Introduction
Portal pressure, assessed by hepatic venous pressure gradient (HVPG) measurement, is a key factor promoting the development of liver-related complications and mortality in patients with advanced chronic liver disease (ACLD; i.e., a novel term for the spectrum of advanced liver fibrosis/cirrhosis) [
1,
2].
Since their introduction in the nineteen-eighties, non-selective beta-blockers (NSBB) are a cornerstone in the treatment of portal hypertension. During the last years, our understanding of potential benefits of early initiation of NSBB treatment as well as potential detrimental effects in patients with advanced disease has continuously evolved [
3••,
4•,
5••].
In patients with medium to large varices who have not bled (i.e., patients with high-risk varices, and, thus, a clear indication for primary prophylaxis of acute variceal bleeding [AVB] [
6,
7]), NSBB treatment decreased the 2-year risk of variceal hemorrhage from 30 to 14% (absolute risk reduction [ARD]: − 16% [− 24% to − 8%]; number needed to treat [NNT]: 6) [
8]. Moreover, NSBB reduced the risk of recurrent variceal bleeding (secondary prophylaxis) from 63% to 42% (ARD: − 21% [− 30% to − 13%]; NNT: 5). Since the NNT ranges from 5 to 6, many patients have to be treated with NSBB to prevent a single variceal bleeding. A crucial factor limiting the efficacy of NSBB is the high intersubjective variability in the reduction of portal pressure [
3••], underlining the need for reliable methods to assess the expectable benefits in the individual patient, i.e., the assessment of HVPG response.
This review summarizes (a) the current evidence for assessing HVPG response to NSBB therapy for prognostication and guiding treatment decisions in different clinical settings/stages of ACLD, (b) the clinical and procedural requirements for obtaining optimal results, and (c) the potential non-invasive markers for HVPG response.
Clinical and Procedural Requirements for HVPG Response-Guided Therapy
To begin with, a high degree of standardization is essential to accurately assess changes in HVPG to pharmacological interventions, such as NSBB, since even small changes (i.e., 1 mmHg) in HVPG may discriminate between hemodynamic responders and non-responders. Details regarding the procedure are reviewed elsewhere [
30]. Moreover, there is a comprehensive protocol for this technique published in a visual format [
31••]. The correct positioning of the balloon catheter, which should be preferred over straight catheters [
32,
33], is one of the most critical steps. Leakage in the wedged position leads to an underestimation of the wedged hepatic vein pressure, while peripheral measurements may result in an overestimation of the free hepatic vein pressure, since the catheter itself narrows the lumen, potentially inducing a hemodynamically relevant stenosis [
34,
35•]. In both situations, HVPG might be underestimated. Sedation, if used at all, should be restricted to low doses of midazolam (0.02 mg/kg body weight) [
36], since higher doses or deep analgosedation with propofol/remifentanil impacts pressure measurements [
37]. Finally, if high-quality pressure tracings are obtained, the interobserver agreement is excellent: In the subgroup of patients with CSPH included in a study by Tandon et al. [
38•], the proportion of readings differing by ≥ 10% was only 9%.
Besides procedure-related factors, several other important points have to be considered, especially when assessing the “chronic” HVPG response to NSBB: To avoid mixing the hemodynamic effects and the evolution of underlying etiology, liver disease should be stable, which is commonly not the case in alcoholic liver disease and patients undergoing etiological treatment.
Alcohol intake leads to an acute increase in portal pressure [
39]. Moreover, alcoholic hepatitis [
40] and, in particular, acute-on-chronic liver failure (ACLF) are associated with a profound increase in HVPG, which is explained by a further rise in intrahepatic resistance [
41].
In contrast, hepatitis C virus (HCV) eradication promptly ameliorates portal hypertension [
42•,
43•] in the majority of patients, most likely due to a decrease in hepatic inflammation [
44•]. Hepatic inflammation increases the vascular tone, which is commonly referred to as the dynamic component of intrahepatic resistance [
45]. This initial rapid decline might be followed by a further decrease in HVPG on the long-term [
46,
47•], potentially indicative of the regression of liver fibrosis [
44•,
48•] (i.e., the structural component of increased intrahepatic resistance). Similarly, HBV suppression by nucleotide analogue treatment for 12 months led to a substantial decrease in HVPG [
49•], which might be followed by further decreases due to liver fibrosis regression [
50]. Owing to limited long-term data and considerable interindividual discrepancies, it is hard to determine whether and at what time point HVPG reaches a stable value after successful antiviral therapy [
51•].
