J Thromb Thrombolysis DOI 10.1007/s11239-014-1084-3
Weight of the bleeding impact on early and late mortality after percutaneous coronary intervention Gjin Ndrepepa • Elena Guerra • Stefanie Schulz Massimiliano Fusaro • Salvatore Cassese • Adnan Kastrati
•
Ó Springer Science+Business Media New York 2014
Abstract The association between bleeding and timing of mortality after percutaneous coronary intervention (PCI) remains poorly investigated. We aimed to investigate the impact of bleeding on early (30-day) and late (30-day to 1 year) mortality after PCI. The study includes 14,180 patients. Bleeding within 30 days after PCI was defined using the Bleeding Academic Research Consortium criteria. Landmark analysis pre-specified at 1 month was performed to assess early and late mortality associated with bleeding. The main outcome was all-cause early and late mortality after PCI. Overall, 414 patients (2.9 %) died within the first year after PCI. Within 30 days after PCI there were 36 deaths among patients with bleeding (n = 1,510) and 44 deaths among patients without bleeding (n = 12,670; Kaplan–Meier [KM] estimates of mortality, 2.4 and 0.3 %; adjusted hazard ratio [HR] = 5.00, 95 % confidence interval 3.16–7.88, P \ 0.001). In the 30-day to 1-year period there were 68 deaths among patients with bleeding and 266 deaths among patients without bleeding (KM estimates, 4.7 and 2.1 %; adjusted HR = 1.65 [1.25–2.17], P \ 0.001. Bleeding was the strongest correlate of 30-day mortality. The association of bleeding with late mortality was significant but was weaker than that of age, diabetes, C-reactive protein, serum creatinine and platelet count. In conclusion, patients with bleeding after PCI continue to be at higher risk of early and G. Ndrepepa (&) E. Guerra S. Schulz M. Fusaro S. Cassese A. Kastrati Deutsches Herzzentrum, Lazarettstrasse 36, 80636 Munich, Germany e-mail: [email protected] A. Kastrati DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
late mortality compared to patients without bleeding. Bleeding was the strongest associate of early mortality whereas the increased risk for late mortality was mostly mediated by cardiovascular risk factors clustered in patients with bleeding. Keywords Bleeding Mortality Percutaneous coronary intervention
Introduction Ample evidence from large registries and randomized trial cohorts supports the existence of a relationship between bleeding and subsequent mortality in patients undergoing percutaneous coronary intervention (PCI) [1–5]. While, studies almost unanimously concur regarding the strong and positive association between bleeding and early mortality (up to 30 days after PCI), they are deeply divided regarding the association of bleeding with late mortality. Some studies have reported that the risk imposed by bleeding is sustainable at 1 year (or beyond) after PCI [4, 6, 7]. Other studies have reported a marked attenuation [8] or a decrease to non-significant levels of the risk for mortality after 30 days (or 40 days) [9, 10] in patients with bleeding compared with patients without bleeding. A trajectory of risk following bleeding and a quantitative assessment of bleeding impact on early and late mortality remain poorly investigated. Moreover, it remains unknown whether in studies that have reported a long-term association between bleeding and mortality, the risk difference is acquired early after bleeding events (i.e. within the first 30 days of the bleeding event) and it simply is sustained over time or patients with bleeding continue to be at higher risk for mortality (or other adverse events) over time
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intervals beyond the early period (30 days) compared with patients without bleeding. We undertook this study with a two-fold objective: first with the help of landmark analysis, we performed a risk analysis of the association between bleeding and mortality in the first 30 days and between 30 days and 1 year after PCI; and second, we comparably analyzed the weight of the bleeding impact on mortality within the first 30 days and 30-day to 1 year time intervals after PCI.
Methods Patients The study includes 14,180 patients recruited in 7 Intracoronary Stenting and Antithrombotic Regimen (ISAR) randomized trials that investigated the efficacy of antithrombotic therapies in patients undergoing PCI. Detailed inclusion/exclusion criteria in these trials are provided in a recent publication from our group [11]. Overall there were 9,035 patients (63.7 %) with stable coronary artery disease and 5,145 patients (36.3 %) with non-ST-segment elevation acute coronary syndromes (2,770 patients with nonST-segment elevation myocardial infarction and 2,375 patients with unstable angina). Patients with ST-segment elevation myocardial infarction were not included in the primary trials and, thus, they are not included in this analysis. Coronary artery disease was confirmed by angiographic criteria: angiographic documentation of coronary stenoses with C50 % lumen obstruction in, at least, one of the three major coronary arteries and/or culprit lesions in patients with acute coronary syndromes. Written informed consent was required for participation. The study conforms to the declaration of Helsinki and each trial was approved by institutional review board(s) at all participating centers. Peri-PCI antithrombotic therapy Patients underwent PCI (mostly with stent implantation) after receiving 325–500 mg of aspirin and 600 mg loading dose of clopidogrel. Peri-PCI antithrombotic/anticoagulant therapy consisted of: (1) glycoprotein IIb/IIIa receptor inhibitor abciximab (bolus of 0.25 mg/kg of weight followed by an infusion of 0.125 lg/kg/min [a maximum of 10 lg/min] for 12 h) plus a 70 U/kg intravenous bolus of unfractionated heparin (3,554 patients; 25.1 %); (2) unfractionated heparin administered as an intravenous bolus of 140 U/kg of weight (4,972 patients; 35.1 %); (3) unfractionated heparin administered as an intravenous bolus of 100 U/kg of weight (2,505 patients; 17.6 %); and 4) bivalirudin administered as a bolus of 0.75 mg/kg of weight, followed by an infusion of 1.75 mg/kg of weight
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per hour for the duration of the procedure (3,149 patients; 22.2 %).
PCI procedure Coronary stenting with either bare-metal or drug-eluting stents was performed as per standard practice. Femoral artery route was used for vascular access. Sheaths were removed and manual compression was applied as soon as the activated partial-thromboplastin time fell below 50 s. Postprocedural therapy included aspirin (80–325 mg/day indefinitely) and clopidogrel (75–150 mg/day until discharge but for no longer than 3 days, followed by 75 mg/day for C1 month in patients with bare-metal stents or C6 months in patients with drug-eluting stents). Other cardiac medications were prescribed at the discretion of the patient’s physician. Angiographic data were analyzed in a single angiographic core laboratory.
