Outcomes of patients with severely calcified aorto-ostial coronary lesions who underwent orbital atherectomy.

OBJECTIVES: We assessed the feasibility and safety of orbital atherectomy in patients with severely calcified aorto-ostial coronary artery lesions. BACKGROUND: The treatment of calcified aorta-ostial coronary artery lesions is technically challenging. Orbital atherectomy can potentially damage the guiding catheter if it is not retracted sufficiently during treatment of ostial lesions. Orbital atherectomy can also excessively whip if the guiding catheter is not close enough to the ostium to provide sufficient support. Several techniques can be performed to successfully treat ostial lesions with orbital atherectomy. METHODS: Our retrospective multicenter registry included 548 real-world patients who underwent orbital atherectomy, 59 (10.8%) of whom underwent treatment for aorto-ostial coronary artery lesions (left main artery [n = 35] and right coronary artery [n = 24]). The primary endpoint was the rate of 30-day major adverse cardiac and cerebrovascular events (MACCE), defined as the occurrence of death, myocardial infarction, target vessel revascularization, and stroke. RESULTS: The primary endpoint was similar in patients with and without ostial lesions (3.4% vs 2.2%, P = 0.2), as were the 30-day rates of death (1.7% vs 1.4%, P = 0.7), myocardial infarction (1.7% vs 1.0%, P = 0.3), target vessel revascularization (0% vs 0%, P > 0.91), and stroke (0% vs 0.2%, P > 0.9). Angiographic complications and stent thrombosis did not occur in patients with ostial lesions. CONCLUSIONS: Despite its technical challenges, orbital atherectomy appears to be a feasible and safe treatment option for calcified aorto-ostial coronary lesions.

Nonsense-mediated decay regulates key components of homologous recombination.

Cells frequently experience DNA damage that requires repair by homologous recombination (HR). Proteins involved in HR are carefully coordinated to ensure proper and efficient repair without interfering with normal cellular processes. In Saccharomyces cerevisiae, Rad55 functions in the early steps of HR and is regulated in response to DNA damage through phosphorylation by the Mec1 and Rad53 kinases of the DNA damage response. To further identify regulatory processes that target HR, we performed a high-throughput genetic interaction screen with RAD55 phosphorylation site mutants. Genes involved in the mRNA quality control process, nonsense-mediated decay (NMD), were found to genetically interact with rad55 phospho-site mutants. Further characterization revealed that RAD55 transcript and protein levels are regulated by NMD. Regulation of HR by NMD extends to multiple targets beyond RAD55, including RAD51, RAD54 and RAD57 Finally, we demonstrate that loss of NMD results in an increase in recombination rates and resistance to the DNA damaging agent methyl methanesulfonate, suggesting this pathway negatively regulates HR under normal growth conditions.

Heparin: Physiology, Pharmacology, and Clinical Application.

Heparin is stored endogenously within the secretory granules of basophils and mast cells, and is only released into the vasculature at sites of injury. At these sites, it helps maintain proper blood flow by balancing the active anticoagulant and procoagulant processes. Pharmaceutical-grade heparin is derived from animal tissue, but one form is made synthetically. Heparin is commonly used in the management of coronary artery disease, deep vein thrombosis, pulmonary embolism, and atrial fibrillation, and in the prevention of thrombosis during cardiopulmonary bypass and extracorporeal membrane oxygenation. Heparin treatment is a key component in elective percutaneous coronary intervention (PCI). It plays an important role in minimizing the risk of thrombotic events during PCI and is one of the most popular anticoagulants used. However, some studies show that higher heparin doses are associated with more frequent bleeding complications, which can increase morbidity and mortality. The optimal heparin dosing regimens are still debated, as well as their efficacy in PCI compared with that of other drugs such as bivalirudin. This review examines the physiology, pharmacology, therapeutic applications, dosing regimens, and efficacy of heparin in the setting of PCI. In addition, included is a review of data on addition of glycoprotein IIb/IIIa inhibitors to heparin and comparison of heparin monotherapy to bivalirudin in PCI.