Moreover, cofactors impacting portal hypertension are increasingly recognized. For instance, a 16-week lifestyle intervention comprising diet and physical exercise has been shown to lead to significant decreases in HVPG in obese patients with portal hypertension, particularly those achieving ≥ 10% of weight loss [
52•].
Therefore, the assessment of “acute,” or possibly, early “chronic” HVPG response to NSBB therapy may be preferred, if HVPG response-guided NSBB therapy is the main objective and if there is uncertainty about whether the underlying etiology and/or cofactors are stable.
Benefits of HVPG Response-Guided NSBB Therapy
Several studies provide evidence supporting the use of HVPG-guided NSBB treatment; however, only four studies were randomized controlled trials (RCT) [
26,
53••,
54,
55••]. The main findings and information on effect size are summarized in Table
2.
Table 2
Studies evaluating the benefits of hepatic venous pressure gradient (HVPG) response-guided non-selective beta-blocker (NSBB) therapy
Bureau et al. | n = 34; n = 21 HVPG-non-responders | Propranolol (fixed dose of 160 mg q.a.d.); “Chronic” HVPG response (median: 4 days) | Propranolol + ISMN | Primary prophylaxis (n = 14; all high-risk) and secondary prophylaxis (n = 20); HVPG ≥ 12 mmHg | 33% of hemodynamic non-responders to propranolol responded to propranolol + ISMN; improvement of overall hemodynamic response rate from 38 to 59%; AVB: decreased if HVPG response |
González et al. | n = 50; n = 42 with information on HVPG response; n = 10 10–19% decrease, “partial responders”; n = 8 < 10% decrease, “non-responders” | Nadolol (titrated according to HR) + ISMN; “Chronic” HVPG response (15 days) | “Partial responders”: add-on EVL; “Non-responders”: TIPS | Secondary prophylaxis | Patients with alcoholic cirrhosis more likely to achieve HVPG response; 12% of patients bled before HVPG response assessment; Bleeding: comparable between groups (limited sample size), numerically “non-responders”—TIPS < “responders” (nadolol + ISMN) < “partial responders” (nadolol + ISMN + EVL) |
Villanueva et al. Aliment Pharmacol Ther 2009 [ 54] | n = 59 randomized to HVPG-guided therapy (n = 30) vs. nadolol + EVL | Nadolol (titrated by HR) + ISMN; 1st “chronic” HVPG response (2–4 weeks); 2nd “chronic” HVPG response (1–2 months after 1st) | Nadolol + prazosin | Secondary prophylaxis | Nadolol + prazosin decreased HVPG in hemodynamic non-responders to nadolol + ISMN; Bleeding: decreased if HVPG response in HVPG-guided therapy arm but not in nadolol + EVL arm, increased in the HVPG-guided arm |
González et al. | n = 53; n = 48 with information on HVPG response; n = 24 HVPG non-responders | Nadolol (titrated according to HR) + ISMN; “Chronic” HVPG response (mean: 13.4 days) | Add-on EVL | Secondary prophylaxis | 9% of patients bled before HVPG response assessment; Bleeding: 9%/12% in HVPG responders (nadolol + ISMN) vs. 4%/4% in HVPG non-responders (nadolol + ISMN + EVL) at 1/2 years; Mortality: decreased if HVPG response |
Reiberger et al. | n = 104; n = 94 with information on HVPG response; n = 67 HVPG non-responders | Propranolol (titrated according to HR and SAP); 1st “chronic” HVPG response (4 weeks); 2nd “chronic” HVPG response (1–2 months after 1st) | Carvedilol (6.25-50 mg/day); EVL monotherapy if non-responder to carvedilol | Primary prophylaxis (small: 39% or large: 61% varices, red wale marks: 31%); HVPG ≥ 12 mmHg | Carvedilol decreased HVPG in hemodynamic non-responders to propranolol; 57% of patients non-responsive/intolerant to propranolol responded to carvedilol; Improvement of overall hemodynamic response rate from 36 to 72%; AVB: 11% (propranolol)/8% (carvedilol) in HVPG responders vs. 24% in non-responders (EVL); Ascites: decreased Hepatic decompensation: trend towards decrease Mortality: decreased |
Sauerbruch et al. Gastroenterology 2015 [ 26] | n = 185 randomized to HVPG-guided therapy (n = 95) vs. TIPS; n = 76 with information on HVPG response; n = 44 HVPG non-responders | Propranolol (titrated according to HR) + ISMN; “Chronic” HVPG response (14 days) | EVL monotherapy | Secondary prophylaxis | 5% of patients bled before HVPG response assessment; Bleeding: 26% in nadolol + ISMN/EVL monotherapy arm vs. 7% in TIPS arm at 2 years, trend towards decrease in HVPG responders vs. non-responders; Mortality: comparable |
