September 2024

Synopsis: This international randomized control trial (RCT) included almost 5,000 intensive care unit (ICU) patients undergoing invasive mechanical ventilation, who were randomized to receive intravenous (IV) pantoprazole or a matching placebo. The authors found that pantoprazole significantly reduced the risk of clinically important upper gastrointestinal bleeding compared to placebo, without affecting overall mortality.

Summary: Recent guidelines have issued weak recommendations for stress ulcer prophylaxis in critically ill patients at high risk of bleeding, particularly those with sepsis, based on moderate-quality evidence. This RCT enrolled 4,821 adult patients across 68 ICUs in 8 countries between July 9, 2019, and October 30, 2023. Patients were randomized to receive either 40 mg IV pantoprazole daily (n = 2,417) or placebo (n = 2,404). The primary efficacy outcome was the incidence of clinically important upper gastrointestinal bleeding, defined as overt bleeding with hemodynamic compromise, therapeutic intervention, or ICU readmission within 90 days of randomization. The primary safety outcome was all-cause mortality at 90 days. Secondary outcomes included ventilator-associated pneumonia, Clostridioides difficile infection, renal-replacement therapy initiation, ICU and hospital mortality, and patient-important upper gastrointestinal bleeding (defined in a prior mixed-methods study).

Clinically important upper gastrointestinal bleeding occurred in 25 of 2,385 patients (1.0%) receiving pantoprazole and 84 of 2,377 patients (3.5%) in the placebo group (hazard ratio 0.30; 95% confidence interval [CI], 0.19 to 0.47; P < 0.001; NNT 40). At 90 days, deaths were reported in 696 of 2,390 patients (29.1%) in the pantoprazole group and 734 of 2,379 patients (30.9%) in the placebo group (hazard ratio 0.94; 95% CI, 0.85 to 1.04; P = 0.25). Patient-important gastrointestinal bleeding occurred less frequently in the pantoprazole group (36 of 2,385 patients [1.5%]) compared to the placebo group (100 of 2,377 patients [4.2%]; hazard ratio 0.36; 95% CI, 0.25 to 0.53; P < 0.001). No significant differences were observed between groups in other secondary outcomes, including C. difficile infections.

This study demonstrates that in mechanically ventilated ICU patients, IV pantoprazole reduces the risk of clinically important upper gastrointestinal bleeding without impacting overall mortality. Additionally, pantoprazole did not increase the risk of ventilator-associated pneumonia or C. difficile infection compared to placebo.

The study has some limitations. First, this is not a particularly controversial topic, given that previous clinical trials have shown similar outcomes regarding stress ulcer prophylaxis. Second, approximately 50% of patients were on corticosteroids during the first two weeks of ICU admission, which could increase stress ulceration and potentially skew the results. Third, the findings are only applicable to patients receiving mechanical ventilation, limiting the generalizability of the results to other patient populations.

Bottom line: This robust RCT provides strong evidence for the clinical and patient-important benefits, as well as the safety, of stress ulcer prophylaxis with proton pump inhibitors (PPIs) in critically ill, mechanically ventilated patients.

Synopsis: This five-year follow-up study of the SECURE trial, a multicenter, randomized, non-inferiority study, compares a restrictive strategy versus usual care for patients with symptomatic cholelithiasis. After five years, no significant difference was found in pain-free rates, biliary, or surgical complications between the two groups.

Summary
The optimal treatment for uncomplicated symptomatic cholelithiasis remains debated. To investigate the potential benefit of a stepwise selective process for cholecystectomy in patients with uncomplicated cholelithiasis, the Scrutinizing (In)efficient Use of Cholecystectomy: A Randomized Trial Concerning Variation in Practice (SECURE) was conducted. The SECURE trial was a multi-centered, randomized, parallel-arm, non-inferiority study performed in 24 academic centers in the Netherlands from 2014-2017. This study compared usual care with a restrictive strategy for laparoscopic cholecystectomy among 1067 patients with biliary colic. At the one-year mark, the restrictive strategy led to a 7.7% reduction in cholecystectomy rates but did not demonstrate non-inferiority regarding pain-free status. To assess longer-term patient outcomes, the operation rate, pain, and complications were evaluated five years post-treatment through interviews.

