Between-group Difference In Survival Research Articles

Podocyte-Specific Deletion of MCP-1 Fails to Protect against Angiotensin II- or Adriamycin-Induced Glomerular Disease.

Investigating the role of podocytes in proteinuric disease is imperative to address the increasing global burden of chronic kidney disease (CKD). Studies strongly implicate increased levels of monocyte chemoattractant protein-1 (MCP-1/CCL2) in proteinuric CKD. Since podocytes express the receptor for MCP-1 (i.e., CCR2), we hypothesized that podocyte-specific MCP-1 production in response to stimuli could activate its receptor in an autocrine manner, leading to further podocyte injury. To test this hypothesis, we generated podocyte-specific MCP-1 knockout mice (Podo-Mcp-1fl/fl) and exposed them to proteinuric injury induced by either angiotensin II (Ang II; 1.5 mg/kg/d, osmotic minipump) or Adriamycin (Adr; 18 mg/kg, intravenous bolus). At baseline, there were no between-group differences in body weight, histology, albuminuria, and podocyte markers. After 28 days, there were no between-group differences in survival, change in body weight, albuminuria, kidney function, glomerular injury, and tubulointerstitial fibrosis. The lack of protection in the knockout mice suggests that podocyte-specific MCP-1 production is not a major contributor to either Ang II- or Adr-induced glomerular disease, implicating that another cell type is the source of pathogenic MCP-1 production in CKD.

One-year outcome of elderly patients with endocarditis: a retrospective observational study

Abstract Background The incidence of infective endocarditis (IE) is rising in general population, especially in elderly, where it is associated with high morbidity and mortality. Health care procedures, degenerative heart valve diseases and intracardiac electronic devices are the main risk factors for IE in elderly population. Cardiac surgery is largely underused in these patients and the few available observational studies seem to confirm the positive outcome of surgery. Purpose The aim of the present study is to assess differences in survival between elderly patients affected by endocarditis treated with a conservative strategy or cardiac surgery. Methods We conducted a retrospective observational study of 143 elderly patients (age ≥ 70 years old) affected by endocarditis with at least one year of follow-up who were hospitalized between 2016 and 2022. The primary endpoint was the difference in one-year all-cause mortality between patients treated with a conservative strategy or cardiac surgery. The secondary endpoint was one-year mortality for sepsis or septic shock. The cumulative probability of survival was calculated using the Kaplan-Meier estimator. The log-rank test was used to compare between-group differences in survival and cox regression was used in the uni and multivariate analysis, a p<0.05 was considered significant. Results Between 2016 and 2022, 242 patients have been diagnosed with IE. Between them, 143 patients were at least 70 years old (59%). Cardiac surgery was performed in 16 patients, while 127 were treated with medical therapy alone. Patients treated with cardiac surgery were younger (74y vs 80y, p=0.005) and had higher prevalence of severe valvular heart disease (69% vs 23%, p< 0.001). The primary endpoint of one-year all-cause mortality occurred in 80 patients in the conservative strategy group and in 5 patients treated with surgery (p=0.015); the secondary endpoint occurred in 42 patients in conservative strategy group, while no patients treated with surgery died for sepsis or septic shock (p=0.006). Finally, surgery was associated with better one-year survival (HR 0.34, 95% CI 0.14 - 0.85). Conclusions IE in elderly patients is an emerging clinical matter since its incidence is rising but mortality has not significantly decreased. Current clinical guidelines do not give specific indication for elderly, who are generally excluded from surgery due to the high risk carried by age and comorbidities. Few previous studies have analyzed the best treatment strategy in this cohort of patients, but data from observational studies shows a better outcome among those undergone surgery. The result of our work confirmed that elderly patients with IE treated with cardiac surgery have better one-year survival and lower rate of death for all causes, sepsis or septic shockKaplan Mayer Curve For One-Year Survival

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

BackgroundThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.MethodsIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.ResultsThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.ConclusionsIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589, NCT04505774, NCT04359277, and NCT02735707.)

