Cost-effectiveness and cost-utility analysis of somatrogon once-weekly injections vs. daily growth hormone injection for treating paediatric growth hormone deficiency in Ireland.

OBJECTIVES: Paediatric growth hormone deficiency (pGHD) manifests as growth failure associated with inadequate growth hormone (GH) production. Daily injections of recombinant human GH (dGH) [somatropin] is the current standard of care, which has been shown to be well tolerated and effective, but associated with suboptimal adherence, leading to reduced effectiveness. Somatrogon, a once-weekly injectable long-acting human GH, has demonstrated clinical non-inferiority and significantly lower life interference (i.e. treatment burden) vs. somatropin in two Phase 3 studies. This work evaluated cost-effectiveness and cost-utility of somatrogon vs dGHs from an Irish payer perspective. METHODS: A Markov model was developed for patients starting somatrogon or dGHs treatment at 3-12 years and continuing up to achievement of near adult height (NAH), with growth driven by trial-based height velocity (HV) and treatment-specific adherence. Patients could discontinue treatment at the end of Year 1 (4%). DGH adherence (95.3%-65% over treatment duration) and adherence-growth relationship were based on published evidence. Higher Year 1 adherence of 4%, tapering over time, for somatrogon vs. dGHs was based on clinical consultation. Treatment costs, monitoring costs and costs due to different wastage types (device setting and adherence) were sourced from local data. Health utilities based on height and injection frequency were derived from published literature. Scenario analysis, deterministic and probabilistic sensitivity analysis were performed. RESULTS: Somatrogon treatment led to 1.87-3.66 cm greater NAH gain and 0.21-0.50 higher quality adjusted life years (QALYs) vs. dGHs, across the base case and scenarios evaluated. Somatrogon treatment was associated with cost savings of €5,699-€21,974 and lower cost per cm gained vs. dGHs (€197-€527), per patient. Somatrogon was cost-effective vs. dGHs, with the result consistent across the sensitivity analyses conducted. CONCLUSION: Somatrogon weekly injections were estimated to result in higher NAH, higher QALYs, lower overall costs and lower costs per cm gained than dGHs, in pGHD.

Ceftaroline Fosamil for the Empiric Treatment of Hospitalized Adults with cSSTI: An Economic Analysis from the Perspective of the Spanish National Health System.

Purpose: Complicated skin and soft tissue infections (cSSTI) are associated with high healthcare resource use and costs. The emergency nature of cSSTI hospitalizations requires starting immediate empiric intravenous (IV) antibiotic treatment, making the appropriate choice of initial antibiotic therapy crucial. Patients and Methods: The use of ceftaroline fosamil (CFT) as an alternative to other IV antibiotic therapies for the empiric treatment of hospitalized adults with cSSTI (vancomycin, linezolid, daptomycin, cloxacillin, tedizolid) was evaluated through cost consequences analysis. The model structure was a decision tree accounting for four different pathways: patients demonstrating early response (ER) either discharged early (with oral antibiotic) or remaining in hospital to continue the initial therapy; non-responders either remaining on the initial IV therapy or switching to a second-line antibiotic. The model perspective was the Spanish National Health System. Results: CFT resulted in average percentage of patients discharged early (PDE) of 24.6% (CI 19.49-30.2%) with average total cost per patient of €6763 (€6268-€7219). Vancomycin, linezolid, daptomycin and tedizolid resulted in average PDE of 22% (17.34-27.09%), 26.4% (20.5-32.32%), 28.6% (22.08-35.79%) and 26.5% (20.39-33.25%), respectively, for a total cost per patient of €6,619 (€5,902-€6,929), €6,394 (€5,881-€6,904), €6,855 (€5,800-€7,410) and €7,173 (€6,608-€7,763), respectively. Key model drivers were ER and antibiotic treatment duration, with hospital costs accounting for over 83% of the total expenditures. Conclusion: Given its clinical and safety profile, CFT is an acceptable choice for cSSTI empiric therapy providing comparable ER and costs to other relevant antibiotic options.

Cost-effectiveness analysis of apixaban versus vitamin K antagonists for antithrombotic therapy in patients with atrial fibrillation after acute coronary syndrome or percutaneous coronary intervention in Spain.

