Liquid Drug Delivery Approaches for the Treatment of Occlusive Arterial Disease: A Systematic Review.

OBJECTIVE: Local Liquid drug (LLD) delivery devices have recently emerged as a novel approach to treat peripheral arterial disease. This systemic review aims to identify and evaluate the clinical utility of the most commonly used delivery devices. METHODS: A systemic review was performed using the Medical Subjects Heading terms of "drug delivery," "liquid," "local," and "cardiovascular disease" in PubMed, Google Scholar, and Scopus. RESULTS: Four commonly used delivery devices were identified, including (1) the Bullfrog Micro-Infusion Device, (2) the ClearWay RX Catheter, (3) the Occlusion Perfusion Catheter, and (4) the Targeted Adjustable Pharmaceutical Administration. All have shown to successfully deliver liquid therapeutic into the target lesion and have exhibited favorable safety and efficacy profiles in preclinical and clinical trials. The LLD devices have the ability to treat very long or multiple lesions with a single device, providing a more economical option. The safety profile in LLD clinical studies is also favorable in view of recent concerns regarding adverse events with crystalline-paclitaxel-coated devices. CONCLUSION: There is clear clinical evidence to support the concept of local liquid delivery to treat occlusive arterial disease. CLINICAL IMPACT: The 'leave nothing behind' strategy has been at the forefront of the most recent innovations in the field of interventional cardiology and vascular interventions. Although drug coated balloons have overcome limitations associated with plain old balloon angioplasty and peripheral stents, recent safety concerns and cost considerations have impacted their usage. In this review, various liquid drug delivery devices are presented, showcasing their capabilities and success in both preclinical and clinical settings. These innovative liquid delivery devices, capable of targeted delivery and their ability to be re-used for multiple treatment sites, may provide solutions for current unmet clinical needs.

LumenRECON Guidewire: Pilot Study of a Novel, Nonimaging Technology for Accurate Vessel Sizing and Delivery of Therapy in Femoropopliteal Disease.

BACKGROUND: Proper vessel sizing during endovascular interventions is crucial to avoid adverse procedural and clinical outcomes. LumenRECON (LR) is a novel, nonimaging, 0.035-inch wire-based technology that uses the physics-based principle of Ohm's law to provide a simple, real-time luminal size while also providing a platform for therapy delivery. This study evaluated the accuracy, reliability, and safety of the LR system in patients presenting for a femoropopliteal artery intervention. METHODS AND RESULTS: This multicenter, prospective pilot study of 24 patients presenting for peripheral intervention compared LR measurements of femoropopliteal artery size to angiographic visual estimation, duplex ultrasound, quantitative angiography, and intravascular ultrasound. The primary effectiveness and safety end point was comparison against core laboratory adjudicated intravascular ultrasound values and major adverse events, respectively. Additional preclinical studies were also performed in vitro and in vivo in swine to determine the accuracy of the LR guidewire system. No intra- or postprocedure device-related adverse events occurred. A balloon or stent was successfully delivered in 12 patients (50%) over the LR wire. Differences in repeatability between successive LR measurements was 2.5±0.40% (R2=0.96) with no significant bias. Differences in measurements of LR to other modalities were 0.5±1.7%, 5.0±1.8%, -1.5±2.0%, and 6.8±3.4% for intravascular ultrasound core laboratory, quantitative angiography, angiographic, and duplex ultrasound, respectively. CONCLUSIONS: This study demonstrates that through a physics-based principle, LR provides a real-time, safe, reproducible, and accurate vessel size of the femoropopliteal artery during intervention and can additionally serve as a conduit for therapy delivery over its wire-based platform.

Clinical utility of regadenoson for assessing fractional flow reserve.

OBJECTIVES: The aim of this study was to evaluate the efficacy of regadenoson, in comparison with adenosine, for assessing fractional flow reserve (FFR) of intermediate coronary artery stenoses (CAS). BACKGROUND: Fractional flow reserve is an established invasive method for assessing the physiological significance of CAS. Regadenoson, a selective A(2A) receptor agonist, is an approved hyperemic agent for pharmacological stress imaging, but its role for measuring FFR is unknown. METHODS: This prospective, single-center study enrolled 25 consecutive patients with intermediate CAS discovered during elective angiography (25 lesions). In each patient, FFR of the CAS was measured first by IV adenosine (140 µg/kg/min), followed by IV regadenoson (400 µg bolus). The intrapatient FFR correlation between adenosine and regadenoson was evaluated. RESULTS: The mean age was 63 ± 11 years, and mean left ventricular ejection fraction was 58 ± 11%. Most patients were male (52%) and had hypertension (84%) and dyslipidemia (84%), with 24% having diabetes mellitus and 20% chronic obstructive pulmonary disease. The CAS was visually estimated during angiography (mean 58 ± 9%) and most often found in the left anterior descending coronary artery (48%). A strong, linear correlation of FFR was noted with adenosine and regadenoson (r = 0.985, p < 0.001). A hemodynamically significant lesion (FFR ≤ 0.80) was present in 52% with no reclassification of significance between adenosine and regadenoson. No serious events occurred with administration of either drug. CONCLUSIONS: Our results suggest that a single IV bolus of regadenoson is as effective as an intravenous infusion of adenosine for measuring FFR and, given its ease of use, should be considered for FFR measurement in the catheterization laboratory.

