Capturing the holistic value of biosimilars in Europe - part 1: a historical perspective.

INTRODUCTION: Approved biosimilars exhibit comparable efficacy, safety, and immunogenicity to reference products. This report provides perspectives on the societal value of biosimilars within Europe and potential factors that have influenced market dynamics. METHODS: An independent, self-administered survey or one-on-one in-depth interview was used to collect viewpoints about the impact of biosimilar medicines within European markets. Key insights were also sought from an expert panel of European stakeholders. RESULTS: Survey respondents were clinicians, pharmacists, and payers from Europe (N = 103). Perceived benefits of biosimilars included increased access to innovative medicines (73% of respondents) or biologic treatments (66%). Biosimilar competition was thought to expand access to biologics (~50% of respondents) or drug combinations (~36%) and reduce biologic access time (34%). Key drivers of biologic access after biosimilar competition included increased biologic awareness (51%) and changes to prescribing guidelines (37%) and/or treatment paradigms (28%). The expert panel developed a market maturity framework of biosimilar adoption/opportunities comprising three stages: 'Invest,' 'Expand,' and 'Harvest.' Findings were supported by published literature. CONCLUSIONS: In Europe, the perceptions of well-informed survey/interview respondents are that biosimilars have improved patient outcomes via increased access to biologics and innovative biologic products, contributing to earlier and longer treatment of a broader population.

Leveraging the holistic benefits of biosimilars in Europe - part 2: how payers can safeguard the future of a healthy biosimilar market environment.

INTRODUCTION: Biosimilars have improved access to biologic medicines; however, historical thinking may jeopardize the viability of future markets. AREAS COVERED: An expert panel of eight diverse European stakeholders provided insights about rethinking biosimilars and cost-savings, reducing patient access inequalities, increasing inter-market equity, and improving education. The insights reported here (Part 2) follow a study that provides perspectives on leveraging the holistic benefits of biosimilars for market sustainability based on independent survey results and telephone interviews of stakeholders from diverse biosimilar markets (Part 1). Directional recommendations are provided for payers. EXPERT OPINION: The panel's market maturity framework for biosimilars has three stages: 'Invest,' 'Expand' and 'Harvest.' Across market stages, re-thinking the benefits of biosimilars beyond cost-savings, considering earlier or expanded access/new indications, product innovations, and re-investment of biosimilar-generated cost-savings should be communicated to stakeholders to promote further engagement. During 'Expand' and 'Harvest' stages, development of efficient, forward-looking procurement systems and mechanisms that drive uptake and stabilize competition between manufacturers are key. Future biosimilars will target various therapy areas beyond those targeted by existing biosimilars. To ensure a healthy, accessible future market, stakeholders must align their objectives, communicate, collaborate, and coordinate via education, incentivization, and procurement, to maximize the totality of benefits.

Initial experience of temperature-controlled irrigated radiofrequency ablation for ischaemic cardiomyopathy ventricular tachycardia ablation.

BACKGROUND: The DiamondTemp ablation (DTA) catheter system delivers high power, open-irrigated, temperature-controlled radiofrequency (RF) ablation. This novel ablation system has not been previously used for ventricular tachycardia (VT) ablation. OBJECTIVE: Feasibility of using the DTA catheter system for VT ablation in ischaemic cardiomyopathy (ICM) patients. METHOD: Ten ICM patients with optimal anti-arrhythmic drug therapy and implantable cardiac defibrillators (ICD) were recruited. VT inducibility testing was performed at the end of the procedure. ICD data for device detected VT episodes and device treated VT episodes were collected for 6-months pre- and post-ablation. RESULTS: Substrate analysis demonstrated reductions in the borderzone area of 4.4 cm2 (p = 0.026) and late potential area of 3.5 cm2 (p = 0.0449) post-ablation, with reductions in the mean bipolar and unipolar voltages of the ablation target areas (0.14 mV (p = 0.0007); 0.59 mV (p = 0.0072) respectively). Complete procedural success was achieved in 9 procedures. Post-ablation VT inducibility testing was not performed in 1 procedure due to a steam pop complication resulting in pericardial tamponade requiring drainage. Mean follow-up of 214 ± 33 days revealed an 88% reduction in total VT episodes (n = 266 median 16 [IQR 3-57] to n = 33 median 0; p = 0.0164) and 77% reduction in ICD therapies (n = 128 median 5 [IQR 2-15] to n = 30 median 0; p = 0.0181). CONCLUSION: The DTA system resulted in adequate lesion characteristics with effective substrate modification, acute procedural success and improved outcomes at intermediate-term follow-up. Randomised controlled trials are required to compare the performance of the DTA system against conventional ablation catheters.