BACKGROUND/OBJECTIVE: AUGUSTUS trial demonstrated that, for patients with atrial fibrillation (AF) having acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI), an antithrombotic regimen with apixaban and P2Y12 resulted in less bleeding, fewer hospitalizations, and similar ischemic events than regimens including a vitamin K antagonist (VKA), aspirin, or both. This study objective was to evaluate long-term health and economic outcomes and the cost-effectiveness of apixaban over VKA, as a treatment option for patients with AF having ACS/PCI. METHODS: A lifetime Markov cohort model was developed comparing apixaban versus VKA across multiple treatment strategies (triple [with P2Y12 + aspirin] or dual [with P2Y12] therapy followed by monotherapy [apixaban or VKA]; triple followed by dual and then monotherapy; dual followed by monotherapy). The model adopted the Spanish healthcare perspective, with a 3-month cycle length and costs and health outcomes discounted at 3%. RESULTS: Treatment with apixaban resulted in total cost savings of €883 and higher life years (LYs) and quality-adjusted LYs (QALYs) per patient than VKA (net difference, LYs: 0.13; QALYs: 0.11). Bleeding and ischemic events (per 100 patients) were lower with apixaban than VKA (net difference, -13.9 and -1.8, respectively). Incremental net monetary benefit for apixaban was €3,041, using a willingness-to-pay threshold of €20,000 per QALY. In probabilistic sensitivity analysis, apixaban was dominant in the majority of simulations (92.6%), providing additional QALYs at lower costs than VKA. CONCLUSIONS: Apixaban was a dominant treatment strategy than VKA from both the Spanish payer's and societal perspectives, regardless of treatment strategy considered.

Impact of coronary artery disease on contractile function and ventricular-arterial coupling during exercise: Simultaneous assessment of left-ventricular pressure-volume and coronary pressure and flow during cardiac catheterization.

Coronary artery disease (CAD) can adversely affect left ventricular (LV) performance during exercise by impairment of contractile function in the presence of increasing afterload. By performing invasive measures of LV pressure-volume and coronary pressure and flow during exercise, we sought to accurately measure this with comparison to the control group. Sixteen patients, with CCS class >II angina and CAD underwent invasive simultaneous measurement of left ventricular pressure-volume and coronary pressure and flow velocity during cardiac catheterization. Measurements performed at rest were compared with peak exercise using bicycle ergometry. The LV contractile function was measured invasively using the end-systolic pressure-volume relationship, a load independent marker of contractile function (Ees). Vascular afterload forces were derived from the ratio of LV end-systolic pressure to stroke volume to generate arterial elastance (Ea). These were combined to assess cardiovascular performance (ventricular-arterial [VA] coupling ratio [Ea/Ees]). Eleven patients demonstrated flow-limiting (FL) CAD (hyperemic Pd/Pa <0.80; ST-segment depression on exercise); five patients without flow-limiting (NFL) CAD served as the control group. Exercise in the presence of FL CAD was associated impairment of Ees, increased Ea, and deterioration of VA coupling. In the control cohort, exercise was associated with increased Ees and improved VA coupling. The backward compression wave energy directly correlated with the magnitude contraction as measured by dP/dTmax (r = 0.88, p = 0.004). This study demonstrates that in the presence of flow-limiting CAD, exercise to maximal effort can lead to impairment of LV contractile function and a deterioration in VA coupling compared to a control cohort.

Physiological Impact of Afterload Reduction on Cardiac Mechanics and Coronary Hemodynamics Following Isosorbide Dinitrate Administration in Ischemic Heart Disease.

Understanding the cardiac-coronary interaction is fundamental to developing treatment strategies for ischemic heart disease. We sought to examine the impact of afterload reduction following isosorbide dinitrate (ISDN) administration on LV properties and coronary hemodynamics to further our understanding of the cardiac-coronary interaction. Novel methodology enabled real-time simultaneous acquisition and analysis of coronary and LV hemodynamics in vivo using coronary pressure-flow wires (used to derive coronary wave energies) and LV pressure-volume loop assessment. ISDN administration resulted in afterload reduction, reduced myocardial demand, and increased mechanical efficiency (all P<0.01). Correlations were demonstrated between the forward compression wave (FCW) and arterial elastance (r=0.6) following ISDN. In the presence of minimal microvascular resistance, coronary blood flow velocity exhibited an inverse relationship with LV elastance. In summary this study demonstrated a reduction in myocardial demand with ISDN, an inverse relationship between coronary blood flow velocity and LV contraction-relaxation and a direct correlation between FCW and arterial elastance. The pressure volume-loop and corresponding parameters b The pressure volume loop before (solid line) and after (broken line) Isosorbide dintrate.

Economic analysis of ceftaroline fosamil for treating community-acquired pneumonia in Spain.