Improvement in hemodynamics with a new, larger-volume (50 cc) intra-aortic balloon for high-risk percutaneous coronary intervention.

A primary cause of adverse outcomes among high-risk patients undergoing percutaneous coronary intervention (PCI) may be a diminished capacity to tolerate the hemodynamic and ischemic insults that can occur during the procedure. A common means of mechanical support during PCI has been the intra-aortic balloon pump (IABP). We describe successful periprocedural mechanical support with a new, 50 cc IABP in a patient with both severe left ventricular dysfunction and extensive coronary arteriosclerosis, for whom PCI with stenting was indicated. The prophylactic use of this 50 cc IABP, which traditionally would be contraindicated because of the patient's height (162.6 cm), markedly increased the diastolic aortic pressure (by approximately 110 mmHg) over the baseline level, while promptly reducing left-sided heart pressures. This finding appears to exceed the average diastolic augmentation reported for smaller-volume balloons. Although the role of the IABP in high-risk PCI remains controversial, further research is warranted to clarify and compare this new 50 cc IABP to smaller-volume balloons, and ascertain whether the observed hemodynamic benefits can translate into improved clinical outcomes among patients requiring mechanical support during PCI.

Stents and statins: history, clinical outcomes and mechanisms.

The 1980s witnessed the inception of both stents and 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins). While they evolved separately, it was soon realized that they each offered a unique and powerful mechanism for targeting the major offender in cardiovascular disease, namely atherosclerosis. Coincidentally, the first statin was approved by the US FDA in 1987, the same year that the coronary stent was conceived. Since that time, stents and statins have revolutionized the field of cardiovascular medicine and their paths have been intertwined. Several pivotal randomized clinical trials have established statins as an effective therapy for improving clinical outcomes after percutaneous coronary intervention (PCI) among patients presenting with stable coronary artery disease and acute coronary syndromes. In addition, chronic statin therapy and acute loading of statins prior to PCI has consistently been shown to limit periprocedural myocardial necrosis. The mechanism for improved clinical outcomes with statins has clearly been associated with statin-induced reductions in LDL. In addition, statins may also exert 'pleiotropic' effects, independent of LDL lowering, that might counteract the inflammatory and prothrombotic mileu created with PCI. This article provides a brief historical perspective of the evolution of the use of statins and stents in patients with coronary artery disease, an evaluation of the available clinical data supporting the use of statins in patients undergoing PCI across a wide spectrum of clinical scenarios, and a discussion of the potential mechanisms of the benefit of statins in these patients.

Pulsatile left ventricular assist device support as a bridge to decision in patients with end-stage heart failure complicated by pulmonary hypertension.

BACKGROUND: Severe pulmonary hypertension (PH) in heart failure (HF) is a risk factor for adverse outcomes after heart transplantation (HTx). Left ventricular assist devices (LVADs) improve pulmonary hemodynamics, but our understanding of the degree of improvement and the effect on outcomes is still evolving. METHODS: We reviewed invasive pulmonary hemodynamics from 58 consecutive patients receiving LVAD support as a bridge to HTx from 1996 to 2003. The primary outcome was change in baseline transpulmonary gradient (TPG) during LVAD support and after HTx/recovery. The secondary outcome was post-HTx survival. RESULTS: All patients (age, 49 +/- 14 years, 79% male, 40% ischemic) received a pulsatile LVAD (median support, 97 days; interquartile range [IQR], 31-222). Hemodynamic measurements were obtained at baseline (median, 1 day; IQR, 1-3), during early (median, 1 day; IQR, 0-4) and late (median, 75 days; IQR, 24-186) LVAD support, and after HTx/recovery (median, 28 days; IQR, 17-40). Improvement in TPG occurred throughout LVAD support and was sustained after HTx/recovery. Levels of TPG reductions in patients with a baseline TPG in the highest quartile (14.1-26.0 mm Hg) were 8.6 +/- 3.5 vs 6.5 +/- 3.1 mm Hg in the lowest quartile (2.0-7.7 mm Hg) during LVAD support (p = 0.102), with 90% vs 100% 30-day post-HTx survival (P = 0.113). CONCLUSION: Pulmonary hemodynamics and post-HTx survival were similar after pulsatile LVAD support in patients with and without pre-implant PH. LVAD support may be a useful strategy to reverse PH in carefully selected patients, thus improving candidacy for HTx.