Authors: Nima Moghaddam MD (biography, no disclosures), Christopher Cheung MD (biography, no disclosures) and Kenneth Gin MD (biography and disclosures) Disclosures: Research for Bayer, Ad board Bayer, BI, Pfizer. Mitigating potential bias: Only published trial data is presented. Recommendations are consistent with current practice patterns.
What care gaps or frequently asked questions I have noticed
Stable ischemic heart disease, or more recently termed chronic coronary syndrome, is generally defined as an established pattern of angina or anginal equivalents in the presence of either risk factors for or known atherosclerotic cardiovascular disease 1. The debate over the optimal management in stable ischemic heart disease has grown over the past decade with more evidence supporting a conservative medical therapy approach over an upfront invasive strategy with coronary revascularization. However, there remains significant practice variation in deciding when to pursue coronary revascularization.
Coronary revascularization has been compared with optimal medical therapy (OMT) in several landmark randomized controlled trials. In 2007, the COURAGE trial compared a strategy of revascularization with percutaneous coronary intervention (PCI) versus aggressive medical therapy in patients with stable coronary artery disease (CAD) 2. The composite outcome of death and non-fatal myocardial infarction (MI) was no different between the PCI and medical therapy groups (19.0% vs. 18.5%, p=0.62). There was a slight reduction in angina among those revascularized, but patients were not blinded to the intervention.
Some critics argued that COURAGE did not include patients with severe ischemia or high-risk features, as patients with CCS class IV angina, markedly positive exercise stress tests (substantial ST depression or hypotensive response in Stage 1 Bruce protocol), refractory heart failure or cardiogenic shock, and severe left ventricular (LV) dysfunction (ejection fraction [EF] <30%) were excluded. Additionally, the findings of COURAGE trial pre-dated the widespread use of drug-eluting stents.
Almost one decade later, the ORBITA trial compared PCI to a sham procedure in patients with stable angina and single-vessel CAD 3. In the ORBITA trial, contemporary PCI with drug-eluting stents did not significantly improve exercise tolerance or reduce anginal frequency compared to a sham procedure, despite the presence of anatomically significant stenosis and improvements in peak stress wall motion score.
Data that answers these questions or gaps
The recently published ISCHEMIA trial is the largest randomized trial of an initial invasive versus conservative management strategy for patients with stable CAD 4. ISCHEMIA enrolled 5179 patients with stable ischemic heart disease and moderate-to-severe ischemia based on abnormal imaging (nuclear, echocardiography, or MRI) or exercise stress tests 5. Among patients with an estimated GFR > 60 mL/min/1.73m2, a blinded coronary computed tomography angiogram (CCTA) was performed to exclude high-grade left main disease (≥50% stenosis). Those with severe LV dysfunction (EF < 35%) and NYHA class 3 or 4 heart failure were also excluded.
Patients were randomized in a 1:1 allocation to an invasive strategy with cardiac catheterization followed by revascularization with PCI or coronary artery bypass surgery versus a conservative strategy with optimal medical therapy. Optimal medical therapy consisted of intensive secondary prevention with lifestyle and pharmacological interventions. These included modifying behavioural risk factors (i.e. smoking cessation, regular physical activity, limiting saturated fats) and treating physiological risk factors with guideline-based medical therapy goals (SBP < 130 mmHg, LDL < 1.8 mmol/L, 10% weight loss or BMI < 25, HgbA1C < 7% or <8% in select individuals). The median age of patients was 64 years (Interquartile range [IQR]: 58 to 70), 23% were women, 42% diabetic, and median EF was 60%. Around 90% of patients had a history of angina and 54% had severe baseline inducible ischemia on stress testing.
After a median follow-up of 3.3 years (IQR 2.2 to 4.4), the composite primary endpoint including cardiovascular death, MI, heart failure, cardiac arrest, or hospitalization for unstable angina did not differ significantly between the invasive and conservative groups (13.3% and 15.5%, respectively, p=0.34). There were no differences in the primary outcome when stratified by subgroups, including diabetes, single versus multi-vessel disease, or severity of baseline ischemia. The individual components of the composite primary outcome were also similar between groups. Revascularization was significantly better than medical therapy for angina relief among patients with moderate-severe anginal symptoms at baseline (45% vs. 15% probability of no angina at 3 months) 6. However, in patients without baseline angina, revascularization had minimal symptom or quality of life benefits, compared to optimal medical therapy.
Although patients with advanced chronic kidney disease (CKD; eGFR < 30 mL/min/1.73m2) were excluded from the ISCHEMIA trial, the parallel ISCHEMIA-CKD study enrolled 777 patients with stable ischemic heart disease and advanced CKD, showing no reduction in death or MI with a routine invasive strategy compared with optimal medical therapy (HR 1.01, 95% CI [0.79 – 1.29], p-value 0.95) 7. It should be noted that no patients in ISCHEMIA-CKD underwent screening with CCTA.
