Improving Symptoms and Quality of Life in Stable Coronary Artery Disease

An Evolving Paradigm

Krishna K. Patel, MD, MSc


Circulation. 2022;145(16) 

Key goals of treatment in patients with coronary artery disease (CAD) are to mitigate disease progression and reduce future adverse cardiac events so the patient can live longer, and to reduce symptom burden and improve their functional status and quality of life so the patient can feel better. Clinical trials often place more emphasis on evaluating mortality and adverse cardiovascular outcomes, deprioritizing quality of life and health status outcomes, which are important to the patients. When patients are asked to choose between survival versus quality of life, a quarter to two-thirds are willing to trade off some duration of survival in exchange for a better quality of life.[1,2] In this regard, the ISCHEMIA trial investigators are to be commended for including health status assessment as a key outcome for all patients enrolled in the trial using a short form of the Seattle Angina Questionnaire (SAQ-7), results of which have been extensively discussed since the publication of the trial results.[3] In contrast to the Canadian Cardiovascular Society angina classification system, which relies on subjective and variable assessment of anginal symptoms and functional status of the patient by clinicians,[4] the SAQ was designed to be a self-administered standardized questionnaire that captures the burden of angina on 5 domains of health status from a patient perspective: physical limitation, angina frequency, quality of life, anginal stability, and treatment satisfaction.[5] Although the SAQ is specific to angina, other domains of health status such as general physical and emotional function, depression, and stress are also important to the patients. In this issue of Circulation, the ISCHEMIA investigators present a detailed report of quality of life outcomes collected in 1819 of 5179 patients enrolled in the parent trial.[6] The authors provide a rich and broad assessment of patient-reported outcomes that capture diverse aspects of quality of life that are important from a patient perspective, including the disease-specific 19-item SAQ and many other general health status measures.

These results expand our understanding of the role of revascularization in stable CAD as it relates to angina relief and improvement of quality of life. In the CASS study (Coronary Artery Surgery Study), where medical therapy was underused, 66% of the patients randomized to bypass surgery were angina-free at 1 year compared with 30% in the medical therapy group, a difference that persisted at 5 years of follow-up.[7] In BARI-2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes), nearly half of the patients with diabetes and stable CAD were angina-free 1 year after revascularization compared with a quarter of patients in the medical therapy arm.[8] With improvements in medical therapy over time, the difference in symptom benefit between revascularization and medical therapy narrowed. In COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation), patients randomized to percutaneous coronary intervention had an early improvement in symptoms starting at 1 month, and by 12 months, 57% of patients in the revascularization group were angina-free compared with 50% in the optimal medical therapy arm.[9] However, more recently, there was no difference in SAQ angina frequency score or treadmill exercise time among patients with percutaneous coronary intervention versus the placebo-control group among patients with stable angina and severe single-vessel disease in the ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina),[10] although a later analysis showed greater freedom from angina among patients randomized to percutaneous coronary intervention.[11] These trials included patients across the spectrum of physiological severity. Given that increase in coronary flow after revascularization is believed to be the primary mechanism driving the improvement in symptoms, it is conceivable that patients with significant amounts of myocardium jeopardized by ischemia may have greater improvement in symptoms with revascularization. The results of the ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches)[3] and the present quality of life substudy[6] validate this hypothesis, showing greater improvement in angina and quality of life with invasive compared with conservative management in patients with stable CAD and moderate to severe ischemia on testing. As expected, this benefit in health status was a function of symptom burden at baseline, being primarily driven by patients who had more frequent symptoms at baseline.

