Randomized Clinical Trials In Patients Research Articles

A pilot randomized controlled trial of 7 versus 14\u2009days of antibiotic treatment for bloodstream infection on non-intensive care versus intensive care wards

BackgroundThe optimal treatment duration for patients with bloodstream infection is understudied. The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) pilot randomized clinical trial (RCT) determined that it was feasible to enroll and randomize intensive care unit (ICU) patients with bloodstream infection to 7 versus 14 days of treatment, and served as the vanguard for the ongoing BALANCE main RCT. We performed this BALANCE-Ward pilot RCT to examine the feasibility and impact of potentially extending the BALANCE main RCT to include patients hospitalized on non-ICU wards.MethodsWe conducted an open pilot RCT among a subset of six sites participating in the ongoing BALANCE RCT, randomizing patients with positive non-Staphylococcus aureus blood cultures on non-ICU wards to 7 versus 14 days of antibiotic treatment. The co-primary feasibility outcomes were recruitment rate and adherence to treatment duration protocol. We compared feasibility outcomes, patient/pathogen characteristics, and overall outcomes among those enrolled in this BALANCE-Ward and prior BALANCE-ICU pilot RCTs. We estimated the sample size and non-inferiority margin impacts of expanding the BALANCE main RCT to include non-ICU patients.ResultsA total of 134 patients were recruited over 47 site-months (mean 2.9 patients/site-month, median 1.0, range 0.1–4.4 patients/site-month). The overall recruitment rate exceeded the BALANCE-ICU pilot RCT (mean 1.10 patients/site-month, p < 0.0001). Overall protocol adherence also exceeded the adherence in the BALANCE-ICU pilot RCT (125/134, 93% vs 89/115, 77%, p = 0.0003). BALANCE-Ward patients were older, with lower Sequential Organ Failure Assessment scores, and higher proportions of infections caused by Escherichia coli and genito-urinary sources of bloodstream infection. The BALANCE-Ward pilot RCT patients had an overall 90-day mortality rate of 17/133 (12.8%), which was comparable to the 90-day mortality rate in the ICU pilot RCT (17/115, 14.8%) (p = 0.65). Simulation models indicated there would be minimal sample size and non-inferiority margin implications of expanding enrolment to increasing proportions of non-ICU versus ICU patients.ConclusionIt is feasible to enroll non-ICU patients in a trial of 7 versus 14 days of antibiotics for bloodstream infection, and expanding the BALANCE RCT hospital-wide has the potential to improve the timeliness and generalizability of trial results.Trial registrationClinicaltrials.gov, NCT02917551. Registered on September 28, 2016.

Coronary Bypass Grafting for High-Risk Patients (Literature review)

Ischemic heart disease still remains one of the leading causes) of morbidity and mortality of population of high-developed countries. Annually we notice an increase of coronary artery bypass grafting (CABG) procedures, especially for high-risk patients. Objective. To perform literature review of CABG for high-risk patients. Results. According to literature data’s we reviewed and compared risks scores used in cardiovascular surgery for determination of patients’ severity and probability of death. The basic errors of the EuroSCORE I, II scales and the possibilities of their use in minimally invasive surgery were identified. According to modern randomized clinical trials (RCTs) comparing the OPCAB (off-pump coronary artery bypass (OPCAB) and ONCAB (on-pump coronary artery bypass) techniques, there is no clear difference in complications. Despite the small percentage of high-risk patients in RCTs (18% in the CORONARY trial), many authors consider that OPCAB has a lot of advantages for high-risk patients. Better results were obtained in elderly patients with neurocognitive disorders, porcelain aorta, diabetes mellitus, kidney insufficiency and low ejection fraction of left ventricle. Kowalewski et al. studied high-risk patients and used special statistical methods to compare patients by their risk profile. They concluded that high-risk patients have linear correlation between risk profile and increase in benefits from OPCAB: all-cause mortality (P&lt;0.01), myocardial infarction (P&lt;0.01) and stroke (P&lt;0.01). According to Raja, Shahzad G., total arterial revascularization with all its advantages and improvement of survival, reduction in the number of repeated revascularizations and low stroke rates can be considered as the Holy Grail in myocardial revascularization. However, larger randomized research is needed to justify this status. Followers of ONCAB technique claim that OPCAB leads to incomplete revascularization, poor quality of grafts and repeated hospitalizations and revascularization. It should be noted that high-risk patients should be operated in expert centres by the team of skilled heart surgeons, anaesthesiologists and with competent medical support of cardiologist.

Potential mechanisms of beneficial effect of sacubitril/valsartan on glycemic control.

