Abstract
Objective
To evaluate the prevalence and one-year prognosis associated with frailty in a contemporary cohort of older patients with non-ST-elevation acute coronary syndrome (NSTEACS).
Methods
The IMPACT-TIMING-GO registry (IMPACT of Time of Intervention in patients with Myocardial Infarction with Non-ST seGment elevation. ManaGement and Outcomes) prospectively included 1020 patients with NSTEACS undergoing invasive coronary angiography between April and May 2021. For this sub-study, patients ≥ 65 years were selected. Frailty was assessed according to FRAIL scale. We studied all-cause mortality and the composite of all-cause mortality or all-cause hospitalizations at one-year follow-up after discharge.
Results
Five hundred and sixty seven patients (mean age: 75.8 ± 6.7 years, 28.2% women) were included: 316 (55.7%) were robust, 183 (32.3%) prefrail, and 68 (12.0%) frail. Frail patients were significantly older, more often women, and presented a worse baseline clinical profile. There were no differences among groups regarding pretreatment with a P2Y12 inhibitor. An urgent angiography (< 24 h) was less frequently performed in frail patients, with no differences regarding revascularization approach or in main in-hospital adverse events, although acute kidney disease occurred more frequently in frail patients. At 1-year follow-up, 20 patients died (3.6%). Chronic kidney disease was independently associated with 1-year all-cause death, although a trend towards higher mortality was observed in frail patients (HR = 3.01; 95% CI: 0.93–9.78; P = 0.065). Frailty was independently associated with higher 1-year all-cause mortality or all-cause rehospitalizations (HR = 2.23; 95% CI: 1.43–3.46; P < 0.001)
Conclusions
In older patients with NSTEACS, frailty independently associates higher all-cause mortality or all-cause hospital admissions at one-year follow-up
Age constitutes a major risk factor for cardiovascular disease, one of the leading causes of morbidity and mortality worldwide.[1] Regarding ischemic heart disease, the number of patients admitted with diagnosis of non-ST-elevation acute coronary syndrome (NSTEACS) has importantly increased during the last years, in part due to aging population.[2] Currently, most patients are managed invasively, since coronary revascularization, especially with percutaneous coronary intervention (PCI), has been associated with lower in-hospital and one-year mortality.[3] Such findings have been related to better patient selection and advances in pharmacological and interventional therapies.[4] However, older patients, especially those who are frail, less frequently receive acute coronary syndrome (ACS) pharmacotherapies and invasive assessment,[5] although ESC Guidelines for the management of ACS state no differences should be made just because of age. Thus, there is growing interest in moving beyond the simple concept of chronological age but shifting towards the more complex notion of biological age.[6,7]
The IMPACT-TIMING-GO registry (IMPACT of Time of Intervention in patients with Myocardial Infarction with Non-ST seGment elevation. ManaGement and Outcomes) was designed to assess current clinical practices[8] and the effects of recommendations outlined in the current European Society of Cardiology guidelines regarding the diagnosis and treatment of NSTEACS in Spain.[4] Our aim is to evaluate the management and outcomes based on the frailty status in a contemporary and representative cohort of older patients admitted for NSTEACS in Spain.
METHODS
Study Design and Population
The IMPACT-TIMING-GO registry is a prospective, observational, and multicenter study performed in 23 Spanish hospitals. All patients admitted with NSTEACS (defined as NSTE myocardial infarction (NSTEMI) or unstable angina) in whom coronary angiography revealed unstable atherosclerotic cardiovascular disease or a culprit lesion were consecutively included. The design of the study has been previously described.[9] The flowchart of the study is presented in Figure S1. Exclusion criteria were type 2 myocardial infarction, takotsubo cardiomyopathy, spontaneous coronary artery dissection, a history of nonrevascularizable coronary artery disease (CAD), and any cause of troponin elevation without evidence of CAD (myocarditis, coronary spasm, etc).[9] For the purpose of this sub-study, patients aged ≥ 65 years were included. Baseline characteristics, pharmacological management, angiographic findings, procedural results and in-hospital evolution were recorded in a dedicated standardized database. The choice of treatment (antithrombotic treatment, timing of angiography, and CAD management) was based on the criteria of the attending medical staff.
The protocol was approved by the drug research ethics committees at all participating hospitals and complies with the principles of the Declaration of Helsinki. Written informed consent was obtained from all participants.
