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Foundational Trials

CONFIRM

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Publication

  • Title: Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome
  • Acronym: CONFIRM
  • Year: 2021
  • Journal published in: The New England Journal of Medicine
  • Citation: Wong F, Pappas SC, Curry MP, et al. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. N Engl J Med. 2021;384(9):818-828.

Context & Rationale

  • Background
    • Type 1 hepatorenal syndrome (HRS-1) represents rapidly progressive renal dysfunction in advanced cirrhosis, with very high short-term mortality and limited disease-modifying options beyond liver transplantation.
    • Vasoconstrictor therapy combined with albumin had longstanding biological plausibility (splanchnic vasodilatation, reduced effective arterial volume) and was used in many settings, but robust confirmatory evidence with a clinically meaningful endpoint and contemporary trial conduct was needed.
    • Earlier studies and varied endpoints (biochemistry-only reversal vs harder outcomes) left uncertainty about the balance between renal benefit, transplant bridging, and clinically important harms (particularly respiratory complications) in an advanced, fragile population.
  • Research Question/Hypothesis
    • In adults with cirrhosis, ascites, and HRS-1, does terlipressin (added to albumin) increase the rate of verified reversal of HRS compared with placebo (with albumin), without unacceptable harm?
  • Why This Matters
    • Renal recovery can reduce the need for renal-replacement therapy (RRT), support candidacy for transplantation, and potentially improve peri-transplant outcomes in a group with severe multi-organ dysfunction.
    • Because adverse events (especially respiratory failure) could plausibly offset renal benefits, a high-quality, blinded, multicentre efficacy-and-safety dataset was essential to inform practice and guideline recommendations.

Design & Methods

  • Research Question: Whether terlipressin plus albumin improves verified reversal of HRS-1 versus placebo plus albumin in adults with cirrhosis and ascites meeting HRS-1 criteria.
  • Study Type: Phase 3, randomised, multicentre, double-blind, placebo-controlled trial (sites in the United States and Canada).
  • Population:
    • Adults with cirrhosis and ascites with HRS-1 (serum creatinine ≥2.25 mg/dL with a trajectory consistent with doubling within 2 weeks), evaluated after diuretic withdrawal and an albumin challenge.
    • Key exclusions included severe intrinsic renal disease, serum creatinine >7 mg/dL, shock, sepsis/uncontrolled infection or inadequate antibiotic duration, and recent large-volume paracentesis ≥4 L within 2 days (per protocol details).1
    • Baseline illness severity was high (mean MELD ~33; mean Child–Pugh ~10; baseline serum creatinine 3.5 ± 1.0 mg/dL in both groups).
  • Intervention:
    • Terlipressin 1 mg intravenously every 6 hours.
    • Protocolised dose escalation to 2 mg every 6 hours at day 4 if serum creatinine had not decreased by ≥30% from baseline; treatment for up to 14 days or until HRS reversal or discontinuation criteria were met.1
    • Concomitant intravenous albumin was recommended/used as standard care (in 165/199 [83%] in the terlipressin group; mean total dose 199.4 ± 146.8 g over median 5.0 days).
  • Comparison:
    • Placebo intravenously every 6 hours with matching escalation rules to preserve blinding.
    • Concomitant intravenous albumin used in 92/101 (91%); mean total dose 239.5 ± 183.6 g over median 5.5 days.
    • RRT and other supportive care delivered per local practice.
  • Blinding: Double-blind (participants, clinicians, and investigators); matching placebo with protocolised titration to maintain concealment.
  • Statistics: Power targeted detection of an increase in verified HRS reversal from 13.28% (placebo) to 28.36% (terlipressin) with 90% power at a two-sided 5% significance level; planned total sample size 300 with interim monitoring (O’Brien–Fleming-type boundaries per protocol); primary analysis in the intention-to-treat population using stratified testing; multiple imputation used for selected endpoints where prespecified.1
  • Follow-Up Period: Treatment up to 14 days; key renal endpoints assessed through day 14 and day 30; RRT, transplantation, and mortality tracked through day 90.

Key Results

This trial was not stopped early. A total of 300 patients were randomised (199 to terlipressin; 101 to placebo).

