Clinical Outcomes in Patients With Refractory Anemia With Excess Blasts (RAEB) Who Receive Hypomethylating Agents (HMAs).

BACKGROUND: We sought to understand the clinical effectiveness associated with use of hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) for patients with refractory anemia with excess blasts (RAEB; an established proxy for higher-risk myelodysplastic syndromes/neoplasms) in contemporary and representative real-world settings. PATIENTS AND METHODS: We used the Surveillance, Epidemiology and End Results (SEER)-Medicare database, a linkage of cancer registry and Medicare claims data, to identify patients aged ≥ 66 years diagnosed with RAEB, between 2009 and 2017 in the United States, and who received AZA or DEC as first-line therapy. Outcomes measured were overall survival (OS), event-free survival (EFS), and incidence of progression-related acute myeloid leukemia (AML). RESULTS: Of 973 eligible patients, 738 (75.8%) received AZA and 235 (24.2%) received DEC; 6.4% received hematopoietic cell transplantation during follow-up. In the overall population, median OS was 13.9 months (95% confidence interval [CI]: 12.9-15.0), median EFS was 5.2 months (95% CI: 4.9-5.7), and 38.0% of patients progressed to AML. Incidences of AML progression and death were 25.6% and 29.9%, respectively, at Year 1, and 34.3% and 44.8%, respectively, at Year 2. There were no significant differences in clinical benefits between AZA and DEC. CONCLUSION: Median OS with both HMAs remained significantly shorter than in the AZA-001 clinical trial, highlighting how patient outcomes vary between clinical and real-world settings. Further research is required to understand why these disparities exist.

The synthetic localizer radiograph - A new CT scan planning method.

OBJECTIVE: To investigate if the conventional localizer radiograph (LR) can be replaced by a synthetic LR (SLR), generated from a low-dose spiral CT scan, for CT scan planning with minimal changes to current clinical workflows. METHODS: A dosimetric comparison of SLRs and LRs was made using Monte Carlo methods. Water equivalent diameters (WEDs) of a centered and mis-centered phantom were estimated from low-dose spiral CT scans and LRs acquired at different angles. Body sizes, in the form of two lengths and two diameters obtained from SLRs and LRs, were compared for 10 patients (4 men and 6 women with a mean age of 74.8 and 76.2 years respectively) undergoing CT of thorax and abdomen. The image quality of SLRs for CT scan planning relative to LRs was rated using a 5-grade scale by four radiologists and two CT radiographers. RESULTS: An SLR can be obtained at a comparable effective dose to that of traditionally acquired LRs: 0.14 mSv. WEDs from LRs were more affected by mis-centering than WEDs calculated from low-dose spiral scans. One significant discrepancy of estimated body sizes was observed, the broadest part of the patient that on lateral localizers showed a mean deviation of 17.7 mm (range: 7.3-28.7 mm, p < 0.001). The anteroposterior/posteroanterior SLR image quality was assessed as better compared to an LR while the same could not be shown for lateral localizers. CONCLUSIONS: SLRs based on low-dose spiral scans can replace LRs for CT planning.

Homeostasis Model Assessment of Insulin Resistance and Survival in Patients With Diabetes and Acute Coronary Syndrome.

Objective: Insulin resistance has been linked to development and progression of atherosclerosis and is present in most patients with type 2 diabetes. Whether the degree of insulin resistance predicts adverse outcomes in patients with type 2 diabetes and acute coronary syndrome (ACS) is uncertain. Design: The Effect of Aleglitazar on Cardiovascular Outcomes after Acute Coronary Syndrome in Patients with Type 2 Diabetes Mellitus trial compared the peroxisome proliferator-activated receptor-α/γ agonist aleglitazar with placebo in patients with type 2 diabetes and recent ACS. In participants not treated with insulin, we determined whether baseline homeostasis model assessment of insulin resistance (HOMA-IR; n = 4303) or the change in HOMA-IR on assigned study treatment (n = 3568) was related to the risk of death or major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in unadjusted and adjusted models. Because an inverse association of HOMA-IR with N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been described, we specifically examined effects of adjustment for the latter. Results: In unadjusted analysis, twofold higher baseline HOMA-IR was associated with lower risk of death [hazard ratio (HR): 0.79, 95% CI: 0.68 to 0.91, P = 0.002]. Adjustment for 24 standard demographic and clinical variables had minimal effect on this association. However, after further adjustment for NT-proBNP, the association of HOMA-IR with death was no longer present (adjusted HR: 0.99, 95% CI: 0.83 to 1.19, P = 0.94). Baseline HOMA-IR was not associated with major adverse cardiovascular events, nor was the change in HOMA-IR on study treatment associated with death or major adverse cardiovascular events. Conclusions: After accounting for levels of NT-proBNP, insulin resistance assessed by HOMA-IR is not related to the risk of death or major adverse cardiovascular events in patients with type 2 diabetes and ACS.

Improving clinical trials for cardiovascular diseases: a position paper from the Cardiovascular Round Table of the European Society of Cardiology.