Study Endpoints and Definitions
NSTEACS and myocardial infarction were respectively defined according to the current European Society of Cardiology guidelines,[4] and the current fourth universal definition.[10] Frailty was assessed during admission, after informed consent was obtained, by trained physicians through interviews with the patient and/or family/caregivers and referring to the patient’s status before admission. To avoid selection bias, investigators were encouraged to include all patients during the first 72 h of admission.
Patients were classified as robust, prefrail or frail according to FRAIL scale.[11,12] An invasive strategy (cardiac catheterization) was defined as early if coronary angiography was performed within 24 h of admission and deferred if performed later. In-hospital complications were collected, and defined as all-cause mortality, reinfarction, and stent thrombosis,[13] acute renal failure (defined as a 50% increase in baseline creatinine values or the need for extrarenal clearance), the onset of atrial fibrillation or ventricular arrhythmias, acute confusional syndrome, and mechanical complications of infarction. Major bleeding was considered as type 3, 4, and 5 on the Bleeding Academic Research Consortium (BARC) scale.[14]
In-hospital and 1-year events were collected in all patients according to frailty status. The endpoints of the study were all-cause mortality and the composite of all-cause mortality and all-cause hospitalizations at one-year follow-up after hospital discharge.
Statistical Analysis
Categorical variables are presented as frequencies (percentages), assessing the differences by Chi-square test (or Fisher test when necessary). Continuous variables are presented as a mean ± SD or as a median (interquartile range). The Kolmogorov-Smirnov test was applied to ensure normal distribution. Continuous variables were compared using the analysis of variance (ANOVA) test or the Kruskal-Wallis test, as appropriate. Survival curves using all available follow-up data were constructed for the time-to-first-event variables using the Kaplan-Meier method. A multivariable Cox regression model was used where covariates were selected if they were significantly different between the three groups or had predictive values. The assumption of proportionality was assessed graphically by the log-minus-log plot, and Cox proportional hazard models for the primary endpoint satisfied the proportional hazards assumption. For all analyses, a two tailed P < 0.05 was used as the criterion for statistical significance. Follow-up was considered to terminate at the date of the last follow-up or at 1-year, whichever came first. Analyses were performed using STATA software (V 14.0, StataCorp LP, College Station, TX).
RESULTS
A total of 567 (55.6%) patients aged ≥ 65 years were included. Mean age was 75.8 ± 6.7 years, and 28.2% were women. Of them, 316 (55.7%) patients were classified as robust, 183 (32.3%) as prefrail, and 68 (12.0%) as frail. Baseline characteristics according to frailty status are depicted in Table 1. Frail patients were significantly older and more often women. They also had a worse baseline clinical profile and higher comorbidity burden, together with more geriatric conditions and lower self-referred quality of life.
Table 1. Baseline characteristics.
| Total (n = 567) | Robust (n = 316) | Prefrail (n = 183) | Frail (n = 68) | P-value | |
| Results are shown as n (%) and median ± SD. ASA: acetylsalicylic acid; CABG: coronary artery bypass grafting; COPD: chronic obstructive pulmonary disease; PCI: percutaneous coronary intervention; P2y12i: P2Y12 receptor inhibitor; *Chronic kidney disease defined as estimated glomerular filtration rate < 60 mlL/min per m2. | |||||
| Age, yrs | 75.8 ± 6.7 | 74.1 ± 6.2 | 77.5 ± 6.8 | 78.9 ± 6.7 | < 0.001 |
