Vascular complications associated with intraaortic balloon pump supported percutaneous coronary intervention (PCI) and clinical outcomes from the British Cardiovascular Intervention Society National PCI Database.

INTRODUCTION: The impact of a vascular complication (VC) in the setting of intraaortic balloon pump (IABP) supported PCI on clinical outcomes is unclear. METHODS: Using data from the BCIS National PCI Database, multivariate logistic regression was used to identify independent predictors of a VC. Propensity scoring was used to quantify the association between a VC and outcomes. RESULTS: Between 2007 and 2014, 9,970 PCIs in England and Wales were supported by IABP (1.6% of total PCI), with 224 femoral VCs (2.3%). Annualized rates of a VC reduced as the use of radial access for PCI increased. The independent predictors of a VC included a procedural complication (odds ratio [OR] 2.9, p < .001), female sex (OR 2.3, p < .001), PCI for stable angina (OR 3.47, p = .028), and use of a glycoprotein inhibitor (OR 1.46 [1.1:2.5], p = .04), with a lower likelihood of a VC when radial access was used for PCI (OR 0.48, p = .008). A VC was associated with a higher likelihood of transfusion (OR 5.7 [3.5:9.2], p < .0001), acute kidney injury (OR 2.6 [1.2:6.1], p = .027), and periprocedural MI (OR 3.2 [1.5:6.7], p = .002) but not with adjusted mortality at discharge (OR 1.2 [0.8:1.7], p = .394) or 12-months (OR 1.1 [0.76:1.56], p = .639). In sensitivity analyses, there was a trend towards higher mortality in patients experiencing a VC who underwent PCI for stable angina (OR 4.1 [1.0:16.4], p value for interaction .069). Discussion and Conclusions Although in-hospital morbidity was observed to be adversely affected by occurrence of a VC during IABP-supported PCI, in-hospital and 1-year survival were similar between groups.

The influence of Elixhauser comorbidity index on percutaneous coronary intervention outcomes.

BACKGROUND: Clinical outcomes with respect to the evolution of comorbidity burden in national cohorts of patients undergoing PCI have not been reported. OBJECTIVES: We sought to explore the association between comorbidity burden and periprocedural outcomes in patients treated with PCI in the National Inpatient Sample. METHODS: 6,601,526 PCI procedures were identified between 2004 and 2014 and comorbidities were defined by the Elixhauser classification system (ECS) consisting of 30 comorbidity measures. Endpoints included in-hospital mortality, periprocedural complications, length of stay and cost. Patients were classified based on their ECS in five categories (ECS I < 0, ECS II = 0, ECS III = 1-5, ECS IV = 6-13, and ECS V ≥ 14). RESULTS: Patients with a score over 13 had a fivefold increase in the odds of mortality (OR: 5.13, 95% CI: 4.76-5.54), major bleeding (OR: 11.46, 95% CI: 10.66-12.33) and doubled the hospitalization costs ($31,452 vs $17.566). CONCLUSIONS: Our study of over six million PCI procedures demonstrates that patients with the greatest comorbid burden (as defined by an ECS of >13) have a fivefold increase risk of in-hospital mortality, a fourfold increase in in-hospital periprocedural complications and an 11-fold increase in major bleeding events once differences in baseline patient characteristics are adjusted for. In addition, ECS significantly impacts the length of stay and doubles the healthcare costs. Comorbid burden is an important predictor of poor outcomes after PCI and should be considered as part of the decision-making processes in patients undergoing PCI.

Radiation exposure in relation to the arterial access site used for diagnostic coronary angiography and percutaneous coronary intervention: a systematic review and meta-analysis.

