Survival Following Recanalization of Chronic Total Occlusion: The Devil Is in the Details

Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has traditionally received intense scrutiny because of higher procedural complexity, lower success, and higher complication rates compared with non‐CTO PCI. ¹ Over the past decade, the field has witnessed notable enhancements in success rates and safety margins. Appropriately selected patients undergoing CTO PCI have demonstrated significant improvements across various parameters, including angina status, quality of life, depression, ischemic burden, and physical performance. ¹ , ² Several observational studies have previously reported that unsuccessful CTO PCI is associated with worse long‐term clinical outcomes (including mortality) compared with successful CTO PCI, but these observations are plagued by the intrinsic limitations of their nonrandomized design, which are centered on their inability to appropriately identify and control for clinical confounders. ³ , ⁴ , ⁵ In fact, randomized clinical trials have failed to demonstrate a difference in hard clinical end points between CTO PCI and optimal medical therapy, ⁶ highlighting the challenges in designing and conducting randomized studies in this area of research.

Against such background, a new perspective on this topic is provided in this issue of the Journal of the American Heart Association (JAHA) by Holck et al, ⁷ who analyzed the outcomes of 19 033 patients undergoing non‐CTO PCI and 2108 patients undergoing CTO PCI between 2009 and 2019 within the Central Region of Denmark. Their study was based on 2 main hypotheses: compared with patients undergoing PCI for non‐CTO indications, (1) patients who underwent successful CTO revascularization have similar all‐cause mortality; and (2) patients with residual CTOs after failed CTO PCI have worse all‐cause mortality. In the entire population, mean age was 66.7±11.8 years. The prevalence of prior PCI was 19.0%, prior coronary artery bypass grafting, 4.1%; and diabetes, 18.3%. Mean left ventricular ejection fraction was 51.7±11.9%. The success rate of all CTO lesions at the patient level was 74% in the CTO group. A total of 5496 patients (26.0%) died within 9 years of follow‐up, and the median follow‐up was 5.7 years. All‐cause mortality was higher in patients with CTO versus non‐CTO patients (29.7% versus 25.6%; P<0.001), but this difference lost statistical significance on multivariable analysis (adjusted hazard ratio [HR], 1.08 [95% CI, 0.97–1.20]; P=0.165). Intriguingly, although successful CTO PCI had a similar risk of all‐cause death compared with non‐CTO PCI (adjusted HR, 0.99 [95% CI, 0.87–1.12]; P=0.873), unsuccessful CTO PCI was independently associated with worse survival compared with non‐CTO PCI (adjusted HR, 1.35 [95% CI, 1.13–1.63]; P=0.001). Notably, compared with non‐CTO PCI patients, patients who underwent unsuccessful CTO PCI had worse prognosis in both the early post‐PCI period and the long‐term, with an HR of 2.23 (95% CI, 1.65–3.01) between 0 and 30 days, and an HR of 1.74 (95% CI, 1.50–2.02) between 30 days and 9 years.

These observations bring us to the core of the debate elicited by the study by Holck et al ⁷ : what is the underlying cause for the increased all‐cause mortality observed in cases of unsuccessful CTO PCI? In our view, 3 possible explanations can be entertained. First, the completeness of revascularization: patients with unsuccessful CTO PCI receive, by definition, incomplete revascularization, which has been associated with worse outcomes (including survival) by several studies. ⁸ , ⁹ However, it seems unlikely that the effects of incomplete revascularization become manifest in the early (0–30 days) postinterventional period. The second explanation pertains to the potential detrimental effects of an unsuccessful procedure. Interestingly, Guan et al reported that suboptimal CTO PCI (defined as persistence of significant side branch occlusion, final thrombolysis in myocardial infarction flow grade 1 or 2, or residual percentage diameter stenosis >30%) was associated with higher incidence of 5‐year cardiac death or myocardial infarction compared with both successful and failed CTO PCI. ¹⁰ Unfortunately, the study by Holck et al ⁷ does not distinguish between suboptimal and failed CTO PCI, which hampers further speculations. The third explanation is that an unknown, residual confounder is still present despite multivariable adjustment, which is surely a possibility, as it has previously been identified as a strong limitation of observational studies in this particular area of research.

Holck and colleagues are to be congratulated for their efforts in addressing this relevant clinical question. The strengths of their study include their large cohort, representative of a moderate‐sized geographic region of their country, the long follow‐up, and the systematic tracking of the outcome of interest (all‐cause mortality) via a national administrative repository. Nevertheless, the study also presents certain limitations that merit discussion. Foremost, the choice of all‐cause mortality as the primary end point of this study is particularly controversial, as all‐cause death is confounded by a variety of nonischemic (and non–CTO‐related) conditions that can lead to death (eg, cancer and infections). In fact, it has been reported that the excess noncardiac mortality seen in PCI‐treated patients (compared with coronary artery bypass grafting) is most likely attributable to coding errors (cardiac deaths being coded as noncardiac). ¹¹ Moreover, the choice of mortality as the primary end point is controversial. Randomized data have consistently shown that, with the exception of primary PCI for ST‐segment–elevation myocardial infarction, ¹² PCI in all comers does not improve survival, ¹³ , ¹⁴ which has been proven also for CTO PCI. ⁶ Yet, paradoxically, the study by Holck et al ⁷ suggests that failing to recanalize a CTO is associated with a higher risk of death. Again, this may be attributable to 1 of the mechanisms previously described, but we can only speculate because the present study does not elucidate on the pathophysiological mechanisms linking a failed CTO PCI with higher mortality. ¹⁰ Furthermore, additional limitations of the present study include lack of granularity with regard to coronary anatomy and procedural variables, as well as data on complications. Finally, the lack of quantification of incomplete revascularization (reasonably incomplete versus truly incomplete) and how repeated CTO PCI attempts were handled in the analyses does not allow parsing out the true impact of CTO PCI on clinical outcomes and leads to further speculation on the mechanisms underlying the study findings.

CTO PCI remains a persistent clinical and research challenge, stemming from the complex patient population and procedural techniques it encompasses. As stated by Holck et al, ⁷ the determination of whether CTO PCI should be undertaken on the basis of prognostic indications necessitates forthcoming CTO trials, given the inherent bias associated with observational studies. Further light on this topic will be shed by the ISCHEMIA‐CTO trial (NCT03563417), which is randomizing >1500 patients to CTO PCI versus optimal medical therapy, with the goal to test 2 hypotheses: (1) in asymptomatic patients with ≥10% of myocardial ischemia, PCI is superior to optimal medical therapy in terms of relative reduction in major adverse cardiovascular and cerebrovascular events; and (2) in symptomatic patients with ≥5% of myocardial ischemia, PCI is superior to optimal medical therapy in terms of improved quality of life. Although this trial holds the potential to provide more definitive answers on the clinical impact of CTO recanalization, its results are expected no earlier than 2029. In the meantime, the jury is still out, and this topic will likely continue to fuel heated debates across peer‐reviewed publications, conferences, and social media.

Disclosures

Dr Azzalini received honoraria from Teleflex, Abiomed, GE Healthcare, Asahi Intecc, Philips, Abbott Vascular, Reflow Medical, and Cardiovascular System, Inc; serves on the advisory board of GE Healthcare; and owns equity in Reflow Medical. Dr Masoomi has no disclosures to report.