Repeated subileus due to angioedema during renin-angiotensin system blockade

A 77-year-old man with membranous nephropathy was treated with triple blockade of the renin-angiotensin-aldosterone system and developed subileus six times in 5 months. The resection of his sigmoid colon uncovered angioedema. It should be noted that angiotensin-converting enzyme or angiotensin receptor blocker can cause angioedema of the intestine and induce subileus.     

Meta-analysis of randomized controlled trials on effect of angiotensin-converting enzyme inhibitors on cancer risk

The renin-angiotensin system is an important mediator of tumor progression and metastasis. A recent meta-analysis of randomized controlled trials reported an increased risk of cancer with angiotensin receptor blockers. It is unknown whether angiotensin-converting enzyme (ACE) inhibitors may have a similar effect. Our primary objective was to determine the effect of ACE inhibitors on cancer occurrence and cancer death. Our secondary objective was to determine the effect of ACE inhibitors on occurrence of gastrointestinal (GI) cancers given previous concerns of increased risk. Systematic searches of SCOPUS (covering MEDLINE, EMBASE, and other databases) and the Food and Drug Administration official web site were conducted for all randomized controlled trials of ACE inhibitors. Trials with ≥1 year of follow-up and enrolling a minimum of 100 patients were included. Fourteen trials reported cancer data in 61,774 patients. This included 10 trials of 59,004 patients providing information on cancer occurrence, 7 trials of 37,515 patients for cancer death, and 5 trials including 23,291 patients for GI cancer. ACE inhibitor therapy did not have an effect on occurrence of cancer (I(2) 0%, risk ratio [RR] 1.01, 95% confidence interval [CI] 0.95 to 1.07, p = 0.78), cancer death (I(2) 0%, RR 1.00, 95% CI 0.88 to 1.13, p = 0.95), or GI cancer (RR 1.09, 95% CI 0.88 to 1.35, p = 0.43). In conclusion, ACE inhibitors did not significantly increase or decrease occurrence of cancer or cancer death. There was also no significant difference in risk of GI cancer.     

肾素-血管紧张素系统与肝纤维化发生

目的：组织纤维化的发生与局部肾素－血管肾张素系统（renin-angiotensin system,RAS)激活有关,本研究,旨在通达观察血管紧张素转化酶抑制剂和血管紧张素1型（AT1）受体阻断剂对实验性肝纤维化的疗效,以期明确RAS在肝纤维化发病中的作用,并对AT1受体在肝内表达的特点及肝星状细胞（HSC）的是否表达该受体作初步探讨,方法：给预SD大鼠CCl4的同时,给预血管紧张素转化酶抑制剂依那普利（10mg.kg^-1,d^-1)和AT1受体阻断剂氯沙坦（10mg.kg^-1.d^-1),共6周,利用图像分析系统对肝纤维化程度进行评价,肝组织AT1受体表达受用免疫组化法检测,结果：依那普利和氯沙坦均可显著抑制大鼠肝纤维化的发生（P＜0．05）,联合应用相同剂量的依那普利和氯沙坦疗效与单独应用比较,差异无显著性（P＞0．05）,但可抑制氯沙坦治疗后血清血管紧张素II水平的升高（P＜0．05）,正常大鼠AT1受体主要表达于血管壁,在肝纤维化,该受体分布与α－平滑肌动蛋白（α-SMA)G表达纤维间隔分布一致,结论：肝纤维化的发生与RAS激活有关,RAS抑制剂具有良发的抗纤维化作用,但联合应用转化酶抑制剂和AT1受体阻断剂,并不断加其抗纤维化疗效,肝纤维化发生过程中,肝星状细胞功能的改变可能与其表达AT1受体有关。     

Myositis as an adverse event of immune checkpoint blockade for cancer therapy

Objectives

Immune checkpoint inhibitors (ICIs) can successfully treat cancer, but their use can be hindered by serious immune-related adverse events. We report six patients receiving ICIs who presented with de novo myositis.