Study outcome and definitions The main outcome of this study was all-cause mortality at 30 days (early mortality) and in the time period between 30 days and 1 year after PCI (late mortality). Bleeding events occurring within the first 30 days after PCI were defined according to the Bleeding Academic Research Consortium (BARC) criteria [12]. BARC bleeding criteria were retrospectively applied. Class 5 bleeding (fatal bleeding) was not assessed as a distinct class but it was distributed to other classes depending on the initial classification. Details of the application of the BARC criteria to the study patients and the criteria used to classify bleeding events according to the bleeding site are shown in a prior publication from our group [11]. Adjudication and classification of the bleeding events was performed by personnel not involved in the primary studies. All patients were either seen by their physician or interviewed by telephone at 30 days, 6 months, and 1 year after the procedure. Patients who had cardiac complaints at those time points or any time during the follow-up underwent a complete clinical, ECG, and laboratory evaluation. Information on mortality was obtained from hospital records, death certificates or phone contact with the referring physician(s), relatives of the patient, insurance companies and registration of address office. Cardiac death was defined according to Academic Research Consortium criteria and included any death due to proximate cardiac cause (e.g. myocardial infarction, low-output failure, fatal arrhythmia), unwitnessed death and death of unknown cause, and all procedure-related deaths, including those related to concomitant treatment.
Bleeding and mortality association Table 1 Baseline clinical and angiographic characteristics Characteristic
Survivors (n = 13,766)
30-day non-survivors (n = 80)
30-day to 1-year non-survivors (n = 334)
P1*
P2**
P3***
Age (years)
67.2 [59.7; 74.1]
74.5 [67.2; 81.8]
74.8 [67.1; 80.9]
\0.001
\0.001
Women
3,243 (23.6)
19 (23.6)
91 (27.2)
0.967
0.117
0.525
Diabetes mellitus
4,131 (30.0)
35 (43.7)
163 (48.8)
0.007
\0.001
0.416
0.98
Requiring insulin
1,122 (8.1)
14 (17.5)
68 (20.4)
0.002
\0.001
0.564
Body mass index (kg/m2)
27.1 [24.8; 29.8]
26.3 [24.0; 29.1]
26.3 [23.3; 29.1]
0.094
\0.001
0.998
Arterial hypertension
10,744 (78.0)
55 (68.7)
267 (80.0)
0.033
0.542
0.030
Hypercholesterolemia (C220 mg/dL) Current smoker
9,418 (68.4) 2,394 (17.4)
44 (55.0) 14 (17.5)
197 (59.0) 48 (14.3)
0.007 0.979
\0.001 0.149
0.516 0.481
Prior myocardial infarction
4,087 (29.7)
30 (37.5)
130 (38.9)
0.138
\0.001
0.814
Prior coronary artery bypass surgery
1,542 (11.2)
8 (10.0)
61 (18.2)
0.719
\0.001
0.074
Acute coronary syndrome
4,941 (35.9)
57 (71.2)
147 (44.0)
\0.001
0.003
\0.001
Elevated cardiac troponin ([0.03 lg/L)
2,626 (19.1)
48 (60.0)
96 (28.7)
\0.001
\0.001
\0.001
Serum creatinine (mg/dL)
0.94 [0.80; 1.10]
1.08 [0.84; 1.30]
1.10 [0.90; 1.40]
\0.001
\0.001
0.853
C-reactive protein (mg/L)
1.6 [0.0; 5.4]
10.0 [3.0; 30.6]
6.0 [1.2; 20.9]
\0.001
\0.001
\0.001
Platelet count (9 109/L)
216 [183; 255]
226 [192; 283]
214 [177; 271]
Number of narrowed coronary arteries 1
2,822 (20.5)
5 (6.3)
30 (9.0)
2
3,848 (28.0)
13 (16.2)
73 (21.9)
3
7,096 (51.5)
62 (77.5)
231 (69.1)
10,944 (79.5)
75 (93.7)
304 (91.0)
Multivessel disease
0.023
0.004
0.618
\0.001
\0.001
0.336
0.002
\0.001
0.430
Data are median [25th; 75th percentiles] or number of patients (%) * Compares 30-day non-survivors with survivors ** Compares 30-day to 1-year non-survivors with survivors *** Compares 30-day to 1-year non-survivors with 30-day non-survivors
Statistical analysis The data are presented as median [25th, 75th percentiles], Kaplan–Meier estimates (%) or number of events/patients (%). The normality of data distribution was assessed using the one-sample Kolmogorov–Smirnov test. Continuous data were compared with the Kruskal–Wallis rank-sum test and the inter-group comparisons were performed with the Tukey’s HSD (honestly significant difference) test. Categorical data were compared with Chi square test. The survival analysis was performed using the Kaplan–Meier method and the differences in survival were compared with the log-rank test. Landmark analysis with a pre-specified landmark at 1 month was performed to assess the early and late risk of mortality associated with bleeding. The number needed to harm (NNH) or the number of patients needed to be exposed to bleeding within the 30 days after PCI to be associated with 1 death within the first 30 days or 31–60 days was calculated. Multivariable Cox proportional hazards model was used to assess independent correlates of 30-day and 30-day–1-year mortality. All variables of Table 1 plus bleeding and type of study were entered into the model(s). The proportional hazards assumption was
checked using the method by Grambsch and Therneau [13]. Discriminatory power of multivariable model(s) before (with baseline variables only) and after inclusion of bleeding events was assessed by calculating the Harrell’s c statistic the integrated discrimination improvement (IDI) [14]. All analyses were performed using R package. A twosided P value \0.05 was considered to indicate statistical significance.
