A systematic review and network meta-analysis of the safety of early interventional treatments in rheumatoid arthritis.

OBJECTIVES: To evaluate the safety of treatment strategies in patients with early RA. METHODS: Systematic searches of MEDLINE, EMBASE and PubMed were conducted up to September 2020. Double-blind randomized controlled trials (RCTs) of licensed treatments conducted on completely naïve or MTX-naïve RA patients were included. Long-term extension studies, post-hoc and pooled analyses and RCTs with no comparator arm were excluded. Serious adverse events, serious infections and non-serious adverse events were extracted from all RCTs, and event rates in intervention and comparator arms were compared using meta-analysis and network meta-analysis (NMA). RESULTS: From an initial search of 3423 studies, 20 were included, involving 9202 patients. From the meta-analysis, the pooled incidence rates per 1000 patient-years for serious adverse events were 69.8 (95% CI: 64.9, 74.8), serious infections 18.9 (95% CI: 16.2, 21.6) and non-serious adverse events 1048.2 (95% CI: 1027.5, 1068.9). NMA showed that serious adverse event rates were higher with biologic monotherapy than with MTX monotherapy, rate ratio 1.39 (95% CI: 1.12, 1.73). Biologic monotherapy rates were higher than those for MTX and steroid therapy, rate ratio 3.22 (95% CI: 1.47, 7.07). Biologic monotherapy had a higher adverse event rate than biologic combination therapy, rate ratio 1.26 (95% CI: 1.02, 1.54). NMA showed no significant difference between strategies with respect to serious infections and non-serious adverse events rates. CONCLUSION: The study revealed the different risk profiles for various early RA treatment strategies. Observed differences were overall small, and in contrast to the findings of established RA studies, steroid-based regimens did not emerge as more harmful.

IL-6 inhibition in the treatment of COVID-19: A meta-analysis and meta-regression.

OBJECTIVES: Multiple RCTs of interleukin-6 (IL-6) inhibitors in COVID-19 have been published, with conflicting conclusions. We performed a meta-analysis to assess the impact of IL-6 inhibition on mortality from COVID-19, utilising meta-regression to explore differences in study results. METHODS: Systematic database searches were performed to identify RCTs comparing IL-6 inhibitors (tocilizumab and sarilumab) to placebo or standard of care in adults with COVID-19. Meta-analysis was used to estimate the relative risk of mortality at 28 days between arms, expressed as a risk ratio. Within-study mortality rates were compared, and meta-regression was used to investigate treatment effect modification. RESULTS: Data from nine RCTs were included. The combined mortality rate across studies was 19% (95% CI: 18, 20%), ranging from 2% to 31%. The overall risk ratio for 28-day mortality was 0.90 (95% CI: 0.81, 0.99), in favour of benefit for IL-6 inhibition over placebo or standard of care, with low treatment effect heterogeneity: I2 0% (95% CI: 0, 53%). Meta-regression showed no evidence of treatment effect modification by patient characteristics. Trial-specific mortality rates were explained by known patient-level predictors of COVID-19 outcome (male sex, CRP, hypertension), and country-level COVID-19 incidence. CONCLUSIONS: IL-6 inhibition is associated with clinically meaningful improvements in outcomes for patients admitted with COVID-19. Long-term benefits of IL-6 inhibition, its effectiveness across healthcare systems, and implications for differing standards of care are currently unknown.

Surgical interventions for the prevention or treatment of lymphoedema after breast cancer treatment.