Cangrelor infusion is associated with an increased risk for bleeding: Meta-analysis of randomized trials

Context

Aggressive antiplatelet strategies unquestionably cause extra hemorrhagic risks. Bleeding episodes are associated with poor outcomes including increased mortality. However, lack of uniform reporting and adjudication of bleeding events might prevent objective evaluation of the efficacy/safety profile of antithrombotic agents.

Objective

We analyzed the bleeding rates by several previously used bleeding scales (TIMI, GUSTO, ACUITY, and BARC) after cangrelor in recent head-to-head randomized, controlled clinical trials (RCTs).

Results

Data for meta-analyses were pooled from 3 RCTs (CHAMPION-PLATFORM, CHAMPION-PCI and CHAMPION-PHOENIX) including 25,106 patients. In addition, the bleeding risks were also assessed from the small (n = 210) BRIDGE RCT. Cangrelor caused a significantly increased risk for major bleeding at 48 h according to the ACUITY scale (RR: 1.51, 95% CI: 1.32–1.72, p < 0.00001); however, this impact was less prominent according to less sensitive bleeding scales (GUSTO severe: RR: 1.21, 95% CI: 0.70–2.11, p = 0.49; TIMI major: RR: 1.00, 95% CI: 0.59–1.68, p = 0.99). There was also an obvious trend towards an increased risk for any transfusions (RR: 1.31, 95% CI: 0.97–1.77, p = 0.08) and TIMI major + minor bleeding events (RR: 1.30, 95% CI: 0.96–1.76, p = 0.09).

Conclusions

Cangrelor on top of aspirin or/and clopidogrel increases the risk for early bleeding events after PCI; however, it largely depends on the bleeding definition used, and how this excess risk of bleeding was captured. The bleeding hazard needs to be verified in the ongoing FDA secondary cangrelor review.     

IgA vasculitis as an immune-related adverse event of durvalumab: A case report

A 78-year-old man with lung cancer underwent concurrent chemoradiotherapy followed by durvalumab for 24 cycles. After 6 months, he presented with anorexia and palpable purpura of the lower extremities, with increased proteinuria, hematuria, and elevated creatinine levels. Skin and kidney biopsies suggested a diagnosis of IgA vasculitis. No evidence of cancer progression was found; moreover, no infection or drug could be identified as the cause. Therefore, he was diagnosed with IgA vasculitis as an immune-related adverse event (irAE) caused by durvalumab. Because immune checkpoint inhibitors can cause vasculitis, clinicians should be cautious during their administration and after their discontinuation.     

Meta-analysis of randomized trials of glycoprotein IIb/IIIa inhibitors in high-risk acute coronary syndromes patients undergoing invasive strategy

It is still unknown whether upstream administration of glycoprotein (Gp) IIb/IIIa inhibitors, aiming at cooling the culprit lesion before angioplasty, is superior to its selective downstream administration in high-risk patients with acute coronary syndromes (ACSs) undergoing coronary angioplasty. Therefore, the aim of the present study was to perform a meta-analysis of randomized trials comparing upstream to downstream administration of Gp IIb/IIIa inhibitors in high-risk patients with ACS undergoing early invasive strategy. We obtained results from all randomized trials on this issue. The literature was scanned by formal searches of electronic databases from January 1990 to March 2010. The following key words were used: "randomized trial," "myocardial infarction," "ACS," "coronary angioplasty," "upstream," "downstream," "Gp IIb/IIIa inhibitors," "abciximab," "tirofiban," and "eptifibatide." Primary and secondary clinical end points were mortality and myocardial infarction at 30 days, respectively. Major bleeding complications were assessed as a safety end point. Seven randomized trials were included in the meta-analysis, involving 19,929 patients (9,981 or 50.0% in the upstream Gp IIb/IIIa inhibitors group and 9,948 or 50% in the downstream Gp IIb/IIIa inhibitors group). Upstream Gp IIb/IIIa inhibitors did not decrease 30-day mortality (2.0% vs 2.0%, p = 0.84) or recurrence of myocardial infarction (7.0% vs 7.6%, p = 0.11) but were associated with higher risk of major bleeding complications (1.8% vs 1.3%, p = 0.0002). In conclusion, this meta-analysis shows that in high-risk patients with ACS undergoing an early invasive strategy, upstream administration of Gp IIb/IIIa inhibitors does not improve clinical outcome compared to a downstream selective administration, and it is associated with an increased risk of major bleeding complications. Therefore, a strategy of upstream Gp IIb/IIIa inhibitors cannot be recommended.     