Long-term Survival Benefit of Tafamidis in Patients with Transthyretin Amyloid Cardiomyopathy

Introduction In the pivotal ATTR-ACT study, tafamidis was associated with a 30% lower mortality risk than placebo (PBO) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) over 30 months. Because patients receiving PBO in ATTR-ACT switched to tafamidis in the ongoing, open-label long-term extension (LTE), the long-term efficacy of tafamidis cannot be directly compared with PBO. A statistical extrapolation method has been used to estimate between-group differences in survival beyond the 30-month trial duration. Hypothesis Comparing observed long-term survival with tafamidis in the LTE with estimated survival with PBO extrapolated from ATTR-ACT will allow fuller assessment of tafamidis survival benefits. Methods In ATTR-ACT, patients with ATTR-CM received tafamidis (80 or 20 mg) or PBO for 30 months. In the LTE, patients previously receiving tafamidis continued on the same tafamidis dose, and those previously receiving PBO were randomized to tafamidis 80 mg or 20 mg. Based on a protocol amendment (July 20, 2018), all patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis 80 mg). All-cause mortality was assessed using a Cox proportional hazards model for tafamidis 80/61 mg or PBO/tafamidis in ATTR-ACT/LTE. A gamma model based on patient-level data for the PBO group in ATTR-ACT and best model fitting criteria (AIC, BIC) was used to extrapolate survival beyond 30 months. Results In this interim analysis of all-cause mortality, 75/176 (42.6%) and 108/177 (61.0%) patients in the tafamidis 80/61 mg and PBO/tafamidis groups, respectively, died (median follow-up: 51.9 and 51.4 months). Long-term continuous tafamidis treatment was superior to PBO/tafamidis treatment (Figure). Mortality risk was reduced by 41.1% with tafamidis 80/61 mg (n = 176) vs PBO/tafamidis (n = 177) (hazard ratio, 0.5888 [95% CI: 0.4370-0.7931]; P = 0.0004). In the extrapolated PBO group, the estimated median overall survival was 35.2 months, vs 35.8 months in the observed PBO/tafamidis group. The curves for PBO/tafamidis and estimated PBO diverged after ∼44 months in favor of tafamidis. Conclusions Extrapolation of PBO data from ATTR-ACT was a valuable tool allowing comparison of potential outcomes with and without tafamidis treatment. Although these extrapolated data suggest that delayed initiation of tafamidis may provide some survival benefit, early continuous treatment with tafamidis results in significantly better survival outcomes in patients with ATTR-CM.

To SIPAT or Not to SIPAT: The Stanford Integrated Psychosocial Assessment for Transplant

The Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) is a tool used to standardize and objectify the pre-transplant evaluation. We sought to assess whether the SIPAT score is associated with outcomes of acute cellular rejection (ACR), graft failure (GF) and survival. Retrospective study in HTx recipients between 01/2008 and 05/2019 at a single institution. Post-transplant outcomes included: incidence of ACR, GF, and death, comparing HTx recipients with a SIPAT score <21 [acceptable] vs. ≥21 [minimally acceptable]. The KM method was used to assess survival, and a competing risk model was used for GF. Cox proportional hazard regression was applied to quantify the association of ACR (a time dependent variable) with mortality, adjusted for demographic characteristics. Independent estimating equations were used to assess the association of the SIPAT score with longitudinal biopsy ACR grades RESULTS: Overall 393 HTx recipients had a SIPAT evaluation. Patients included were more likely Caucasian (55.5%) and male (70.2%), with a median age of 55.2 (46-61.7) years. The median (IQR) SIPAT score was 14 (10-19) and 68 patients (17.2%) had a SIPAT score ≥ 21. Women were more likely to have a low (acceptable) SIPAT score (33% vs. 16%, p-value = 0.008). Recipients with a SIPAT score ≥21 were not at higher risk for ACR (p= 0.99) (Figure 1A), when adjusted for recipients' demographics. Between-group differences in survival and graft failure were not statistically significant (5-year survival: ≤21 vs. >21, 84.5% [79.3%, 88.5%] vs. 81.6% [65.0%, 90.8%], p= 0.74; 5-year GF CIF: ≤21 vs. >21, 6.5% [3.9%, 10.9%] vs. 10.2% [3.7%, 28.2%], p= 0.65 [GF]). The study did not show evidence that minimally acceptable recipients, according to psychosocial criteria, experienced an increased risk of rejection, graft failure or death. While the SIPAT tool has become an integral tool for heart transplant evaluation, a high SIPAT score alone may not be sufficient to risk stratify candidates.