Kirnake et al. J Clin Experiment Hepatol 2016 [ 25] | n = 69 n = 76 with information on “acute” HVPG response; n = 23 “acute” HVPG non-responders | “Acute” HVPG response to p.o. carvedilol (25 mg); Carvedilol (12.5 mg/day); “Chronic” HVPG response (median: 6 months) | EVL monotherapy | Primary (n = 25; small: 22% or large: 78% varices, red wale marks: 29%) and secondary prophylaxis (n = 44); HVPG ≥ 12 mmHg | Bleeding: trend towards decrease if “acute” HVPG response (vs. EVL monotherapy); Ascites: Comparable; HE: comparable; Mortality: comparable; Maintenance of hemodynamic response: 92%, 70% in intention-to-treat analysis |
Villanueva et al. | n = 169 randomized to HVPG-guided therapy (n = 84) vs. nadolol plus ISMN + EVL; n = 70 HVPG non-responders | “Acute” HVPG response to i.v. propranolol (0.15 mg/kg); Nadolol (titrated according to HR); 1st “chronic” HVPG response (2–4 weeks); 2nd “chronic” HVPG response (2–4 weeks after 1st) | Nadolol + ISMN; Nadolol + prazosin If non-response to nadolol + ISMN; EVL until HVPG response | Secondary prophylaxis | Further decompensation: HVPG-guided: 52% vs. control: 72%; lower in patients with “acute” or “chronic” HVPG response to propranolol or nadolol ± ISMN; Bleeding: HVPG-guided: 19% vs. control: 31% (independent association); Ascites: comparable; HE: trend towards decrease if HVPG-guided; Mortality: HVPG-guided: 29% vs. control: 43% (independent association); lower in patients with “acute” or “chronic” HVPG response to propranolol or nadolol ± ISMN |
Villanueva et al. Lancet 2019 | n = 201 randomized to HVPG-guided therapy vs. placebo | “Acute” HVPG response to i.v. propranolol (0.15 mg/kg); | Carvedilol | Pre-primary prophylaxis in patients with HVPG ≥ 10 mmHg or primary prophylaxis | Hepatic decompensation or death: trend towards decrease; Hepatic decompensation or liver-related death: decreased; 9% in HVPG-guided vs. 20% in placebo arm |
Villanueva and co-workers conducted the only two trials providing direct evidence for a clinical benefit of a HVPG-guided approach. First, they randomized
n = 59 patients to HVPG-guided therapy (nadolol plus ISMN; the latter being changed to prazosin in patients with hemodynamic non-response) or nadolol plus endoscopic variceal ligation (EVL) [
54]. Prazosin was able to induce hemodynamic response in non-responders to nadolol plus ISMN. Further, HVPG response was linked to a decrease in bleeding. However, this study has been underpowered to directly detect a potential clinically meaningful benefit of the HVPG-guided treatment approach. In their second study [
53••], 169 patients in secondary prophylaxis were randomized to either HVPG-guided therapy or nadolol plus ISMN plus EVL. In the HVPG-guided arm, ISMN was replaced by prazosin in the case of HVPG non-response to nadolol plus ISMN. Moreover, EVL was performed until HVPG response was achieved. Importantly, this study demonstrated that HVPG-guided therapy might improve mortality. Another RCT allocated patients in secondary prophylaxis to HVPG-guided therapy or TIPS [
26]. Using propranolol plus ISMN (“chronic” HVPG responders) or EVL monotherapy (“chronic” HVPG non-responders), the bleeding rate in the HVPG-guided therapy arm was only 26% at 2 years, however, still higher than that in the TIPS arm (7% in 2 years). Importantly, this did not result in a difference in mortality. Of note, nearly half of the patients included in this study were Child-Turcotte-Pugh stage A. Nevertheless, the relatively low bleeding/mortality rates could also be interpreted as indirect evidence for the effectiveness of the HVPG-guided approach. In the fourth RCT, which was restricted to patients with CSPH in the setting of pre-primary prophylaxis (no or small varices without red wale marks), treatment with propranolol (HVPG decrease ≥ 10% to i.v. propranolol) or carvedilol (hemodynamic non-responders to i.v. propranolol) decreased (vs. placebo) the risks of hepatic decompensation or liver-related death, mostly by decreasing the incidence of ascites [
55••]. Importantly, the statistical analysis of this study also followed the concept of competing risks. Next to the use of HVPG-guided therapy, improvements in patient selection, such as the exclusion of patients without CSPH and inclusion of patients with low-risk varices, may have contributed to the positive result of this trial.