Outcome Terlipressin + albumin Placebo + albumin Effect p value / 95% CI Notes
Primary: verified reversal of HRS 63/199 (32%) 17/101 (17%) Not reported P=0.006 Composite included serum creatinine ≤1.5 mg/dL twice (≥2 h apart) by day 14, no RRT for ≥10 days, and survival for ≥10 days.
Secondary: HRS reversal 77/199 (39%) 18/101 (18%) Not reported P<0.001 Renal endpoint without the full “verification” components.
Secondary: HRS reversal with no RRT through day 30 69/199 (35%) 18/101 (18%) Not reported P=0.001 Clinically relevant to avoidance of dialysis in advanced cirrhosis.
Secondary: received RRT by day 90 58/199 (29%) 39/101 (39%) Not reported Not reported Table 3 (time-point proportions reported; no P value provided).
Secondary: died by day 90 101/199 (51%) 45/101 (45%) Difference 6 percentage points 95% CI −6 to 18 No survival advantage despite higher HRS reversal.
Adverse event: respiratory failure 28/200 (14%) 5/99 (5%) Not reported Not reported Safety population denominators; higher respiratory toxicity signal.2
Adverse events leading to death (respiratory disorders) by day 90 22/199 (11%) 2/101 (2%) Not reported Not reported Likely contributor to the numerical mortality difference; also highlighted in the Supplementary Appendix.2
  • Verified reversal of HRS occurred in 63/199 (32%) with terlipressin versus 17/101 (17%) with placebo (P=0.006).
  • HRS reversal with no RRT through day 30 occurred in 69/199 (35%) with terlipressin versus 18/101 (18%) with placebo (P=0.001), with fewer patients receiving RRT by day 90 (29% vs 39%).
  • There was no improvement in 90-day survival (51% vs 45%), alongside a higher respiratory failure signal (14% vs 5%) and more deaths attributed to respiratory disorders (11% vs 2%).2

Internal Validity

  • Randomisation and allocation: Central randomisation with stratification and matching placebo supported allocation concealment and reduced selection bias.
  • Blinding and detection bias: Double-blinding with objective renal laboratory criteria for primary endpoint reduced detection bias; however, clinically overt adverse events (e.g., ischaemia, respiratory decompensation) could plausibly threaten blinding at bedside.
  • Dropout/exclusions: Intention-to-treat efficacy denominators were 199 vs 101 (total 300); safety denominators differed slightly (200 vs 99) because of treatment exposure/misdosing.
  • Protocol adherence: Albumin was administered in 165/199 (83%) vs 92/101 (91%), with mean total albumin exposure 199.4 ± 146.8 g (median 5.0 days) vs 239.5 ± 183.6 g (median 5.5 days).
  • Separation of the variable of interest: Terlipressin exposure was protocolised (1 mg IV q6h with escalation to 2 mg q6h at day 4 if creatinine response was inadequate), while placebo mimicked identical escalation rules.1
  • Baseline characteristics: Groups were broadly comparable in key severity markers (serum creatinine 3.5 ± 1.0 vs 3.5 ± 1.1 mg/dL; MELD 32.7 ± 6.6 vs 33.1 ± 6.2; mean arterial pressure 78.7 ± 12.1 vs 77.5 ± 9.4; SIRS 42% vs 48%).
  • Timing: Screening and randomisation occurred within a constrained window after meeting criteria (including albumin challenge), supporting early treatment relative to HRS-1 recognition; applicability to earlier HRS-AKI phenotypes remains uncertain.
  • Dose optimisation: Bolus q6h dosing with protocolised up-titration may not be the only viable strategy (continuous infusion strategies exist in the literature), and the trial design did not test alternative dosing approaches.
  • Outcome assessment: Primary endpoint was a composite integrating renal recovery plus short-term survival without RRT, increasing clinical meaningfulness but also potentially diluting interpretability versus single hard endpoints.
  • Statistical rigour: Prespecified power, stratified analysis, and the use of multiple imputation for selected endpoints were consistent with a regulatory-quality design; interpretation still hinges on composite endpoint components and competing events.

Conclusion on Internal Validity: Overall, internal validity appears moderate-to-strong, supported by double-blinding, objective endpoint definitions, and prespecified statistical methods, but tempered by composite endpoint complexity, imputation, and a clinically important harm signal that could influence adherence and co-interventions.

External Validity

  • Population representativeness: Participants had very advanced liver disease (mean MELD ~33; Child–Pugh ~10) and severe renal dysfunction (baseline creatinine ~3.5 mg/dL), aligning with sick inpatient populations but representing a late-stage phenotype of HRS compared with modern earlier HRS-AKI definitions.
  • Key exclusions: Exclusion of shock and uncontrolled infection limits direct translation to mixed ICU populations where sepsis, vasopressors, and multi-organ failure are common.
  • Health-system context: Conducted in US/Canadian centres with access to transplantation and RRT; applicability may be limited where these resources are constrained.
  • Comparators: Placebo-controlled design informs efficacy versus supportive care, but does not directly answer comparative effectiveness against ICU norepinephrine-based strategies used in many critical care environments.

Conclusion on External Validity: Findings are most generalisable to hospitalised patients with advanced cirrhosis meeting severe HRS-1 criteria in high-resource settings; generalisability is more limited for earlier HRS-AKI, septic/shocked ICU patients, and settings where close respiratory monitoring or transplant access is reduced.