Results Baseline data There were 414 deaths (2.9 %) within the first year after PCI. Landmark analysis with a pre-specified landmark at 1 month was performed to assess the 30-day and 30-day– 1 year risk of mortality associated with bleeding (Fig. 1). Eighty deaths occurred within the first 30 days after PCI (30-day non-survivors) and 334 deaths occurred between 30 days and 1 year after PCI (30-day–1-year non-survivors). The remaining 13,766 patients survived the first year of follow-up (survivors). Baseline data in survivors and
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events; 41.9 %), class 2 (230 events; 15.2 %), class 3a (468 events; 31.0 %), class 3b (159 events; 10.5 %), class 3c (12 events; 0.8 %) and class 4 (9 events (0.6 %). Bleeding occurred at the vascular access site in 905 patients and in other locations (non-access site) in 605 patients. Bleeding events and the risk of 30-day mortality
Fig. 1 Landmark analysis showing probability of death at 30 days and from 30 days–1 year in patients with and without bleeding within the 30 days after PCI
non-survivors are shown in Table 1. Overall, patients who died within the first 30 days as well as those who died between 30 days and 1 year after PCI showed a significantly worse cardiovascular risk profile compared with patients who survived the first year after PCI. Baseline characteristics of patients who died within the first 30 days and those who died between 30 days and 1 year after PCI appear to differ little with the exception of proportions of patients with arterial hypertension, acute coronary syndrome, elevated troponin level and C-reactive protein level (Table 1). Coronary stents were implanted in 76 patients (95.0 %) among non-survivors at 30 days, 306 patients (91.7 %) among 30-day–1-year non-survivors and 12,662 patients (92.0 %) among 1-year survivors (P = 0.592). Drug-eluting stents were implanted in 49 patients (61.2 %) among non-survivors at 30 days, 181 patients (54.2 %) among 30-day to 1-year non-survivors and 8,522 patients (61.9 %) among 1-year survivors. Bleeding events Bleeding events within 30 days after PCI occurred in 1,510 patients. Bleeding events occurred in 446 patients (12.5 %) treated with abciximab plus 70 U/kg of weight unfractionated heparin, 517 patients (10.4 %) treated with 140 U/kg of weight unfractionated heparin, 254 patients (10.1 %) treated with 100 U/kg of weight unfractionated heparin and 293 patients (9.3 %) treated with bivalirudin (P \ 0.001). According to patient’s status there were 36 bleeding events (45.0 %) among non-survivors at 30 days, 68 bleeding events (20.4 %) among 30-day–1-year nonsurvivors and 1,406 bleeding events (10.3 %) among 1-year survivors (P \ 0.001). According to the BARC classes, bleeding events were as follows: class 1 (632
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There were 80 deaths within the first 30 days after PCI: 36 deaths (2.4 %) among patients with bleeding and 44 deaths (0.3 %) among patients without bleeding (odds ratio [OR] = 6.95, 95 % confidence interval 4.76–10.15, P \ 0.001). There were 10 deaths (1.1 %) among patients with access site bleeding and 26 deaths (4.3 %) among patients with non-access site bleeding (OR = 3.20 [1.67– 6.13] for access site bleeding vs. no bleeding and OR = 12.66 [8.70–18.44] for non-access site bleeding vs. no bleeding). The NNH i.e. the number of bleeding events associated with 1 death within the 30-day period was 49 (25 for patients with non-access site bleeding and 132 for patients with access site bleeding). Cardiac deaths occurred in 66 patients (82.5 %). The Cox proportional hazards model showed that bleeding within the 30 days after PCI was associated with a fivefold increase in the adjusted risk of 30-day mortality (adjusted hazard ratio [HR] = 5.00 [3.16–7.88], P \0.001; Table 2). Based on the Wald Chi square values, bleeding showed the strongest correlation with mortality. The inclusion of bleeding in the multivariable model improved the discriminatory power of the model for prediction of the 30-day mortality. The c statistic of the model with baseline variables without bleeding was 0.8434 [0.8118– 0.8744] and it increased to 0.8672 [0.8261–0.9016] after inclusion of bleeding (absolute and relative IDI 0.019 and 69.5 %, respectively, P = 0.004). Bleeding events and the risk of 30-day–1-year mortality The landmark analysis showed that the risk of mortality in patients with bleeding continued to increase in the 11-month period between 30-day and 1 year after PCI (Fig. 1). In the 30-day–1-year period there were 68 deaths (4.7 %) among patients with bleeding and 266 deaths (2.1 %) among patients with no bleeding (OR = 2.24 [1.73–2.90], P \ 0.001). According to bleed location there were 34 deaths (3.9 %) among patients with access site bleeding and 34 deaths (5.9 %) among patients with nonaccess site bleeding (OR = 1.84 [1.30–2.62], P \ 0.001 for access site bleeding vs. no bleeding and OR = 2.86 [2.03–4.02] for non-access site bleeding vs. no bleeding). NNH i.e. the number of bleeding events associated with 1 death within 31–60 days after PCI was 122 (87 for patients with non-access site bleeding and 167 for patients with
Bleeding and mortality association Table 2 Results of Cox proportional hazards model applied to assess predictors of 30-day mortality
CI confidence interval, HR hazard ratio * The Wald Chi square values from the Cox model show the strength of association of various variables with mortality
Characteristic
Thirty-day mortality Chi square*
b-Coefficient
Adjusted HR [95 % CI]
P value
Bleeding (vs. no bleeding)
47.64
1.608
5.00 [3.16–7.88]
\0.001
Age (for a 10-year increase)
11.51
0.046
1.59 [1.22–2.07]
\0.001
Women
1.38
-0.329
0.72 [0.41–1.25]
0.240
Diabetes mellitus
4.33
0.492
1.64 [1.03–2.60]
0.037
Body mass index (for 5 kg/m2 increase)
0.51
-0.021
0.90 [0.68–1.20]
0.476
Arterial hypertension
5.21
-0.583
0.56 [0.34–0.92]
0.022
Hypercholesterolemia Current smoker
0.80 0.28
-0.209 0.172
0.81 [0.51–1.28] 1.19 [0.63–2.25]
0.371 0.599
Prior myocardial infarction
3.21
0.431
1.54 [0.96–2.47]
0.073
Prior coronary artery bypass surgery
1.53
-0.484
0.62 [0.29–1.33]
0.215
Acute coronary syndrome
1.11
0.419
1.52 [0.70–3.31]
0.291
Elevated cardiac troponin
10.30
1.180
3.25 [1.58–6.69]
0.001
Serum creatinine (for 1 mg/dL increase)
2.09
0.213
1.02 [0.99–1.05]
0.148
C-reactive protein (for 5 mg/L increase)
18.17
0.008
1.04 [1.02–1.06]
\0.001
Multivessel disease (vs. single vessel disease)
5.61
1.122
3.07 [1.21–7.77]
0.018
Platelet count (for 50 9 109/L increase)
4.59
0.003
1.13 [1.01–1.27]
0.032
access site bleeding). NNH increased further during the follow-up for all categories of bleeding. Cardiac deaths occurred in 182 patients (54.5 %; P \ 0.001 compared with the proportion of cardiac deaths in the 30-day mortality). The Cox proportional hazards model was used also to show independent associates of 30-day to 1-year mortality. The model showed that bleeding within the first 30 days after PCI was associated with a 65 % increase in the adjusted risk of 30-day to 1 year mortality (adjusted HR = 1.65 [1.25–2.17], P \ 0.001; Table 3). Although independently associated, the strength of association between bleeding and mortality was weaker than that of age, diabetes, C-reactive protein, serum creatinine and platelet count (Wald Chi square values in Table 3). The inclusion of bleeding in the multivariable model improved the discriminatory power of the model for prediction of the 30-day to 1-year mortality. The c statistic of the model with baseline variables was 0.7650 [0.7390–0.7960] without bleeding and 0.7669 [0.7465–0.7929] after inclusion of bleeding (absolute and relative IDI 0.0028 and 8.2 %, respectively, P = 0.009).
