February 2021

Synopsis: Atrial fibrillation is a very common sequalae of mitral valve disease, resulting from the elevated left atrial pressures and left atrial distention that accompany a dysfunctional mitral valve. Current guidelines for long-term anticoagulation in patients with atrial fibrillation and a prior mitral valve replacement recommend vitamin K antagonists, namely warfarin, rather than direct oral anti-coagulants (DOACs). However, these long-standing recommendations are based on limited evidence from prior randomized studies. Recent landmark trials that demonstrated the non-inferiority of DOACs to warfarin in the general atrial fibrillation population either included a very limited subset of patients with bioprosthetic heart valves or excluded these patients altogether. Therefore, the RIVER (Rivaroxaban for Valvular Heart Disease and Atrial Fibrillation) trial was conducted to assess the safety and efficacy of rivaroxaban compared with warfarin in patients with atrial fibrillation and a bioprosthetic mitral valve.

RIVER was an multi-center, open-labeled, randomized trial. It included patients >18 years old with a history of permanent, persistent or paroxysmal atrial fibrillation or atrial flutter and a bioprosthetic mitral valve who were receiving oral anticoagulation for thromboembolism prophylaxis. Eligible patients were randomly assigned in a 1:1 ratio to receive either 20mg rivaroxaban daily (or a renally adjusted dose) or warfarin dose targeting an INR of 2.0 to 3.0, measured at least every 4 weeks. The primary study outcome was a composite of death, major cardiovascular events (including stroke, TIA, valve thrombosis, other VTE, and heart failure hospitalization), and major bleeding events. Secondary outcome was a composite of death from cardiovascular or thromboembolic cause. Data were analyzed per an intention-to-treat protocol, and patients were followed for at least 12 months. 

A total of 1005 patients were enrolled at 49 sites in Brazil from 2016 to 2019—500 were randomized to the rivaroxaban group and 505 to the warfarin group. Median time from mitral valve replacement to randomization was between 1 and 5 years. The mean time until a primary-outcome event was 347.5 days in the rivaroxaban group and 340.1 days in the warfarin group (restricted mean survival time difference, 7.4 days; 95% confidence interval [CI], −1.4 to 16.3; P<0.001 for noninferiority and P = 0.10 for superiority). At 12 months, the composite secondary outcome of death from cardiovascular or thromboembolic events occurred in 17 patients (3.4%) in the rivaroxaban group and in 26 (5.1%) in the warfarin group (hazard ratio, 0.65; 95% CI, 0.35 to 1.20). The incidence of total stroke was 0.6% in the rivaroxaban group and 2.4% in the warfarin group (hazard ratio, 0.25; 95% CI, 0.07 to 0.88). Major bleeding occurred in 7 patients (1.4%) in the rivaroxaban group and in 13 (2.6%) in the warfarin group (hazard ratio, 0.54; 95% CI, 0.21 to 1.35). The frequency of other serious adverse events was similar in the two groups. 

Bottom line: In patients with atrial fibrillation and a bioprosthetic mitral valve, rivaroxaban was shown to be noninferior to warfarin with respect to risk of death, major cardiovascular events, or major bleeding at 12 months. The total incidence of stroke was lower in the rivaroxaban group (0.6% vs 2.4%) as was the incidence of major safety events, though overall such events were rare in both groups. Since rivaroxaban does not require close monitoring of a therapeutic level and has a more consistent anticoagulant effect than warfarin, it represents an attractive alternative for this patient population based on the results of this trial. 

Synopsis: Colorectal cancer has two well-described categories of genetic defects that drive genome instability and lead to cancer: chromosomal instability and microsatellite instability. The microsatellite instability group makes up the minority of colorectal cancers at about 15%. Although these two genetic subtypes are known to have core differences such as in gene expression, current treatment guidelines for metastatic colorectal cancer include relatively uniform chemotherapy regimens such as FOLFOX or FOLFIRI alone or in combination with EGFR or VEGF inhibitors. There is evidence to suggest that tumors high in microsatellite instability are less responsive to these conventional chemotherapy regimens. In patients with microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) metastatic colorectal cancer refractory to standard chemotherapy combinations, programmed death 1 (PD-1) inhibitors such as pembrolizumab and nivolumab have shown good responses. In this study, the KEYNOTE-177 trial aims to evaluate the PD-1 inhibitor pembrolizumab as first line therapy on metastatic colorectal cancer with high microsatellite instability.