| Age ≥ 75 yrs | 284 (50.1%) | 126 (39.9%) | 108 (59.0%) | 50 (73.5%) | < 0.001 |
| Women | 160 (28.2%) | 72 (22.8%) | 56 (30.6%) | 32 (47.1%) | < 0.001 |
| Body mass index, kg/m2 | 27.4 ± 4.5 | 27.3 ± 4.3 | 27.6 ± 4.7 | 26.9 ± 4.8 | 0.53 |
| Hypertension | 444 (78.3%) | 237 (75.0%) | 149 (81.4%) | 58 (85.3%) | 0.081 |
| Diabetes | 245 (43.2%) | 117 (37.0%) | 87 (47.5%) | 41 (60.3%) | < 0.001 |
| Dyslipidemia | 399 (70.4%) | 210 (66.5%) | 129 (70.5%) | 60 (88.2%) | 0.002 |
| Smoker | 85 (15.3%) | 46 (14.8%) | 29 (16.5%) | 10 (14.7%) | 0.88 |
| COPD | 83 (14.7%) | 34 (10.8%) | 30 (16.5%) | 19 (30.0%) | 0.001 |
| Atrial fibrillation/flutter | 65 (11.5%) | 30 (9.5%) | 23 (12.6%) | 12 (17.6%) | 0.14 |
| Peripherical artery disease | 77 (13.6%) | 27 (8.5%) | 35 (19.1%) | 15 (22.4%) | < 0.001 |
| Ischemic stroke | 51 (9.0%) | 17 (5.4%) | 22 (12.1%) | 12 (17.6%) | 0.001 |
| *Chronic kidney disease | 98 (17.3%) | 37 (11.7%) | 40 (21.9%) | 21 (31.3%) | < 0.001 |
| Cancer (active or remission) | 87 (15.3%) | 40 (12.7%) | 33 (18.0%) | 14 (20.6%) | 0.12 |
| Dementia | 20 (3.5%) | 4 (1.3%) | 11 (6.0%) | 5 (7.4%) | 0.004 |
| Depression mayor | 60 (10.6%) | 17 (5.4%) | 26 (14.2%) | 17 (25.0%) | < 0.001 |
| Comorbidity scale ≥ 3 | 48 (8.5%) | 11 (3.5%) | 24 (13.1%) | 13 (19.1%) | < 0.001 |
| Quality of life (self-referred) | 70 (50–81) | 75 (60-90) | 70 (50-80) | 60 (50-70) | < 0.001 |
| Number of medications | 7 (4–10) | 6 (3–9) | 8 (5–10) | 10.5 (8–13) | < 0.001 |
| Previous myocardial infarction | 157 (27.7%) | 74 (23.4%) | 57 (31.1%) | 26 (38.2%) | 0.021 |
| Previous PCI | 161 (28.4%) | 76 (24.1%) | 58 (31.7%) | 27 (39.7%) | 0.017 |
| Previous CABG | 38 (6.7%) | 18 (5.7%) | 14 (7.7%) | 6 (8.8%) | 0.53 |
| Heart failure | 37 (6.5%) | 9 (2.8%) | 19 (10.4%) | 9 (13.2%) | < 0.001 |
| Previous ASA | 270 (47.9%) | 129 (41.1%) | 98 (53.8%) | 43 (63.2%) | < 0.001 |
| Previous P2y12i | 80 (14.2%) | 31 (9.8%) | 36 (19.8%) | 13 (19.1%) | 0.004 |
| Previous oral anticoagulation | 65 (11.5%) | 27 (8.6%) | 27 (14.9%) | 11 (16.2%) | 0.045 |
Clinical presentation, angiographic characteristics, and therapeutic management are shown in Table 2. Four hundred and thirty-six patients (76.9%) met the criteria for NSTEMI, similarly among groups. Frail patients were admitted with the highest Killip class. More than two-thirds of the included patients received pretreatment with a P2Y12 inhibitor (P2Y12i), without significant differences according to frail status. Nevertheless, prefrail and frail patients were more likely to receive clopidogrel than other P2Y12i (68.4% and 67.4% in the prefrail and frail groups vs 48.8% in the robust group, P = 0.002). An urgent angiography (< 24 h) was less frequently performed in frail patients. Regarding angiographic findings, we observed a non-significant lower incidence of left main disease in frail patients, as well as similar extension of coronary artery disease (three vessels disease) among groups. Interestingly, no differences were observed concerning revascularization approach, since most patients underwent PCI in the three groups. Notably, although not statistically significant, coronary artery bypass grafting was less often performed in frail patients. A comparison of clinical outcomes and pharmacological treatment of patients at hospital discharge between frail groups is presented in Table S1. Regarding antiplatelet therapy at discharge, frail patients received more often clopidogrel than other P2Y12i, which may be related, at least in part, to higher anticoagulation prescription. No significant differences were observed in main in-hospital adverse events (all-cause death, reinfarction, and major bleeding) although acute kidney disease occurred more frequently in frail patients. Finally, patients with frailty received different medical treatment at discharge and were less often referred to cardiac rehabilitation programs.