Discussion The main findings of this study may be summarized as follows: (1) Patients with bleeding complications after PCI remain at a higher risk of mortality up to 1 year after the
PCI compared with patients without bleeding. Although, the risk associated with bleeding diminished with time, patients with bleeding continue to be at higher risk of mortality both in the early (30-day) and late (30-day– 1 year) phase of the follow-up than patients without bleeding. In both time periods, bleeding was associated with increased risk of mortality that was independent of cardiovascular risk factors. (2) The strength of association between bleeding and mortality differs with time. Bleeding was associated with a fivefold increase in the adjusted risk of 30-day mortality and with a 65 % increase in the adjusted risk for 30-day–1 year mortality following PCI. All statistical indices showed that bleeding was the strongest associate of mortality within the first 30 days. Although bleeding remained independently associated with 30-day–1 year mortality, its association with mortality was weaker than that of age, diabetes, C-reactive protein, impaired renal function and platelet count. Studies that have investigated the impact of bleeding on late (beyond 30 days) mortality have given conflicting results. In the study by Rao et al. [15], that included patients with acute coronary syndromes, bleeding was associated with an increased risk of 30-day and 6-month mortality and there was a stepwise increase in the hazards of 30-day and 6-month mortality as bleeding severity increased. A study that included patients recruited in the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events II (REPLACE)-2 trial showed that among patients with major bleeding, mortality was
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G. Ndrepepa et al. Table 3 Results of Cox proportional hazards model applied to assess predictors of 30-day to 1 year mortality
Characteristic
Thirty-day to 1-year mortality Chi square* 12.36
0.498
1.65 [1.25–2.17]
\0.001
73.19
0.059
1.80 [1.58–2.07]
\0.001
0.28
-0.071
0.93 [0.72–1.21]
0.597
34.17
0.678
1.97 [1.57–2.47]
\0.001
Body mass index (for 5 kg/m2 increase)
9.59
-0.045
0.79 [0.68–0.92]
0.002
Arterial hypertension
0.54
-0.105
0.90 [0.68–1.19]
0.461
Hypercholesterolemia Current smoker
4.47 1.61
-0.248 0.217
0.78 [0.62–0.98] 1.24 [0.89–1.74]
0.034 0.204
Prior myocardial infarction
9.00
0.355
1.43 [1.13–1.80]
0.003
Prior coronary artery bypass surgery
5.81
0.362
1.44 [1.07–1.93]
0.016
Acute coronary syndrome
0.59
0.123
1.13 [0.83–1.55]
0.441
Elevated cardiac troponin
2.17
0.261
1.30 [0.92–1.84]
0.141
Serum creatinine (for 1 mg/dL increase)
25.18
0.274
1.03 [1.02–1.04]
\0.001
C-reactive protein (for 5 mg/L increase)
31.86
0.007
1.04 [1.02–1.05]
\0.001
6.09
0.488
1.63 [1.11– 2.40]
0.014
15.62
0.003
1.14 [1.07–1.21]
\0.001
Multivessel disease (vs. single vessel disease) Platelet count (for 50 9 109/L increase)
higher at 30 days, 6 months and 1 year after PCI compared with patients without bleeding [4]. Even after adjustment, bleeding remained an independent correlate of 1-year mortality (odds ratio of 2.66). Among patients recruited in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, major bleeding occurring within 30 days of randomization had a prolonged and steady association with mortality throughout the subsequent year [6]. Recently, Lopes et al. [7] showed that among patients C65 years of age presenting with non-ST-segment elevation myocardial infarction, cumulative mortality was higher among patients who had an inhospital bleeding at 30 days, 1 and 3 years compared with patients without bleeding. Even after adjustment, major bleeding continued to show a significant association with mortality in the time intervals between discharge and 30 days, 31 days–1 year and 1–3 years. Although in the whole cohort, the association between bleeding and mortality attenuated after 3 years, in-hospital bleeding continued to be significantly associated with higher adjusted risk of mortality even beyond 3 years (25 % increase in the adjusted risk) among patients treated with PCI. The study also suggested that the risk imposed by bleeding is weaker and less prolonged in patients undergoing medical treatment compared to those undergoing PCI [7]. Other studies, however, have come to opposite conclusions regarding the trajectory of risk after bleeding. A recent analysis from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial
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P value
Bleeding (vs. no bleeding)
Diabetes mellitus
* The Wald Chi square values from the Cox model show the strength of association of various variables with mortality
Adjusted HR [95 % CI]
Age (for a 10-year increase) Women
CI confidence interval, HR hazard ratio
b-Coefficient
Infarction 38 (TRITON-TIMI 38) showed that serious bleeding was strongly associated with mortality only within the first month of the bleeding. However, the hazard ratio did not differ statistically from baseline risk by 40 days after the bleeding event [9]. In this study, spontaneous bleeding was associated with a higher and more prolonged risk for death than instrumented/traumatic bleeding [9]. In another recent study that included patients with ST-segment elevation myocardial infarction treated with primary PCI, occurrence of bleeding, defined according to the Global Utilization of Streptokinase and Tissue Plasminogen for Occluded Arteries (GUSTO) criteria was associated with a significant increase of the risk for mortality (hazard ratio 5.42) 1 day after the event and the risk decreased subsequently to a nonsignificant level beyond 1 month after the bleeding event [10]. Reasons for the discrepancy between studies remain unknown. However, differences in the baseline risk for bleeding and mortality [7, 9], the use of various bleeding definitions, known to have an impact on bleeding incidence or its association with outcome [16], differences in proportions of patients undergoing medical treatment or PCI [7], or differences in the strength and stability of association between spontaneous and instrumented/traumatic bleeding and mortality [9] may account, at least in part, for the observed discrepancies across the studies. The present study included a large cohort of patients obtained from randomized trials of patients exclusively treated with PCI. Furthermore, bleeding events were defined using the BARC criteria, known to be sensitive
Bleeding and mortality association
and to offer a detailed hierarchical system of quantification of bleeding severity that correlates closely with the risk of mortality [17]. By showing a significant association between bleeding and early and late mortality, the present study offers strong support for those studies that have reported a prolonged impact of bleeding after PCI on mortality. Estimation of the weight of the impact of bleeding relative to other markers of cardiovascular risk on early and late mortality is an important finding of this study. Bleeding was the strongest correlate of early mortality. Thus it outperformed all cardiovascular risk factors in terms of the strength of association with the risk of early (30-day) mortality. When it comes to the strength of association with late mortality, bleeding lost ground to traditional cardiovascular risk factors in terms of the strength of association with the late mortality. Based on the statistical indices (Wald Chi square values from multivariable analysis), bleeding was listed on the sixth place after age, diabetes, C-reactive protein level, creatinine level and platelet count in terms of the strength of association with late mortality. These findings may have implications. First, they show that the association between bleeding and mortality may attenuate with time depending on the degree of baseline cardiovascular risk and the length of time interval. Thus this study may help explain the discrepant results across the studies regarding sustenance of risk after bleeding. Second, the study may offer mechanistic information on the impact of bleeding on mortality. The strong association between bleeding and early mortality may be explained by a direct impact of bleeding itself or of measures aimed to correct bleeding, such as blood transfusion [18] and to a lesser extent by worse cardiovascular risk profile in patients with bleeding. Conversely, the association of bleeding with late mortality may be explained by the influence of cardiovascular risk factors and hidden comorbidities which tend to cluster in patients with bleeding [19]. Third, the findings of this study offer further support for the inclusion of bleeding in composite end points to assess short-term (30-day) efficacy of PCI adjunct therapies, as suggested [3] but not for the efficacy assessment at long-term ([30-day) follow-up. In conclusion, patients with bleeding continue to be at higher risk of early (30-day) and late (30-day–1 year) mortality after PCI compared to patients without bleeding. The weight of the impact of bleeding and cardiovascular risk factors on early and late mortality after PCI differs. Bleeding was the strongest associate of early mortality whereas the increased risk for late mortality was mostly mediated by cardiovascular risk factors clustered in patients with bleeding. Conflict of interest disclose.