The present substudy included only a third of the overall trial population because of poor participation from sites outside of North America. This further underscores the need for the scientific community to prioritize collection of patient-reported outcomes as key end points for clinical trials to facilitate insights on outcomes that are valuable to our patients. Nevertheless, the study provides critical insights. All SAQ subdomains followed the pattern of the SAQ summary score (SS) seen in the overall trial, with an improvement in each subdomain with invasive strategy, but only among patients who were symptomatic at baseline. No between-group differences were seen in other health status outcomes except the SAQ. An important observation from this study is the large temporal improvement in symptom and health status seen in the conservative strategy arm, a difference that is significantly larger than the between-group differences. At 12 months, the conservative arm had a mean improvement in SAQ SS of 9 points from baseline versus 12 points in the invasive arm. In contrast, the largest mean difference in SAQ SS between the 2 treatment groups was 2.3 points at 12 months. What does this mean clinically? Each SAQ domain and the SS are scored from 0 to 100, with higher scores indicating fewer episodes of angina, fewer physical limitations caused by angina, and better quality of life. A change of ≈3 points in the SAQ SS requires only a 1-item shift in response of 1 or 2 of the 19 questions asked in the SAQ (eg, change in angina frequency from 1 to 2 times/week to <1 time/week without change in frequency of nitrate use or a change from moderate to slight limitation of enjoyment).[12] In general, a 5-point change in SS is associated with between 2 to 6 shifts in response on the 19-item SAQ and is considered clinically meaningful.[12] As such, the average benefit of 2.3 points in SS between the 2 arms is much smaller than the within-group improvement in scores in both the study arms. Although the rate of prescription of β-blockers and calcium channel blockers were similar in both invasive and conservative groups throughout the trial, patients in the conservative arm were much more likely to have other anti-anginal medications added to their regimen starting in the first 1 to 3 months, whereas this rate remained constant with a slight decrease over time in the invasive strategy arm.[13] This highlights the crucial role of aggressive anti-anginal medication titration in improving symptoms and quality of life. Also, although the improvement in health status plateaued after 12 months in the invasive arm (≈88), there were steady small improvements in health status over time beyond 12 months in the conservative arm, which contributed to the attenuation in between group differences in SAQ over time. The extent to which the late improvements in health status in the conservative group were from late revascularization, spontaneous myocardial infarction, or optimal anti-anginal titration remains to be seen.

It is also important to note that these changes in SAQ are average treatment effects across the population and combine effect sizes from patients who may have had much larger improvements with those who may have no change or worsening of health status. The responder analyses included in the article by the authors partially address this issue by framing these results in terms of magnitude of improvement in health status. Heterogeneity of treatment effect analyses that identify the clinical characteristics of individual patients who gain large improvements in health status versus those who do poorly can further enhance the applicability of these results for shared decision making with our patients.

These results further cement the key role of symptom assessment in guiding management of patients with chronic, stable CAD. However, patient selection is key. One in 4 patients in ISCHEMIA had persistent symptoms at 12 months after revascularization. Angina is a complex and multifactorial phenomenon influenced by sympathetic dysfunction, psychosocial factors such as stress, inappropriate pain perception, and compromised blood supply to the myocardium. As a result, it has been challenging to demonstrate a relationship between symptoms and ischemia, although recent reports suggest a link between sensitive physiological measures that quantitate myocardial blood flow and health status.[14] Although ISCHEMIA focused on treatment of epicardial atherosclerotic coronary disease, it frequently coexists with disease affecting the coronary microvasculature, which contributes to myocardial ischemia and may help explain why some patients remain symptomatic after revascularization. In stable CAD, the primary effect of revascularization is in decreasing the extent and severity of ischemia,[15] with the greatest benefit seen in patients with more severe ischemia at baseline.[11] Functional testing helps determine ischemia as the cause of symptoms. As such, a combination of ischemia testing and symptom assessment may be able to optimally identify patients with epicardial disease who receive a health status benefit with revascularization (Figure), a hypothesis that is being tested in the ORBITA-2 trial.


Proposed algorithm for management of stable coronary artery disease (CAD).
Cath indicates catheterization.

The fundamental goal of treatment in CAD is to improve patient symptoms, function, and quality of life. The ISCHEMIA trial teaches us that medical therapy is very effective in making our patients feel better. Revascularization provides an incremental benefit, particularly among patients with significant symptom burden despite receipt of optimal medical therapy. Following the lead of the ISCHEMIA investigators, incorporating routine collection of patient-reported outcomes as key end points for clinical trials will be a major step toward provision of patient-centered care.