Achieving safe femoral arterial access.

Percutaneous coronary intervention can lead to vascular access complications that prolong patient hospital stay and costs as well as increase patient morbidity and mortality. Given its ease of use and familiarity, transfemoral access is still the preferred method of approach by many operators. The transfemoral approach is used when large bore access is required or if transradial access is not feasible due to variations in the anatomy of the upper extremity artery. The use of fluoroscopy, ultrasonography, and femoral angiography can help the operator obtain proper arteriotomy of the common femoral artery. Measures to decrease vascular access complications include proper technique, optimal pharmacotherapy, and avoiding the use of arterial sheaths >6 Fr. Optimal pharmacotherapy includes the use of bivalirudin and weight-based unfractionated heparin to avoid supratherapeutic activated clotting times, and to avoid glycoprotein IIb/IIIa inhibitors. When used appropriately, vascular closure devices can decrease the risk of bleeding complications. Randomized trials are needed to confirm these recommendations.

Eligibility and Potential Benefit of Transcatheter Edge-to-Edge Repair in a Contemporary Cohort With Heart Failure: Evidence From a Large Integrated Health Care Delivery System.

Background: The eligibility and potential benefit of transcatheter edge-to-edge repair (TEER) in addition to guideline-directed medical therapy to treat moderate-severe or severe secondary mitral regurgitation (MR) has not been reported in a contemporary heart failure (HF) population. Methods: Eligibility for TEER based on Food and Drug Administration (FDA) labeling: (1) HF symptoms, (2) moderate-severe or severe MR, (3) left ventricular ejection fraction (LVEF) 20% to 50%, (4) left ventricular end-systolic dimension 7.0 cm, and (5) receiving GDMT (blocker + angiotensin-converting enzyme inhibitor/angiotensin receptor blocker). The proportion (%) of patients eligible for TEER. The hypothetical number needed to treat to prevent or postpone adverse outcomes was estimated using relative risk reductions from published hazard ratios in the registration trial and the observed event rates. Results: We identified 50,841 adults with HF and known LVEF. After applying FDA criteria, 2461 patients (4.8%) were considered eligible for transcatheter mitral valve replacement (FDA+), with the vast majority of patients excluded (FDA-) based on a lack of clinically significant MR (N = 47,279). FDA+ patients had higher natriuretic peptide levels and were more likely to have a prior HF hospitalization compared to FDA- patients. Although FDA+ patients had a more dilated left ventricle and lower LVEF, median (25th-75th) left ventricular end-systolic dimension (cm) was low at 4.4 (3.7-5.1) and only 30.8% had severely reduced LVEF. FDA+ patients were at higher risk of HF-related morbidity and mortality. The estimated number needed to treat to potentially prevent or postpone all-cause hospitalization was 4.4, 8.8 for HF hospitalization, and 5.3 for all-cause death at 24 months in FDA+ patients. Conclusions: There is a low prevalence of TEER eligibility based on FDA criteria primarily due to absence of moderate-severe or severe MR. FDA+ patients are a high acuity population and may potentially derive a robust clinical benefit from TEER based on pivotal studies. Additional research is necessary to validate the scope of eligibility and comparative effectiveness of TEER in real-world populations.

