To compare the impact of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on cardiovascular outcomes in adults taking maximally tolerated statin therapy or who are ...statin intolerant.
Network meta-analysis.
Medline, EMBASE, and Cochrane Library up to 31 December 2020.
Randomised controlled trials of ezetimibe and PCSK9 inhibitors with ≥500 patients and follow-up of ≥6 months.
We performed frequentist fixed-effects network meta-analysis and GRADE (grading of recommendations, assessment, development, and evaluation) to assess certainty of evidence. Results included relative risks (RR) and absolute risks per 1000 patients treated for five years for non-fatal myocardial infarction (MI), non-fatal stroke, all-cause mortality, and cardiovascular mortality. We estimated absolute risk differences assuming constant RR (estimated from network meta-analysis) across different baseline therapies and cardiovascular risk thresholds; the PREDICT risk calculator estimated cardiovascular risk in primary and secondary prevention. Patients were categorised at low to very high cardiovascular risk. A guideline panel and systematic review authors established the minimal important differences (MID) of 12 per 1000 for MI and 10 per 1000 for stroke.
We identified 14 trials assessing ezetimibe and PCSK9 inhibitors among 83 660 adults using statins. Adding ezetimibe to statins reduced MI (RR 0.87 (95% confidence interval 0.80 to 0.94)) and stroke (RR 0.82 (0.71 to 0.96)) but not all-cause mortality (RR 0.99 (0.92 to 1.06)) or cardiovascular mortality (RR 0.97 (0.87 to 1.09)). Similarly, adding PCSK9 inhibitor to statins reduced MI (0.81 (0.76 to 0.87)) and stroke (0.74 (0.64 to 0.85)) but not all-cause (0.95 (0.87 to 1.03)) or cardiovascular mortality (0.95 (0.87 to 1.03)). Among adults with very high cardiovascular risk, adding PCSK9 inhibitor was likely to reduce MI (16 per 1000) and stroke (21 per 1000) (moderate to high certainty); whereas adding ezetimibe was likely to reduce stroke (14 per 1000), but the reduction of MI (11 per 1000) (moderate certainty) did not reach MID. Adding ezetimibe to PCSK9 inhibitor and statin may reduce stroke (11 per 1000), but the reduction of MI (9 per 1000) (low certainty) did not reach MID. Adding PCSK9 inhibitors to statins and ezetimibe may reduce MI (14 per 1000) and stroke (17 per 1000) (low certainty). Among adults with high cardiovascular risk, adding PCSK9 inhibitor probably reduced MI (12 per 1000) and stroke (16 per 1000) (moderate certainty); adding ezetimibe probably reduced stroke (11 per 1000), but the reduction in MI did not achieve MID (8 per 1000) (moderate certainty). Adding ezetimibe to PCSK9 inhibitor and statins did not reduce outcomes beyond MID, while adding PCSK9 inhibitor to ezetimibe and statins may reduce stroke (13 per 1000). These effects were consistent in statin-intolerant patients. Among moderate and low cardiovascular risk groups, adding PCSK9 inhibitor or ezetimibe to statins yielded little or no benefit for MI and stroke.
Ezetimibe or PCSK9 inhibitors may reduce non-fatal MI and stroke in adults at very high or high cardiovascular risk who are receiving maximally tolerated statin therapy or are statin-intolerant, but not in those with moderate and low cardiovascular risk.
Receiving a diagnosis of cancer and the subsequent related treatments can have a significant impact on an individual's physical and psychosocial well-being. To ensure that cancer care addresses all ...aspects of well-being, systematic screening for distress and supportive care needs is recommended. Appropriate screening could help support the integration of psychosocial approaches in daily routines in order to achieve holistic cancer care and ensure that the specific care needs of people with cancer are met and that the organisation of such care is optimised.
To examine the effectiveness and safety of screening of psychosocial well-being and care needs of people with cancer. To explore the intervention characteristics that contribute to the effectiveness of these screening interventions.
We searched five electronic databases in January 2018: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, and CINAHL. We also searched five trial registers and screened the contents of relevant journals, citations, and references to find published and unpublished trials.
We included randomised controlled trials (RCTs) and non-randomised controlled trials (NRCTs) that studied the effect of screening interventions addressing the psychosocial well-being and care needs of people with cancer compared to usual care. These screening interventions could involve self-reporting of people with a patient-reported outcome measures (PROMs) or a semi-structured interview with a screening interventionist, and comprise a solitary screening intervention or screening with guided actions. We excluded studies that evaluated screening integrated as an element in more complex interventions (e.g. therapy, coaching, full care pathways, or care programmes).