Patient Pathways in Cardiology: Should Pharmaceutical and Medical Device Companies Care?

A shared goal of patients, providers, and the companies that produce new therapies is to have these therapies used according to guidelines. Health services specialize in patient care and may lack the capabilities to take a product from conception through to everyday use. This results in a mutually beneficial relationship between health services and industry. The market for cardiovascular drugs is significant, which results in competition between companies. While traditional methods of observational analysis may be able to determine to what extent drugs and devices are being prescribed or implanted by health providers, there is less real-world patient level insight as to why patients are taking (or not taking) these treatments and why one agent is chosen over another. Considering patient pathways is a novel approach that can be utilized to understand real-world patient activities. This approach focuses on the patient flow across the healthcare system and barriers at each stage including identification of patients, diagnostic testing, the decisions on treatment, and prescribing can help identify ways of improving the utilization based on guidelines. It overcomes several assumptions related to patient and clinician decision-making and practical considerations such as geography and availability of health services. In this article, we introduce the concept of patient pathways and why considering them maybe of interest to companies. As significant resources are invested to bring a product to market, this approach can help define if there are missed opportunities for their products to be utilized and potential barriers to implementation.

Safety and feasibility of trans-venous cardiac device extraction using conscious sedation alone-Implications for the post-COVID-19 era.

BACKGROUND: Transvenous lead extraction (TLE) for implantable cardiac-devices is traditionally performed under general anesthesia (GA). This can lead to greater risk of exposure to COVID-19, longer recovery-times and increased procedural-costs. We report the feasibility/safety of TLE using conscious-sedation alone with immediate GA/cardiac-surgery back-up if needed. METHODS: Retrospective case-series of consecutive TLEs performed using conscious-sedation alone between March 2016 and December 2019. All were performed in the electrophysiology-laboratory using intravenous Fentanyl, Midazolam/Diazepam with a stepwise approach using locking-stylets/cutting-sheaths, including mechanical-sheaths. Baseline patient-characteristics, procedural-details and TLE outcomes (including procedure-related complications/death) were recorded. RESULTS: A total of 130 leads were targeted in 54 patients, mean age ± SD 74.6 ± 11.8years, 47(87%) males; dual-chamber pacemakers (n = 26; 48%), cardiac resynchronization therapy-defibrillators (n = 17; 31%) and defibrillators (n = 8; 15%) were commonest extracted devices. Mean ± SD/median (range) lead-dwell times were 11.0 ± 8.8/8.3 (0.3-37) years, respectively. Extraction indications included systemic infection (n = 23; 43%) and lead/pulse-generator erosion (n = 27; 50%); mean 2.1 ± 2.0 leads were removed per procedure/mean procedure-time was 100 ± 54 min. Local anesthetic (LA) was used for all (mean-dose: 33 ± 8 ml 1% lidocaine), IV drug-doses used (mean ± SD) were: midazolam: 3.95 ± 2.44 mg, diazepam: 4.69 ± 0.89 mg and fentanyl: 57 ± 40 µg. Complete lead-extraction was achieved in 110 (85%) leads, partial lead-extraction (<4 cm-fragment remaining) in 5 (4%) leads. Sedation-related hypotension requiring IV fluids occurred in 2 (managed without adverse-consequences) and hypoxia requiring additional airway-management in none. No procedural deaths occurred, one patient required emergency cardiac surgery for localized ventricular perforation, nine had minor complications (transient hypotension/bradycardia/pericardial effusion not requiring intervention). CONCLUSION: TLE undertaken using LA/conscious-sedation was safe/feasible in our series and associated with good clinical outcome/low procedural complications. Reduced risk of aerosolization of COVID-19 and quicker patient recovery/reduced anesthetic risk are potential benefits that warrant further study.

Impact of a high-density grid catheter on long-term outcomes for structural heart disease ventricular tachycardia ablation.