Heart failure (HF) and diabetes mellitus (DM) frequently coexist, with a prevalence of DM of 35–40% in patients with HF, independent of the level of impairment of the ejection fraction (EF). Furthermore, DM is considered a strong independent risk factor for the progression of HF with either preserved or reduced EF and is associated with poor prognosis. The ability of neprilysin inhibitors to elevate levels of biologically active natriuretic peptides has made them a potential therapeutic approach in HF. In the Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, a dual-acting angiotensin-receptor–neprilysin inhibitor, sacubitril/valsartan was superior to enalapril in reducing the risks of death and HF hospitalization in patients with HF with reduced EF. In addition, in a post-hoc analysis of this trial, among patients with DM, treatment with sacubitril/valsartan resulted in improved glycemic control compared with enalapril. Also, there are additional studies suggesting beneficial metabolic effects of this class of drugs. In this review we discuss potential mechanisms of sacubitril/valsartan effect on glycemic control. Sacubitril/valsartan concomitantly blocks the renin–angiotensin system and inhibits neprilysin, a ubiquitous enzyme responsible for the breakdown of more than 50 vasoactive peptides, including the biologically active natriuretic peptides, bradykinin, angiotensin I and II, endothelin 1, glucagon, glucagon-like peptide-1, insulin-B chain, and others. There are a number of potential mechanisms by which inhibition of neprilysin may lead to improvement in glycemic control, with most evidence suggesting modulation of neprilysin circulating substrates. Although there is some evidence suggesting the improvement of glucose metabolism by renin–angiotensin system inhibition, this effect is most likely modest. As these mechanisms are not fully understood, detailed mechanistic studies, as well as large randomized clinical trials in patients with DM, are needed to further clarify beneficial metabolic properties of sacubitril/valsartan.

Effects of vitamin D supplementation on red cell indices and cytokines in patients with thalassemia: An open-label randomized clinical trial

Background and aim&#x0D; Deficiency of vitamin D is known as a health problem all over the world and a recognized clinical complication of beta thalassemia patients. Vitamin D acts as a hormone at the nuclear receptor rendering it a beneficial medication for a number of diseases. It is believed that vitamin D&#x0D; &#x0D; is important in the modulation of the inflammation system by regulating the formation of inflammatory cytokines and immune cells. This study aimed to investigate the effect of vitamin D supplementation on the red cell indices and cytokines levels in patients with beta thalassemia major, in an open label randomized clinical trial.&#x0D; Patients and Methods: this study performed an open-label randomized clinical trial in patients with beta thalassemia major. Forty-six patients completed the eight weeks clinical trial and were allocated to administer oral vitamin D3 supplement of 100,000 IU every two weeks as an add-on treatment. During the study, hematological indices, serum iron, ferritin, vitamin D, calcium and inflammatory markers (interleukin-6, interleukin-2 and interleukin-10) were evaluated before (at baseline) and after vitamin D supplementation for 8 weeks.&#x0D; Results: Vitamin D3 supplements significantly decreases interleukin-6 levels and elevates the serum levels of anti-inflammatory cytokines IL-2 and IL-10, it also significantly reduced serum ferritin level, but it did not alter the hematological indices.&#x0D; Conclusion: &#x0D; Our results suggest that administration of vitamin D has a potential anti-inflammatory role in beta thalassemia patients and reduces serum ferritin levels, which may reduce the burdens of iron overload in thalassemia patients.&#x0D;

Clinical Effectiveness of Sacubitril/valsartan among Patients Hospitalized for Heart Failure with Reduced Ejection Fraction

Background Sacubitril/valsartan has been highly efficacious in randomized clinical trials of patients with HFrEF. However, the effectiveness of sacubitril/valsartan in routine US clinical practice is unclear. Methods This study included patients age ≥65 years who were hospitalized for HFrEF (ejection fraction ≤40%), were eligible for sacubitril/valsartan at discharge, and were enrolled in the Get With The Guidelines-Heart Failure registry linked to Medicare claims between October 2015 and September 2017. Patients prescribed sacubitril/valsartan at discharge were compared with (1) patients not prescribed sacubitril/valsartan, and (2) patients prescribed ACEI/ARB at discharge. Study endpoints were post-discharge mortality and hospitalization outcomes at 12 months. Negative control (falsification) endpoints included hospitalization for urinary tract infection and hospitalization for nutritional disorder. To adjust for selection bias, inverse probability of treatment weighting and adjustment for other HFrEF medications prescribed at discharge were performed. Results Overall, 746 (8.1%) patients were discharged on sacubitril/valsartan and 8,466 (91.9%) were not. Of those not prescribed sacubitril/valsartan, 5,286 (62.4%) were prescribed an ACEI/ARB. As compared with no sacubitril/valsartan, discharge prescription of sacubitril/valsartan was independently associated with lower risk of all-cause mortality, all-cause hospitalization, and the composite of mortality or HF hospitalization at 12-month follow-up (Table). These findings were consistent in comparisons between sacubitril/valsartan and ACEI/ARB. Discharge sacubitril/valsartan prescription was not significantly associated with the negative control endpoints, suggesting the findings were unlikely due to residual confounding. Conclusions In this contemporary real-world population of US patients hospitalized for HFrEF and eligible for sacubitril/valsartan, prescription of sacubitril/valsartan at discharge was independently associated with substantial reductions in post-discharge mortality and hospitalization. These findings suggest that the significant benefits of sacubitril/valsartan observed in clinical trials extend to patients seen in routine US clinical practice.