Table 2. Clinical presentation, medical management, and initial laboratory test.
| Total (n = 567) | Robust (n = 316) | Prefrail (n = 183) | Frail (n = 68) | P-value | |
| Results are shown as n (%), mean ± SD or median (IQR). CABG: coronary artery bypass graft; ECG: electrocardiogram; HbA1c: hemoglobin A1C; LVEF: left ventricular ejection fraction; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; LVEF: left ventricular ejection fraction; NSTEMI: non-ST segment elevation myocardial infarction; PCI: percutaneous coronary intervention; STEMI: ST-elevation myocardial infarction; TIMI: thrombolysis in myocardial infarction. | |||||
| Clinical presentation | |||||
| Prior rest chest pain | 385 (67.9%) | 206 (65.2%) | 125 (68.3%) | 54 (79.4%) | 0.074 |
| Initial ECG | 0.006 | ||||
| Normal | 233 (41.1%) | 147 (46.5%) | 62 (33.9%) | 24 (35.3%) | |
| Negative T wave | 117 (20.6%) | 67 (21.2%) | 31 (16.9%) | 19 (27.9%) | |
| ST segment depression | 161 (28.4%) | 74 (23.4%) | 66 (36.1%) | 21 (30.9%) | |
| Others | 56 (9.9%) | 28 (8.9%) | 24 (13.1%) | 4 (5.9%) | |
| Transient ST elevation | 40 (7.1%) | 24 (7.6%) | 13 (7.1%) | 3 (4.4%) | 0.65 |
| Non-STEMI diagnosis | 436 (76.9%) | 244 (77.2%) | 143 (78.1%) | 49 (72.1%) | 0.58 |
| Killip ≥ II classification | 89 (15.8%) | 29 (9.2%) | 40 (21.9%) | 20 (29.9%) | < 0.001 |
| Malignant arrythmia | 3 (0.5%) | 0 | 3 (1.6%) | 0 | 0.043 |
| Refractory angina | 16 (2.8%) | 11 (3.5%) | 4 (2.2%) | 1 (1.5%) | 0.54 |
| High-risk NSTEMI | 458 (80.8%) | 253 (80.1%) | 152 (83.1%) | 53 (77.9%) | 0.59 |
| Therapeutic management | |||||
| P2Y12i pretreatment | 385 (68.0%) | 203 (64.2%) | 136 (74.7%) | 46 (67.6%) | 0.054 |
| P2Y12i type | 0.002 | ||||
| Clopidogrel | 223 (57.9%) | 99 (48.8%) | 93 (68.4%) | 31 (67.4%) | |
| Prasugrel | 8 (2.1%) | 4 (2.0%) | 2 (1.5%) | 2 (4.3%) | |
| Ticagrelor | 154 (40.0%) | 100 (49.3%) | 41 (30.1%) | 13 (28.3%) | |
| Time from diagnosis to angiography, hours | 67 (19–76) | 69 (19–76) | 60 (17–73) | 76 (26–94) | 0.11 |
| Urgent angiography (< 24 h) | 186 (32.8%) | 110 (34.8%) | 62 (33.9%) | 14 (20.6%) | 0.071 |
| Initial TIMI flow < 3 | 167 (29.7%) | 87 (27.8%) | 53 (29.1%) | 27 (39.7%) | 0.15 |
| Multivessel disease | 341 (60.1%) | 190 (60.1%) | 112 (61.2%) | 39 (57.4%) | 0.86 |
| Left main disease | 98 (17.5%) | 57 (18.3%) | 36 (19.8%) | 5 (7.5%) | 0.065 |
| Treatment decision | 0.13 | ||||
| CABG | 63 (11.1%) | 41 (13.0%) | 20 (10.9%) | 2 (2.9%) | |
| PCI | 441 (77.8%) | 245 (77.5%) | 140 (76.5%) | 56 (82.4%) | |
| Medical | 63 (11.1%) | 30 (9.5%) | 23 (12.6%) | 10 (14.7%) | |
| Hospitalization unit | 0.019 | ||||
| Intensive care unit | 82 (14.5%) | 41 (13.0%) | 34 (18.6%) | 7 (10.3%) | |
| Coronary unit | 162 (28.6%) | 93 (29.4%) | 55 (30.1%) | 14 (20.6%) | |
| Cardiology ward | 267 (47.1%) | 156 (49.4%) | 76 (41.5%) | 35 (51.5%) | |
| Emergency unit | 38 (6.7%) | 22 (7.0%) | 9 (4.9%) | 7 (10.3%) | |
| Others | 18 (3.2%) | 4 (1.3%) | 9 (4.9%) | 5 (7.4%) | |
| Laboratory test | |||||
| Hemoglobin, mg/dL | 13.8 (12.6–14.8) | 14 (13–14.9) | 13.5 (12.3–14.8) | 13 (11.3–13.9) | < 0.001 |
| Creatinine, mg/dL | 0.93 (0.78–1.2) | 0.89 (0.77–1.1) | 0.97 (0.8–1.3) | 1.02 (0.86–1.43) | < 0.001 |
| Total cholesterol (n = 478) | 149 (123–180) | 152 (131–184) | 141.5 (110-180) | 142 (116–170) | 0.008 |
