A 60-year-old man with known chronic coronary artery disease (CAD) is referred to you because of an abnormal stress test. He has a history of angina beginning 3 years ago, at which point he had coronary angiography. This demonstrated a 60% mid-left-interior-descending stenosis (Figure 1) and fractional flow reserve of 0.85. He had other lesions in the right coronary artery and circumflex artery that were less than 50%. It was elected to treat him medically at that time, and his antianginal medications were intensified. His angina abated, and he has been feeling well on medical therapy. He exercises 30 minutes 4-5 times per week with no limitations. He has presumed familial hypercholesterolemia; two of his children and one grandchild have significantly elevated lipids (low-density lipoprotein cholesterol [LDL-C] > 200 mg/dl). His father died of a myocardial infarction at age 50. The patient has hypertension but no history of diabetes mellitus, cigarette smoking, obesity, or sedentary lifestyle. His current medications include atorvastatin 80 mg, ezetimibe 10 mg, aspirin 81 mg, bisoprolol 10 mg, amlodipine 5 mg, and perindopril 8 mg, all daily.
Figure 1
He recently had an exercise stress test as part of an executive evaluation. He walked for 9 minutes on a Bruce protocol and achieved a maximum heart rate of 140 bpm and blood pressure of 155/70 mm Hg. He had no chest pain, and there was 1.5 mm ST depression in the third stage in his inferolateral leads. This recovered within 2 minutes of exercise cessation. He has a normal physical examination with a body mass index of 26 kg/m2. He has LDL-C of 3.5 mmol/L (135 mg/dl), high-density lipoprotein cholesterol of 1.1 mmol/L (42 mg/dl), glycated hemoglobin of 5.9%, and estimated glomerular filtration rate > 60 ml/min/1.73m2.
What feedback is appropriate for this gentleman at this time?
Show Answer
The correct answer is: E. Ongoing optimal medical therapy with consideration of the addition of proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors without further testing would be appropriate.
It is well known that there is a disconnect between angina symptoms and the documentation of ischemia. The article by Steg et al. again reminds us of this in a large cohort of subjects with chronic CAD.1 Although the majority of patients had neither ischemia nor angina, there were equal numbers of subjects with angina alone, ischemia alone, or both. Thus, answer A is not correct.
The presence of ischemia without symptoms in someone with good exercise tolerance and quality of life would not necessarily dictate the need for invasive evaluation.2 It is known that the burden of ischemia is an important prognostic indicator for adverse events, but it is not clear that treatment of the ischemia beyond medications reduces this risk. This is best demonstrated in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial, in which subjects with demonstrated obstructive disease by angiography did not have a reduction in events with a strategy of mandated coronary intervention.3 The ongoing ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) will study this question based on the presence of ischemia where the coronary anatomy has not been defined.4 However, current guidelines would support a medical strategy for this patient. Thus answer B is not completely correct either.
The Steg et al. article highlighted the fact that angina with or without ischemia was a higher risk condition than having neither or ischemia alone. Based on this, answer C is not correct.
Routine noninvasive testing has not been shown to be an effective method to reduce cardiovascular (CV) events. One might argue that this patient is unique because he has documented ischemia with known CAD. A decrease in exercise tolerance, earlier ST segment shift, or blood pressure abnormalities might portend a change in his coronary status. However, the patient's continued ability to exercise on a daily basis without a change in his symptoms is likely an effective metric of his status. In the 2012 American College of Cardiology and American Heart Association guidelines for stable ischemic heart disease, yearly testing in someone with known silent ischemia is only a Class IIb indication.2 I would agree that further testing would be more appropriate for a change in status as opposed to a yearly routine. Thus, answer D is not quite correct either.
Optimal medical therapy is the backbone of chronic CAD therapy. This patient is on good prevention and anti-ischemic therapy. He has probable familial hypercholesterolemia based on his history. His LDL-C remains much higher than current guidelines. Given the recent approval of both evolocumab and alirocumab in the United States, Canada, and Europe, this is the type of patient who would be considered for the addition of a PCSK9 inhibitor to his current regime.5 Thus, until further information is available from ISCHEMIA, answer E is the most appropriate.