CTEPH: A Kaiser Permanente Northern California Experience.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and life-threatening form of pulmonary hypertension and the only potentially curable form of the World Health Organization Pulmonary Hypertension classes. Thus, the prompt and accurate diagnosis of this condition is imperative. Despite widespread chronic symptoms following acute pulmonary embolism (PE), the condition is rarely considered, and an externally validated inexpensive diagnostic algorithm is lacking. METHODS: A long-term, retrospective cohort study was conducted to assess the incidence of CTEPH following acute PE in a real-world study population. Additional data were collected regarding the practice patterns of diagnostic testing and imaging, particularly in patients with persistent or recurrent symptoms. Amongst diagnosed CTEPH patients, previously established risk factors were evaluated for degree of risk and commonly used diagnostic tests (electrocardiogram [ECG] right ventricular hypertrophy [RVH] pattern, B-type natriuretic peptide [BNP] elevations) employed during this period were evaluated and assessed for feasibility as screening tests. The study population was obtained from the MAPLE study cohort, comprised of patients presenting with acute PE in 21 community medical centers across the Kaiser Permanente Northern California system from January 2013 to April 2015. Diagnosis of CTEPH was confirmed via pulmonary vascular imaging (ventilation/perfusion [V/Q] scanning, computed tomography angiography, pulmonary angiography) and diagnostic right heart catheterization (RHC). Probable diagnoses were defined as a combination of suggestive echocardiographic and RHC findings. Additional inclusion criteria included age (≥18 years) with at least 2 years follow up and no previous diagnosis of CTEPH or PE during the prior 30 days. RESULTS: There were 1973 patients who met inclusion criteria (mean age 62.4 years). Despite 75 % of patients developing symptoms consistent with CTEPH >3 months following acute PE, only 5.6 % of these symptomatic patients underwent V/Q scanning. There was overall a very low cumulative incidence of CTEPH (2.3 %), which was significantly higher amongst patients with symptoms compared to those without symptoms. When controlled for confounding in the multivariate analysis, only recurrent PE (HR 19.3, P < 0.001) and pulmonary artery systolic pressure >50 mmHg (HR 10.4, P < 0.001) were statistically significant predictors of CTEPH. Of the non-invasive diagnostic tests, ECG criteria for RVH were found to be poorly sensitive (2.6 %), but very specific (98.8 %) for CTEPH. Elevated levels of BNP alone were more sensitive than RVH ECG criteria (76.3 %) but poorly specific (44.4 %). CONCLUSIONS: The diagnosis of CTEPH is uncommonly made following acute PE. Despite the frequency of persistent symptoms consistent with CTEPH following acute PE, the appropriate diagnostic work-up is rarely undertaken as evidenced in this cohort. This suggests that CTEPH is underappreciated and rarely considered, likely underestimating the true incidence in this cohort. Future studies are needed to elucidate the true prevalence of CTEPH and further investigate both the optimal diagnostic tools and timing of appropriate screening. These discoveries may help guide future development of diagnostic algorithms that can effectively rule out and accurately identify this potentially curable disease in a timely manner.

Incidence, Predictors, and Outcomes Associated With Worsening Renal Function in Patients With Heart Failure and Secondary Mitral Regurgitation: The COAPT Trial.

Background The incidence and implications of worsening renal function (WRF) after mitral valve transcatheter edge-to-edge repair (TEER) in patients with heart failure (HF) are unknown. Therefore, the aim of this study was to determine the proportion of patients with HF and secondary mitral regurgitation who develop persistent WRF within 30 days following TEER, and whether this development portends a worse prognosis. Methods and Results In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, 614 patients with HF and severe secondary mitral regurgitation were randomized to TEER with the MitraClip plus guideline-directed medical therapy (GDMT) versus GDMT alone. WRF was defined as serum creatinine increase ≥1.5× or ≥0.3 mg/dL from baseline persisting to day 30 or requiring renal replacement therapy. All-cause death and HF hospitalization rates between 30 days and 2 years were compared in patients with and without WRF. WRF at 30 days was present in 11.3% of patients (9.7% in the TEER plus GDMT group and 13.1% in the GDMT alone group; P=0.23). WRF was associated with all-cause death (hazard ratio [HR], 1.98 [95% CI, 1.3-3.03]; P=0.001) but not HF hospitalization (HR, 1.47 [ 95% CI, 0.97-2.24]; P=0.07) between 30 days and 2 years. Compared with GDMT alone, TEER reduced both death and HF hospitalization consistently in patients with and without WRF (Pinteraction=0.53 and 0.57, respectively). Conclusions Among patients with HF and severe secondary mitral regurgitation, the incidence of WRF at 30 days was not increased after TEER compared with GDMT alone. WRF was associated with greater 2-year mortality but did not attenuate the treatment benefits of TEER in reducing death and HF hospitalization compared with GDMT alone. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01626079.