Background: Adults admitted to hospital with community-acquired pneumonia (CAP) impose significant burden upon limited hospital resources. To achieve early response and possibly early discharge, thus reducing hospital expenditure, the choice of initial antibiotic therapy is pivotal.Methods: A cost-consequences model was developed to evaluate ceftaroline fosamil (CFT) as an alternative to other antibiotic therapies (ceftriaxone, co-amoxiclav, moxifloxacin, levofloxacin) for the empiric treatment of hospitalized adults with moderate/severe CAP (PORT score III-IV) from the perspective of the Spanish National Health System (NHS).Findings: Compared with ceftriaxone, the model predicted an increase in the number of CFT-treated patients discharged early (PDE) (30.6% vs. 26.1%) while decreasing initial antibiotic failures (3.8% vs. 7.6%). For patients with pneumococcal pneumonia, CFT was cost-saving vs. ceftriaxone (by 1.2%) and significantly increased PDE (32.1% vs. 24.6%). CFT resulted in cost-saving vs. levofloxacin, due lower initial antibiotic therapy costs and increased PDE (30.6% vs. 14.9%). Moxifloxacin and co-amoxiclav early response rate of 53.63% and 54.24% resulted in cost neutrality vs. CFT, with direct comparison hampered by the significantly different early response criteria utilized in the literature.Conclusions: Despite a higher unit cost, CFT is a reasonable alternative to other agents for adults hospitalized with moderate/severe CAP, given the projected higher PDE achieved with similar or lower total costs.

Intra-aortic Balloon Counterpulsation for High-Risk Percutaneous Coronary Intervention: Defining Coronary Responders.

The effect of intra-aortic balloon counterpulsation (IABC) varies, and it is unknown whether this is due to a heterogeneous coronary physiological response. This study aimed to characterise the coronary and left ventricular (LV) effects of IABC and define responders in terms of their invasive physiology. Twenty-seven patients (LVEF 31 ± 9%) underwent coronary pressure and Doppler flow measurements in the target vessel and acquisition of LV pressure volume loops after IABC supported PCI, with and without IABC assistance. Through coronary wave intensity analysis, perfusion efficiency (PE) was calculated as the proportion of total wave energy comprised of accelerating waves, with responders defined as those with an increase in PE with IABC. The myocardial supply/demand ratio was defined as the ratio between coronary flow and LV pressure volume area (PVA). Responders (44.4%) were more likely to have undergone complex PCI (p = 0.03) with a higher pre-PCI disease burden (p = 0.02) and had lower unassisted mean arterial (87.4 ± 11.0 vs. 77.8 ± 11.6 mmHg, p = 0.04) and distal coronary pressures (88.0 ± 11.0 vs. 71.6 ± 12.4 mmHg, p < 0.001). There was no effect overall of IABC on the myocardial supply/demand ratio (p = 0.34). IABC has minimal effect on demand, but there is marked heterogeneity in the coronary response to IABC, with the greatest response observed in those patients with the most disordered autoregulation.

Myocardial strain computed at multiple spatial scales from tagged magnetic resonance imaging: Estimating cardiac biomarkers for CRT patients.

Abnormal cardiac motion can indicate different forms of disease, which can manifest at different spatial scales in the myocardium. Many studies have sought to characterise particular motion abnormalities associated with specific diseases, and to utilise motion information to improve diagnoses. However, the importance of spatial scale in the analysis of cardiac deformation has not been extensively investigated. We build on recent work on the analysis of myocardial strains at different spatial scales using a cardiac motion atlas to find the optimal scales for estimating different cardiac biomarkers. We apply a multi-scale strain analysis to a 43 patient cohort of cardiac resynchronisation therapy (CRT) patients using tagged magnetic resonance imaging data for (1) predicting response to CRT, (2) identifying septal flash, (3) estimating QRS duration, and (4) identifying the presence of ischaemia. A repeated, stratified cross-validation is used to demonstrate the importance of spatial scale in our analysis, revealing different optimal spatial scales for the estimation of different biomarkers.

Accurate and Standardized Coronary Wave Intensity Analysis.