BACKGROUND: Transradial access for cardiac catheterisation results in lower bleeding and vascular complications than the traditional transfemoral access route. However, the increased radiation exposure potentially associated with transradial access is a possible drawback of this method. Whether transradial access is associated with a clinically significant increase in radiation exposure that outweighs its benefits is unclear. Our aim was therefore to compare radiation exposure between transradial access and transfemoral access for diagnostic coronary angiograms and percutaneous coronary interventions (PCI). METHODS: We did a systematic review and meta-analysis of the scientific literature by searching the PubMed, Embase, and Cochrane Library databases with relevant terms, and cross-referencing relevant articles for randomised controlled trials (RCTs) that compared radiation parameters in relation to access site, published from Jan 1, 1989, to June 3, 2014. Three investigators independently sorted the potentially relevant studies, and two others extracted data. We focused on the primary radiation outcomes of fluoroscopy time and kerma-area product, and used meta-regression to assess the changes over time. Secondary outcomes were operator radiation exposure and procedural time. We used both fixed-effects and random-effects models with inverse variance weighting for the main analyses, and we did confirmatory analyses for observational studies. FINDINGS: Of 1252 records identified, we obtained data from 24 published RCTs for 19 328 patients. Our primary analyses showed that transradial access was associated with a small but significant increase in fluoroscopy time for diagnostic coronary angiograms (weighted mean difference [WMD], fixed effect: 1·04 min, 95% CI 0·84-1·24; p<0·0001) and PCI (1·15 min, 95% CI 0·96-1·33; p<0·0001), compared with transfemoral access. Transradial access was also associated with higher kerma-area product for diagnostic coronary angiograms (WMD, fixed effect: 1·72 Gy·cm(2), 95% CI -0·10 to 3·55; p=0·06), and significantly higher kerma-area product for PCI (0·55 Gy·cm(2), 95% CI 0·08-1·02; p=0·02). Mean operator radiation doses for PCI with basic protection were 107 µSv (SD 110) with transradial access and 74 µSv (68) with transfemoral access; with supplementary protection, the doses decreased to 21 µSv (17) with transradial access and 46 µSv (9) with transfemoral. Meta-regression analysis showed that the overall difference in fluoroscopy time between the two procedures has decreased significantly by 75% over the past 20 years from 2 min in 1996 to about 30 s in 2014 (p<0·0001). In observational studies, differences and effect sizes remained consistent with RCTs. INTERPRETATION: Transradial access was associated with a small but significant increase in radiation exposure in both diagnostic and interventional procedures compared with transfemoral access. Since differences in radiation exposure narrow over time, the clinical significance of this small increase is uncertain and is unlikely to outweigh the clinical benefits of transradial access. FUNDING: None.

Stroke following percutaneous coronary intervention: type-specific incidence, outcomes and determinants seen by the British Cardiovascular Intervention Society 2007-12.

AIMS: This study aims to evaluate temporal changes in stroke complications and their association with mortality and MACE outcomes in a national cohort of patients undergoing percutaneous coronary interventions (PCIs) in England and Wales. METHODS AND RESULTS: A total of 426 046 patients who underwent PCI in England and Wales between 2007 and 2012 in the British Cardiovascular Intervention Society (BCIS) database were analysed. Statistical analyses were performed evaluating the rates of stroke complications according to the year of PCI and multiple logistic regressions were used to evaluate the odds of 30-day mortality and in-hospital major adverse cardiovascular events (MACE; a composite of in-hospital mortality, myocardial infarction or re-infarction, and revascularization) with stroke complications. Four hundred and thirty-six patients (0.1%) sustained an ischaemic stroke/TIA complication and 107 patients (0.03%) sustained a haemorrhagic stroke complication. Ischaemic stroke/TIA complications increased non-linearly from 0.67 (95% CI 0.47-0.87) to 1.14 (0.94-1.34) per 1000 patients between 2007 and 2012 (P = 0.006), whilst haemorrhagic stroke rates decreased non-linearly from 0.29 (0.19-0.39) to 0.15 (0.05-0.25) per 1000 patients in 2012 (P = 0.009). Following adjustment for baseline clinical and procedural demographics, ischaemic stroke was independently associated with both 30-day mortality (OR 4.92, 3.06-7.92) and in-hospital MACE (OR 3.11, 1.83-5.27). An even greater impact on prognosis was observed with haemorrhagic complications (30-day mortality: OR 13.87, 6.37-30.21), in-hospital MACE (OR 13.50, 6.30-28.92). CONCLUSIONS: Incident ischaemic stroke complications have increased over time, whilst haemorrhagic stroke complications have decreased, driven through changes in clinical, procedural, drug-treatment, and demographic factors. Both ischaemic and haemorrhagic strokes are rare but devastating complications with high 30-day mortality and in-hospital MACE rates.

Arterial access site utilization in cardiogenic shock in the United Kingdom: is radial access feasible?