Effects of vitamin D supplementation on red cell indices and cytokines in patients with thalassemia: An open-label randomized clinical trial

Background and aim Deficiency of vitamin D is known as a health problem all over the world and a recognized clinical complication of beta thalassemia patients. Vitamin D acts as a hormone at the nuclear receptor rendering it a beneficial medication for a number of diseases. It is believed that vitamin D is important in the modulation of the inflammation system by regulating the formation of inflammatory cytokines and immune cells. This study aimed to investigate the effect of vitamin D supplementation on the red cell indices and cytokines levels in patients with beta thalassemia major, in an open label randomized clinical trial. Patients and Methods: this study performed an open-label randomized clinical trial in patients with beta thalassemia major. Forty-six patients completed the eight weeks clinical trial and were allocated to administer oral vitamin D3 supplement of 100,000 IU every two weeks as an add-on treatment. During the study, hematological indices, serum iron, ferritin, vitamin D, calcium and inflammatory markers (interleukin-6, interleukin-2 and interleukin-10) were evaluated before (at baseline) and after vitamin D supplementation for 8 weeks. Results: Vitamin D3 supplements significantly decreases interleukin-6 levels and elevates the serum levels of anti-inflammatory cytokines IL-2 and IL-10, it also significantly reduced serum ferritin level, but it did not alter the hematological indices. Conclusion: Our results suggest that administration of vitamin D has a potential anti-inflammatory role in beta thalassemia patients and reduces serum ferritin levels, which may reduce the burdens of iron overload in thalassemia patients.

COPD EXACERBATION RATE BY BASELINE COPD ASSESSMENT TEST SCORE IN THE DYNAGITO STUDY

COPD EXACERBATION RATE BY BASELINE COPD ASSESSMENT TEST SCORE IN THE DYNAGITO STUDY

Integrating Machine Learning With Microsimulation to Classify Hypothetical, Novel Patients for Predicting Pregabalin Treatment Response Based on Observational and Randomized Data in Patients With Painful Diabetic Peripheral Neuropathy.

PurposeVariability in patient treatment responses can be a barrier to effective care. Utilization of available patient databases may improve the prediction of treatment responses. We evaluated machine learning methods to predict novel, individual patient responses to pregabalin for painful diabetic peripheral neuropathy, utilizing an agent-based modeling and simulation platform that integrates real-world observational study (OS) data and randomized clinical trial (RCT) data.Patients and methodsThe best supervised machine learning methods were selected (through literature review) and combined in a novel way for aligning patients with relevant subgroups that best enable prediction of pregabalin responses. Data were derived from a German OS of pregabalin (N=2642) and nine international RCTs (N=1320). Coarsened exact matching of OS and RCT patients was used and a hierarchical cluster analysis was implemented. We tested which machine learning methods would best align candidate patients with specific clusters that predict their pain scores over time. Cluster alignments would trigger assignments of cluster-specific time-series regressions with lagged variables as inputs in order to simulate “virtual” patients and generate 1000 trajectory variations for given novel patients.ResultsInstance-based machine learning methods (k-nearest neighbor, supervised fuzzy c-means) were selected for quantitative analyses. Each method alone correctly classified 56.7% and 39.1% of patients, respectively. An “ensemble method” (combining both methods) correctly classified 98.4% and 95.9% of patients in the training and testing datasets, respectively.ConclusionAn ensemble combination of two instance-based machine learning techniques best accommodated different data types (dichotomous, categorical, continuous) and performed better than either technique alone in assigning novel patients to subgroups for predicting treatment outcomes using microsimulation. Assignment of novel patients to a cluster of similar patients has the potential to improve prediction of patient outcomes for chronic conditions in which initial treatment response can be incorporated using microsimulation.Clinical trial registrieswww.clinicaltrials.gov: NCT00156078, NCT00159679, NCT00143156, NCT00553475.

