Ian Cawich

Modulation of ADP-Induced Platelet Activation by Aspirin and Pravastatin: Role of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1, Nitric Oxide, Oxidative Stress, and Inside-Out Integrin Signaling

Lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1), a receptor for oxidized-LDL, is up-regulated in activated endothelial cells, and it plays a role in atherothrombosis. However, its role in platelet aggregation is unclear. Both aspirin and HMG CoA reductase inhibitors (statins) reduce LOX-1 expression in endothelial cells. In this study, we investigated the effect of aspirin and pravastatin on LOX-1 expression on plate-lets. After ADP stimulation, mean fluorescence intensity of LOX-1 expression on platelets increased 1.5- to 2.0-fold. Blocking LOX-1 inhibited ADP-induced platelet aggregation in a concentration- and time-dependent manner. We also established that LOX-1 is important for ADP-stimulated inside-out activation of platelet αIIbβ3 and α2β1 integrins (fibrinogen receptors). The specificity of this interaction was determined by arginine-glycine-aspartate-peptide inhibition. Furthermore, we found that LOX-1 inhibition of integrin activation is mediated by inhibition of protein kinase C activity. In other experiments, treatment with aspirin (1–10 mM) and pravastatin (1–5 μM) reduced platelet LOX-1 expression, with a synergistic effect of the combination of aspirin and pravastatin. Aspirin and pravastatin both reduced reactive oxygen species (ROS) released by activated platelets measured as malonyldialdehyde (MDA) release and nitrate/nitrite ratio. Aspirin and pravastatin also enhanced nitric oxide (NO) release measured as nitrite/nitrite + nitrate (NOx) ratio in platelet supernates. Small concentrations of aspirin and pravastatin had a synergistic effect on the inhibition of MDA release and enhancement of nitrite/NOx. Thus, LOX-1 is important for ADP-mediated platelet integrin activation, possibly through protein kinase C activation. Furthermore, aspirin and pravastatin inhibit LOX-1 expression on platelets in part by favorably affecting ROS and NO release from activated platelets.

Final results of the Chronic Total Occlusion Crossing With the Ocelot System II (CONNECT II) study.

Purpose: To evaluate the safety and effectiveness of the optical coherence tomography–guided Ocelot catheter to cross femoropopliteal chronic total occlusions (CTOs). Methods: The CONNECT II study was a prospective, multicenter, non-randomized single-arm study of the safety and effectiveness of the Ocelot catheter in CTO crossing. Key inclusion criteria were a 99% to 100% stenosed femoropopliteal segment, lesion length between 1 and 30 cm, and resistance to guidewire crossing. The main exclusion criterion was a severely calcified target vessel. The primary safety endpoint was 30-day major adverse events (MAE), while the primary effectiveness endpoint was successful CTO crossing (i.e., guidewire placement in the distal true lumen) with the Ocelot catheter. Endpoint analysis was based on pre-specified objective performance criteria. Between February and June 2012, 100 patients (55 men; mean age 69 years) were enrolled. Most of the CTOs (94%) were in the superficial femoral artery (SFA); mean lesion length was 16.6±9.3 cm. Results: Through 30 days, 2 patients experienced MAE (significant perforations) related to the Ocelot catheter. The Ocelot catheter successfully crossed 97% of target CTOs either alone (72%), in conjunction with an assist device (18%), or in conjunction with a re-entry device (7%). Both primary safety and effectiveness endpoints were met. Conclusion: The Ocelot catheter with optical coherence tomography guidance offers physicians a reliable option for crossing femoral and popliteal chronic total occlusions with low MAE rates.