Meta-analysis of randomized trials focusing on prevention of the postpericardiotomy syndrome

The natural history of postpericardiotomy syndrome (PPS), a relatively common complication of cardiac surgery, varies from mild self-limited episodes to cases with protracted courses, recurrences, and readmissions. Preventive strategies may be valuable to decrease morbidity and management costs. We thus aimed to conduct a comprehensive systematic review on available data for pharmacologic primary prevention of PPS. Controlled clinical studies were searched in several databases and were included provided they focused on pharmacologic primary prevention of PPS. Random-effect odds ratios (ORs) were computed for occurrence of PPS. From the initial sample of 343 citations, 4 controlled clinical trials for primary prevention of PPS were finally included (894 patients); 3 studies were double-blind randomized controlled trials (RCTs). Treatment comparisons were colchicine versus placebo (2 RCTs enrolling 471 patients), methylprednisolone versus placebo (1 RCT on 246 pediatric patients), and aspirin versus historical controls (1 nonrandomized study on 177 pediatric patients). Meta-analytic pooling showed that colchicine was associated with decreased risk of PPS (OR 0.38, 0.22 to 0.65). Data on methylprednisolone (OR 1.13, 0.57 to 2.25) or aspirin (OR 1.00, 0.16 to 6.11) were negative but inconclusive because these were based on 1 study and/or a nonrandomized design. In conclusion, clinical evidence for primary prevention of PPS is still limited to few studies of variable quality. Nevertheless, available data suggest a beneficial profile for colchicine and open a new therapeutic strategy for prevention of PPS.     

针灸治疗抑郁随机对照试验的临床文献系统评价

目的对针灸治疗抑郁随机对照试验临床文献进行系统评价,为抑郁的针灸治疗提供循证医学证据。方法采用循证医学方法,利用Review Manage4.2.7软件对1989年1月至2009年9月发表的针灸治疗抑郁的随机对照试验文献调研,筛选出符合纳入标准的235个临床试验,采用描述性分析,对其进行系统评价。结果近年来,针灸治疗抑郁的研究已受到人们较多的关注,相关文献发表篇数呈逐年上升趋势,但研究质量普遍不高。结论重视和加强针灸综合疗法及抑郁状态的大样本研究,提高临床随机对照研究的质量,规范治疗时间,进行随访记录,探索出可行的针灸盲法是急待解决的问题。     

Challenges and progress in adverse event ascertainment and reporting in clinical trials

Toxicity, safety, and tolerability are integral facets of patient risk/benefit decisions, yet the capacity to define, measure, and compare these aspects is underdeveloped compared to aspects of efficacy. There are many reasons for this, scientific and administrative, but all are surmountable. Probably the greatest primary obstacle is the absence of a measurement instrument designed specifically for this purpose. There are increasing calls from various stakeholders for better evidence, and therefore better ascertainment, in this area, especially in randomized trials, and for these reasons OMERACT began deliberations about these concepts in 1994. A prototype coding instrument (the Rheumatology Common Toxicity Criteria) was developed and discussed at OMERACT 5. In the 2 years before OMERACT 7, a process of concept development and iterative design and testing were conducted to develop a patient self-report and investigator-reported adverse event instruments designed for use in trials at the time of visit. The predominant workload is performed by the patient in a self-report checklist, which is then mapped by the trialist onto a medically sophisticated version. This article presents background on the process of developing a dual adverse event instrument, which was presented and critically discussed in detail at OMERACT 7.     

Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials

BackgroundGuidelines for type 2 diabetes (T2D) recommend reducing HbA_1c through lifestyle interventions and glucose-lowering drugs (metformin, then combination with dipeptidyl peptidase-4 inhibitors [DPP-4Is] among other glucose-lowering drugs). However, no double-blind randomized clinical trial (RCT) compared with placebo has so far demonstrated that DDP-4Is reduce micro- and macrovascular complications in T2D. Moreover, the safety of DPP-4Is (with increased heart failure and acute pancreatitis) remains controversial.MethodsA systematic review of the literature (PubMed, Cochrane Library Central Register of Controlled Trials [CENTRAL] and https://clinicaltrials.gov), including all RCTs vs placebo published up to May 2015 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), published June 2015, was performed. Primary endpoints were all-cause mortality and death from cardiovascular causes; secondary endpoints were macrovascular and microvascular events. Safety endpoints were acute pancreatitis, pancreatic cancer, serious adverse events and severe hypoglycaemia.ResultsA total of 36 double-blind RCTs were included, allowing analyses of 54,664 patients. There were no significant differences in all-cause mortality (RR = 1.03, 95% confidence interval [CI] = 0.95–1.12), cardiovascular mortality (RR = 1.02, 95% CI = 0.92–1.12), myocardial infarction (RR = 0.98, 95% CI = 0.89–1.08), strokes (RR = 1.02, 95% CI = 0.88–1.17), renal failure (RR = 1.06, 95% CI = 0.88–1.27), severe hypoglycaemia (RR = 1.14, 95% CI = 0.95–1.36) and pancreatic cancer (RR = 0.54, 95% CI = 0.28–1.04) with the use of DPP-4Is. However, DDP-4Is were associated with an increased risk of heart failure (RR = 1.13, 95% CI = 1.01–1.26) and of acute pancreatitis (RR = 1.57, 95% CI = 1.03–2.39).ConclusionThere is no significant evidence of short-term efficacy of DPP-4Is on either morbidity/mortality or macro-/microvascular complications in T2D. However, there are warning signs concerning heart failure and acute pancreatitis. This suggests a great need for additional relevant studies in future.     

Effect of inhibition of the renin-angiotensin system on development of type 2 diabetes mellitus (meta-analysis of randomized trials)

The increasing prevalence and costs of type 2 diabetes mellitus (DM) make strategies to prevent its development vitally important. This analysis was conducted to determine if angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) prevent the development of DM. Medline and the Cochrane Central Register of Controlled Trials (1966 to May 2006) were queried for prospective, randomized, placebo-controlled or active-controlled trials of ACE inhibitor or ARB therapy in adults that reported rates of new-onset diabetes during follow-up. Meta-analyses of summary statistics from individual trials were performed using a random-effects model. Thirteen trials with a total of 93,451 patients were identified. Renin-angiotensin system antagonists reduced the incidence of DM from 9% in nontreated patients to 7.1% in those treated, a 26% reduction in odds (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.66 to 0.81, p<0.001). The effect sizes were similar in trials that randomized only hypertensive subjects (OR 0.73, 95% CI 0.66 to 0.82, p<0.001) and trials that studied the impact of renin-angiotensin system inhibition on outcomes of patients with vascular disease or heart failure (OR 0.67, 95% CI 0.50 to 0.90, p=0.008). ACE inhibitors and ARBs had comparable effects on the development of DM. In ACE inhibitor trials, the odds of developing DM were reduced by 28% (OR 0.72, 95% CI 0.63 to 0.84, p<0.001), and in the 5 ARB studies, there was a 27% reduction (OR 0.73, 95% CI 0.64 to 0.84, p<0.001) in the odds. In conclusion, evidence accumulated to date indicates that inhibition of the renin-angiotensin system may contribute to the prevention of DM.     

Summary of randomized trials of angiotensin converting enzyme inhibitors.

