[Environmental impact of inhalers in the Netherlands and worldwide: the facts at a glance]. / Milieu-impact van inhalatoren in Nederland en wereldwijd.

Hydrofluorocarbons (HFCs) released from the use of metered-dose inhalers (MDIs) contribute significantly to climate change. Counterintuitively, these HFCs indirectly cause health damage to asthma and COPD patients, as climate change creates more summer smog and pollen in the air. European regulation is urgently needed to ensure that only MDIs with HFCs with a lower global warming potential will be produced in future. Meanwhile, prescribing less MDIs can have a substantial impact on the reduction of greenhouse gases. If a healthcare professional chooses a greener alternative as a maintenance dose of inhalation medication together with twenty patients this saves 1.8 tons of CO2-eq emissions per year. This is as much CO2-eq per year as one person would save per year by replacing his or her petrol car for an electric car.

[Deviating from guideline-recommended diagnostic work-up in general practice: examples involving high-sensitivity troponin and CRP testing]. / Afwijken van richtlijnen bij diagnostiek in de huisartsenpraktijk.

While clinical guidelines are essential for decision-making based on the latest evidence, they are not all-encompassing for any given patient or context. As such, deviating from guideline recommendations is common practice and can be attributed to contextual, ethical, clinical, or scientific factors. In the setting of diagnostic testing deviating from recommended diagnostic work-up may result in both over- and under-testing. In this Clinical Lesson we discuss two scenarios in primary care, one involving high-sensitivity troponin testing in a patient with episodes of chest discomfort, and the other involving CRP testing in a pediatric patient with acute-onset abdominal pain.

Turning green: the impact of changing to more eco-friendly respiratory healthcare - a carbon and cost analysis of Dutch prescription data.

OBJECTIVES: Dry powder inhalers (DPIs) and soft mist inhalers have a substantially lower global warming potential than pressurised metered-dose inhalers (pMDIs). To help mitigate climate change, we assessed the potential emission reduction in CO2 equivalents when replacing pMDIs by non-propellant inhalers (NPIs) in Dutch respiratory healthcare and estimated the associated cost. DESIGN: We performed a descriptive analysis of prescription data from two national databases of two independent governmental bodies. First, we calculated the number of patients with chronic obstructive pulmonary disease (COPD) and asthma that were using inhalation medication (2020). Second, we calculated the number and total of daily defined doses of pMDIs and NPIs including DPIs and soft mist inhalers, as well as the number of dispensed spacers per patient (2020). Third, we estimated the potential emission reduction in CO2 equivalents if 70% of patients would switch from using pMDIs to using NPIs. Fourth, we performed a budget impact analysis. SETTING: Dutch respiratory healthcare. PRIMARY AND SECONDARY OUTCOME MEASURES: The carbon footprint of current inhalation medication and the environmental and financial impact of replacing pMDIs with NPIs. RESULTS: In 2020, 1.4 million patients used inhalers for COPD or asthma treatment. A total of 364 million defined daily doses from inhalers were dispensed of which 49.6% were dispensed through pMDIs. We estimated that this could be reduced by 70% which would lead to an annual reduction in greenhouse gas emission of 63 million kg.CO2 equivalents saving at best EUR 49.1 million per year. CONCLUSIONS: In the Netherlands, substitution of pMDIs to NPIs for eligible patients is theoretically safe and in accordance with medical guidelines, while reducing greenhouse gas emission by 63 million kg.CO2 equivalents on average and saving at best EUR 49.1 million per year. This study confirms the potential climate and economic benefit of delivering a more eco-friendly respiratory care.

[No place for ondansetron in young children with gastroenteritis and persistent vomiting]. / Geen plaats voor ondansetron bij kinderen met gastro-enteritis en braken.

At several out-of-hours services primary care, a single dose of ondansetron was compared with standard care (oral rehydration solution (ORS)) in young children with gastroenteritis and persistent vomiting. Although vomiting decreased more often in the ondansetron group compared to the control group in the first hours, ondansetron had no effect on ORS use and did not lead to fewer referrals to the hospital. Unfortunately, the outcome measure diarrhoea was missing as a possible adverse effect of ondansetron. Diarrhoea was reported around 2-3 times more often with ondansetron compared to placebo in four of five other studies in children with gastroenteritis and vomiting. It is therefore questionable whether the limited clinical benefit of ondansetron in children with vomiting due to gastroenteritis outweighs the possible (as yet insufficiently investigated) side effect diarrhoea.

