Practical Cardiovascular Medicine. Elias B. Hanna

either non-cardiac pain or residual, non-revascularized disease. The same applies to patients with prior CABG (graft disease instead of in-stent restenosis). Repeat the coronary angiogram if typical angina occurs on mild exertion.

      Warranty periods

      When should stress testing be repeated in patients with prior negative studies who present with chest pain? Stress tests have “warranty periods” during which the risk of cardiovascular events is low (<1% per year) and during which there is no need to perform a coronary angiogram unless the patient has objective evidence of new CAD, such as ACS with positive cardiac markers or new, severe ischemia on the ECG.

      This “warranty period” of a stress test varies according to the context, and is generally 1-2 years, less so for pharmacological testing, older age (>70-80), CAD history, or uncontrolled risk factors.²⁶

      When a coronary angiogram shows normal coronary arteries or minimal disease, the risk of coronary events is low for 5 years, and unless there is evidence of MI, the angiogram is not usually repeated within the next 5 years. As per the CASS registry, the 7-year survival is 96% for patients with normal EF and normal coronaries and 92% for patients with mild coronary disease <50% (much better prognosis than obstructive CAD).²⁷

      How about patients who had a coronary angiogram showing single- or multivessel moderate disease (30–70%), or showing severe disease (>70%) in a small branch where PCI is not beneficial? If they present with recurrent or persistent chest pain a few months or 1–2 years later, the coronary angiogram may not need to be repeated unless there is an ischemic ST abnormality, a positive troponin, or a dramatic change in the severity of a typical, exertional angina. Also, the true functional significance of moderate stenoses (50–70%) is worth assessing with stress imaging or FFR.

      Patients with moderate stenoses that are insignificant by FFR have a very low risk of MI from each individual stenosis, yet the summation risk of MI from all nonsignificant lesions is not negligible, ~1.5% per year (FAME 2 trial).²⁸

      These “warranty periods” are used for guidance; ultimately, decisions are based on clinical judgment.

F. Putting it together: diagnostic approach and management of chronic chest pain (Figure 3.2)

Figure 3.2 Proposed diagnostic approach to chronic chest pain. Note that CTA has gained a central role in high CAD probability and high-risk patients, including high-risk stress test, thanks to ISCHEMIA trial. The main goal of CTA in high-risk patients is to rule out left main disease, in which case conservative management is acceptable. The only exception is CKD (GFR<60), wherein stress imaging is preferred for diagnosis, keeping in mind that even a high-risk result is appropriately managed conservatively with no angiographic assessment at all. The solid arrows indicate the preferred strategy.

III. Silent myocardial ischemia. Is there a role for screening asymptomatic patients and post-PCI patients?

      A totally silent severe myocardial ischemia is uncommon (10- 15% of CAD). The more common form of silent myocardial ischemia consists of silent ischemia interspersed with symptomatic ischemia, such as angina or prior MI. Even if asymptomatic, ischemia is a strong predictor of cardiac events and mortality and may have the same prognostic significance as symptomatic ischemia.²⁹

      However, revascularization does not modify this prognosis, and screening asymptomatic patients based solely on risk factors is not indicated, nor is screening of post-PCI patients indicated. In the DIAD study, asymptomatic diabetic patients, who constitute a relatively

high-risk population, were screened for CAD with nuclear stress imaging. These asymptomatic patients actually had a low risk of cardiac events (0.6% per year), and while this risk was higher in the small subgroup of patients with moderate or severe ischemia (2.5% per year), 70% of events eventually occurred in patients with normal testing. In fact, a 0.6% event rate in 90% of the population leads to more total events than a 2.5% event rate in 10% of the population. Even if revascularization reduces the risk of late MI in this small subgroup, the benefit is nullified by the periprocedural risk of MI and by the risk of unnecessary diagnostic angiograms in patients with false positive stress tests. This explains why the event rate was similar in the screened and non-screened diabetic populations. Thus, stress testing is not generally useful in asymptomatic patients, even those at seemingly high risk, particularly if risk factors and hemoglobin A1c are well controlled (as in the DIAD study).³⁰ These findings were corroborated by another study, wherein asymptomatic diabetic patients were randomized to coronary CTA screening vs. routine care. Coronary CTA found significant CAD (>70% stenosis) in 11% of patients and resulted in a 6% revascularization rate, which did not translate into any reduction of death, MI, or unstable angina (FACTOR-64 study).³¹ Moreover, the following 3 ideas argue against testing and stenting asymptomatic patients:

       ~75% of MIs arise from a plaque that was not obstructive (<50%) on a recent CT or coronary angiography (within the last couple of years).³² This is particularly true if the patient is asymptomatic, even more so if asymptomatic despite being active.

       Atherosclerotic burden, as assessed by CT calcium scoring, is at least as good a predictor of coronary events as the presence of obstructive CAD. Stenting does not modify this major driver of outcomes, i.e., plaque burden.³³

       Occlusion of a stenosis>70% is far less likely to cause a large MI than occlusion of mild disease (30% vs. 75% likelihood), and far more likely to be preceded by angina as first presentation (70%). This is because chronic collaterals reduce infarct size in the former. Thus, seeking stenoses >70% is seeking the less deadly disease.³⁴

      The only valuable test in asymptomatic patients is CT calcium scoring, a powerful risk stratifier that dictates more aggressive risk factor modification, not revascularization. If stress testing is done in asymptomatic patients, the detection of severe ischemia would lead to revascularization only in extensive CAD, mainly left main disease.

      Silent ischemia 6 months after PCI, even if severe, is not clearly associated with increased death or MI. In-stent restenosis is asymptomatic ~50% of the time, in which case the prognosis is very good; routine angiographic follow-up and PCI of asymptomatic in-stent restenosis does not improve outcomes compared to angina-driven PCI.³⁵

IV. Medical therapy: antiplatelet therapy

      While the combination of aspirin and clopidogrel is beneficial for up to 1 year after MI or stent placement, this combination has not shown superiority to aspirin monotherapy in stable CAD and peripheral vascular disease (CHARISMA trial). However, in a substudy of CHARISMA, patients with prior MI appeared to derive a benefit from prolonged combination therapy for up to 28 months, especially if they had disease in multiple vascular locations (e.g., MI and PAD).³⁶ In monotherapy, clopidogrel is an alternative to aspirin and may be slightly superior in reducing coronary and cerebrovascular events with a slightly lower risk of GI bleed.³⁷

      Patients with CAD who also have an indication for anticoagulation (AF or a history of DVT) are best treated with standalone anticoagulation beyond 1 year of MI or coronary stenting (warfarin or NOAC). Anticoagulation, per se, effectively reduces coronary events, as in the modern AFIRE trial using rivaroxaban;³⁸ in older trials, warfarin monotherapy or warfarin–aspirin combination was more effective than aspirin in preventing coronary events, at the cost of a higher bleeding risk.³⁹

V. Medical therapy: