Prognostic relevance of GRACE risk score in Takotsubo syndrome

Abstract

Background:

Takotsubo syndrome is an increasingly recognised cardiac condition that clinically mimics an acute coronary syndrome, but data regarding its prognosis remain controversial. It is currently unknown whether acute coronary syndrome risk scores could effectively be applied to Takotsubo syndrome patients. This study aims to assess whether the Global Registry of Acute Coronary Events (GRACE) score can predict clinical outcome in Takotsubo syndrome and to compare the prognosis with matched acute coronary syndrome patients.

Methods:

A total of 561 Takotsubo syndrome patients was included in this prospective registry. According to the GRACE score, the population was divided into quartiles. The primary endpoint was all-cause mortality and the secondary endpoints were cardiocerebrovascular events (a composite of all-cause mortality, cardiovascular death, recurrence of Takotsubo syndrome and stroke).

Results:

The median GRACE risk score was 139±27. Takotsubo syndrome patients with a higher GRACE risk score mostly have a higher rate of physical triggers and lower left ventricular ejection fraction on admission. During long-term follow-up, all-cause mortality rates were 5%, 11%, 12% and 22%, respectively, in the first, second, third and fourth quartile (P<0.001). After multivariate analysis, the GRACE risk score was found to be a strong predictor of all-cause mortality (odds ratio (OR) 1.68, 95% confidence interval (CI) 1.28–2.20; P=0.001) and cardiocerebrovascular events (OR 1.63, 95% CI 1.26–2.11; P=0.001). Moreover, all-cause mortality in Takotsubo syndrome patients was comparable with the matched acute coronary syndrome cohort.

Conclusion:

In Takotsubo syndrome, the GRACE risk score allows us to predict all-cause mortality and cardiocerebrovascular events at long-term follow-up.

Keywords

GRACE risk score Takotsubo syndrome acute coronary syndrome prognostic score mortality major cardiocerebrovascular events

Introduction

Takotsubo syndrome (TTS) is an acute condition with clinical presentation similar to an acute myocardial infarction (AMI). Indeed, TTS has been classified, in the last European Society of Cardiology (ESC) guidelines for ST-segment elevation myocardial infarction (STEMI), as a myocardial infarction without obstructive coronary artery,¹ but it is characterised by transitory abnormalities of the left ventri-cular function that usually recovers within a few weeks after the acute event.² Despite the early recovery of heart function, the short and long-term prognosis of TTS is not benign, because mortality and adverse event rates may be comparable with AMI.³ The Heart Failure Association of the ESC recommends inhospital risk stratification of TTS patients, in order to provide more intensive surveillance and treatment for high-risk patients.⁴ However, a reliable, specific and universally validated prognostic score has not been established to date.^5,6 Clinical prediction models, easily detectable in everyday clinical practice, could be potentially helpful for the clinical management of TTS patients, either in the short or long term. It has recently been demonstrated that scores developed for other cardiac disorders, such as the CHA₂DS₂-VASc score, can be used for risk stratification in TTS.⁷

In recent years, the Global Registry of Acute Coronary Events (GRACE) risk score has been increasingly used in patients with AMI to assess either short or long-term outcomes.^8,9 International guidelines recommend to use the GRACE risk score in all patients with suspected or confirmed acute coronary syndrome (ACS).¹⁰ Nevertheless, its predictive ability in patients with TTS has not been investigated to date.

This study aims to assess the ability of the GRACE risk score to predict all-cause mortality and major adverse cardiocerebrovascular events (MACCE) in an unselected cohort of TTS patients and to compare the prognosis with matched ACS patients.

Methods

Study design and patient population

This was a multicentre and observational study. A total of 561 patients enrolled at 22 participating centres of the Takotsubo Italian Network (TIN) were included in the final analysis. The study population fulfilled the TIN diagnostic criteria:¹¹ (a) typical transient left ventricular wall motion abnormalities extending beyond a single epicardial vascular distribution with complete functional normalisation within 6 weeks; (b) the absence of potentially culprit coronary stenosis, or angiographic evidence of acute plaque rupture, dissection, thrombosis or spasm; (c) new and dynamic ST-segment abnormalities or T-wave inversion or new onset transient or permanent left bundle branch block; (d) a mild increase in myocardial injury markers; (e) clinical and/or instrumental exclusion of myocarditis; (f) post-menopausal woman (optional); (g) antecedent stressful event (optional). An antecedent stressful trigger event was defined as an occurrence that produced short-term physiological change that may lead directly to the onset of acute cardiovascular disease. They could be either emotional or physical (including acute medical or surgical emergencies).¹² Coronary angiography was performed as soon as possible (ideally within 48 hours from admission).

The study was approved by the local ethics committees. All patients provided informed consent.

Comparison between TTS and ACS

We compared a subgroup of 300 TTS patients with 300 age, sex, left ventricular ejection fraction (LVEF) and diabetes-matched ACS patients. LVEF and diabetes were included in the match algorithm as well known risk factors either in TTS or in ACS. LVEF at admission, despite the recovery of systolic dysfuncion, is a key parameter to identify TTS patients at higher risk not only in the acute phase but also at long-term follow-up;¹³ likewise diabetes is an independent predictor of long-term mortality in TTS irrespective of other risk factors.¹⁴

Data for ACS patients were collected from the RECLOSE 2-ACS study, a prospective, single-centre cohort study of consecutive patients undergoing invasive management. All patients were considered eligible for the study irrespective of the clinical presentation of ACS or coronary anatomy.¹⁵

Prognostic score risk

According to the current guidelines,¹⁰ the GRACE risk score was calculated using the risk calculator (http://www.gracescore.org/website/WebVersion.aspx) based on age, pulse rate, systolic blood pressure, Killip class, serum creatinine and cardiac biomarker levels, ST-segment deviation on admission and the presence of cardiac arrest at presentation. CHA₂DS₂-VASc scores were calculated as previously reported.¹⁶ The whole population was divided into quartiles according to GRACE risk scores.

Endpoints

The primary endpoint was all-cause mortality and the secondary endpoints were MACCE (a composite of all-cause mortality, cardiovascular death, recurrence of TTS and stroke). Individual components of the composite endpoint were additional secondary endpoints.

Follow-up

All patients had scheduled follow-up at one, 6 and 12 months after the index event, and annually thereafter. All other possible information gathered from hospital readmission charts and telephone interviews or by referring physicians, relatives, or municipality vital registries were entered into the prospective database.

Statistical analysis

Discrete data were expressed as frequencies, continuous data as mean ± SD or median and interquartile range as appropriate. The χ² test was used to compare categorical variables, and analysis of variance (ANOVA) with the Tukey post hoc test was used to assess differences in the baseline characteristics between the four study groups. Cumulative incidence curves were generated following the Kaplan–Meier method, assessing among groups differences with the log-rank test. Multivariate analyses were performed by the forward stepwise Cox proportional hazards model to evaluate the independent contribution of the GRACE score to the primary endpoint and to the composite secondary endpoint. The variables entered into the model were as follow: GRACE score, age, diabetes mellitus, hypertension, ST-elevation and LVEF of 40 or less.

We used a parsimonious model including variables with P<0.10 by the univariate test as a candidate for the multivariate analysis. For every outcome, the GRACE score has been entered in the model as a continuous variable. Model goodness of fit was assessed with the Hosmer–Lemeshow test. Multicollinearity was assessed using collinearity diagnostics. The variance inflation factors showed no significant collinearity (<2.5) among the covariates. The risk of overfitting was controlled by using a ratio of at least 1:10 for the number of explanatory variables and sample size. The area under the receiver operating characteristic (ROC) curve (AUC) was used as a measure of the predictive accuracy of the GRACE and CHA2DS2-VASc score. The statistical significance of the difference between two AUCs was tested with the method of DeLong. The relative performance of each test was evaluated with a 95% confidence interval for the difference between two AUCs. A propensity score-matched analysis (1:1) was performed because of the expected differences in baseline characteristics between patients with TTS and ACS. We performed nearest neighborhood matching with Mahalanobis distance, 0.25 standard deviation distance tolerance caliper. Bias reduction was assessed by comparing the standardised difference for propensity score and the other covariates before and after matching between the two groups (a value <10% after matching indicates inconsequential imbalance). A P value less than 0.05 was considered significant. All tests were two-sided. Analyses were performed using the SPSS statistical package, version 21 (IBM Corp., Armonk, NY, USA).

Results

Patient population

A total of 561 TTS patients (mean age 73±10, women 92%) were included in the final analysis. The main baseline characteristics are summarised in Table 1.

Table 1.

Baseline characteristics of study patients by quartile of the GRACE score.

Variables	Total cohort (n=561)	1st quartile (n=140)	2nd quartile (n=140)	3rd quartile (n=141)	4th quartile (n=140)	P value
Prognostic risk score
GRACE score, median (IQR)	139 (122–158)	107 (94–117)^{† ‡ §}	133 (128–137)^{* ‡ §}	150 (145–154)^{* † §}	173 (165–182)^{* † ‡}	<0.001
CHA₂DS₂-VASc median (IQR)	3 (2–4)	2 (1–3)^{† ‡ §}	4 (2.2–5)^{* §}	4 (3–5)^*	4 (3–5)^*	<0.001
Demographics
Age, years	73 ± 10	61 ± 10^{† ‡ §}	73 ± 7^{* ‡ §}	76 ± 7^{* † §}	80 ± 6^{* † ‡}	<0.001
Female sex, n (%)	519 (92)	131 (94)	133 (94)	128 (91)	127 (91)	0.677
Menopause, n (%)	494 (88)	122 (87)	123 (88)	128 (91)	120 (86)	0.737
Trigger, n (%)
Physical	172 (31)	34 (24)^§	33 (23)^§	46 (33)	59 (42)^{* ‡}	0.001
Emotional	240 (43)	72 (51)	64 (45)	53 (37)	51 (36)	0.034
No evidence	149 (26)	34 (24)	43 (30)	42 (30)	30 (21)	0.063
ECG, n (%)
ST-elevation	282 (50)	49 (35)^{‡ §}	59 (41)^§	77 (55)^*	97 (70)^{* ‡}	<0.001
ST-depression	42 (7)	11 (8)	8 (6)	10 (7)	13 (9)	0.696
T wave inversion	275 (49)	65 (47)	67 (48)	80 (57)	63 (45)	0.195
Atrial fibrillation	82 (15)	6 (4)^{‡ §}	21 (15)	27 (19)^*	28 (20)^*	0.001
Haemodynamics
Heart rate (bpm) median (IQR)	84 (73–100)	80 (70–90)^§	80 (71–94)^§	85 (73–100)^§	96 (80–106)^{* † ‡}	<0.001
Systolic BP (mmHg) median (IQR)	125 (110–141)	136 (120–155)^{‡ §}	130 (116–144)^§	120 (110–140)^*	114 (100–130)^{* †}	<0.001
Diastolic BP (mmHg) median (IQR)	74 (65–83)	80 (70–90)^{‡ §}	75 (70–84)^§	70 (65–80)^{* §}	70 (60–80)^{* † ‡}	<0.001
LVEF on admission median (IQR)	40 (30–45)	45 (38–50)^{† ‡ §}	40 (38–45)^{* §}	38 (30–43)^{* §}	35 (25–40)^{* † ‡}	<0.001
Killip class III–IV (%)	46 (8)	1 (0.7)^§	6 (4)^§	9(6)^§	30 (22)^{* † ‡}	<0.001
Variant type, n (%)
Apical	394 (70)	99 (71)	106 (75)	94 (66)	95 (68)	0.352
Mid-ventricular	151 (26)	36 (25)	40 (28)	33 (23)	42 (39)	0.700
Basal	22 (4)	6 (4)	7 (5)	5 (3)	4 (3)	0.812
Serum Biomarkers
Abnormal cardiac enzymes	538 (96)	127 (91)^{‡ §}	134 (94)	137 (97)^*	140 (100)^*	0.002
NT-proBNP, pg/ml^# median (IQR)	3643 (1210–9733)	1300 (513–3952)^§	3952 (852–7409)	3388 (1255–12664)	7517 (2916–16236)^*	0.031
CRP, µg/ml^II median (IQR)	9 (1–23)	6.3 (0.7–10.5)^§	9 (1–18)^§	9.5 (2.4–72)	15 (2–88)^{* †}	0.014
WBC, x10³/L^** median (IQR)	9.1 (7.2–11)	8.9 (6.6–10)^§	10 (7.9–11)^§	9.2 (7.6–12)	8.7 (6.9–14)^{* †}	0.009
Coexisting medical condition, n (%)
Hypertension	367 (65)	69 (50)^{† ‡ §}	100 (71)^*	100 (71)^*	98 (70)^*	<0.001
Diabetes mellitus	83 (15)	17 (12)	22 (15)	20 (14)	24 (17)	0.710
Dyslipidemia	188 (33)	48 (34)	53 (37)	47 (34)	40 (29)	0.541
PAD	35 (6)	3 (2)^§	10 (7)	8 (6)	14 (10)^*	0.082
CKD	65 (11)	1 (1)^§	6 (4)^§	22 (16)^§	36 (26)^{* † ‡}	<0.001
Cancer	96 (17)	35 (25)	17 (12)	22 (16)	22 (16)	0.327
Psychiatric disorders	102 (18)	27 (19)	17 (12)	36 (26)	22 (16)	0.244
Medication at discharge, n (%)
ACE-I or ARB	398 (71)	96 (69)	113 (80)	94 (66)	95 (67)	0.369
β-blocker	398 (71)	102 (72)	96 (68)	97 (69)	103 (74)	0.740
Aspirin	404 (72)	94 (67)	91 (65)	103 (74)	110 (79)	0.163
Statin	230 (41)	56 (41)	75 (54)	50 (36)	49 (36)	0.002