Lower Extremity Revascularization Using Optical Coherence Tomography-Guided Directional Atherectomy: Final Results of the e v aluat i on of the Pantheri S Opt i cal C O herence Tomography Imagi N g Atherectomy System for Use in the Peripheral Vasculature (VISION) Study

Purpose: To evaluate the safety and efficacy of a novel optical coherence tomography (OCT)–guided atherectomy catheter in treating patients with symptomatic femoropopliteal disease. Methods: The VISION trial (ClinicalTrials.gov identifier NCT01937351) was a single-arm, multicenter, global investigational device exemption study enrolling 158 subjects (mean age 67.2±10.5 years; 87 men) across 20 participating sites. In this cohort, 198 lesions were treated with an average length of 53±40 mm using the Pantheris catheter alone or Pantheris + adjunctive therapy. The primary safety endpoint was the composite of major adverse events (MAEs) through 6 months (objective performance goal 43.2%). Technical success (primary efficacy outcome) was defined as the percent of target lesions with a residual diameter stenosis ≤50% after treatment with the Pantheris device alone (objective performance goal 87.0%). Procedural success was defined as reduction in stenosis to ≤30% after Pantheris ± adjunctive therapy. Tissue specimens retrieved from each treated lesion were histologically analyzed to evaluate the accuracy and precision of OCT image guidance. Results: The primary efficacy outcome was achieved in 192 (97.0%) of the 198 lesions treated with the Pantheris catheter. Across all lesions, mean diameter stenosis was reduced from 78.7%±15.1% at baseline to 30.3%±11.8% after Pantheris alone (p<0.001) and to 22.4%±9.9% after Pantheris ± adjunctive therapy (p<0.001). Of the 198 target lesions, 104 (52.5%) were treated with the Pantheris alone, 84 (42.4%) were treated with Pantheris + adjunctive angioplasty, and 10 (5.1%) with Pantheris + angioplasty + stenting. The composite MAE outcome through 6 months occurred in 25 (16.6%) of 151 subjects. There were no clinically significant perforations, 1 (0.5%) catheter-related dissection, 4 (2%) embolic events, and a 6.4% clinically driven target lesion revascularization rate at 6 months. The 40-lesion chronic total occlusion (CTO) subset (mean lesion length 82±38 mm) achieved a similar significant reduction in stenosis to 35.5%±13.6% after Pantheris alone (p<0.001). Histological analysis of atherectomy specimens confirmed <1% adventitia in 82.1% of the samples, highlighting the precision of OCT guidance. Characterization of the OCT-guided lesions revealed evidence of an underestimation of disease burden when using fluoroscopy. Conclusion: OCT-guided atherectomy for femoropopliteal disease is safe and effective. Additionally, the precision afforded by OCT guidance leads to greater removal of plaque during atherectomy while sparing the adventitia.

Major Limb Outcomes Following Lower Extremity Endovascular Revascularization in Patients With and Without Diabetes Mellitus

Purpose: To determine whether diabetes mellitus has an independent impact on major limb outcomes at 1 year after endovascular treatment of lower extremity peripheral artery disease (PAD). Methods: The study involved 1906 consecutive patients (mean age 66 years; 1469 men) enrolled in the observational Excellence in Peripheral Artery Disease (XLPAD) registry (ClinicalTrials.gov identifier NCT01904851) between January 2005 and October 2015 after undergoing index endovascular procedures in 2426 limbs for arterial occlusive disease. Patient outcomes included 12-month target limb amputation (above ankle) and target limb revascularization as well as all-cause death. Kaplan-Meier analysis and adjusted Cox proportional hazard models were used for time-to-event analysis of outcomes for the entire study sample as well as for the critical limb ischemia (CLI) and claudication subgroups. Results of the Cox regression models are reported as the hazard ratio (HR) and 95% confidence interval (CI). Results: Diabetics undergoing endovascular procedures had higher rates of comorbid conditions (p<0.001), CLI (p<0.001), heavily calcified lesions (p=0.002), multivessel disease (p=0.030), and fewer infrapopliteal runoff vessels (p<0.001). Regression analysis after adjusting for confounders revealed significantly higher target limb major amputation in diabetics compared with nondiabetics (HR 5.02, 95% CI 1.44 to 17.56, p=0.011). However, repeat revascularization rates were similar. When considering CLI and claudication subgroups, diabetes was associated with a nonsignificant increased risk of 12-month major amputation only for patients presenting with CLI (HR 3.48, 95% CI 0.97 to 12.51, p=0.056). Diabetes was also associated with an increased risk of 12-month all-cause mortality in the overall study sample (HR 4.64, 95% CI 2.01 to 10.70, p<0.001) and in the CLI subgroup (HR 14.15, 95% CI 3.16 to 63.32, p<0.001) but not in the claudication subgroup (HR 1.42, 95% CI 0.45 to 4.54, p=0.552). Conclusion: Diabetes increases the risk of major amputation and all-cause death at 12 months following endovascular revascularization in patients with symptomatic PAD. These risks are especially heightened in patients presenting with CLI.