BACKGROUND: Cardiogenic shock (CS) remains the leading cause of mortality in patients hospitalized with acute myocardial infarction (AMI). The transradial access site (TRA) has become increasingly adopted as a default access site for percutaneous coronary intervention (PCI); however, even in experienced centers that favor the radial artery as the primary access site during PCI, patients presenting in CS are often treated via the transfemoral access site (TFA); and commentators have suggested that CS remains the final frontier that has given even experienced radial operators pause. We studied the use of TRA in patients presenting in CS in a nonselected high-risk cohort from the British Cardiovascular Intervention database over a 7-year period (2006-2012). METHODS: Mortality (30-day) and major adverse cardiac and cerebrovascular events (a composite of in-hospital mortality, in-hospital myocardial reinfarction, target vessel revascularization, and cerebrovascular events) were studied based on TFA and TRA utilization in CS patients. The influence of access site selection was studied in 7,231 CS patients; TFA was used in 5,354 and TRA in 1,877 patients. RESULTS: Transradial access site was independently associated with a lower 30-day mortality (hazard ratio [HR] 0.56, 95% CI 0.46-0.69, P = 0 < .001), in-hospital major adverse cardiac and cerebrovascular events (HR 0.64, 95% CI 0.53-0.76, P < .0001) and major bleeding (HR 0.37, 95% CI 0.18-0.73, P = .004). CONCLUSIONS: Although the majority of PCI cases performed in patients with cardiogenic shock in the United Kingdom are performed through the TFA, the radial artery represents an alternative viable access site in this high-risk cohort of patients in experienced centers.

Analyses of crime patterns in NIBRS data based on a novel graph theory clustering method: Virginia as a case study.

This paper suggests a novel clustering method for analyzing the National Incident-Based Reporting System (NIBRS) data, which include the determination of correlation of different crime types, the development of a likelihood index for crimes to occur in a jurisdiction, and the clustering of jurisdictions based on crime type. The method was tested by using the 2005 assault data from 121 jurisdictions in Virginia as a test case. The analyses of these data show that some different crime types are correlated and some different crime parameters are correlated with different crime types. The analyses also show that certain jurisdictions within Virginia share certain crime patterns. This information assists with constructing a pattern for a specific crime type and can be used to determine whether a jurisdiction may be more likely to see this type of crime occur in their area.

Post-discharge and long-term follow-up after an acute coronary syndrome: International Collaborative Group of CNCF position paper.

Introduction: Long-term follow-up after an acute coronary syndrome (ACS) presents a crucial challenge due to the high residual cardiovascular risk and the potential for major bleeding events. Although several treatment strategies are available, this article focuses on patients who have undergone percutaneous coronary intervention (PCI) for ACS, which is a frequent clinical situation. This position paper aims to support physicians in daily practice to improve the management of ACS patients. Material and methods: A group of recognized international and French experts in the field provides an overview of current evidence-based recommendations - supplemented by expert opinion where such evidence is lacking - and a practical guide for the management of patients with ACS after hospital discharge. Results: The International Collaborative Group underlines the need of a shared collaborative approach, and a care plan individualized to the patient's risk profile for both ischaemia and bleeding. Each follow-up appointment should be viewed as an opportunity to optimize the personalized approach, to reduce adverse clinical outcomes and improve quality of life. As risks - both ischaemic and haemorrhagic - evolve over time, the risk-benefit balance should be assessed in an ongoing dynamic process to ensure that patients are given the most suitable treatment at each time point. Conclusions: This Expert Opinion aims to help clinicians with a practical guide underlying the proven strategies and the remaining gaps of evidence to optimize the management of coronary patients.

Left vs. right radial approach for coronary catheterization: Relation to age and severe aortic stenosis.

Background: Old age and the presence of aortic stenosis are associated with the unfolding of the intrathoracic aorta. This may result in increased difficulties navigating catheters from the right compared to the left radial approach. Objective: To investigate whether increasing age or presence of severe aortic stenosis was associated with increased catheterization success rates from left (LRA) compared to right radial artery approach (RRA). Methods: We compared coronary angiography success rates of RRA and LRA according to different age groups and in a subgroup of patients with severe aortic stenosis. Results: A total of 21,259 coronary angiographies were evaluated. With increasing age, the first pass success rate from either radial access decreased significantly (p < 0.001). In patients aged <85 years, there was no difference between LRA and RRA. However, in patients aged ≥85 years, LRA was associated with significantly higher success rates compared to RRA (90.1 vs. 82.8%, p = 0.003). Patients aged ≥85 years received less contrast agent and had shorter fluoroscopy time when LRA was used [86.6 ± 41.1 vs. 99.6 ± 48.7 ml (p < 0.001) and 4.5 ± 4.1 min vs. 6.2 ± 5.7 min (p < 0.001), mean (±SD)]. In patients with severe aortic stenosis (n = 589) better first pass success rates were observed via LRA compared to the RRA route (91.9 vs. 85.1%, p = 0.037). Conclusion: LRA, compared to RRA, is associated with a higher first-pass catheter success rate for coronary artery angiography in patients aged ≥85 years and those with severe aortic stenosis.