The authors have no conflicts of interest to
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Weight of the bleeding impact on early and late mortality after percutaneous coronary intervention Gjin Ndrepepa • Elena Guerra • Stefanie Schulz Massimiliano Fusaro • Salvatore Cassese • Adnan Kastrati
•
Ó Springer Science+Business Media New York 2014
Abstract The association between bleeding and timing of mortality after percutaneous coronary intervention (PCI) remains poorly investigated. We aimed to investigate the impact of bleeding on early (30-day) and late (30-day to 1 year) mortality after PCI. The study includes 14,180 patients. Bleeding within 30 days after PCI was defined using the Bleeding Academic Research Consortium criteria. Landmark analysis pre-specified at 1 month was performed to assess early and late mortality associated with bleeding. The main outcome was all-cause early and late mortality after PCI. Overall, 414 patients (2.9 %) died within the first year after PCI. Within 30 days after PCI there were 36 deaths among patients with bleeding (n = 1,510) and 44 deaths among patients without bleeding (n = 12,670; Kaplan–Meier [KM] estimates of mortality, 2.4 and 0.3 %; adjusted hazard ratio [HR] = 5.00, 95 % confidence interval 3.16–7.88, P \ 0.001). In the 30-day to 1-year period there were 68 deaths among patients with bleeding and 266 deaths among patients without bleeding (KM estimates, 4.7 and 2.1 %; adjusted HR = 1.65 [1.25–2.17], P \ 0.001. Bleeding was the strongest correlate of 30-day mortality. The association of bleeding with late mortality was significant but was weaker than that of age, diabetes, C-reactive protein, serum creatinine and platelet count. In conclusion, patients with bleeding after PCI continue to be at higher risk of early and G. Ndrepepa (&) E. Guerra S. Schulz M. Fusaro S. Cassese A. Kastrati Deutsches Herzzentrum, Lazarettstrasse 36, 80636 Munich, Germany e-mail: [email protected] A. Kastrati DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
late mortality compared to patients without bleeding. Bleeding was the strongest associate of early mortality whereas the increased risk for late mortality was mostly mediated by cardiovascular risk factors clustered in patients with bleeding. Keywords Bleeding Mortality Percutaneous coronary intervention
Introduction Ample evidence from large registries and randomized trial cohorts supports the existence of a relationship between bleeding and subsequent mortality in patients undergoing percutaneous coronary intervention (PCI) [1–5]. While, studies almost unanimously concur regarding the strong and positive association between bleeding and early mortality (up to 30 days after PCI), they are deeply divided regarding the association of bleeding with late mortality. Some studies have reported that the risk imposed by bleeding is sustainable at 1 year (or beyond) after PCI [4, 6, 7]. Other studies have reported a marked attenuation [8] or a decrease to non-significant levels of the risk for mortality after 30 days (or 40 days) [9, 10] in patients with bleeding compared with patients without bleeding. A trajectory of risk following bleeding and a quantitative assessment of bleeding impact on early and late mortality remain poorly investigated. Moreover, it remains unknown whether in studies that have reported a long-term association between bleeding and mortality, the risk difference is acquired early after bleeding events (i.e. within the first 30 days of the bleeding event) and it simply is sustained over time or patients with bleeding continue to be at higher risk for mortality (or other adverse events) over time
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intervals beyond the early period (30 days) compared with patients without bleeding. We undertook this study with a two-fold objective: first with the help of landmark analysis, we performed a risk analysis of the association between bleeding and mortality in the first 30 days and between 30 days and 1 year after PCI; and second, we comparably analyzed the weight of the bleeding impact on mortality within the first 30 days and 30-day to 1 year time intervals after PCI.
Methods Patients The study includes 14,180 patients recruited in 7 Intracoronary Stenting and Antithrombotic Regimen (ISAR) randomized trials that investigated the efficacy of antithrombotic therapies in patients undergoing PCI. Detailed inclusion/exclusion criteria in these trials are provided in a recent publication from our group [11]. Overall there were 9,035 patients (63.7 %) with stable coronary artery disease and 5,145 patients (36.3 %) with non-ST-segment elevation acute coronary syndromes (2,770 patients with nonST-segment elevation myocardial infarction and 2,375 patients with unstable angina). Patients with ST-segment elevation myocardial infarction were not included in the primary trials and, thus, they are not included in this analysis. Coronary artery disease was confirmed by angiographic criteria: angiographic documentation of coronary stenoses with C50 % lumen obstruction in, at least, one of the three major coronary arteries and/or culprit lesions in patients with acute coronary syndromes. Written informed consent was required for participation. The study conforms to the declaration of Helsinki and each trial was approved by institutional review board(s) at all participating centers. Peri-PCI antithrombotic therapy Patients underwent PCI (mostly with stent implantation) after receiving 325–500 mg of aspirin and 600 mg loading dose of clopidogrel. Peri-PCI antithrombotic/anticoagulant therapy consisted of: (1) glycoprotein IIb/IIIa receptor inhibitor abciximab (bolus of 0.25 mg/kg of weight followed by an infusion of 0.125 lg/kg/min [a maximum of 10 lg/min] for 12 h) plus a 70 U/kg intravenous bolus of unfractionated heparin (3,554 patients; 25.1 %); (2) unfractionated heparin administered as an intravenous bolus of 140 U/kg of weight (4,972 patients; 35.1 %); (3) unfractionated heparin administered as an intravenous bolus of 100 U/kg of weight (2,505 patients; 17.6 %); and 4) bivalirudin administered as a bolus of 0.75 mg/kg of weight, followed by an infusion of 1.75 mg/kg of weight
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per hour for the duration of the procedure (3,149 patients; 22.2 %).
