🪣

TPE for ACLF — Therapeutic Plasma Exchange in Acute-on-Chronic Liver Failure

1. Publication

Title: Therapeutic plasma exchange improves short-term survival in patients with acute-on-chronic liver failure: A randomized controlled trial
Acronym: None assigned
Year & Journal: Hepatology, epublished March 30, 2026
Citation: Swaroop S, Biswas S, Aggarwal A, et al. Therapeutic plasma exchange improves short-term survival in patients with acute-on-chronic liver failure: A randomized controlled trial. Hepatology. 2026. doi:10.1097/HEP.0000000000001755

2. Context & Rationale

Background: ACLF is associated with organ failures and high short-term mortality (ACLF-3 carries 68-89% 28-day mortality without transplant). Prior propensity-matched analyses by the same group suggested TPE improved short-term but not long-term survival; a definitive RCT was needed.

Research Question/Hypothesis: In adults with ACLF (EASL CLIF-C grades 1-3b), does standard medical therapy (SMT) plus therapeutic plasma exchange (TPE) reduce 28-day all-cause mortality compared with SMT alone?

Why This Matters: ACLF has few effective therapeutic options beyond liver transplantation, which is not universally accessible; an effective bridging or standalone therapy would address a major unmet need in a syndrome with high short-term mortality.

3. Design & Methods

Study Type: Single-center, open-label RCT
Setting & Centers: All India Institute of Medical Sciences, New Delhi, India; conducted February 2022 – March 2025
Population:

Inclusion: Adults 18-60y with ACLF (EASL CLIF-C grades 1-3b); baseline: 64.5% Grade 2, median 2 organ failures, alcohol the most common etiology (67.5%)
Exclusions: Not detailed in available trial text

Intervention: SMT plus 5 sessions of TPE (n=97)
Comparator: SMT alone (n=97)
Randomization: 1:1, 194 patients
Blinding: Open-label
Statistical Power & Follow-Up: Primary outcome: all-cause mortality at 28 days. Secondary: 90-day mortality, prognostic score changes, organ failure resolution, infections, adverse events. Registered CTRI/2022/01/039094.

4. Key Results

194 randomized (97/97); 72 (74.2%) completed ≥3 TPE sessions, 56 (57.7%) completed all 5.

Outcome	SMT + TPE	SMT Alone	Effect Size	95% CI	p-value	Notes
28-day all-cause mortality (primary)	43/97 (44.3%)	62/97 (63.9%)	Absolute risk reduction 19.6 pp	5.8 to 33.3	0.006	Significant benefit with TPE
90-day mortality	Similar between groups	Similar between groups	Not reported	Not reported	Not significant	Benefit did not persist to 90 days
Ammonia reduction	Greater with TPE	—	Not reported	Not reported	—	—
Hepatic/coagulation failure resolution by day 7	Higher rates with TPE	—	Not reported	Not reported	—	—
TPE discontinuation (leading cause)	18/41 (43.9%) due to hemodynamic instability	—	—	—	—	Reflects real procedural tolerability challenges

Subgroup analysis: No significant heterogeneity across ACLF grade or etiology. Most common TPE complications: dyselectrolytemia and shivering.

5. Internal Validity Assessment

Randomization & Allocation: 1:1 randomization; specific concealment mechanics not detailed in available trial text.
Protocol Adherence & Separation: Meaningful incomplete dosing: only 57.7% completed all 5 sessions, with hemodynamic instability the leading cause of discontinuation (43.9% of discontinuations) — a real-world tolerability signal for a procedure-intensive intervention in a critically ill population.
Blinding & Detection Bias: Open-label; mortality is an objective endpoint, limiting detection bias despite lack of blinding.
Missing Data & Sensitivity Analyses: Baseline characteristics reported as comparable between groups.
Overall Internal Validity Conclusion: Moderate — single-center design and open-label conduct are limitations, but the large, statistically significant, and biologically plausible 28-day mortality benefit (with mechanistic support from ammonia/organ-failure-resolution secondary outcomes) is compelling; the lack of 90-day durability and substantial incomplete dosing are important caveats.