BACKGROUND: Breast cancer is the most common type of cancer amongst women worldwide, and one distressing complication of breast cancer treatment is breast and upper-limb lymphoedema. There is uncertainty regarding the effectiveness of surgical interventions in both the prevention and management of lymphoedema affecting the arm after breast cancer treatment. OBJECTIVES: 1. To assess and compare the efficacy of surgical interventions for the prevention of the development of lymphoedema (LE) in the arm after breast cancer treatment.2. To assess and compare the efficacy of surgical interventions for the treatment of established LE in the arm after breast cancer treatment. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the WHO International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for all prospectively registered and ongoing trials on 2 November 2017. Reference lists of included studies were also handsearched by three review authors for additional eligible trials. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing a surgical intervention for the prevention or treatment of lymphoedema of the arm after breast cancer treatment to either standard intervention, placebo intervention, or another surgical intervention were included. Patients of both sexes and all ages who have had treatment for their breast cancer were considered. No limits were applied to language or study location. Three authors independently determined the eligibility of each study. DATA COLLECTION AND ANALYSIS: Three authors independently extracted data for each included study using a pre-designed data extraction pro forma and used Cochrane's 'risk of bias' tool for assessing risk of bias. Dichotomous variables were analysed using the Mantel-Haenszel method to estimate risk ratios (RRs). Differences in continuous variables were expressed as mean differences (MDs). GRADE was used to assess the certainty of the evidence provided by the included studies. MAIN RESULTS: Two studies involving 95 participants examined surgical interventions for preventing breast cancer-related lymphoedema. Both studies evaluated the efficacy of the lymphaticovenular anastomosis technique as part of a preventative management protocol. Both studies were deemed to be at unclear risk of bias overall. Statistical variation between the studies was low, which increases the reliability of the evidence. However, the two studies were conducted in the same centre. Lymphaticovenular anastomosis appears to result in a reduction in the incidence of lymphoedema compared to nonoperative management with a risk ratio of 0.20 (95% CI 0.06 to 0.63, P = 0.006; 95 participants; low-certainty evidence). The RCTs did not evaluate any of the secondary outcomes.One study involving 36 participants evaluated the effectiveness of vascularised lymph node transfer for treating breast cancer-related lymphoedema. The trial was deemed to be at unclear risk of bias. For participants suffering from stage 2 lymphoedema, the evidence suggested reductions in limb volume (MD -39.00%, 95% CI -47.37% to -30.63%, very low-certainty evidence), pain scores (MD -4.16, 95% CI -5.17 to -3.15, very low-certainty evidence), heaviness sensation (MD -4.27, 95% CI -5.74 to -2.80, very low-certainty evidence), mean number of infections/year (MD -1.22, 95% CI -2.00 to -0.44, very low-certainty evidence), and an improvement in overall function scores (MD -3.77, 95% CI -4.89 to -2.65, very low-certainty evidence) for those who had undergone vascularised lymph node transfer compared to those who had undergone no treatment. AUTHORS' CONCLUSIONS: There is low-certainty evidence that lymphaticovenular anastomosis is effective in preventing the development of lymphoedema after breast cancer treatment based on the findings from two studies. One study providing very low-certainty evidence found that vascularised lymph node transfer is an efficacious option in the treatment of established stage 2 lymphoedema related to breast cancer. Important secondary outcomes in this review were rarely reported in the included studies. More high-quality RCTs are required to further elucidate the effectiveness of surgical interventions in the prevention and treatment of lymphoedema after breast cancer treatment. At the time of this review, no ongoing trials on this topic were identified.

Diagnostic accuracy of laparoscopy following computed tomography (CT) scanning for assessing the resectability with curative intent in pancreatic and periampullary cancer.