For the five-year follow-up, the original cohort was reassessed for primary and secondary outcomes. Eligible patients were aged 18-95 years with abdominal pain and ultrasound-confirmed gallstones and had been referred to a surgical outpatient clinic for cholecystectomy discussion. Patients were randomized 1:1 to receive usual care or follow a restrictive strategy before their first clinic visit. The restrictive strategy was based on five prespecified symptomatic criteria: 1) severe pain attacks, 2) pain lasting more than 15-30 minutes, 3) pain localized to the epigastrium or right upper quadrant, 4) pain radiating to the back, and 5) a positive response to analgesics. The primary non-inferiority endpoint was the proportion of pain-free patients, assessed by the Izbicki pain score and a visual analog scale at five years. Secondary outcomes included the cholecystectomy rate, biliary complications, surgical complications, and patient satisfaction. Follow-up was conducted through structured telephone interviews, emailed questionnaires, and patient chart reviews.

At five years, all 1067 patients were contacted, with 970 (90.9%) completing the telephone survey. No significant differences were found between responders and non-responders. In the usual care group, 62.8% of patients were pain-free compared to 61.2% in the restrictive strategy group (non-inferiority p=0.18). After cholecystectomy, 63.6% of patients in the usual care group and 63% in the restrictive strategy group were pain-free (p=0.88). The restrictive strategy was associated with 357 of 529 (73.2%) cholecystectomies compared to 437 of 536 (81.5%) in the usual care group (difference: 8.3%, p=0.001). There were no observed differences between groups regarding biliary or surgical complications, nor in patient satisfaction scores.

Limitations of this study include the patient adherence rate, as 30% of patients in the restrictive arm did not adhere to the protocol, primarily due to surgeon judgment or patient preference. Another limitation was the 30% non-response bias for emailed surveys, as only 70% of participants completed the survey. Additionally, the justification for performing long-term non-inferiority testing after failure to demonstrate non-inferiority at one year may be questioned. However, the investigators justified this approach due to the modification of the pain-free definition from the initial SECURE protocol.

Bottom Line: In the five-year follow-up of patients enrolled in the SECURE trial, a restrictive strategy for managing uncomplicated cholelithiasis resulted in a significant, albeit small, reduction in operative rates compared to usual care. No increase in biliary or surgical complications was observed. However, only two-thirds of patients were pain-free after treatment, regardless of the strategy. Improved criteria for selecting patients with uncomplicated cholelithiasis for cholecystectomy are needed to enhance patient outcomes.

Synopsis: This retrospective study utilizes a large, matched cohort of patients with early-stage multinodular hepatocellular carcinoma (HCC) to assess the impact of primary treatment—liver resection (LR), percutaneous radiofrequency ablation (PRFA), or transarterial chemoembolization (TACE)—on overall survival (OS). The authors found that patients who underwent liver resection had superior 5-year overall survival rates compared to those treated with PRFA or TACE.

Summary: For patients with early-stage multinodular hepatocellular carcinoma (≤3 nodules of ≤3 cm), the 2022 Barcelona Clinic Liver Cancer (BCLC) guidelines recommend transplantation or percutaneous radiofrequency ablation (PRFA) as first-line therapies, with transarterial chemoembolization (TACE) as second-line, rather than liver resection (LR). This study evaluates the overall survival (OS) of patients with early-stage multinodular hepatocellular carcinoma (HCC) treated with LR, PRFA, or TACE.

The authors used data from the HE.RC.O.LE.S. and ITA.LI.CA databases to construct a cohort of newly diagnosed BCLC stage A multinodular HCC patients treated from 2008–2020. Patients were excluded if they underwent additional "hierarchically superior" treatments per the BCLC guidelines during the follow-up period. Statistical analysis used matching-adjusted indirect comparison (MAIC) with Cox models and Kaplan-Meier survival curves for the entire cohort and subgroup analyses. MAIC weighting incorporated patient demographics, comorbidities, and various measures of liver dysfunction.

Out of 720 patients, 296 underwent LR, 240 PRFA, and 184 TACE. The number of incompletely treated cases was lower in LR patients (10.1% with positive margins) compared to PRFA and TACE (18.3% and 49.5%, respectively, with residual HCC on imaging at 1 month). Multivariable analysis found that LR was independently associated with lower mortality compared to PRFA and TACE in the unweighted cohort. Child-Pugh class B cirrhosis was also a significant independent factor for OS. After MAIC weighting, the Kaplan-Meier OS rates for 1, 3, and 5 years were 89.11%, 70.98%, 56.44% for LR; 94.01%, 65.20%, 39.93% for PRFA, and 90.88%, 48.95%, 29.24% for TACE. In subgroup analyses, LR showed an HCC-specific survival benefit compared to PRFA (HR 1.38, p=.07) and TACE (HR 1.91, p=.006). Among patients with Child-Pugh class B cirrhosis, LR was associated with similar OS compared to PRFA (HR 1.44, p=.21), and improved OS compared to TACE (HR 2.79, p=.001).