| Triglycerides (n = 478) | 114 (85–150) | 111 (86.5–147.5) | 118 (83–153) | 129 (100–173) | 0.16 |
| LDL-C (n = 478) | 81 (59–111) | 88 (68–113.5) | 75 (51.2–107) | 71 (55–81) | < 0.001 |
| HDL-C (n =478) | 40 (34–47) | 40 (35–47) | 41 (34–50) | 38 (32–46) | 0.27 |
| HbA1c (n = 434) | 6 (5.6–6.9) | 5.9 (5.6–6.8) | 6 (5.6–6.9) | 6.7 (5.9–7.3) | 0.008 |
| Echocardiography findings | |||||
| LVEF, % | 54.9 ± 10.2 | 57.0 ± 8.8 | 52.5 ± 11.3 | 52.1 ± 11.2 | < 0.001 |
| Mitral regurgitation ≥ 2 | 50 (8.9%) | 24 (7.7%) | 20 (11.0%) | 6 (9.0%) | 0.45 |
| Tricuspid regurgitation ≥ 2 | 21 (3.8%) | 5 (1.6%) | 12 (6.7%) | 4 (6.0%) | 0.010 |
At 1-year follow-up, 20 patients died (3.6%). The risk of 1-year all-cause mortality was significantly higher in the frail group as compared to that in the prefrail or robust groups (9.0% vs. 4.5% vs. 1.9%; respectively; P = 0.016) (Table 3; Figure 1A). Moreover, all-cause and cardiac rehospitalizations were all significantly more frequent in frail patients, who also presented higher percentage of composite endpoints at 1-year follow-up, including all-cause death or rehospitalization (Figure 1B). Interestingly, 41 patients (7.2%) in our study experienced major bleeding events, with no differences according to frailty status. Among these, 18 patients had previously received P2Y12i pretreatment (50% under ticagrelor/prasugrel and 50% under clopidogrel). Notably, a significant percentage of these major bleeding events occurred in patients who underwent coronary artery bypass grafting (CABG), accounting for 16% of the total number of CABG patients.
Table 3. Outcomes at one-year follow-up.
| Total (n = 553) |
Robust (n = 308) |
Prefrail (n = 178) |
Frail (n = 67) |
P-value | |
| Results are shown as n (%), mean ± SD or median (IQR). BARC: bleeding academic research consortium; MACE: major adverse cardiovascular events; MI: myocardial infarction. | |||||
| Outcomes | |||||
| All-cause death | 20 (3.6%) | 6 (1.9%) | 8 (4.5%) | 6 (9.0%) | 0.016 |
| Cardiovascular death | 8 (40.0%) | 2 (33.3%) | 3 (37.5%) | 3 (50.0%) | 0.83 |
| Reinfarction | 33 (5.9%) | 13 (4.2%) | 13 (7.1%) | 7 (10.6%) | 0.097 |
| Any revascularization | 46 (8.3%) | 23 (7.4%) | 16 (8.8%) | 7 (10.6%) | 0.66 |
| Stent thrombosis | 5 (0.9%) | 1 (0.3%) | 4 (2.2%) | 0 (0.0%) | 0.074 |
| Stroke | 3 (0.5%) | 2 (0.6%) | 1 (0.5%) | 0 (0.0%) | 0.81 |
| All bleeding | 47 (8.5%) | 22 (7.1%) | 20 (11.0%) | 5 (7.6%) | 0.32 |
| Major bleeding (BARC ≥ 3) | 41 (7.2%) | 18 (5.7%) | 19 (10.4%) | 4 (5.9%) | 0.14 |
| All-cause rehospitalization | 147 (26.4%) | 65 (21.0%) | 48 (26.4%) | 34 (51.5%) | < 0.001 |
| Cardiac rehospitalization | 45 (8.0%) | 16 (5.1%) | 18 (9.8%) | 11 (16.2%) | 0.005 |
| Composite endpoints | |||||
| MACE (all-cause death, MI, stroke) | 49 (8.9%) | 19 (6.2%) | 18 (10.1%) | 12 (17.9%) | 0.007 |
| Patient-oriented endpoint (all-cause death, MI, stroke, any revascularization) |
72 (13.0%) | 33 (10.7%) | 25 (14.0%) | 14 (20.9%) | 0.07 |
| Safety endpoint (all-cause death, MI, stroke, major bleeding) | 102 (18.5%) | 47 (15.3%) | 38 (21.4%) | 17 (25.8%) | 0.067 |
| MACE + Cardiac rehospitalization | 68 (12.3%) | 27 (8.8%) | 24 (13.5%) | 17 (25.4%) | 0.001 |
Figure 1.