BACKGROUND: Substrate mapping has highlighted the importance of targeting diastolic conduction channels and late potentials during ventricular tachycardia (VT) ablation. State-of-the-art multipolar mapping catheters have enhanced mapping capabilities. The purpose of this study was to investigate whether long-term outcomes were improved with the use of a HD Grid mapping catheter combining complementary mapping strategies in patients with structural heart disease VT. METHODS: Consecutive patients underwent VT ablation assigned to either HD Grid, Pentaray, Duodeca, or point-by-point (PbyP) RF mapping catheters. Clinical endpoints included recurrent anti-tachycardia pacing (ATP), appropriate shock, asymptomatic non-sustained VT, or all-cause death. RESULTS: Seventy-three procedures were performed (33 HD Grid, 22 Pentaray, 12 Duodeca, and 6 PbyP) with no significant difference in baseline characteristics. Substrate mapping was performed in 97% of cases. Activation maps were generated in 82% of HD Grid cases (Pentaray 64%; Duodeca 92%; PbyP 33% (p = 0.025)) with similar trends in entrainment and pace mapping. Elimination of all VTs occurred in 79% of HD Grid cases (Pentaray 55%; Duodeca 83%; PbyP 33% (p = 0.04)). With a mean follow-up of 372 ± 234 days, freedom from recurrent ATP and shock was 97% and 100% respectively in the HD Grid group (Pentaray 64%, 82%; Duodeca 58%, 83%; PbyP 33%, 33% (log rank p = 0.0042, p = 0.0002)). CONCLUSIONS: This study highlights a step-wise improvement in survival free from ICD therapies as the density of mapping capability increases. By using a high-density mapping catheter and combining complementary mapping strategies in a strict procedural workflow, long-term clinical outcomes are improved.

Pain during cardiac implantable electronic device implantation.

In order to evaluate the extent and causes of pain during cardiac implantable electronic device (CIED) implantation in our hospital, a prospective audit over a 23-month period using a patient selfreporting questionnaire was undertaken. In total, 599 procedures were reported, 52.9% for de novo pacemaker implantation and 23.4% for high-energy devices (cardiac resynchronisation therapy defibrillator [CRT-D], implantable cardiac defibrillator [ICD], subcutaneous ICD). Overall, the median pain score was 2/10 (interquartile range 2-4). In total, 61.6% (367/599) reported no pain or mild pain (pain scores 0-3/10), 27.7% (165/599) reported moderate pain (pain score of 4-6/10) and 10.7% (64/599) reported severe pain (pain score of 7-10/10) during the procedure. Significant preimplant worry (odds ratio [OR] 2.13, 95% confidence interval [CI] 1.22 to 3.73) and higher lidocaine doses (OR 1.06, 95%CI 1.00 to 1.11) were associated with severe patient-reported pain. In conclusion, most patients underwent CIED implantation with minimum stress and maximum comfort. An important minority reported severe pain during the procedure. Optimising surgical technique and interventions targeted at reducing pre- and peri-implant worry, particularly in women, and especially in those receiving ICDs, warrants further investigation to reduce patient-reported pain during CIED implantation.

Enhanced ventricular tachycardia substrate resolution with a novel omnipolar high-density mapping catheter: the omnimapping study.

BACKGROUND: Defining diastolic slow-conduction channels within the borderzone (BZ) of scar-dependent re-entrant ventricular tachycardia (VT) is key for effective mapping and ablation strategies. Understanding wavefront propagation is driving advances in high-density (HD) mapping. The newly developed Advisor™ HD Grid Mapping Catheter (HD GRID) has equidistant spacing of 16, 1 mm electrodes in a 4 × 4 3 mm interspaced arrangement allowing bipolar recordings along and uniquely across the splines (orthogonal vector) to facilitate substrate mapping in a WAVE configuration (WAVE). The purpose of this study was to determine the relative importance of the WAVE configuration compared to the STANDARD linear-only bipolar configuration (STANDARD) in defining VT substrate. METHODS: Thirteen patients underwent VT ablation at our institution. In all cases, a substrate map was constructed with the HD GRID in the WAVE configuration (conWAVE) to guide ablation strategy. At the end of the procedure, the voltage map was remapped in the STANDARD configuration (conSTANDARD) using the turbo-map function. Detailed post-hoc analysis of the WAVE and STANDARD maps was performed blinded to the configuration. Quantification of total scar area, BZ and dense scar area with assessment of conduction channels (CC) was performed. RESULTS: The substrate maps conSTANDARD vs conWAVE showed statistically significant differences in the total scar area (56 ± 32 cm2 vs 51 ± 30 cm2; p = 0.035), dense scar area (36 ± 25 cm2 vs 29 ± 22 cm2; p = 0.002) and number of CC (3.3 ± 1.6 vs 4.8 ± 2.5; p = 0.026). conWAVE collected more points than the conSTANDARD settings (p = 0.001); however, it used fewer points in map construction (p = 0.023). CONCLUSIONS: The multipolar Advisor™ HD Grid Mapping Catheter in conWAVE provides more efficient point acquisition and greater VT substrate definition of the borderzone particularly at the low-voltage range compared to conSTANDARD. This greater resolution within the low-voltage range facilitated CC definition and quantification within the scar, which is essential in guiding the ablation strategy.