OBJECTIVE: Coronary wave intensity analysis (cWIA) has increasingly been applied in the clinical research setting to distinguish between the proximal and distal mechanical influences on coronary blood flow. Recently, a cWIA-derived clinical index demonstrated prognostic value in predicting functional recovery postmyocardial infarction. Nevertheless, the known operator dependence of the cWIA metrics currently hampers its routine application in clinical practice. Specifically, it was recently demonstrated that the cWIA metrics are highly dependent on the chosen Savitzky-Golay filter parameters used to smooth the acquired traces. Therefore, a novel method to make cWIA standardized and automatic was proposed and evaluated in vivo. METHODS: The novel approach combines an adaptive Savitzky-Golay filter with high-order central finite differencing after ensemble-averaging the acquired waveforms. Its accuracy was assessed using in vivo human data. The proposed approach was then modified to automatically perform beat wise cWIA. Finally, the feasibility (accuracy and robustness) of the method was evaluated. RESULTS: The automatic cWIA algorithm provided satisfactory accuracy under a wide range of noise scenarios (≤10% and ≤20% error in the estimation of wave areas and peaks, respectively). These results were confirmed when beat-by-beat cWIA was performed. CONCLUSION: An accurate, standardized, and automated cWIA was developed. Moreover, the feasibility of beat wise cWIA was demonstrated for the first time. SIGNIFICANCE: The proposed algorithm provides practitioners with a standardized technique that could broaden the application of cWIA in the clinical practice as enabling multicenter trials. Furthermore, the demonstrated potential of beatwise cWIA opens the possibility investigating the coronary physiology in real time.

Impact of coronary bifurcation morphology on wave propagation.

The branching pattern of the coronary vasculature is a key determinant of its function and plays a crucial role in shaping the pressure and velocity wave forms measured for clinical diagnosis. However, although multiple scaling laws have been proposed to characterize the branching pattern, the implications they have on wave propagation remain unassessed to date. To bridge this gap, we have developed a new theoretical framework by combining the mathematical formulation of scaling laws with the wave propagation theory in the pulsatile flow regime. This framework was then validated in multiple species using high-resolution cryomicrotome images of porcine, canine, and human coronary networks. Results demonstrate that the forward well-matchedness (no reflection for pressure/flow waves traveling from the coronary stem toward the microcirculation) is a salient feature in the coronary vasculature, and this result remains robust under many scenarios of the underlying pulse wave speed distribution assumed in the network. This result also implies a significant damping of the backward traveling waves, especially for smaller vessels (radius, <0.3 mm). Furthermore, the theoretical prediction of increasing area ratios (ratio between the area of the mother and daughter vessels) in more symmetric bifurcations found in the distal circulation was confirmed by experimental measurements. No differences were observed by clustering the vessel segments in terms of transmurality (from epicardium to endocardium) or perfusion territories (left anterior descending, left circumflex, and right coronary artery).

In silico coronary wave intensity analysis: application of an integrated one-dimensional and poromechanical model of cardiac perfusion.

Coronary wave intensity analysis (cWIA) is a diagnostic technique based on invasive measurement of coronary pressure and velocity waveforms. The theory of WIA allows the forward- and backward-propagating coronary waves to be separated and attributed to their origin and timing, thus serving as a sensitive and specific cardiac functional indicator. In recent years, an increasing number of clinical studies have begun to establish associations between changes in specific waves and various diseases of myocardium and perfusion. These studies are, however, currently confined to a trial-and-error approach and are subject to technological limitations which may confound accurate interpretations. In this work, we have developed a biophysically based cardiac perfusion model which incorporates full ventricular-aortic-coronary coupling. This was achieved by integrating our previous work on one-dimensional modelling of vascular flow and poroelastic perfusion within an active myocardial mechanics framework. Extensive parameterisation was performed, yielding a close agreement with physiological levels of global coronary and myocardial function as well as experimentally observed cumulative wave intensity magnitudes. Results indicate a strong dependence of the backward suction wave on QRS duration and vascular resistance, the forward pushing wave on the rate of myocyte tension development, and the late forward pushing wave on the aortic valve dynamics. These findings are not only consistent with experimental observations, but offer a greater specificity to the wave-originating mechanisms, thus demonstrating the value of the integrated model as a tool for clinical investigation.

Measurement and modeling of coronary blood flow.

Ischemic heart disease that comprises both coronary artery disease and microvascular disease is the single greatest cause of death globally. In this context, enhancing our understanding of the interaction of coronary structure and function is not only fundamental for advancing basic physiology but also crucial for identifying new targets for treating these diseases. A central challenge for understanding coronary blood flow is that coronary structure and function exhibit different behaviors across a range of spatial and temporal scales. While experimental studies have sought to understand this feature by isolating specific mechanisms, in tandem, computational modeling is increasingly also providing a unique framework to integrate mechanistic behaviors across different scales. In addition, clinical methods for assessing coronary disease severity are continuously being informed and updated by findings in basic physiology. Coupling these technologies, computational modeling of the coronary circulation is emerging as a bridge between the experimental and clinical domains, providing a framework to integrate imaging and measurements from multiple sources with mathematical descriptions of governing physical laws. State-of-the-art computational modeling is being used to combine mechanistic models with data to provide new insight into coronary physiology, optimization of medical technologies, and new applications to guide clinical practice.

