A total of 656 patients with hemoglobin levels below 12 mg/dL and who had acute coronary syndrome between 2014 and 2021 were included in the study. In the first year after acute coronary syndrome, 82% (538) of the patients received Clopidogrel and 18% (118) Ticagrelor treatment. The mean age of patients receiving ticagrelor treatment was lower than patients receiving clopidogrel (58.5 ± 10.5, 66.4 ± 13.0, p = < 0.001). 60.8% of patients receiving clopidogrel and 70.3% of patients receiving ticagrelor were male. Diabetes, hypertension, and coronary artery disease were similar in both groups (p = 0.60, p = 0.45, p = 0.10, respectively). CRF and CHF were more common in patients receiving clopidogrel (p = 0.03 and p < 0.001, respectively). The shock rate, LVEF, and PRECISE DAPT, and Killip scores of the patients at admission were similar in both groups (p = 0.59, p = 0.57, p = 0.71, p = 0.56, respectively). In both groups, the majority of patients were NSTEMI patients (93.1% in those receiving clopidogrel, 94.1% in those receiving ticagrelor). LAD was the most common culprit vessel in both groups, and patients receiving interventional or medical therapy were similar in both groups. Other clinical and demographic characteristics are shown in Table 1.
Table 1 Clinical and Demographic Characteristics of The Study Population
Patient Characteristics
|
Clopidogrel
(n=538)
|
Ticagrelor
(n=118)
|
P value
|
Age (year)
|
66.4±13.0
|
58.5±10.5
|
<0.001*
|
Gender (male) %
|
60.8(327)
|
70.3(83)
|
0.052
|
BMI (kg/m2)
|
28.2±5.1
|
29.2± 5.6
|
0.065
|
Dislipidemia %
|
9.9(53)
|
4.2(5)
|
0.052
|
DM %
|
39.0(210)
|
36.4(43)
|
0.600
|
HT %
|
64.7(348)
|
61.0(72)
|
0.452
|
History of CAD %
|
71.9(387)
|
64.4(76)
|
0.104
|
History of PCI %
|
31.2(168)
|
38.1(45)
|
0.147
|
History of CABG %
|
14.7(79)
|
9.3(11)
|
0.125
|
CRF %
|
16.4(88)
|
8.5(10)
|
0.030*
|
CHF %
|
12.8(69)
|
3.4(4)
|
0.003*
|
Current Smoking %
|
39.2(211)
|
50.8(60)
|
0.020*
|
COPD %
|
5.9(32)
|
6.8(8)
|
0.732
|
High Precise DAPT Score
|
81.6(439)
|
83.1(98)
|
0.711
|
Killip III-IV %
|
5.6(30)
|
4.2(5)
|
0.558
|
Shock at admission %
|
1.5(8)
|
0.8(1)
|
0.589
|
Length of stay in the hospital
|
4.6±1.6
|
4.6±1.6
|
0.941
|
LVEF (%)
|
45.2±11.6
|
44.5±11.8
|
0.570
|
Type of ACS
STEMI %
NSTEMI %
|
6.9(37)
93.1(501)
|
5.9(7)
94.1(111)
|
0.710
|
WBC (103/mL)
|
10.1±4.0
|
10.1±3.7
|
0.955
|
eGFR (ml/dk/1.78m2)
|
60.2±27.5
|
59.2(27.6)
|
0.710
|
ASA %
|
100.0(538)
|
100.0(118)
|
1.000
|
Beta-Blocker %
|
92.4 (497)
|
95.8(113)
|
0.192
|
CCB %
|
14.1(76)
|
11.0(13)
|
0.372
|
ACEI/ARB %
|
66.2(356)
|
67.8(80)
|
0.735
|
MRA %
|
8.6(46)
|
6.8(8)
|
0.526
|
PPI %
|
95.4(513)
|
99.2(117)
|
0.055
|
Number of vessels with severe stenosis
No-Vessel
One-Vessel disease
Two-Vessel disease
Three-Vessel disease
|
17.5(94)
26.2 (141)
23.0(124)
33.3(179)
|
7.6(9)
32.2(38)
31.4(37)
28.8(34)
|
0.014*
|
Culprit Vessel
None
Left anterior descending
Circumflex
Right coronary
Graft
|
12.8(69)
37.5(202)
22.1(119)
22.1(119)
5.4(29)
|
4.2(5)
43.2(51)
22.9(27)
23.7(28)
5.9(7)
|
0.120
|
Treatment Method
PCI
CABG
Medical follow-up
|
68.8(370)
16.7(90)
14.5(78)
|
70.3(83)
13.6(16)
16.1(19)
|
0.716
|
ACEI/ARB: Angiotensin-converting enzyme inhibitors/Angiotensin receptor blockers, ASA: Acetylsalicylic acid, BMI: Body mass index, CABG: Coronary artery By-pass grafting, CAD: Coronary artery disease, CCB: Calcium channel blocker, CHF: Congestive heart failure, COPD: Chronic obstructive pulmonary disease, DM: Diabetes mellitus, GFR: Glomerular filtration rate, HT: Hypertension, LVEF: Left ventricular ejection fraction, MACE: Major adverse cardiovascular events MI: myocardial infarction, PAD: Peripheric artery disease, PCI: Percutaneous intervention, STEMI: ST-elevation myocardial infarction, WBC: White blood cell
- Continuous variables are given as mean ± SD.