The Development of Practice Recommendations for Drug-Disease Interactions by Literature Review and Expert Opinion.

BACKGROUND: Drug-disease interactions negatively affect the benefit/risk ratio of drugs for specific populations. In these conditions drugs should be avoided, adjusted, or accompanied by extra monitoring. The motivation for many drug-disease interactions in the Summary of Product Characteristics (SmPC) is sometimes insufficiently supported by (accessible) evidence. As a consequence the translation of SmPC to clinical practice may lead to non-specific recommendations. For the translation of this information to the real world, it is necessary to evaluate the available knowledge about drug-disease interactions, and to formulate specific recommendations for prescribers and pharmacists. The aim of this paper is to describe a standardized method how to develop practice recommendations for drug-disease interactions by literature review and expert opinion. METHODS: The development of recommendations for drug-disease interactions will follow a six-step plan involving a multidisciplinary expert panel (1). The scope of the drug-disease interaction will be specified by defining the disease and by describing relevant effects of this drug-disease interaction. Drugs possibly involved in this drug-disease interaction are selected by checking the official product information, literature, and expert opinion (2). Evidence will be collected from the official product information, guidelines, handbooks, and primary literature (3). Study characteristics and outcomes will be evaluated and presented in standardized reports, including preliminary conclusions on the clinical relevance and practice recommendations (4). The multidisciplinary expert panel will discuss the reports and will either adopt or adjust the conclusions (5). Practice recommendations will be integrated in clinical decision support systems and published (6). The results of the evaluated drug-disease interactions will remain up-to-date by screening new risk information, periodic literature review, and (re)assessments initiated by health care providers. ACTIONABLE RECOMMENDATIONS: The practice recommendations will result in advices for specific DDSI. The content and considerations of these DDSIs will be published and implemented in all Clinical Decision Support Systems in the Netherlands. DISCUSSION: The recommendations result in professional guidance in the context of individual patient care. The professional will be supported in the decision making in concerning pharmacotherapy for the treatment of a medical problem, and the clinical risks of the proposed medication in combination with specific diseases.

[Diagnostics on suspicion of a bleeding disorder]. / Diagnostiek bij een vermeende stollingsstoornis.

Bleeding symptoms occur frequently in the general population, but the possibility of an underlying bleeding disorder is not always recognised. Women with a bleeding disorder are disproportionally affected due to blood loss during menstruation and giving birth. Taking a thorough family history and a history of bleeding are most important in the workup to detect a potential underlying bleeding disorder. In patients with a bleeding disorder, potentially life-threatening complications due to bleeding can be prevented by compiling an individualized treatment plan and timely targeted blood coagulation treatment. If a bleeding disorder is suspected, initial diagnostic testing consists of determining the aPTT, PT, platelet count and von Willebrand factor activity; global tests for disorders of haemostasis, such as the coagulation time and platelet function are not of any added value. It cannot be excluded that a patient in whom test results are normal may still have a platelet function disorder or a rare bleeding disorder. If there is a strong suspicion of a bleeding disorder this should always be discussed with a coagulation specialist.

Treatment of Lower Extremity Superficial Thrombophlebitis.

Clinical Question: Which treatments for lower extremity superficial thrombophlebitis (ST) are associated with lower rates of venous thromboembolic events (VTEs) vs placebo? Bottom Line: A dose of 2.5 mg of fondaparinux administered subcutaneously once daily for 45 days is associated with fewer cases of symptomatic VTE without an increase in major bleeding vs placebo. Low-molecular-weight heparin (LMWH) and nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with lower rates of ST extension or recurrence vs placebo, but data regarding symptomatic VTE remain inconclusive. Oral rivaroxaban requires further evaluation.

Treatment for superficial thrombophlebitis of the leg.

