Author + information
- aStructural Interventional Cardiology Division, University Hospital Careggi Florence, Italy
- bNational Institute for Health Research (NIHR) Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom
- cMedizinische Klinik I (Cardiology & Intensive care), Klinikum Darmstadt GmbH, Darmstadt, Germany
- ↵∗Address for correspondence:
Prof. Carlo Di Mario, Careggi Hospital, Department of Cardiology, Viale Morgagni 1, Florence I-50134, Italy.
The generally accepted principle is that registries complement the information provided by randomized trials, but only the rigor of the randomization process can eliminate the confounding factors, including the placebo effect, so frequent after interventional treatments, and ensure that true differences are present between conventional and novel therapies. Frequently, the large and significant differences observed in randomized trials lose some of their shine when applied to all-comers groups including suboptimal candidates for the tested therapies.
For chronic total occlusion (CTO) recanalization, the opposite seems to be true. Two recently published trials, EXPLORE (Evaluating Xience and Left Ventricular Function in Percutaneous Coronary Intervention on Occlusions After ST-Segment Elevation Myocardial Infarction) (1) and DECISION-CTO (Drug-Eluting Stent Implantation Versus Optimal Medical Treatment in Patients With Chronic Total Occlusion) (2), the first randomized studies comparing CTO recanalization and optimal medical therapy (if you except the OAT trial [Occluded Artery Trial] [3,4], which was a trial performed in subacute occlusions, but not CTOs), showed no advantage in the percutaneous coronary intervention (PCI) arm. In particular, despite higher success rate and fewer complications than in this registry, DECISION CTO showed no difference in quality of life (QoL). In the OPEN-CTO (Outcomes, Patient Health Status, and Efficiency IN in Chronic Total Occlusion Hybrid Procedures) registry (5) in this issue of JACC: Cardiovascular Interventions, the stunning 90% technical success and 85% procedural success reported by the investigators are trimmed to 86% and 81%, respectively, by the core lab reviewing all angiograms. This is still a remarkable performance considering the extreme complexities of the occlusions treated (J-CTO score 2.3 ± 1.3, occlusion length 29.1 ± 23.8 mm, calcifications in 33% of lesions). When the patients were approached by an independent assessor unaware of the procedure outcome before and 1 month post-PCI, the improvement in all parameters is stunning (Seattle Angina Questionnaire QoL increased from 49.5 ± 27.5 to 76.1 ± 21.4 after 1 month; p < 0.01). Maybe a question they should have asked directly was whether the patients were willing to undergo the same process again if they had a second chance to choose. The procedure was long (total procedural time 120.7 ± 64.4 min, but less than in historical series, because the hybrid approach leads to rapid changes in strategies without persisting into “failure mode”), required a bilateral puncture, and had relatively frequent complications, especially perforations, which occurred in 8.8% of cases (50% Ellis grade II, 37.5% Ellis grade III). After such a large QoL change post-procedure it is likely that most patients were satisfied of having undergone the CTO procedure, despite its hardships. In the DECISION-CTO and EXPLORE trials, not only hard endpoints such as mortality and myocardial infarction, but also QoL and indices of left ventricular function, respectively, showed no differences between treated and untreated patients.
Why this unusual result, opposite from the expected, with an outcome worse in the randomized trials? Because the investigators of the OPEN-CTO registry had no reason to avoid randomizing a patient; they were expected to have consecutive enrolment checked against the NCDR registry (National Cardiovascular Data Registry), and they were motivated to contribute to the effort of the hybrid group. Investigators in a randomized trial excluding one-half of the patients from receiving PCI were in a completely different mindset, ready to avoid enrolling a patient when they believed angioplasty was the best option. This explains why a trial like the DECISION-CTO trial, with so many high-volume centers enrolling, required almost 7 years to be completed, much more than the 18 months of the OPEN-CTO registry, and enrolled fewer patients (834 patients in 78 months vs. 1,000 patients in 18 months, respectively). Excessive scrutiny means heavy selection bias that may jeopardize the applicability of results to the general population, with a majority of patients relatively asymptomatic, and vessels and lesions treated unlikely to be of prognostic relevance. Crossover to the treatment group also affects the validity of the comparison, always performed on an intention-to-treat basis. Difficulties in recruitment also meant a change halfway into the design that added among its endpoints QoL parameters that were probably imperfectly or retrospectively collected by the investigators. The EuroCTO trial (6) also suffered from some of the bias reported in the previous text, but with a 2:1 randomization in favor of treatment and more disciplined investigators, enrolment was more rapid and crossover minimized. One of the primary endpoints focused from the start on QoL, ensuring a continuous effort for optimal data collection. The improvement in QoL was assessed with the Seattle Angina Questionnaire in both studies, whereas the EuroQol 5 dimensions questionnaire was used in the EuroCTO trial and Rose Dyspnea Scale and the Patient Health Questionnaire in the OPEN-CTO registry. Despite OPEN-CTO Registry these differences in the assessed parameters, the overall trend in the OPEN-CTO and EuroCTO studies is a major symptomatic improvement after PCI CTO (Table 1). This change was confirmed in many other registries (7) capturing this “soft,” but clinically very relevant, endpoint, the very reason why patients approach a cardiologist in the first place, to control or avoid altogether their disabling symptoms. Sometimes patients attribute their tiredness and dyspnea to old age or poor fitness, but they recognize after reopening the occlusion, how much of their limitation was caused by the occluded artery.
The aforementioned trials and the registry included also multivessel-disease patients in a considerable number, and it needs to be discriminated as to which clinical improvement resulted from PCI in general and the CTO PCI specifically. Here, the DECISION-CTO trial’s disadvantage is that the randomization was done before treating the non-CTO lesions, so in effect, the subsequent improvement of symptoms observed in the optimal medical therapy group was likely due to non-CTO PCI. In the EuroCTO trial and the OPEN-CTO registry, symptomatic improvement can only be related to CTO treatment directly, because the baseline observation was done after non-CTO PCI.
A limitation of this, as well as other registries and studies of CTO recanalization, is that they are conducted by a selected group of very experienced investigators, achieving results that were unattainable by “normal” operators without specific training in lesions of similar complexity. The rigorous monitoring process can explain the higher complication rate, especially perforations in need of further interventions, of this registry compared with previous, less tightly controlled studies. In the absence of randomized trials comparing a liberal use of dissection–re-entry, the final successful opening technique in 24.3% of lesions in this trial, and the persistence of a conventional wire escalating technique for anterograde approach, we may assume that the hybrid approach with frequent use of the stiff CrossBoss (Boston Scientific, Natick, Massachusetts) and of aggressive wire knuckling may pay a higher price in complications for its proven efficacy and shorter PCI duration.
In conclusion, the claim that opening CTOs saves lives, despite concordant results from a thousand registries comparing successful and unsuccessful CTO recanalizations (8), is not yet supported by randomized trials. There is no doubt, however, that QoL is improved by CTO recanalization. Failures are much less than 10 to 20 years ago, and our U.S. colleagues managed to catch up very well with Japan, Korea, and Europe. The price to pay is higher than for non-CTO PCI, but complications, especially perforations, are successfully handled in most cases without surgery.
↵∗ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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