Furthermore, HVPG-guided therapy has been applied in a series of clinical trials without randomized treatment assignment. Importantly, there is considerable heterogeneity in the studied patient populations (i.e., primary or secondary prophylaxis or a combination of both), the initial treatments (propranolol [
56,
57] or nadolol monotherapy [
53••] as well as propranolol [
26] or nadolol plus ISMN [
27,
28,
54]), the time points of the first assessment of “chronic” HVPG response (ranging from 4 days [
56] to 4 weeks [
57]), and the alternative treatment strategies applied in HVPG non-responders (carvedilol [
57], propranolol [
26,
56] or nadolol plus ISMN [
53••], nadolol plus prazosin [
53••,
54], [add-on] EVL [
26‐
28,
53••,
57], or even TIPS [
28]). Importantly, neither ISMN nor prazosin are considered as first-line treatments for portal hypertension [
6,
7,
58•,
59] and there are concerns about the safety of these potent vasodilators, which substantially limits the clinical applicability of HVPG-guided treatment strategies using these drugs. In contrast, carvedilol, a NSBB with additional anti-α1-adrenergic activity [
3••,
5••], is a first-line option for primary prophylaxis of variceal bleeding [
6,
7,
58•,
59]. Using carvedilol in “chronic” hemodynamic non-responders to propranolol doubled the overall rate of HVPG response (from 36 to 72%) and, thus, decreased the incidence of AVB, development/worsening of ascites, and mortality in HVPG responders, as compared to EVL monotherapy [
57]. Still, carvedilol is not recommended for secondary prophylaxis by Baveno VI consensus [
6] and the American Association for the Study of Liver Diseases (AASLD) guidelines [
58•]. This is due to the absence of adequately designed trials comparing carvedilol to NSBB plus EVL, the current standard of care in this setting. Moreover, carvedilol should be avoided in patients with severe ascites [
3••,
5••,
7,
58•,
59] restricting its use to patients with less severe hepatic dysfunction.
Limitations of HVPG Response-Guided Therapy
HVPG response is sensitive in predicting (recurrent) AVB but, in general, lacks specificity [
60]. This is particularly problematic in patients on primary (or even pre-primary) prophylaxis, as the incidence of (further) hepatic decompensation is considerably lower, when compared to secondary prophylaxis. In these settings, “chronic” HVPG non-response has a particularly low positive predictive value (PPV). For instance, in a meta-analysis by Villanueva et al. [
61], the PPV for variceal bleeding was only 32% in primary prophylaxis, while the negative predictive value (NPV) was as high as 94%. However, the positive likelihood ratio, which is not affected by the prevalence of the condition, was still 2.01, which is comparable to secondary prophylaxis (2.1) [
60]. Importantly, the PPV in primary prophylaxis has improved with the Baveno VI consensus [
6], which, as mentioned previously, adopted the more specific 10% cut-off for both “acute” and “chronic” assessments (e.g., PPV increase from 24 to about 42% [
20]). Still, the PPV remains suboptimal, indicating that, at least in primary prophylaxis, it is not justified to subject HVPG non-responders to more aggressive and eventually harmful treatment strategies, such as TIPS [
26,
28].