Long-term follow-up of normal and structural heart ventricular tachycardia catheter ablation: real-world experience from a UK tertiary centre.

Background: Ventricular tachycardia (VT) is associated with increased morbidity and mortality. There is growing evidence for the effectiveness of catheter ablation in improving outcomes in patients with recurrent VT. Consequently the threshold for referral for VT ablation has fallen over recent years, resulting in increased number of procedures. Objective: To evaluate the effectiveness and safety of VT ablation in a real-world tertiary centre setting. Methods: This is a prospective analysis of all VT ablation cases performed at University Hospital Coventry. Follow-up data were obtained from review of electronic medical records and patient interview. The primary endpoint for normal heart VT was death, cardiovascular hospitalisation and VT recurrence, and for structural heart VT was arrhythmic death, VT storm (>3 episodes within 24 hours) or appropriate shock. Results: Forty-seven patients underwent 53 procedures from January 2012 to January 2018. The mean age ±SD was 57±15 years, 68% were male, 81% were Caucasian and 66% were elective cases. The aetiology of VT included normal heart (49%), ischaemic cardiomyopathy (ICM, 36%), dilated cardiomyopathy (9%), hypertrophic cardiomyopathy (4%) and valvular heart disease (2%). Procedural success occurred in 83%, with six major complications. After a median follow-up of 231 days (lower quartile 133, upper quartile 631), the primary outcome occurred in 28% of patients. There were two non-arrhythmic deaths (4%). At a median follow-up of 193 days (129-468), the primary outcome occurred in 19% of patients with ICM, while VT storm/appropriate shocks occurred in three patients (17%). Conclusions: Our real-world registry confirms that VT ablation is safe, and is associated with high acute procedural success and long-term outcomes comparable with randomised controlled studies.

An observational study of endothelial function in early arthritis.

BACKGROUND: Endothelial dysfunction is present in established rheumatoid arthritis, but it is not clear at what stage of the disease this abnormality develops. We set out to determine whether endothelial damage/dysfunction is present in a group of patients with early arthritis (EA) (new onset inflammatory arthritis, EA). MATERIALS AND METHODS: Eighteen patients with EA, 48 healthy controls and 25 disease controls were recruited. Plasma was obtained for endothelial [von Willebrand factor (vWF) and soluble E-selectin] and angiogenesis markers (vascular endothelial growth factor and its receptor sFlt-1), adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1) and circulating endothelial cells (CECs, as a marker of endothelial damage). Microvascular endothelial function was assessed using laser Doppler perfusion imaging and macrovascular function using flow-mediated dilatation of the brachial artery. RESULTS: von Willebrand factor and CECs (both P < 0.05) were significantly elevated in EA suggesting endothelial dysfunction and damage but were unrelated to classical laboratory markers of inflammation C-reactive protein, erythrocyte sedimentation rate or IL6. No other biomarkers was elevated in EA. Microvascular and macrovascular abnormalities were confined to endothelium-independent (smooth muscle cell) responses. CONCLUSIONS: Endothelial damage/dysfunction is present early in the course of inflammatory arthritis but is not directly related to inflammation markers.

Inflammation and microvascular and macrovascular endothelial dysfunction in rheumatoid arthritis: effect of treatment.