Association With Hospitalization and All-Cause Discontinuation Among Patients With Schizophrenia on Clozapine vs Other Oral Second-Generation Antipsychotics

Recent meta-analyses of randomized clinical trials (RCTs) comparing clozapine with nonclozapine second-generation antipsychotics (NC-SGAs) in schizophrenia have challenged clozapine's superiority in treatment-resistant patients. However, patients in RCTs are not necessarily generalizable to those in clinical practice. To conduct a systematic review and meta-analysis to compare various outcomes of clozapine vs oral NC-SGAs in cohort studies. Systematic literature search in PubMed, PsycINFO, and CINAHL without language restriction from database inception until December 17, 2018. Nonrandomized cohort studies reporting effectiveness and/or safety outcomes comparing clozapine with NC-SGAs in schizophrenia or schizoaffective disorder. Independent investigators assessed studies and extracted data. Using a random-effects model, the study calculated risk ratio (RR) unadjusted for covariates and follow-up duration, number needed to treat/number needed to harm (NNT/NNH) for dichotomous data, and standardized mean difference (SMD) or mean difference (MD) for continuous data. Coprimary outcomes were hospitalization and all-cause discontinuation. Secondary outcomes included all effectiveness and safety outcomes reported in at least 3 analyzable studies. Of 8446 hits, 68 articles from 63 individual cohort studies (n = 109 341) (60.3% male; mean [SD] age of 38.8 [6.5] years, illness duration of 11.0 [5.1] years, and study duration of 19.1 [23.3] months) were meta-analyzed. Compared with NC-SGAs, despite greater illness severity (17 studies [n = 38 766]; Hedges g, 0.222; 95% CI, 0.013-0.430; P = .04), clozapine was significantly associated with lower hospitalization risk (19 studies [n = 49 453]; RR, 0.817; 95% CI, 0.725-0.920; P = .001; NNT, 18; 95% CI, 12-40) and all-cause discontinuation (16 studies [n = 56 368]; RR, 0.732; 95% CI, 0.639-0.838; P < .001; NNT, 8; 95% CI, 6-12). Associations were statistically significant for comparisons with quetiapine fumarate and aripiprazole regarding hospitalization and all NC-SGAs, except aripiprazole, for all-cause discontinuation. Clozapine was also significantly associated with better outcomes regarding overall symptoms (SMD, -0.302; 95% CI, -0.572 to -0.032; P = .03) and Clinical Global Impressions scale severity (SMD, -1.182; 95% CI, -2.243 to -0.122; P = .03). Clozapine was significantly associated with increases in body weight (MD, 1.70; 95% CI, 0.31-3.08 kg; P = .02), body mass index (MD, 0.96; 95% CI, 0.24-1.68; P = .009), and type 2 diabetes (RR, 1.777; 95% CI, 1.229-2.570; P = .002; NNH, 27; 95% CI, 13-90). In cohort studies, despite more severely ill patients being treated with clozapine, use of clozapine was associated with better key efficacy outcomes and higher cardiometabolic-related risk outcomes vs NC-SGAs.

Medication Adherence: does Patient Participation in Randomized Clinical Trials Affect on it?

The article focuses on the problem of low adherence to treatment among patients, in general, and provides data on the high adherence among patients in randomized controlled trials. Low adherence remains one of the most debated and difficult problems to solve nowadays. Poor medication adherence of the patient can significantly worsen the effectiveness of treatment and leads to increased health care costs. And although the factors that improve adherence are varied, and include the skills of the doctor, the patient’s personal characteristics, the external environment, an individual approach to each patient and etc., the absence of a “gold standard” for assessing adherence in clinical practice makes it difficult to predict and significantly improve it among patients. Nevertheless, the article discusses the existing doctor-patient interaction model, which strictly regulates the algorithms and technical means to achieve the best medication adherence. Randomized clinical trials (RCT) are the basis of evidence-based medicine, the results obtained in RCT form the basis of existing clinical guidelines. While participating in RCT patients can receive comprehensive information about the disease, the effectiveness of drug therapy, possible side effects of the therapy being conducted, the research objectives and prognosis from their attending physician; patients are trained to be disciplined and adhere to the recommendations of the doctor. The RCT, for a number of objective reasons, uses a variety of methods for assessing adherence and ways to improve it, which leads to higher patient adherence then among patients in general.

Using real-world cohorts to assess the generalizability and relevance of randomized clinical trials (RCTs).