In vivo strain assessment of the abdominal aortic aneurysm.

The only criteria currently used to inform surgical decision for abdominal aortic aneurysms are maximum diameter (>5.5 cm) and rate of growth, even though several studies have identified the need for more specific indicators of risk. Patient-specific biomechanical variables likely to affect rupture risk would be a valuable addition to the science of understanding rupture risk and prove to be a life saving benefit for patients. Local deformability of the aorta is related to the local mechanical properties of the wall and may provide indication on the state of weakening of the wall tissue. We propose a 3D image-based approach to compute aortic wall strain maps in vivo. The method is applicable to a variety of imaging modalities that provide sequential images at different phases in the cardiac cycle. We applied the method to a series of abdominal aneurysms imaged using cine-MRI obtaining strain maps at different phases in the cardiac cycle. These maps could be used to evaluate the distensibility of an aneurysm at baseline and at different follow-up times and provide an additional index to clinicians to facilitate decisions on the best course of action for a specific patient.

Enhancing coronary Wave Intensity Analysis robustness by high order central finite differences.

BACKGROUND: Coronary Wave Intensity Analysis (cWIA) is a technique capable of separating the effects of proximal arterial haemodynamics from cardiac mechanics. Studies have identified WIA-derived indices that are closely correlated with several disease processes and predictive of functional recovery following myocardial infarction. The cWIA clinical application has, however, been limited by technical challenges including a lack of standardization across different studies and the derived indices' sensitivity to the processing parameters. Specifically, a critical step in WIA is the noise removal for evaluation of derivatives of the acquired signals, typically performed by applying a Savitzky-Golay filter, to reduce the high frequency acquisition noise. METHODS: The impact of the filter parameter selection on cWIA output, and on the derived clinical metrics (integral areas and peaks of the major waves), is first analysed. The sensitivity analysis is performed either by using the filter as a differentiator to calculate the signals' time derivative or by applying the filter to smooth the ensemble-averaged waveforms. Furthermore, the power-spectrum of the ensemble-averaged waveforms contains little high-frequency components, which motivated us to propose an alternative approach to compute the time derivatives of the acquired waveforms using a central finite difference scheme. RESULTS AND CONCLUSION: The cWIA output and consequently the derived clinical metrics are significantly affected by the filter parameters, irrespective of its use as a smoothing filter or a differentiator. The proposed approach is parameter-free and, when applied to the 10 in-vivo human datasets and the 50 in-vivo animal datasets, enhances the cWIA robustness by significantly reducing the outcome variability (by 60%).

Automatic selection of optimal Savitzky-Golay filter parameters for Coronary Wave Intensity Analysis.

Coronary Wave Intensity Analysis (cWIA) is a technique capable of separating the effects of proximal arterial haemodynamics from cardiac mechanics. The cWIA ability to establish a mechanistic link between coronary haemodynamics measurements and the underlying pathophysiology has been widely demonstrated. Moreover, the prognostic value of a cWIA-derived metric has been recently proved. However, the clinical application of cWIA has been hindered due to the strong dependence on the practitioners, mainly ascribable to the cWIA-derived indices sensitivity to the pre-processing parameters. Specifically, as recently demonstrated, the cWIA-derived metrics are strongly sensitive to the Savitzky-Golay (S-G) filter, typically used to smooth the acquired traces. This is mainly due to the inability of the S-G filter to deal with the different timescale features present in the measured waveforms. Therefore, we propose to apply an adaptive S-G algorithm that automatically selects pointwise the optimal filter parameters. The newly proposed algorithm accuracy is assessed against a cWIA gold standard, provided by a newly developed in-silico cWIA modelling framework, when physiological noise is added to the simulated traces. The adaptive S-G algorithm, when used to automatically select the polynomial degree of the S-G filter, provides satisfactory results with ≤ 10% error for all the metrics through all the levels of noise tested. Therefore, the newly proposed method makes cWIA fully automatic and independent from the practitioners, opening the possibility to multi-centre trials.