BACKGROUND: The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is the third update of a review first published in 2007. OBJECTIVES: To assess the efficacy and safety of topical, medical, and surgical treatments for ST of the leg in improving local symptoms and decreasing thromboembolic complications. SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register (March 2017), CENTRAL (2017, Issue 2), and trials registries (March 2017). We handsearched the reference lists of relevant papers and conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the legs that included people with a clinical diagnosis of ST of the legs or objective diagnosis of a thrombus in a superficial vein. DATA COLLECTION AND ANALYSIS: Two authors assessed the trials for inclusion in the review, extracted the data, and assessed the quality of the studies. Data were independently extracted from the included studies and any disagreements resolved by consensus. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We identified three additional trials (613 participants), therefore this update considered 33 studies involving 7296 people with ST of the legs. Treatment included fondaparinux; rivaroxaban; low molecular weight heparin (LMWH); unfractionated heparin (UFH); non-steroidal anti-inflammatory drugs (NSAIDs); compression stockings; and topical, intramuscular, or intravenous treatment to surgical interventions such as thrombectomy or ligation. Only a minority of trials compared treatment with placebo rather than an alternative treatment and many studies were small and of poor quality. Pooling of the data was possible for few outcomes, and none were part of a placebo-controlled trial. In one large, placebo-controlled RCT of 3002 participants, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (risk ratio (RR) 0.15, 95% confidence interval (CI) 0.04 to 0.50; moderate-quality evidence), ST extension (RR 0.08, 95% CI 0.03 to 0.22; moderate-quality evidence), and ST recurrence (RR 0.21, 95% CI 0.08 to 0.54; moderate-quality evidence) relative to placebo. Major bleeding was infrequent in both groups with very wide CIs around risk estimate (RR 0.99, 95% CI 0.06 to 15.86; moderate-quality evidence). In one RCT on 472 high-risk participants with ST, fondaparinux was associated with a non-significant reduction of symptomatic VTE compared to rivaroxaban 10 mg (RR 0.33, 95% CI 0.03 to 3.18; low-quality evidence). There were no major bleeding events in either group (low-quality evidence). In another placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (prophylactic: RR 0.44, 95% CI 0.26 to 0.74; therapeutic: RR 0.46, 95% CI 0.27 to 0.77) and NSAIDs (RR 0.46, 95% CI 0.27 to 0.78) reduced the extension (low-quality evidence) and recurrence of ST (low-quality evidence) in comparison to placebo, with no significant effects on symptomatic VTE (low-quality evidence) or major bleeding (low-quality evidence). Overall, topical treatments improved local symptoms compared with placebo, but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatments, topical treatments, or surgery did not report VTE, ST progression, adverse events, or treatment adverse effects. AUTHORS' CONCLUSIONS: Prophylactic dose fondaparinux given for 45 days appears to be a valid therapeutic option for ST of the legs for most people. The evidence on topical treatment or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE. Further research is needed to assess the role of rivaroxaban and other direct oral factor-X or thrombin inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment in people at various risk of recurrence; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.

Treatment for superficial thrombophlebitis of the leg.

BACKGROUND: The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is the second update of a review first published in 2007. OBJECTIVES: To assess the efficacy and safety of topical, medical, and surgical treatments in patients presenting with ST of the legs. SEARCH METHODS: For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched November 2012) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 11). We handsearched the reference lists of relevant papers and conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the legs that included participants with a clinical diagnosis of ST of the legs or an objective diagnosis of a thrombus in a superficial vein. DATA COLLECTION AND ANALYSIS: Two authors assessed the trials for inclusion in the review, extracted the data, and assessed the quality of the studies. Data were independently extracted from the included studies and any disagreements resolved by consensus. MAIN RESULTS: We identified four additional trials (986 patients), so this update considered 30 studies involving 6507 participants with ST of the legs.Treatment ranged from fondaparinux, low molecular weight heparin (LMWH), unfractionated heparin (UFH), non-steroidal anti-inflammatory agents (NSAIDs), topical treatment, oral treatment, intramuscular treatment, and intravenous treatment to surgery. Only a minority of trials compared treatment with placebo rather than an alternative treatment, none evaluated the same treatment comparisons on the same study outcomes (which precluded meta-analysis), and many of the studies were small and of poor quality. In one large, placebo-controlled RCT of about 3000 patients, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (RR 0.15; 95% CI 0.04 to 0.50), ST extension (RR 0.08; 95% CI 0.03 to 0.22), and ST recurrence (RR 0.21; 95% CI 0.08 to 0.54) with comparable rates of major bleeding (RR 0.99; 95% CI 0.06 to 15.86) relative to placebo. In a further placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (RR 0.40; 95% CI 0.22 to 0.72 and RR 0.42; 95% CI 0.23 to 0.75, respectively) and NSAIDs (RR 0.41; 95% CI 0.23 to 0.75) reduced the extension and recurrence of ST in comparison to placebo, with no significant effects on symptomatic VTE nor major bleeding. Overall, topical treatments improved local symptoms compared with placebo but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatment, topical treatment, or surgery did not report VTE, ST progression, adverse events, or treatment side effects. AUTHORS' CONCLUSIONS: Prophylactic dose fondaparinux given for six weeks appears to be a valid therapeutic option for ST of the legs. The evidence on oral treatments, topical treatment, or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE and ST progression. Further research is needed to assess the role of the new oral direct thrombin and activated factor-X inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.