6540 Background: RCTs are the gold standard for understanding the efficacy of new treatments, however, patients (pts) in RCTs often differ from those treated in the real-world. Further, selecting a standard of care (SOC) arm is challenging as treatment options may evolve during the course of a RCT. Our objective was to assess the generalizability and relevance of RCTs supporting recent FDA approvals of anticancer therapies. Methods: RCTs were identified that supported FDA approvals of anticancer therapies (1/1/2016 - 4/30/2018). Relevant pts were selected from the Flatiron Health longitudinal, EHR-derived database, where available. Two metrics were calculated: 1) a trial’s pt generalizability score (% of real-world pts receiving treatment consistent with the control arm therapy for the relevant indication who actually met the trial's eligibility criteria) and 2) a trial’s SOC relevance score (% of real-world pts with the relevant indication and meeting the trial's eligibility criteria who actually received treatment consistent with the control arm therapy). All analyses excluded real-world pts treated after the relevant trial’s enrollment ended. Results: 14 RCTs across 5 cancer types (metastatic breast, advanced non-small cell lung cancer, metastatic renal cell carcinoma, multiple myeloma, and advanced urothelial) were included. There was wide variation in the SOC relevance and pt generalizability scores. The median pt generalizability score was 63% (range 35% - 88%), indicating that most real-world pts would have met the RCT eligibility criteria. The median SOC relevance score was 37% (range 15% - 74%), indicating that most RCT control arms did not reflect the way trial-eligible real-world pts in the US were actually treated. Conclusions: There is great variability across recent RCTs in terms of pt generalizability and relevance of SOC arms. Real-world data can be used to inform selection of control arms, predict impact of inclusion/exclusion criteria, and also assess the generalizability of the results of completed trials. Incorporating real-world data in planning and interpretation of prospective clinical trials could improve accrual and enhance relevance of RCT outcomes.

A prospective pilot study of an elemental nutritional supplement for prevention of oral mucositis during S-1 adjuvant chemotherapy for gastric cancer

PurposesOral mucositis is one of the most common reasons for discontinuation of S-1 adjuvant chemotherapy after radical gastrectomy. Some studies suggest that nutritional support with amino acids may improve oral mucositis. We conducted a prospective, randomized clinical trial of patients who underwent adjuvant chemotherapy for gastric cancer to examine whether an oral elemental diet prevents chemotherapy associated oral mucositis and body weight loss. MethodsPatients were randomly assigned to a group consuming Elental® (the treatment group, n = 11) or a control diet group (n = 11). Patients in the treatment group consumed one pack of Elental® per day during adjuvant chemotherapy. The primary endpoint was the presence and grade of oral mucositis. Secondary endpoints included adherence to Elental® based on the doses recorded in a diary, changes in nutrition parameters, and frequency and severity of adverse events. ResultsThe incidence of oral mucositis was significantly lower in the treatment group (9.1%) than in the control group (27.3%). The median body weight loss in the treatment group was significantly smaller than that in the control group (P = .015). According to Kaplan-Meier estimates the treatment group was significantly associated with high cumulative S-1 continuation rates (log-rank P = .047). ConclusionWe conclude that the amino-acid-rich elemental diet Elental® may be useful as a countermeasure for S-1 adjuvant chemotherapy-induced mucositis.

Povidone-iodine 1% is the most effective vaginal antiseptic for preventing post-cesarean endometritis: a systematic review and network meta-analysis

Direct comparison metaanalyses have reported benefits with presurgical vaginal preparation before cesarean delivery for the reduction of endometritis. These reports did not perform a multitreatment comparison of the various antiseptic solutions assessed in previous studies. The purpose of this study was to review the literature systematically and quantitate and summarize indirectly the comparative efficacy of antiseptic formulations and their concentrations that are used for the preparation of the vagina before cesarean delivery in the prevention of endometritis and other infectious complications. We used MEDLINE, EMBASE (from their inception to November 2018) and Cochrane databases, biographies, and conference proceedings. We used randomized clinical trials of patients who underwent surgical preparation of the vagina with antiseptic formulations before cesarean delivery with the aim of reducing the risk of infectious morbidity. Our systematic review was registered and followed the Preferred Reporting Items for Systematic Review and Meta-analysis Extension for network meta-analysis guidelines. Network meta-analysis was performed with computerized software and used user-written programs to assess consistency, inconsistency, ranking probabilities, and graphing results. Direct and indirect pairwise comparisons of the various formulations and their concentrations were performed with the use of multivariate random-effects models and metaregression. A frequentist inference method was employed for the fitted model to estimate the ranking probabilities. Subgroup analyses for patients in labor, not in labor, and with ruptured membranes were conducted. For the prevention of endometritis, we identified 23 studies that comprised 7097 women who were allocated to the following treatments: povidone-iodine (1%, 5%, 10%), chlorhexidine (0.2%, 0.4%), metronidazole gel, cetrimide, or normal saline solution/no treatment. Direct and indirect pairwise comparisons indicated that, when compared with saline solution or no treatment, all antiseptic formulations decreased rates of endometritis (5.2% vs 9.1%; odds ratio, 0.48; 95% confidence interval, 0.35-0.65; 22 studies/6994 women). Individually, povidone-iodine (odds ratio, 0.43; 95% confidence interval, 0.28-0.64; 16 studies/5968 women), cetrimide (odds ratio, 0.34; 95% confidence interval, 0.13-0.90; 1 study/200 women), and metronidazole (odds ratio, 0.38; 95% confidence interval, 0.16-0.90; 1 study/224 women) significantly reduced the risk of endometritis. Rankings of vaginal preparations indicated that povidone-iodine 1% had the highest probability (72.7%) of being the most effective treatment for the prevention of endometritis. For the secondary outcomes of postoperative wound infection and fever, a significant reduction was found only with povidone-iodine (odds ratio, 0.61; 95% confidence interval, 0.48-0.78; 16 studies/5968 women; and odds ratio, 0.58; 95% confidence interval, 0.40-0.83; 12 studies/4667 women). Subgroup analyses also found that povidone-iodine significantly reduced risk of endometritis for women in labor (odds ratio, 0.42; 95% confidence interval, 0.20-0.88; 5 studies/1211 women), with ruptured membranes(odds ratio, 0.21; 95% confidence interval, 0.10-0.44; 4 studies/476 women), and undergoing planned cesarean delivery (odds ratio, 0.39; 95% confidence interval, 0.27-0.57; 8 studies/1825 women). Among patients who underwent cesarean delivery, presurgical vaginal irrigation with povidone-iodine had the highest probability of reducing the risk of endometritis, postoperative wound infections, and fever.

