1.1 PCI for QoL in Stable Ischemic Coronary Artery Disease

These proceedings summarize the educational activity of the 16th Biennial Meeting of the International Andreas Gruentzig Society held January 31-February 3, 2022 in Punta Cana, Dominican Republic

Faculty Disclosures     Vendor Acknowledgments

2022 IAGS Summary Document

Statement of the problem or issue

Elective PCI was embraced for many years as a means of reducing risk of serious adverse cardiovascular events among patients with SIHD. To test this hypothesis, multiple randomized clinical trials (RCTs) comparing optimal medical therapies (OMTs) against OMT+PCI were conducted over several decades, initially hoping to demonstrate the extent of presumed benefit with PCI. Instead, these RCTs found, with reasonable consistency, that patients with SIHD do just as well with OMT alone as with OMT+PCI, at least for several years. As these trials were completed, concern then turned toward the risks associated with PCI: did premature use of PCI expose patients to the possibility of harm unnecessarily? ­Consistent with findings from earlier trials, the most recent relevant RCT, the ISCHEMIA trial (Maron, 2020),¹ found that an initial strategy of OMT yielded similar rates of a composite adverse outcome as an initial strategy of PCI, over an average follow-up of more than 3 years. Most patients (77%) in ISCHEMIA had multivessel disease, and about three-fourths of patients had a screening cardiac CT scan before enrollment and were excluded if they had either no disease, very severe disease, or left main disease. Interestingly, ISCHEMIA did not find any relationship between baseline ischemic burden and the degree of benefit with invasive therapies; in fact, adverse event rates did not increase in parallel with the extent of coronary disease or ischemia in either treatment group. The takeaways from ISCHEMIA were: (1) early use of PCI in the enrolled SIHD patients did not lower risk of aggregated ischemic events; (2) early use of PCI was not associated with increased risk of meaningful harm, although PCI uniquely exposes patients to risk of procedural MIs; and (3) neither the extent of coronary disease nor the ischemic burden defined by stress testing helped identify patients who might be best suited for an invasive care plan. The ability of PCI to improve QoL more than medical therapies alone has also been called into question: the ORBITA trial (Al-Lamee, 2018)² found PCI offered no improvement in exercise tolerance among SIHD patients with single-vessel coronary artery disease receiving OMT. Contrary to ORBITA, ISCHEMIA found QoL was improved with early use of PCI, although the benefit was largely seen among patients with frequent angina at baseline (Spertus, 2020).³ The safety of an initial conservative approach, coupled with questions about the ability of PCI to enhance QoL consistently, has led some to suggest that a symptom-driven care pathway, developed without any anatomic or physiologic studies and which reserves use of PCI for only those patients with refractory symptoms, is preferable to an ischemia-based or anatomy-based approach, since practitioners won’t be tempted to reach for PCI if they are worried by the diagnostic study findings (Mancini and Boden, 2020).⁴ So, is this a reasonable way to approach SIHD patients?

Gaps in knowledge

Left main disease was found in approximately 5% of those screened for enrollment in ISCHEMIA. If these patients are at higher risk with medical therapies alone, and therefore deserving of consideration for revascularization (the pretext for excluding them from randomization in ISCHEMIA), then reliance solely on symptoms may put a small but not insignificant number of patients at unnecessary risk. On the other side, about 18% of screened ISCHEMIA patients were found to have no obstructive coronary artery disease by cardiac CT; so, exposure to cardiac medications, likely to be ratcheted up as noncardiac symptoms fail to improve, offers risk without benefit. In other words, the safety of a care plan that relies on no anatomic or physiologic data is undefined. Also undefined is the optimal utility of PCI in reducing the frequency and intensity of angina among patients with multivessel disease who improve with medications but are still having occasional angina. In this regard, it’s worth noting that ISCHEMIA found reductions in angina frequency with early PCI even among patients with angina occurring only a few times per month, and of course clinical experience suggests PCI is useful in this type of patient. Should patients be required to endure activity-limiting ischemic symptoms as their medications are maximized, when PCI might restore them to full or nearly full function with fewer daily medications? Finally, the observation from ISCHEMIA that spontaneous myocardial infarction rates are reduced if PCI is used early in the care plan for SIHD, raises questions about whether early invasive therapy, coupled with guideline-directed medical therapies, may offer benefits that lie beyond angina relief.