What I recommend (practice tip)
From the COURAGE to ISCHEMIA trials, the first take home message is that medical therapy is safe and as effective as upfront revascularization in management of stable ischemic heart disease in the majority of patients. In ISCHEMIA, 77% of patients had multi-vessel CAD, and 87% had left anterior descending (LAD) stenosis (47% proximal LAD). Even in these high-risk patients, a routine invasive strategy did not significantly improve outcomes. If a patient experiences breakthrough or crescendo angina despite optimal medical therapy, proceeding with revascularization remains warranted, with a number needed to treat of 3 for anginal relief in ISCHEMIA. However, these findings should be interpreted with caution as this was an unblinded study, without a sham procedure. It is equally important to remember that patients with left main disease (≥50% stenosis) on CCTA were excluded from the ISCHEMIA trial, and that results of ISCHEMIA are not applicable to patients with acute coronary syndrome, significant or disabling angina, heart failure, or severe LV dysfunction.
Although CCTA was used regularly prior to randomization in ISCHEMIA, roughly one quarter of the patients in the main study and none of the patients in the ancillary ISCHEMIA-CKD study underwent CCTA. Routine use of CCTA or any single testing modality for all patients with stable ischemic heart disease was not the intention of this study. The choice of any testing strategy should be based on patient-specific factors (pre-test probability) and testing availability.
The second important implication from ISCHEMIA is that medical therapy is the cornerstone to preventing progression of underlying atherosclerotic disease. It is more imperative to manage the atherosclerotic disease process rather than the focal stenosis itself. Optimal medical therapy along with the intensive management of underlying CAD risk factors including hypertension, diabetes mellitus, smoking cessation, and lifestyle modification can substantially lower cardiovascular morbidity and mortality 6,7.
The long-term outcomes among ISCHEMIA participants remains unknown and extended follow-up studies have been planned. In ISCHEMIA, the cumulative incidence rates for both the primary endpoint and the major secondary endpoint (cardiovascular death or MI) crossed at approximately 2-years. There appeared to be fewer cardiovascular events with a conservative strategy at 6-months, but fewer events with an invasive strategy at 4 years (absolute difference of 2.2%, p=0.34). This may be due to higher rate of procedural MIs in the invasive group occurring early after randomization, but a lower rate of spontaneous MIs occurring during follow-up.
Lastly, ISCHEMIA emphasizes the role of shared decision making between physicians and patients in management of stable ischemic heart disease. Management of stable CAD should be individualized with strong emphasis on patients’ preferences and symptoms. We should be reassured that it is safe to manage most patients with stable ischemic heart disease with optimal medical therapy rather than pursuing upfront coronary revascularization.
- Knuuti J., Wijns W., Saraste A., et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: the task force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC). Eur Heart J. 2019;41(3):407–77. DOI: 10.1093/eurheartj/ehz425. (Request with CPSBC or view with UBC)
- Boden WE., O’Rourke RA., Teo KK., et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356(15):1503–16. DOI: 10.1056/NEJMoa070829. (Request from CSPBC or view with UBC)
- Al-Lamee R., Thompson D., Dehbi H-M., et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. The Lancet. 2018;391(10115):31–40. DOI: 10.1016/S0140-6736(17)32714-9. (View with CPSBC or UBC)
- Maron DJ., Hochman JS., O’Brien SM., et al. International study of comparative health effectiveness with medical and invasive approaches (ISCHEMIA) trial: rationale and design. J Am Heart Assoc. 2018; 201:124–135. DOI: 10.1016/j.ahj.2018.04.011. (View)
- Hochman JS., Reynolds HR., Bangalore S., et al. Baseline Characteristics and Risk Profiles of Participants in the ISCHEMIA Randomized Clinical Trial. JAMA Cardiology. 2019;4(3):273–86. DOI: 10.1001/jamacardio.2019.0014. (View)
- Spertus JA., Jones PG., Maron DJ., et al. Health-Status Outcomes with Invasive or Conservative Care in Coronary Disease. N Engl J Med. 2020; 382:1408-1419. DOI: 10.1056/NEJMoa1916370. (Request with CPSBC or view with UBC)
- Bangalore S., Maron DJ., O’Brien SM., et al. Management of coronary disease in patients with advanced kidney disease. N Engl J Med. 2020;0(0):null. DOI: 10.1056/NEJMoa1915925. (Request with CPSBC or view with UBC)
- Mancini GBJ., Gosselin G., Chow B., et al. Canadian cardiovascular society guidelines for the diagnosis and management of stable ischemic heart disease. Can J Cardiol. 2014;30(8):837–49. DOI: 10.1016/j.cjca.2014.05.013. (View with CPSBC or UBC)
- Fihn SD., Blankenship JC., Alexander KP., et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease. Circulation. 2014;130(19):1749–67. DOI: 10.1161/CIR.0000000000000095. (View with CPSBC or UBC)