Treatment for superficial thrombophlebitis of the leg.

BACKGROUND: The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is an update of a review first published in 2007. OBJECTIVES: To assess the efficacy and safety of topical, medical, and surgical treatments in patients presenting with ST of the legs. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched 29 November 2011) and CENTRAL (2011, Issue 4). We handsearched reference lists of relevant papers and conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the leg that included participants with a clinical diagnosis of ST of the legs or objective diagnosis of a thrombus in the superficial vein. DATA COLLECTION AND ANALYSIS: Two authors assessed the trials for inclusion in the review, extracted the data, and assessed the quality of the studies. Data were independently extracted from the included studies and any disagreements resolved by consensus. MAIN RESULTS: Twenty-six studies involving 5521 participants with ST of the legs were included in this review. The methodological quality of most of the trials was poor. Treatment ranged from fondaparinux, low molecular weight heparin (LMWH), unfractionated heparin (UFH), non-steroidal anti-inflammatory agents (NSAIDs), topical treatment, oral treatment, intramuscular treatment, and intravenous treatment to surgery. In a placebo-controlled RCT of about 3000 patients, fondaparinux was associated with a significant reduction in symptomatic VTE (RR 0.15; 95% CI 0.04 to 0.50), extension (RR 0.08; 95% CI 0.03 to 0.22), and recurrence of ST (RR 0.21; 95% CI 0.08 to 0.54) with comparable rates of major bleeding (RR 0.99; 95% CI 0.06 to 15.86) relative to placebo. Both prophylactic and therapeutic doses of LMWH (RR 0.40; 95% CI 0.22 to 0.72 and RR 0.42; 95% CI 0.23 to 0.75, respectively) and NSAIDs (RR 0.41; 95% CI 0.23 to 0.75) reduced the extension and recurrence of ST in comparison to placebo, with no significant effects on symptomatic VTE nor major bleeding. Overall, topical treatments improved local symptoms. However, no data were provided on the effects of these treatments on VTE and ST extension. Surgical treatment combined with elastic stockings in ST was associated with a lower VTE rate and ST progression compared with elastic stockings alone. AUTHORS' CONCLUSIONS: Prophylactic dose fondaparinux given for six weeks appears to be a valid therapeutic option for ST of the legs. Further research is needed to assess the role of new oral direct thrombin and activated factor-X inhibitors, LMWH, NSAIDs; the optimal doses and duration of treatment; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.

Assessment of coagulation and fibrinolysis in families with unexplained thrombophilia.

Despite knowledge of various inherited risk factors associated with venous thromboembolism (VTE), no definite cause can be found in about 50% of patients. The lack of an intermediate phenotype in VTE impedes the discovery of new familial risk factors. We set out to define an intermediate phenotype for VTE by performing global coagulation analyses in unexplained thrombophilic families. Families were selected through a proband with VTE but without one of the known thrombophilic defects and at least one 1st or two 2nd degree family members with VTE. Clinical data were collected using a standardized questionnaire. Blood samples were collected for overall haemostasis assays (i.e. thrombin generation time [TGT], endogenous thrombin potential [ETP], prothrombin fragment 1+2 [F1+2] and activated protein C-sensitivity ratio [APC-sr] and clot lysis time [CLT]). Data were analysed using logistic regression. Coagulation assays were performed in 353 individuals of whom 41 (12%) had a history of VTE; these belonged to 17 thrombophilic families. Of the tested variables only the ETP was associated with VTE (odds ratio [OR] 1.03 for each % increase, 95% confidence interval [CI] 1.01-1.05). However, the relatively low number of cases does not firmly exclude the other assays as candidate intermediate phenotypes for venous thrombosis. We found that an increased ETP may serve as an intermediate phenotype for VTE and may be used to discover novel inherited risk factors by genetic linkage analysis.

