Short-term Clinical Trials Research Articles

Statins and New-Onset Diabetes Mellitus and Diabetic Complications: A Retrospective Cohort Study of US Healthy Adults.

Statin use is associated with increased incidence of diabetes and possibly with increased body weight and reduced exercise capacity. Data on the long-term effects of these associations in healthy adults, however, are very limited. In addition, the relationship between these effects and diabetic complications has not been adequately studied. To examine the association between statin use and new-onset diabetes, diabetic complications, and overweight/obesity in a cohort of healthy adults. This was a retrospective cohort study. Subjects were Tricare beneficiaries who were evaluated between October 1, 2003 and March 1, 2012. Patients were divided into statin users and nonusers. We excluded patients who, at baseline, had a preexisting disease indicative of cardiovascular diseases, any positive element of the Charlson comorbidity index (including diabetes mellitus), or life-limiting chronic diseases. Using 42 baseline characteristics, we generated a propensity score to match statin users and nonusers. Outcomes assessed included new-onset diabetes, diabetic complications, and overweight/obesity. A total of 25,970 patients (3982 statin users and 21,988 nonusers) were identified as healthy adults at baseline. Of these, 3351 statins users and 3351 nonusers were propensity score-matched. Statin users had higher odds of new-onset diabetes (odds ratio [OR] 1.87; 95% confidence interval [95 % CI] 1.67-2.01), diabetes with complications (OR 2.50; 95 % CI 1.88-3.32), and overweight/obesity (OR 1.14; 95 % CI 1.04-1.25). Secondary and sensitivity analyses demonstrated similar findings. Diabetes, diabetic complications, and overweight/obesity were more commonly diagnosed among statin-users than similar nonusers in a healthy cohort of adults. This study demonstrates that short-term clinical trials might not fully describe the risk/benefit of long-term statin use for primary prevention.

The use of sugar free chewing gum as a supplement in the prevention of dental caries. Narrative Review

Tooth decay is one of the diseases most prevalent, being ranked as one of the major public health problems worldwide. For this reason it has been emphasized the development of new preventive methods, as the use of sugar-free gum. With this strategy it is possible to obtain significant benefits for oral health product by: (1) stimulation of salivation, which favors the clearance and regulates the pH; (2) promotion of remineralization as a consequence of this stimulation and the addition of minerals to the gum; (3) mechanical plaque control; (4) replacement of sugar with sweeteners harmful for bacteria, of which the most widely used is the xylitol; and (5) addition of active agents such as bicarbonate, casein, urea, chlorhexidine and chitosan, among others. Despite providing these benefits, is considered that the effect of gum is weak in preventing caries when the order is sought in the absence of toothbrushing and therefore should be proposed for implementation in addition to routine oral hygiene and not as a preventive measure alone, being necessary to perform a greater number of short and long term clinical trials to evaluate the effectiveness in a context of high biological variability, including patients of different sex, age, socioeconomic status and systemic health.

Concordance with DASH Diet and Blood Pressure Change: Result from Framingham Offspring Cohort (1991‐2008)

The Dietary Approaches to Stop Hypertension (DASH) diet was developed to prevent and lower high blood pressure (BP).However, inconsistent results exist between short‐term clinical trials and long‐term observational studies. We evaluated associations of concordance with the DASH diet and BP trajectories and incidence of hypertension in 2,187 men and women (mean age=53y at exam 5) participating in the Framingham Offspring cohort. Diet and BP was assessed at exams 5 through 8 (1991 to 2008), ~13y of follow‐up. DASH scores were calculated by summing 10 food components including food groups that have been shown to influence BP outcomes (e.g. fruits and vegetables, low‐fat dairy products, lean meat and plant‐based protein). Mixed effect and Cox regression models were applied to assess the association of concordance with the DASH diet and BP longitudinal change and incidence of hypertension adjusted for age, sex, smoking, history of diabetes, BMI and physical activity. A modest positive change in systolic BP of 0.054 mmHg/year per unit increase in DASH score (p=0.028) was observed. No significant associations were observed for diastolic BP or incidence of hypertension. Our findings suggest that concordance with DASH diet may not play a role in BP longitudinal change and incidence of hypertension in a population of older adults.

