Novel therapy using liposomal alendronate failed to meet its primary endpoint of decreasing neointimal hyperplasia (NIH) and did not improve clinical outcomes in diabetes patients undergoing percutaneous coronary intervention (PCI), according to results presented Sunday at Transcatheter Cardiovascular Therapeutics 2019 in San Francisco.
It has been established that diabetes mellitus (DM) is an important predictor of NIH and adverse ischemic events after PCI. In addition, DM patients exhibit more aggressive progression of coronary atherosclerosis partly because of heightened systemic inflammation. Finding ways to reduce this inflammation, along with subsequent NIH, is important to help minimize adverse ischemic events after PCI in patients with DM, Philippe Genereux, MD, of Morristown Medical Center, Morristown, New Jersey.
BIOrest Liposomal Alendronate is a novel liposomal intravenous formulation of alendronate (LABR-312). The therapy has been shown in animal models to decrease NIH via transient modulation of circulating monocytes and permanent reduction of monocyte accumulation at vascular injury sites and around stent struts. In this trial, investigators sought to assess the safety, effectiveness and dose response of LABR-312 administered intravenously at the time of PCI with a drug-eluting stent (DES) in reducing restenosis as measured by optical coherence tomography (OCT) at 9 months postprocedure in patients with DM.
The BLADE-PCI (Biorest Liposomal Alendronate Administration for Diabetic Patients Undergoing Drug-Eluting Stent Percutaneous Coronary Intervention) trial is a phase IIb, prospective, multicenter, international (Canada, United Kingdom, Israel), randomized 1:1 (stratified by insulin treatment and site), double-blind, two-arm, placebo-controlled clinical trial. The study population was composed of DM patients (on pharmacologic treatment of insulin, oral or injectable hypoglycemic agents) undergoing PCI for angina (stable or unstable), ischemia, or non-ST-segment elevation myocardial infarction (MI). In both study arms, all target lesions were treated with the Resolute DES (Medtronic) during PCI. Given the condition to ongoing safety monitoring, dose escalation of LABR-312 in the study arm was planned: 0.01 mg (low dose), 0.03 mg (intermediate dose), and 0.08 mg (high dose). The primary efficacy endpoint was in-stent percentage NIH at 9 months. The value percentage NIH is defined as NIH volume/stent volume x 100 as measured by OCT. Primary statistical analysis was superiority of LABR-312 to placebo, and the analysis cohort was the as-treated population, meaning as all randomized patients who received the actual study drug.
The study enrolled 271 patients with DM from September 2016 to December 2017 from 18 sites, with 135 patients randomized to placebo and 136 patients to LABR-312. A total of 358 lesions were treated: 182 in the LABR-312 arm and 176 in the placebo arm. Among the 136 patients randomized to LABR-312, 43 received the low dose (0.01 mg), 48 received theintermediate dose (0.03 mg) and 45 received the high dose (0.08 mg). At 9 months, 222 patients (82%) underwent follow-up angiography and had an OCT qualifying for analysis of the primary endpoint, with a total of 248 lesions analyzed: 123 lesions in the LABR-312 arm and 125 in the placebo arm. Average age of patients was about 64 years, and the majority had type 2 diabetes with an average HgbA1c of 7.0%.
At 9 months, the trial demonstrated that percentage NIH volume using OCT was 13.3% ± 9.2% in the LABR-312 arm and 14.6% ± 8.5% in the placebo arm (p=0.35). In addition, there was no difference when stratified by LABR-312 dose (p=0.17). Finally, LABR-312 did not improve 9-month clinical outcomes.
Investigators concluded that among a population of patients with DM undergoing contemporary DES PCI, a bolus of LABR-312 injected systematically at the time of intervention did not result in a lower rate of in-stent percentage NIH volume at 9-month follow-up as determined by OCT compared to placebo. In addition, LABR-312 dose escalation did not show any significant dose response in regard to the primary endpoint. Finally, LABR-312 injected at the time of PCI did not improve 9-month clinical outcomes.