Kaplan-Meier survival estimates for 1-year all-cause death and for the composite endpoint for 1-year all-cause death or all-cause rehospitalization.
(A): One-year survival rates; (B): One-year composite endpoint for all-cause death and all-cause rehospitalization.
Multivariable Cox proportional hazard models identified independent predictors of 1-year all-cause mortality and composite endpoint of all cause death or rehospitalization (Table 4). Frailty was not independently associated with an increased risk of 1-year all-cause death although a trend towards higher mortality was observed in frail patients (HR = 3.01; 95% CI: 0.93–9.78; P = 0.065). On the other hand, frailty was independently associated with higher risk of 1-year all-cause mortality or all-cause rehospitalizations (HR = 2.23; 95% CI: 1.43–3.46; P < 0.001). Chronic kidney disease was independently associated with an increased risk of 1-year all cause death.
Table 4. Predictors of all-cause death and all-cause death or rehospitalization at 12-months follow-up at one-year follow-up.
| Characteristic | Univariate Analysis | Multivariate Analysis | |||
| HR (95%CI) | P-value | HR (95%CI) | P-value | ||
| Variables identified following univariable survival analysis (Cox regression) of p value < 0.10 included in the final multivariable survival analysis model. Multivariable analysis data are presented as hazard ratio with corresponding 95% CIs. CI: confidence interval; COPD: chronic obstructive pulmonary disease; HR: hazard ratio; MI: myocardial infarction; NSTEMI: non-ST segment elevation myocardial infarction. | |||||
| Predictors of all-cause death at one-year follow-up | |||||
| Age | 1.05 (0.99–1.12) | 0.10 | |||
| Male sex | 0.74 (0.30–1.85) | 0.52 | |||
| Hypertension | 1.13 (0.38–3.37) | 0.83 | |||
| Diabetes mellitus | 1.98 (0.81–4.86) | 0.13 | |||
| Stroke | 1.61 (0.67–4.25) | 0.31 | |||
| Chronic kidney disease | 4.05 (1.67–9.77) | 0.002 | 2.87 (1.14–7.21) | 0.024 | |
| COPD | 1.64 (0.66–4.07) | 0.31 | |||
| Previous MI | 2.67 (1.11–6.41) | 0.028 | 1.95 (0.79–4.78) | 0.14 | |
| Previous IC | 2.44 (0.72–8.32) | 0.15 | |||
| Frailty | |||||
| Prefrail | 2.33 (0.81–6.71) | 0.12 | |||
| Frail | 4.72 (1.52–14.65) | 0.007 | 3.01 (0.93–9.78) | 0.065 | |
| NSTEMI diagnosis | 0.92 (0.33–2.52) | 0.87 | |||
| Killip ≥ II classification | 3.77 (1.54–9.22) | 0.004 | 2.42 (0.95–6.21) | 0.065 | |
| Multivessel disease | 1.55 (0.59–4.04) | 0.37 | |||
| Left main disease | 0.85 (0.20–1.78) | 0.80 | |||
| TIMI initial < 3 | 0.60 (0.27–1.69) | 0.33 | |||
| Complete revascularization | 0.86 (0.32–2.29) | 0.76 | |||
| P2Y12i pretreatment | 0.69 (0.28–1.69) | 0.42 | |||
| Urgent angiography (< 24 h) | 1.11 (0.44–2.78) | 0.83 | |||
| All-cause death or rehospitalization at 12-months follow-up at one-year follow-up | |||||
| Age | 1.00 (0.98–1.03) | 0.14 | |||
| Male sex | 0.91 (0.64–1.29) | 0.58 | |||
| Hypertension | 1.50 (0.97–2.34) | 0.066 | 1.03 (0.65–1.63) | 0.89 | |
| Diabetes mellitus | 1.83 (1.32–2.54) | < 0.001 | 1.32 (0.94–1.88) | 0.11 | |
| Stroke | 0.97 (0.14–6.96) | 0.94 | |||
| Chronic kidney disease | 1.81 (1.99–3.97) | < 0.001 | 2.06 (1.43–2.96) | < 0.001 | |
| COPD | 0.16 (0.03–1.15) | 0.15 | |||
| Previous MI | 1.98 (1.43–2.74) | < 0.001 | 1.71 (1.22–2.40) | 0.002 | |
| Previous heart failure | 1.88 (1.12–3.16) | 0.017 | 0.91 (0.51–1.60) | 0.74 | |
| Frailty | |||||
| Prefrail | 1.35 (0.93–1.96) | 0.12 | |||
| Frail | 3.13 (2.07–4.75) | < 0.001 | 2.23 (1.43–3.46) | < 0.001 | |
| NSTEMI diagnosis | 0.74 (0.51–1.13) | 0.12 | |||
| Killip ≥ II classification | 2.08 (1.43–3.03) | < 0.001 | 1.63 (1.10–2.41) | 0.015 | |
| Multivessel disease | 0.87 (0.62–1.20) | 0.40 | |||
| Left main disease | 1.10 (0.73–1.68) | 0.41 | |||
| TIMI initial < 3 | 0.94 (0.66–1.33) | 0.72 | |||
| Complete revascularization | 0.73 (0.51–1.04) | 0.08 | |||
| P2Y12i pretreatment | 0.94 (0.67–1.32) | 0.73 | |||
| Urgent angiography (< 24 h) | 0.87 (0.62–1.23) | 0.43 | |||
DISCUSSION
