1. Invasive Versus Conservative Strategy in Patients Aged 80 years or Older with NSTEMI or Unstable Angina(After Eighty study)
Nicolai Tegn, Michael Abdelnoor, Lars Aaberge, Knut Endresen, Pål Smith, Svend Aakhus, Erik Gjertsen, Ola Dahl-Hofseth, Anette Hylen Ranhoff , Lars Gullestad, Bjørn Bendz

2. Background
During past two decades mortality from ACS has reduced because of development of modern treatment strategies such as revascularization, medical treatment, and risk factor reduction post- discharge. Improvements have mainly been realized in younger people, median age of 65, and men.
NSTEMI and USA are frequent causes of hospital admission in the patient population over 80 years old. However, they are less likely to receive invasive and medical treatment based on guidelines and are at a higher risk of adverse events.
In larger, randomized controlled trials of the effect of revascularization versus medical treatment, the population aged 80 years and older is under-represented.

3. This Trial’s Aim and Value
The aim of the present randomized controlled trial was to investigate whether patients aged 80 years or older would benefit from an early invasive strategy versus a conservative strategy, in terms of a composite primary endpoint of myocardial infarction, need for urgent revascularization, stroke, and death.
The After Eighty study is the first, randomized controlled trial to be specifically designed for the population aged 80 years or older with NSTEMI and USA.

4. Design and Participants
The After Eighty study was an open-label, randomized, controlled multicenter trial. Between Dec 10, 2010, and Feb 21, 2014, patients admitted to 16 academic and teaching hospitals without PCI facilities in the South-East Health Region of Norway were included.
The trial enrolled clinically stable patients aged 80 or older with NSTEMI or USA, with or without ST depression and with or without raised troponin concentration.
Patients were excluded if they were clinically unstable with continuing chest pain or other ischemic signs/symptoms, cardiogenic shock, continuing bleeding problems, or life expectancy less than 12 months because of comorbidities. They were also excluded if they had substantial mental disorder that interfered with ability to comply with protocol.

5. Baseline characteristics
Invasive strategy group (n=229)
Conservative strategy group (n=228)
Mean age (range)
84·7 (80–93)
84·9 (80–94)
Sex
Male
125 (55%)
100 (44%)
Female
104 (45%)
128 (56%)
Medical history
Previous myocardial infarction
107 (47%)
90 (39%)
Previous angina
124 (54%)
115 (50%)
Previous PCI
55 (24%)
46 (20%)
Previous CABG
44 (19%)
32 (14%)
Hypertension
131 (57%)
139 (61%)
Type 2 diabetes
45 (20%)
Peripheral vascular disease
19 (8%)
29 (13%)
Atrial fibrillation
49 (21%)
52 (23%) EF
EF <30%
12 (5%)
7 (3%)
EF 30–50%
64 (28%)
70 (31%)
EF >50%
127 (56%)
ECG at admission
42 (18%)
Pathological Q wave
35 (15%)
40 (18%)
ST depression
43 (19%)
Negative T wave
34 (15%)
48 (21%)
Right bundle branch block
21 (9%)
17 (7%)
Left bundle branch block
22 (10%)
24 (11%)
Troponin elevation*
216 (94%)
209 (92%)
Creatinine (mg/dL)
1·15 (0·50)
1·19 (0·94)
Glomerular filtration rate
52 (12)
54 (11)

6. Procedure and Outcomes
Patients were randomly assigned to one of two groups, receiving either invasive or conservative treatment strategies.
Invasive strategy included early coronary angiography with immediate assessment for PCI, CABG, or optimum medical treatment, whereas the conservative strategy was optimum medical treatment alone.
If patients in conservative group had reinfarction, refractory angina, malignant ventricular arrhythmia, or increasing heart failure symptoms, they were considered for urgent angiography.
Primary outcome was a composite of MI, need for urgent revascularization, stroke, and death-the first occurring event. Secondary outcome was death from any cause.

7. Study Details Median follow-up was 1.53 years.
During the inclusion period, 4187 patients aged 80 years or older were admitted to the participating hospitals with the diagnosis NSTEMI or unstable angina (47%) patients were candidates for inclusion (23%) of the candidates for inclusion gave written consent and were randomly assigned to the invasive group (229 patients) or the conservative group (228 patients).
Of the 39 cases of MI in the invasive group, 11 were related to PCI.
In conservative group, two patients had a reinfarction and eight had refractory angina a few days after inclusion. Eight of these patients underwent PCI.
No crossovers occurred between the two strategy groups. Reinfarction, refractory angina pectoris, development of malignant ventricular arrhythmias, or increasing symptoms of heart failure were deemed to require urgent revascularization, which was an endpoint.

