Beyond Chronological Age: Frailty, Vulnerability, and Invasive Decision-Making in Older Adults with Acute Coronary Syndromes

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review is generally well-written and focused on the relevance of frailty and geriatric comorbidities for the prognosis of ACS patients. 

Major Comments:

1. Before engaging in the discussion of frailty as an outcome predictor the authors should first show evidence in favor of an interventional strategy in elderly patients. Contrary to intuition aged ACS patients have a far better prognosis when managed interventionally - despite higher complication rates. 
2. The authors should make clear that their recommendations regarding frailty assessment are not intended to delay or defer revascularization in  ACS - particularly in STEMI patients - but have their role in optimizing treatment and recovery after survived ACS. I thank the authors for making it clear that "frailty should not automatically be interpreted as evidence of futility.
3. In line with comment # 2 I disagree with Fig. 1 - though a very nice drawing (made with AI support?) - because it suggests a thorough geriatric individual assessment before any decision on intervention is made. This may be reasonable in ACS/NSTEMI or unstable angina when patients are free of symptoms with low troponin. In STEMI patients geriatric assessment should never defer revascularization. 
4. The authors should be more specific which frailty assessments they recommend as evidence based in clinical routine. Currently, principles are discussed at great length, however, it still remains unclear how the principles should change practice. 

Minor Comments:

Spelling p. 2, l. 42: "graphical abstract" instead of "graph abstract". 

 

Author Response

Reviewer 1 – Major Comment 1

Comment:
Before engaging in the discussion of frailty as an outcome predictor, the authors should first show evidence in favor of an interventional strategy in elderly patients. Contrary to intuition, aged ACS patients have a far better prognosis when managed interventionally, despite higher complication rates.

Response:
We thank the reviewer for this important comment. We agree that the evidence regarding invasive management in older adults should be presented before discussing frailty as a prognostic marker. This sequencing is essential to avoid conveying the impression that advanced age or frailty should lead primarily to therapeutic restriction.

Accordingly, we have added a new subsection at the beginning of Section 5 entitled “Evidence Supporting Invasive Management in Older Adults with Acute Coronary Syndromes.” In this subsection, we now summarize the principal randomized trials and contemporary meta-analyses comparing invasive and conservative strategies in older adults with non-ST-segment elevation acute coronary syndromes.

We have emphasized that advanced age alone should not preclude coronary angiography or revascularization and that an invasive strategy can reduce recurrent myocardial infarction and the need for subsequent or urgent revascularization in appropriately selected older patients. We have also reflected the nuances of the available evidence: although some studies have demonstrated reductions in composite ischemic outcomes, the most recent randomized evidence has not consistently shown a mortality benefit. This revised discussion therefore establishes the clinical value of invasive management while preserving the need for individualized assessment of ischemic benefit, procedural burden, and recovery potential.

We have added the following paragraph:

5.1. Evidence Supporting Invasive Management in Older Adults with Acute Coronary Syndromes

Before considering frailty as a prognostic or treatment-modifying factor, it is important to recognize that advanced age alone should not preclude an invasive strategy in patients with acute coronary syndromes. Older adults frequently have a high absolute ischemic risk and may derive clinically meaningful benefit from coronary angiography and revascularization when these procedures are otherwise indicated. Therapeutic decisions should therefore begin with the evidence supporting guideline-directed ACS management rather than with assumptions regarding limited benefit based on chronological age.

Randomized evidence has demonstrated that invasive management can reduce recurrent ischemic events in selected older adults with non-ST-segment elevation acute coronary syndromes. In the After Eighty trial, an invasive strategy reduced the composite of myocardial infarction, urgent revascularization, stroke, and death compared with a conservative strategy in patients aged 80 years or older. More recently, the SENIOR-RITA trial enrolled patients aged 75 years or older, including individuals with frailty and multimorbidity. Although the invasive strategy did not significantly reduce the primary composite of cardiovascular death or nonfatal myocardial infarction, it was associated with fewer nonfatal myocardial infarctions, with a low incidence of procedural complications.