In this Phase 3 open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer were randomly assigned to receive pembrolizumab or chemotherapy as first line therapy. Chemotherapy regimens included mFOLFOX alone, with bevacizumab or cetuximab, and FOLFIRI alone, with bevacizumab or cetuximab. Primary outcomes were progression-free survival and overall survival. 153 patients were randomized into the pembrolizumab group and 154 patients into the chemotherapy group. 

Median follow-up time was 32.4 months. Progression-free survival was significantly higher with pembrolizumab at 16.5 months than with chemotherapy 8.2 months. Estimated percentages of alive and progression-free patients at 12 and 24 months were 55.3% and 48.3%, respectively, in the pembrolizumab group and 37.3% and 18.6%, respectively, in the chemotherapy group. Estimated restricted mean survival after 24 months of follow-up was 13.7 months in the pembrolizumab group compared with 10.8 months in the chemotherapy group. Among most subgroups (fully active performance-status, patients ≤ 70 years old in age, either gender, recurrent metachronous stage, BRAF wild and V600E), progression-free survival was generally higher with pembrolizumab than chemotherapy. Progression-free survival was not significantly different in subgroups of patients aged > 70 years old, with lower performance status, located in Asia, with newly diagnosed, L sided, or KRAS/NRAS mutated tumors. 

Overall, patients experienced significantly longer progression-free survival with PD-1 blockade (pembrolizumab) than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer along with fewer high grade adverse events. This suggests PD-1 blockade as a reasonable first-line treatment in patients with microsatellite high metastatic colorectal cancer. 

Next steps would include identification of which patients were more likely to experience complete/partial response versus disease progression with pembrolizumab to further delineate which patients are best suited for pembrolizumab as first line therapy. Care must be taken to identify patients with progressive disease while on pembrolizumab as first line therapy. Some proposed markers of progression during PD-1 blockade therapy include low tumor mutation burden, Janus kinase mutations, loss of beta-2-microglobulin. In this particular study, tumors with hot-spot mutations in RAS (KRAS and NRAS) genes did not show progression-free survival benefit with pembrolizumab, but conclusions are limited due to small sample size and missing information. As this study and overall survival analysis are ongoing, other studies are also working to evaluate anti-PD-1/anti-PD-L1 immunotherapy in conjunction with standard chemotherapy or other immunotherapies such as cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitors. 

Synopsis: Obesity is a worldwide epidemic with increasing prevalence. In patients with end-stage organ dysfunction, obesity and obesity-related complications impact access to transplant, technical consideration and posttransplant outcomes. A survey of American Society of Transplant Surgeon (ASTS) members found the average BMI cutoff for transplant candidates as the following:

This article reviews the current literature on the impact of obesity on transplant candidates, transplant recipients, and interventions that combine weight-loss surgery and transplant. Below is a quick-hits summary for kidney and liver transplant. 

Kidney Transplant:

• Waitlisted patient with obesity have lower rates of transplant and higher likelihood of organ offer bypass
• With respect to BMI, graft and recipient survival has a U-shaped distribution, with patients with lower BMI (≤20 or ≥26 kg/m²) associated with worse outcomes
  • Obesity has been associated with increased biopsy-proven rejection and delayed graft function, consistent with the notion that obesity encompasses and inflammatory state
• Recipients with a BMI > 30 have a 4x increase in SSI and 3x increase in hernias
• Small single institution studies (n=20) showed patients with pre-transplant lap sleeve gastrectomy (LSG) have lower rates of DGF (5% vs 20%) and renal dysfunction-related readmissions (10% vs 27.5%) than similarly matched BMI patients without weight loss surgery (P < .05 each)

Liver Transplant:

• Nonalcoholic fatty liver disease (NAFLD) is the second most common indication for listing and third most common indication for receiving a liver transplant in the US.
• Surgical complications, such as wound infections, dehiscence and biliary complications are increased in patients with obesity (some studies report 4-6 fold higher complications)
• LSG has advantages over RYGB because of: (1) the technical ease of the procedure and (2) preservation of the GI tract continuity, in case of future requirements for a Roux-limb as part of an LT or endoscopically accessing the biliary tract
• A number of studies have shown favorable outcomes when LSG is combined with transplant, either pre-transplant, simultaneous, or post-transplant. There is no consensus or data on the preferred timing of LSG relative to liver transplant.