BACKGROUND: Surgical resection is the only potentially curative treatment for pancreatic and periampullary cancer. A considerable proportion of patients undergo unnecessary laparotomy because of underestimation of the extent of the cancer on computed tomography (CT) scanning. Laparoscopy can detect metastases not visualised on CT scanning, enabling better assessment of the spread of cancer (staging of cancer). This is an update to a previous Cochrane Review published in 2013 evaluating the role of diagnostic laparoscopy in assessing the resectability with curative intent in people with pancreatic and periampullary cancer. OBJECTIVES: To determine the diagnostic accuracy of diagnostic laparoscopy performed as an add-on test to CT scanning in the assessment of curative resectability in pancreatic and periampullary cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via PubMed, EMBASE via OvidSP (from inception to 15 May 2016), and Science Citation Index Expanded (from 1980 to 15 May 2016). SELECTION CRITERIA: We included diagnostic accuracy studies of diagnostic laparoscopy in people with potentially resectable pancreatic and periampullary cancer on CT scan, where confirmation of liver or peritoneal involvement was by histopathological examination of suspicious (liver or peritoneal) lesions obtained at diagnostic laparoscopy or laparotomy. We accepted any criteria of resectability used in the studies. We included studies irrespective of language, publication status, or study design (prospective or retrospective). We excluded case-control studies. DATA COLLECTION AND ANALYSIS: Two review authors independently performed data extraction and quality assessment using the QUADAS-2 tool. The specificity of diagnostic laparoscopy in all studies was 1 because there were no false positives since laparoscopy and the reference standard are one and the same if histological examination after diagnostic laparoscopy is positive. The sensitivities were therefore meta-analysed using a univariate random-effects logistic regression model. The probability of unresectability in people who had a negative laparoscopy (post-test probability for people with a negative test result) was calculated using the median probability of unresectability (pre-test probability) from the included studies, and the negative likelihood ratio derived from the model (specificity of 1 assumed). The difference between the pre-test and post-test probabilities gave the overall added value of diagnostic laparoscopy compared to the standard practice of CT scan staging alone. MAIN RESULTS: We included 16 studies with a total of 1146 participants in the meta-analysis. Only one study including 52 participants had a low risk of bias and low applicability concern in the patient selection domain. The median pre-test probability of unresectable disease after CT scanning across studies was 41.4% (that is 41 out of 100 participants who had resectable cancer after CT scan were found to have unresectable disease on laparotomy). The summary sensitivity of diagnostic laparoscopy was 64.4% (95% confidence interval (CI) 50.1% to 76.6%). Assuming a pre-test probability of 41.4%, the post-test probability of unresectable disease for participants with a negative test result was 0.20 (95% CI 0.15 to 0.27). This indicates that if a person is said to have resectable disease after diagnostic laparoscopy and CT scan, there is a 20% probability that their cancer will be unresectable compared to a 41% probability for those receiving CT alone.A subgroup analysis of people with pancreatic cancer gave a summary sensitivity of 67.9% (95% CI 41.1% to 86.5%). The post-test probability of unresectable disease after being considered resectable on both CT and diagnostic laparoscopy was 18% compared to 40.0% for those receiving CT alone. AUTHORS' CONCLUSIONS: Diagnostic laparoscopy may decrease the rate of unnecessary laparotomy in people with pancreatic and periampullary cancer found to have resectable disease on CT scan. On average, using diagnostic laparoscopy with biopsy and histopathological confirmation of suspicious lesions prior to laparotomy would avoid 21 unnecessary laparotomies in 100 people in whom resection of cancer with curative intent is planned.

Continuous versus interrupted skin sutures for non-obstetric surgery.