- Median, interquartile range (range, [25% percentile-75% percentile])
The lower level of hemoglobin affecting MACE was determined using ROC analysis. In anemia patients, a hemoglobin level below 9.7 mg/dL was associated with an increase in MACE with 43.3% sensitivity and 42.4% specificity (AUC: 0.427, p = 0.05) (Fig. 1).
Patients treated with clopidogrel and ticagrelor were compared for the efficacy and safety outcomes of 1-year MACE and major bleeding. MACE and major bleeding were similar in P2Y12 treatment groups (MACE: clopidogrel 10.0% vs. ticagrelor 11.0%, p = 0.75; major bleeding: clopidogrel 2.8%, ticagrelor 2.5%, p = 0.88). Similarly, both groups had similar total mortality, cardiovascular mortality, reinfarction, and hemorrhagic stroke. While ischemic stroke was observed in 16 patients in the clopidogrel group, it was not observed in the ticagrelor group (p = 0.04) (Table 2).
Table 2
Comparison of Patients Followed up with Clopidogrel wr Ticagrelor in Terms of 1-Year MACE and Major Hemorrhage
Primary Efficacy and Safety Endpoints %(n)
|
Study endpoints
|
1-Year Cardiovascular Outcomes
|
Clopidogrel
|
Ticagrelor
|
P Value
|
MACE
|
10.0(54)
|
11.0(13)
|
0.750
|
Major Bleeding
|
2.8(15)
|
2.5(3)
|
0.882
|
Secondary Endpoints %(n)
|
Total Mortality
|
5.8(31)
|
5.9(7)
|
0.943
|
CV Mortality
|
4.3(23)
|
3.4(4)
|
0.661
|
Reinfarction
|
2.4(13)
|
1.7(2)
|
0.635
|
Ischemic Stroke
|
3.0(16)
|
0.0(0)
|
0.041*
|
Hemorrhagic Stroke
|
0.9(5)
|
0.0(0)
|
0.293
|
CV: Cardiovascular, MACE: Major adverse cardiac events |
• Continuous variables are given as mean ± SD. |
• Median, interquartile range (range, [25% percentile-75% percentile]) |
Table 3
Comparative Analysis of Primary and Secondary Endpoints Across Different Hemoglobin Levels (≤ 8, 8–10, and 10–12 mg/dL) in Patients Receiving Clopidogrel and Ticagrelor Treatment.