Discussion
The article by Steg et al. demonstrated several important points for subjects with chronic CAD. CLARIFY (Prospective Observational Longitudinal Registry of Patients With Stable Coronary Artery Disease) enrolled subjects with documented CAD, previous revascularization, or documented myocardial infarction. In a cohort of over 32,000 subjects, more than 20,000 had a noninvasive test of ischemia within the previous year. The median time since diagnosis of CAD was approximately 5 years. Patients were enrolled from 45 countries but not the United States. More than 80% of the patients had no angina, and only 25% had documented ischemia. The majority of patients had neither angina nor ischemia. After correcting for traditional risk factors or the Reduction of Atherothrombosis for Continued Health (REACH) risk score,6 angina was found to be an important predictor of recurrent CV events. The combination of angina and ischemia carried the highest risk, but ischemia alone did not increase risk.
Take home messages from the Steg et al. article and this illustrative case include the following:
Noninvasive testing remains very common (>60% of the cohort) despite the fact that guidelines tend to reserve recommendation for those with a change in symptom status. Because 80% of the cohort did not have angina, we could assume that a large portion of the testing was routine and probably outside of current guidelines.7
Ischemia alone did not increase the risk of adverse CV events. There is extensive evidence suggesting that the burden of ischemia is a risk marker for adverse events, but this was not borne out in the current analysis. In addition, revascularization in subjects with documented CAD and ischemia did not reduce CV events in the COURAGE trial.3 The COURAGE trial assumed knowledge of the coronary anatomy, but this was the case for the majority of subjects in CLARIFY. As such, one could argue that there was probably little justification for the majority of noninvasive testing in this population.
Angina was a powerful predictor of recurrent CV events in the cohort, especially when coupled with ischemia. As has been outlined in the guidelines, recurrent testing or revascularization is most appropriate in subjects with symptoms. In addition, medical therapy in chronic CAD remains very important, particularly in subjects with angina even in the absence of ischemia. The patient in this case was on optimal medical therapy except for the treatment of his dyslipidemia. The recent introduction of the PCSK9 inhibitors will allow us to achieve LDL-C treatment target and improve medical therapy. The controversial American College of Cardiology and American Heart Association dyslipidemia guidelines have been recently updated to include a recommendation about non-statin medications driven by data from recent randomized clinical trials.8
There is still clinical equipoise for patients who have angina and ischemia documented by noninvasive testing.4 This was not addressed by Steg et al. Currently, the majority of these patients do undergo angiography (invasive or, less often, computed tomography coronary angiography) to define anatomy and treatment options. However, given the lack of clear data demonstrating benefit of revascularization in stable CAD patients, it is logical to ascertain if medical therapy without catheterization is an appropriate approach. ISCHEMIA is currently enrolling subjects and will be an important study to determine the optimal diagnostic approach to subjects with stable angina. It will be interesting to see if the interaction between symptoms and ischemia as reported by Steg et al. is reproduced in ISCHEMIA.
References
Steg PG, Greenlaw N, Tendera M, et al. Prevalence of anginal symptoms and myocardial ischemia and their effect on clinical outcomes in outpatients with stable coronary artery disease: data from the International Observational CLARIFY Registry. JAMA Intern Med 2014;174:1651-9.
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.
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.
Stone GW, Hochman JS, Williams DO, et al. Medical Therapy With Versus Without Revascularization in Stable Patients With Moderate and Severe Ischemia: The Case for Community Equipoise. J Am Coll Cardiol 2016;67:81-99.
Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.
Wilson PW, D'Agostino R Sr, Bhatt DL, et al. An international model to predict recurrent cardiovascular disease. Am J Med 2012;125:695-703.e1.
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: 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.
Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016 Mar 28 [Epub ahead of print].
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