Moreover, NSBB seems to exert additional, so-called non-hemodynamic effects, which might not be reflected by HVPG response. NSBB treatment decreases markers of intestinal permeability and bacterial translocation, independently of hemodynamic response [
62]. This finding provides a convincing pathophysiologic mechanism for the reduced risk of SBP development observed in NSBB-treated patients, even in the case of HVPG non-response [
63,
64]. However, other studies suggested that HVPG response further decreases the risk of SBP (vs. hemodynamic non-response), which could be explained by its effect on the occurrence/worsening of ascites [
16,
19,
20,
23]. Only recently, another potential non-hemodynamic effect has been proposed: Mookerje et al. [
65] investigated the impact of NSBB treatment (mostly propranolol at a low median dose of 40 mg/day) on survival in patients who went on to develop ACLF in the CANONIC study. Interestingly, ACLF was less severe and showed a higher probability of improvement in the NSBB group, which also translated into a mortality benefit. Since patients in the NSBB group had a lower white cell count, the authors hypothesized that NSBB treatment modulates the systemic inflammatory response driving ACLF. However, causality has yet to be demonstrated, especially since NSBB treatment had already been stopped prior to inclusion or discontinued after inclusion in the vast majority of patients.
Although it is clear that NSBB treatment is particularly beneficial in HVPG responders, these potential non-hemodynamic effects question the discontinuation of NSBB treatment in HVPG non-responders without clinically significant side effects, which has been performed in some of the studies investigating HVPG-guided therapy approaches. This might be particularly problematic in secondary prophylaxis, in which NSBB are the key component of combination treatment to reduce mortality [
66•,
67].
HVPG measurement is generally safe and well-tolerated [
68,
69]; nevertheless, its clinical use is limited by its invasiveness and its availability mostly restricted to academic centers. Thus, the development of non-invasive methods for monitoring NSBB efficacy should be promoted to facilitate personalized medicine in the field of portal hypertension [
70••,
71].
Non-Invasive Markers for HVPG Response
Initial ultrasound (US)-based attempts, such as Doppler-based assessments, did not sufficiently reflect (changes in) HVPG, and, thus, cannot substitute HVPG measurement [
70••]. More recently, sophisticated contrast-enhanced US-based methods have shown encouraging results and are currently investigated in clinical trials.
Liver stiffness assessed by US-based elastography methods, such as transient elastography (TE), might be useful for monitoring the evolution of portal hypertension after etiological therapy in patients without evidence of CSPH prior to the removal of the primary etiological factor [
42•,
72]. However, liver stiffness measured by US-based elastography methods is of limited value for assessing HVPG response due to its weak correlation with HVPG in patients with HVPG values ≥ 10 to ≥ 12 mmHg [
73], i.e., patients which are considered as candidates for response-guided NSBB therapy. Of note, there is evidence suggesting that changes in liver stiffness under/following portal pressure-lowering treatments (i.e., NSBB [
71] and transjugular intrahepatic portosystemic shunt [
74]) hold prognostic information even beyond their relation to portal pressure; however, the underlying pathophysiological mechanisms are yet to be fully elucidated.
Spleen stiffness assessed by US-based elastography showed very promising results with a numerically (TE [
75]) or even statistically significantly (point shear-wave elastography (pSWE)/virtual touch quantification (VTQ) [
76]) stronger (vs. liver stiffness) correlation with HVPG. This might be explained by the fact that spleen stiffness more directly reflects portal hypertension, as it is mostly a measure of portal venous congestion, while liver stiffness is also strongly influenced by liver fibrosis [
70••] and other factors, including arterial blood pressure [
71,
77]. However, the superiority of spleen stiffness (vs. liver stiffness) has not been confirmed by another study using both TE and two-dimensional shear-wave elastography (2D-SWE)/supersonic imaging (SSI) [
78]. Moreover, similar to liver stiffness, the strength of the correlation between spleen stiffness and HVPG decreases with increasing severity of portal hypertension. In a recent study using 2D-SWE/SSI [
79], for instance, Spearman’s
ρ in patients with HVPG values ≥ 12 mmHg was 0.464, indicating a positive correlation of only moderate strength. In contrast, a substantially stronger correlation was observed in the overall study population (
ρ = 0.665).