Contemporary meta-analyses of randomized trials similarly suggest that routine invasive management in older patients reduces recurrent myocardial infarction and the need for subsequent or urgent revascularization. However, a consistent reduction in all-cause or cardiovascular mortality has not been demonstrated. These findings indicate that the principal benefits of an invasive strategy may lie in preventing recurrent ischemic events and future procedures rather than in universally improving survival. Accordingly, older age should not be used as a reason to withhold invasive evaluation, but neither should invasive management be applied indiscriminately without consideration of clinical presentation, comorbidity, frailty, procedural risk, and patient preferences.

Major Comment 2

Comment:
The authors should make clear that their recommendations regarding frailty assessment are not intended to delay or defer revascularization in ACS—particularly in STEMI patients—but have their role in optimizing treatment and recovery after survived ACS. I thank the authors for making it clear that "frailty should not automatically be interpreted as evidence of futility."

Response:
We sincerely thank the reviewer for this valuable observation. We fully agree that frailty assessment should never delay or defer evidence-based reperfusion therapy, particularly in patients presenting with ST-segment elevation myocardial infarction or other time-critical acute coronary syndromes.

To address this point, we have revised the manuscript to explicitly state that frailty assessment is intended to complement—not replace or postpone—urgent guideline-directed management. We now emphasize that, in time-sensitive clinical scenarios, reperfusion decisions should follow established ACS pathways, whereas frailty assessment is primarily intended to refine individualized management after initial stabilization by identifying vulnerabilities that may influence procedural planning, prevention of complications, rehabilitation, discharge planning, recovery, and long-term patient-centered care.

We believe this clarification strengthens the manuscript and avoids any potential misunderstanding that frailty assessment could justify delaying lifesaving therapies.

We have included the following statements to the manuscript:

“Importantly, the integration of frailty assessment should not delay evidence-based reperfusion or invasive management in time-critical presentations such as ST-segment elevation myocardial infarction. Rather, frailty assessment should complement guideline-directed ACS care by informing individualized management after initial stabilization and throughout the subsequent phases of treatment and recovery.”

 

“Frailty assessment should therefore be integrated in a manner that does not interfere with time-sensitive reperfusion strategies. In patients with STEMI or other emergent ACS presentations, guideline-recommended reperfusion should not be delayed to perform formal frailty assessment. Instead, vulnerability assessment should be used to optimize procedural planning, anticipate complications, guide multidisciplinary care, and support rehabilitation, discharge planning, and long-term recovery once the patient has been stabilized.”

 

Major Comment 3

Comment:
In line with comment #2 I disagree with Fig. 1—though a very nice drawing (made with AI support?)—because it suggests a thorough geriatric individual assessment before any decision on intervention is made. This may be reasonable in ACS/NSTEMI or unstable angina when patients are free of symptoms with low troponin. In STEMI patients geriatric assessment should never defer revascularization.

Response:
We sincerely thank the reviewer for this insightful comment. We fully agree that Figure 1 should not suggest that multidimensional vulnerability assessment precedes or delays urgent invasive management in patients with time-sensitive acute coronary syndromes.

To address this concern, we have clarified the intended message of Figure 1 by revising its legend and by incorporating explicit statements in the manuscript emphasizing that frailty assessment should complement—but never delay—guideline-directed emergency management. In particular, we now explicitly state that, in patients with ST-segment elevation myocardial infarction (STEMI) and other time-critical ACS presentations, formal vulnerability assessment should not postpone urgent reperfusion or other evidence-based invasive therapies.

We believe these revisions eliminate the potential misunderstanding identified by the reviewer and reinforce that the figure is intended as a conceptual framework illustrating the transition from age-based to vulnerability-informed cardiovascular care, rather than a chronological sequence of clinical actions.

The figure legend has been revised as follows:

Figure 1. From Chronological Age to Vulnerability-Informed Decision-Making in Older Adults with Acute Coronary Syndromes.Traditional age-based approaches frequently use chronological age as a surrogate for risk and may contribute to both undertreatment and overtreatment. A vulnerability-based framework incorporates frailty, functional status, cognition, comorbidity burden, social support, and patient goals to guide proportional and individualized treatment strategies throughout the continuum of ACS care. Importantly, this conceptual framework is intended to complement, rather than delay, guideline-directed emergency management. In patients with time-sensitive presentations, particularly ST-segment elevation myocardial infarction (STEMI), multidimensional vulnerability assessment should not postpone urgent reperfusion or other evidence-based invasive therapies.

