Stage C2D Heart Failure

Executive Summary

The ACC/AHA heart failure stages were built as a one-way ladder: A (at risk), B (structural disease, asymptomatic), C (symptomatic), D (refractory). In practice stage C and stage D are wildly unequal. Stage C holds nearly everyone with symptomatic heart failure. Stage D is defined by what we offer — transplant, durable mechanical circulatory support, inotropes, or hospice — and so it effectively holds only the patients a transplant center has accepted.

Between them sits a large ambulatory population that the June 2026 JACC: Heart Failure position statement names stage C2D ("C-to-D") and, for the first time, defines operationally [1].

Stage C2D requires all three core features [1]:

1. Consistent limitation of routine daily life by NYHA functional class III or ambulatory NYHA functional class IV symptoms, despite use of stage C GDMT
2. Ambulatory life at home without intravenous inotropic support
3. Reduced exercise capacity — typically 6-minute walk distance <300–350 m and/or peak VO₂ 11–15 mL/kg/min

The statement maps this directly onto the classification Andy already uses: most individuals with stage C2D would be characterized as INTERMACS profiles 4 to 7, while profiles 1 to 3 describe the non-ambulatory patients who would receive advanced therapies while hospitalized on intensive hemodynamic support [1].

Two framing points in the original are easy to miss and change everything:

• C2D is a stage, not an event. The statement is explicit that C2D is distinct from an episode of worsening heart failure, which is defined by acute diuretic escalation and can occur anywhere in stage C as well as in C2D [1].
• The paper deliberately scopes itself to HFrEF, on the grounds that most heart failure staging and recommendations for symptomatic heart failure were developed for reduced ejection fraction — while acknowledging that many C2D features occur at any LVEF [1].

The statement's therapeutic message is equally direct: ambulatory NYHA III/IV patients have been under-represented in the trials of every Class I therapy except diuretics; SGLT2 inhibitors and MRAs benefit more advanced heart failure and are usually well tolerated; optimal pharmacotherapy has not been established for patients with hemodynamic or renal limitations; and the single named unmet need is an oral therapy to increase cardiac output enough to support activities of daily living [1].

Prognosis justifies the effort. In a complete geographic population 13.7% of all heart failure patients met the 2018 ESC advanced criteria, with median survival of 12.2 months from the moment those criteria were met [2]. In a national claims cohort of 60,197 adults median survival was 2.0 years [3]. Among 400 ambulatory patients referred to advanced centers on genuinely optimal therapy — 92% INTERMACS profiles 5 to 7 — 22% reached death, durable VAD, or urgent transplant within a year and 37% within two [4].

1. Why Two Stages Were Never Enough

Stage C and stage D were never symmetric categories. Stage C is defined by the patient (symptomatic structural heart disease). Stage D is defined by the therapy. A definition anchored to therapy inherits the access problems of that therapy.

The statement gives three reasons to name the intermediate population [1]:

1. Clinical identification — recognizing typical C2D features identifies patients at higher risk, enabling closer monitoring, timely referral, and earlier goals-aligned care.
2. Health system planning — understanding the distribution and burden of C2D is essential for care models, staffing, and training that extend beyond transplant and durable MCS programs.
3. Therapeutic innovation — the size of the population should itself prompt development of new therapies and adaptation of existing stage C therapies.

The measurement failure it corrects is stated plainly in the companion NHLBI workshop summary: national databases "selectively capture the small groups accepted for heart transplant listing or left ventricular assist devices," so the epidemiology, trajectories, and therapies for everyone else are poorly understood [5].

1.1 Where the Term Came From

"Stage C2" first appeared in a January 2022 JAMA Cardiology editorial by Yancy, Hernandez, and Fonarow [6], accompanying a post hoc analysis of GALACTIC-HF in severe heart failure — defined there as NYHA III–IV and LVEF ≤30% and HF hospitalization within 6 months [7].