A National Evaluation of Emergency Cardiac Surgery After Percutaneous Coronary Intervention and Postsurgical Patient Outcomes.

There is limited national data regarding emergency cardiac surgery for complications sustained after percutaneous coronary intervention (PCI). This study aimed to examine emergency cardiac surgery after PCI in England and Wales and postsurgical patient outcomes. We analyzed patients in the British Cardiovascular Intervention Society database who underwent PCI between 2007 and 2014 and compared characteristics and outcomes for patients with and without emergency cardiac surgery. A total of 549,303 patients were included in the analysis and 362 (0.07%) underwent emergency cardiac surgery. There was a modest decline in the annual rate of emergency cardiac surgery from 0.09% to 0.06% between 2007 and 2014. Variables associated with emergency cardiac surgery included receipt of circulatory support (Odds ratio (OR) 39.20 95% confidence interval (CI) 27.75 to 55.36), aortic dissection (OR 28.39 95%CI 14.59 to 55.26), coronary dissection (OR 18.50 95%CI 13.60 to 25.18), coronary perforation (OR 7.86 95%CI 4.27 to 14.46), cardiac tamponade (OR 6.77 95%CI 3.13 to 14.66), and on-site surgical cover (OR 2.15 95%CI 1.56 to 2.97). After adjustments, patients with emergency cardiac surgery were at increased odds of 30-day mortality (OR 4.41 95%CI 2.94 to 6.62) and in-hospital major adverse cardiac and cerebrovascular events (OR 1.63 95%CI 1.07 to 2.48). On site surgical cover was independently associated with increased odds of mortality (OR 1.26 95%CI 1.20 to 1.33) following emergency cardiac surgery. In conclusion, emergency cardiac surgery after PCI is a rarely required procedure and in England and Wales there appears to be a decline in recent years. Patients who underwent emergency cardiac surgery have higher risk of adverse outcomes and longer length of hospital stay.

Outcomes of Percutaneous Coronary Intervention in Patients With Crohn's Disease and Ulcerative Colitis (from a Nationwide Cohort).

Patients with inflammatory bowel disease (IBD) are at an increased risk of ischemic heart disease. However, there is limited evidence on how their outcomes after percutaneous coronary intervention (PCI) compare with those without IBD. All PCI-related hospitalizations from the National Inpatient Sample from 2004 to 2015 were included, stratified into 3 groups: no-IBD, Crohn's disease (CD), and ulcerative colitis (UC). We assessed the association between IBD subtypes and in-hospital outcomes. A total of 6,689,292 PCI procedures were analyzed, of which 0.3% (n = 18,910) had an IBD diagnosis. The prevalence of IBD increased from 0.2% (2004) to 0.4% (2015). Patients with IBD were less likely to have conventional cardiovascular risk factors and more likely to undergo PCI for an acute indication, and to receive bare metal stents. In comparison to patients without IBD, those with IBD had reduced or similar adjusted odds ratios (OR) of major adverse cardiovascular and cerebrovascular events (CD OR 0.69, 95% confidence interval (CI) 0.62 to 0.78; UC OR 0.75, 95% CI 0.66 to 0.85), mortality (CD: OR 0.94, 95% CI 0.79 to 1.11; UC OR 0.35, 95% CI 0.27 to 0.45) or acute cerebrovascular accident (CD: OR 0.73, 95% CI 0.60 to 0.89; UC: OR 0.94, 95% CI 0.77 to 1.15). However, IBD patients had an increased odds for major bleeding (CD: OR 1.42 95% CI 1.23 to 1.63, and UC: OR 1.35 95% CI 1.16 to 1.58). In summary, IBD is associated with a decreased risk of in-hospital post-PCI complications other than major bleeding that was significantly higher in this group. Long term follow-up is required to evaluate the safety of PCI in IBD patients from both bleeding and ischemic perspectives.