Sodium Intake and Cardiovascular Health

Sodium is an essential nutrient. Increasing sodium intake is associated with increasing blood pressure, whereas low sodium intake results in increased renin and aldosterone levels. Randomized controlled trials have reported reductions in blood pressure with reductions in sodium intake, to levels of sodium intake <1.5 g/d, and form the evidentiary basis for current population-wide guidelines recommending low sodium intake. Although low sodium intake (<2.0 g/d) has been achieved in short-term feeding clinical trials, sustained low sodium intake has not been achieved by any of the longer term clinical trials (>6-month duration). It is assumed that the blood pressure-lowering effects of reducing sodium intake to low levels will result in large reductions in cardiovascular disease globally. However, current evidence from prospective cohort studies suggests a J-shaped association between sodium intake and cardiovascular events, based on studies from >300 000 people, and suggests that the lowest risk of cardiovascular events and death occurs in populations consuming an average sodium intake range (3-5 g/d). The increased risk of cardiovascular events associated with higher sodium intake (>5 g/d) is most prominent in those with hypertension. A major deficit in the field is the absence of large randomized controlled trials to provide definitive evidence on optimal sodium intake for preventing cardiovascular events. Pending such trials, current evidence would suggest a recommendation for moderate sodium intake in the general population (3-5 g/d), with targeting the lower end of the moderate range among those with hypertension.

Ziconotide Combination Intrathecal Therapy for Noncancer Pain Is Limited Secondary to Delayed Adverse Effects: A Case Series With a 24-Month Follow-Up.

The efficacy and safety of ziconotide as a single agent has been evaluated in few short-term clinical trials and open-label studies. Ziconotide use is challenging given its adverse effect (AE) profile. The objective of this study is to describe the long-term efficacy and AEs of ziconotide used as an adjunct to other intrathecal (IT) agents in chronic noncancer pain patients. A case series of chronic noncancer pain patients who had suboptimal pain control from IT therapy. Ziconotide was introduced in the IT infusion mixture after a successful ziconotide trial. Pain scores, IT doses, as well as AEs were recorded and analyzed from trial to initial ziconotide infusion and up to 24 months. Fifteen patients underwent ziconotide trials. Four subjects failed the trial, and 11 proceeded to continuous ziconotide treatment. Seven out of 11 patients experienced AEs resulting in ziconotide discontinuation. Two of the seven subjects who required discontinuation of ziconotide had improved pain. Four subjects were able to continue IT ziconotide through 24 months. A high incidence of AEs limits the usefulness of IT ziconotide as adjunct therapy. Our results are limited by the size of our patient population; however, they represent a long follow-up period, which is limited in most current publications on this IT peptide. While ziconotide is a needed IT agent, more studies are necessary to better understand the factors that would improve the treatment to trial ratio as well as the long-term efficacy of IT ziconotide treatment.

Pharmacological Properties of Resveratrol. A Pre-Clinical and Clinical Review

Resvertrol (Resv) is an extensively studied molecule – as of 2015 PubMed held more than 7100 publications on the subject. The First International Resveratrol Conference in 2010 found insufficient evidence to justify recommending chronic administration of Resv in humans, a finding in stark contrast with the claims of its therapeutic effects often made by the media, based on its supposed role in the beneficial properties of red wine and in the so-called French Paradox. However, pharmacological studies carried out on different formulations of Resv from 2010 onwards suggest that these recommendations should be reviewed. Pharmacokinetic Resv is characterized by high inter-individual variability within pharmacokinetic parameters. Resv exhibits a rapid absorption rate, with extensive pre-systemic metabolism by human cytochrome P 450 and intestinal microbiota. Its metabolism leads mainly to conjugation products, the biological activity of which is still under discussion. It is also rapidly cleared by the kidneys. Finally, the estimated bioavailability of Resv is around 1% of orally-administered doses. Clinical trials have shown that Resv seems to exert a therapeutic effect on endothelial dysfunction consistent with in vitro observations demonstrating that Resv stimulates the eNOS enzyme. Inflammatory markers and CRP reductions obtained from doses of Resv equal to or less than 20 mg/day are not observed in larger doses, which imply hermetic behavior. Resv has also been shown to reduce the atherogenic potential of LDL cholesterol by reducing oxidized LDL and ApoB levels, which would in turn reduce atherogenesis. Resv is a well-tolerated compound; short-term clinical trials have shown frequent gastrointestinal discomfort or spontaneously resolving diarrhea only with the administration of high doses.

