Economic burden and health-related quality of life in tenosynovial giant-cell tumour patients in Europe: an observational disease registry.

BACKGROUND: Tenosynovial Giant-Cell Tumour (TGCT) is a benign clonal neoplastic proliferation arising from the synovium, causing a variety of symptoms and often requiring repetitive surgery. This study aims to define the economic burden-from a societal perspective-associated with TGCT patients and their health-related quality of life (HRQOL) in six European countries. METHODS: This article analyses data from a multinational, multicentre, prospective observational registry, the TGCT Observational Platform Project (TOPP), involving hospitals and tertiary sarcoma centres from six European countries (Austria, France, Germany, Italy, the Netherlands, and Spain). It includes information on TGCT patients' health-related quality of life and healthcare and non-healthcare resources used at baseline (the 12-month period prior to the patients entering the registry) and after 12 months of follow-up. RESULTS: 146 TGCT patients enrolled for the study, of which 137 fulfilled the inclusion criteria. Their mean age was 44.5 years, and 62% were female. The annual average total costs associated with TGCT were €4866 at baseline and €5160 at the 12-month follow-up visit. The annual average healthcare costs associated with TGCT were €4620 at baseline, of which 67% and 18% corresponded to surgery and medical visits, respectively. At the 12-month follow-up, the mean healthcare costs amounted to €5094, with surgery representing 70% of total costs. Loss of productivity represented, on average, 5% of the total cost at baseline and 1.3% at follow-up. The most-affected HRQOL dimensions, measured with the EQ-5D-5L instrument, were pain or discomfort, mobility, and the performance of usual activities, both at baseline and at the follow-up visit. Regarding HRQOL, patients declared a mean index score of 0.75 at baseline and 0.76 at the 12-month follow-up. CONCLUSION: The results suggest that TGCT places a heavy burden on its sufferers, which increases after one year of follow-up, mainly due to the healthcare resources required-in particular, surgical procedures. As a result, this condition has a high economic impact on healthcare budgets, while the HRQOL of TGCT patients substantially deteriorates over time.

Elderly patients with atrial fibrillation in routine clinical practice-peri-procedural management of edoxaban oral anticoagulation therapy is associated with a low risk of bleeding and thromboembolic complications: a subset analysis of the prospective, observational, multinational EMIT-AF study.

BACKGROUND: Annually > 10% of patients with atrial fibrillation on oral anticoagulation undergo invasive procedures. Optimal peri-procedural management of anticoagulation, as judged by major bleeding and thromboembolic events, especially in the elderly, is still debated. METHODS: Procedures from 1442 patients were evaluated. Peri-procedural edoxaban management was guided only by the experience of the attending physician. The primary safety outcome was the rate of major bleeding. Secondary outcomes included the peri-procedural administration of edoxaban, other bleeding events, and the main efficacy outcome, a composite of acute coronary syndrome, non-hemorrhagic stroke, transient ischemic attack, systemic embolic events, deep vein thrombosis, pulmonary embolism, and mortality. RESULTS: Of the 1442 patients, 280 (19%) were < 65, 550 (38%) were 65-74, 514 (36%) 75-84, and 98 (7%) were 85 years old or older. With increasing age, comorbidities and risk scores were higher. Any bleeding complications were uncommon across all ages, ranging from 3.9% in patients < 65 to 4.1% in those 85 years or older; major bleeding rates in any age group were ≤ 0.6%. Interruption rates and duration increased with advancing age. Thromboembolic events were more common in the elderly, with all nine events occurring in those > 65, and seven in patients aged > 75 years. CONCLUSION: Despite increased bleeding risk factors in the elderly, bleeding rates were small and similar across all age groups. However, there was a trend toward more thromboembolic complications with advancing age. Further efforts to identify the optimal management to reduce ischemic complications are needed. TRIAL REGISTRATION: NCT# 02950168, October 31, 2016.

The pharmacokinetic and metabolic profile of olmesartan medoxomil limits the risk of clinically relevant drug interaction.