6. External Validity Assessment

Population Representativeness: Younger ACLF population (18-60y) than typical decompensated cirrhosis cohorts; alcohol-predominant etiology (67.5%) reflects the study's Indian setting — may differ from Western ACLF populations with more viral or metabolic etiologies.
Practice Context: Requires apheresis/TPE capability and expertise, plus tolerance for a hemodynamically demanding procedure in critically ill patients — resource and expertise requirements limit universal applicability.
Overall External Validity Conclusion: Moderate — single-center, single-country trial in a specific (younger, alcohol-predominant) ACLF population; generalizability to broader/older/different-etiology ACLF populations and to centers without TPE expertise requires caution.

7. Strengths & Limitations

Strengths:

Adequately powered RCT (194 patients) building on the same group's prior propensity-matched observational signal
Statistically significant, clinically substantial 28-day mortality benefit (19.6 percentage point absolute risk reduction)
Mechanistic plausibility supported by ammonia reduction and faster organ-failure resolution
No significant subgroup heterogeneity by ACLF grade or etiology

Limitations:

Single-center, open-label design
Only 57.7% completed all 5 planned TPE sessions — a substantial real-world adherence/tolerability limitation
90-day mortality benefit not sustained
Younger, alcohol-predominant population may limit generalizability

8. Interpretation & Practice Impact

Clinical Implications: TPE added to SMT significantly improves 28-day survival in ACLF, representing (per contemporaneous EASL Congress commentary on a related trial, APACHE) part of a broader, encouraging shift toward positive plasma-exchange-based studies in this historically difficult-to-treat field.
Mechanistic Coherence: Greater ammonia reduction and faster resolution of hepatic/coagulation organ failure by day 7 support a biologically plausible mechanism (removal of harmful circulating mediators, replenishment of functional proteins) underlying the observed short-term survival benefit.
Systems-Level Takeaway: The substantial rate of session discontinuation due to hemodynamic instability (43.9% of discontinuations) means TPE protocols for ACLF need careful hemodynamic monitoring and support infrastructure; TPE should be viewed as a potential short-term bridging/stabilization strategy rather than a durable long-term solution given the lack of 90-day benefit.

9. Controversies & Subsequent Evidence

Editorial Commentary: This trial is discussed alongside the separately reported APACHE trial (Fernández et al., presented EASL Congress 2026), which found plasma exchange with 5% albumin significantly increased 90-day overall survival in ACLF — described by its lead investigator as "the first positive study demonstrating an improvement in survival in ACLF" with an expectation it will "change clinical practice." The apparent discrepancy in 90-day durability between this trial (no 90-day benefit) and APACHE (90-day benefit) may reflect differences in patient selection, plasma exchange protocol/replacement fluid, or population (India vs. Spain/Europe) — an important area for careful comparative reading rather than assuming the two trials are interchangeable.
Guideline Integration: Together with APACHE and a 2025 updated meta-analysis (Kumar et al., Liver International) showing TPE survival benefit at 1, 3 months, and up to 1 year, this trial contributes to a genuinely shifting evidence landscape for TPE in ACLF, moving the field from "many negative studies" toward accumulating positive short-to-medium-term survival evidence.

10. Summary & Executive Takeaway

Summary: This single-center Indian RCT randomized 194 ACLF patients (grades 1-3b) to SMT plus 5 sessions of TPE or SMT alone. TPE significantly reduced 28-day mortality (44.3% vs 63.9%, absolute risk reduction 19.6 percentage points, P=0.006), with faster organ-failure resolution and greater ammonia reduction, though the survival benefit was not sustained at 90 days.

Overall Takeaway: TPE added to standard medical therapy significantly improves short-term (28-day) survival in ACLF through a biologically plausible mechanism, though real-world procedural tolerability (only 57.7% completing all sessions) and lack of 90-day durability temper enthusiasm — positioning TPE as a promising short-term stabilization/bridging strategy in a field that has historically seen predominantly negative trials, alongside the contemporaneously reported, similarly positive APACHE trial.

11. Bibliography

Fernández J, et al. Plasma exchange with albumin 5% significantly increases 90-day overall survival in acute-on-chronic liver failure: topline results of the APACHE trial. EASL Congress 2026, Abstract LBO-002.
Kumar SE, Sithamparapillai K, Choudhury AK, et al. Therapeutic Plasma Exchange in Patients With Acute-On-Chronic Liver Failure Improves Survival—An Updated Meta-Analysis. Liver Int. 2025;45(5):e70018.
Swaroop S, Arora U, Biswas S, et al. Therapeutic plasma-exchange improves short-term, but not long-term, outcomes in ACLF: propensity score-matched analysis. J Clin Apher. 2023;38(4):376-389.