Design, Development and Evaluation of Solifenacin Succinate Tablets

Solifenacin Succinate is used in the treatment of over active bladder with symptoms of urge urinary incontinence, urgency, and increased urinary frequency, and anti spasmodic. Solifenacin Succinate was launched in 2005 and has been shown in both short and long term clinical trials to fulfill these requirements. Solifenacin is a competitive M3 receptor antagonist with a long half-life (45–68 hours). It is available in two dosage strengths namely a 5 or 10 mg once-daily tablet. Ten different trial batches were carried out using different concentrations of excipients like binder (Methocel E5 premium LV), super disintegrant (sodium starch glycolate, cross carmellose sodium, cross povidone), lubricant (Magnesium stearate), glidant (Aerosil) by direct compression technique. The pre-compression parameters and post compression parameters of Solifenacin Succinate tablets were evaluated. The tablets were evaluated for in-vitro drug release studies. Based on similarity factor f2 cross povidone (1.17%), Methocel E5 premium LV (3%), Magnesium starate (1.47%), Aerosil (0.529%) was selected.

Role of phytoestrogens in prevention and management of type 2 diabetes.

Type 2 diabetes (T2D) has become a major public health threat across the globe. It has been widely acknowledged that diet plays an important role in the development and management of T2D. Phytoestrogens are polyphenols that are structurally similar to endogenous estrogen and have weak estrogenic properties. Emerging evidence from pre-clinical models has suggested that phytoestrogens may have anti-diabetic function via both estrogen-dependent and estrogen-independent pathways. In the current review, we have summarized the evidence linking two major types of phytoestrogens, isoflavones and lignans, and T2D from epidemiological studies and clinical trials. The cross-sectional and prospective cohort studies have reported inconsistent results, which may due to the large variations in different populations and measurement errors in dietary intakes. Long-term intervention studies using isoflavone supplements have reported potential beneficial effects on glycemic parameters in postmenopausal women, while results from short-term small-size clinical trials are conflicting. Taken together, the current evidence from different study designs is complex and inconsistent. Although the widespread use of phytoestrogens could not be recommended yet, habitual consumption of phytoestrogens, particularly their intact food sources like soy and whole flaxseed, could be considered as a component of overall healthy dietary pattern for prevention and management of T2D.

Glucagon signaling in the heart: Activation or inhibition?

Glucagon signaling in the heart: Activation or inhibition?

Long-term experience with onabotulinumtoxinA in the treatment of chronic migraine: What happens after one year?

OnabotulinumtoxinA (onabotA) has shown its efficacy over placebo in chronic migraine (CM), but clinical trials lasted only up to one year. The objective of this article is to analyse our experience with onabotA treatment of CM, paying special attention to what happens after one year. We reviewed the charts of patients with CM on onabotA. Patients were injected quarterly during the first year but the fifth appointment was delayed to the fourth month to explore the need for further injections. We treated 132 CM patients (mean age 47 years; 119 women). A total of 108 (81.8%) showed response during the first year. Adverse events, always transient and mild-moderate, were seen in 19 (14.4%) patients during the first year; two showed frontotemporal muscle atrophy after being treated for more than five years. The mean number of treatments was 7.7 (limits 2-29). Among those 108 patients with treatment longer than one year, 49 (45.4%) worsened prior to the next treatment, which obliged us to return to quarterly injections and injections were stopped in 14: in 10 (9.3%) due to a lack of response and in four due to the disappearance of attacks. In responders, after an average of two years of treatment, consumption of any acute medication was reduced by 53% (62.5% in triptan overusers) and emergency visits decreased 61%. Our results confirm the long-term response to onabotA in three-quarters of CM patients. After one year, lack of response occurs in about one out of 10 patients and injections can be delayed, but not stopped, to four months in around 40% of patients. Except for local muscle atrophy in two cases treated more than five years, adverse events are comparable to those already described in short-term clinical trials.