Two review authors independently extracted the data and assessed methodological quality for each included study using the Cochrane tool for RCTs and the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool for NRCTs. Due to the high level of heterogeneity in the included studies, only three were included in meta-analysis. Results of the remaining 23 studies were analysed narratively.
We included 26 studies (18 RCTs and 8 NRCTs) with sample sizes of 41 to 1012 participants, involving a total of 7654 adults with cancer. Two studies included only men or women; all other studies included both sexes. For most studies people with breast, lung, head and neck, colorectal, prostate cancer, or several of these diagnoses were included; some studies included people with a broader range of cancer diagnosis. Ten studies focused on a solitary screening intervention, while the remaining 16 studies evaluated a screening intervention combined with guided actions. A broad range of intervention instruments was used, and were described by study authors as a screening of health-related quality of life (HRQoL), distress screening, needs assessment, or assessment of biopsychosocial symptoms or overall well-being. In 13 studies, the screening was a self-reported questionnaire, while in the remaining 13 studies an interventionist conducted the screening by interview or paper-pencil assessment. The interventional screenings in the studies were applied 1 to 12 times, without follow-up or from 4 weeks to 18 months after the first interventional screening. We assessed risk of bias as high for eight RCTs, low for five RCTs, and unclear for the five remaining RCTs. There were further concerns about the NRCTs (1 = critical risk study; 6 = serious risk studies; 1 = risk unclear).Due to considerable heterogeneity in several intervention and study characteristics, we have reported the results narratively for the majority of the evidence.In the narrative synthesis of all included studies, we found very low-certainty evidence for the effect of screening on HRQoL (20 studies). Of these studies, eight found beneficial effects of screening for several subdomains of HRQoL, and 10 found no effects of screening. One study found adverse effects, and the last study did not report quantitative results. We found very low-certainty evidence for the effect of screening on distress (16 studies). Of these studies, two found beneficial effects of screening, and 14 found no effects of screening. We judged the overall certainty of the evidence for the effect of screening on HRQoL to be very low. We found very low-certainty evidence for the effect of screening on care needs (seven studies). Of these studies, three found beneficial effects of screening for several subdomains of care needs, and two found no effects of screening. One study found adverse effects, and the last study did not report quantitative results. We judged the overall level of evidence for the effect of screening on HRQoL to be very low. None of the studies specifically evaluated or reported adverse effects of screening. However, three studies reported unfavourable effects of screening, including lower QoL, more unmet needs, and lower satisfaction.Three studies could be included in a meta-analysis. The meta-analysis revealed no beneficial effect of the screening intervention on people with cancer HRQoL (mean difference (MD) 1.65, 95% confidence interval (CI) -4.83 to 8.12, 2 RCTs, 6 months follow-up); distress (MD 0.0, 95% CI -0.36 to 0.36, 1 RCT, 3 months follow-up); or care needs (MD 2.32, 95% CI -7.49 to 12.14, 2 RCTs, 3 months follow-up). However, these studies all evaluated one specific screening intervention (CONNECT) in people with colorectal cancer.In the studies where some effects could be identified, no recurring relationships were found between intervention characteristics and the effectiveness of screening interventions.
We found low-certainty evidence that does not support the effectiveness of screening of psychosocial well-being and care needs in people with cancer. Studies were heterogeneous in population, intervention, and outcome assessment.The results of this review suggest a need for more uniformity in outcomes and reporting; for the use of intervention description guidelines; for further improvement of methodological certainty in studies and for combining subjective patient-reported outcomes with objective outcomes.
Attention deficit hyperactivity disorder (ADHD) is a prevalent neurobiological condition, characterised by behavioral and cognitive symptoms such as inattention, impulsivity and/or excessive ...activity. The syndrome is commonly accompanied by psychiatric comorbidities and is associated with educational and occupational underachievement.Although psychostimulant medications are the mainstay of treatment for ADHD, not all adults respond optimally to, or can tolerate, these medicines. Thus, alternative non-stimulant treatment approaches for ADHD have been explored. One of these alternatives is bupropion, an aminoketone antidepressant and non-competitive antagonism of nicotinic acetylcholine receptors. Bupropion is registered for the treatment of depression and smoking cessation, but is also used off-label to treat ADHD.
To assess the effects and safety of bupropion for the treatment of adults with ADHD.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and seven other databases in February 2017. We also searched three trials registers and three online theses portals. In addition, we checked references of included studies and contacted study authors to identify potentially relevant studies that were missed by our search.