Strengths & Limitations

  • Strengths:
    • Randomised, double-blind, placebo-controlled design with protocolised dosing and escalation.
    • Multicentre North American conduct and a predefined clinically anchored primary endpoint (renal recovery plus short-term survival without RRT).
    • Clear signal for improved renal endpoints (verified reversal and HRS reversal) with consistent direction across related measures.
  • Limitations:
    • No improvement in 90-day mortality (51% vs 45%) despite higher reversal rates, challenging assumptions that renal reversal translates into survival benefit.
    • Clinically important respiratory harm signal (respiratory failure 14% vs 5%; respiratory-disorder deaths 11% vs 2%), raising patient-selection and monitoring concerns.2
    • Use of a severe HRS-1 definition (high creatinine threshold and rapid progression) limits applicability to earlier HRS-AKI presentations.
    • Placebo comparator does not resolve comparative effectiveness versus norepinephrine-based ICU strategies.

Interpretation & Why It Matters

  • Renal efficacy is real
    CONFIRM demonstrated higher verified reversal (32% vs 17%) and HRS reversal (39% vs 18%), supporting terlipressin as an effective vasoconstrictor strategy for severe HRS-1 in appropriately selected patients.
  • Hard outcomes remain challenging
    Despite reduced use of RRT at multiple time points (e.g., 29% vs 39% by day 90), there was no survival signal at 90 days (51% vs 45%), reinforcing that advanced cirrhosis mortality is driven by multi-organ complications beyond renal vasodysregulation.
  • Safety constraints shape bedside use
    Respiratory failure and respiratory-related deaths were more frequent with terlipressin, implying that fluid status, albumin strategy, baseline respiratory reserve, and close monitoring are not optional adjuncts but core to safe implementation.2

Controversies & Subsequent Evidence

  • Benefit–harm tension (renal recovery vs respiratory toxicity): The accompanying editorial emphasised that terlipressin’s renal benefits must be interpreted alongside a meaningful respiratory harm signal, raising questions about patient selection, albumin/volume management, and how to operationalise safety monitoring in real-world practice.3
  • “Reversal without survival” debate: Correspondence highlighted that improved renal endpoints did not translate into increased 90-day survival or transplantation rates, and pressed for clarity on co-interventions (including albumin strategy and beta-blocker exposure) that might modify both benefit and harm; the investigators’ reply contextualised the endpoint choice and reiterated the complexity of mortality drivers in advanced cirrhosis.4
  • Post-CONFIRM synthesis: Subsequent meta-analytic work continues to support improved HRS reversal with vasoconstrictors, but survival effects remain inconsistent and safety (particularly respiratory complications) is emphasised as a key determinant of net clinical value.89
  • Guideline incorporation: Major post-2021 guidance and consensus documents addressing decompensated cirrhosis/HRS-AKI incorporate vasoconstrictor-plus-albumin approaches and explicitly acknowledge the need to balance renal efficacy with adverse-event risk, reflecting the CONFIRM-era evidence base.567
  • Risk stratification for pulmonary complications: Emerging observational work has explored pulmonary congestion/respiratory reserve as prognostic modifiers in HRS-AKI, aligning mechanistically with the respiratory adverse-event concerns raised by CONFIRM.10

Summary

  • CONFIRM was a multicentre, double-blind, randomised, placebo-controlled phase 3 trial of terlipressin plus albumin for HRS-1 (199 vs 101; total 300).
  • Verified reversal of HRS occurred in 32% with terlipressin versus 17% with placebo (P=0.006).
  • Terlipressin increased related renal endpoints, including HRS reversal (39% vs 18%; P<0.001) and HRS reversal with no RRT through day 30 (35% vs 18%; P=0.001).
  • There was no improvement in 90-day mortality (51% vs 45%; difference 6 percentage points, 95% CI −6 to 18).
  • Respiratory safety signals were clinically prominent (respiratory failure 14% vs 5%; respiratory-disorder deaths 11% vs 2%), strongly shaping real-world risk–benefit assessment.2

Further Reading

Other Trials

Systematic Review & Meta Analysis

Observational Studies

Guidelines

Notes

  • Several seminal pre-CONFIRM RCTs (e.g., earlier terlipressin placebo-controlled trials; ICU norepinephrine comparators; alternative dosing strategies) are highly relevant but could not be included here with DOI-linked references because DOIs were not retrievable from the provided source materials in this environment.

Overall Takeaway

CONFIRM established that terlipressin plus albumin improves clinically anchored renal recovery endpoints in severe HRS-1, including verified reversal and reduced RRT use, but it did not improve 90-day survival and carried a clear respiratory safety signal. Its landmark status rests on simultaneously clarifying efficacy and forcing the field to confront implementation-limiting toxicity, making patient selection and respiratory/volume monitoring central to modern practice.

Overall Summary

  • Higher verified HRS reversal with terlipressin (32% vs 17%; P=0.006).
  • Reduced RRT use at follow-up timepoints (e.g., day 90: 29% vs 39%).
  • No 90-day survival benefit (51% vs 45%; 95% CI for difference −6 to 18).
  • Respiratory harm signal (respiratory failure 14% vs 5%; respiratory-disorder deaths 11% vs 2%).

Bibliography