The result that prompted the editorial remains the strongest single argument that C2D is a biological category rather than a bookkeeping convenience. Among 2,258 of 8,232 GALACTIC-HF patients (27.4%) meeting those criteria, omecamtiv mecarbil reduced first HF event or cardiovascular death (HR 0.80, 95% CI 0.71–0.90), while in patients without severe HF there was no benefit (HR 0.99, 95% CI 0.91–1.08), P interaction 0.005 [7]. Cardiovascular death moved the same way (HR 0.88 vs 1.10, P interaction 0.03) [7].

In December 2022 the NHLBI convened a three-day workshop on ambulatory stage pre-D and D heart failure, published as a call to action in JAMA Cardiology in April 2025 [5]. The JACC: Heart Failure position statement followed in June 2026 [1]. Its authorship is the architecture's own authors — Stevenson co-wrote the original INTERMACS profiles [8], Crespo-Leiro led the HFA-ESC advanced heart failure definition [9], Bozkurt led the Universal Definition. That group identifying a gap in a system they built is a meaningful signal.

1.2 The Ten Key Points of the NHLBI Workshop

The 2025 workshop summary distils its findings into ten points, reproduced here in substance [5]:

1. There is a large underrecognized population of patients with advanced heart failure that has progressed to late-stage C and ambulatory stage D.
2. Social determinants of health influence access to all heart failure therapies and perpetuate inequities of care and outcomes before and after progression to stage C2D.
3. Cardiac transplant remains inadequate for this ambulatory population, which is at least 25-fold larger than the supply of donor hearts.
4. There are major knowledge gaps about patients referred but not accepted at transplant centers, and even larger gaps about ambulatory C2D patients who lack any access to specialized heart failure care.
5. LVADs are currently underutilized for ambulatory C2D heart failure.
6. Ambulatory patient preferences range from living longer to feeling better and often continue to favor meaningful survival.
7. Large knowledge gaps exist about therapies for stage C2D, including uncertainty about the benefits of therapies currently used.
8. Delineation of overlapping phenotypes should encourage strategies addressing social determinants and the phenotypes of right ventricular failure, cardiorenal syndrome, low cardiac reserve, congestive hepatopathy, and frailty.
9. Target populations can be identified in expanding circles, beginning with ambulatory patients on home inotropic infusions and those declined for transplant, extending to demonstration projects serving underserved populations.
10. Curation of these cohorts should capture prospective phenotyping, therapeutic decisions, and outcomes — recorded objectively and reported by patients in relation to their values, goals, and preferences.

2. The Published Definition

2.1 Core Features — All Three Required

Reproduced from Table 1 of the position statement [1]:

On criterion 3 the statement is candid: those ranges are "recognized to be influenced by multiple factors including previous athletic activity, age, and sex," and more systematic use of cardiopulmonary exercise testing is needed both to define the boundary and to determine how often inadequate cardiac reserve is the limiting problem [1].

2.2 Supportive Common Features — Usually Several Present

Also Table 1 [1]:

• LVEF typically <25%–30%
• Intolerance or decreasing tolerance for neurohormonal modulation (e.g., circulatory–renal limitations to ARNI/ACEI/ARB or beta-blockers)
• Recurrent or persistent clinical congestion requiring diuretic escalation and combination
• Systolic blood pressure frequently <100 mm Hg; may be <90 mm Hg
• Labile and/or declining renal function
• Hospitalizations common; may include intensive care and temporary intravenous inotropes
• Recurrent ventricular arrhythmias
• Worsening mitral and/or tricuspid regurgitation
• High natriuretic peptide levels
• Hyponatremia that is not medication-induced
• Quality of life limited primarily by HF, with KCCQ Clinical Summary Score of 45 to 65

2.3 The INTERMACS Mapping

The statement places C2D on the INTERMACS scale explicitly: stage C2D excludes the non-ambulatory patients who would undergo advanced therapies while hospitalized on intensive hemodynamic support — INTERMACS profiles 1 to 3 — and therefore most individuals with stage C2D would be characterized as INTERMACS profiles 4 to 7 [1].

See Advanced Heart Failure: Classification, Staging, and Referral Criteria §2 for the full profile definitions and modifiers.

2.4 A Stage, Not an Event

The statement draws a distinction that is routinely blurred in practice: C2D is a stage of advanced heart failure, distinct from an event of worsening heart failure [1]. As codified by heart failure trial event committees, worsening heart failure is an episode of worsening symptoms requiring acute diuretic escalation, and it can occur throughout stage C as well as into C2D [1].