PCI procedure Coronary stenting with either bare-metal or drug-eluting stents was performed as per standard practice. Femoral artery route was used for vascular access. Sheaths were removed and manual compression was applied as soon as the activated partial-thromboplastin time fell below 50 s. Postprocedural therapy included aspirin (80–325 mg/day indefinitely) and clopidogrel (75–150 mg/day until discharge but for no longer than 3 days, followed by 75 mg/day for C1 month in patients with bare-metal stents or C6 months in patients with drug-eluting stents). Other cardiac medications were prescribed at the discretion of the patient’s physician. Angiographic data were analyzed in a single angiographic core laboratory.
Study outcome and definitions The main outcome of this study was all-cause mortality at 30 days (early mortality) and in the time period between 30 days and 1 year after PCI (late mortality). Bleeding events occurring within the first 30 days after PCI were defined according to the Bleeding Academic Research Consortium (BARC) criteria [12]. BARC bleeding criteria were retrospectively applied. Class 5 bleeding (fatal bleeding) was not assessed as a distinct class but it was distributed to other classes depending on the initial classification. Details of the application of the BARC criteria to the study patients and the criteria used to classify bleeding events according to the bleeding site are shown in a prior publication from our group [11]. Adjudication and classification of the bleeding events was performed by personnel not involved in the primary studies. All patients were either seen by their physician or interviewed by telephone at 30 days, 6 months, and 1 year after the procedure. Patients who had cardiac complaints at those time points or any time during the follow-up underwent a complete clinical, ECG, and laboratory evaluation. Information on mortality was obtained from hospital records, death certificates or phone contact with the referring physician(s), relatives of the patient, insurance companies and registration of address office. Cardiac death was defined according to Academic Research Consortium criteria and included any death due to proximate cardiac cause (e.g. myocardial infarction, low-output failure, fatal arrhythmia), unwitnessed death and death of unknown cause, and all procedure-related deaths, including those related to concomitant treatment.
Bleeding and mortality association Table 1 Baseline clinical and angiographic characteristics Characteristic
Survivors (n = 13,766)
30-day non-survivors (n = 80)
30-day to 1-year non-survivors (n = 334)
P1*
P2**
P3***
Age (years)
67.2 [59.7; 74.1]
74.5 [67.2; 81.8]
74.8 [67.1; 80.9]
\0.001
\0.001
Women
3,243 (23.6)
19 (23.6)
91 (27.2)
0.967
0.117
0.525
Diabetes mellitus
4,131 (30.0)
35 (43.7)
163 (48.8)
0.007
\0.001
0.416
0.98
Requiring insulin
1,122 (8.1)
14 (17.5)
68 (20.4)
0.002
\0.001
0.564
Body mass index (kg/m2)
27.1 [24.8; 29.8]
26.3 [24.0; 29.1]
26.3 [23.3; 29.1]
0.094
\0.001
0.998
Arterial hypertension
10,744 (78.0)
55 (68.7)
267 (80.0)
0.033
0.542
0.030
Hypercholesterolemia (C220 mg/dL) Current smoker
9,418 (68.4) 2,394 (17.4)
44 (55.0) 14 (17.5)
197 (59.0) 48 (14.3)
0.007 0.979
\0.001 0.149
0.516 0.481
Prior myocardial infarction
4,087 (29.7)
30 (37.5)
130 (38.9)
0.138
\0.001
0.814
Prior coronary artery bypass surgery
1,542 (11.2)
8 (10.0)
61 (18.2)
0.719
\0.001
0.074
Acute coronary syndrome
4,941 (35.9)
57 (71.2)
147 (44.0)
\0.001
0.003
\0.001
Elevated cardiac troponin ([0.03 lg/L)
2,626 (19.1)
48 (60.0)
96 (28.7)
\0.001
\0.001
\0.001
Serum creatinine (mg/dL)
0.94 [0.80; 1.10]
1.08 [0.84; 1.30]
1.10 [0.90; 1.40]
\0.001
\0.001
0.853
C-reactive protein (mg/L)
1.6 [0.0; 5.4]
10.0 [3.0; 30.6]
6.0 [1.2; 20.9]
\0.001
\0.001
\0.001
Platelet count (9 109/L)
216 [183; 255]
226 [192; 283]
214 [177; 271]
Number of narrowed coronary arteries 1
2,822 (20.5)
5 (6.3)
30 (9.0)
2
3,848 (28.0)
13 (16.2)
73 (21.9)
3
7,096 (51.5)
62 (77.5)
231 (69.1)
10,944 (79.5)
75 (93.7)
304 (91.0)
Multivessel disease
0.023
0.004
0.618
\0.001
\0.001
0.336
0.002
\0.001
0.430
Data are median [25th; 75th percentiles] or number of patients (%) * Compares 30-day non-survivors with survivors ** Compares 30-day to 1-year non-survivors with survivors *** Compares 30-day to 1-year non-survivors with 30-day non-survivors
Statistical analysis The data are presented as median [25th, 75th percentiles], Kaplan–Meier estimates (%) or number of events/patients (%). The normality of data distribution was assessed using the one-sample Kolmogorov–Smirnov test. Continuous data were compared with the Kruskal–Wallis rank-sum test and the inter-group comparisons were performed with the Tukey’s HSD (honestly significant difference) test. Categorical data were compared with Chi square test. The survival analysis was performed using the Kaplan–Meier method and the differences in survival were compared with the log-rank test. Landmark analysis with a pre-specified landmark at 1 month was performed to assess the early and late risk of mortality associated with bleeding. The number needed to harm (NNH) or the number of patients needed to be exposed to bleeding within the 30 days after PCI to be associated with 1 death within the first 30 days or 31–60 days was calculated. Multivariable Cox proportional hazards model was used to assess independent correlates of 30-day and 30-day–1-year mortality. All variables of Table 1 plus bleeding and type of study were entered into the model(s). The proportional hazards assumption was
checked using the method by Grambsch and Therneau [13]. Discriminatory power of multivariable model(s) before (with baseline variables only) and after inclusion of bleeding events was assessed by calculating the Harrell’s c statistic the integrated discrimination improvement (IDI) [14]. All analyses were performed using R package. A twosided P value \0.05 was considered to indicate statistical significance.