Protease mutations emerging on darunavir in protease inhibitor-naïve and experienced patients in the UK.

IntroductionDarunavir (DRV) is a preferred agent in treatment guidelines for ART-naïve and experienced patients [1]. It is considered to have a high genetic barrier to resistance and 11 resistance-associated mutations (RAMs) are recognized by IAS-USA [2]. These have largely been identified by analyses examining the correlation between baseline genotype and virological response [3]. However, there is little information on RAMs that are directly selected by DRV, outside of short-term clinical trials. We aimed to identify emerging mutations by comparing the genotypes of individuals before and after DRV exposure.Materials and MethodsThe UK HIV Drug Resistance Database was used to identify patients aged over 16 who had received at least 30 days of a DRV-containing regimen. Patients were included if they had a “baseline” resistance test, prior to DRV exposure, and a “repeat” test, either on DRV or within 30 days of stopping this agent. To avoid attributing the effects of other PIs on emerging RAMs to DRV, patients were excluded if they had received another PI for greater than 90 days between the baseline genotype and the start of DRV. The baseline and repeat tests were compared to determine the nature of mutations stratified by PI history.ResultsA total of 5623 patients had DRV, of whom 306 met the inclusion criteria. A total of 228 (74.5%) were male, median age at the start of DRV was 42 years (IQR 37–47), and half had subtype B infection. The mode of transmission was homosexual contact for 50%, heterosexual for 38%, and 3% were injection drug users. The median CD4 count at the start of DRV was 257 cells/mm3 (IQR 94–453). A total of 149 patients (49%) had a history of PI use prior to DRV, and 157 (51%) were PI-naïve. The most common previous PIs were lopinavir, atazanavir, and saquinavir. Baseline DRV RAMs were present in 1 (0.6%) PI-naïve and 20 (13.4%) PI-experienced patients. Mutations emerged under DRV pressure in a further 3 (1.9%) PI-naïve patients, and in 7 (4.7%) PI-experienced patients, 5 of whom had other DRV RAMs present at baseline (Table 1). The median time from the start of DRV to the repeat test was 196 days for PI-naïve patients and 296 days for PI-experienced.ConclusionsPI-experienced patients had a greater prevalence of DRV RAMs at baseline than PI-naïve individuals, probably due to the fact that some DRV RAMs can be selected by other PIs. This group also accumulated more RAMs during DRV exposure, possibly because previous PIs had caused minority variants which then emerged on DRV therapy. Overall, only 10 patients accumulated 16 RAMs, which supports the perception that DRV has a high genetic barrier to resistance. Repeat genotyping in the case of virological failure on DRV may still be warranted to detect emerging resistance and guide management decisions.

Effect of Combined Manual Acupuncture and Massage on Body Weight and Body Mass Index Reduction in Obese and Overweight Women: A Randomized, Short-term Clinical Trial

Obesity is one of the leading health risk factors worldwide and is associated with several other risk factors and health problems. Acupuncture is utilized to treat a variety of health problems, one of which is obesity. Fifty-six obese women with body mass index (BMI) ≥25 kg/m2 were recruited for this trial and were randomly divided into two groups, one with combined manual acupuncture and massage therapy (MAMT), and the other with only manual acupuncture therapy (MAT). In addition, 40 overweight women with BMI 23–25 kg/m2 were randomly divided into two groups, one with MAMT and the other with MAT. Therapy was carried out once per day for 21 days, and the body weights and the BMIs were recorded every day. The results showed that both MAMT and MAT could reduce body weight and BMI significantly, compared with the pretreatment values, for all the participants (p < 0.001); however, the differences in body weight and BMI reductions between pre- and posttreatment for the MAMT and the MAT groups were not statistically significant. The optimal periods for reductions in both body weight and in BMI were the first 4 days. Accounting for the economic strategy (time and money) in alternative therapy, MAT alone may present a reasonable option in the treatment of overweight and obesity in adults.