Orally administered olmesartan medoxomil was rapidly absorbed from the gastrointestinal tract and converted during absorption to olmesartan, the pharmacologically active metabolite that was subsequently excreted without further metabolism. The medoxomil moiety was released as diacetyl that was rapidly cleared by further metabolism and excretion. Peak plasma concentrations of olmesartan occurred 1-3 h after administration, after which concentrations decreased quickly. The elimination half-life was 10-15 h. Olmesartan medoxomil was not measurable in plasma and excreta. The volume of distribution was low, consistent with limited extravascular tissue distribution. Bioavailability (Cmax and area under the curve) increased approximately in proportion with dose, after single and multiple daily oral doses, over the therapeutic dose range (up to 40-80 mg daily), above which systemic availability of olmesartan increased less than proportionally with increase in dose. Steady-state plasma concentrations of olmesartan were reached within the first few daily oral doses. On average, approximately 40% of systemically available olmesartan was excreted by the kidneys, the remainder being excreted in faeces, following secretion in bile. Renal clearance (0.5-0.7 l/h) was independent of dose, accounting for approximately 9-12% of an oral dose. The absolute bioavailability of olmesartan from olmesartan medoxomil tablets was 28.6%. Olmesartan exhibited little or no binding to blood cells. No clinically significant steady-state pharmacokinetic interactions were observed following co-administration of olmesartan medoxomil with digoxin, warfarin and aluminium magnesium hydroxide (antacid), supporting the low potential for clinically significant pharmacokinetic interactions to occur between olmesartan medoxomil and co-administered drugs.

Olmesartan medoxomil: influence of age, renal and hepatic function on the pharmacokinetics of olmesartan medoxomil.

Olmesartan medoxomil was rapidly absorbed and converted to olmesartan in elderly hypertensive patients, and in patients with renal and hepatic dysfunction. No olmesartan medoxomil itself was detected in plasma. Pharmacokinetic steady state was reached within the first few days after oral dosing. In elderly (65-75 years old), after 80 mg olmesartan medoxomil once daily, and very elderly (> or = 75 years old) hypertensive patients after 10 mg daily, steady-state Cmax and area under the curve (AUC(0-24 h)) values were up to 44% higher compared with young patients (< 46 years). Steady-state elimination half-life values were also longer in elderly (12.8 h) and very elderly patients (16.5 h) compared with young patients (10.6 and 12.3 h, respectively). At steady state after 10 mg olmesartan medoxomil daily in patients with renal impairment, both Cmax and AUC(0-24 h) increased as creatinine clearance (CLCR) decreased, and renal clearance (CLR) decreased with decreasing CLCR. Steady-state Cmax and AUC(0-24 h) values in patients with mild (CLCR, 40-59 ml/min) and moderate (CLCR, 20-30 ml/min) were up to 39 and 82% higher than the values in healthy subjects. After single oral doses of 10 mg olmesartan medoxomil daily to patients with mild (Child-Pugh score < or = 6) and moderate (score 7-9) hepatic impairment, Cmax was generally similar to that in healthy matched subjects, but AUC increased by 30 and 48%, respectively, and was reflected in small increases in absolute bioavailability values compared with healthy subject controls. Excretion of olmesartan in urine also increased with the degree of hepatic impairment, indicating a compensatory excretion mechanism in this disease state. Since the increased plasma concentrations (Cmax and AUC(0-24 h)) in elderly and very elderly patients, and in mild and moderate renal and hepatic impairment, were several-fold lower than plasma concentrations observed in other studies after 80 mg olmesartan medoxomil daily that were well tolerated, a dosing adjustment in these groups is not considered necessary. In patients with severe renal impairment, however, consideration should be given to a lower starting dose, and it is recommended that the daily dose should not exceed 20 mg daily (compared with 40 mg daily for the general patient population).

Blood pressure response, but not adverse event incidence, correlates with dose of angiotensin II antagonist.

OBJECTIVE: To assess the efficacy and safety of the novel angiotensin II antagonist olmesartan medoxomil in patients with mild to moderate essential hypertension, using a meta-analysis of the combined database from seven US and European clinical trials. DESIGN: Studies were randomized, double-blind, placebo-controlled and dose-finding (2.5-80 mg), with treatment duration of 6-52 weeks. SETTING: Hospital outpatient clinics. PATIENT POPULATION: A total of 3,095 patients in the safety population and 3,055 patients in the intent-to-treat (efficacy) population. METHODS: All studies used conventional sphygmomanometry for blood pressure measurements at trough (end of the dosing interval). Three studies also used 24-h ambulatory blood pressure monitoring for the principal efficacy evaluations. MAIN OUTCOME MEASURES: Percentage of patients achieving diastolic blood pressure (DBP) < or = 90 mmHg or decrease > or = 10 mmHg (responder rate), percentage of patients achieving a target DBP < or = 90 mmHg or target systolic blood pressure (SBP) < or = 140 mmHg (normalization rate), and mean decrease in DBP from baseline to last visit. RESULTS: Efficacy variables tended to be dose related up to the 40 mg dose level. All olmesartan medoxomil doses were statistically significantly more effective than placebo for responder rate, DBP and SBP normalization rates, and mean decrease in DBP. A clinically relevant decrease of > or = 5 mmHg from baseline in sitting DBP was also observed at doses of 20 mg and above after correction for placebo effect The safety profile of olmesartan medoxomil was similar to that of placebo and was not dose related. CONCLUSIONS: Olmesartan medoxomil was safe and highly effective in lowering blood pressure in patients with mild to moderate essential hypertension in these studies.