 

Major Comment 4

Comment:
The authors should be more specific which frailty assessments they recommend as evidence based in clinical routine. Currently, principles are discussed at great length; however, it still remains unclear how the principles should change practice.

Response:
We thank the reviewer for this important suggestion. We agree that, although the manuscript discusses the conceptual principles of frailty assessment, greater practical guidance is valuable for clinicians managing older adults with acute coronary syndromes.

Accordingly, we have revised Section 4.2 to better distinguish between comprehensive geriatric assessment as the reference multidimensional evaluation and the tools that are most feasible in routine cardiovascular practice. We now emphasize that the Clinical Frailty Scale (CFS) is currently the most pragmatic instrument for acute ACS care because of its simplicity, rapid bedside application, and extensive validation in cardiovascular populations. We also clarify that comprehensive geriatric assessment remains the reference standard whenever feasible but should complement, rather than delay, acute management. Finally, Table 1 has been expanded to highlight the practical applicability of the main frailty instruments in routine ACS care, including their strengths, limitations, and recommended clinical setting.

We have added the following paragraph to 4.2:

“Among currently available frailty instruments, the Clinical Frailty Scale (CFS) is probably the most pragmatic tool for routine ACS practice. It can be completed rapidly at the bedside without physical performance testing, has been extensively validated in cardiovascular populations, and is feasible even in acutely ill patients. By contrast, although the Comprehensive Geriatric Assessment remains the reference standard for multidimensional evaluation, its implementation is more resource-intensive and should complement, rather than delay, acute cardiovascular management. Physical phenotype-based instruments such as the Fried Frailty Phenotype provide valuable prognostic information but are generally less practical during the acute phase of ACS because they require performance-based assessments that may not be feasible in unstable patients.”

 

We have modified table 1 accordingly:

Table 1. Common Frailty Assessment Instruments Applicable to Older Adults with Acute Coronary Syndromes

Tool	Domains Assessed	Time Required	Main Strengths	Main Limitations	Feasibility in Acute ACS	Recommended Clinical Use in ACS
Clinical Frailty Scale (CFS)	Functional status, dependence, cognition	<1 min	Rapid bedside assessment; extensively validated; highly feasible in acute settings	Subjective; potential inter-observer variability	Excellent	Preferred first-line screening tool for routine clinical practice
Fried Frailty Phenotype	Weight loss, exhaustion, weakness, slowness, low physical activity	5–10 min	Widely validated biological frailty model	Requires physical performance testing; difficult during acute illness	Limited	Best suited for stable patients and research settings
Frailty Index (Rockwood)	Accumulation of multidimensional deficits	Variable	Comprehensive characterization of biological aging	Time-consuming; limited bedside practicality	Limited	Comprehensive risk stratification when sufficient clinical data are available
Edmonton Frail Scale	Physical, cognitive, social, and functional domains	5–10 min	Multidimensional and relatively simple	Less extensively studied in ACS populations	Moderate	Alternative multidimensional screening tool when resources permit
Essential Frailty Toolset (EFT)	Physical performance, cognition, hemoglobin, albumin	3–5 min	Objective and clinically practical; integrates biological and functional domains	Validation mainly derived from structural heart disease populations	Good	Particularly useful in patients undergoing invasive cardiovascular procedures; promising for selected ACS patients
Comprehensive Geriatric Assessment (CGA)	Functional, cognitive, nutritional, social, and medical domains	>30 min	Reference standard for multidimensional assessment	Resource-intensive; difficult to implement routinely during acute ACS	Excellent after stabilization; limited in the acute phase	Reference standard after initial stabilization to guide individualized management, rehabilitation, discharge planning, and long-term care

Comparison of the principal frailty assessment instruments applicable to older adults with acute coronary syndromes. The Clinical Frailty Scale (CFS) is currently the most pragmatic instrument for routine bedside assessment in acute ACS because of its simplicity, rapid administration, and extensive cardiovascular validation. Comprehensive Geriatric Assessment (CGA) remains the reference standard for multidimensional evaluation but is generally performed after initial stabilization and should not delay guideline-directed acute management.