Treatment of superficial vein thrombosis to prevent deep vein thrombosis and pulmonary embolism: a systematic review.

BACKGROUND AND OBJECTIVES: The aim of this systematic review was to summarize the evidence from randomized controlled trials (RCT) concerning the efficacy and safety of medical or surgical treatments of superficial vein thrombosis (SVT) for the prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE). DESIGN AND METHODS: A systematic search was performed in MEDLINE, EMBASE and the Cochrane (CENTRAL) database to identify all randomized trials that evaluated the effect of surgical or medical treatment in the prevention of venous thromboembolism (VTE) in patients with SVT of the legs. RESULTS: Five studies were included. Pooling of the data was not possible due to the heterogeneity among the studies. Moreover, three studies had major methodological drawbacks limiting the clinical applicability of the results. One of the remaining (pilot) studies showed a non-significant trend in favor of high- compared to low-dose unfractionated heparin for the prevention of VTE. The last remaining study showed a non-significant trend in favor of short-term treatment with low-molecular-weight heparin (LMWH) or a non-steroidal anti-inflammatory drug (NSAID) as compared to placebo shortly after treatment with respect to VTE, but the apparent benefit disappeared after three months of follow-up. Active treatment of SVT reduced the incidences of SVT extension or recurrence. INTERPRETATION AND CONCLUSIONS: Treatment with a therapeutic or prophylactic dose of LMWH or a NSAID reduces the incidence of SVT extension or recurrence, but not VTE. More RCT are needed before any evidence-based recommendations on the treatment of SVT for the prevention of VTE can be given. With the present lack of solid evidence we would suggest treating patients with at least intermediate doses of LMWH.

Use of ML dipstick as a tool to classify leprosy patients

Leprosy control services face the problem of leprosy patients being misclassified by the lack of or the poor quality of skinsmear examination services. Misclassification increases the risk of relapse due to insufficient treatment if a multibacillary (MB) patient is classified as paucibacillary (PB), thereby also prolonging the time that the patient is infectious. The World Health Organization (WHO) recommends at present an alternative classification based on the number of skin lesions. Its reliability, however, has been questioned. Our investigation sought to determine the usefulness of the ML Dipstick, a simple field assay to detect IgM antibodies to phenolic glycolipid-I of Mycobacterium leprae, for the classification of leprosy patients in addition to lesion count. In this study, 264 leprosy patients were investigated. Of 130 patients with a positive bacterial index (BI), 19 (14.6%) had less than 6 lesions and would have been classified as PB. Out of 134 patients with a negative BI, 26 (19.4%) had 6 or more lesions and would have been classified as MB patients if the lesion counting system would apply. Thus, the classification based on the number of lesions only was found to be 85% sensitive and 81% specific (using the BI as the gold standard) at detecting MB cases among the studied population. Sensitivity would have increased if patients would have been classified according to a combination of the number of lesions and the dipstick result. In that case patients are classified as MB when they are either dipstick positive (N = 16), have more than 6 lesions (N = 43), or both (N = 94). Patients negative for both dipstick and number of lesions would have been classified as PB (N = 111). The classification based on the number of lesions alone left 19 BI-positive cases classified as PB, while the combination method of the ML Dipstick and number of lesions left only 8 BI-positive cases classified as PB (5 borderline, 2 borderline lepromatous and 1 tuberculoid), thus preventing undertreatment. The combination method of the ML Dipstick and lesion counting was found to be 94% sensitive and 77% specific, which is an improvement of 9% (chi-squared test, p = 0.025) in sensitivity compared to lesion counting only. The results of this study indicate that testing all patients initially classified by lesion counting as PB (48% in our study population) with the dipstick can significantly contribute to improved classification of leprosy patients for treatment purposes.