Pulse Pressure, Cardiovascular Events, and Intensive Blood-Pressure Lowering in the Systolic Blood Pressure Intervention Trial (SPRINT)

The efficacy and tolerability of intensive blood-pressure lowering may vary by pulse pressure (systolic minus diastolic blood pressure). SPRINT randomized 9361 high-risk adults without diabetes and who were ≥50 years with systolic blood pressure 130-180 mm Hg to intensive or standard antihypertensive treatment. The primary efficacy end point was the composite of acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. The primary safety end point was composite serious adverse events. We examined the prognostic implications of baseline pulse pressure and the effects of intensive blood-pressure lowering on clinical outcomes across the spectrum of pulse-pressure values using restricted cubic splines. Mean baseline pulse pressure was similar between the 2 study groups (intensive treatment 61±14 mm Hg vs standard treatment 62±14 mm Hg; P = 0.59). Except stroke, for which the association with pulse pressure was best defined as linear, pulse pressure displayed a nonlinear U-shaped relationship with the risk of all tested clinical end points (P <0.05), though no association remained significant upon multivariable adjustment (P >0.05). The benefit of intensive blood-pressure management on mortality appeared greatest in patients with a pulse pressure ∼60 mm Hg (P = 0.03 for interaction). Pulse pressure did not modify the effect of intensive blood-pressure lowering for other clinical end points (P >0.05 for interaction). In a large randomized clinical trial of patients with a high risk of cardiovascular events, risks and benefits of intensive blood-pressure lowering did not appear to be modified by baseline pulse pressure. Selection of appropriate candidates for intensive blood-pressure lowering should not be limited by this parameter.

Mean age and gender distribution of patients with major mental disorders participating in clinical trials.

The mean age and gender distribution of patients seeking help for mental disorders have not yet been investigated systematically. Epidemiological surveys can provide data on gender distribution of disorders and an age range in which a disorder is most frequent, but do not offer data on the average help-seeking patient, and they are usually conducted by lay interviewers with non-clinical subjects. However, this information on age and gender can be simply extracted from randomized clinical trials (RCTs) in which consecutive clinical patients are included. As it can be assumed that the average patient tends to participate in a clinical trial when her/his illness severity has reached its highpoint, the mean age of patients in RCTs is a good estimator of the peak severity of a disorder. In RCTs, diagnoses are made by psychiatrists and only clinical patients fulfilling a minimum degree of severity are included. From 10.465 records found by electronic and hand search, we extracted 832 eligible RCTs with 151,336 patients with the 19 most relevant mental disorders. We provide a table with the mean age, standard deviation and gender distributions of all major mental disorders. These results can be used in scientific articles and educational materials and can help health care providers or researchers planning treatment programs. Patients can be informed about the natural course of the disorder. By determining the reasons why some disorders occur predominantly in a certain age or have an unbalanced gender distribution information the aetiology of these disorders may further be elucidated.

Renoprotective Effects of Additional SGLT2 inhibitor Therapy in Patients With Type 2 Diabetes Mellitus and Chronic Kidney Disease Stages 3b-4: A Real World Report From A Japanese Specialized Diabetes Care Center.

