Time to TAVI: streamlining the pathway to treatment.

INTRODUCTION: Severe aortic stenosis is a major cause of morbidity and mortality. The existing treatment pathway for transcatheter aortic valve implantation (TAVI) traditionally relies on tertiary Heart Valve Centre workup. However, this has been associated with delays to treatment, in breach of British Cardiovascular Intervention Society targets. A novel pathway with emphasis on comprehensive patient workup at a local centre, alongside close collaboration with a Heart Valve Centre, may help reduce the time to TAVI. METHODS: The centre performing local workup implemented a novel TAVI referral pathway. Data were collected retrospectively for all outpatients referred for consideration of TAVI to a Heart Valve Centre from November 2020 to November 2021. The main outcome of time to TAVI was calculated as the time from Heart Valve Centre referral to TAVI, or alternative intervention, expressed in days. For the centre performing local workup, referral was defined as the date of multidisciplinary team discussion. For this centre, a total pathway time from echocardiographic diagnosis to TAVI was also evaluated. A secondary outcome of the proportion of referrals proceeding to TAVI at the Heart Valve Centre was analysed. RESULTS: Mean±SD time from referral to TAVI was significantly lower at the centre performing local workup, when compared with centres with traditional referral pathways (32.4±64 to 126±257 days, p<0.00001). The total pathway time from echocardiographic diagnosis to TAVI for the centre performing local workup was 89.9±67.6 days, which was also significantly shorter than referral to TAVI time from all other centres (p<0.003). Centres without local workup had a significantly lower percentage of patients accepted for TAVI (49.5% vs 97.8%, p<0.00001). DISCUSSION: A novel TAVI pathway with emphasis on local workup within a non-surgical centre significantly reduced both the time to TAVI and rejection rates from a Heart Valve Centre. If adopted across the other centres, this approach may help improve access to TAVI.

Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma.

Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clinical trials.

Implementation of NICE clinical guideline 95 on chest pain of recent onset: experience in a district general hospital.

The National Institute for Health and Care Excellence (NICE) CG95 clinical guideline on chest pain of recent onset was published in 2010. There is debate over whether the proposed strategy improves patient care and its implications on service costs. Following a six-month pilot, 472 consecutive patient records were audited for pre-test probability of significant coronary artery disease, investigations performed and outcomes. Low- and moderate-risk patients had an unexpectedly low rate of coronary disease and revascularisation. Computerised tomography coronary angiography (CTCA) and stress echocardiography performed similarly, though the latter was more resource intensive. High-/very high-risk patients frequently required revascularisation and greater than 10% of each group had prognostically significant disease, going against the recommendation that very high risk patients do not undergo angiography. There were frequent protocol deviations and training clinic staff in the new approach was challenging. In conclusion, implementing NICE CG95 is feasible but presents challenges. Staff require training to follow the protocol consistently. Functional testing had no benefits over anatomical testing with CTCA, which may allow cost savings in some departments.

Design, structure-activity relationship, and in vivo characterization of the development candidate NVP-HSP990.

Utilizing structure-based drug design, a novel dihydropyridopyrimidinone series which exhibited potent Hsp90 inhibition, good pharmacokinetics upon oral administration, and an excellent pharmacokinetic/pharmacodynamic relationship in vivo was developed from a commercial hit. The exploration of this series led to the selection of NVP-HSP990 as a development candidate.

Evaluating stent optimisation technique (StentBoost®) in a dedicated bifurcation stent (the Tryton™).

BACKGROUND/PURPOSE: To evaluate the use of StentBoost® in the Tryton™ dedicated SideBranch Stent. METHODS & RESULTS: The Tryton™ SideBranch Stent has been effectively used to manage complex bifurcations. However, the paucity of scaffolding in the proximal part of the stent makes it often difficult to visualise under standard radiographic imaging. We set out to evaluate whether by using an augmented radiographic imaging technique it was possible to aid visualisation of the stent. In particular the so call 'wedding ring' band which is crucial to the procedural success. We further evaluated whether it was possible to determine the apposition of the stent at the carina, its coverage and the ability to aid recrossing of the struts closest to the carina as well as the added radiation exposure. CONCLUSIONS: StentBoost® was found to be invaluable to the procedural success of the Tryton™ deployment without adding any extra cost to the procedure and with only a 3.7% increase in radiation to the patient. It allowed enhanced visualisation in all cases to aid apposition, recrossing and coverage.

Spontaneous coronary artery dissection as a cause of sudden cardiac death in the peripartum period.

Spontaneous coronary artery dissection is a rare cause of acute coronary syndromes and can be potentially fatal. The authors describe a case of multi-vessel coronary artery dissection occurring in a young postpartum mother. The diagnosis was established by coronary artery angiography. However, the patient died following a cardiac arrest. The authors discuss the methods of investigation available and the different treatment options.

Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors.

The inhibition of key receptor tyrosine kinases (RTKs) that are implicated in tumor vasculature formation and maintenance, as well as tumor progression and metastasis, has been a major focus in oncology research over the last several years. Many potent small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases have been evaluated. More recently, compounds that act through the complex inhibition of multiple kinase targets have been reported and may exhibit improved clinical efficacy. We report herein a series of potent, orally efficacious 4-amino-3-benzimidazol-2-ylhydroquinolin-2-one analogues as inhibitors of VEGF, PDGF, and fibroblast growth factor (FGF) receptor tyrosine kinases. Compounds in this class, such as 5 (TKI258), are reversible ATP-competitive inhibitors of VEGFR-2, FGFR-1, and PDGFRbeta with IC(50) values <0.1 microM. On the basis of its favorable in vitro and in vivo properties, compound 5 was selected for clinical evaluation and is currently in phase I clinical trials.

Capecitabine induced acute coronary syndrome.

Capecitabine is an oral chemotherapeutic agent recommended by the National Institute for Clinical Excellence as first line treatment for metastatic bowel cancer and second line for breast cancer. With the increasing prevalence and diagnosis of these common malignancies, it is essential that physicians are made aware of the rare, but potentially fatal, cardiac effects of capecitabine. This case report demonstrates a typical presentation of suspected acute coronary syndrome with associated ECG changes in a patient who had started capecitabine 2 days before admission. His troponin was mildly elevated and his ECGs resolved on discontinuation of the drug, but a positive exercise tolerance test precipitated coronary angiography; which was essentially normal, as was his echocardiogram and computed tomography scan. Previous literature has highlighted potential cardiac complications of a similar chemotherapeutic agent 5-fluorouracil, which is the active metabolite present in capecitabine. The possible presentations, complications and clinical management are discussed in this case report.