Patients newly diagnosed with heart failure are not initially stage C2D, but can progress quickly to a C2D designation if they fail to tolerate or fail to respond favorably to recommended stage C therapies [1].

2.5 Scope — This Paper Is About HFrEF

The statement says directly that although many features of C2D can occur at any LVEF, this position paper focuses on HFrEF, because that is where most heart failure staging and recommendations for symptomatic heart failure were developed [1].

This is an honest declaration of scope rather than an oversight, but it leaves a real gap. When the 2018 ESC advanced criteria were applied to a complete population, 43.4% of advanced heart failure patients had HFpEF and 14.3% had HFmrEF, and survival did not differ by ejection fraction [2]. The majority of advanced heart failure sits outside the scope of the document that defines the ambulatory advanced stage.

3. The Five Physiologic Phenotypes

The NHLBI workshop named five physiologic phenotypes offering distinct therapeutic targets: low cardiac output, right heart failure, cardiorenal syndromes, congestive hepatopathy, and frailty [5].

The position statement reinforces the first of these in its own words: an unknown proportion of C2D patients are limited primarily by fatigue with exertion because of inadequate cardiac output rather than apparent congestion — the "cold and dry" profile — and these limitations of cardiac reserve are best detected by careful activity history supplemented by objective measurement of exercise capacity [1].

Three observations follow.

Two of the five are nephrology's core business. The framework does not treat renal dysfunction as a comorbidity complicating heart failure management; it treats it as a phenotype of the disease with its own therapeutic target.

Three of the five are venous congestion wearing different clothes. Right heart failure, cardiorenal syndrome, and congestive hepatopathy are largely the same elevated right atrial pressure expressed in the kidney, the liver, and the gut. See RHC Comprehensive Interpretation Guide §12–13.

They are not mutually exclusive, and that is the point. A patient can be low-output and right-sided and cardiorenal. The purpose is to identify which physiology is currently dominant, because that determines the next move.

4. What the Statement Says About Treatment

The full therapeutic synthesis lives in Advanced Heart Failure: Therapeutics and Evidence. The statement's own Key Points, reproduced in substance [1]:

• Vigorous effort should be made in all patients with stage C2D HFrEF to optimize the guideline Class I recommended therapies as tolerated.
• HFrEF patients with ambulatory NYHA III/IV symptoms have been under-represented in trials of the Class I recommended therapies except for the use of diuretics.
• SGLT2 inhibitors and MRAs have been shown to benefit patients with more advanced HF and are usually well tolerated.
• Extension of the benefits of renin-angiotensin system inhibition and beta-blockers has been shown for subgroups with NYHA functional class III/IV HF.
• Optimal pharmacotherapy has not been established for patients with hemodynamic or renal limitations to recommended therapies.
• Hydralazine/nitrates and digitalis have long been used in NYHA class III HF, with benefits shown in randomized trials both before and after 2000.
• The newer agents ivabradine and vericiguat have each shown benefit for high-risk subgroups.
• An urgent unmet need for ambulatory stage C2D HFrEF is oral therapy to increase cardiac output to support activities of daily living.

The statement also divides the four pillars by hemodynamic risk: MRAs and SGLT2 inhibitors are most likely to be tolerated, having minimal to no effect on perfusion or blood pressure after initiation, whereas the renin-angiotensin and beta-blocker pillars "require finesse to assemble when cardiac output and blood pressure are less robust" [1]. It notes that a modest reduction in blood pressure is often tolerated without symptoms, that hypotension has less adverse impact when it results from GDMT up-titration, and that a history of previous intolerance is a risk marker but should not preclude attempts to reinitiate or up-titrate in selected stable patients [1].

5. Prognosis of the Stage C to Stage D Transition

5.1 The Population Answer

Olmsted County, Minnesota, 2007–2017: the 2018 ESC advanced criteria operationalized and applied to all 6,836 adults with heart failure [2].