One major objective of our study was to assess the predicted value of frailty, as measured by the FRAIL scale, in NSTEACS patients over 65 years of age after hospital admission. We found frailty was associated with higher all-cause mortality and all-cause and cardiac rehospitalizations at one-year follow-up. However, in the multivariate analysis, only CKD was independently associated with one-year all-cause mortality, whilst a trend toward higher mortality was observed in patients with frailty and higher Killip class on admission. On the other hand, frailty, together with CKD, previous MI and Killip class, was significantly associated with the combined event of one-year all-cause mortality and all-cause rehospitalization.
Frailty is an age-associated clinical condition characterized by a decrease in physiological reserve in situations of stress, constituting a state of vulnerability that involves a higher risk of adverse events.[15] The overall prevalence of frailty increases with age,[16] especially in patients with acute cardiovascular disease, though such findings may vary depending on frailty approach.[15,17] Some prior studies have addressed the adverse prognostic impact related to frailty, mainly focused on mortality events, in old and very old patients with NSTEACS.[18–20] In our study, frail patients showed important baseline differences when compared with non-frail patients, since they were, as expected, significantly older and more often women. In addition, they showed a poorer clinical profile, with higher comorbidity burden and geriatric conditions, like dementia and major depression, as well as higher number of medications, similarly to previous studies.[20] Furthermore, and despite having a worse Killip class on admission together with other conditions associating higher risk of developing a complication requiring ICU care, frail patients were less often admitted in acute care units.[21] Likewise, they were more often managed conservatively, as previously observed in a recent study comprising more than 3 million patients aged ≥ 65 years,[22] although such difference did not reach statistical difference in our registry. In addition to the above, in previous studies including NSTEACS patients, frailty has been independently associated with an increased risk of major complications and more adverse events during follow-up.[20,23,24] On the other hand, comorbidity also plays an important role in this clinical setting. In two recent studies including very old patients with NSTEACS (≥ 70 and ≥ 80 years old, respectively) some conditions like advanced age and high comorbidity burden were related to lower benefit of an invasive approach, with CKD associating, together with PAD and chronic lung disease, the most unfavorable prognosis.[25,26] As previously described, all such conditions were significantly more prevalent in frail patients in our cohort. Remarkably, CKD was found to be the only condition independently associated with both all-cause mortality and all-cause mortality and rehospitalization at one-year follow-up in older patients included in our study. In contrast, in a prior study including nearly 350 patients ≥ 65 years hospitalized for ACS (79% NSTEACS), renal dysfunction was independently associated with higher mortality during a 30-month median follow-up in the clinical model, but it was not statistically significant when fragility was incorporated into the predictive model (which was indeed significantly associated with higher mortality).[23] In that study, 80% of patients underwent coronary angiography and only 44% underwent PCI. Similarly, a recent study including very old patients with NSTEACS suggests the association between renal function impairment and adverse outcomes was only significant in patients without frailty.[27] Finally, previous studies, including a recent metanalysis performed by Leszek, et al with more than 3400 patients, demonstrated CKD, defined as estimated glomerular filtration rate < 60 ml/min per m2 or maintenance on dialysis, is significantly associated with more adverse events in patients with NSTEACS, with a trend towards lower incidence of all-cause mortality in patients undergoing revascularization.[28]