Readmissions to Hospital After Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis of Factors Associated with Readmissions.

BACKGROUND: Readmissions after PCI are a burden to patients and health services that are not well understood. METHODS: A systematic review was performed to identify studies of readmission after PCI. Readmission rates and causes of readmission were examined and factors associated with 30-day readmissions were combined using meta-analyses. RESULTS: A total of 39 studies evaluated readmissions after PCI (6,569,690 patients, 31 studies). The 30-day readmission rate varied from 3.3%-15.8%. Beyond 30-days, the readmission rate was 6% at 2 months, 31.5% at 6 months, 18.6-50.4% at 12 months and 26.3-71% beyond 48 months. The pooled proportion of patients with cardiac cause for readmissions ranged from 4.6%-75.3%. The range of rates of 30-day readmissions for reinfarction/stent thrombosis, heart failure, chest pain and bleeding were 2.5%-9.5%, 5.9%-12%, 6.7-38.1% and 0.7-7.5%, respectively. Meta-analysis suggests that female gender (RR 1.25(1.20-1.30), I2 = 65.2%), diabetes (RR 1.22(1.20-1.25), I2 = 0%), heart failure (RR 1.43(CI 1.28-1.60), I2 = 92.8%), renal failure (RR 1.50(1.45-1.55), I2 = 0%), chronic lung disease (RR 1.34(1.26-1.44), I2 = 87.5%), peripheral artery disease (RR 1.20(1.15-1.25), I2 = 46.5%) and cancer (RR 1.35(1.15-1.58), I2 = 72.8%) were associated with 30-day readmissions. The average cost of unplanned and all 30-day readmissions has been reported to be $12,636 and $17,576, respectively. CONCLUSIONS: We estimate that 1 in 7 patients who undergo PCI are readmitted within 30-days and the rate can rise to up to 3 in 4 patients beyond 3 years. Interventions should be considered to reduce readmissions such as discharge checklists, evaluation of medication compliance at follow-up and prompt management when patients re-present to emergency department.

Transcatheter aortic valve replacement outcomes in bicuspid compared to trileaflet aortic valves.

AIM: TAVR in patients with bicuspid aortic valves (BAV) is more challenging compared to individuals with trileaflet aortic valves (TAV). BAV have been excluded from the large randomized clinical trials assessing transcatheter aortic valve replacements (TAVR) and has been considered as a relative contraindication to TAVR. To report the outcomes of TAVR in BAV and compare them to TAV in the National Inpatient Sample (NIS). METHODS AND RESULTS: TAVR procedures were identified between 2011 and 2014 in the NIS dataset. Endpoints assessed included in-hospital mortality, periprocedural complications, length of stay and cost. Of 40,604 identified TAVR procedures, 407 (1%) were BAV and the 40,197 (99%) were TAV. Patients with BAV were younger and had a lower comorbidity burden. In hospital mortality (4.89% vs 4.17%, OR: 1.71, 95%CI: 0.57-5.12, P = 0.21), AMI (3.49% vs 3.58%, OR: 1.12, 95%CI: 0.36-3.54, P = 0.85), stroke and TIA (2.49% vs 3.55%, OR: 0.75, 95%CI: 0.18-3.16, P = 0.70), vascular complications (2.39% vs 5.58%, OR:0.47, 95%CI: 0.11-1.93, P = 0.29), major bleeding (16.96% vs 23.50%, OR: 0.63, 95%CI: 0.34-1.17, P = 0.15) and rates of permanent pacemaker (PPM) (9.88% vs 10.88%, OR: 1.19, 95%CI: 0.57-2.51, P = 0.64) were similar in both cohorts. CONCLUSIONS: With multimodality imaging and further improvement in technology, our study demonstrates off-label TAVR should not be considered prohibitive and can be successfully performed for BAV with similar peri-procedural outcomes compared to those with TAV. However, there is a need for robust large prospective studies.

Changes in Periprocedural Bleeding Complications Following Percutaneous Coronary Intervention in The United Kingdom Between 2006 and 2013 (from the British Cardiovascular Interventional Society).