Results Baseline data There were 414 deaths (2.9 %) within the first year after PCI. Landmark analysis with a pre-specified landmark at 1 month was performed to assess the 30-day and 30-day– 1 year risk of mortality associated with bleeding (Fig. 1). Eighty deaths occurred within the first 30 days after PCI (30-day non-survivors) and 334 deaths occurred between 30 days and 1 year after PCI (30-day–1-year non-survivors). The remaining 13,766 patients survived the first year of follow-up (survivors). Baseline data in survivors and
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events; 41.9 %), class 2 (230 events; 15.2 %), class 3a (468 events; 31.0 %), class 3b (159 events; 10.5 %), class 3c (12 events; 0.8 %) and class 4 (9 events (0.6 %). Bleeding occurred at the vascular access site in 905 patients and in other locations (non-access site) in 605 patients. Bleeding events and the risk of 30-day mortality
Fig. 1 Landmark analysis showing probability of death at 30 days and from 30 days–1 year in patients with and without bleeding within the 30 days after PCI
non-survivors are shown in Table 1. Overall, patients who died within the first 30 days as well as those who died between 30 days and 1 year after PCI showed a significantly worse cardiovascular risk profile compared with patients who survived the first year after PCI. Baseline characteristics of patients who died within the first 30 days and those who died between 30 days and 1 year after PCI appear to differ little with the exception of proportions of patients with arterial hypertension, acute coronary syndrome, elevated troponin level and C-reactive protein level (Table 1). Coronary stents were implanted in 76 patients (95.0 %) among non-survivors at 30 days, 306 patients (91.7 %) among 30-day–1-year non-survivors and 12,662 patients (92.0 %) among 1-year survivors (P = 0.592). Drug-eluting stents were implanted in 49 patients (61.2 %) among non-survivors at 30 days, 181 patients (54.2 %) among 30-day to 1-year non-survivors and 8,522 patients (61.9 %) among 1-year survivors. Bleeding events Bleeding events within 30 days after PCI occurred in 1,510 patients. Bleeding events occurred in 446 patients (12.5 %) treated with abciximab plus 70 U/kg of weight unfractionated heparin, 517 patients (10.4 %) treated with 140 U/kg of weight unfractionated heparin, 254 patients (10.1 %) treated with 100 U/kg of weight unfractionated heparin and 293 patients (9.3 %) treated with bivalirudin (P \ 0.001). According to patient’s status there were 36 bleeding events (45.0 %) among non-survivors at 30 days, 68 bleeding events (20.4 %) among 30-day–1-year nonsurvivors and 1,406 bleeding events (10.3 %) among 1-year survivors (P \ 0.001). According to the BARC classes, bleeding events were as follows: class 1 (632
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There were 80 deaths within the first 30 days after PCI: 36 deaths (2.4 %) among patients with bleeding and 44 deaths (0.3 %) among patients without bleeding (odds ratio [OR] = 6.95, 95 % confidence interval 4.76–10.15, P \ 0.001). There were 10 deaths (1.1 %) among patients with access site bleeding and 26 deaths (4.3 %) among patients with non-access site bleeding (OR = 3.20 [1.67– 6.13] for access site bleeding vs. no bleeding and OR = 12.66 [8.70–18.44] for non-access site bleeding vs. no bleeding). The NNH i.e. the number of bleeding events associated with 1 death within the 30-day period was 49 (25 for patients with non-access site bleeding and 132 for patients with access site bleeding). Cardiac deaths occurred in 66 patients (82.5 %). The Cox proportional hazards model showed that bleeding within the 30 days after PCI was associated with a fivefold increase in the adjusted risk of 30-day mortality (adjusted hazard ratio [HR] = 5.00 [3.16–7.88], P \0.001; Table 2). Based on the Wald Chi square values, bleeding showed the strongest correlation with mortality. The inclusion of bleeding in the multivariable model improved the discriminatory power of the model for prediction of the 30-day mortality. The c statistic of the model with baseline variables without bleeding was 0.8434 [0.8118– 0.8744] and it increased to 0.8672 [0.8261–0.9016] after inclusion of bleeding (absolute and relative IDI 0.019 and 69.5 %, respectively, P = 0.004). Bleeding events and the risk of 30-day–1-year mortality The landmark analysis showed that the risk of mortality in patients with bleeding continued to increase in the 11-month period between 30-day and 1 year after PCI (Fig. 1). In the 30-day–1-year period there were 68 deaths (4.7 %) among patients with bleeding and 266 deaths (2.1 %) among patients with no bleeding (OR = 2.24 [1.73–2.90], P \ 0.001). According to bleed location there were 34 deaths (3.9 %) among patients with access site bleeding and 34 deaths (5.9 %) among patients with nonaccess site bleeding (OR = 1.84 [1.30–2.62], P \ 0.001 for access site bleeding vs. no bleeding and OR = 2.86 [2.03–4.02] for non-access site bleeding vs. no bleeding). NNH i.e. the number of bleeding events associated with 1 death within 31–60 days after PCI was 122 (87 for patients with non-access site bleeding and 167 for patients with
Bleeding and mortality association Table 2 Results of Cox proportional hazards model applied to assess predictors of 30-day mortality
CI confidence interval, HR hazard ratio * The Wald Chi square values from the Cox model show the strength of association of various variables with mortality
Characteristic
Thirty-day mortality Chi square*
b-Coefficient
Adjusted HR [95 % CI]
P value
Bleeding (vs. no bleeding)
47.64
1.608
5.00 [3.16–7.88]
\0.001
Age (for a 10-year increase)
11.51
0.046
1.59 [1.22–2.07]
\0.001
Women
1.38
-0.329
0.72 [0.41–1.25]
0.240
Diabetes mellitus
4.33
0.492
1.64 [1.03–2.60]
0.037
Body mass index (for 5 kg/m2 increase)
0.51
-0.021
0.90 [0.68–1.20]
0.476
Arterial hypertension
5.21
-0.583
0.56 [0.34–0.92]
0.022
Hypercholesterolemia Current smoker
0.80 0.28
-0.209 0.172
0.81 [0.51–1.28] 1.19 [0.63–2.25]
0.371 0.599
Prior myocardial infarction
3.21
0.431
1.54 [0.96–2.47]
0.073
Prior coronary artery bypass surgery
1.53
-0.484
0.62 [0.29–1.33]
0.215
Acute coronary syndrome
1.11
0.419
1.52 [0.70–3.31]
0.291
Elevated cardiac troponin
10.30
1.180
3.25 [1.58–6.69]
0.001
Serum creatinine (for 1 mg/dL increase)
2.09
0.213
1.02 [0.99–1.05]
0.148
C-reactive protein (for 5 mg/L increase)
18.17
0.008
1.04 [1.02–1.06]
\0.001
Multivessel disease (vs. single vessel disease)
5.61
1.122
3.07 [1.21–7.77]
0.018
Platelet count (for 50 9 109/L increase)
4.59
0.003
1.13 [1.01–1.27]
0.032
access site bleeding). NNH increased further during the follow-up for all categories of bleeding. Cardiac deaths occurred in 182 patients (54.5 %; P \ 0.001 compared with the proportion of cardiac deaths in the 30-day mortality). The Cox proportional hazards model was used also to show independent associates of 30-day to 1-year mortality. The model showed that bleeding within the first 30 days after PCI was associated with a 65 % increase in the adjusted risk of 30-day to 1 year mortality (adjusted HR = 1.65 [1.25–2.17], P \ 0.001; Table 3). Although independently associated, the strength of association between bleeding and mortality was weaker than that of age, diabetes, C-reactive protein, serum creatinine and platelet count (Wald Chi square values in Table 3). The inclusion of bleeding in the multivariable model improved the discriminatory power of the model for prediction of the 30-day to 1-year mortality. The c statistic of the model with baseline variables was 0.7650 [0.7390–0.7960] without bleeding and 0.7669 [0.7465–0.7929] after inclusion of bleeding (absolute and relative IDI 0.0028 and 8.2 %, respectively, P = 0.009).