 

Minor Comment

Comment:
Spelling p. 2, l. 42: "graphical abstract" instead of "graph abstract".

Response:
We thank the reviewer for identifying this typographical error. The text has been corrected throughout the manuscript to read "graphical abstract."

 

Reviewer 2 Report

Comments and Suggestions for Authors

In this narrative review, Lourdes Vicent et al. address the increasingly recognized role of frailty and multidimensional vulnerability in guiding invasive decision-making among older adults presenting with acute coronary syndromes (ACS), a timely and clinically relevant topic in contemporary geriatric cardiology. The authors provide a comprehensive overview of the biological and clinical concepts underlying frailty, summarize the currently available frailty assessment tools and discuss the association between frailty and adverse clinical outcomes. They also propose a vulnerability-based, patient-centered framework that integrates frailty, functional status, cognition, comorbidities and patient preferences to support individualized therapeutic decision-making.

Overall, this reviewer consider the manuscript to be well organized, clearly written and characterized by a logical progression from the conceptual foundations of frailty to its practical implications in the management of ACS. The authors have the strong merit of addressing a clinically important issue with a balanced perspective, emphasizing that frailty should not be regarded as a contraindication to invasive treatment but rather as an additional dimension to inform personalized, patient-centered therapeutic decisions.

However, this reviewer believes that some minor aspects require further refinement before the manuscript can be considered for publication.

1) The review is largely descriptive, with several sections summarizing established concepts without providing a sufficiently critical appraisal of the available evidence, including the strength and limitations of the underlying data. In particular, the section addressing the evidence base would benefit from a more structured and critical synthesis of landmark randomized clinical trials rather than a predominantly narrative overview. A summary table reporting the key characteristics of the major studies, including study design, patient population, intervention strategies, principal outcomes and clinical implications would substantially enhance the educational value and clinical applicability of the review. The authors have partially addressed this aspect in Table 3; however, this approach could be further expanded to incorporate the main randomized trials and relevant registries evaluating ACS populations, with specific attention to medically managed patients and elderly/frail subgroups, who remain consistently underrepresented in clinical trials.
In this context, the review by Menozzi et al. (PMID: 28874297) and the accompanying editorial (PMID: 28874299) provide a valuable framework by emphasizing the heterogeneity of medically managed NSTE-ACS patients, the prognostic implications of conservative strategies and the complexity of therapeutic decision-making in individuals with advanced age, frailty and comorbidities. Incorporating a similar critical perspective would strengthen the manuscript by better highlighting current evidence gaps and improving the translation of trial findings into real-world clinical practice.

2) Some sections contain elements of redundancy that may affect the overall readability of the manuscript. Key concepts, including the principle that frailty should “inform rather than dictate” therapeutic decisions, the distinction between chronological and biological age and the importance of individualized patient-centered care, are reiterated across multiple sections with substantial overlap in wording and content. A more concise presentation and consolidation of these concepts would improve the flow of the review and enhance its scientific impact.

Author Response

Reviewer 2 – Comment 1

Comment:
The review is largely descriptive, with several sections summarizing established concepts without providing a sufficiently critical appraisal of the available evidence, including the strength and limitations of the underlying data. In particular, the section addressing the evidence base would benefit from a more structured and critical synthesis of landmark randomized clinical trials rather than a predominantly narrative overview. A summary table reporting the key characteristics of the major studies, including study design, patient population, intervention strategies, principal outcomes and clinical implications would substantially enhance the educational value and clinical applicability of the review. The authors have partially addressed this aspect in Table 3; however, this approach could be further expanded to incorporate the main randomized trials and relevant registries evaluating ACS populations, with specific attention to medically managed patients and elderly/frail subgroups, who remain consistently underrepresented in clinical trials.

In this context, the review by Menozzi et al. (PMID: 28874297) and the accompanying editorial (PMID: 28874299) provide a valuable framework by emphasizing the heterogeneity of medically managed NSTE-ACS patients, the prognostic implications of conservative strategies and the complexity of therapeutic decision-making in individuals with advanced age, frailty and comorbidities. Incorporating a similar critical perspective would strengthen the manuscript by better highlighting current evidence gaps and improving the translation of trial findings into real-world clinical practice.