Moving towards an Induction-Free Era: Short-Term Renal and Infectious Outcomes

Currently, 50% of heart transplant (HTx) programs worldwide use an induction therapy strategy despite limited evidence. Recently, our program moved from universal induction to a limited-induction strategy (only for high-risk individuals). The purpose of this analysis was to compare incidence of early infection and renal function in HTx recipients stratified by use induction therapy. Retrospective study in HTx recipients between 01/2012 and 05/2019 at a single institution. Post-transplant outcomes included survival, risk of infection, serum creatine trends and need for dialysis in HTx recipients by induction status. The KM method was used for survival and competing risk models for infection and dialysis. Between-group differences in survival and cumulative incidence rate were evaluated using log-rank and Gray's tests, respectively. Overall, 260 HTx recipients were included. Of those, 239 (91%) received induction while 21 (8%) did not. Patients were more likely male (70.8%) and Caucasian (55.8%). Overall 1-year survival [95%CI] was 89.7% [85.2%,92.8%]. The cumulative proportion of infection was significantly higher in the induction group (55.6% [48.7%, 61.5%] vs. no-Induction 39.2% [10.2%, 58.9%]) (Figure 1A). Need for dialysis was not significantly different between groups (Induction 6.8% [3.5%, 9.9%] vs. no induction 5.0% [0.0%, 14.1%] at 1 year (Figure 1B). Serum creatinine (mg/dL) trends are shown in Figure 1C. Baseline creatinine (IQR) was significantly higher the induction group (1.4 (1.1-1.8) vs. 1.14 (0.90-1.40), p=0.035) and on day 1 (1.6 (1.2-2.0) vs. 1.26 (0.90-1.60), p=0.22) but there were no significant differences thereafter. In our early experience with a selective induction strategy, we found a reduction in infection rates and no significant worsening in short term renal function in those who were not induced. This strategy appears safe yet warrants ongoing surveillance for long term patient outcomes.

Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial

Treatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to established guidelines. Therefore, we aimed to investigate the efficacy of the combination drug device Amikacin Inhale as an adjunctive therapy to intravenous standard-of-care antibiotics for pneumonia caused by Gram-negative pathogens in intubated and mechanically ventilated patients. INHALE was a prospective, double-blind, randomised, placebo-controlled, phase 3 study comprising two trials (INHALE 1 and INHALE 2) done in 153 hospital intensive-care units in 25 countries. Eligible patients were aged 18 years or older; had pneumonia that had been diagnosed by chest radiography and that was documented as being caused by or showing two risk factors for a Gram-negative, multidrug-resistant pathogen; were intubated and mechanically ventilated; had impaired oxygenation within 48 h before screening; and had a modified Clinical Pulmonary Infection Score of at least 6. Patients were stratified by region and disease severity (according to their Acute Physiology and Chronic Health Evaluation [APACHE] II score) and randomly assigned (1:1) via an interactive voice-recognition system to receive 400 mg amikacin (Amikacin Inhale) or saline placebo, both of which were aerosolised, administered every 12 h for 10 days via the same synchronised inhalation system, and given alongside standard-of-care intravenous antibiotics. All patients and all staff involved in administering devices and monitoring outcomes were masked to treatment assignment. The primary endpoint, survival at days 28-32, was analysed in all patients who received at least one dose of study drug, were infected with a Gram-negative pathogen, and had an APACHE II score of at least 10 at diagnosis. Safety analyses were done in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, numbers NCT01799993 and NCT00805168. Between April 13, 2013, and April 7, 2017, 807 patients were assessed for eligibility and 725 were randomly assigned to Amikacin Inhale (362 patients) or aerosolised placebo (363 patients). 712 patients received at least one dose of study drug (354 in the Amikacin Inhale group and 358 in the placebo group), although one patient assigned to Amikacin Inhale received placebo in error and was included in the placebo group for safety analyses. 508 patients (255 in the Amikacin Inhale group and 253 in the placebo group) were assessed for the primary endpoint. We found no between-group difference in survival: 191 (75%) patients in the Amikacin Inhale group versus 196 (77%) patients in the placebo group survived until days 28-32 (odds ratio 0·841, 95% CI 0·554-1·277; p=0·43). Similar proportions of patients in the two treatment groups had a treatment-emergent adverse event (295 [84%] of 353 patients in the Amikacin Inhale group vs 303 [84%] of 359 patients in the placebo group) or a serious treatment-emergent adverse event (101 [29%] patients vs 97 [27%] patients). Our findings do not support use of inhaled amikacin adjunctive to standard-of-care intravenous therapy in mechanically ventilated patients with Gram-negative pneumonia. Bayer AG.