Association between serum albumin and outcomes in heart failure and secondary mitral regurgitation: the COAPT trial.

AIMS: Low serum albumin levels are associated with poor prognosis in numerous chronic disease states but the relationship between albumin and outcomes in patients with heart failure (HF) and secondary mitral regurgitation (SMR) has not been described. METHODS AND RESULTS: The randomized COAPT trial evaluated the safety and effectiveness of transcatheter edge-to-edge repair (TEER) with the MitraClipTM plus guideline-directed medical therapy (GDMT) versus GDMT alone in patients with symptomatic HF and moderate-to-severe or severe SMR. Baseline serum albumin levels were measured at enrolment. Among 614 patients enrolled in COAPT, 559 (91.0%) had available baseline serum albumin levels (median 4.0 g/dl, interquartile range 3.7-4.2 g/dl). Patients with albumin <4.0 g/dl compared with ≥4.0 g/dl were older and more likely to have ischaemic cardiomyopathy and a hospitalization within the year prior to enrolment. After multivariable adjustment, patients with albumin <4.0 g/dl had higher 4-year rates of all-cause death (63.7% vs. 47.6%; adjusted hazard ratio 1.34, 95% confidence interval 1.02-1.74; p = 0.032), but there were no significant differences in HF hospitalizations (HFH) or all-cause hospitalizations according to baseline serum albumin level. The relative effectiveness of TEER plus GDMT versus GDMT alone was consistent in patients with low and high albumin levels (pinteraction  = 0.19 and 0.35 for death and HFH, respectively). CONCLUSION: Low baseline serum albumin levels were independently associated with reduced 4-year survival in patients with HF and severe SMR enrolled in the COAPT trial, but not with HFH. Patients treated with TEER derived similarly robust reductions in both death and HFH regardless of baseline albumin level.

Impact of the Use of Intravascular Imaging on Patients Who Underwent Orbital Atherectomy.

OBJECTIVES: We assessed the impact of intravascular ultrasound (IVUS)/optical coherence tomography (OCT) on outcomes of patients who underwent orbital atherectomy. BACKGROUND: Intravascular imaging provides enhanced lesion morphology assessment and optimization of percutaneous coronary intervention (PCI) outcomes. Severe coronary artery calcification increases the complexity of PCI and is associated with worse clinical outcomes. Orbital atherectomy modifies calcified plaque, facilitating stent delivery and optimizing stent expansion. The impact of IVUS/OCT on clinical outcomes after orbital atherectomy is unknown. METHODS: Of the 458 consecutive real-world patients in our retrospective multicenter registry, a total of 138 patients (30.1%) underwent orbital atherectomy with IVUS/OCT. The primary safety endpoint was the rate of 30-day major adverse cardiac and cerebrovascular events, comprised of death, myocardial infarction (MI), target-vessel revascularization (TVR), and stroke. RESULTS: The IVUS/OCT group and no-imaging group had similar rates of the primary endpoint (1.5% vs 2.5%; P=.48) as well as death (1.5% vs 1.3%; P=.86), MI (1.5% vs 0.9%; P=.63), TVR (0% vs 0%; P=NS), and stroke (0% vs 0.3%; P=.51). The 30-day stent thrombosis rates were low in both groups (0.7% vs 0.9%; P=.82). Emergent coronary artery bypass graft surgery was uncommonly performed in both groups (0.0% vs 0.9%; P=.25). CONCLUSION: Orbital atherectomy guided by intravascular imaging is feasible and safe. A large prospective randomized trial is needed to determine the clinical benefit of IVUS/OCT during PCI with orbital atherectomy.

