Beyond the Four Pillars: A Risk-Targeted Framework for Vericiguat—A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 

Congratulations to the authors for their interesting manuscript; despite its undeniable quality I have some comments about it:

Although the authors describe the manuscript as a narrative review supported by a focused PubMed/MEDLINE search, the search methodology is not sufficiently transparent or reproducible. The review should include the full search strategy, including search strings, MeSH terms, inclusion and exclusion criteria, language restrictions, article-selection process, and the number of records screened and ultimately included. In addition, the manuscript should better clarify its added value, since vericiguat in worsening HFrEF has already been discussed in several recent reviews, meta-analyses, and guideline documents. A dedicated section comparing current guideline recommendations, regulatory indications, pivotal trial data, and the authors’ proposed risk-targeted adjunctive framework would help define the novelty of the review. The interpretation of VICTOR also requires greater caution. Although the manuscript correctly reports that the primary endpoint was neutral, some statements imply an expanded role for vericiguat in stable ambulatory HFrEF. Mortality findings from VICTOR should instead be framed as secondary and hypothesis-generating. Also, the clinical benefit should be quantified more consistently by reporting absolute event rates, hazard ratios, confidence intervals, number needed to treat when available, and whether the observed effect was primarily driven by reduced HF hospitalization rather than cardiovascular mortality.Also authors are encouraged to include the latest evidences regarding the HF drugs effects (doi: 10.1159/000541393.) to their discussion in order to make it more complete and up to date.

 

Author Response

Dear Editor,

We would like to sincerely thank the Reviewers for their thoughtful, constructive, and insightful comments. We have carefully revised the manuscript accordingly, which we believe has significantly improved its clarity, clinical relevance, and overall quality. Below, we provide a detailed point-by-point response.

 

 

Response to Reviewer 1

We thank the Reviewer for the assessment of our manuscript and valuable suggestions.

 

Comment

Congratulations to the authors for their interesting manuscript; despite its undeniable quality I have some comments about it:

Although the authors describe the manuscript as a narrative review supported by a focused PubMed/MEDLINE search, the search methodology is not sufficiently transparent or reproducible. The review should include the full search strategy, including search strings, MeSH terms, inclusion and exclusion criteria, language restrictions, article-selection process, and the number of records screened and ultimately included.

 

Response

We sincerely thank the Reviewer for this valuable suggestion. We agree that greater transparency regarding the literature search methodology improves the scientific rigor of a narrative review. Accordingly, the Methods section has been substantially expanded. We now provide a detailed description of the literature search strategy, including the database searched (PubMed/MEDLINE), the search period, representative search strings and MeSH terms, language restrictions, eligibility criteria, and the process used for study selection. We also specify the approximate numbers of records identified, screened, and ultimately included. We emphasize that, consistent with the narrative design of this review, the literature was selected to provide a comprehensive and clinically relevant overview rather than according to a formal systematic review framework.

 

Comment

In addition, the manuscript should better clarify its added value, since vericiguat in worsening HFrEF has already been discussed in several recent reviews, meta-analyses, and guideline documents. A dedicated section comparing current guideline recommendations, regulatory indications, pivotal trial data, and the authors’ proposed risk-targeted adjunctive framework would help define the novelty of the review.

 

Response
We thank the Reviewer for this valuable suggestion. We agree that the added value of the present review should be stated more explicitly. Accordingly, we have substantially revised the manuscript to better distinguish our review from previously published narrative reviews, meta-analyses, and guideline documents.

Specifically, we have:

• added a dedicated section entitled "Positioning Vericiguat in Contemporary Heart Failure Management: From Guidelines to a Risk-Targeted Framework", which directly compares current guideline recommendations, regulatory indications, pivotal randomized trials, and our proposed clinical framework;
• introduced a new summary table comparing regulatory indications, ESC guideline recommendations, pivotal trial evidence (SOCRATES-REDUCED, VICTORIA, VICTOR), and the proposed risk-targeted positioning of vericiguat;
• expanded the Discussion to explicitly emphasize that the novelty of this review lies not in repeating available evidence, but in integrating the recently published VICTOR program with current guidelines and proposing a practical risk-oriented strategy for identifying patients who may derive the greatest benefit from vericiguat as an adjunct to optimized GDMT.

We believe these additions substantially strengthen the manuscript and clarify its originality.