BACKGROUND: Most surgical procedures involve a cut in the skin, allowing the surgeon to gain access to the surgical site. Most surgical wounds are closed fully at the end of the procedure; this review focuses on these closed wounds. There are many ways to close the surgical incision, for example, using sutures (stitches), staples, tissue adhesives or tapes. Skin sutures can be continuous or interrupted. In general, continuous sutures are usually subcuticular and can be absorbable or non-absorbable, while interrupted sutures are usually non-absorbable and involve the full thickness of the skin - although some surgeons do use absorbable interrupted sutures. OBJECTIVES: To compare the benefits and harms of continuous compared with interrupted skin closure techniques in participants undergoing non-obstetric surgery. SEARCH METHODS: In August 2013 we searched the following databases: Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid Embase; and EBSCO CINAHL. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) that compared skin closure using continuous sutures with skin closure using interrupted sutures, irrespective of whether there were differences in the nature of the suture materials used in the two groups. We included all relevant RCTs in the analysis, irrespective of language of publication, publication status, publication year or sample size. DATA COLLECTION AND ANALYSIS: Two review authors independently identified the trials and extracted data. We calculated the risk ratio (RR) with 95% confidence intervals (CI) for comparing binary outcomes between the groups, and calculated the mean difference (MD) with 95% CI for comparing continuous outcomes. We performed meta-analysis using a fixed-effect model and a random-effects model. We performed intention-to-treat analysis whenever possible. MAIN RESULTS: We included five RCTs with a total of 827 participants. Outcomes were available for 730 participants (384 participants randomised to continuous sutures and 346 participants to interrupted sutures). All the trials were of unclear or high risk of bias. The participants underwent abdominal or groin operations. The only outcomes reported in the trials were superficial surgical site infection, superficial wound dehiscence (breakdown) and length of hospital stay. Other important outcomes such as quality of life, long-term patient outcomes and use of healthcare resources were not reported in these trials.Overall, 6.5% (39/602 participants, four trials) developed superficial surgical site infections. There was no significant difference between the groups in the proportion of participants who developed superficial surgical site infections (RR 0.73; 95% CI 0.40 to 1.33). A total of 23 participants (23/625 (3.7%), four trials) developed superficial wound dehiscence. Twenty-two of the 23 participants belonged to the interrupted suture group.The proportion of participants who developed superficial wound dehiscence was statistically significantly lower in the continuous suture group compared to the interrupted suture group (RR 0.08; 95% CI 0.02 to 0.35). Most of these wound dehiscences were reported in two recent trials in which the continuous skin suture groups received absorbable subcuticular sutures while the interrupted skin suture groups received non-absorbable transcutaneous sutures. The non-absorbable sutures were removed seven to nine days after surgery in the interrupted sutures groups whilst sutures in the comparator groups were not removed, being absorbable. The continuous suture technique with absorbable suture does not require suture removal and provides support for the wound for a longer period of time. This may have contributed to the difference between the two groups in the proportion of participants who developed superficial wound dehiscence. There was no significant difference in the length of the hospital stay between the two groups (MD -1.40 days; 95% CI -7.14 to 4.34). AUTHORS' CONCLUSIONS: Superficial wound dehiscence may be reduced by using continuous subcuticular sutures. However, there is uncertainty about this because of the quality of the evidence. Besides, the nature of the suture material used may have led to this observation, as the continuous suturing technique used suture material that did not need to be removed, whereas the comparator used interrupted (non-absorbable) sutures that did need to be removed. Differences in the methods of skin closure have the potential to affect patient outcomes and use of healthcare resources. Further well-designed trials at low risk of bias are necessary to determine which type of suturing is better.

Is sustained virological response a marker of treatment efficacy in patients with chronic hepatitis C viral infection with no response or relapse to previous antiviral intervention?

BACKGROUND: Randomised clinical trials (RCTs) of antiviral interventions in patients with chronic hepatitis C virus (HCV) infection use sustained virological response (SVR) as the main outcome. There is sparse information on long-term mortality from RCTs. METHODS: We created a decision tree model based on a Cochrane systematic review on interferon retreatment for patients who did not respond to initial therapy or who relapsed following SVR. Extrapolating data to 20 years, we modelled the outcome from three scenarios: (1) observed medium-term (5 year) annual mortality rates continue to the long term (20 years); (2) long-term annual mortality in retreatment responders falls to that of the general population while retreatment non-responders continue at the medium-term mortality; (3) long-term annual mortality in retreatment non-responders is the same as control group non-responders (i.e., the increased treatment-related medium mortality "wears off"). RESULTS: The mean differences in life expectancy over 20 years with interferon versus control in the first, second, and third scenarios were -0.34 years (95% confidence interval (CI) -0.71 to 0.03), -0.23 years (95% CI -0.69 to 0.24), and -0.01 (95% CI -0.3 to 0.27), respectively. The life expectancy was always lower in the interferon group than in the control group in scenario 1. In scenario 3, the interferon group had a longer life expectancy than the control group only when more than 7% in the interferon group achieved SVR. CONCLUSIONS: SVR may be a good prognostic marker but does not seem to be a valid surrogate marker for assessing HCV treatment efficacy of interferon retreatment. The SVR threshold at which retreatment increases life expectancy may be different for different drugs depending upon the adverse event profile and treatment efficacy. This has to be determined for each drug by RCTs and appropriate modelling before SVR can be accepted as a surrogate marker.