We included all randomised controlled trials (RCTs) that evaluated the effects (including adverse effects) of bupropion compared to placebo in adults with ADHD.
Two review authors (WV, GB) independently screened records and extracted data using a data extraction sheet that we tested in a pilot study. We extracted all relevant data on study characteristics and results. We assessed risks of bias using the Cochrane 'Risk of bias' tool, and assessed the overall quality of evidence using the GRADE approach. We used a fixed-effect model to pool the results across studies.
We included six studies with a total of 438 participants. Five studies were conducted in the USA, and one in Iran. All studies evaluated a long-acting version of bupropion, with the dosage ranging from 150 mg up to 450 mg daily. Study intervention length varied from six to 10 weeks. Four studies explicitly excluded participants with psychiatric comorbidity and one study included only participants with opioid dependency. Four studies were funded by industry, but the impact of this on study results is unknown. Two studies were publicly funded and in one of these studies, the lead author was a consultant for several pharmaceutical companies and also received investigator-driven funding from two companies, however none of these companies manufacture bupropion. We judged none of the studies to be free of bias because for most risk of bias domains the study reports failed to provide sufficient details. Using the GRADE approach, we rated the overall quality of evidence as low. We downgraded the quality of the evidence because of serious risk of bias and serious imprecision due to small sample sizes.We found low-quality evidence that bupropion decreased the severity of ADHD symptoms (standardised mean difference -0.50, 95% confidence interval (CI) -0.86 to -0.15, 3 studies, 129 participants), and increased the proportion of participants achieving clinical improvement (risk ratio (RR) 1.50, 95% CI 1.13 to 1.99, 4 studies, 315 participants), and reporting an improvement on the Clinical Global Impression - Improvement scale (RR 1.78, 95% CI 1.27 to 2.50, 5 studies, 337 participants). There was low-quality evidence that the proportion of participants who withdrew due to any adverse effect was similar in the bupropion and placebo groups (RR 1.20, 95% CI 0.35 to 4.10, 3 studies, 253 participants). The results were very similar when using a random-effects model and when we analysed only studies that excluded participants with a psychiatric comorbidity.
The findings of this review, which compared bupropion to placebo for adult ADHD, indicate a possible benefit of bupropion. We found low-quality evidence that bupropion decreased the severity of ADHD symptoms and moderately increased the proportion of participants achieving a significant clinical improvement in ADHD symptoms. Furthermore, we found low-quality evidence that the tolerability of bupropion is similar to that of placebo. In the pharmacological treatment of adults with ADHD, extended- or sustained-release bupropion may be an alternative to stimulants. The low-quality evidence indicates uncertainty with respect to the pooled effect estimates. Further research is very likely to change these estimates. More research is needed to reach more definite conclusions as well as clarifying the optimal target population for this medicine. Treatment response remains to be reported in a DSM5-diagnosed population. There is also a lack of knowledge on long-term outcomes.
User-friendly information at the point of care should be well structured, rapidly accessible, and comprehensive. Also, this information should be trustworthy, as it will be used by health care ...practitioners to practice evidence-based medicine. Therefore, a standard, validated tool to evaluate the trustworthiness of such point-of-care information resources is needed.
This systematic review sought to search for tools to assess the trustworthiness of point-of-care resources and to describe and analyze the content of these tools.
A systematic search was performed on three sources: (1) we searched online for initiatives that worked off of the trustworthiness of medical information; (2) we searched Medline (PubMed) until June 2019 for relevant literature; and (3) we scanned reference lists and lists of citing papers via Web of Science for each retrieved paper. We included all studies, reports, websites, or methodologies that reported on tools that assessed the trustworthiness of medical information for professionals. From the selected studies, we extracted information on the general characteristics of the tools. As no standard, risk-of-bias assessment instruments are available for these types of studies, we described how each tool was developed, including any assessments on reliability and validity. We analyzed the criteria used in the different tools and divided them into five categories: (1) author-related information; (2) evidence-based methodology; (3) website quality; (4) website design and usability; and (5) website interactivity. The percentage of tools in compliance with these categories and the different criteria were calculated.
Included in this review was a total of 17 tools, all published between 1997 and 2018. The tools were developed for different purposes, from a general quality assessment of medical information to very detailed analyses, all specifically for point-of-care resources. However, the development process of the tools was poorly described. Overall, seven tools had a scoring system implemented, two were assessed for reliability only, and two other tools were assessed for both validity and reliability. The content analysis showed that all the tools assessed criteria related to an evidence-based methodology: 82% of the tools assessed author-related information, 71% assessed criteria related to website quality, 71% assessed criteria related to website design and usability, and 47% of the tools assessed criteria related to website interactivity. There was significant variability in criteria used, as some were very detailed while others were more broadly defined.
