Many patients with hypertension require ≥3 agents to achieve target blood pressure (BP). The efficacy/safety of the dual combinations of valsartan (Val)/hydrochlorothiazide (HCTZ) and amlodipine (A...

Triple Antihypertensive Therapy With Amlodipine, Valsartan, and Hydrochlorothiazide: A Randomized Clinical Trial

An important step in simplifying asthma and chronic obstructive pulmonary disease (COPD) management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Therefore, the incorporation of once-daily dose administration is an important strategy to improve adherence and is a regimen preferred by most patients, which may also lead to enhancement of compliance, and may have advantages leading to improved overall clinical outcomes. Once-daily beta2-agonists or ultra long-acting beta2-agonists (LABAs) such as carmoterol, indacaterol, GSK-159797, GSK-597901, GSK-159802, GSK-642444 and GSK-678007 are under development for the treatment of asthma and COPD. Also some new long-acting antimuscarinic agents (LAMAs) such as aclidinium, LAS-35201, GSK656398, GSK233705, NVA-237 (glycopyrrolate) and OrM3 are under development. In any case, the current opinion is that it will be advantageous to develop inhalers containing combination of several classes of long-acting bronchodilator drugs in an attempt to simplify treatment regimens as much as possible. Consequently, several options for once-daily dual-action ultra LABA+LAMA combination products are currently being evaluated. A different approach is to have a dimer molecule in which both pharmacologies are present (these molecules are known as M3 antagonist-beta2 agonist (MABA) bronchodilators). The advent of a successful MABA product will revolutionize the field and open the door for a new range of combination products.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/bjp.2008.284

Novel long-acting bronchodilators for COPD and asthma

Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.

The Identification of Indacaterol as an Ultralong-Acting Inhaled β2-Adrenoceptor Agonist

Bronchodilators remain central to the symptomatic management of chronic obstructive pulmonary disease and asthma, and, for this reason and also because the patent protection of many bronchodilators has expired, several companies have reinitiated research into the field. The only limits set for the development of a long-lasting bronchodilator with a new product profile are medical needs and marketing opportunities. The incorporation of once-daily dose administration is an important strategy for improving adherence and is a regimen preferred by most patients. A variety of beta(2)-agonists and antimuscarinic agents with longer half-lives and inhalers containing a combination of several classes of long-acting bronchodilator are currently under development. The present article reviews all of the most important compounds under development, describing what has been done and discussing their genuine advantage.

https://erj.ersjournals.com/content/erj/34/3/757.full.pdf

Emerging inhaled bronchodilators: an update

Given the emerging knowledge that circadian rhythmicity exists in every cell and all organ systems, there is increasing interest in the possible benefits of chronotherapy for many diseases. There is a well-documented 24-h pattern of blood pressure with a morning surge that may contribute to the observed morning increase in adverse cardiovascular events. Historically, antihypertensive therapy involves morning doses, usually aimed at reducing daytime blood pressure surges, but an absence of nocturnal dipping blood pressure is also associated with increased cardiovascular risk. To more effectively reduce nocturnal blood pressure and still counteract the morning surge in blood pressure, a number of studies have examined moving one or more antihypertensives from morning to bedtime dosing. More recently, such studies of chronotherapy have studied comorbid populations including obstructive sleep apnea, chronic kidney disease, or diabetes. Here, we summarize major findings from recent research in this area (2013–2017). In general, nighttime administration of antihypertensives improved overall 24-h blood pressure profiles regardless of disease comorbidity. However, inconsistencies between studies suggest a need for more prospective randomized controlled trials with sufficient statistical power. In addition, experimental studies to ascertain mechanisms by which chronotherapy is beneficial could aid drug design and guidelines for timed administration.

Chronotherapy for Hypertension

In this randomized, double-blind, multicenter study, patients whose blood pressure (BP) was uncontrolled by monotherapy were switched directly to amlodipine/valsartan 5/160 mg (n=443) or 10/160 mg (n=451). After 16 weeks, BP control (levels <140/90 mm Hg or <130/80 mm Hg for diabetics) was achieved in 72.7% (95% confidence interval [CI], 68.6-76.9) of patients receiving amlodipine/valsartan 5/160 mg and in 74.8% (95% CI, 70.8-78.9) receiving amlodipine/valsartan 10/160 mg. Incremental reductions from baseline in mean sitting systolic and diastolic BP were significantly greater with the higher dose (20.0+/-0.7 vs 17.5+/-0.7 mm Hg; P=.0003 and 11.6+/-0.4 vs 10.4+/-0.4 mm Hg; P=.0046). Incremental BP reductions were also achieved with both regimens irrespective of previous monotherapy, hypertension severity, diabetic status, body mass index, and age. Peripheral edema was the most frequent adverse event. These results provide support for the BP-lowering benefits of complementary antihypertensive therapy with amlodipine and valsartan in patients with hypertension uncontrolled by previous monotherapy.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1751-7176.2008.07516.x

Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: the Exforge in Failure after Single Therapy (EX-FAST) study.

