In the simultaneously published letter to the editor, the authors report the common practice of exaggerating the benefits and underestimating adverse events in patients undergoing percutaneous coronary intervention for chronic total occlusions (CTO PCI). They also highlighted challenges in our recently published article “Long-term improvement of symptoms of angina pectoris after successful revascularization of coronary artery chronic total occlusions.”
The authors reply
In response to {first author’s name in the letter to the editor} and colleagues:
The primary endpoint in our study was the determination of long-term symptomatic benefits after CTO PCI. We concluded attainment of long-term symptomatic relief with the procedure. In the letter to the editor, the authors critiqued that our study ignored the effects of placebo on the long-term angina benefits.
Our study demonstrated long-term symptomatic benefits merely in patients with a successful procedure. In patients with an unsuccessful CTO PCI symptomatic improvements were also identified, but the effect was lost by 12 months. Placebo effect was considered as one of the possible explanations for the finding in our article discussion. Our results support the common understanding of considerable placebo effect on short-term follow up time. In-long term follow up, as also our study suggests, the effect of placebo is diminished and it poorly explains symptomatic improvements. In addition, we studied symptomatic benefits of successful versus unsuccessful CTO PCI and comprehensive investigation of placebo versus CTO PCI was out of our study scope.
Overall, compelling evidence on placebo effect in long-term angina relief is lacking. The ORBITA trial [Citation1] was the first blinded study to assess the influence of placebo procedure on angina relief in patients with a non-CTO PCI. Patients with CTO were excluded and the follow-up time was only 6 weeks. The trial indicated similar symptom relief in both medical treatment and PCI arms. In the 12-week ORBITA2 trial [Citation2], PCI resulted in superior symptomatic relief in comparison with placebo procedure. Importantly, all antianginal medications were discontinued before the randomisation. Similarly to ORBITA, patients with a CTO were excluded. ORBITA-CTO [Citation3] is an ongoing pilot study investigating the rationale of a sham-controlled study design and the effect of placebo procedure in patients with CTOs.
In conclusion, placebo and nocebo effects have undoubtedly influenced our study, but they are inadequate to explain the observed results. Placebo and nocebo should not be utilised to overrule our statistically confirmed long-term findings. Comprehensive evidence of the placebo effect, especially on long-term symptomatic outcomes in patients with a CTO, remains scarce.
Considering secondary endpoints in our study, the authors of the letter state that our higher-than-expected reported long-term major adverse cardiac events (MACE) rate is unacceptable. The high MACE rate in our study derives from a structural bias identified during the analysis, which was meticulously discussed. In our study design, second or third planned CTO PCI attempts were included to target vessel revascularisation (TVR) outcome, a component of MACE. We indicated that the groupwise difference in MACE in unsuccessful versus successful CTO PCI is driven primarily by the less frequent TVR. Consequently, the true frequency of MACE in patients with unsuccessful procedures is substantially overestimated. We conducted an additional secondary analysis to overcome this factor.
In the letter, the authors state the MACE rate of stable angina pectoris is very low [Citation4, Citation5] and in conflict with our MACE rate. On closer inspection of the cited studies, rates of adverse clinical events are concordant with our article. The two studies had longer follow-up times and the inclusion of CTO patients was not specified, but can be assumed that most had no CTO. Patients with a CTO have a high atherosclerotic disease burden and overall impaired health status, which needs to be considered. Eventually, all patients with coronary artery disease suffer from MACE.
The authors of the letter additionally suggest that the 3.0% coronary artery perforation rate in the unsuccessful PCI arm could explain the higher reported MACE. However, a large meta-analysis [Citation6] reported over two-fold higher perforation rate in unsuccessful procedures compared to our study, and in successful procedures the difference was even more pronounced. In addition, according to a recent publication based on a multicenter prospective registry [Citation7], coronary artery perforation was not associated with adverse clinical outcomes at long-term follow-up. It is acknowledged that perforation rate is higher in patients receiving CTO PCI in comparison with a non-CTO PCI procedure. On the other hand, perforation less frequently leads to serious complications such as cardiac tamponade. This is due to the absent blood flow in the lesion under intervention. Thus, we are unable to concur with the authors' speculation. Other in-hospital complications reported in our study are comparable with previous literature [Citation6, Citation8].
Our study MACE rate derives from structural bias identified in our study, specific prognosis impairing features of patients with a CTO and the long-term follow-up. The MACE rate should not be considered as a result from CTO PCI or as an indication to reduce CTO PCI procedures.
In conclusion: structural bias in our study design led to overestimation of MACE in patients with unsuccessful procedures. MACE in successful procedures on the other hand is comparable to that previously reported. The rate of in-hospital complications in our study was in line with the existing literature. Finally, the placebo may have an effect on symptomatic improvement in short-term follow-up, but in long-term follow-up, its effect is diminished as our study demonstrates. Distinct symptomatic improvements are established with a successful CTO PCI in long-term.
Disclosure statement
No potential conflict of interest was reported by the author(s).
References
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- Khan S, Fawaz S, Simpson R, et al. The challenges of a randomised placebo-controlled trial of CTO PCI vs. placebo with optimal medical therapy: the ORBITA-CTO pilot study design and protocol. Front Cardiovasc Med. 2023;10:1172763. doi: 10.3389/fcvm.2023.1172763.
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- Brilakis ES, Banerjee S, Karmpaliotis D, et al. Procedural outcomes of chronic total occlusion percutaneous coronary intervention: a report from the NCDR (National Cardiovascular Data Registry). JACC Cardiovasc Interv. 2015;8(2):245–253. doi: 10.1016/j.jcin.2014.08.014.