Angiotensin converting enzyme (ACE) inhibitors have been shown to reduce the risk of death, worsening heart failure and recurrent infarction in patients with left ventricular dysfunction and heart failure. They have also been shown to reduce mortality in the acute phase of myocardial infarction. They have been demonstrated to reduce major vascular events and progression of renal disease in diabetes with hypertension, compared to placebo and to calcium channel blockers. Current trials are evaluating their role in preventing major vascular events in patients with coronary artery disease, strokes and Type II diabetes who are normotensive.     

Probiotic supplementation decreases intestinal transit time: Meta-analysis of randomized controlled trials

AIM: To determine the efficacy of probiotic supplementation on intestinal transit time (ITT) and to identify factors that influence these outcomes. METHODS: A systematic review of randomized controlled trials (RCTs) of probiotic supplementation that measured ITT in adults was conducted by searching MEDLINE and EMBASE using relevant combinations. Main search limits included RCTs of probiotic supplementation in healthy or constipated adults that measured ITT. Study quality was assessed using the Jadad scale. A random effects meta-analysis was performed with standardized mean difference (SMD) of ITT between probiotic and control groups as the primary outcome. Meta-regression and subgroup analyses were conducted to examine the impact of moderator variables on ITT SMD. RESULTS: A total of 11 clinical trials with 13 treatment effects representing 464 subjects were included in this analysis. Probiotic supplementation was associated with decreased ITT in relation to controls, with an SMD of 0.40 (95%CI: 0.20-0.59, P < 0.001). Constipation (r 2 = 39%, P = 0.01), higher mean age (r 2 = 27%, P = 0.03), and higher percentage of female subjects (r 2 = 23%, P < 0.05) were predictive of decreased ITT with probiotics in meta-regression. Subgroup analyses demonstrated statistically greater reductions in ITT with probiotics in subjects with vs without constipation and in older vs younger subjects [both SMD: 0.59 (95%CI: 0.39-0.79) vs 0.17 (95%CI: -0.08-0.42), P = 0.01]. Medium to large treatment effects were identified with Bifidobacterium Lactis (B. lactis ) HN019 (SMD: 0.72, 95%CI: 0.27-1.18, P < 0.01) and B. lactis DN-173 010 (SMD: 0.54, 95%CI: 0.15-0.94, P < 0.01) while other single strains and combination products yielded small treatment effects. CONCLUSION: Overall, short-term probiotic supplementation decreases ITT with consistently greater treatment effects identified in constipated or older adults and with certain probiotic strains.     

Magnetic endoscopic imaging vs standard colonoscopy: Meta-analysis of randomized controlled trials

AIM:To assess the theoretical advantages of magnetic endoscope imaging(MEI)over standard colonoscopies(SCs)and to compare their efficacies.METHODS:Electronic databases,including PubMed,EMBASE,the Cochrane library and the Science Citation Index,were searched to retrieve relevant trials.In addition,abstracts from papers presented at professional meetings and the reference lists of retrieved articles were reviewed to identify additional studies.The metaanalyses were performed using RevMan 5.1.A random effect model with the Mantel-Haenszel method was used for pooling dichotomous and continuous data.A sensitivity analysis was performed by excluding the trials with a small number of patients and by excluding the trials performed by inexperienced providers.RESULTS:Eight randomized controlled trials(RCTs),including 2967 patients,were included in the metaanalysis to compare cecal intubation rates and times,sedation dose,abdominal pain scores and the use of ancillary maneuvers between MEI and SC.The overall OR was 1.92(95%CI:1.13-3.27,eight RCTs),as indicated by the cecal intubation rate of MEI compared with SC,but MEI did not have any distinct advantage over SC for cecal intubation time(MD=-0.07,95%CI:-0.16-0.02;three RCTs).MEI did not generally result in lower pain scores.Outcomes were also analyzed for the two subgroups based on the endoscopists’experience level to evaluate cecal intubation rates.MEI presented better outcomes for non-experienced colonoscopists than experienced colonoscopists.CONCLUSION:The real-time magnetic imaging system is of benefit in training and educating inexperienced endoscopists and improves the cecal intubation rate for experienced and inexperienced endoscopists.