Diets higher in protein predict lower high blood pressure risk in Framingham Offspring Study adults.

Short-term clinical trials suggest that dietary protein lowers blood pressure (BP); however, long-term effects of total, animal, and plant proteins are less clear. Our goal was to evaluate effects of these dietary proteins on mean systolic BP (SBP) and diastolic BP (DBP) and incident high BP (HBP) risk among middle-aged adults in the Framingham Offspring Study. Men and women (aged 30-54 years) without prevalent HBP, cardiovascular disease, or diabetes with 3-day dietary records from exams 3 or 5 (n = 1,361) were included and followed for a mean of 11.3 years for development of HBP. Protein intakes adjusted for body size were derived using the residual method. Analysis of covariance and Cox proportional hazard's models were used to adjust for age, sex, education, height, activity, smoking, fat calories, diet quality, and body mass index. Higher protein intakes were associated with lower mean SBP and DBP. Both animal and plant proteins lowered BP and led to statistically significant reductions in HBP risk (hazard ratios of 0.68 and 0.51, respectively). Participants in the highest tertile of total protein intake had 40% less risk (95% confidence interval [CI], 0.45-0.78) of developing HBP. Beneficial effects of protein were apparent for men and women and for normal-weight and overweight individuals. Higher protein diets also characterized by higher fiber intakes led to a 59% reduction (95% CI, 0.37-0.66) in HBP risk. Adults consuming more dietary protein from either plant or animal sources had lower long-term risks of HBP.

Cost effectiveness of liraglutide in type II diabetes: a systematic review.

As novel treatments for type II diabetes enter the market, there is a need to assess their long-term clinical and economic outcomes against currently available treatment alternatives. Objective compilation and evaluation of current pharmacoeconomic evidence can assist payers and decision makers in determining the appropriate place in therapy of a new medication. Our objective was to review the existing pharmacoeconomic literature evaluating the cost effectiveness and overall costs of treatment associated with liraglutide in type II diabetes. Medical literature indexed in MEDLINE, EMBASE, PsycINFO, CINAHL, and EconLit through 1 June 2014 was searched. Full-text, English-language cost-effectiveness, cost-utility, and other cost analyses in type II diabetes that compared liraglutide to one or more anti-diabetic agents were included. Initial screening was based on relevance of titles and abstracts followed by examination of the study methods of each remaining manuscript. Studies conducting original pharmacoeconomic analyses were chosen for inclusion. Articles meeting the inclusion criteria were retrieved, and information on the study design and results was abstracted. Abstracted data elements were chosen and assessed based on the authors' experience as well as criteria set forth by the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Health Economic Evaluation Publication Guidelines Task Force. Additionally, reported incremental cost-effectiveness ratios (ICERs) and selected sensitivity analysis results were converted to $US, year 2012 values, in order to facilitate comparison across studies. A total of six cost studies and seven cost-utility studies were identified for inclusion. Across cost studies, liraglutide treatment resulted in costs ranging from a loss of $US2,730 (liraglutide 1.8 mg vs. sitagliptin; pharmacy costs only) over a 1-year time horizon to a savings of $US9,367 (liraglutide 1.8 mg vs. glimepiride; diabetes-related complication costs only) over a 30-year time horizon. Cost-utility analysis results reported base-case ICERs ranging from $US15,774 (vs. glimepiride) to $US40,128 (vs. rosiglitazone) per quality-adjusted life-year (QALY) ($US, year 2012) for liraglutide 1.2 mg and $US8,497 (vs. exenatide) to $US66,031 (vs. rosiglitazone)/QALY ($US, year 2012) for liraglutide 1.8 mg. Estimates were most sensitive to variations in time horizon and cardiovascular complication rates. Based on frequently cited, country-specific cost-utility thresholds, liraglutide was determined to have a probability of being cost effective of between 58 % (liraglutide 1.8 mg vs. sitagliptin) and 93 % (liraglutide 1.2 mg vs. glimepiride). Weaknesses of included studies related primarily to study model inputs that assumed long-term morbidity and mortality benefits in favor of liraglutide based on improvements in clinical biomarkers observed in short-term clinical trials. The exclusion of drug acquisition costs in two identified cost studies as well as the assumed lifetime duration of treatment with liraglutide in several cost-utility studies were also identified as weaknesses. The authors' review was limited by the possibility of incomplete literature retrieval, unintended omission of relevant data elements, and comparison of costs and ICERs generated from healthcare systems from differing countries. The current literature presents liraglutide as a cost-effective adjunct treatment for type II diabetes that may also be associated with a reduction in diabetes-related complication costs; however, ICER values are largely dependent on assumptions regarding the benefits of long-term liraglutide treatment and the time horizon of the analysis. Real-world use may make liraglutide unattractive from a payer and policy-maker perspective.