P<0.05 vs. 1st quartile; ^†P<0.05 vs. 2^nd quartile; ^‡P<0.05 vs. 3rd quartile; ^§ P<0.05 vs. 4th quartile.

Data available in 297 patients.

Data available in 111 patients.

Data available in 210 patients.

BP: blood pressure; LVEF: left ventricular ejection fraction; CRP: C-related protein; WBC: white blood cell; PAD: peripheral artery disease; CKD: chronic kidney disease; ACE-I: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker.

The median GRACE risk score was 139, interquartile range 122–158. Based on their GRACE scores, patients were divided into quartiles.

TTS related to physical trigger was mostly detected in the higher GRACE score risk quartile (24%, 23%, 33% and 42%, respectively, in the first, second, third and fourth group; total P<0.001), while TTS related to emotional trigger had an inverse relationship (51%, 45%, 37% and 36%, respectively, in the first, second, third and fourth quartiles; total P=0.034). Of note, the rate of ST-elevation electrocardiographic pattern raised with the GRACE score (35%, 41%, 55% and 70%, respectively, in the first, second, third and fourth quartiles; total P<0.001) and LVEF on admission was significantly lower in patients with a higher GRACE risk score (43±10, 39±11, 36±10 and 22±11, respectively, in the first, second, third and fourth quartiles; total P<0.001).

Comparison of TTS patients with age, sex, LVEF and diabetes-matched ACS patients

A subgroup of 300 TTS patients was compared with an age, sex, LVEF and diabetes-matched cohort of 300 ACS patients. Patient characteristics and outcomes of the TTS and ACS matched cohort are summarised in Supplementary Table 1.

Long-term mortality analysis revealed a trend towards worse prognosis in ACS patients, without statistical significance (Figure 1).

GRACE score and outcomes in TTS patients

The median follow-up length was 29 months (interquartile range 12–70) and the follow-up rate was 95%. The incidence of all-cause mortality was significantly higher in patients in the higher GRACE score quartiles (5%, 11%, 12% and 22%, respectively, in the first, second, third and fourth quartiles; total P<0.001) as well as the MACCE rates (6%, 13%, 13% and 23%, respectively, in the first, second, third and fourth quartiles; total P=0.001). No difference in the TTS recurrence rate was observed among quartiles. Table 2 summarises the outcomes according to GRACE score quartiles.

Table 2.

Outcomes of the study population according to GRACE quartiles.

	Total cohort (n=561)	1st quartile (n=140)	2st quartile (n=140)	3rd quartile (n=141)	4th quartile (n=140)	P value^†
MACCE, n (%)	77 (14)	8 (6)	19 (13)	18 (13)	32 (23)	0.001
All-cause mortality	69 (12)	7 (5)	16 (11)	17 (12)	29 (22)	<0.001
Cardiovascular death	14 (2)	0 (0)	1 (0.7)	5 (3)	8 (6)	0.004
Recurrence of TTS	8 (1.4)	1 (0.7)	2 (1.4)	1 (0.7)	4 (3)	0.305
Stroke	8 (1.4)	0 (0)	1 (0.7)	5 (3)	2 (1.4)	0.083

†

By log-rank test.

MACCE: major adverse cardiocerebrovascular event; TTS: Takotsubo syndrome.