Despite the limited strength of correlation between liver/spleen stiffness and HVPG in patients with HVPG values ≥ 12 mmHg, three studies evaluated the performance of changes in liver/spleen stiffness for monitoring the dynamics of HVPG during NSBB treatment. The first study by Choi et al. [
80] observed a strong correlation between changes in HVPG and liver stiffness measured by 2D-SWE/SSI and also reported an AUROC of 0.794 for diagnosing HVPG response. However, the significance of the findings of this study is limited by the small number (
n = 23) of patients undergoing a follow-up HVPG measurement on NSBB treatment. In a second study by Kim et al. [
81••], a model based on the change in spleen stiffness (baseline vs. carvedilol; median dose: 25 mg/day), as assessed by 106 patients with high-risk varices undergoing paired pSWE/VTQ and HVPG measurements, had an AUROC of 0.803. In the independent validation cohort (
n = 63; median dose: 12.5 mg/day), the AUROC was even numerically higher (0.848). Accordingly, spleen stiffness measurement shows some promise as a non-invasive surrogate of HVPG response.
However, even in highly standardized study settings, the diagnostic performance of US-based elastography methods for HVPG response is suboptimal. Importantly, these methods measure portal venous congestion (spleen stiffness; the result of increased intrahepatic resistance and portal venous blood flow) and liver fibrosis (liver stiffness; static component of increased intrahepatic resistance) but do not specifically assess hyperdynamic circulation (i.e., increased cardiac output and splanchnic vasodilatation) [
70••]. However, these features of hyperdynamic circulation are the main therapeutic target of conventional NSBB [
3••,
5••]. Accordingly, magnetic resonance imaging (MRI)-based blood flow measurements may be considered a more direct, and, thus, highly promising approach for monitoring hemodynamic response to NSBB. A MRI-derived model of HVPG combining spin-echo echo planar imaging T
1 relaxation time and splenic artery velocity showed a strong positive correlation with HVPG (Spearman’s
ρ = 0.9), which was maintained in the subgroup of patients with CSPH (Spearman’s
ρ = 0.85) [
82•]. Nevertheless, the ability of MRI-derived parameters to monitor NSBB-induced changes in HVPG has yet to be investigated.
Finally, non-imaging-based surrogates of HVPG response have been developed. Ras homolog family member A and Rho-kinase 2 transcription in the mucosa of the antrum [
83] as well as serum levels of a phosphatidylcholine and a free fatty acid (AUROC: 0.801) [
84•] have been shown to predict HVPG response to propranolol.
In conclusion, the performance of these novel, non-invasive approaches for predicting HVPG response warrants further evaluation, since non-invasive surrogates with high diagnostic accuracy might pave the way for NSBB treatment individualization outside of centers with sufficient resources and expertise for HVPG-guided therapy [
6,
7].
Conclusions
HVPG response reduces the risks of AVB, the development of hepatic decompensation due to ascites and its complications, and, finally, even mortality. Clinical benefits of HVPG response have been established throughout a broad spectrum of ACLD severity, ranging from clinical stage 1 (compensated without varices) with CSPH to stage 5 (further hepatic decompensation). Accordingly, the assessment of HVPG response provides important prognostic information. In hemodynamic non-responders to NSBB, their effectiveness is suboptimal, although there is increasing evidence for non-hemodynamic effects of NSBB therapy. Accordingly, it is unclear whether NSBB therapy should be discontinued in HVPG non-responders with good treatment tolerance. HVPG-guided NSBB therapy facilitates personalized medicine in the field of portal hypertension. Of note, the “chronic” HVPG response is strongly influenced by dynamics of the underlying etiology, and, thus, may not always mirror the effect of a pharmaceutical intervention. This might have implications for HVPG response-guided NSBB therapy. Patients with non-response to conventional NSBB might benefit from carvedilol, which is more potent in decreasing HVPG. Furthermore, hemodynamic non-responders may also benefit from (the addition of) other HVPG-lowering drugs which are in clinical development, and, depending on the clinical setting, complimentary or alternative treatment strategies. Nevertheless, the clinical use of HVPG measurement is limited by its invasiveness and its availability is mostly restricted to academic centers. Accordingly, the development of non-invasive surrogates of HVPG response is of utmost importance.
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