AIMS: Cardiovascular disease is the most common cause of mortality and morbidity in the world, but the pharmaceutical industry's willingness to invest in this field has declined because of the many challenges involved with bringing new cardiovascular drugs to market, including late-stage failures, escalating regulatory requirements, bureaucracy of the clinical trial business enterprise, and limited patient access after approval. This contrasts with the remaining burden of cardiovascular disease in Europe and in the world. Thus, clinical cardiovascular research needs to adapt to address the impact of these challenges in order to ensure development of new cardiovascular medicines. METHODS AND RESULTS: The present paper is the outcome of a two-day workshop held by the Cardiovascular Round Table of the European Society of Cardiology. We propose strategies to improve development of effective new cardiovascular therapies. These can include (i) the use of biomarkers to describe patients who will benefit from new therapies more precisely, achieving better human target validation; (ii) targeted, mechanism-based approaches to drug development for defined populations; (iii) the use of information technology to simplify data collection and follow-up in clinical trials; (iv) streamlining adverse event collection and reducing monitoring; (v) extended patent protection or limited rapid approval of new agents to motivate investment in early phase development; and (vi) collecting data needed for health technology assessment continuously throughout the drug development process (before and after approval) to minimize delays in patient access. Collaboration across industry, academia, regulators, and payers will be necessary to enact change and to unlock the existing potential for cardiovascular clinical drug development. CONCLUSIONS: A coordinated effort involving academia, regulators, industry, and payors will help to foster better and more effective conduct of clinical cardiovascular trials, supporting earlier availability of innovative therapies and better management of cardiovascular diseases.

Long-term fiscal implications of subsidizing in-vitro fertilization in Sweden: a lifetime tax perspective.

AIMS: In Sweden approximately 3% of annual births are conceived using assisted reproductive technologies (ART). In light of increasing use of ART in Sweden we estimate the lifetime future tax revenues of a child conceived by in-vitro fertilization (IVF) to establish whether public subsidy of IVF represents sound fiscal policy. METHODS: A modified generational accounting model was developed to calculate the net present value (NPV) of average investment costs required to achieve an IVF-conceived child. The model simulates direct lifetime financial interactions between the child and the Swedish government. Within the model we assume average direct financial transfers are made to the individual (eg, child allowance, education, health care, pension, etc). In return, the individual transfers resources to the government through taxation based on anticipated average earnings. The difference between direct transfers and gross taxes paid equals the net-tax contribution. Individual tax contributions were held constant in the model. RESULTS: Based on average life-expectancy an individual born in 2005 will pay an undiscounted 32.5 million SEK in taxes to the Swedish government and receive 20.9 million SEK in direct financial transfers over their lifetime. When these figures are discounted and IVF costs are included in the analysis we obtain a lifetime NPV of 254,000 SEK with a break-even point at age 41 (the age of achieving a positive NPV) for an individual conceived through IVF. CONCLUSIONS: Based on results presented here we conclude that State-funded IVF in Sweden does not negatively impact the long run fiscal budget. Conversely, over an average lifetime an IVF offspring returns a positive net value to the State.

Cost implications of development of diabetes in the ALPINE study.

OBJECTIVE: To present a cost-effectiveness analysis of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation study (ALPINE). DESIGN: In newly diagnosed hypertensive individuals as yet untreated with drugs, the ALPINE study compared the 1-year metabolic effects of inexpensive treatment with a diuretic (hydrochlorothiazide), alone or in combination (84%) with a beta-adrenoceptor blocker (atenolol), with that of newer but also more expensive antihypertensive treatment with an angiotensin II receptor blocker (candesartan), alone or in combination (71%) with a calcium antagonist (felodipine). No crossover of medication was allowed. The cost-effectiveness analysis included costs for antihypertensive treatment during follow-up, and lifetime costs for care of diabetes mellitus diagnosed during follow-up. Cost per patient was calculated using Swedish prices and costs, translated into US dollars (US$), at 2004 prices. RESULTS: Diabetes mellitus was diagnosed in nine patients during the 1-year follow-up period of the study, eight in the hydrochlorothiazide group (4.1%) and one (0.5%) in the candesartan/felodipine group (P < 0.05). The cost of antihypertensive treatment per patient was US$92 in the hydrochlorothiazide/atenolol group and US$422 in the candesartan/felodipine group. Lifetime cost for care of diabetes mellitus per patient in the two groups was US$1013 and US$127, respectively. Total cost per patient was US$556 less in the candesartan/felodipine group. In sensitivity analyses, the outcome for the candesartan/felodipine group ranged from cost savings to an incremental cost of US$30 000 per case of diabetes mellitus prevented. In all analyses but one, the additional cost for antihypertensive treatment in the candesartan/felodipine group could be balanced by the reduced lifetime cost for care of diabetes mellitus. CONCLUSIONS: The results suggest that an antihypertensive treatment strategy with candesartan and felodipine may have a favourable health economic impact in the longer term.