The Kaplan–Meier curves for all-cause mortality of the study groups are reported in Figure 2(a); the Kaplan–Meier-1 curves depicting cardiovascular death of the four quartiles are reported in Figure 2(b). Using multivariate analysis, the GRACE risk score emerged as a strong predictor of all-cause mortality (hazard ratio (HR) 1.25 per 10 points increase, 95% confidence interval (CI) 1.3–2.2; P =0.001) and for MACCE (HR 1.18 per 10 points increase, 95% CI 1.3– 2.1; P =0.001) (Table 3). The GRACE score remained significantly associated with these endpoints after the assessment of the goodness of fit with the Hosmer–Lemeshow test (P=0.83 and P=0.72 for the Hosmer–Lemeshow test, respectively, all-cause mortality and MACCE).

Table 3.

Predictors of all-cause mortality and MACCE.

	HR	95% CI	P value
MACCE
GRACE score	1.18	1.07–1.31	0.001
Age (years)	1.08	0.67–1.79	0.715
Diabetes mellitus	1.96	1.16–3.23	0.012
Hypertension	1.30	0.80–2.10	0.287
ST-elevation	0.66	0.43–1.07	0.066
LVEF ≤ 40	1.08	0.80–2.10	0.287
All-cause mortality
GRACE score	1.25	1.10–1.42	0.001
Age (years)	1.97	1.02–3.78	0.042
Diabetes mellitus	2.90	1.53–5.40	0.001
Hypertension	0.78	0.42–1.43	0.427
ST-elevation	0.70	0.39–1.24	0.221
LVEF ≤40	1.09	0.60–1.96	0.780

HR: hazard ratio; CI: confidence interval; MACCE: major adverse cardiocerebrovascular event; LVEF: left ventricular ejection fraction.

Predictor abilities of risk scores

In Figure 3, ROC curves depict the ability of the GRACE risk score and CHA₂DS₂-VASc scores to predict long-term outcome. The GRACE score was able to discriminate overall mortality in patients with TTS (GRACE score AUC 0.67, 95% CI 0.60–0.73; P<0.001). Moreover, a higher discriminatory ability was demonstrated to detect cardiovascular death as compared with non-cardiovascular death (AUC 0.81, 95% CI 0.72–0.90 vs. AUC 0.62, 95% CI 0.54–0.70; P=0.025, respectively, cardiovascular death and non-cardiovascular death).

Supplementary Table 2 lists the AUC for the GRACE and CHA₂DS₂-VASc scores in predicting all-cause mortality, cardiovascular death and non-cardiovascular death, respectively. The GRACE and CHA₂DS₂-VASc scores were able to discriminate all-cause mortality and non-cardiovascular death in TTS. The discriminatory performance of the two risk scores in predicting the risk of all-cause mortality and non-cardiovascular death was not significantly different. Moreover, the GRACE score demonstrated better discrimination than the CHA₂DS₂-VASc score in predicting cardiovascular death (AUC 0.81 vs. AUC 0.54; P=0.012, respectively, GRACE and CHA₂DS₂-VASc score).

Discussion

The main findings of this study are the following:

TTS patients had a similar long-term outcome compared with age, sex, diabetes and LVEF-matched ACS patients.

The GRACE risk score calculated on admission can reliably predict outcomes in patients with TTS.

The GRACE risk score provided significant prognostic information both for non-cardiovascular and cardiovascular mortality, albeit with higher discrimination for the latter.

Our study confirms that TTS is a less benign disease than previously thought,³ and notes that the short and long-term all-cause mortality of TTS is similar to an age, sex, LVEF and diabetes- matched cohort of ACS patients.

Current ACS guidelines recommend early risk stratification in order to plan appropriate management.¹⁰ This can be achieved using an established risk scoring system that predicts mortality. A consistent number of clinical risk scores has been proposed for ACS patients.^17,18 The American College of Cardiology Foundation/American Heart Association¹⁹ and the ESC suggest the use of the GRACE score as one of the most accurate in this setting.¹⁰ As TTS presentation commonly mimics ACS and the prognosis is comparable, the initial diagnostic and prognostic work-up should be similar.⁴

Consequently, a widely used risk stratification tool, such as the GRACE risk score, should also be used in TTS patients. Hence, the GRACE risk score requires no additional evaluations other than those routinely carried out in ACS patients. After the diagnosis of TTS, risk stratification may help physicians in selecting treatment for patients at greatest risk of complications and to minimise interventions in patients at low risk.⁴

The InterTAK diagnostic score, a reliable algorithm to differentiate between ACS and TTS, has recently been validated in TTS patients.²⁰ Therefore, the InterTAK diagnostic score and the GRACE score might both be used to help physicians in the diagnosis and clinical management in suspected TTS.