Comparative effectiveness and cost-effectiveness of a computer-delivered psychosocial treatment program for prisoners with substance use disorders

Comparative effectiveness and cost-effectiveness of a computer-delivered psychosocial treatment program for prisoners with substance use disorders

Ranolazine &amp;#58; Effects on Ischemic Heart

Coronary artery disease is the major cause of mortality and morbidity in the industrialized countries; in the United States of America and in Europe, it is responsible for one of every six deaths per year. In the setting of ischemic heart disease, angina pectoris and chest pain, in particular, are the major causes of emergency department accesses. Angina pectoris is a clinical syndrome characterized by discomfort typically in the chest, neck, chin and left arm induced by physical exertion, emotional stress and cold and is relieved by rest or by taking of nitrates. The main targets of treatment of angina pectoris are to improve quality of life by reducing the frequency and the severity of symptoms, to increase functional capacity and to improve prognosis. Ranolazine is a recent antianginal drug with unique methods of action. It was approved by the US Food and Drug Administration in 2006 as add-on therapy in patients symptomatic for stable angina. With the inhibition of the late sodium current, Ranolazine protects against ion deregulation, prevents cellular calcium overload and the subsequent increase in diastolic tension without impacting heart rate and blood pressure. Short term clinical trials and patent research show that add on therapy with Ranolazine in patients with chronic stable angina significantly improves exercise duration, exercise time to angina and reduces the use of nitro glycerine. Long term clinical trials showed no significant differences in the rate of cardiovascular death and myocardial infarction in patients with non-ST segment elevation acute coronary syndromes but a reduction in terms of recurrent ischemia. Ranolazine is generally well tolerated and even if it increases the duration of QTc interval it is not associated with atrial and ventricular arrhythmias. Therefore Ranolazine represents a good therapeutic approach in patients with chronic stable angina still symptomatic, while on optimal anti-ischemic therapy, or intolerant to traditional anti-ischemic drugs.

Tu1844 Symptom Stability and Economic Burden in Patients With Functional Dyspepsia: Observational 12 Month Follow-Up After a Short-Term Clinical Trial

Background: Serotonin (5-HT) signaling in the small intestine is involved in motor, sensory and secretory pathways. Studies of neuroendocrine cell mapping in functional dyspepsia (FD), characterized by upper gastrointestinal motor and sensory disturbances, are scarce although it has been previously noted that there is no significant difference in numbers of 5HT cells in duodenum in post infectious FD vs. controls1. In patients with irritable bowel syndrome, another functional bowel disorder, a low density of duodenal neuroendocrine cells is also described2.Aim: To examine the content of neuroendocrine cells in the duodenum of subjects with FD, specifically the relative content of serotonin (5-HT) containing cells and to investigate a possible relationship between neuroendocrine cell numbers and FD subtypes. Methods: A random sample of an adult Swedish population (n = 1000) (the Kalixanda study) underwent upper endoscopy and biopsies taken from the duodenal bulb (D1) and the second part of duodenum (D2). From this study 23 subjects with FD were identified, 13 with postprandial distress syndrome (PDS), 10 with epigastric pain syndrome (EPS) and 12 healthy controls. Immunocytochemistry was performed for Chromogranin A (CGA) and 5-HT. Positive cells were quantified per mm2. Results: Cases and controls showed similar demographics. The number of CGA stained cells was significantly lower in FD patients both in D1 (p = 0.01) and D2 (p = 0.04) whereas there was no significant difference in 5-HT content. See figure. When EPS and PDS were studied separately, the number of CGA stained cells was significantly decreased in D1 in patients with EPS (p = 0.03). Conclusions: The number of duodenal neuroendocrine cells is decreased in FD compared with control subjects, but this is not due to a reduction in the number of 5-HT containing cells. It is possible that this reduction reflects reduced cellular densities of other hormones (e.g. somatostatin) which could result in a high secretion of gastric acid, with a change in motility or visceral sensitivity leading to dyspeptic symptoms in these cases. 1. Futagami S et al. Am J Gastroenterol. 2010 ;105:1835-42. 2. El-Salhy M et al. Scand J Gastroenterol. 2010 ;45:1435-9.