Primary Efficacy and Safety Endpoints %(n)
|
Study Endpoints
|
Clopidogrel (N = 538)
|
P Value
|
Ticagrelor (N = 118)
|
P Value
|
≤ 8 mg/dL
|
8–10 mg/dL
|
10–12 mg/dL
|
≤ 8 mg/dL
|
8–10 mg/dL
|
10–12 mg/dL
|
MACE
|
12.5(6)
|
10.2(24)
|
9.4(24)
|
0.810
|
36.4(4)
|
11.9(7)
|
4.2(2)
|
0.008*
|
Major Bleeding
|
6.3(3)
|
2.1(5)
|
2.8(7)
|
0.286
|
18.2(2)
|
0(0)
|
2.1(1)
|
0.002*
|
Secondary Endpoints %(n)
|
Total Mortality
|
8.3(4)
|
5.5(13)
|
5.5(14)
|
0.727
|
36.4(4)
|
3.4(2)
|
2.1(1)
|
< 0.001*
|
CV Mortality
|
8.3(4)
|
3.8(9)
|
3.9(10)
|
0.347
|
27.3(3)
|
1.7(1)
|
0(0)
|
< 0.001*
|
Reinfarction
|
2.1(1)
|
3.4(8)
|
1.6(4)
|
0.422
|
9.1(1)
|
1.7(1)
|
0(0)
|
0.110
|
Ischemic Stroke
|
2.1(1)
|
3.4(8)
|
2.8(7)
|
0.855
|
0(0)
|
0(0)
|
0(0)
|
-
|
Hemorrhagic Stroke
|
2.1(1)
|
0.8(2)
|
0.8(2)
|
0.683
|
0(0)
|
0(0)
|
0(0)
|
-
|
CV: Cardiovascular, MACE: Major adverse cardiovascular events |
• Continuous variables are given as mean ± SD. |
• Median, interquartile range (range, [25% percentile-75% percentile]) |
Tablo 4 Analysis of the Impact of Clinical and Demographic Characteristics on MACE Using Univariate and Multivariate Cox Regression
Patient Characteristics
|
Univariate Analysis
|
HR
|
95% CI
Lower-Upper
|
P value
|
Age
|
1.001
|
0.974-1.029
|
0.931
|
Gender (male)
|
0.835
|
0.426-1.639
|
0.601
|
BMI
|
1.045
|
0.993-1.099
|
0.090
|
Dislipidemia
|
1.843
|
0.887 3.829
|
0.101
|
DM
|
0.810
|
0.428 1.531
|
0.516
|
HT
|
0.884
|
0.440-1.776
|
0.730
|
History of CAD
|
0.506
|
0.165-1.556
|
0.235
|
History of PCI
|
6.970
|
3.385-14.352
|
<0.001
|
History of CABG
|
7.729
|
3.834-15.581
|
<0.001
|
CRF
|
2.636
|
1.418-4.900
|
0.002
|
CHF
|
1.997
|
0.942-4.233
|
0.071
|
Current Smoking
|
0.771
|
0.415-1.432
|
0.410
|
COPD
|
2.450
|
0.963-6.229
|
0.060
|
High Precise DAPT Score
|
1.054
|
1.023-1.086
|
<0.001
|
Killip III-IV
|
1.145
|
0.341 3.839
|
0.827
|
Shock at admission
|
0.349
|
0.021-5.834
|
0.464
|
Length of stay in the hospital
|
0.820
|
0.684-0.983
|
0.032
|
LVEF (%)
|
0.956
|
0.932-0.980
|
<0.001
|
Type of ACS
|
1.135
|
0.024-2.246
|
0.345
|
Betablocker
|
1.128
|
0.361-4.548
|
0.702
|
ACEi/ARB
|
0.949
|
0.462-1.949
|
0.886
|
Number of vessels with severe stenosis
|
0.799
|
0.195-3.274
|
0.755
|
Culprit vessel
|
0.264
|
0.063-1.102
|
0.068
|
Treatment method
|
1.408
|
0.020-97.70
|
0.874
|
Patient Characteristics
|
Multivariate Analysis
|
HR
|
95% CI
Lower-Upper
|
P value
|
History of PCI
|
3.961
|
2.366-6.631
|
<0.001
|
History of CABG
|
5.327
|
3.250-8.732
|
<0.001
|
CRF
|
2.261
|
1.338-3.820
|
0.002
|
High Precise DAPT Score
|
1.034
|
1.013-1.055
|
<0.001
|
Length of stay in the hospital
|
0.897
|
0.768-1.047
|
0.169
|
LVEF (%)
|
0.977
|
0.9560.999
|
0.037
|
ACEI/ARB: Angiotensin-converting enzyme inhibitors/Angiotensin receptor blockers, BMI: Body mass index, CABG: Coronary artery By-pass grafting, CAD: Coronary artery disease, CHF: Congestive heart failure, COPD: Chronic obstructive pulmonary disease, DM: Diabetes mellitus, HT: Hypertension, LVEF: Left ventricular ejection fraction, MI: myocardial infarction, PCI: Percutaneous intervention.