BackgroundLarge randomized clinical trials of patients with type 2 diabetes mellitus (T2DM) and at high risk for cardiovascular disease revealed that sodium-glucose cotransporter 2 (SGLT2) inhibitors significantly reduced renal events. However, the trials included small numbers of patients with moderate-to-severe chronic kidney disease (CKD). Therefore, the renoprotective effects of SGLT2 inhibitors remain unknown in T2DM patients complicated with impaired renal function. We examined if SGLT2 inhibitors conferred beneficial effects on kidney function in T2DM patients with CKD.MethodsWe retrospectively recruited T2DM patients who were newly treated with add-on of SGLT2 inhibitors and suffered from moderate-to-severe renal impairment with CKD stages 3b-4 (15 < estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2), at initiation of SGLT2 inhibitor therapy. We analyzed T2DM patients with moderate-to-severe renal impairment who continued to use SGLT2 inhibitors for at least 1 year. We investigated the effects of SGLT2 inhibitor therapy on 1-year changes in eGFR and urinary protein excretion before and after the treatment.ResultsWe analyzed 42 T2DM patients with median eGFR of 40.4 mL/min/1.73 m2. One-year SGLT2 inhibitor therapy lowered median hemoglobin A1c (HbA1c) levels from 7.6% to 7.5% (not significant). Body weight and blood pressure were significantly decreased, and hemoglobin was significantly increased. The median value of eGFR after 1 year of SGLT2 inhibitor therapy was 41.0 mL/min/1.73 m2, with no significant difference compared with baseline. The annual decline in eGFR improved significantly after SGLT2 inhibitor therapy (eGFR: (median), pre: -3.8, vs. post: 0.1 mL/min/1.73 m2 per year, P < 0.01). We also found a significant decrease in urinary protein excretion after SGLT2 inhibitor therapy (urinary protein-to-creatinine ratio: (median), pre: 0.36, vs. post: 0.23 g/g creatinine, n = 35, P < 0.01).ConclusionsThis study revealed the promising observations that add-on treatment with SGLT2 inhibitors exerted significant renoprotective effects, culminating in improvements in annual decline in eGFR and urinary protein excretion in T2DM patients with CKD stages 3b-4, but did not significantly reduce HbA1c. Further prospective clinical trials are warranted to fully elucidate the effects of SGLT2 inhibitors on glycemic control and renal function in T2DM patients with moderate-to-severe renal impairment.

Selective Referral Using CCTA Versus Direct Referral for Individuals Referred to Invasive Coronary Angiography for Suspected CAD: A Randomized, Controlled, Open-Label Trial

ObjectivesThis study compared the safety and diagnostic yield of a selective referral strategy using coronary computed tomographic angiography (CCTA) compared with a direct referral strategy using invasive coronary angiography (ICA) as the index procedure. BackgroundAmong patients presenting with signs and symptoms suggestive of coronary artery disease (CAD), a sizeable proportion who are referred to ICA do not have a significant, obstructive stenosis. MethodsIn a multinational, randomized clinical trial of patients referred to ICA for nonemergent indications, a selective referral strategy was compared with a direct referral strategy. The primary endpoint was noninferiority with a multiplicative margin of 1.33 of composite major adverse cardiovascular events (blindly adjudicated death, myocardial infarction, unstable angina, stroke, urgent and/or emergent coronary revascularization or cardiac hospitalization) at a median follow-up of 1-year. ResultsAt 22 sites, 823 subjects were randomized to a selective referral and 808 to a direct referral strategy. At 1 year, selective referral met the noninferiority margin of 1.33 (p = 0.026) with a similar event rate between the randomized arms of the trial (4.6% vs. 4.6%; hazard ratio: 0.99; 95% confidence interval: 0.66 to 1.47). Following CCTA, only 23% of the selective referral arm went on to ICA, which was a rate lower than that of the direct referral strategy. Coronary revascularization occurred less often in the selective referral group compared with the direct referral to ICA (13% vs. 18%; p < 0.001). Rates of normal ICA were 24.6% in the selective referral arm compared with 61.1% in the direct referral arm of the trial (p < 0.001). ConclusionsIn stable patients with suspected CAD who are eligible for ICA, the comparable 1-year major adverse cardiovascular events rates following a selective referral and direct referral strategy suggests that both diagnostic approaches are similarly effective. In the selective referral strategy, the reduced use of ICA was associated with a greater diagnostic yield, which supported the usefulness of CCTA as an efficient and accurate method to guide decisions of ICA performance. (Coronary Computed Tomographic Angiography for Selective Cardiac Catheterization [CONSERVE]; NCT01810198)

Economic analysis of acupuncture for migraine prophylaxis.