Objective: This study compared the bronchodilator efficacy and safety of indacaterol with placebo, salbutamol and salmeterol, in patients with persistent asthma, at single therapeutic and supratherapeutic doses.Research design and methods: This was a randomised, open-label crossover study in adult subjects with asthma (forced expiratory volume in 1 second [FEV1] ≥ 60% predicted). In part A, patients (n = 20) received single doses of indacaterol 200 µg, salbutamol 200 µg, salmeterol 50 µg and placebo. In part B, patients (n = 19) received single doses of indacaterol 1000 µg, salbutamol 1000 µg, salmeterol 250 µg and placebo.Main outcomes measures; Results: For the primary endpoint, FEV1 area under the effect curve during 0–24 h, indacaterol 200 µg was statistically superior to placebo and salbutamol. Indacaterol 200 µg FEV1 was higher than placebo (5 min to 24 h), salbutamol 200 µg (4–24 h), and salmeterol 50 µg (5 and 15 min and 22 and 24 h). Few adverse events were reported; all were mild or mode...

Efficacy and safety of single therapeutic and supratherapeutic doses of indacaterol versus salmeterol and salbutamol in patients with asthma.

Treatments for Metastatic Hormone-sensitive Prostate Cancer: Systematic Review, Network Meta-analysis, and Benefit-harm assessment.

Background The success of colorectal cancer (CRC) screening depends mainly on screening quality, patient adherence to surveillance, and costs. Consequently, it is essential to assess the performance over time. Methods In 2000, a closed cohort study on CRC screening in individuals aged 50 to 80 was initiated in Uri, Switzerland. Participants who chose to undergo colonoscopy were followed over 18 years. We investigated the adherence to recommended surveillance and collected baseline characteristics and colonoscopy data. Risk factors at screening for the development of advanced adenomas were analyzed. Costs for screening and follow-up were evaluated retrospectively. Results 1278 subjects with a screening colonoscopy were included, of which 272 (21.3%; 69.5% men) had adenomas, and 83 (6.5%) had advanced adenomas. Only 59.8% participated in a follow-up colonoscopy, half of them within the recommended time interval. Individuals with advanced adenomas at screening had nearly five times the risk of developing advanced adenomas compared to individuals without adenomas (24.3% vs. 5.0%, OR 4.79 CI 2.30–9.95). Individuals without adenomas developed advanced adenomas in 4.9%, including four cases of CRC; three of them without control colonoscopy. The villous component in adenomas smaller than 10 mm was not an independent risk factor. Costs for screening and follow-up added up to CHF 1’934’521 per 1’000 persons screened, almost half of them for follow-up examinations; 60% of these costs accounted for low-risk individuals. Conclusion Our findings suggest that follow-up of screening colonoscopy should be reconsidered in Switzerland; in particular, long-term adherence is critical. Costs for follow-up could be substantially reduced by adopting less expensive long-term screening methods for low-risk individuals.

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Colorectal cancer surveillance by colonoscopy in a prospective, population-based long-term Swiss screening study – outcomes, adherence, and costs

Background In metastatic hormone-sensitive prostate cancer (mHSPC) treatment, survival benefits have been shown by adding docetaxel or recent androgen receptor axis-targeted therapies (ARATs) abiraterone, apalutamide, or enzalutamide to androgen deprivation therapy (ADT). However, the optimal treatment strategy in terms of costs and effects is unclear, not least due to high ARAT costs. Methods To assess treatment cost-effectiveness, we developed a Markov cohort model with health states of progression-free disease, progressive disease and death for men with newly diagnosed mHSPC, with a 30-year time horizon. Survival data, adverse events and utilities were informed by randomized controlled trial results, our meta-analysis of re-created individual patient survival data, and publicly available sources of unit costs. We applied a Swiss healthcare payer perspective and discounted costs and effects by 3%. Results We found a significant overall survival benefit for ADT+abiraterone versus ADT+docetaxel. The corresponding incremental cost-effectiveness ratio (ICER) was predicted to be EUR 39,814 per quality-adjusted life-year (QALY) gained. ADT+apalutamide and ADT+enzalutamide incurred higher costs and lower QALYs compared to ADT+abiraterone. For all ARATs, drug costs constituted the most substantial cost component. Results were stable except for a large univariable reduction in the pre-progression utility under ADT+abiraterone and very large variations in drug prices. Conclusions Our model projected ADT+abiraterone to be cost-effective compared to ADT+docetaxel at a willingness-to-pay threshold of EUR 70,400/QALY (CHF 100,000 applying purchasing power parities). Given lower estimated QALYs for ADT+apalutamide and ADT+enzalutamide compared to ADT+abiraterone, the former only became cost-effective (the preferred) treatment option(s) at substantial 75–80% (80–90%) price reductions.

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0277282&type=printable

Michaela Barbier

Papers

Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: the Exforge in Failure after Single Therapy (EX-FAST) study.

Efficacy and safety of single therapeutic and supratherapeutic doses of indacaterol versus salmeterol and salbutamol in patients with asthma.

Treatments for Metastatic Hormone-sensitive Prostate Cancer: Systematic Review, Network Meta-analysis, and Benefit-harm assessment.

Colorectal cancer surveillance by colonoscopy in a prospective, population-based long-term Swiss screening study – outcomes, adherence, and costs

Survival modelling and cost-effectiveness analysis of treatments for newly diagnosed metastatic hormone-sensitive prostate cancer