Ocelot catheter for the treatment of long SFA occlusion

Long saphenous femoral artery (SFA) chronic total occlusions (CTOs) are considered the “Achilles heel” of the lower extremity percutaneous interventions. Antegrade, retrograde, or transcollateral approaches, intraluminal or subintimal techniques with re‐entry and specialized CTO devices using microdissection, vibrational energy, and laser have all been tried for the management of such challenging lesions with various success rates. Ocelot is the first CTO crossing device using real‐time OCT technology. Its crossing catheter utilizes spiral wedges to corkscrew the CTO cap, while real‐time OCT offers direct visualization to facilitate intravascular true‐lumen orientation. The recently presented results of the CONNECT‐II study demonstrated crossing success of 97% and freedom from major adverse events of 98%. We present one of the most challenging SFA CTOs with ambiguous proximal cap in the ostium of the SFA, heavy calcification and involving almost the entire length of the SFA. The Ocelot catheter assisted to the successful true‐lumen recanalization of that complex lesion.

Ocelot catheter for the recanalization of lower extremity arterial chronic total occlusion

Peripheral arterial disease (PAD) is a growing clinical condition affecting more than 10 million patients in the United States and it is responsible for more than 120,000 amputations annually. The presence of chronic total occlusions (CTO) increases the complexity of endovascular procedures and open surgery may often be the preferred approach. Despite the optimization of the CTO devices and technique, percutaneous CTO revascularization remains a challenging procedure even for experienced operators with important complication rates. The Ocelot(TM) system is a novel CTO device to use real-time optical coherence tomography (OCT) imaging guidance for the recanalization of peripheral CTOs. We review the mechanism of the Ocelot system, the initial results from the multi-center Connect-II trial and two cases of Ocelot-assisted CTO recanalization.

Impact of ticagrelor and aspirin versus clopidogrel and aspirin in symptomatic patients with peripheral arterial disease: Thrombus burden assessed by optical coherence tomography

PURPOSE To compare OCT identified white thrombus decline, neointimal hyperplasia and clinical outcomes of patients treated with ticagrelor plus aspirin with those patients treated with clopidogrel plus aspirin after peripheral interventions. BACKGROUND Ticagrelor is a potent platelet inhibitor. In patients with coronary artery disease, ticagrelor and aspirin demonstrated reduced rates of stent thrombosis, compared to aspirin and clopidogrel. The clinical importance of potent antiplatelet inhibition after peripheral endovascular interventions is unknown. METHODS We enrolled 18 patients with superficial femoral artery disease and the presence of OCT-detected clot post-stent placement. Patients were randomized to 75 mg clopidogrel once daily for 1 month vs. 90 mg ticagrelor twice daily for 6 months, both in addition to 81 mg aspirin for 6 months. Clot volumes, ankle-brachial index (ABI), 6-minute walk test, and Rutherford classification were measured at baseline and 6-month follow-up. Neointimal hyperplasia and neovascularization were calculated at 6-month follow-up. RESULTS N = 11 patients were enrolled in the clopidogrel group and N = 7 in the ticagrelor group. There was a significantly greater decrease in white thrombus in the ticagrelor group (median volume/stent length (0.067 vs 0.014 mm3/mm, p = 0.05)). No differences were found in % neointima (0.412 vs 0.536 mm3/mm, p = 0.44) and neovascularization (28 vs 44, p = 0.16). ABI and Rutherford classification were improved significantly after 6 months in the clopidogrel group, with no difference between groups at 6 months in ABI or Rutherford. CONCLUSION In symptomatic patients with PAD, ticagrelor showed significant improvement relative to clopidogrel with respect to white thrombus burden decline.