Although initially developed only in ACS patients,⁸ the GRACE has score demonstrated a prognostic value in different clinical settings (i.e. pulmonary embolism²¹ and heart failure)²² suggesting its ability in the global evaluation of patients.

Our study, for the first time, demonstrated the prognostic ability of the GRACE score in predicting clinical outcome in a cohort of unselected TTS patients.

The ability of the GRACE risk score in TTS risk stratification may be related to its individual variables, such as higher heart rate,²³ lower blood pressure,²⁴ older age, Killip class,²⁵ serum creatinine²⁶ and the presence of cardiac arrest or other malignant arrhythmias²⁷ that have previously been correlated to prognosis in TTS.

In our population, considering the old age and high comorbidities,²⁸ TTS mortality was driven by non-cardiovascular death in accordance with previous observations.²⁵ The GRACE risk score demonstrated a lower predictive ability than previously described in ACS patients,⁸ and its original cutoff for risk categories, although showing a trend in favour of discrimination, did not reach the statistical significance in our cohort of TTS patients (STEMI patients log-rank 0.10; non-STEMI patients log-rank 0.21, see Supplementary Figure 1), possibly due to the low cardiovascular death incidence in TTS. Nevertheless, the GRACE risk score can also predict the occurrence of non-cardiovascular death, albeit with a lower discriminatory ability. Therefore the GRACE risk score, although having better discrimination in cardiovascular events, can reliably predict the whole risk profile of TTS patients.

The GRACE risk score, although not specifically developed, proves to be a quick and simple tool in the risk stratification of a complex and variegated entity such as TTS. Furthermore, it showed good discriminatory ability in predicting cardiovascular death in this cohort of patients.

These findings have relevant clinical implications: first, the use of widespread prognostic risk scores, such as the GRACE score, always available in the routine work-up of TTS patients, can help physicians in selecting the patients who may benefit the most from admission to the intensive care unit; second, due to the high predictive value of cardiovascular death, the GRACE risk score may identify TTS patients to be planned for a strict cardiovascular follow-up.

Our study must be evaluated in light of some limitations. First, the study results are based on a multicentre observational study and can be considered as only hypothesis generating. Wider and randomised clinical studies are needed to validate the prognostic value of the GRACE risk score in TTS patients and to verify its impact on clinical decision-making. Second, the predictive ability of the GRACE score should be further assessed in an external validation cohort.

Conclusion

In conclusion, the GRACE risk score demonstrated significant discriminatory ability to predict mortality and MACCE in TTS and the clinical outcome between TTS patients and the age, sex, LVEF and diabetes-matched ACS cohort are similar. Further analyses are needed to identify the features of high-risk TTS in order to select patients who may benefit the most from admission to intensive care units and from a strict cardiovascular follow-up.

Supplemental Material

Supplemental_Material – Supplemental material for Prognostic relevance of GRACE risk score in Takotsubo syndrome

Supplemental material, Supplemental_Material for Prognostic relevance of GRACE risk score in Takotsubo syndrome by Fernando Scudiero, Luca Arcari, Luca Cacciotti, Elena De Vito, Rossella Marcucci, Ilaria Passaseo, Luca Rosario Limite, Maria Beatrice Musumeci, Camillo Autore, Rodolfo Citro, Eduardo Bossone, Giuseppe D Sanna, Beatrice Bacchi, Massimo Volpe, Carlo Di Mario and Guido Parodi in European Heart Journal: Acute Cardiovascular Care

Footnotes

Conflict of interest

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: GP reported receiving consulting or lecture fees from AstraZeneca, Bayer, Chiesi, Daiichi Sankyo/Eli Lilly and Merck Sharp Dohme. RM received honoraria for lectures from Daiichi Sankyo/Eli Lilly and Merck Sharp Dohme. CDM received research grants from Abbott and Medtronic.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: GP was supported by the A.R. CARD Foundation, Florence, Italy. LA and LRL were supported by a type 2 Start Research Grant (AR21816436B0B884) by Sapienza, University of Rome, Italy. All other authors have nothing to disclose.

Supplementary material

Supplementary material for this article is available online.

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