Possible solutions and future directions

Additional RCTs in the future for this patient population seem unlikely at this time, but if one is undertaken, the aims and endpoints of the RCT should change. The question is no longer whether an initial strategy of medical therapies alone offers sufficient safety (as measured by composite ischemic endpoints), or whether PCI is potentially too hazardous to use early. The question is: how can PCI be best incorporated into a comprehensive care plan, based on a background of OMT, to optimize clinical outcomes including QoL over a long time period. ISCHEMIA, the largest and most contemporary RCT on this topic, found no increased harm with a strategy of early invasive care for SIHD patients, and it holds the possibility for benefit evolving after 24 months or so, but with the caveat that PCI exposes patients to the risk of early periprocedural MIs. Periprocedural MIs have not been associated with the same degree of morbidity or mortality as spontaneous MIs; nonetheless, a periprocedural MI is an MI, so a blunt instrument for measuring events will find fault with an early invasive strategy. MI definitions with appropriate sensitivity and specificity, and that stratify by MI type, can minimize this problem, which is the reason for the definitions used in the ISCHEMIA trial. Advocates for conservative care have complained that more sensitive MI definitions would have ruled PCI more hazardous than the conservative care plan. While this concern has been thoroughly reviewed by the ISCHEMIA trial workgroup (Chaitman, 2021),⁵ the debate over appropriate thresholds for capturing procedural MIs remains ongoing. Defining how MI thresholds of varying sensitivity correlate with clinical outcomes (including QoL measures), and not just event rates, would be a suitable focus area for future trials. Intriguingly, ISCHEMIA found a reduction in the occurrence of spontaneous MIs with early use of invasive therapy during 3 years of follow-up. While not definitive, this observation raises the possibility that performing early PCI may mean accepting the risk of less perilous periprocedural MIs in exchange for fewer higher-risk spontaneous MIs later. Perhaps one unintended consequence of ISCHEMIA is the re-energized focus on cardiac CT. The spatial and temporal resolution of modern cardiac CT scanners has improved substantially over older models. While the ISCHEMIA trial was enrolling patients, cardiac CT-FFR methods were perfected and then made commercially available. It seems likely that going forward, despite the lack of correlation found between disease severity or ischemic burden and outcomes found in ISCHEMIA, clinicians will base their recommendations according to those clinical features that have always been trusted indicators of risk, and which are biologically plausible as being related to risk. For this reason, a symptom-driven care plan is unlikely to dominate, but a gradual shift away from traditional electrocardiographic, echocardiographic, or nuclear-based diagnostic cardiac testing and toward a more cardiac CT-based testing approach is expected.

References

1. Maron DJ, Hochman JS, Reynolds HR, et al. Initial invasive or conservative strategy for stable coronary disease. N Engl J Med. 2020;382(15):1395-1407. Epub 2020 Mar 30. doi:10.1056/NEJMoa1915922

2. Al-Lamee R, Thompson D, Dehbi HM, et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomized controlled trial. Lancet. 2018;391(10115):31-40. doi:10.1016/S0140-6736(17)32714-9

3. 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(15):1408-1419. Epub 2020 Mar 30. doi:10.1056/NEJMoa1916370

4. Mancini GB, Boden WE. Diagnostic implications in the aftermath of the ISCHEMIA trial. Am J Cardiol. 2020;125(9):1438-1440. Epub 2020 Feb 12. doi:10.1016/j.amjcard.2020.01.039

5. Chaitman BR, Alexander KP, Cyr DD, et al. Myocardial infarction in the ISCHEMIA trial. Circulation. 2021;143(8):790-804. doi:10.1161/CIRCULATIONAHA.120.047987