Response:
We sincerely thank the reviewer for this detailed and constructive comment. We agree that the previous version of the manuscript placed greater emphasis on describing the available evidence than on critically examining its methodological limitations, applicability, and implications for real-world clinical practice.

To address this concern, we substantially revised the evidence synthesis. In Section 5, we incorporated a new subsection entitled "Evidence Supporting Invasive Management in Older Adults with Acute Coronary Syndromes", before discussing frailty as an outcome predictor. This subsection summarizes the principal randomized trials and contemporary meta-analyses supporting invasive management in selected older adults while acknowledging the limitations of the available evidence, including the absence of a consistent mortality benefit despite reductions in recurrent ischemic events.

In addition, Table 3 has been substantially expanded and redesigned as a critical appraisal of the major studies evaluating invasive and conservative management in older adults with NSTE-ACS. The revised table now includes the study design, patient population and frailty representation, compared strategies, principal outcomes, major limitations, and clinical implications. We incorporated the landmark randomized trials and the most relevant observational evidence, including After Eighty, the Italian Elderly ACS Trial, MOSCA, MOSCA-FRAIL, SENIOR-RITA, SENIOR-NSTEMI, LONGEVO-SCA, and cohorts of medically managed patients.

Following the reviewer's suggestion, we also incorporated the perspective proposed by Menozzi et al. and the accompanying editorial into the discussion of the available evidence. We now explicitly emphasize that medically managed patients with NSTE-ACS constitute a heterogeneous clinical population and that "conservative management" should not be considered a single therapeutic strategy. We further discuss that observational comparisons between invasive and conservative management are particularly susceptible to confounding by indication and selection bias, and that treatment allocation frequently reflects frailty, multimorbidity, coronary anatomy, clinical judgement, and patient preferences rather than treatment effect alone.

We believe these revisions provide a more balanced and critical interpretation of the available evidence and strengthen the translation of randomized trial findings into routine clinical practice for older and frail patients.

Changes made in the manuscript

New subsection in Section 5

A new subsection entitled:

5.1. Evidence Supporting Invasive Management in Older Adults with Acute Coronary Syndromes

has been incorporated before the discussion of frailty as an outcome predictor. This section summarizes the principal randomized clinical trials and contemporary meta-analyses supporting invasive management in selected older adults and discusses the limitations of the current evidence.

New discussion incorporating Menozzi et al.

The following paragraphs have been incorporated into the manuscript:

An important limitation when interpreting this evidence is that medically managed patients with NSTE-ACS do not constitute a homogeneous clinical group. They include patients in whom coronary angiography is not performed, patients without obstructive coronary artery disease, and patients with significant coronary disease in whom revascularization is not pursued because of anatomical complexity, comorbidity, frailty, limited expected benefit, patient preferences, or clinical judgment. These distinct pathways are frequently combined under the label of "conservative management," despite carrying different prognostic and therapeutic implications, as previously highlighted by Menozzi et al. and the accompanying editorial.

Previous analyses have shown that medically managed patients are generally at higher baseline risk and experience worse outcomes than those undergoing revascularization. However, these associations cannot be interpreted as definitive evidence of a causal benefit from intervention because treatment allocation is strongly influenced by age, comorbidity, frailty, clinical instability, coronary anatomy, and perceived treatment futility. Consequently, observational comparisons are particularly vulnerable to selection bias and confounding by indication. Conservative management may represent appropriate proportional care in some patients, whereas in others it may reflect potentially avoidable undertreatment.

This heterogeneity also complicates the translation of randomized trial findings into routine practice. Many trials have excluded or underrepresented patients with severe frailty, cognitive impairment, extensive multimorbidity, limited life expectancy, or inability to provide consent. Furthermore, crossover to angiography for recurrent ischemia may reduce the contrast between randomized strategies. The available evidence should therefore support neither routine invasive treatment nor systematic therapeutic restriction based on age or frailty alone. Instead, it should inform individualized decisions grounded in clinical presentation, coronary anatomy, biological reserve, expected benefit, treatment burden, and patient preferences.