5.2 The Claims Answer

OptumLabs 2009–2019, 60,197 adults identified by a validated algorithm (two HF hospitalizations plus one additional advanced sign within 12 months), mean age 73 [3]:

• Median survival 2.0 years (IQR 0.4–5.5)
• Adjusted mortality higher in older, male, non-Hispanic White, and rural patients
• Advanced therapies used less in older patients and in women
• Black patients more likely to receive an LVAD (P = 0.010), less likely to receive a transplant than White patients (P = 0.034)

5.3 The Referred-Ambulatory Answer

REVIVAL: 400 ambulatory patients at 21 MCS and transplant centers, mean LVEF 21%, median 6MWD 341 m, 92% INTERMACS profiles 5–7, robust GDMT and device adherence [4]:

Patients surviving to two years maintained GDMT intensity with no decline in health-related quality of life [4]. Stratified by profile, the 12-month composite was 39%, 27%, 24%, and 14% for profiles 4, 5, 6, and 7 (p = 0.004) [10].

5.4 Reconciling the Three

The spread is the referral funnel made visible, and it is itself the C2D argument.

5.5 The Renal Trajectory Through the Transition

In the same Olmsted advanced heart failure cohort (n = 936, mean age 77) [11]:

• At the time advanced criteria were met: 22% had eGFR <30, 22% 30–44, 23% 45–59, 32% ≥60 mL/min/1.73 m²
• Annual eGFR decline accelerated from 7.6% before to 10.9% after advanced heart failure
• Greater post-transition decline in patients with diabetes and preserved ejection fraction
• eGFR <30 at advanced diagnosis vs ≥60: adjusted HR for death 1.30 (95% CI 1.07–1.57)

The C→D transition is simultaneously a renal inflection point.

6. The Capacity Argument

The statement's most uncomfortable section is about supply, and it reframes referral as a systems problem rather than an individual one [1]:

The statement's conclusion is blunt: board certification requirements, training curricula, and hospital financial incentives have directed almost all heart failure specialists toward the roughly 7,000 patients per year who receive a transplant or an LVAD [1].

7. Critical Appraisal

7.1 Strengths

• It publishes operational criteria. Three required core features with numeric thresholds, plus eleven supportive features — enough to apply to a patient today, which is more than "advanced heart failure" has usually offered.
• It anchors to INTERMACS. Mapping C2D to profiles 4–7 connects the new construct to a classification with existing prognostic validation [10].
• It separates stage from event. The stage/worsening-HF distinction prevents the commonest misclassification.
• It names the unmet need precisely — an oral agent to raise cardiac output enough to support daily activity — rather than gesturing at "new therapies."
• It is honest about the evidence. "Under-represented in trials of the Class I recommended therapies except for the use of diuretics" is a fair and uncomfortable summary.
• It includes a practical adaptation table (Table 2) rather than stopping at principles.

7.2 Limitations

• The criteria are proposed, not validated. No cohort has been assembled by these criteria; no trial has enrolled by them. The statement concedes the definitions "will remain fluid."
• The exercise thresholds are soft. 6MWD <300–350 m and peak VO₂ 11–15 mL/kg/min are ranges, explicitly confounded by age, sex, and prior athleticism — and CPET is not universally available.
• HFrEF-only scope leaves the majority behind. 57.7% of advanced heart failure is HFmrEF or HFpEF with identical survival [2], and this framework does not address them.
• Much of the therapeutic evidence is old or indirect — CONSENSUS, RALES, DIG, V-HeFT, A-HeFT — because the modern trials excluded these patients. Extending a 1987 result to a 2026 patient on quadruple therapy is a real inferential leap.
• "Despite use of stage C GDMT" is the weakest link. The statement itself notes that some patients with typical features may have had premature discontinuation of GDMT, or delayed recognition and delayed introduction of GDMT. A patient mislabeled C2D because nobody tried properly is a patient denied a therapy that would have worked.