Wound drains after incisional hernia repair.

BACKGROUND: Incisional hernias are caused by the failure of the wall of the abdomen to close after abdominal surgery, leaving a hole through which the viscera protrude. Incisional hernias are repaired by further surgery. Surgical drains are frequently inserted during hernia repair with the aim of facilitating fluid drainage and preventing complications. Traditional teaching has recommended the use of drains after incisional hernia repair other than for laparoscopic ventral hernia repair. More than 50% of open mesh repairs of ventral hernias have drains inserted. However, there is uncertainty as to whether drains are associated with benefits or harm to the patient. OBJECTIVES: To determine the effects on wound infection and other outcomes, of inserting a wound drain during surgery to repair incisional hernias, and, if possible, to determine the comparative effects of different types of wound drain after incisional hernia repair. SEARCH METHODS: In November 2013, for this fourth update we searched the Cochrane Wounds Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library, Ovid MEDLINE, Ovid EMBASE, and EBSCO CINAHL. SELECTION CRITERIA: We considered all randomised trials performed in adult patients who underwent incisional hernia repair and that compared using a drain with no drain. We also considered trials that compared different types of drain. DATA COLLECTION AND ANALYSIS: We extracted data on the characteristics of the trial, methodological quality of the trials, outcomes (e.g. infection and other wound complications) from each trial. For each outcome, we calculated the risk ratio (RR) with 95% confidence intervals (CI) and based on intention-to-treat analysis. MAIN RESULTS: No new trials were identified by the updated searches. Only one trial was eligible for inclusion in the review with a total of 24 patients randomised to an electrified drain (12 patients) compared with a corrugated drain (12 patients). There were no statistically significant differences between the groups for wound infection or in the length of stay in hospital. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether wound drains after incisional hernia repair are associated with better or worse outcomes than no drains.

Diagnostic accuracy of laparoscopy following computed tomography (CT) scanning for assessing the resectability with curative intent in pancreatic and periampullary cancer.