 

 

Comment

The interpretation of VICTOR also requires greater caution. Although the manuscript correctly reports that the primary endpoint was neutral, some statements imply an expanded role for vericiguat in stable ambulatory HFrEF. Mortality findings from VICTOR should instead be framed as secondary and hypothesis-generating. Also, the clinical benefit should be quantified more consistently by reporting absolute event rates, hazard ratios, confidence intervals, number needed to treat when available, and whether the observed effect was primarily driven by reduced HF hospitalization rather than cardiovascular mortality.Also authors are encouraged to include the latest evidences regarding the HF drugs effects (doi: 10.1159/000541393.) to their discussion in order to make it more complete and up to date.

 

Response:
We thank the Reviewer for these important comments. We have revised the manuscript accordingly. Specifically:

• we have adopted a more cautious interpretation of the VICTOR trial throughout the manuscript, consistently emphasizing that the primary endpoint was neutral and that the mortality findings represent secondary, hypothesis-generating analyses;
• statements implying an expanded clinical indication for vericiguat in stable ambulatory HFrEF have been modified to better reflect the available evidence;
• we have supplemented the description of the pivotal trials with quantitative efficacy measures, including absolute event rates, hazard ratios, confidence intervals, and clarification that the benefit observed in VICTORIA was primarily driven by a reduction in HF hospitalizations rather than cardiovascular mortality;
• the Discussion has been revised to better contextualize the VICTOR findings within the current evidence base;
• we have expanded the Discussion by incorporating recent comparative evidence on contemporary heart failure pharmacotherapy, including the study suggested by the Reviewer (Cardiorenal Medicine 2024; doi:10.1159/000541393)

Reviewer 2 Report

Comments and Suggestions for Authors

This narrative review addresses a clinically important topic but suffers from several issues that must be addressed.

• Both figures are labeled "Figure 1"
• There are two sections both numbered 4.5:
• Duplicate Section 5 Numbering
• Line 297 reads: "comparison with ARANI or SGLT2 inhibitors"; this should be ARNI (angiotensin receptor–neprilysin inhibitor).
• The Discussion contains no dedicated limitations paragraph.

Limitations include

This is a narrative (not systematic) review, susceptibility to selection bias in evidence synthesis

Most evidence derives from industry-sponsored trials (VICTORIA, VICTOR)

No head-to-head trials comparing vericiguat to other add-on therapies

Patient selection criteria for optimal benefit remain incompletely defined

Real-world (registry) data for vericiguat are lacking

Long-term outcomes beyond the trial follow-up windows are unknown

 

• Missing Guideline Context. The manuscript never explicitly references the current guideline recommendations for vericiguat:

 

• The manuscript is entirely trial-based. Brief acknowledgment that real-world registry data for vericiguat remain sparse (compared to, e.g., SGLT2 inhibitors which have extensive post-trial registry evidence) would be appropriate.

 

 

• Lines 349–355 list open questions but appear mid-Discussion without a header. Consider adding a brief "Unresolved Questions and Future Directions" subheading here (could be Section 5.2 or a paragraph within Discussion), covering:

 

Optimal biomarker-driven patient selection

Role in HFmrEF

Integration with phenotype-driven digital care models

Sequencing relative to finerenone and other add-ons

 

• several language editing is required.

 

• The section on HFmrEF (heart failure with mildly reduced ejection fraction) is introduced receives only one brief in-text mention (line 198). Given the growing clinical interest in HFmrEF, this warrants at least one dedicated sentence on vericiguat's evidence gap in this phenotype.

 

• Cost effectiveness deserves intext discussion

 

• Table 2 (Clinical checklist for vericiguat initiation and monitoring) is excellent and practically valuable. Consider adding:

 

An explicit contraindications row (symptomatic hypotension, SBP <90 mmHg, eGFR <15 mL/min/1.73m²)

A drug interactions row (especially combined with nitrates)

• Lines 337–348 introduce AI-supported remote monitoring and GDMT optimization models. While forward-looking, this digression feels loosely connected to the vericiguat narrative. Either: (a) tighten to 1–2 sentences directly explaining how digital tools could identify the optimal vericiguat candidate, or (b) move it to the "Future Directions" subsection recommended above.

Comments on the Quality of English Language

Minor editing is required

Author Response

Dear Editor,

We would like to sincerely thank the Reviewers for their thoughtful, constructive, and insightful comments. We have carefully revised the manuscript accordingly, which we believe has significantly improved its clarity, clinical relevance, and overall quality. Below, we provide a detailed point-by-point response.

 

 

Response to Reviewer 2

We thank the Reviewer for the assessment of our manuscript and valuable suggestions.

 

 

Comment:

This narrative review addresses a clinically important topic but suffers from several issues that must be addressed.

