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What Matters for Liver Transplant in Severe ACLF? (CME/CE)

Action Points

  • Investigators found that waitlist mortality peaked for patients with acute-on-chronic liver failure ACLF category 3 and a MELD score <25. And for this group, liver transplantation increases the odds of survival, especially if performed within 30 days of placement on the waitlist.
  • Intubated patients had the strongest association with reduced post-transplant survival.

CME Author: Zeena Nackerdien

Study Authors: Vinay Sundaram, Rajiv Jalan, et al.

Target Audience and Goal Statement:

Gastroenterologists and surgeons

The goals were to compare liver waitlist mortality or removal according to model for end-stage liver disease (MELD) score versus acute-on-chronic liver failure (ACLF) category and to study factors associated with reduced odds of survival for 1 year after liver transplantation.

Questions Addressed:

There is a growing demand for preoperative predictive criteria to determine which patients with ACLF will benefit most from transplantation. ACLF is a syndrome that has been described as occurring in cirrhosis and that is characterized by acute liver decompensation (ALD), organ failure(s), and high short-term mortality. Although systemic inflammation is a hallmark of ACLF, considerable ambiguity and heterogeneity exist regarding the disease definition, thus complicating diagnosis and allocation of appropriate patients that would derive the most benefit from a liver transplant.

Therefore, the investigators sought to address the following questions:

  • What is the waitlist mortality for different grades of ACLF?
  • Is there a correlation between the aforementioned variable and increasing MELD scores?
  • What are the characteristics of recipients with ACLF-3 (failure of ≥3 organs) that are associated with greater post-transplant survival?

Synopsis and Perspective:

From 2005 to 2016, Vinay Sundaram, MD, MSc of Cedars-Sinai Medical Center in Los Angeles, and colleagues, identified 100,594 patients on the waitlist and 50,552 liver transplant recipients from the United Network for Organ Sharing (UNOS) Database. Patients with ACLF were identified using the European Association for the Study of the Liver-chronic liver failure (EASL-CLIF) Consortium definition. According to a review by Hernaez and colleagues, the “EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study is the most comprehensive registry to understand outcomes on hospitalized patients with cirrhosis.”

Based on the number of organ failures (liver, renal, coagulation, cerebral, respiratory, and circulatory), ACLF can be stratified into ACLF-1 (one renal failure or one non-renal organ failure if associated to renal dysfunction and/or cerebral dysfunction), ACLF-2 (2 organ failures), and ACLF-3.

A serum sodium (Na) level parameter was also taken into account to assess the contribution of significant hyponatremia to the MELD score (MELD-Na).

In the current study, the number of eligible patients with ACLF-3, ACLF-2, ACLF-1, and no ACLF were 6,381 (12.6%), 7,513 (14.9%), 7,375 (14.6%), and 29,283 (57.9%), respectively. Other demographic criteria of patients with ACLF-3 included a low proportion of hepatitis-C-virus-induced cirrhosis, a high percentage of patients with ALD (34.9%) and a high mean MELD-Na score (37.4). Patients with ACLF-3 also received younger donor organs (mean age 38.7), many of whom had died from head trauma (38%). Additional descriptors included fewer organs received from diabetic donors (8.8%), more organs received from donors dying of head trauma (38.0%), and the smallest percentage of organs received from high-risk donors with a donor risk index of 1.7 or more (22.9%).

Predefined 1-year waitlist mortality, 28-day, and 90-day survival outcomes were compared among patients with different ACLF grades at listing across a range of MELD score (estimation of the relative disease severity and likely survival of patients awaiting liver transplantation) categories (i.e., <25, 25-29, 30-34, and ≥35). The primary outcome was patient survival at 1 year.

One-year survival after transplant was lowest among patients with ACLF-3 (81.8%) compared with other groups (88.1%-91.9%, P<0.001). Those who survived for 1 year had a lower prevalence of mechanical ventilation use (33.1% vs 49.0%, P<0.001) and circulatory failure (49.8% vs 60.6%, P<0.001).

The following variables were found to be independently associated with survival at 1 year after transplantation: Mechanical ventilation at liver transplantation (HR 1.49, 95% CI 1.22-1.84), donor risk index above 1.7 (HR 1.22, 95% CI 1.09-1.35), and liver transplantation within 30 days of listing (HR 0.89, 95% CI 0.81-0.98).

The investigators concluded that certain patients with ACLF-3 have poor outcomes irrespective of their MELD-Na scores. Compared to other ACLF groups, patients with ACLF-3 were more likely to be removed from the waitlist or die, irrespective of their MELD-Na scores. This was particularly true for patients with ACLF-3 and MELD-Na score <25 (43.8% at 28 days). For this group, liver transplantation increases the odds of survival, especially if performed within 30 days of placement on the waitlist. The risk of death is increased with the use of mechanical ventilation or marginal organs.

Because this was a retrospective analysis, there is the possibility of misclassification with respect to diagnosis of patients with ACLF and the presence of organ failure. It is also possible that bacterial infection rates could have been overlooked during the investigation. Additionally, mechanical ventilation was used as a metric for respiratory failure; however, it is possible that this method could have been employed for another reason (e.g., for airway protection due to a patient’s altered mental status). On the other hand, patients with significant lung injury may not have been intubated at the time of liver transplantation.

Source Reference: Gastroenterology online, Dec. 18, 2018; DOI: 10.1053/j.gastro.2018.12.007

Study Highlights: Explanation of Findings

A liver transplant is often the only way to treat patients with ACLF. But the role of extrahepatic organ failures in prioritizing allocation for transplants is still a subject of ongoing investigation. Moreover, there is a scarcity of data regarding actual outcomes of liver transplant recipients.

Patients with ACLF-3 had the poorest outcomes (highest mortality and removal from the waiting list) in this study irrespective of MELD score category. The investigators noted that “nearly 44% of patients with ACLF-3 with a MELD score <25 would die or be removed within 28 days of listing."

Caution should be exercised with intubated patients, as mechanical ventilation at liver transplantation had the strongest link to lower post-transplant survival.

It is worth noting that the investigators assessed other predictive risk scores beyond the MELD score and organ failure (i.e., Karnofsky’s Performance Status Scale (KPS) and the futility risk score). Neither score was associated with 1-year post-transplant mortality. Possible reasons for these results include the fact that the futility risk score was validated for five-year patient survival, whereas the authors evaluated shorter-term outcomes. In addition, the proportion of patients with ACLF-3 and a high KPS score was very low (2.0%). More studies are therefore needed to determine whether frailty, as measured by KPS or other assessments, can provide extra information regarding post-liver transplantation outcomes for patients with ACLF-3.

Overall, the findings supported the investigators’ initial hypothesis that some patients with ACLF-3 would be at high risk for premature death irrespective of MELD or MELD-Na score. Thus, they would be candidates for timely intervention. Evidence from the literature supported this notion. For instance, a recent registry analysis showed a 1-year post transplant survival >80% for patients with ACLF-3. Similar trends were observed in prior retrospective analyses of small numbers of patients with ACLF-3 (i.e., a 1-year post-transplant survival of more than 80%).

Sundaram told MedPage Today. “Many of these patients will have significantly improved survival if they undergo liver transplant, particularly if performed early after listing,” he added, calling for additional research into the prioritization of patients with severe ACLF on waiting lists.

Diana Swift wrote the original story for MedPage Today.

  • Reviewed by
    Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner
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