Major adverse cardiovascular events
A MACE occurred in 18 (18/24, 75.0%) patients in the VEGF-D group (21.5 per 100 patient-years) and in five (5/6, 83.3%) patients in the control group (24.9 per 100 patient-years) with no difference in the incidence between the groups (hazard ratio in the VEGF-D group, 0.97; 95% CI, 0.36–2.63; P = 0.95) (Fig. 1a). In addition, the observed differences with respect to the individual MACE components were not significant between the VEGF-D and control groups (Fig. 1b).
A The solid line represents the cumulative incidence of MACE in the VEGF-D group and the dashed line represents the incidence in the control group. B The bars show the proportion of patients with MACE or its individual component during the follow-up. ACS acute coronary syndrome, CABG coronary artery bypass grafting, CV cardiovascular, GT gene therapy, MACE major adverse cardiovascular event, PCI percutaneous coronary intervention, VEGF-D vascular endothelial growth factor D.
Seeing that nearly half of the patients had undergone PCI, it was interesting to evaluate the indications for these interventions, as the inclusion criteria for KAT301 trial was a non-eligibility for the invasive coronary procedures. Reinterventions were performed to treat the symptoms caused either by a de novo lesion, i.e., lesion not present at the time of screening or to recanalize a chronic total occlusion using advanced PCI techniques that became available after KAT301. De novo lesion was treated in seven patients (7/24, 29.2%) in the VEGF-D group (5.9 per 100 patient-years) and in two patients (2/6, 33.3%) in the control group (6.3 per 100 patient-years) (P = 1.00), whereas chronic total occlusion recanalization was performed to three patients (3/24, 12.5%) in the VEGF-D group (2.0 per 100 patient-years) and to one patient (1/6, 12.7%) in the control group (2.6 per 100 patient-years) P = 1.00). These interventions were spread evenly throughout the course of the follow-up in both groups.
Mortality
During the follow-up, eight (8/24, 33.3%) patients deceased in the VEGF-D group (5.3 per 100 patient-years) and one (1/6, 16.7%) patient in the control group (2.7 per 100 patient-years) with no observed difference between the VEGF-D and control groups (P = 0.64) (Table 2). Seven deaths were cardiac deaths (7/9, 77.8%), consisting of two sudden cardiac deaths, and one that was due to exacerbation of congestive heart failure. Rest of the cardiac deaths were caused by a myocardial infarction. A hepatic tumor was described as the cause of death in two patients (2/9, 22.2%), both of which belonged to the VEGF-D group.
New-onset comorbidities
In total, new malignancies were diagnosed in six (6/24, 25.0%) patients in the VEGF-D group (4.2 per 100 patient-years) and one (1/6, 16.7%) patient in the control group (2.4 per 100 patient-years) with the observed incidence showing no difference between the groups (P = 1.00) (Table 3). The diagnoses included small lymphocytic lymphoma, two prostate cancers, basal cell carcinoma, chromophobe renal cell carcinoma, hepatocellular carcinoma, myelodysplastic syndrome, and an unspecified tumor of the liver with no biopsy taken. One patient had both prostate cancer and basal cell carcinoma.
New clinical arrhythmias were encountered in seven (7/14, 50.0%) patients in the VEGF-D group (8.3 per 100 patient-years) and in three (3/4, 75.0%) patients in the control group (12.9 per 100 patient-years) (P = 0.59). New-onset type 2 diabetes was diagnosed in three (3/11, 27.3%) patients, all of which belonged to the VEGF-D group (3.7 per 100 patient-years) (P = 1.00). Proliferative diabetic retinopathy was not found in any of the patients. During the screening, three (3/24, 12.5%) patients in the VEGF-D group and two (2/6, 33.3%) patients in the control group presented with reduced kidney function (eGFR < 45 mL/min/1.73 m2); further development of chronic kidney disease with a severely decreased eGFR (<30 mL/min/1.73 m2) was encountered in four (4/24, 16.7%) patients in the VEGF-D group (2.9 per 100 patient-years) and one (1/6, 16.7%) patient in the control group (3.3 per 100 patient-years) (P = 1.00).
Angina pectoris and perceived benefit from gene therapy
At the time of the interview, seven (7/16, 43.8%) patients in the VEGF group and one (1/5, 20.0%) patient in the control group reported no chest pain or equivalent symptoms. In addition, patients in the VEGF group reported less severe angina symptoms (CCS) compared to the baseline (1.9; 95% CI 1.3–2.5 vs. 2.9; 95% CI 2.7–3.1; P = 0.006), but there was also a trend of less severe symptoms in the controls (2.2; 95% CI 0.6–3.8 vs. 2.6; 95% CI 1.9–3.3; P = 0.414) (Fig. 2).
The bars represent mean with 95% confidence interval. CCS Canadian Cardiovascular Society, VEGF-D vascular endothelial growth factor D.
In general, patients in both groups reported a benefit from the intervention (12/16, 75.0% vs. 2/5, 40.0% in the VEGF-D and control groups, respectively) (Table 4). None of the patients reported worsening of their symptoms.