Major bleeding is a common complication after percutaneous coronary intervention (PCI), although little is known about how bleeding rates have changed over time and what has driven this. We analyzed all patients who underwent PCI in England and Wales from 2006 to 2013. Multivariate analyses using logistic regression models were performed to identify predictors of bleeding to identify potential factors influencing bleeding trends over time. 545,604 participants who had PCI in England and Wales between 2006 and 2013 were included in the analyses. Overall bleeding rates decreased from 7.0 (CI 6.2 to 7.8) per 1,000 procedures in 2006 to 5.5 (CI 4.7 to 6.2) per 1,000 in 2013. Increasing age, female sex, GPIIb/IIIa inhibitors use, and circulatory support were independently associated with increased risk of bleeding complications whereas radial access and vascular closure device use were independently associated with decreases in risk. Decreases in bleeding rates over time were associated with radial access site, and changes in pharmacology, but this was offset by greater proportion of ACS cases and the adverse patient clinical demographics. In conclusion, major bleeding complications after PCI have decreased due to changes in access site practice and decreased usage of GPIIb/IIIa inhibitors, but this is offset by the increase of patients with higher propensity to bleed. Changes in access site practice nationally have the potential to significantly reduce major bleeding after PCI.

A Quality by Design Approach to Developing and Manufacturing Polymeric Nanoparticle Drug Products.

The translation of nanomedicines from concepts to commercial products has not reached its full potential, in part because of the technical and regulatory challenges associated with chemistry, manufacturing, and controls (CMC) development of such complex products. It is critical to take a quality by design (QbD) approach to developing nanomedicines-using a risk-based approach to identifying and classifying product attributes and process parameters and ultimately developing a deep understanding of the products, processes, and platform. This article exemplifies a QbD approach used by BIND Therapeutics, Inc., to industrialize a polymeric targeted nanoparticle drug delivery platform. The focus of the approach is on CMC affairs but consideration is also given to preclinical, clinical, and regulatory aspects of pharmaceutical development. Processes are described for developing a quality target product profile and designing supporting preclinical studies, defining critical quality attributes and process parameters, building a process knowledge map, and employing QbD to support outsourced manufacturing.

A novel in situ hydrophobic ion paring (HIP) formulation strategy for clinical product selection of a nanoparticle drug delivery system.

The present studies were aimed at formulating AZD2811-loaded polylactic acid-polyethylene glycol (PLA-PEG) nanoparticles with adjustable release rates without altering the chemical structures of the polymer or active pharmaceutical ingredient (API). This was accomplished through the use of a hydrophobic ion pairing approach. A series of AZD2811-containing nanoparticles with a variety of hydrophobic counterions including oleic acid, 1-hydroxy-2-naphthoic acid, cholic acid, deoxycholic acid, dioctylsulfosuccinic acid, and pamoic acid is described. The hydrophobicity of AZD2811 was increased through formation of ion pairs with these hydrophobic counterions, producing nanoparticles with exceptionally high drug loading-up to five fold higher encapsulation efficiency and drug loading compared to nanoparticles made without hydrophobic ion pairs. Furthermore, the rate at which the drug was released from the nanoparticles could be controlled by employing counterions with various hydrophobicities and structures, resulting in release half-lives ranging from about 2 to 120h using the same polymer, nanoparticle size, and nanoemulsion process. Process recipe variables affecting drug load and release rate were identified, including pH and molarity of quench buffer. Ion pair formation between AZD2811 and pamoic acid as a model counterion was investigated using solubility enhancement as well as nuclear magnetic resonance spectroscopy to demonstrate solution-state interactions. Further evidence for an ion pairing mechanism of controlled release was provided through the measurement of API and counterion release profiles using high-performance liquid chromatography, which had stoichiometric relationships. Finally, Raman spectra of an AZD2811-pamoate salt compared well with those of the formulated nanoparticles, while single components (AZD2811, pamoic acid) alone did not. A library of AZD2811 batches was created for analytical and preclinical characterization. Dramatically improved preclinical efficacy and tolerability data were generated for the pamoic acid lead formulation, which has been selected for evaluation in a Phase 1 clinical trial (ClinicalTrials.gov Identifier NCT 02579226). This work clearly demonstrates the importance of assessing a wide range of drug release rates during formulation screening as a critical step for new drug product development, and how utilizing hydrophobic ion pairing enabled this promising nanoparticle formulation to proceed into clinical development.

Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo.

