Discussion
ReGenHeart is the first phase 2 trial to investigate the efficacy and safety of intramyocardially administered AdVEGF-D for the treatment of RA. The study protocol has been designed to address the limitations and combine the best methods of the earlier larger-scale trials.
Although definitive evidence to support the clinical use of AdVEGF GT is still lacking, previous trials have yielded positive signals. In 2003, the phase 2 Kuopio Angiogenesis Trial showed as its secondary endpoint that intracoronary infusion of AdVEGF-A resulted in improved myocardial perfusion assessed with SPECT.15 However, the primary endpoint, in-stent restenosis rate, and other secondary endpoints, functional capacity and anginal symptoms, remained unchanged. Conversely, in the REVASC trial, AdVEGF-A GT via mini-thoracotomy led to increased functional capacity and a lower CCS class but no change in SPECT perfusion was observed.16 Paradoxically, myocardial perfusion results were in favour of the control group. The NOVA trial was terminated prematurely due to a slow recruitment rate, and the results from the 17 already enrolled patients demonstrated no improvement in exercise capacity, time to the ischaemic threshold or myocardial perfusion.17
ReGenHeart has several advantages over the above-discussed phase 2 trials. First, its vector is based on adenoviruses, which are superior to plasmid vectors in their gene transfer efficacy.18 The negative results in trials that have used the latter might be accounted for, at least to some extent, by the vector choice.19 20 Second, the translated protein, VEGF-DΔNΔC, has many attractive properties over other members of the VEGF family, such as VEGF-A. In contrast to the other VEGFs, VEGF-D is more angiogenic and produces diffuse angiogenesis extending well beyond the local injection sites.8 21 Owing to its affinity to VEGF receptor 3, VEGF-D is also lymphangiogenic, theoretically reducing the accumulation of pericardial effusion observed with higher AdVEGF doses.
The administration with NOGA mapping and injection catheter allows direct intramyocardial targeting of the myocardium, achieving higher vector concentration in the target tissue with less biodistribution to the periphery than with the intracoronary infusion.22 The gene transfer efficacy also remains better.23 24 Electroanatomical mapping provides essential support for reaching the designed target area,12 and the risk of complications is most likely reduced as well. A robust double-blinded setup can be maintained because the endovascular procedure is identical to the control group.19
In many previous studies, patient selection has allowed recruitment of participants with anginal symptoms as severe as CCS class 4.16 17 19 20 CCS class 4 is associated with a higher cumulative hazard of revascularisation procedures and all-cause mortality as compared with the lower angina grades, including CCS class 3.25 Based on our clinical experience, the most severely symptomatic patients who are non-eligible for revascularisation are often affected by complex comorbidity and difficult overall situation and thus likely exhibit an insufficient regenerative capacity to benefit from the intervention. Therefore, the patient selection in ReGenHeart is optimised by including only patients with CCS class 2–3 symptoms.
6MWT was chosen as the method for evaluating functional capacity based on the recommendation from the Finnish Medicines Agency and international regulatory bodies and because it is practical and cost-effective to perform in each site without prior experience with ergometry or a treadmill. 6MWT has an excellent correlation to other types of exercise tests; however, it is considered more acceptable by the patients. It also reflects better daily activity of cardiac patients13 26
We prefer PET instead of SPECT to assess the change in myocardial perfusion after GT. PET renders it possible to detect more subtle perfusion defects compared with SPECT due to its superior sensitivity and accuracy.27 28 In addition, the more favourable tracer kinetics allow dynamic and reliable imaging of myocardial tracer uptake through the series of acquired time frames.29 Thus, the perfusion can be assessed in absolute terms and, consequently, also diffuse myocardial ischaemia can be detected, for example, in patients with left-main or three-vessel disease and those with a history of CABG.12 In contrast to PET, ischaemia detection in SPECT depends on a reference zone with normal blood flow; thus, it may underestimate the degree of myocardium under jeopardy in patients with balanced ischaemia patterns.30 This is important because all but one patient in KAT301 had CABG in their history,9 in addition to our general observation that RA patients often present with advanced and complex CAD phenotype.
Limitations
Despite its aim to employ the best designs from previous studies, ReGenHeart still has some limitations. First, the patient recruitment was significantly affected by the COVID-19 pandemic, leading to lockdowns and closure of trial-related operations in the invasive cardiology units for almost 2 years. Furthermore, because the availability of PET is still limited in some countries, SPECT is allowed to be used as a substitute. As discussed, PET is the preferred imaging modality, as it is superior to SPECT in accuracy and can quantify myocardial perfusion in absolute terms. However, results from both scans can still be processed comparably. As an added benefit, incorporating both imaging modalities allows us to compare the performance of PET and SPECT in assessing changes in myocardial perfusion after AdVEGF-D GT.