Clinical background
Wild-type transthyretin amyloid cardiomyopathy (ATTRwt) is a progressive disease with a poor prognosis. In the derivation cohort, median survival from diagnosis was 3.6 years, and it did not improve over the study period [1]. With tafamidis as the only approved disease-modifying treatment, the need for a simple prognostic instrument has grown. Tafamidis improves survival, but the effect emerges only after approximately 18 months of treatment [2]. The decision is therefore not only about identifying patients at high risk, but about distinguishing those whose prognosis is so poor that a slow-acting treatment is unlikely to take effect in time. The Grogan staging system serves this purpose by dividing patients into three prognostic groups at diagnosis using two widely available biomarkers.
Applying the Grogan staging system
The staging rests on two biomarkers measured at diagnosis: troponin T and NT-proBNP. The cut-offs are a troponin T of 0.05 ng/mL and an NT-proBNP of 3,000 pg/mL.
The derivation cohort consisted of 360 patients with ATTRwt diagnosed at the Mayo Clinic up to and including 2013 [1]. The median age was 75 years (range 47 to 94) and 91% were men. The commonest presenting symptoms were dyspnoea or heart failure (67%) and atrial arrhythmia (62%). The multivariable predictors of mortality were age, ejection fraction, pericardial effusion, NT-proBNP and troponin T. Of these, troponin T and NT-proBNP were chosen for a practical staging system because they are objective, reproducible and widely available.
Interpretation in practice
The three stages translate into clearly different prognoses. In the derivation cohort, the estimated 4-year survival was 57% for stage I, 42% for stage II and 18% for stage III [1]. The hazard ratio for stage III compared with stage I was 3.6 after adjustment for age and sex (p < 0.001).
| Stage | Criteria | 4-year survival | Clinical action |
|---|---|---|---|
| I | Troponin T < 0.05 and NT-proBNP < 3,000 | 57% | A good prognosis relative to the disease. A suitable candidate for tafamidis. |
| II | One biomarker above the cut-off | 42% | An intermediate prognosis. Tafamidis should be considered. The stage is broad and should be supplemented by clinical assessment of frailty and renal function. |
| III | Both biomarkers above the cut-off | 18% | A poor prognosis. Tafamidis may be considered, but the benefit is uncertain in patients with very high biomarker levels and marked frailty. |
Stage III is not an absolute contraindication to tafamidis, but it flags that the patient may have too short an expected survival for a slow-acting treatment to take effect. An Italian study of 691 patients with ATTRwt showed that stage III by the Mayo system could be stratified further: patients with an NT-proBNP >4,200 ng/L, a troponin I >92 ng/L, an age >80 years and an ECOG performance status >1 had a median survival of only 17 months compared with 57 months for the other stage III patients [2]. This "stage IIIb" concept is not part of Grogan's original classification but illustrates that stage III is a heterogeneous group.
Validation and performance
A Japanese study validated the Mayo staging system in 176 patients with ATTRwt (median age 78 years, 85% men) [3]. Since NT-proBNP was not routinely used in Japan, it was replaced by BNP with a threshold of 250 pg/mL, while the troponin T threshold was kept at 0.05 ng/mL. The system stratified significantly for both all-cause mortality and heart failure hospitalisation. Patients with two or three biomarkers above the thresholds (corresponding to stages II and III) had an adjusted hazard ratio for death of 6.96 (95% CI 2.88 to 16.83) compared with patients with none or one abnormal biomarker. Median survival in the high-risk group was 32.0 months. The study also showed that stage II could be stratified further with the eGFR, while stages I and III were not affected by adding a third variable.
The Italian multicentre study by Milani et al. confirmed that both the Mayo and the NAC/Mondor staging systems stratified significantly in a cohort of 691 patients with ATTRwt [2]. When a high-risk definition based on NT-proBNP, troponin I, age and ECOG-PS was added to stage III, the ability to identify patients who died within 3 months improved (AUC 0.79 compared with 0.76 for the traditional Mayo stage, p = 0.012).
A multicentre study from 2025 examined whether high-sensitivity troponin I (hs-cTnI) could replace troponin T in the Mayo system [4]. With a threshold of 80 ng/L for hs-cTnI and an NT-proBNP >3,000 ng/L, the three stages were reproduced with significantly different prognoses in an independent validation cohort of 345 patients. This is relevant because many laboratories now use hs-cTnI instead of conventional troponin T.
Limitations
The Grogan staging system was derived specifically for ATTRwt and should not be applied to hereditary (variant) ATTR cardiomyopathy without separate validation. The Gillmore system (NAC staging), which uses NT-proBNP and eGFR, is validated for both wild-type and hereditary ATTR and may be the better choice when the patient population is mixed [5].
The system rests on biomarkers measured at a single point in time and does not capture disease progression. A patient who is in stage I at diagnosis may move rapidly to stage II or III on deterioration, and reassessment at clinical deterioration is warranted.
Stage II is a broad intermediate category. As the Japanese validation showed, the eGFR can be added to stratify stage II patients further, but this is not part of Grogan's original system [3]. Clinical assessment of frailty and functional status should always complement the staging, particularly when deciding on tafamidis.
Renal function is not included in the system, even though a reduced eGFR is an independent predictor of mortality in ATTR-CM and influences NT-proBNP levels. This is a weakness particularly in older patients with concurrent renal failure, in whom a raised NT-proBNP may in part reflect reduced clearance rather than the severity of heart failure alone.
The troponin T cut-off (0.05 ng/mL) refers to a conventional troponin T assay. Many laboratories now use high-sensitivity methods. An adaptation study has shown that hs-cTnI with a threshold of 80 ng/L can replace troponin T in the system, but the threshold is assay-specific and cannot be transferred directly to other hs-cTnI methods without validation [4].
References
- Grogan M et al. Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk Stratification Using a Novel Staging System. J Am Coll Cardiol 2016. PMID: 27585505
- Milani P et al. Predictors of Early Death in Patients With Wild-Type Transthyretin Cardiac Amyloidosis. J Am Heart Assoc 2025. PMID: 39719432
- Nakashima N et al. A simple staging system using biomarkers for wild-type transthyretin amyloid cardiomyopathy in Japan. ESC Heart Fail 2022. PMID: 35191205
- De Michieli L et al. High-Sensitivity Cardiac Troponin I for Risk Stratification in Wild-Type Transthyretin Amyloid Cardiomyopathy. Circ Heart Fail 2025. PMID: 40371473
- Gillmore JD et al. A new staging system for cardiac transthyretin amyloidosis. Eur Heart J 2018. PMID: 29048471