The 17 included tools encompass a variety of items important for the assessment of the trustworthiness of point-of-care information. Overall, two tools were assessed for both reliability and validity, but they lacked some essential criteria for the assessment of the trustworthiness of medical information for use at the point-of-care. Currently, a standard, validated tool does not exist. The results of this review may contribute to the development of such an instrument, which may enhance the quality of point-of-care information in the long term.
PROSPERO CRD42019122565; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=122565.
Objectives
The objective is to assess the effectiveness of occupational therapy to improve performance in daily living activities in community‐dwelling physically frail older people.
Design
We ...conducted a systematic review and meta‐analysis. We included randomized controlled trials reporting on occupational therapy as intervention, or as part of a multidisciplinary approach. This systematic review was carried out in accordance with the Cochrane methods of systematic reviews of interventions.
Measurements
Meta‐analyses were performed to pool results across studies using the standardized mean difference. The primary outcome measures were mobility, functioning in daily living activities, and social participation. Secondary outcome measures were fear of falling, cognition, disability, and number of falling persons.
Results
Nine studies met the inclusion criteria. Overall, the studies were of reasonable quality with low risk of bias. There was a significant increase in all primary outcomes. The pooled result for functioning in daily living activities was a standardized mean difference of −0.30 (95% CI −0.50 to −0.11; P = .002), for social participation −0.44 (95% CI −0.69, −0.19; P = .0007) and for mobility −0.45 (95% CI −0.78 to −0.12; P = .007). All secondary outcomes showed positive trends, with fear of falling being significant. No adverse effects of occupational therapy were found.
Conclusion
There is strong evidence that occupational therapy improves functioning in community‐dwelling physically frail older people.
Objective
This systematic review assesses the effectiveness and side effects of celiac plexus neurolysis (CPN) in the treatment of upper abdominal cancer pain, and evaluates whether there are any ...differences between the percutaneous and endoscopic ultrasound‐guided (EUS) denervation techniques.
Methods
Five databases were searched, expanded by assessing the reference lists of all retrieved papers. Sixty‐six publications fulfilled the inclusion/exclusion criteria and were included in the systematic review. Randomized controlled trials were available for the percutaneous CPN, and therefore meta‐analyses were performed for pain, opioid consumption, and specific side effects. The quality of life data were too heterogeneous to be assessed by a meta‐analysis, and evidence for EUS CPN could only be evaluated by observational studies.
Results
Meta‐analyses show that percutaneous CPN significantly improves pain in patients with upper abdominal cancer, with a decrease in opioid consumption and side effects. It is unclear whether there is any change in quality of life. Case series suggest that EUS CPN improves pain. No conclusion can be made about EUS CPN's influence on opioid consumption. Although CPN is a safe procedure, side effects and complications can occur with both the percutaneous and EUS techniques.
Conclusions
Following this review, evidence suggests that CPN should be considered in patients with upper abdominal cancer where the pain is not adequately controlled with systemic analgesics or when significant opioid‐induced side effects are present. The percutaneous approach remains the standard technique as robust evidence for EUS CPN is lacking.
Abstract Context Symptom control is an essential part of palliative care and important to achieve optimal quality of life. Studies showed that patients with all types of advanced cancer suffer from ...diverse and often severe symptoms. Research focusing on older persons is scarce because this group is often excluded from studies. Consequently, it is unclear which symptoms older palliative care patients with cancer experience and what is the prevalence of these symptoms. To date, no systematic review has been performed on the prevalence of symptoms in older cancer patients receiving palliative care. Objectives The objective of this systematic review was to search and synthesize the prevalence figures of symptoms in older palliative care patients with cancer. Methods A systematic search through multiple databases and other sources was conducted from 2002 until April 2012. The methodological quality was evaluated. All steps were performed by two independent reviewers. A meta-analysis was performed to pool the prevalence of symptoms. Results Seventeen studies were included in this systematic review. Thirty-two symptoms were identified. The prevalence of these symptoms ranged from 3.5% to 77.8%. The most prevalent symptoms were fatigue, excretory symptoms, urinary incontinence, asthenia, pain, constipation, and anxiety and occurred in at least 50% of patients. Conclusion There is a high degree of uncertainty about the reported symptom prevalence because of small sample sizes, high heterogeneity among studies, and the extent of instrument validation. Research based on rigorous methods is needed to allow more conclusive results.