BACKGROUND: Surgical resection is the only potentially curative treatment for pancreatic and periampullary cancer. A considerable proportion of patients undergo unnecessary laparotomy because of underestimation of the extent of the cancer on computed tomography (CT) scanning. Laparoscopy can detect metastases not visualised on CT scanning, enabling better assessment of the spread of cancer (staging of cancer). There has been no systematic review or meta-analysis assessing the role of diagnostic laparoscopy in assessing the resectability with curative intent in patients with pancreatic and periampullary cancer. OBJECTIVES: To determine the diagnostic accuracy of diagnostic laparoscopy performed as an add-on test to CT scanning in the assessment of curative resectability in pancreatic and periampullary cancer. SEARCH METHODS: We searched the Cochrane Register of Diagnostic Test Accuracy Studies, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via PubMed, EMBASE via OvidSP (from inception to 13 September 2012), and Science Citation Index Expanded (from 1980 to 13 September 2012). SELECTION CRITERIA: We included diagnostic accuracy studies of diagnostic laparoscopy in patients with potentially resectable pancreatic and periampullary cancer on CT scan, where confirmation of liver or peritoneal involvement was by histopathological examination of suspicious (liver or peritoneal) lesions obtained at diagnostic laparoscopy or laparotomy. We accepted any criteria of resectability used in the studies. We included studies irrespective of language, publication status, or study design (prospective or retrospective). We excluded case-control studies. DATA COLLECTION AND ANALYSIS: Two authors independently performed data extraction and quality assessment using the QUADAS-2 tool. The specificity of diagnostic laparoscopy in all studies was 1 because there were no false positives since laparoscopy and the reference standard are one and the same if histological examination after diagnostic laparoscopy is positive. Therefore, the sensitivities were meta-analysed using a univariate random-effects logistic regression model. The probability of unresectability in patients who had a negative laparoscopy (post-test probability for patients with a negative test result) was calculated using the median probability of unresectability (pre-test probability) from the included studies and the negative likelihood ratio derived from the model (specificity of 1 assumed). The difference between the pre-test and post-test probabilities gave the overall added value of diagnostic laparoscopy compared to the standard practice of CT scan staging alone. MAIN RESULTS: Fifteen studies with a total of 1015 patients were included in the meta-analysis. Only one study including 52 patients had a low risk of bias and low applicability concern in the patient selection domain. The median pre-test probability of unresectable disease after CT scanning across studies was 40.3% (that is 40 out of 100 patients who had resectable cancer after CT scan were found to have unresectable disease on laparotomy). The summary sensitivity of diagnostic laparoscopy was 68.7% (95% CI 54.3% to 80.2%). Assuming a pre-test probability of 40.3%, the post-test probability of unresectable disease for patients with a negative test result was 0.17 (95% CI 0.12 to 0.24). This indicates that if a patient is said to have resectable disease after diagnostic laparoscopy and CT scan, there is a 17% probability that their cancer will be unresectable compared to a 40% probability for those receiving CT alone.A subgroup analysis of patients with pancreatic cancer gave a summary sensitivity of 67.9% (95% CI 41.1% to 86.5%). The post-test probability of unresectable disease after being considered resectable on both CT and diagnostic laparoscopy was 18% compared to 40% for those receiving CT alone. AUTHORS' CONCLUSIONS: Diagnostic laparoscopy may decrease the rate of unnecessary laparotomy in patients with pancreatic and periampullary cancer found to have resectable disease on CT scan. On average, using diagnostic laparoscopy with biopsy and histopathological confirmation of suspicious lesions prior to laparotomy would avoid 23 unnecessary laparotomies in 100 patients in whom resection of cancer with curative intent is planned.

Wound drains after incisional hernia repair.

BACKGROUND: Incisional hernias are caused by the failure of the wall of the abdomen to close after abdominal surgery, leaving a hole through which the viscera protrude. Incisional hernias are repaired by further surgery. Surgical drains are frequently inserted during hernia repair with the aim of facilitating fluid drainage and preventing complications. Traditional teaching has recommended the use of drains after incisional hernia repair other than for laparoscopic ventral hernia repair. More than 50% of open mesh repairs of ventral hernias have drains inserted. However, there is uncertainty as to whether drains are associated with benefits or harm to the patient. OBJECTIVES: To determine the effects on wound infection and other outcomes, of inserting a wound drain during surgery to repair incisional hernias, and, if possible, to determine the comparative effects of different types of wound drain after incisional hernia repair. SEARCH METHODS: For this third update we searched the Cochrane Wounds Group Specialised Register (Searched September 8, 2011), the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library Issue 8, 2011, Ovid MEDLINE (2010 to September 2011), Ovid EMBASE (2007 to September 2011), and EBSCO CINAHL (2010 to September 2011). SELECTION CRITERIA: We considered all randomised trials performed in adult patients who underwent incisional hernia repair and that compared using a drain with no drain. We also considered trials that compared different types of drain. DATA COLLECTION AND ANALYSIS: We extracted data on the characteristics of the trial, methodological quality of the trials, outcomes (e.g. infection and other wound complications) from each trial. For each outcome, we calculated the risk ratio (RR) with 95% confidence intervals (CI) and based on intention-to-treat analysis. MAIN RESULTS: No new trials were identified by the updated searches. Only one trial was eligible for inclusion in the review with a total of 24 patients randomised to an electrified drain (12 patients) compared with a corrugated drain (12 patients). There were no statistically significant differences between the groups for wound infection or in the length of stay in hospital. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether wound drains after incisional hernia repair are associated with better or worse outcomes than no drains.