Orbital atherectomy for the treatment of small (2.5mm) severely calcified coronary lesions: ORBIT II sub-analysis.

OBJECTIVES: We assessed the safety and efficacy of orbital atherectomy to modify severely calcified coronary plaque prior to stent implantation in patients with small vessel (2.5mm) disease. BACKGROUND: Severe coronary artery calcification increases the risk of adverse clinical events during percutaneous coronary intervention (PCI). Patients who undergo PCI of small vessels have worse clinical outcomes including higher rates of perforation and dissection. The outcomes of orbital atherectomy of small diameter vessels (2.5mm) are unknown. METHODS: ORBIT II was a single-arm, multicenter trial which prospectively enrolled patients with severely calcified coronary lesions treated with orbital atherectomy prior to stenting in 49U.S. sites. The primary endpoint was the 3year rate of major adverse cardiac events, which was the composite of cardiac death, myocardial infarction, and target vessel revascularization. RESULTS: Of the 443 patients, 55 (12.4%) had reference vessel diameters (RVD) of 2.5mm and 388 (87.6%) had RVD >2.5. The rates of severe angiographic complications were similar in both groups. The primary endpoint was similar in both groups (30.6% vs. 22.5%, p=0.22), as were the rates of cardiac death (9.8% vs. 6.3%, p=0.33) and myocardial infarction (12.8% vs. 10.9%, p=0.67). Target vessel revascularization was numerically higher in the small vessel group (16.8% vs. 9.3%, p=0.13). CONCLUSIONS: Patients with small coronary vessel disease had comparable clinical outcomes compared to the larger diameter group following orbital atherectomy. Subsequent studies are required to establish the optimal revascularization approach for such patients with small coronary vessel disease burdened by heavily calcified lesions.

Current State of the Art in Approaches to Saphenous Vein Graft Interventions.

Saphenous vein grafts (SVGs), used during coronary artery bypass graft surgery for severe coronary artery disease, are prone to degeneration and occlusion, leading to poor long-term patency compared with arterial grafts. Interventions used to treat SVG disease are susceptible to high rates of periprocedural MI and no-reflow. To minimise complications seen with these interventions, proper stents, embolic protection devices (EPDs) and pharmacological selection are crucial. Regarding stent selection, evidence has demonstrated superiority of drug-eluting stents over bare-metal stents in SVG intervention. The ACCF/AHA/SCA American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Society for Cardiovascular Angiography and Interventions guidelines recommend the use of EPDs during SVG intervention to decrease the risk of periprocedural MI, distal embolisation and no-reflow. The optimal pharmacological treatment for slow or no-reflow remains unclear, but various vasodilators show promise.

Outcomes of patients with myocardial infarction who underwent orbital atherectomy for severely calcified lesions.

OBJECTIVES: This study analyzed the outcomes of patients who presented with non-ST-elevation myocardial infarction (NSTEMI) and subsequently underwent orbital atherectomy for severe coronary artery calcification (CAC). BACKGROUND: Patients who present with NSTEMI have increased risk for death and recurrent MI after percutaneous coronary intervention (PCI). Patients with severe CAC have worse outcomes after PCI.Orbital atherectomy modifies calcified plaque, facilitating stent delivery and optimizing stent expansion. There are no data on these patients who present with NSTEMI who undergo orbital atherectomy. METHODS: Of the 454 consecutive real-world patients who underwent orbital atherectomy in our retrospective multicenter registry, 51 patients (11.2%) presented with NSTEMI. The primary safety endpoint was the rate of major adverse cardiac and cerebrovascular events (MACCE) at 30days. RESULTS: Patients with NSTEMI had a higher prevalence of chronic kidney disease, lower mean ejection fraction, and required more vessels to be treated. The primary endpoint was similar in patients who presented with and without NSTEMI (2.0% vs. 2.2%, p=0.9), as were the 30-day rates of death (2.0% vs. 1.2%, p=0.67), MI (0% vs. 1.2%, p=0.42), target vessel revascularization (0% vs. 0%, p>0.91), and stroke (0% vs. 0.2%, p=0.72). The rates of angiographic complications and stent thrombosis rate were low in both groups. CONCLUSIONS: Despite having worse baseline characteristics, patients who presented with NSTEMI and subsequently underwent orbital atherectomy had similar clinical outcomes compared with patients without NSTEMI.