 

• Both figures are labeled "Figure 1"

 

Response

We thank the Reviewer for identifying this oversight. The figure numbering has been corrected. The mechanistic illustration is now labeled as Figure 1, whereas the schematic illustrating the proposed clinical positioning of vericiguat is now labeled as Figure 2.

 

Comment:

• There are two sections both numbered 4.5

 

Response

We thank the Reviewer for pointing out this formatting error. The section numbering has been corrected throughout the manuscript. The practical considerations section has been renumbered, and all subsequent sections have been updated accordingly.

 

Comment:

• Duplicate Section 5 Numbering

 

Response

We appreciate the Reviewer’s careful reading. The duplicated section numbering has been corrected, and the Conclusions section is now appropriately numbered.

 

Comment:

• Line 297 reads: "comparison with ARANI or SGLT2 inhibitors"; this should be ARNI (angiotensin receptor–neprilysin inhibitor).

 

Response

We thank the Reviewer for identifying this typographical error. "ARANI" has been corrected to "ARNI" throughout the manuscript.

 

Comment:

• The Discussion contains no dedicated limitations paragraph.

 

Response:

We thank the Reviewer for this helpful suggestion. We agree that explicitly acknowledging the limitations of the review improves its transparency and scientific rigor. Accordingly, we have added a dedicated "Limitations" paragraph at the end of the Discussion section. This paragraph clarifies that the present work is a narrative review rather than a systematic review, acknowledges the absence of formal quality assessment and risk-of-bias evaluation, recognizes the potential for selection bias in the literature included, emphasizes the need for cautious interpretation of recent findings from the VICTOR program given the neutral primary endpoint and hypothesis-generating nature of the secondary analyses, and states that the proposed risk-targeted framework represents the authors' interpretation of the currently available evidence rather than a modification of existing guideline recommendations.

 

Comment:
Limitations include: This is a narrative (not systematic) review, susceptibility to selection bias in evidence synthesis. Most evidence derives from industry-sponsored trials (VICTORIA, VICTOR).

 

Response:
We thank the Reviewer for this valuable suggestion. We have expanded the Limitations section accordingly. In addition to explicitly acknowledging the narrative nature of the review and the potential for selection bias, we now also state that much of the currently available evidence for vericiguat is derived from large industry-sponsored randomized clinical trials (particularly VICTORIA and VICTOR). We further note that, although these studies were rigorously conducted and independently peer-reviewed, the predominance of industry-sponsored evidence should be taken into account when interpreting the current evidence base.

 

Comment: No head-to-head trials comparing vericiguat to other add-on therapies; patient selection criteria for optimal benefit remain incompletely defined; real-world (registry) data for vericiguat are lacking; long-term outcomes beyond the trial follow-up windows are unknown.

 

Response: We thank the Reviewer for these valuable observations. We fully agree that these issues represent important limitations of the current evidence base rather than shortcomings of the present review. Accordingly, we have revised the Discussion by adding a dedicated paragraph highlighting the remaining evidence gaps, including: (1) the absence of direct head-to-head randomized comparisons between vericiguat and other adjunctive heart failure therapies, (2) the need for better phenotypic characterization of patients most likely to benefit from treatment, (3) the limited availability of contemporary real-world registry data, and (4) the lack of long-term outcome data beyond the follow-up duration of existing randomized trials. In addition, these points have been incorporated into the Limitations section to provide a more balanced interpretation of the available evidence and to identify priorities for future research.

 

Comment: Missing Guideline Context. The manuscript never explicitly references the current guideline recommendations for vericiguat.

 

Response: We thank the Reviewer for this important suggestion. We fully agree that the role of vericiguat should be interpreted within the context of contemporary heart failure guidelines. Accordingly, we substantially revised the manuscript by adding a dedicated section entitled "Positioning Vericiguat in Contemporary Heart Failure Management: From Guidelines to a Risk-Targeted Framework" (Section 4.7). In this section, we explicitly summarize current international guideline recommendations and regulatory indications for vericiguat, discuss how these recommendations are supported by the pivotal VICTORIA trial, and clarify that the more recent VICTOR findings should not be interpreted as expanding the current indication. We also compare guideline recommendations, regulatory positioning, pivotal clinical evidence, and our proposed risk-targeted framework in a new summary table (Table 3). We believe these additions substantially improve the clinical context and clearly define both the established role of vericiguat and the conceptual contribution of the present review.

 

Comment: The manuscript is entirely trial-based. Brief acknowledgment that real-world registry data for vericiguat remain sparse (compared to, e.g., SGLT2 inhibitors which have extensive post-trial registry evidence) would be appropriate.