Table 3

Table 3 has been redesigned as a critical appraisal of the available evidence and expanded to include:

• Study design
• Patient population and frailty representation
• Compared strategies
• Principal outcomes
• Major limitations
• Clinical implications

The revised table now includes After Eighty, Italian Elderly ACS Trial, MOSCA, MOSCA-FRAIL, SENIOR-RITA, SENIOR-NSTEMI, LONGEVO-SCA, and observational cohorts of medically managed patients.

Table 3. Critical Appraisal of Major Studies Evaluating Invasive and Conservative Management in Older Adults with NSTE-ACS

 

Study	Population and frailty representation	Design	Compared strategies	Principal outcomes	Main limitations	Clinical implications
After Eighty	≥80 years with NSTEMI or unstable angina; selected trial population	Randomized, open-label trial	Routine invasive vs conservative strategy	Invasive strategy reduced the composite ischemic endpoint, largely through fewer myocardial infarctions and urgent revascularizations	Limited representation of patients with severe frailty; benefit attenuated with increasing age; open-label design	Advanced age alone should not preclude invasive evaluation; benefit appears principally ischemic rather than clearly mortality-related
Italian Elderly ACS Trial	Older adults with NSTE-ACS; subgroup heterogeneity	Randomized trial	Early invasive vs initially conservative strategy	No significant overall reduction in the primary composite; possible benefit in selected higher-risk subgroups	Limited sample size and statistical power; subgroup findings exploratory	Routine invasive management may not provide uniform benefit across all older adults
MOSCA	Patients ≥70 years with substantial comorbidity and NSTE-ACS	Randomized pilot trial	Invasive vs conservative strategy	No clear overall survival advantage; possible early reduction in ischemic events	Small sample; limited power; high competing noncardiovascular risk	Multimorbidity may attenuate long-term benefit and should be incorporated into treatment decisions
MOSCA-FRAIL	≥70 years, NSTEMI, CFS ≥4	Multicenter randomized trial	Routine invasive vs conservative/watchful-observation strategy	No improvement in days alive and out of hospital or ischemic events at 1 year	Premature termination; only 167 patients; clinicians excluded patients for whom either strategy was considered clearly inappropriate	In frail patients, routine invasive management cannot be assumed to improve patient-centered outcomes; individualized selection remains essential
SENIOR-RITA	≥75 years with NSTEMI; mean age 82; 32% frail; multimorbidity permitted	Large multicenter randomized trial	Invasive strategy plus medical therapy vs conservative medical therapy	No significant reduction in cardiovascular death or nonfatal MI; fewer nonfatal MIs; procedural complications <1%	Open-label; conservative arm allowed angiography for recurrent ischemia; results may not apply to unstable STEMI or patients requiring mandatory intervention	Routine invasive management is safe in selected older adults but does not uniformly improve the primary clinical outcome; treatment should be individualized
SENIOR-NSTEMI	Older adults with NSTEMI in routine clinical practice	Observational cohort	Invasive vs non-invasive management	Invasive management associated with lower adjusted mortality	Residual confounding, immortal-time bias and selection of fitter patients cannot be excluded	Supports potential benefit but cannot establish causality
LONGEVO-SCA	Very old patients with ACS; systematic geriatric assessment	Prospective observational registry	Treatment selected in clinical practice	Frailty independently predicted mortality and influenced treatment allocation	Observational design; limited sample size; heterogeneous ACS management	Demonstrates the prognostic value of frailty but not whether frailty modifies the causal effect of invasive treatment
Medically managed NSTE-ACS cohorts	Heterogeneous patients without angiography, without obstructive CAD, or with CAD not revascularized	Registries and observational studies	Medical management without routine revascularization	Higher event rates and less frequent use of guideline-directed pharmacotherapy	Strong confounding by indication; heterogeneous reasons for non-revascularization	“Conservative management” should not be treated as a single strategy; reasons for non-invasive care must be explicitly characterized

 

 

Comment 2

Comment:
Some sections contain elements of redundancy that may affect the overall readability of the manuscript. Key concepts, including the principle that frailty should “inform rather than dictate” therapeutic decisions, the distinction between chronological and biological age and the importance of individualized patient-centered care, are reiterated across multiple sections with substantial overlap in wording and content. A more concise presentation and consolidation of these concepts would improve the flow of the review and enhance its scientific impact.