Efforts to apply nanotechnology in cancer have focused almost exclusively on the delivery of cytotoxic drugs to improve therapeutic index. There has been little consideration of molecularly targeted agents, in particular kinase inhibitors, which can also present considerable therapeutic index limitations. We describe the development of Accurin polymeric nanoparticles that encapsulate the clinical candidate AZD2811, an Aurora B kinase inhibitor, using an ion pairing approach. Accurins increase biodistribution to tumor sites and provide extended release of encapsulated drug payloads. AZD2811 nanoparticles containing pharmaceutically acceptable organic acids as ion pairing agents displayed continuous drug release for more than 1 week in vitro and a corresponding extended pharmacodynamic reduction of tumor phosphorylated histone H3 levels in vivo for up to 96 hours after a single administration. A specific AZD2811 nanoparticle formulation profile showed accumulation and retention in tumors with minimal impact on bone marrow pathology, and resulted in lower toxicity and increased efficacy in multiple tumor models at half the dose intensity of AZD1152, a water-soluble prodrug of AZD2811. These studies demonstrate that AZD2811 can be formulated in nanoparticles using ion pairing agents to give improved efficacy and tolerability in preclinical models with less frequent dosing. Accurins specifically, and nanotechnology in general, can increase the therapeutic index of molecularly targeted agents, including kinase inhibitors targeting cell cycle and oncogenic signal transduction pathways, which have to date proved toxic in humans.

Major Bleeding and Adverse Outcome following Percutaneous Coronary Intervention.

Advances in anti-thrombotic and anti-platelet therapies have improved outcomes in patients undergoing percutaneous coronary interventions (PCIs) through a reduction in ischaemic events, at the expense of peri-procedural bleeding complications. These may occur through either the access site through which the PCI was performed or through non-access-related sites. There are currently over 10 definitions of major bleeding events consisting of clinical events, changes in laboratory parameters and clinical outcomes, where different definitions will differentially influence the reported incidence of major bleeding events. Use of different major bleeding definitions has been shown to change the reported outcome of a number of therapeutic strategies in randomised controlled trials but as yet a universal bleeding definition has not gained widespread adoption in assessing the efficacy of such therapeutic interventions. Major bleeding complications are independently associated with adverse mortality and major adverse cardiovascular event (MACE) outcomes, irrespective of the definition of major bleeding used, with the worst outcomes associate with non-access-site related bleeds. We consider the mechanisms through which bleeding complications may affect longer-term outcomes and discuss bleeding avoidance strategies, including access site choice, pharmacological considerations and formal bleeding risk assessment to minimise such bleeding events.

Blood transfusion after percutaneous coronary intervention and risk of subsequent adverse outcomes: a systematic review and meta-analysis.

OBJECTIVES: This study sought to define the prevalence and prognostic impact of blood transfusions in contemporary percutaneous coronary intervention (PCI) practice. BACKGROUND: Although the presence of anemia is associated with adverse outcomes in patients undergoing PCI, the optimal use of blood products in patients undergoing PCI remains controversial. METHODS: A search of EMBASE and MEDLINE was conducted to identify PCI studies that evaluated blood transfusions and their association with major adverse cardiac events (MACE) and mortality. Two independent reviewers screened the studies for inclusion, and data were extracted from relevant studies. Random effects meta-analysis was used to estimate the risk of adverse outcomes with blood transfusions. Statistical heterogeneity was assessed by considering the I(2) statistic. RESULTS: Nineteen studies that included 2,258,711 patients with more than 54,000 transfusion events were identified (prevalence of blood transfusion 2.3%). Crude mortality rate was 6,435 of 50,979 (12.6%, 8 studies) in patients who received a blood transfusion and 27,061 of 2,266,111 (1.2%, 8 studies) in the remaining patients. Crude MACE rates were 17.4% (8,439 of 48,518) in patients who had a blood transfusion and 3.1% (68,062 of 2,212,730) in the remaining cohort. Meta-analysis demonstrated that blood transfusion was independently associated with an increase in mortality (odds ratio: 3.02, 95% confidence interval: 2.16 to 4.21, I(2) = 91%) and MACE (odds ratio: 3.15, 95% confidence interval: 2.59 to 3.82, I(2) = 81%). Similar observations were recorded in studies that adjusted for baseline hematocrit, anemia, and bleeding. CONCLUSIONS: Blood transfusion is independently associated with increased risk of mortality and MACE events. Clinicians should minimize the risk for periprocedural transfusion by using available bleeding-avoidance strategies and avoiding liberal transfusion practices.