Comparison of Heparin and Bivalirudin in Patients Undergoing Orbital Atherectomy.

OBJECTIVE: We compared the angiographic and clinical outcomes of heparin and bivalirudin in patients who underwent orbital atherectomy for severely calcified coronary lesions. BACKGROUND: Severely calcified coronary lesions are associated with increased ischemic complications. Orbital atherectomy modifies calcified plaque, thereby facilitating stent delivery and stent expansion. The ideal antithrombotic agent during orbital atherectomy is unknown. Previous studies reported that bivalirudin was associated with lower bleeding rates compared with heparin plus glycoprotein IIb/IIa inhibitors during percutaneous coronary intervention. METHODS: This retrospective multicenter analysis included 458 consecutive real-world patients with severely calcified coronary arteries who underwent orbital atherectomy. Patients were stratified based on the antithrombotic agent that was used. The primary safety endpoint was the 30-day rate of major adverse cardiac and cerebrovascular events, defined as death, myocardial infarction, target-vessel revascularization, and stroke. RESULTS: Heparin was used in 356/458 cases (77.2%) and bivalirudin was used in 102/458 cases (22.8%). The primary endpoint was similar in the heparin and bivalirudin groups (2% vs 3%; P=.55), as were the 30-day rates of death (1% vs 2%; P=.51), myocardial infarction (1% vs 1%; P=.90), target-vessel revascularization (0% vs 0%; P>.99), and stroke (0% vs 0%; P=.59). Angiographic complication, stent thrombosis, and major bleeding complication rates were similarly low in both groups. CONCLUSION: Both heparin and bivalirudin were safe and effective antithrombotic agents for patients who underwent orbital atherectomy. A randomized trial is needed to determine the antithrombotic agent of choice for orbital atherectomy.

Comparison of diabetic and non-diabetic patients undergoing endovascular revascularization for peripheral arterial disease.

OBJECTIVE: Peripheral arterial disease (PAD) is associated with poor outcomes. We assessed the clinical outcomes of diabetic versus non-diabetic patients with PAD who underwent peripheral transluminal angioplasty (PTA). METHODS: The outcomes of 239 consecutive patients with symptomatic PAD who underwent PTA were analyzed. Restenosis and clinical outcomes were assessed at a follow-up of 2 years. RESULTS: Diabetic patients had a higher percentage of wound as the initial diagnosis for PTA (72.7% vs. 14.2%; P<.001), chronic kidney disease (26.7% vs. 6.3%; P<.01), need for dialysis (19.3% vs. 3.1%; P<.01), and coronary artery disease (67.6% vs. 50.7%; P=.02). Infrapopliteal PTA was more commonly performed in the diabetic group (70.4% vs. 25.3%; P<.001). Diabetic patients had lower rates of angiographic follow-up at 8 months (38.6% vs. 60.3%; P<.01). Diabetic patients had higher binary restenosis (54.4% vs. 31.5%; P=.02) and had a trend toward a higher incidence of total occlusion (34.0% vs. 19.5%; P=.08). At 2-year follow-up, the amputation rate was higher in the diabetic group (24.4% vs. 1.5%; P<.001) despite PTA. CONCLUSION: Diabetic patients more frequently presented with critical limb ischemia compared with non-diabetic patients and had higher rates of restenosis and amputation at 2 years following standard PTA. Improved therapies are needed for this high-risk group of patients.