This study concludes that liver resection was associated with improved overall survival compared to percutaneous radiofrequency ablation and transarterial chemoembolization in the management of early-stage multinodular HCC. However, there are several limitations: (1) the exclusion of patients who underwent "hierarchically superior" treatment following their initial HCC treatment, despite a multi-modal approach often being considered for many patients, (2) the 13-year study period does not account for technical improvements and changes in clinical practice over that time, and (3) the inherent association between certain risk factors, e.g., clinically relevant portal hypertension, and the chosen treatment intervention, though the authors attempted to mitigate this bias through MAIC weighting. Despite these limitations, this study uses rigorous methods to demonstrate that liver resection is a feasible and effective treatment option for BCLC stage A multinodular hepatocellular carcinoma.

Bottom Line: Liver resection for the treatment of patients with BCLC Stage A multinodular HCC is associated with overall survival outcomes that are comparable to, or better than, PRFA and TACE. Surgery may, therefore, be considered an effective alternative or addition to PRFA or TACE for patients who are not candidates for liver transplantation.

Synopsis: This was a prospective, multicenter, non-randomized single-arm study of fifty patients across sixteen centers in the US that evaluates the safety and effectiveness of the RelayPro thoracic endograft for the treatment of blunt traumatic aortic injury (BTAI). The study focused on assessing 30-day mortality, and the authors concluded that RelayPro provides incremental improvements in managing BTAI.

Summary: Given the unique challenges presented by blunt traumatic aortic injury (BTAI) patients, which include smaller aortic diameters, higher arch angulation, and younger age, this prospective study aimed to evaluate the next-generation RelayPro stent graft in treating BTAI. The primary endpoint was 30-day all-cause mortality. Results were compared to comparable IDE studies in BTAI populations, where all-cause mortality at 30 days was reported as 7.8% (4/51) in the Gore study and 8% (4/50) in the Medtronic study. Secondary endpoints included all-cause mortality, aortic-related deaths, major adverse events, technical success of stent deployment, endoleaks, erosion, migration (>10 mm), and other adverse events.

In the index operation, 56 devices were implanted, with 88% requiring the shortest length and 21% receiving the smallest proximal diameter (22 mm). The mean procedure duration was 73.5 ± 39.6 minutes, while the mean implantation duration (time from delivery system insertion to withdrawal) was 10.9 ± 6.2 minutes (90% of patients had a single device implanted). Technical success was achieved in 98% of cases, with only one patient experiencing a type Ia endoleak.

At 30 days, all-cause mortality was 2.0% (n=1, 95% CI, 0.1%-10.6%). In terms of secondary endpoints, one major adverse event occurred at 6 months involving a 26-year-old female who developed a thrombus in the stent graft, leading to paraplegia. There were three early secondary interventions and three additional interventions within one year. Three cases of mural thrombus were noted within the graft. No cases of aortic rupture, endograft infections, aortic dilation, migration, compression, twisting, extrusion/erosion, fracture, suture breaks, type Ib endoleaks, or type III endoleaks were reported at any timepoint. Additionally, no conversions to open surgery were required.

The results demonstrate that the RelayPro stent offers incremental improvements in managing BTAI, particularly with a comparatively lower 30-day mortality rate than alternative thoracic endovascular aortic repair (TEVAR) devices (Gore, Medtronic). The study highlights shorter procedural times, reduced length of stay (LOS), fewer complications, and a lower profile better suited to the younger BTAI population with smaller access diameters.

This study had several limitations. It was a single-arm, non-randomized trial, so there was no control group for reliable comparison of outcomes. The small sample size limits the statistical power and generalizability of the findings. Furthermore, the short follow-up duration precludes assessment of long-term durability. The predominantly male cohort (74%) also limits the study's applicability to female patients. Additionally, the exclusion of patients with complex aortic anatomies and certain comorbidities further restricts the generalizability. Lastly, being an industry-sponsored study raises concerns about potential bias in reporting.

Bottom Line: RelayPro offers incremental improvements in the endovascular treatment of BTAI, including a lower profile and non-bare stent (NBS) configuration. It may provide an early survival benefit, particularly for younger patients with smaller access diameters.