In our study, we did not find differences according to frailty status during one-year follow-up in accordance with revascularization. Notably, two other interesting studies, including patients ≥ 80 years with NSTEACS, have also evaluated the benefit of revascularization in this setting, associating lower events during follow-up.[2] However, frailty was not routinely assessed in those studies, also comprising patients much older than those in our cohort. On the other hand, a recent clinical trial including 167 frail patients admitted with NSTEACS demonstrated no benefit from a routine invasive strategy in terms of days alive and out of the hospital from discharge to one year.[29] Of note, patients included in that study were all ≥ 70 years (mean age 85 ± 6 years, older than patients included in our cohort) and frailty was assessed according to Clinical Frailty Scale. Despite these differences, and according to the study by Sanchís et al,[29] a routine invasive strategy does not seem to provide benefits in terms of lower adverse clinical events in elderly frail patients with NSTEACS.
As in previous studies, patients with frailty received different medical treatment at discharge.[5,30] Again, and compared with patients without frailty, frail patients showed a higher incidence of MACE and other adverse events at one-year follow-up, highlighting the importance of a holistic and integrated approach, as recommended in recent scientific statements specifically addressing the management of ACS in patients ≥ 65 years.[30] In this regard, geriatric conditions should always be addressed in older patients admitted for an ACS, since their presence, irrespective of age, associates worse prognosis.[15] Accordingly, it is recommended to individualize interventional and pharmacological management according to patients´ baseline situation and characteristics, with a care plan adapted to the needs of each patient and their prognosis. Of note, previous studies addressing the role of frailty in patients with NSTEACS were specifically conducted in older patients or using other scales.[18,20] These issues, along with the low proportion of frail patients in our cohort and the relatively low incidence of mortality at one-year follow-up may explain our results.
Our study has some limitations that merit discussion. First, it is an observational study so we cannot rule out the possibility of selection bias. Although participating centers were instructed to include all NSTEACS patients, it is possible that some patients, especially those exhibiting higher frailty, were not included in the study. In fact, the prevalence of frailty in our cohort was lower than that previously described in studies including patients ≥ 65 years, although using other frailty scales.[20] Furthermore, our registry only included patients undergoing coronary angiography and demonstrated coronary artery disease. It is plausible that an invasive management was not performed in patients with greater fragility or in those with worse clinical profile, and some of these high-risk patients may have dyed before undergoing coronary angiography (i.e., frail patients with left main disease), thus not being included in our study.[5] Finally, a longer clinical follow-up will be required to reveal potential additional differences in events according to frailty, since the incidence of one-year mortality was low in our cohort. Notwithstanding these limitations, this multicenter nationwide study provides new and interesting information, as well as novel insights, on the different prognosis according to frailty of NSTEACS patients from a current, large prospective cohort of consecutive unselected patients.
In conclusion, frailty independently associates higher all-cause mortality and all-cause hospital admissions at one-year follow-up in older NSTEACS patients. Frailty should be assessed when planning patients´ care plan from hospital admission.
DECLARATIONS
SUPPLEMENTARY DATA
Supplementary data to this article can be found online.
Authors' Contributions
P. Cepas-Guillén, P. Diez-Villanueva, designed and performed the analysis, and wrote the manuscript. All the authors collected the data, reviewed, and edited the manuscript.
Conflict of Interests
None.
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Supplementary Materials
Supplementary data to this article can be found online.