Immediate and intermediate-term results of optical coherence tomography guided atherectomy in the treatment of peripheral arterial disease: Initial results from the VISION trial

BACKGROUND Long-term patency rates for percutaneous peripheral arterial interventions are suboptimal. Optical coherence tomography (OCT) guided atherectomy may yield superior patency by optimizing plaque removal while preserving the tunica media and adventitia. METHODS The VISION study is a multicenter prospective study of patients with peripheral arterial disease undergoing OCT guided atherectomy with the Pantheris™ device. In 11 patients enrolled in a single center, we report procedural and clinical outcomes, at 30days and 6months. RESULTS The mean age was 63±11years and 73% (n=8) were men. The target lesion was in the superficial femoral artery in 82% (n=9) of the patients. Mean stenosis severity was 87%±10% and mean lesion length was 39±31mm. Procedural success was observed in all patients with no device related complications. Mean post-atherectomy stenosis was 18%±15%. Almost all excised tissue consisted of intimal plaque (94%). At 30days, significant improvements in Rutherford class, VascuQoL scores and ABI were observed, 0.9±0.8 vs. 3.1±0.7 (p=0.01), 4.9±1.9 vs. 3.6±1.5 (p=0.03) and 1.04±0.19 vs. 0.80±0.19 (p<0.01) respectively. At 6months, there were significant improvements in Rutherford class (1.0±1.0 vs. 3.1±0.7, p=0.01) and ABI (0.93±0.19 versus 0.80±0.19, p=0.02) but not in VascuQoL scores (3.7±1.4 versus 3.6±1.5, p=0.48). Target lesion revascularization occurred in 18% (n=2) of the patients. CONCLUSION OCT guided atherectomy resulted in high procedural success, no device related complications and encouraging results up to 6months. Histological analysis suggested little injury to the media and adventitia. Larger studies are needed to confirm the efficacy of this approach.

Same versus next day discharge after elective transradial PCI: The RAdial SAme Day DischArge after PCI trial. (The RASADDA-PCI trial)

BACKGROUND AND PURPOSE Transradial percutaneous coronary intervention (TR-PCI) has been increasingly popular over the last decade in the US. Previous studies have shown that same-day (SD) discharge after elective PCI is as safe as overnight (ON) observation. Our study was performed to assess the clinical and financial impact of early discharge in patients undergoing TR-PCI. METHODS This is a single center registry of patients undergoing elective TR-PCI. Timing of discharge was determined by the treating physician. (Groups: Same Day Discharge -SD-; Overnight Stay -ON-). Demographic data, procedural characteristics and adverse outcomes were recorded. Outcomes included 30 day-MACE and procedure- related complications, as well as total operative costs in patients from both groups. Propensity score matching for patient demographics, coronary symptoms and procedure indicators was used to compare both groups. RESULTS The entire cohort included 852 patients (429 in SD group and 423 in ON group) and the propensity score matched groups of 245 patients in the SD group and 245 patients in the ON group. The two groups had no significant baseline clinical differences, and had similar clinical outcomes. Specifically, no significant difference was noted in procedural complications (3.7% vs 2.5%, p = 0.43), re-hospitalization (4.1% vs 4.1%, p = 0.92), re-intervention (2.5% vs 2.1%, p = 0.77), myocardial infarction (0% vs 0.08%, p = 0.15), stroke (0% vs 0%, p = 1.0) and all-cause mortality (0% vs 0%, p = 1.0). SD Group patients had a significant lower procedure-related cost compared to overnight stay patients (

SAFETY AND EFFECT ON HEALTHCARE EXPENSES WITH SAME VERSUS NEXT DAY DISCHARGE AFTER ELECTIVE TRANSRADIAL PERCUTANEOUS CORONARY INTERVENTION

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