PMH2 - Meta-analysis of drivers of cost-effectiveness from short-term lurasidone clinical trials: Effect of changing daily dose on panss total score and weight

PMH2 - Meta-analysis of drivers of cost-effectiveness from short-term lurasidone clinical trials: Effect of changing daily dose on panss total score and weight

Cost-effectiveness of asenapine in the treatment of bipolar I disorder patients with mixed episodes

Objective:Around one-third of patients with bipolar I disorder (BD-I) experience mixed episodes, characterized by both mania and depression, which tend to be more difficult and costly to treat. Atypical antipsychotics are recommended for the treatment of mixed episodes, although evidence of their efficacy, tolerability, and cost in these patients is limited. This study evaluates, from a UK National Health Service perspective, the cost-effectiveness of asenapine vs olanzapine in BD-I patients with mixed episodes.Methods:Cost-effectiveness was assessed using a Markov model. Efficacy was informed by a post-hoc analysis of two short-term clinical trials, with response measured as a composite Young Mania Rating Score and Montgomery-Åsberg Depression Rating Scale end-point. Probabilities of discontinuation and relapse to manic, mixed, and depressive episodes were sourced from published meta-analyses. Direct costs (2012–2013 values) included drug acquisition, monitoring, and resource use related to bipolar disorder as well as selected adverse events. Benefits were measured as quality-adjusted life years (QALYs).Results:For treating mixed episodes, asenapine generated 0.0187 more QALYs for an additional cost of £24 compared to olanzapine over a 5-year period, corresponding to a £1302 incremental cost-effectiveness ratio. The higher acquisition cost of asenapine was roughly offset by the healthcare savings conferred through its greater efficacy in treating these patients. The model shows that benefits were driven by earlier response to asenapine during acute treatment and were maintained during longer-term follow-up. Results were sensitive to changes in key parameters including short and longer-term efficacy, unit cost, and utilities, but conclusions remained relatively robust.Conclusions:Results suggest that asenapine is a cost-effective alternative to olanzapine in mixed episode BD-I patients, and may have specific advantages in this population, potentially leading to healthcare sector savings and improved outcomes. Limitations of the analysis stem from gaps in clinical and economic evidence for these patients and should be addressed by future clinical trials.

Current evidence for the use of coffee and caffeine to prevent age-related cognitive decline and Alzheimer's disease.

Although nothing has been proven conclusively to protect against cognitive aging, Alzheimer's disease or related dementias, decades of research suggest that specific approaches including the consumption of coffee may be effective. While coffee and caffeine are known to enhance short-term memory and cognition, some limited research also suggests that long-term use may protect against cognitive decline or dementia. In vitro and pre-clinical animal models have identified plausible neuroprotective mechanisms of action of both caffeine and other bioactive components of coffee, though epidemiology has produced mixed results. Some studies suggest a protective association while others report no benefit. To our knowledge, no evidence has been gathered from randomized controlled trials. Although moderate consumption of caffeinated coffee is generally safe for healthy people, it may not be for everyone, since comorbidities and personal genetics influence potential benefits and risks. Future studies could include short-term clinical trials with biomarker outcomes to validate findings from pre-clinical models and improved epidemiological studies that incorporate more standardized methods of data collection and analysis. Given the enormous economic and emotional toll threatened by the current epidemic of Alzheimer's disease and other dementias, it is critically important to validate potential prevention strategies such as coffee and caffeine.