Views on primary prevention of cardiovascular disease - an interview study with Swedish GPs

Background: General practitioners (GPs) have gradually become more involved in the prevention of cardiovascular disease (CVD), both through more frequent prescribing of pharmaceuticals and by giving advice regarding lifestyle factors. Most general practitioners are now faced with decisions about pharmaceutical or non-pharmaceutical treatment for primary prevention every day. The aim of this study was to explore, structure and describe the views on primary prevention of cardiovascular disease in clinical practice among Swedish GPs. Methods: Individual interviews were conducted with 21 GPs in southern Sweden. The interview transcripts were analysed using a qualitative approach, inspired by phenomenography. Results: Two main categories of description emerged during the analysis. One was the degree of reliance on research data regarding the predictability of real risk and the opportunities for primary prevention of CVD. The other was the allocation of responsibility between the patient and the doctor. The GPs showed different views, from being convinced of an actual and predictable risk for the individual to strongly doubting it; from relying firmly on protection from disease by pharmaceutical treatment to strongly questioning its effectiveness in individual cases; and from reliance on prevention of disease by non-pharmaceutical interventions to a total lack of reliance on such measures. Conclusions: The GPs' different views, regarding the rationale for and practical management of primary prevention of CVD, can be interpreted as a reflection of the complexity of patient counselling in primary prevention in clinical practice. The findings have implications for development and implementation of standard treatment guidelines, regarding long-time primary preventive treatment

The Anticoagulation of Calf Thrombosis (ACT) project: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Half of all lower limb deep vein thrombi (DVT) in symptomatic ambulatory patients are located in the distal (calf) veins. While proximal disease warrants therapeutic anticoagulation to reduce the associated risks, distal DVT often goes untreated. However, a proportion of untreated distal disease will undoubtedly propagate or embolize. Concern also exists that untreated disease could lead to long-term post thrombotic changes. Currently, it is not possible to predict which distal thrombi will develop such complications. Whether these potential risks outweigh those associated with unrestricted anticoagulation remains unclear. The Anticoagulation of Calf Thrombosis (ACT) trial aims to compare therapeutic anticoagulation against conservative management for patients with acute symptomatic distal deep vein thrombosis.</p> <p>Methods</p> <p>ACT is a pragmatic, open-label, randomized controlled trial. Adult patients diagnosed with acute distal DVT will be allocated to either therapeutic anticoagulation or conservative management. All patients will undergo 3 months of clinical and assessor blinded sonographic follow-up, followed by 2-year final review. The project will commence initially as an external pilot study, recruiting over a 16-month period at a single center to assess feasibility measures and clinical event rates. Primary outcome measures will assess feasibility endpoints. Secondary clinical outcomes will be collected to gather accurate data for the design of a definitive clinical trial and will include: (1) a composite endpoint combining thrombus propagation to the popliteal vein or above, development of symptomatic pulmonary embolism or sudden death attributable to venous thromboembolic disease; (2) the incidence of major and minor bleeding episodes; (3) the incidence of post-thrombotic leg syndrome at 2 years using a validated screening tool; and (4) the incidence of venous thromboembolism (VTE) recurrence at 2 years.</p> <p>Discussion</p> <p>The ACT trial will explore the feasibility of comparing therapeutic anticoagulation to conservative management in acute distal DVT, within a modern cohort. We also aim to provide contemporary data on clot propagation, bleeding rates and long-term outcomes within both groups. These results will inform the conduct of a definitive study if feasibility is established.</p> <p>Trial registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN75175695">ISRCTN75175695</a></p

Cost-effectiveness of oral alitretinoin in patients with severe chronic hand eczema - a long-term analysis from a Swiss perspective

BACKGROUND: The impact on patients suffering from chronic hand eczema (CHE) is enormous, as no licensed systemic treatment option with proven efficacy for CHE is available. Alitretinoin is a novel agent which showed high clinical efficacy in patients with severe, refractory CHE. We assessed the cost-effectiveness of alitretinoin for CHE patient treatment from a Swiss third party payer perspective. A further objective of this study was to determine the burden of disease in Switzerland. METHODS: A long-term Markov cohort simulation model was used to estimate direct medical costs (euro) and clinical effectiveness (quality adjusted life years, QALYs) of treating severe CHE patients with alitretinoin. Comparison was against the standard treatment of supportive care (optimised emollient therapy). Information on response rates were derived from a randomized controlled clinical trial. Costs were considered from the perspective of the Swiss health system. Swiss epidemiological data was derived from official Swiss Statistic institutions. RESULTS: Annual costs of alitretinoin treatment accounted for 2'212 euro. After a time horizon of 22.4 years, average remaining long-term costs accounted for 42'208 euro or 38'795 euro in the alitretinoin and the standard treatment arm, respectively. Compared with the standard therapy, the addition of alitretinoin yielded an average gain of 0.230 QALYs at the end of the simulation. Accordingly, the incremental cost-effectiveness ratio resulted in 14'816 euro/QALY gained. These results were robust to changes in key model assumptions. CONCLUSION: The therapy for CHE patients is currently insufficient. In our long-term model we identified the treatment with alitretinoin as a cost-effective alternative for the therapy of CHE patients in Switzerland

Maintenance or Discontinuation of Antidepressants in Primary Care

BACKGROUND: Patients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant therapy in this setting. METHODS: We conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings. RESULTS: A total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; P<0.001). Secondary outcomes were generally in the same direction as the primary outcome. Patients in the discontinuation group had more symptoms of depression, anxiety, and withdrawal than those in the maintenance group. CONCLUSIONS: Among patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy

MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours

Combining drugs, which target different signalling pathways, often decreases adverse side effects while increasing the efficacy of treatment. The objective of our study was to determine if the combination of our novel atypical retinoic acid metabolism-blocking agent (RAMBA) VN/66-1 and a promising histone deacetylase inhibitor N-(2-aminophenyl)4-[N-(pyridine-3-yl-methoxy-carbonyl)aminomethyl]benzamide (MS-275) would show enhanced antineoplastic activity on human PC-3 prostate cancer cells/tumours and also to decipher the molecular mechanisms of action. The combination of VN/66-1+MS-275 was found to be synergistic in inhibiting PC-3 cell growth, caused cell cytostaticity/cytotoxicity and induced marked G2/M phase arrest and apoptosis. In mice with well-established PC-3 tumours, VN/66-1 (5 and 10 mg kg−1 day−1) caused significant suppression of tumour growth compared with mice receiving vehicle alone. Furthermore, treatment with VN/66-1 (10 mg kg−1 day−1)+MS-275 (2.5 mg kg−1 day−1) for 18 days resulted in an 85% reduction in final mean tumour volume compared with control and was more effective than either agent alone. Mechanistic studies indicated that treatment of PC-3 cells/tumours with VN/66-1+MS-275 caused DNA damage (upregulation of γH2AX), hyperacetylation of histones H3 and H4, upregulation of retinoic acid receptor-β, p21WAF1/CIP1, E-cadherin, and Bad and downregulation of Bcl-2. These data suggest that the mechanism of action of the combination of agents is DNA damage-induced p21 activation, resulting in inhibition of the Cdc2/cyclin B complex and accumulation of cells in G2/M phase. In addition, the combination caused modulation and induction of apoptosis. These results suggest that VN/66-1 or its combination with MS-275 may be a novel therapy for the treatment of prostate carcinoma

Antidepressant medication to prevent depression relapse in primary care: the ANTLER RCT

Background: There has been a steady increase in the number of primary care patients receiving long-term maintenance antidepressant treatment, despite limited evidence of a benefit of this treatment beyond 8 months. Objective: The ANTidepressants to prevent reLapse in dEpRession (ANTLER) trial investigated the clinical effectiveness and cost-effectiveness of antidepressant medication in preventing relapse in UK primary care. Design: This was a Phase IV, double-blind, pragmatic, multisite, individually randomised parallel-group controlled trial, with follow-up at 6, 12, 26, 39 and 52 weeks. Participants were randomised using minimisation on centre, type of antidepressant and baseline depressive symptom score above or below the median using Clinical Interview Schedule – Revised (two categories). Statisticians were blind to allocation for the outcome analyses. Setting: General practices in London, Bristol, Southampton and York. Participants: Individuals aged 18–74 years who had experienced at least two episodes of depression and had been taking antidepressants for ≥ 9 months but felt well enough to consider stopping their medication. Those who met an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis of depression or with other psychiatric conditions were excluded. Intervention: At baseline, participants were taking citalopram 20 mg, sertraline 100 mg, fluoxetine 20 mg or mirtazapine 30 mg. They were randomised to either remain on their current medication or discontinue medication after a tapering period. Main outcome measures: The primary outcome was the time, in weeks, to the beginning of the first depressive episode after randomisation. This was measured by a retrospective Clinical Interview Schedule – Revised that assessed the onset of a depressive episode in the previous 12 weeks, and was conducted at 12, 26, 39 and 52 weeks. The depression-related resource use was collected over 12 months from medical records and patient-completed questionnaires. Quality-adjusted life-years were calculated using the EuroQol-5 Dimensions, five-level version. Results: Between 9 March 2017 and 1 March 2019, we randomised 238 participants to antidepressant continuation (the maintenance group) and 240 participants to antidepressant discontinuation (the discontinuation group). The time to relapse of depression was shorter in the discontinuation group, with a hazard ratio of 2.06 (95% confidence interval 1.56 to 2.70; p < 0.0001). By 52 weeks, relapse was experienced by 39% of those who continued antidepressants and 56% of those who discontinued antidepressants. The secondary analysis revealed that people who discontinued experienced more withdrawal symptoms than those who remained on medication, with the largest difference at 12 weeks. In the discontinuation group, 37% (95% confidence interval 28% to 45%) of participants remained on their randomised medication until the end of the trial. In total, 39% (95% confidence interval 32% to 45%) of participants in the discontinuation group returned to their original antidepressant compared with 20% (95% confidence interval 15% to 25%) of participants in maintenance group. The health  economic evaluation demonstrated that participants randomised to discontinuation had worse utility scores at 3 months (–0.037, 95% confidence interval –0.059 to –0.015) and fewer quality-adjusted life-years over 12 months (–0.019, 95% confidence interval –0.035 to –0.003) than those randomised to continuation. The discontinuation pathway, besides giving worse outcomes, also cost more [extra £2.71 per patient over 12 months (95% confidence interval –£36.10 to £37.07)] than the continuation pathway, although the cost difference was not significant. Conclusions: Patients who discontinue long-term maintenance antidepressants in primary care are at increased risk of relapse and withdrawal symptoms. However, a substantial proportion of patients can discontinue antidepressants without relapse. Our findings will give patients and clinicians an estimate of the likely benefits and harms of stopping long-term maintenance antidepressants and improve shared decision-making. The participants may not have been representative of all people on long-term maintenance treatment and we could study only a restricted range of antidepressants and doses. Identifying patients who will not relapse if they discontinued antidepressants would be clinically important