In adults with low density lipoprotein (LDL) cholesterol levels >1.8 mmol/L (>70 mg/dL) who are already taking the maximum dose of statins or are intolerant to statins, should another lipid-lowering ...drug be added, either a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor or ezetimibe, to reduce the risk of major cardiovascular events? If so, which drug is preferred? Having decided to use one, should we add the other lipid-lowering drug?
Most guidelines emphasise LDL cholesterol targets in their recommendations for prescribing PCSK9 inhibitors and/or ezetimibe in adults at high risk of experiencing a major adverse cardiovascular event. However, to achieve these goals in very high risk patients with statins alone is almost impossible, so physicians are increasingly considering other lipid-lowering drugs solely for achieving LDL cholesterol treatment goals rather than for achieving important absolute cardiovascular risk reduction. Most guidelines do not systematically assess the cardiovascular benefits of adding PCSK9 inhibitors and/or ezetimibe for all risk groups across primary and secondary prevention, nor do they report, in accordance with explicit judgments of assumed patients' values and preferences, absolute benefits and harms and potential treatment burdens.
The guideline panel provided mostly weak recommendations, which means we rely on shared decision making when applying these recommendations. For adults already using statins, the panel suggests adding a second lipid-lowering drug in people at very high and high cardiovascular risk but recommends against adding it in people at low cardiovascular risk. For adults who are intolerant to statins, the panel recommends using a lipid-lowering drug in people at very high and high cardiovascular risk but against adding it in those at low cardiovascular risk. When choosing to add another lipid-lowering drug, the panel suggests ezetimibe in preference to PCSK9 inhibitors. The panel suggests further adding a PCSK9 inhibitor to ezetimibe for adults already taking statins at very high risk and those at very high and high risk who are intolerant to statins.
An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified four risk groups of patients (low, moderate, high, and very high cardiovascular risk) and primarily applied an individual patient perspective in moving from evidence to recommendations, though societal issues were a secondary consideration. The panel considered the balance of benefits and harms and burdens of starting a PCSK9 inhibitor and/or ezetimibe, making assumptions of adults' average values and preferences. Interactive evidence summaries and decision aids accompany multi-layered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that also allows re-use and adaptation.
A linked systematic review and network meta-analysis (14 trials including 83 660 participants) of benefits found that PCSK9 inhibitors or ezetimibe probably reduce myocardial infarctions and stroke in patients with very high and high cardiovascular risk, with no impact on mortality (moderate to high certainty evidence), but not in those with moderate and low cardiovascular risk. PCSK9 inhibitors may have similar effects to ezetimibe on reducing non-fatal myocardial infarction or stroke (low certainty evidence). These relative benefits were consistent, but their absolute magnitude varied based on cardiovascular risk in individual patients (for example, for 1000 people treated with PCSK9 inhibitors in addition to statins over five years, benefits ranged from 2 fewer strokes in the lowest risk to 21 fewer in the highest risk). Two systematic reviews on harms found no important adverse events for these drugs (moderate to high certainty evidence). PCSK9 inhibitors require injections that sometimes result in injection site reactions (best estimate 15 more per 1000 in a 5 year timeframe), representing a burden and harm that may matter to patients. The MATCH-IT decision support tool allows you to interact with the evidence and your patients across the alternative options: https://magicevidence.org/match-it/220504dist-lipid-lowering-drugs/.
The stratification into four cardiovascular risk groups means that, to use the recommendations, physicians need to identify their patient's risk first. We therefore suggest, specific to various geographical regions, using some reliable risk calculators that estimate patients' cardiovascular risk based on a mix of known risk factors. The largely weak recommendations concerning the addition of ezetimibe or PCSK9 inhibitors reflect what the panel considered to be a close balance between small reductions in stroke and myocardial infarctions weighed against the burdens and limited harms.Because of the anticipated large variability of patients' values and preferences, well informed choices warrant shared decision making. Interactive evidence summaries and decision aids linked to the recommendations can facilitate such shared decisions. The strong recommendations against adding another drug in people at low cardiovascular risk reflect what the panel considered to be a burden without important benefits. The strong recommendation for adding either ezetimibe or PCSK9 inhibitors in people at high and very high cardiovascular risk reflect a clear benefit.The panel recognised the key uncertainty in the evidence concerning patient values and preferences, namely that what most people consider important reductions in cardiovascular risks, weighed against burdens and harms, remains unclear. Finally, availability and costs will influence decisions when healthcare systems, clinicians, or people consider adding ezetimibe or PCSK9 inhibitors.
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