We sincerely thank the reviewer for this thoughtful and constructive suggestion. We agree that some of the central concepts of the review were reiterated across different sections, reflecting their importance as the manuscript's conceptual framework. Nevertheless, we carefully revised the manuscript to improve readability by reducing unnecessary overlap while preserving the logical progression of the review.

Specifically, we shortened the Introduction by removing a repetitive statement introducing the vulnerability-based framework, as this concept is fully developed in the following paragraph describing the novelty and scope of the review.

We also revised Section 6.2 ("Frailty Should Inform, Not Dictate, Clinical Decisions") to improve conciseness and avoid reiteration. In particular, we consolidated several overlapping paragraphs emphasizing that frailty should not be equated with futility, that it should not be interpreted as a binary determinant of treatment eligibility, and that it should be integrated within a broader multidimensional assessment. We also removed the final paragraph introducing the transition from a frailty-centered to a vulnerability-centered approach, as this concept is developed in detail in the subsequent dedicated section (Section 9. Toward Vulnerability-Based Cardiovascular Care).

Finally, we streamlined the Conclusions by removing repetitive formulations of the manuscript's central message while preserving the principal take-home points.

We believe these revisions have improved the flow, readability, and overall scientific impact of the manuscript while maintaining the coherence of its central conceptual framework.

Changes made in the manuscript

Introduction

The following sentence has been removed to avoid redundancy with the subsequent paragraph describing the novelty of the review:

"Finally, we propose a vulnerability-based framework for cardiovascular care in which frailty guides proportional treatment rather than justifying therapeutic nihilism."

Section 6.2

This section has been condensed by:

• consolidating repeated discussions regarding the concepts that frailty should inform rather than dictate clinical decisions;
• integrating the descriptions of frailty as a multidimensional rather than binary construct into a single paragraph;
• removing the final paragraph introducing the transition from frailty to vulnerability, as this topic is fully addressed in Section 9.

The revised final paragraphs now read:

Importantly, frailty should not be interpreted as a binary determinant of treatment eligibility. Patients with similar frailty scores may differ substantially in cognition, mobility, comorbidity burden, social support, nutritional status, symptom burden, and personal goals. Consequently, frailty should be interpreted within a broader multidimensional vulnerability assessment that integrates biological reserve, functional status, cognition, social circumstances, and patient preferences. This broader perspective allows clinicians to balance expected benefit, procedural burden, and recovery potential rather than relying on frailty alone to guide therapeutic decisions.

This distinction is particularly relevant because treatment benefit and procedural risk do not necessarily move in parallel. Patients with greater vulnerability often have both more to gain and more to lose from invasive management. While high ischemic risk may increase the potential benefit of revascularization, reduced physiological reserve may simultaneously increase the risk of bleeding, acute kidney injury, delirium, functional decline, and other complications. Clinical decisions therefore require balancing competing probabilities rather than applying rigid treatment thresholds.

Frailty may also intersect with broader healthcare inequities. Women, individuals with disability, socially vulnerable populations, and very old adults frequently experience lower rates of invasive cardiovascular treatment. When interpreted without appropriate clinical context, frailty may inadvertently reinforce existing disparities by providing an apparently objective justification for unequal treatment intensity [22]. Careful consideration of potential bias is therefore essential when incorporating frailty into therapeutic decision-making.

Ultimately, the purpose of frailty assessment is not to determine whether treatment should be offered, but to improve the quality of decision-making. Rather than functioning as a gatekeeping mechanism, frailty should facilitate discussions regarding anticipated benefits, potential harms, realistic recovery trajectories, and patient priorities. Used in this way, it supports proportional, individualized, and patient-centered cardiovascular care.

Conclusions

The Conclusions have been shortened by removing repetitive closing statements while maintaining the principal messages regarding:

• the role of frailty beyond chronological age;
• individualized and proportional cardiovascular care;
• the need to integrate frailty within a broader vulnerability-based framework.

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have addressed the issues raised in my review. The manuscript is significantly improved and it is now clearly stated, that frailty assessment should not defer revascularization in ACS patients.