 

Response: We thank the Reviewer for this valuable observation. We agree that the currently available evidence for vericiguat is derived predominantly from randomized clinical trials, whereas real-world evidence remains comparatively limited. Accordingly, we have revised the Discussion by adding a dedicated paragraph acknowledging the relative scarcity of contemporary registry and observational data compared with therapies such as SGLT2 inhibitors. We also emphasize that prospective real-world studies and registries will be essential to better define patient selection, implementation, long-term safety, adherence, and effectiveness of vericiguat in routine clinical practice.

 

Comment: Lines 349–355 list open questions but appear mid-Discussion without a header. Consider adding a brief "Unresolved Questions and Future Directions" subheading here (could be Section 5.2 or a paragraph within Discussion), covering:

 

Optimal biomarker-driven patient selection

Role in HFmrEF

Integration with phenotype-driven digital care models

Sequencing relative to finerenone and other add-ons

 

Response: We thank the Reviewer for this constructive suggestion. We agree that the discussion of future research priorities benefits from a clearer structure. Accordingly, we introduced a new subsection entitled "5.2. Unresolved Questions and Future Directions", which consolidates the previously dispersed discussion on remaining evidence gaps. This subsection now explicitly addresses unresolved issues regarding biomarker-guided patient selection, the potential role of vericiguat in HFmrEF, integration into phenotype-driven and AI-supported heart failure care models, the limited availability of real-world evidence, and the optimal sequencing of vericiguat relative to other adjunctive therapies, including finerenone.

 

Comment: Several language editing is required.

 

Response: We thank the Reviewer for this observation. The manuscript has undergone comprehensive language editing to improve grammar, style, clarity, consistency, and overall readability. We also carefully revised terminology throughout the manuscript to ensure consistency with current heart failure literature and guideline terminology.

 

Comment: The section on HFmrEF (heart failure with mildly reduced ejection fraction) receives only one brief in-text mention. Given the growing clinical interest in HFmrEF, this warrants at least one dedicated sentence on vericiguat's evidence gap in this phenotype.

 

Response: We thank the Reviewer for this valuable suggestion. We agree that the evidence gap regarding HFmrEF deserves more explicit discussion. Accordingly, we expanded the section on efficacy across the spectrum of ejection fraction by adding a dedicated sentence emphasizing that the current uncertainty primarily reflects the absence of randomized clinical trials specifically enrolling patients with HFmrEF and highlighting the need for future studies to determine whether selected HFmrEF phenotypes may benefit from vericiguat therapy.

 

Comment: Cost effectiveness deserves in-text discussion.

 

Response: Thank you for this valuable suggestion. We agree that the economic implications of vericiguat are clinically relevant. We have therefore added a dedicated paragraph discussing the available cost-effectiveness evidence, including analyses based on the VICTORIA trial and a US Medicare perspective. This addition better contextualizes vericiguat not only from a clinical but also from a health-economic perspective.

 

 Comment: Table 2 (Clinical checklist for vericiguat initiation and monitoring) is excellent and practically valuable. Consider adding an explicit contraindications row (symptomatic hypotension, SBP <90 mmHg, eGFR <15 mL/min/1.73m²) and a drug interactions row (especially combined with nitrates).

 

Response: Thank you for this helpful suggestion. We have expanded Table 2 by adding a dedicated row addressing situations in which vericiguat should generally not be initiated or requires particular caution, including symptomatic hypotension, very low systolic blood pressure, and severe renal impairment with limited clinical evidence. We have also added a separate row summarizing clinically relevant drug interactions, particularly the concomitant use of nitrates and other vasodilators, together with practical monitoring recommendations.

 

 Comment: Lines 337–348 introduce AI-supported remote monitoring and GDMT optimization models. While forward-looking, this digression feels loosely connected to the vericiguat narrative. Either: (a) tighten to 1–2 sentences directly explaining how digital tools could identify the optimal vericiguat candidate, or (b) move it to the "Future Directions" subsection.

 

Response: Thank you for this thoughtful suggestion. We agree that this section was more appropriately positioned within the future perspectives of the review. Accordingly, we have moved the discussion on AI-supported remote monitoring and GDMT optimization to the "Unresolved Questions and Future Directions" subsection, where it is now presented as a potential future strategy for improving identification of patients most likely to benefit from vericiguat and facilitating timely treatment optimization.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Congratulations to the authors for the revised version of their manuscript. 

Reviewer 2 Report

Comments and Suggestions for Authors

the authors responded to the comments thoroughly