁴ recent data have questioned the advantages of CABG on OMT even in high-risk patients, likely due to the considerable improvement in secondary prevention.¹⁵ Unfortunately, both Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) and FREEDOM trials lack a medical group arm for comparison.^8,10

References

1. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/ SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012;60:e44-e164.
2. Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med 2008;359:2324-36.
3. Lamas GA, Goertz C, Boineau R, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA 2013;309:1241—50.
4. Lawson WE, Hui JC, Lang G. Treatment benefit in the enhanced external counterpulsation consortium. Cardiology 2000;94:31-5.
5. Braith RW, Conti CR, Nichol WW, et al. Enhanced external counterpulsation improves peripheral artery flow-mediated dilation in patients with chronic angina. A randomized sham-controlled study. Circulation 2010;122:1612-20.
6. Arora RR, Chou TM, Jain D, et al. The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol 1999;33:1833-40.
7. Chu D, Anastacio MM, Mulukutla SR. Safety and efficacy of implementing a multidisciplinary heart team approach for revascularization in patients with complex coronary artery disease. an observational cohort pilot study. JAMA Surg 2014;149:1109-1112.
8. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961—72.
9. Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year followup of the randomised, clinical SYNTAX trial. Lancet 2013;381:629—38.
10. Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367:2375—84.
11. Windecker S, Stortecky S, Stefanini GG, et al. Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis. BMJ 2014;348:g3859.
12. Mills EJ, Thorlund K, Ioannidis JPA. Demystifying trial networks and network meta-analysis. BMJ 2013;346:f2914.
13. Stergiopoulos K, Brown DL. Initial coronary stent implantation with medical therapy vs medical therapy alone for stable coronary artery disease: meta-analysis of randomized controlled trials. Arch Intern Med 2012;172:312-319.
14. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 1994;344:563-70.
15. Velazquez EJ, Lee KL, Deja MA, et al. Coronary-artery bypass surgery in patients with left ventricular dysfunction. N Engl J Med 2011;364:1607-16.

Keywords: Angina Pectoris, Chelation Therapy, Coronary Angiography, Coronary Artery Bypass, Coronary Artery Disease, Counterpulsation, Diabetes Mellitus, Drug-Eluting Stents, Edetic Acid, Ethylenes, Exercise Test, Exercise Tolerance, Follow-Up Studies, Hospitalization, Infarction, Infusions, Intravenous, Myocardial Infarction, Nitroglycerin, Percutaneous Coronary Intervention, Prognosis, Proliferating Cell Nuclear Antigen, Secondary Prevention, Stroke, Surgeons, Thoracic Surgery, Tomography, Ventricular Function, Left

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