8. Why This Matters to Nephrology Specifically

1. We see the transition first. Diuretic escalation, neurohormonal intolerance, labile renal function, and non-medication hyponatremia are four of the eleven supportive features [1].
2. We hold the GDMT ceiling. When we tolerate a creatinine rise to preserve an ARNI or an MRA — or fail to — we are determining whether a patient meets criterion 1.
3. The statement asks for us by name. Table 2 routes renal-limited patients through RAASi/MRA dose review, loop diuretic bioavailability switching, sequential nephron blockade, and right heart catheterization [1].
4. The HFpEF majority is ours by default, with no device pathway and no C2D framework [2].
5. Referral timing is a renal decision. The patient who meets criteria at eGFR 45 has options the same patient at eGFR 22 may not.

9. Open Questions

1. Can the three core features be operationalized from routinely collected data, and do they identify a cohort with distinct outcomes?
2. Does GDMT benefit persist, attenuate, or reverse in C2D? LIFE was negative for sacubitril/valsartan in advanced HFrEF [12]; GALACTIC-HF suggested benefit concentrated in severe HF [7].
3. What replaces CPET where it is unavailable, given that criterion 3 depends on objective exercise measurement?
4. What does C2D mean for the HFmrEF/HFpEF majority?
5. Will an oral inotrope — the statement's named unmet need — arrive, and will it repeat the omecamtiv pattern of working only in the sickest?

References

1. Dunlay SM, Colvin M, Cowger JA, et al. Ambulatory stage C2D heart failure definitions and current therapeutic approaches: JACC: Heart Failure position statement. JACC Heart Fail. 2026;14(6):103101. PMID: 42230068
2. Dunlay SM, Roger VL, Killian JM, et al. Advanced heart failure epidemiology and outcomes: a population-based study. JACC Heart Fail. 2021;9(10):722-732. PMID: 34391736
3. Subramaniam A, van Houten H, Redfield MM, et al. Advanced heart failure characteristics and outcomes in commercially insured U.S. adults. JACC Heart Fail. 2023;11(11):1595-1606. PMID: 37589611
4. Aaronson KD, Stewart GC, Stevenson LW, et al. Optimizing triage of ambulatory patients with advanced heart failure: 2-year outcomes from REVIVAL. JACC Heart Fail. 2024;12(10):1734-1746. PMID: 38970587
5. Dunlay SM, Pinney SP, Lala A, et al. Recognition of the large ambulatory C2D stage of advanced heart failure — a call to action. JAMA Cardiol. 2025;10(4):391-398. PMID: 39908057
6. Yancy CW, Hernandez AF, Fonarow GC. Identifying treatments for stage C2 heart failure. JAMA Cardiol. 2022;7(1):34-35. PMID: 34643645
7. Felker GM, Solomon SD, Claggett B, et al. Assessment of omecamtiv mecarbil for the treatment of patients with severe heart failure: a post hoc analysis of data from the GALACTIC-HF randomized clinical trial. JAMA Cardiol. 2022;7(1):26-34. PMID: 34643642
8. Stevenson LW, Pagani FD, Young JB, et al. INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant. 2009;28(6):535-541. PMID: 19481012
9. Crespo-Leiro MG, Metra M, Lund LH, et al. Advanced heart failure: a position statement of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2018;20(11):1505-1535. PMID: 29806100
10. Kittleson MM, Shah P, Lala A, et al. INTERMACS profiles and outcomes of ambulatory advanced heart failure patients: a report from the REVIVAL Registry. J Heart Lung Transplant. 2020;39(1):16-26. PMID: 31522912
11. Quiram BJ, Killian JM, Redfield MM, et al. Changes in kidney function after diagnosis of advanced heart failure. J Card Fail. 2023;29(12):1617-1625. PMID: 37451601
12. Mann DL, Givertz MM, Vader JM, et al. Effect of treatment with sacubitril/valsartan in patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA Cardiol. 2022;7(1):17-25. PMID: 34730769

Related Reading

• Advanced Heart Failure: Classification, Staging, and Referral Criteria — The seven INTERMACS profiles, the formal definitions of advanced heart failure, and the diuretic thresholds that should trigger referral.
• Advanced Heart Failure: Therapeutics and Evidence — What the trials actually show once a patient crosses out of stage C: GDMT at the ceiling, decongestion, hemodynamics, MCS, and palliative care.
• HFpEF Diagnostic Criteria 2025 — relevant because most advanced heart failure is not HFrEF.
• Cardiorenal Module index