8. Details regarding medical treatment at inclusion and coronary angiography
Invasive strategy group (n=229)
Conservative strategy group (n=228)
Medical treatment at inclusion
Aspirin
226 (99%)
222 (97%)
Clopidogrel
195 (85%)
188 (82%)
Ticagrelor
11 (5%)
12 (5%)
Warfarin
39 (17%)
21 (9%)
Low molecular weight heparin
173 (76%)
Dabigatran
1 (<1%)
β blocker
192 (84%)
196 (86%)
Statins
206 (90%)
193 (85%)
ACE inhibitor or ARB
99 (43%)
116 (51%)
Calcium channel blocker
46 (20%)
47 (21%)
Nitrates
106 (46%)
126 (55%)
Coronary angiographic data (based on the 220 given angiography)
Three-vessel disease or left main
105 (48%) NA
Two-vessel disease
40 (18%)
One-vessel disease
35 (16%)
Calcification, no significant stenosis
38 (17%)
Normal
2 (1%)
Revascularization therapy
PCI
107 (47%)
CABG
6 (3%)
Angiography not done
9 (4%)
228 (100%)

9. Results
Mean time to angiography was 3 days; mean length of overall hospital stay was 6 days in the invasive group and 5 days in the conservative group.
During follow-up the primary endpoint occurred in 93 (41%) patients in invasive group and in 140 (61%) patients in conservative group. Hazard Ratio=0.53 and p= The estimated number needed to treat was 4.8
12-month mortality in the invasive group was 12.7% in the invasive group and 14.1% in the conservative group. After 12 months the cumulative hazard incidence of MI was 11.8% (invasive) versus 27.7% (conservative).
Age 84 or younger had an HR of 0.36 and age more than 84 had an HR of Age 90 or younger had an HR of 0.47 and age more than 90 had an HR of This shows change of effect with age, but the study could not be conclusive in patients over 90 years old due to low number (34 patients).

10. Clinical outcomes and complications
Invasive strategy group (n=229) Conservative strategy group (n=228) Rate ratio p value
Primary endpoint
Composite endpoint (41%) (61%) (0.37–0.63)
Components of the primary endpoint
Myocardial infarction (17%) (30%) (0.33–0.75)
Urgent revascularisation (2%) (11%) (0.05–0.52)
Stroke (3%) (6%) (0.22–1.60)
Death from any cause (25%) (27%) (0.59–1.27)
Complications (bleeding)
Major (2%) (2%)
Minor (10%) (7%)

11. Kaplan-Meier curves of survival free from composite outcome
The primary outcome was a composite of myocardial infarction, need for urgent revascularisation, stroke, and death.

12. Comparison to Prior Studies
Median age in previous trials was younger than 65 years but was older in this trial and is also older in community populations. Previous trials did not have adequate sample sizes to enable subgroup analysis in patients older than 80 years.
The Italian Elderly Acute Coronary Syndrome studied population over 80 but was underpowered (196 patients).
A meta-analysis of the FRISC II, ICTUS, and RITA-3 trials suggested that patients older than 75 years benefit from a routine invasive strategy, but data are not available for patients aged 80 years or more.
In the 2003–10 Nationwide Inpatient Sample database and the GRACE registry an early invasive strategy in patients aged 80 or older was associated with a reduction in endpoints.
Comparison to previous trials difficult because of different study designs and different combinations and components of composite endpoints.

13. Conclusions
Results indicate that an invasive strategy is superior to a conservative strategy in the reduction of composite events in clinically stable patients aged 80 years or more after presenting w/ NSTEMI or USA.
Of the four components of the primary outcome, MI and need for urgent revascularization reached statistical significance whereas stroke and death from any cause were not significant.
There is a dilution of the efficacy occurring with increasing age, however. For patients older than 90 years the study cannot conclude if the invasive strategy is beneficial.
Bleeding complications did not differ between the two groups.

14. Hazard ratio of efficacy versus age
Lowess smoother of hazard ratio versus age controlling for logcreatinine.

15. Discussion
Treatment of elderly patients is challenging because they are more likely to present with atypical symptoms in ACS, such as an absence of chest pain.
This population of patients over 80 is rarely included in clinical trials and guidelines are based on extrapolation of data from younger populations. Thus, management of this subgroup of elderly patients is not yet evidence based.
Practice patterns continue to show less use of cardiac drugs and invasive care, even in elderly patients likely to benefit. Uncertainty about risks and benefits could explain this.

16. Implications
Previous randomized trials suggest an invasive strategy is beneficial after NSTEMI and USA. The results from this study support use of an invasive strategy in patients aged 80 years or older.
For patients older than 90 the efficacy of an invasive strategy remains unclear.