William Wijns, MD, PhD Stylianos A. Pyxaras, MD
Adoption of invasive imaging for guidance during percutaneous coronary interventions (PCI) varies largely between clinical sites and between geographies, being greatest in Japan, intermediate to low in the United States and Asia, and very low to nonexistent in Europe. Yet nearly every interventional cardiologist will agree that intracoronary images obtained by intravascular ultrasound (IVUS) and optical coherence tomography (OCT) add significant information content to what is provided by angiography alone, thereby improving the understanding of and our capacity to interpret angiographic images. Although Japanese colleagues have the opportunity to use either IVUS or OCT in the majority of cases as part of their regular procedural strategy, use of invasive imaging in the rest of the world is hampered by inadequate or restricted reimbursement. Payers and some physicians are indeed claiming that adding IVUS or OCT imaging to simple angiographic guidance has not been shown unequivocally to affect patient outcomes. Observational or retrospective data obtained with use of the more recently developed OCT are even less conclusive than those obtained over the years with IVUS guidance.1
The study reported here by Meneveau et al2 is an important milestone in the journey to accumulating sufficient global evidence to support the role of OCT-guidance eventually during complex PCI and to extend the Practice Guidelines recommendations supporting its use.
KEY FEATURES OF THE FRENCH COLLABORATIVE STUDY
As mentioned in the original article,3 the DOCTORS (Does Optical Coherence To- mography Optimize Results of Stenting?) randomized trial is an investigator-driven initiative, supported by central analyses performed at the leading participating center, and funded by the French government. DOCTORS is the first, randomized, multicenter study specifically evaluating the impact of combined angiographic and OCT imaging on PCI optimization. The study confirms prior observational or retrospec- tive studies4–7 in identifying OCT findings that jeopardize the immediate PCI result, namely stent underexpansion, strut malapposition, edge dissection, or most often, combinations of the above. In the group randomized to combined guidance with OCT and angiography, suboptimal findings were seen commonly when OCT was performed after stent placement using angiographic guidance: underexpansion in 42%, edge dissection in 37.5%, malapposition in 32%, and prompting correction in 50% of patients. Additional balloon inflations were applied in 43% with OCT guidance versus 12.5% with angiographic guidance (P<0.0001). Tissue protrusion (plaque or thrombus) was seen with OCT in 79%, resulting in increased use of GP2b3a inhibi- tors (53.3% versus 35.8%, P=0.007). Final dimensional metrics such as minimal stent area or residual intrastent diameter stenosis were superior after OCT guidance.
The primary efficacy end point was reached with significantly higher post-PCI fractional flow reserve (FFR) with OCT guidance than with angiographic guidance (0.94±0.04 versus 0.92±0.05, P<0.005). Other secondary and safety end points were neutral, with the exception of increased contrast use (+70 mL), longer procedure (+20 minutes), and higher radiation exposure (+1.663 cGy/cm2), all in the OCT group (all P<0.0001).
There are a number of remarkable aspects of this trial that deserve to be highlighted. The fact that DOCTORS was initiated, conducted, and completed successfully through an initiative of enthusiastic teams from the public sector, with some governmental support, is refreshing and stimulating. Secondly, mostly patients with non–ST-segment– elevation acute coronary syndrome (92.1%) were included. This subset of patients with acute presentation of coronary artery disease is known to be at higher risk, both acutely and during the first year after presentation. PCI procedures are performed in a complex milieu with potential plaque disruption, high thrombus load, coronary spasm, and microcirculatory dysfunction. The complexity of this specific patient and lesion subset offers opportunities for unraveling the value of adding OCT to angiographic guidance.
Thirdly, the study is all about optimization of the immediate PCI result; thus all efficacy and safety end points are focusing on procedure-related outcomes. Of note, event rates for clinical outcomes at 6 months are extremely low in both groups. Instead, final post-PCI FFR was used as an independent primary efficacy end point to power the study, an innovative “first-in-man” approach that needs to be discussed.
POST-PCi FFR AS AN INDEPENDANT METRIC OF PCi SUCCESS
The purpose of PCI with stent implantation is to restore the normal conductance of the epicardial coronary conduit, which in the absence of coronary artery disease, offers very limited if any obstacle to maximal coronary flow (that is why normal FFR is 1, indicating no pressure loss from the coronary ostium to the most distal epicardial location). In young subjects with no or minimal coronary artery disease, FFR values range between 0.92 and 1.00.8 Conversely, massive stent malapposition documented by IVUS during progressive stent deployment at increasing pressures was associated with low FFR values that improved incrementally with progressive proper stent expansion.9 Similar crosstalk between anatomy assessed by OCT and function assessed by FFR was reported recently.10 The next logical step was to explore the value of post-PCI FFR is predicting later clinical outcomes. Pi-jls et al11 were the first to show stepwise increases in reintervention rates with lower (suboptimal) post-PCI FFR values. Of note, this study was retrospective and the data were acquired in the bare-metal stent era, with in-stent restenosis rates as high as 30% at 1 year. More recently, a comprehensive meta-analysis in 6951 patients (9173 lesions) with coronary artery disease, showed a continuous and independent relationship of FFR with subsequent outcomes.12 In a subset of 966 patients, FFR measured immediately after stenting showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80–0.93; P<0.001). Thus, post-PCI FFR can indeed be used as a validated intermediate end point for an independent assessment of the immediate procedural result and for comparison of various optimization strategies. In and of itself, this approach may become increasingly meaningful in an evolving environment with compelling emphasis on treatment effectiveness and value-based care. Whether post-PCI FFR could be used as a surrogate end point for later clinical outcomes requires prospective long-term testing in large populations with event rates high enough to allow meaningful predictive discrimination.