OBJECTIVE: To determine whether abnormalities in microvascular and macrovascular function in rheumatoid arthritis (RA) are associated with plasma markers [von Willebrand factor (VWF)] of endothelial dysfunction and inflammation [C-reactive protein (CRP)] and whether the abnormalities would be altered by treatment. Endothelial dysfunction and inflammation in RA may contribute to adverse cardiovascular events. Although endothelial dysfunction in RA has been demonstrated by altered plasma markers, the relationships with macrovascular and microvascular function are relatively unexplored. METHODS: We recruited 66 patients with chronic RA, 48 community controls (CC), and 25 patients with diabetes and hypertension as a disease control group (DC). Subjects had venous blood sampled for plasma markers, and underwent laser Doppler perfusion imaging of forearm skin (to assess microvascular circulation) following acetylcholine and sodium nitroprusside iontophoresis, to assess endothelium-dependent and endothelium-independent responses, respectively. Brachial artery flow-mediated dilatation assessed endothelial dysfunction in a macrovascular bed. A subgroup of 29 patients with RA were assessed pretherapy and after 2-4 weeks of antirheumatic therapy. RESULTS: As expected, patients with RA had higher CRP, erythrocyte sedimentation rate (ESR), and VWF. Endothelium-independent vasoreactivity was abnormal in RA, and this correlated negatively with CRP. All aspects of microvascular function were abnormal in the DC compared to the CC. Macrovascular function was preserved in RA but was abnormal in the DC group. Four weeks of antiinflammatory therapy reduced CRP and ESR but had no effect on any vascular function index in the patients with RA. CONCLUSION: Patients with RA have abnormal endothelium-independent microvascular function that correlates with inflammation but is not altered by short-term antiinflammatory therapy.

Inflammatory cytokines, endothelial markers and adhesion molecules in rheumatoid arthritis: effect of intensive anti-inflammatory treatment.

Tumour necrosis factor alpha (TNF-alpha) and interlekin-6 (IL-6) are key inflammatory cytokines in the pathogenesis of rheumatoid arthritis (RA), a disease also associated with endothelial perturbation and increased serum levels of adhesion molecules. As relationships between these processes and molecules are unclear, we tested the hypotheses (a) that TNF-alpha and IL-6 are linked to endothelial activation/damage and levels of soluble adhesion molecules, and (b) that intensive anti-inflammatory treatment improves levels of these indices. We recruited 66 patients with RA, 48 community controls (CC), and 25 disease controls (DC). Plasma TNF-alpha and IL-6 were compared to markers of vascular biology (vWF, sE-sel), soluble adhesion molecules (sICAM, sVCAM) and routine inflammatory markers (CRP and ESR). Blood was obtained at baseline and at 1 week and again 4 weeks after anti-inflammatory treatment in a subgroup of 29 patients with RA. With the exception of sE-selectin, RA patients had increased levels of all plasma markers compared to the HCs, whilst levels in the DCs were largely intermediate between RA and the CCs. Within the RA group, sEsel correlated with both CRP and ESR whilst TNF-alpha correlated with sVCAM (all r > 0.32, P < 0.01). After 1 week of combined anti-inflammatory therapy, only CRP, ESR, sEsel and sVCAM were significantly reduced (all P < 0.05). In RA, endothelial activation (as sEsel) correlates with classical markers of inflammation and is reduced by intensive anti-inflammatory medications.

Circulating endothelial cells and rheumatoid arthritis: relationship with plasma markers of endothelial damage/dysfunction.

OBJECTIVES: RA is associated with endothelial cell dysfunction (ECD) and increased cardiovascular mortality and morbidity. Circulating endothelial cells (CECs) are a novel marker of severe endothelial damage. We hypothesized altered CECs in patients with RA compared with community controls (CCs) and hospital controls (HCs, with diabetes and hypertension) correlate with established plasma markers of inflammation and of ECD. METHODS: CECs (CD146-immunobeads), von Willebrand factor, soluble E-selectin, soluble intercellular adhesion molecule-1, soluble vascular endothelial adhesion molecule-1 (sVCAM, all ELISA) and C-reactive protein (CRP, immunonephelometry) were measured in 57 patients with RA, 45 CC and 23 HC patients. RESULTS: CECs in RA [median/interquartile range 8 (5-13.5) cells/ml] were elevated compared with either CC [4 (2-8.5) cells/ml] or HC [4 (1-8) cells/ml] (both P < 0.001). Levels of CECs did not correlate with other markers of ECD or of inflammation but did correlate inversely with sVCAM. CONCLUSION: Evidence of endothelial damage in the form of mildly increased numbers of CECs is present in RA and is independent of plasma markers of inflammation and of ECD.