Combination of lymphovascular invasion and the AJCC TNM staging system improves prediction of prognosis in N0 stage gastric cancer: results from a high-volume institution

BackgroundThis study sought to explore whether lymphovascular invasion can affect the prognosis of patients with stage N0 gastric cancer and to evaluate the survival benefit of adjuvant chemotherapy for such patients.MethodFrom January 2006 to December 2011, a total of 2102 gastric cancer patients undergoing radical gastric resection were enrolled in this study. Homogeneity, discriminatory ability, and monotonicity of gradients in the combination of lymphovascular invasion and the 8th edition of the AJCC staging system and the 8th edition of the AJCC staging system alone were compared using linear trend χ2, likelihood ratio χ2 statistics, and Akaike information criterion (AIC) calculations. The Kaplan-Meier method and the log-rank test were used to analyze between-group differences in survival rate.ResultThe median follow-up time of the whole group was 58 months, and the average age of the whole group was 63.9 years (range 21–89 years). The 3-year and 5-year overall survival rates in N0 patients with lymphovascular invasion were lower than those in N0 patients without lymphovascular invasion (3-year OS: 78.3% vs 92.5%, 5-year OS: 70.0% vs 88.3%, p < 0.001). A multivariate analysis showed that age (p < 0.001), lymphovascular invasion (p < 0.001), and pT (p < 0.001) were independent risk factors for the prognosis of N0 patients. Compared with the 8th edition of the AJCC staging system alone, the 8th AJCC staging system combined with lymphovascular invasion demonstrated a better linear trend χ2, likelihood ratio χ2 statistics, and AIC value (68.99 vs 58.58, 70.18 vs 58.36, 1473.38 vs 1485.04). In pT3N0M0 patients with lymphovascular invasion, the 3-year and 5-year overall survival rates of the adjuvant chemotherapy group were higher than those of the surgery alone group (3-year OS: 83.3% vs 68.2%, 5-year OS: 72.3% vs 50.0%, p = 0.048).ConclusionLymphovascular invasion is an independent prognostic factor in N0 patients. The 8th AJCC staging system combined with lymphovascular invasion can improve the accuracy of the AJCC staging system for N0 patients. Moreover, adjuvant chemotherapy improves the survival of pT3N0M0 patients with lymphovascular invasion.

Regional Nodal Irradiation in Early-Stage Breast Cancer

BackgroundMost women with breast cancer who undergo breast-conserving surgery receive whole-breast irradiation. We examined whether the addition of regional nodal irradiation to whole-breast irradiation improved outcomes.MethodsWe randomly assigned women with node-positive or high-risk node-negative breast cancer who were treated with breast-conserving surgery and adjuvant systemic therapy to undergo either whole-breast irradiation plus regional nodal irradiation (including internal mammary, supraclavicular, and axillary lymph nodes) (nodal-irradiation group) or whole-breast irradiation alone (control group). The primary outcome was overall survival. Secondary outcomes were disease-free survival, isolated locoregional disease-free survival, and distant disease-free survival.ResultsBetween March 2000 and February 2007, a total of 1832 women were assigned to the nodal-irradiation group or the control group (916 women in each group). The median follow-up was 9.5 years. At the 10-year follow-up, there was no significant between-group difference in survival, with a rate of 82.8% in the nodal-irradiation group and 81.8% in the control group (hazard ratio, 0.91; 95% confidence interval [CI], 0.72 to 1.13; P=0.38). The rates of disease-free survival were 82.0% in the nodal-irradiation group and 77.0% in the control group (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Patients in the nodal-irradiation group had higher rates of grade 2 or greater acute pneumonitis (1.2% vs. 0.2%, P=0.01) and lymphedema (8.4% vs. 4.5%, P=0.001).ConclusionsAmong women with node-positive or high-risk node-negative breast cancer, the addition of regional nodal irradiation to whole-breast irradiation did not improve overall survival but reduced the rate of breast-cancer recurrence. (Funded by the Canadian Cancer Society Research Institute and others; MA.20 ClinicalTrials.gov number, NCT00005957.)

Collider bias in trauma comparative effectiveness research: The stratification blues for systematic reviews