Effect of lifibrol on the metabolism of low density lipoproteins and cholesterol.

Lifibrol is a powerful cholesterol-lowering drug of unknown mechanism of action. This investigation was carried out to determine whether the major action of lifibrol is to enhance clearance of low density lipoproteins (LDL) through the LDL-receptor pathway, and if so, whether the drug exerts its action by altering the excretion of bile acids (acidic steroids), the absorption of cholesterol, or the synthesis of cholesterol. In a first study, in two patients with complete absence of LDL receptors, lifibrol therapy had essentially no effect on plasma LDL concentrations; in two others who had a marked reduction in LDL-receptor activity, response to the drug was attenuated. These findings suggest that lifibrol requires an intact LDL-receptor pathway to exert its action. In a second study, in patients with primary moderate hypercholesterolemia, isotope kinetic studies showed that lifibrol enhanced the fractional catabolic rate of LDL-apolipoprotein B (apo B), but had no effect on transport rates of LDL; these observations likewise support the probability that lifibrol acts mainly to increase the activity of the LDL-receptor pathway. However, in a third study in hypercholesterolemic patients, lifibrol therapy failed to increase acidic steroid excretion, inhibit cholesterol absorption, or reduce net cholesterol balance. Furthermore, lifibrol treatment did not significantly reduce urinary excretion of mevalonic acid. In contrast, in a parallel study, simvastatin therapy, which is known to inhibit cholesterol synthesis, gave the expected decrease in net cholesterol balance and reduction in urinary excretion of mevalonic acid. Thus, lifibrol, like statins, appears to increase the activity of LDL receptors; but in contrast to findings with statins, it was not possible to detect a significant decreased synthesis of cholesterol, either from balance studies or from urinary excretion of mevalonic acid. This finding raises the possibility that lifibrol activates the LDL-receptor pathway through a different mechanisms which remains to be determined.

Blood pressure and endocrine effects of single doses of CS-866, a novel angiotensin II antagonist, in salt-restricted hypertensive patients.

OBJECTIVE: This study was conducted to assess the dose-response relationship of the new angiotensin II (Ang II) antagonist CS-866 on blood pressure and on endocrine parameters in hypertensive patients with an activated renin-angiotensin system. DESIGN: Following a four-way crossover protocol, two groups of eight patients with mild-to-moderate hypertension received a sodium-restricted diet (60 mmol daily) and ingested single doses of 2.5, 10 and 40 mg or 5, 20 and 80 mg of CS-866, respectively, or placebo. Twenty-four hour ambulatory blood pressure measurements, plasma renin activity (PRA), Ang II and concentrations of RNH-6270, the pharmacologically active metabolite of CS-866, were monitored up to 24 h after medication. RESULTS: CS-866 was well tolerated. There was a significant decrease in 24 h diastolic blood pressure (DBP) at all doses of CS-866 above 5 mg. Increasing doses of CS-866 from 2.5 to 10 mg and from 5 to 20 mg lowered the mean 24 h DBP and DBP AUC(0-24h) values considerably more than increasing doses from 10 to 40 mg and from 20 to 80 mg, respectively. The mean 24 h DBP was lowered by 6.9 and 8.4 mmHg after oral doses of 10 and 20 mg CS-866, respectively, compared with placebo and by 8.9 mmHg after 80 mg CS-866. The drug increased PRA and Ang II concentrations in plasma, maximum concentrations of which occurred within 3 h post-dose. The highest RNH-6270 concentrations were also found at the first post-dose measurement 3 h after administration of CS-866. CONCLUSION: The new Ang II receptor antagonist CS-866 is effective and well tolerated. In salt-restricted hypertensive patients, CS-866 lowered blood pressure and increased PRA and Ang II concentrations at low doses. A single oral dose of 10-20 mg CS-866 resulted in almost maximal effects.