Patients receiving clopidogrel and ticagrelor were analysed in terms of their effect on primary and secondary endpoints, divided into 3 groups according to hemoglobin levels as ≤ 8, 8–10, and 10–12 mg/dL. Hemoglobin level was ≤ 8 mg/dL in 59 (9%) patients, 8–10 mg/dL in 295 (45%) patients, and 10–12 mg/dL in 302 (46%) patients. There was no significant difference in primary efficacy and safety outcomes and secondary outcomes according to the anemia subgroups in patients receiving clopidogrel treatment. MACE and major hemorrhage were significantly higher in patients treated with ticagrelor than in patients with a hemoglobin level of ≤ 8 mg/dL (p = 0.008 and p = 0.002, respectively). In patients receiving ticagrelor treatment, MACE was observed in 36.4% of patients and major bleeding in 18.2% at 1 year. When the secondary endpoints were examined, it was observed that the difference in MACE rates was mainly due to total mortality and cardiovascular mortality. In patients with hemoglobin level ≤ 8 mg/dL, 36.4% total mortality and 27.3% cardiovascular mortality were observed at 1 year. Since fewer patients received ticagrelor treatment, reinfarction was observed in only 2 patients, while stroke was not observed in any patient (Table 2).
Patients with and without MACE in the clopidogrel and ticagrelor treatment groups were compared according to their hemoglobin levels. Hemoglobin levels were similar according to MACE outcome in patients receiving clopidogrel treatment (MACE (-) 9.91 mg/dL, MACE (+) 9.55 mg/dL, p = 0.39). Hemoglobin levels in patients receiving ticagrelor treatment were statistically significantly lower in MACE (+) patients than in MACE (-) patients (MACE (-) 9.90 mg/dL, MACE (+) 8.60 mg/dL, p < 0.001) (Fig. 2).
The effects of clinical and demographic characteristics of the patients on MACE were analysed by univariate and multivariate Cox Regression analysis. In the univariate analysis, PCI history, CABG history, CRF, high PRECISE DAPT score, length of stay in hospital, and LVEF were determined as factors affecting MACE (p < 0.001, p < 0.001, p = 0.002, p < 0.001 and p < 0.001, respectively). In the Multivariate Cox regression analysis, the relationship between the length of stay in hospital and MACE lost its significance, while PCI history, CABG history, CRF, high PRECISE DAPT score and LVEF were determined as factors affecting MACE (p < 0.001, p < 0.001, p = 0.002, p < 0.001 and p < 0.037, respectively) (Table 4)
Survival analysis was conducted to compare patients across three hemoglobin level categories: ≤8, 8–10, and 10–12 mg/dL. Additionally, patients were stratified into two groups based on hemoglobin levels below and above 9.7 mg/dL, a threshold impacting MACE as determined by ROC analysis. MACE was more common in patients with hemoglobin levels below 8 than in the other two groups. However, MACE was observed at similar rates in the other two groups (Log Rank p = 0.11). Patients with a hemoglobin level below 9.7 had a higher MACE than patients with a hemoglobin level above 9.7 (Log Rank p = 0.03) (Fig. 3).
In the analysis of survival according to the P2Y12 treatment group, 1-year MACE and major hemorrhage were similar in the clopidogrel and ticagrelor groups (Log Rank p = 0.76 for MACE; Log Rank p = 0.89 for major hemorrhage) (Fig. 4)
In the study, 154 (23.5%) patients were 75 years or older. MACE was observed in 17 patients and major hemorrhage was observed in 4 patients within 1 year. In these patients, survival analysis was performed in terms of 1 year MACE and major hemorrhage compared to the P2Y12 treatment group. In patients with anemia over 75 years of age, 1st year MACE rates were found to be similar in both groups (Log Rank p = 0.74), while 1st year major hemorrhage was higher in patients who received ticagrelor treatment (Log Rank p = 0.04) (Fig. 5)