BackgroundCollider bias, or stratifying data by a covariate consequence rather than cause (confounder) of treatment and outcome, plagues randomised and observational trauma research. Of the seven trials of prehospital hypertonic saline in dextran (HSD) that have been evaluated in systematic reviews, none found an overall between-group difference in survival, but four reported significant subgroup effects. We hypothesised that an avoidable type of collider bias often introduced inadvertently into trauma comparative effectiveness research could explain the incongruous findings. MethodsThe two most recent HSD trials, a single-site pilot and a multi-site pivotal study, provided data for a secondary analysis to more closely examine the potential for collider bias. The two trials had followed the a priori statistical analysis plan to subgroup patients by a post-randomisation covariate and well-established surrogate for bleeding severity, massive transfusion (MT), ≥10unit of red blood cells within 24h of admission. Despite favourable HSD effects in the MT subgroup, opposite effects in the non-transfused subgroup halted the pivotal trial early. In addition to analyzing the data from the two trials, we constructed causal diagrams and performed a meta-analysis of the results from all seven trials to assess the extent to which collider bias could explain null overall effects with subgroup heterogeneity. ResultsAs in previous trials, HSD induced significantly greater increases in systolic blood pressure (SBP) from prehospital to admission than control crystalloid (p=0.003). Proportionately more HSD than control decedents accrued in the non-transfused subgroup, but with paradoxically longer survival. Despite different study populations and a span of over 20 years across the seven trials, the reported mortality effects were consistently null, summary RR=0.99 (p=0.864, homogeneity p=0.709). ConclusionsHSD delayed blood transfusion by modifying standard triggers like SBP with no detectable effect on survival. The reported heterogeneous HSD effects in subgroups can be explained by collider bias that trauma researchers can avoid by improved covariate selection and data capture strategies.

Laparoscopic and open abdominal staging for early-stage ovarian cancer: our experience, systematic review, and meta-analysis of comparative studies.

The aim of this study was to analyze perioperative and long-term survival outcomes after either laparoscopic or open abdominal staging for apparent early-stage ovarian cancer. Data of consecutive women with early-stage ovarian cancer undergoing comprehensive laparoscopic staging between 2003 and 2010 were matched with a historical cohort of patients undergoing open surgery. Five-year survival outcomes were analyzed using the Kaplan-Meier method. In addition, a systematic review of the literature and meta-analysis of comparative studies was performed A total of 35 women undergoing staging via laparoscopy were compared with a cohort of 32 patients undergoing open surgery. Baseline characteristics were similar between groups. Spillage occurred in 6 and 4 patients in laparoscopic and open group, respectively (P = 0.59). Patients undergoing laparoscopy experienced longer operative time (P < 0.001), shorter hospital stay (P = 0.03), and lower postoperative complication rate (3% vs 28%; P = 0.005) than patients undergoing staging via open surgery. The median (range) follow-up period was 64 (37-106) and 100 (61-278) months for case and control, respectively (P < 0.001). Five-year disease-free survival (P = 0.12, log-rank test) and overall survival (P = 0.26, log-rank test) were not influenced by surgical approach. Pooled analyses of the literature results corroborate our results suggesting an improvement of perioperative results in the laparoscopic group in comparison with the open abdominal one. In comparison with open surgery, laparoscopy did not influenced spillage (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.35-1.73) and upstaging rate (OR, 0.7; 95% CI, 0.38-1.27). No between-group differences in survival were observed (OR, 0.5; 95% CI, 0.21-1.21). Laparoscopy upholds open surgery in long-term oncologic control, reducing morbidity.

Standard Retrograde Pancreatosplenectomy versus Radical Antegrade Modular Pancreatosplenectomy for Body and Tail Pancreatic Adenocarcinoma

Pancreatic surgery remains the only established curative treatment for pancreatic cancer. Radical antegrade pancreatosplenectomy (RAMPS) is a modification of the standard retrograde pancreatosplenectomy (SRPS) developed to achieve a complete N1 node resection and R0 resection (posterior extent). The aim of this study is to compare the short-, mid-, and long-term outcomes of RAMPS and SRPS. From a database that included 143 consecutive patients who underwent resection for pancreatic carcinoma at the St. Andrea Hospital, University of Rome, 25 patients who underwent pancreatosplenectomy were retrospectively reviewed. Among these 25 patients, eight (32%) underwent RAMPS (Group 1) and 17 (68%) underwent SRPS (Group 2). Clinicopathologic and oncological characteristics of the RAMPS group were compared with those of the SRPS group. RAMPS was longer than SRPS (315 vs 265 minutes, respectively, P < 0.001). No differences were encountered for perioperative outcomes (estimated blood loss, intraoperative blood transfusions, postoperative morbidity and mortality, and hospital stay). The margin status rates were similar: noteworthy, the two patients with positive tangential margins belonged to Group 2. No between-group differences in survival were encountered: the actuarial 5-year overall survival for Groups 1 and 2 were 26 and 29 per cent, respectively (P = 0.6608; hazard ratio, 1.2621; 95% confidence interval, 0.4462 to 3.5699). RAMPS and SRPS did not differ statistically in terms of perioperative outcomes. RAMPS seems to allow better control of tangential margins; however, no difference was found in actuarial survival compared with standard pancreatosplenectomy.