SOME LIMITATIONS OF THE “DOCTORS” RANDOMIZED TRIAL
As mentioned already, the study was not powered to demonstrate improved long-term clinical outcomes with OCT guidance. Instead, this trial is paving the way for a definitive outcome-based guidance trial, with only 1 or 2 additional steps required. The study design does not allow the evalu- ation of the impact of pre-PCI OCT imaging on selection of stent length and diameter. ILUMIEN I study (Observational Study of Optical Coherence Tomography in Patients Undergoing Fractional gov Identifier Flow Reserve and Percu- taneous Coronary Intervention) has shown that a pre-PCI strategy planned using angiography is changed in 57% of cases when OCT becomes available.5 Other findings are surprising: stent length and diameter were the same on average in both randomization groups, although larger and longer stents are expected to be selected with OCT guidance.3,5 Also incomplete lesion coverage was similar between groups, 20% with OCT versus 17% with angiography (P=0.51). As a result, the need for additional stent placement was not significantly different: 27 versus 17.5%, respectively (P=0.09). It is possible that these operators, who are all experts in OCT guidance, are interpreting angio- grams with their OCT knowledge in mind, even when the case was randomized to angiographic guidance only. This raises one major issue, namely the ability to teach proper procedural behavior. In other words, when OCT guidance is used by nonexperts, how likely is it that the same deci- sions will be made? The current protocol was not very pre- scriptive, with several items for decision left to the operator’s opinion, including the decision to treat or not to treat malapposition. It so happens that strut malapposition seen in isolation was corrected in only 2 cases, because experts know that early malapposition must be extensive to be a significant risk factor.13 This decision pattern is at variance from what can be expected from non-OCT experts who tend to overreact to abnormal OCT findings. To improve on the standardization of procedural behavior in response to the information provided by OCT, much more prescriptive criteria have been developed from the ILUMIEN II7 study and implemented in the ongoing ILUMIEN III trial.14 Both proper stent sizing and proper stent expansion criteria are defined precisely per protocol and set as procedural targets (Figure 1). This simplified approach was proposed by Stone and Ali,14 and is expected to be applicable at large. By focusing primarily on targeting stent dimensions as close as possible to normal, OCT guidance is anticipated to take care of underexpansion, incomplete lesion coverage, and malapposition in one go. The compelling data relating outcomes to stent size (the bigger the better paradigm) are providing a strong rationale in support of this approach.15 Of inter- est, in the present study, minimal stent area was indeed the best predictor of post-PCI FFR values >0.90 by ROC analysis (area under the curve 0.79).
LESSONS LEARNED FOR THE DESIGN OF FUTURE OUTCOME DRIVEN GUIDANCE TRIALS
How important the study by Meneveau et al2 may be, it remains to be investigated whether the use of additional interventions prompted by OCT findings will translate into improved clinical outcomes. Important lessons from the DOCTORS trial should be remembered when the time will be right to design a definitive, properly sized, outcome-driven guidance trial. Mid-term outcomes after PCI typically are very good. It will be essential to select for inclusion patient and lesion subsets with high enough residual event rates at 1 year, to even be amenable to significant improvement. At the same time, pre- and post-PCI FFR should be measured in order to confirm the indication and evaluate the procedural success, respectively. A simplified and teachable proto- col is essential to standardize both angiography-guided and OCT-guided procedural technique. Treatment decisions being made in the catheterization laboratory must be robust and essential measurements readily available online, with minimal operator interference. Importantly, patient outcomes in studies that compare procedural techniques are exquisitely sensitive to operator ex- perience. When comparing on-pump versus off-pump surgery,16 the question arises: how well did on-pump surgeons perform when assigned to off-pump surgery, and the reverse. In trials comparing vascular access sites, operators who are predominantly either radial or femoral users are assigned to an access route for which they may not be entirely familiar.17,18 The same concern applies when non-OCT experts are assigned to OCT guidance, and the reverse. Ideally, patients randomized to one or the other guidance strategy should be treated at each site by a certified OCT expert or by a certified excellent operator who relies primarily on angiographic guidance, depending on the randomization assignment. Finally, blinding of the medical teams who are taking care of the patient during follow-up should be encouraged.
Dr Wijns reports institutional grants to the Cardiovascular Research Center Aalst from Boston Scientific, Opsense, St. Jude Medical, Volcano, and other device and pharmaceutical companies. He is nonexecutive board member of Argonauts Partners and Genae. Dr Pyxaras received speaker fees from St. Jude Medical.
From Lambe Institute for Translational Medicine and Curam, National University of Ireland, Galway, and Saolta University Healthcare Group, Galway, Ireland (W.W.); Cardiovascular Re- search Center Aalst, Belgium (W.W.); and Medizinische Klinik II, Klinikum Coburg, Coburg, Germany (S.A.P.).
Circulation is available at http://circ.ahajournals.org.
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