BackgroundAcupuncture has become a viable option for migraine prophylaxis in Europe; however, despite its wide use, more data on the short- and long-term cost-effectiveness are needed when considering the perspectives of a paying third-party, the patient, and of society in general. The aim was to evaluate the cost and effectiveness of adjuvant acupuncture to pharmacologic treatment vs pharmacologic treatment alone in migraine patients after a 3-month acupuncture course and a 6-month follow-up from all perspectives.MethodsThe study involved an open-label randomized clinical trial of patients receiving acupuncture (n=42), and a waiting list control group (n=44). The number of migraine days during the last 28 days, as well as direct and indirect costs were considered. The trial was registered under DRKS00009803.ResultsThe total cost per patient reached €696 vs €285 after 3 months of acupuncture and €66 vs €132 in the acupuncture and control groups after a 6-month follow-up, respectively (P=0.071). The trends observed in effectiveness and costs from all perspectives are discussed.ConclusionThe inclusion of acupuncture in health care results beneficial mainly for its observed trend in reduced losses of productivity and income, with the latter often exceeding the costs of acupuncture treatment. As such, acupuncture may be recommended as an adjuvant treatment in migraine prophylaxis to standard pharmacotherapy.

Abscess Incision and Drainage With or Without Ultrasonography: A Randomized Controlled Trial

We hypothesize that clinical failure rates will be lower in patients treated with point-of-care ultrasonography and incision and drainage compared with those who undergo incision and drainage after physical examination alone. We performed a prospective randomized clinical trial of patients presenting with a soft tissue abscess at a large, academic emergency department. Patients presenting with an uncomplicated soft tissue abscess requiring incision and drainage were eligible for enrollment and randomized to treatment with or without point-of-care ultrasonography. The diagnosis of an abscess was by physical examination, bedside ultrasonography, or both. Patients randomized to the point-of-care ultrasonography group had an incision and drainage performed with bedside ultrasonographic imaging of the abscess. Patients randomized to the non-point-of-care ultrasonography group had an incision and drainage performed with physical examination alone. Comparison between groups was by comparing means with 95% confidence intervals. The primary outcome was failure of therapy at 10 days, defined as a repeated incision and drainage, following a per-protocol analysis. Multivariate analysis was performed to control for study variables. Our study was designed to detect a clinically important difference between groups, which we defined as a 13% difference. A total of 125 patients were enrolled, 63 randomized to the point-of-care ultrasonography group and 62 to physical examination alone. After loss to follow-up and misallocation, 54 patients in the ultrasonography group and 53 in the physical examination alone group were analyzed. The overall failure rate for all patients enrolled in the study was 10.3%. Patients who were evaluated with ultrasonography were less likely to fail therapy and have repeated incision and drainage, with a difference between groups of 13.3% (95% confidence interval 0.0% to 19.4%). Abscess locations were predominantly torso (21%), buttocks (21%), lower extremity (18%), and axilla or groin (16%). There was no difference in baseline characteristics between groups relative to abscess size, duration of symptoms before presentation, percentage with cellulitis, and treatment with antibiotics. Patients with soft tissue abscesses who were undergoing incision and drainage with point-of-care ultrasonography demonstrated less clinical failure compared with those treated without point-of-care ultrasonography.

Trials and Frontiers in Carotid Endarterectomy and Stenting.

Based on the strength of randomized trials from the 1990s, major societal guidelines recommend carotid endarterectomy (CEA) for severe (≥70%), symptomatic carotid stenosis if an operative stroke/death rate of <6% can be maintained (history and major trials in carotid revascularization are summarized in the online-only Data Supplement).1–4 Though the benefit is less evident, most guidelines also recommend consideration of CEA for 50% to 69% symptomatic stenosis.2–4 There are subtle differences in recommendations regarding carotid artery stenting (CAS) in symptomatic patients. Some guidelines stipulate that CEA should be preferred over CAS in patients with severe (≥70%) symptomatic carotid stenosis,2,5 especially if >70 years old,4 whereas others position CAS as an alternative.1,3 Though the risk of operative stroke/death is higher with CAS, major randomized clinical trials (RCTs) report event rates under the recommended 6% cutoff for both treatment modalities. Regarding asymptomatic disease, CEA is recommended for patients with stenosis ≥60% to 70% in highly selected patients as long as operative stroke/death rates <3% can be maintained.1 A predicted life expectancy of at least 3 to 5 years has also been suggested.2 The 3% threshold has been easily met by CEA cohorts in the CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial; 1.4%)6 and the ACT1 (Asymptomatic Carotid Trial; 1.7%),7 suggesting that an even lower threshold may be appropriate. Controversially, some guidelines have recommended that CAS can be considered in highly selected patients with asymptomatic carotid stenosis ≥60% to 70%,1,4,8 whereas others argue that the evidence remains insufficient.2 The lack of consensus in the management of asymptomatic carotid stenosis is reflective of an ongoing need for high-quality RCT data to guide practice. ### CEA Operative Stroke Risk and High Risk Designation Most clinical trials in carotid revascularization have focused …