Discussion The main findings of this study may be summarized as follows: (1) Patients with bleeding complications after PCI remain at a higher risk of mortality up to 1 year after the
PCI compared with patients without bleeding. Although, the risk associated with bleeding diminished with time, patients with bleeding continue to be at higher risk of mortality both in the early (30-day) and late (30-day– 1 year) phase of the follow-up than patients without bleeding. In both time periods, bleeding was associated with increased risk of mortality that was independent of cardiovascular risk factors. (2) The strength of association between bleeding and mortality differs with time. Bleeding was associated with a fivefold increase in the adjusted risk of 30-day mortality and with a 65 % increase in the adjusted risk for 30-day–1 year mortality following PCI. All statistical indices showed that bleeding was the strongest associate of mortality within the first 30 days. Although bleeding remained independently associated with 30-day–1 year mortality, its association with mortality was weaker than that of age, diabetes, C-reactive protein, impaired renal function and platelet count. Studies that have investigated the impact of bleeding on late (beyond 30 days) mortality have given conflicting results. In the study by Rao et al. [15], that included patients with acute coronary syndromes, bleeding was associated with an increased risk of 30-day and 6-month mortality and there was a stepwise increase in the hazards of 30-day and 6-month mortality as bleeding severity increased. A study that included patients recruited in the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events II (REPLACE)-2 trial showed that among patients with major bleeding, mortality was
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G. Ndrepepa et al. Table 3 Results of Cox proportional hazards model applied to assess predictors of 30-day to 1 year mortality
Characteristic
Thirty-day to 1-year mortality Chi square* 12.36
0.498
1.65 [1.25–2.17]
\0.001
73.19
0.059
1.80 [1.58–2.07]
\0.001
0.28
-0.071
0.93 [0.72–1.21]
0.597
34.17
0.678
1.97 [1.57–2.47]
\0.001
Body mass index (for 5 kg/m2 increase)
9.59
-0.045
0.79 [0.68–0.92]
0.002
Arterial hypertension
0.54
-0.105
0.90 [0.68–1.19]
0.461
Hypercholesterolemia Current smoker
4.47 1.61
-0.248 0.217
0.78 [0.62–0.98] 1.24 [0.89–1.74]
0.034 0.204
Prior myocardial infarction
9.00
0.355
1.43 [1.13–1.80]
0.003
Prior coronary artery bypass surgery
5.81
0.362
1.44 [1.07–1.93]
0.016
Acute coronary syndrome
0.59
0.123
1.13 [0.83–1.55]
0.441
Elevated cardiac troponin
2.17
0.261
1.30 [0.92–1.84]
0.141
Serum creatinine (for 1 mg/dL increase)
25.18
0.274
1.03 [1.02–1.04]
\0.001
C-reactive protein (for 5 mg/L increase)
31.86
0.007
1.04 [1.02–1.05]
\0.001
6.09
0.488
1.63 [1.11– 2.40]
0.014
15.62
0.003
1.14 [1.07–1.21]
\0.001
Multivessel disease (vs. single vessel disease) Platelet count (for 50 9 109/L increase)
higher at 30 days, 6 months and 1 year after PCI compared with patients without bleeding [4]. Even after adjustment, bleeding remained an independent correlate of 1-year mortality (odds ratio of 2.66). Among patients recruited in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, major bleeding occurring within 30 days of randomization had a prolonged and steady association with mortality throughout the subsequent year [6]. Recently, Lopes et al. [7] showed that among patients C65 years of age presenting with non-ST-segment elevation myocardial infarction, cumulative mortality was higher among patients who had an inhospital bleeding at 30 days, 1 and 3 years compared with patients without bleeding. Even after adjustment, major bleeding continued to show a significant association with mortality in the time intervals between discharge and 30 days, 31 days–1 year and 1–3 years. Although in the whole cohort, the association between bleeding and mortality attenuated after 3 years, in-hospital bleeding continued to be significantly associated with higher adjusted risk of mortality even beyond 3 years (25 % increase in the adjusted risk) among patients treated with PCI. The study also suggested that the risk imposed by bleeding is weaker and less prolonged in patients undergoing medical treatment compared to those undergoing PCI [7]. Other studies, however, have come to opposite conclusions regarding the trajectory of risk after bleeding. A recent analysis from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial
123
P value
Bleeding (vs. no bleeding)
Diabetes mellitus
* The Wald Chi square values from the Cox model show the strength of association of various variables with mortality
Adjusted HR [95 % CI]
Age (for a 10-year increase) Women
CI confidence interval, HR hazard ratio
b-Coefficient
Infarction 38 (TRITON-TIMI 38) showed that serious bleeding was strongly associated with mortality only within the first month of the bleeding. However, the hazard ratio did not differ statistically from baseline risk by 40 days after the bleeding event [9]. In this study, spontaneous bleeding was associated with a higher and more prolonged risk for death than instrumented/traumatic bleeding [9]. In another recent study that included patients with ST-segment elevation myocardial infarction treated with primary PCI, occurrence of bleeding, defined according to the Global Utilization of Streptokinase and Tissue Plasminogen for Occluded Arteries (GUSTO) criteria was associated with a significant increase of the risk for mortality (hazard ratio 5.42) 1 day after the event and the risk decreased subsequently to a nonsignificant level beyond 1 month after the bleeding event [10]. Reasons for the discrepancy between studies remain unknown. However, differences in the baseline risk for bleeding and mortality [7, 9], the use of various bleeding definitions, known to have an impact on bleeding incidence or its association with outcome [16], differences in proportions of patients undergoing medical treatment or PCI [7], or differences in the strength and stability of association between spontaneous and instrumented/traumatic bleeding and mortality [9] may account, at least in part, for the observed discrepancies across the studies. The present study included a large cohort of patients obtained from randomized trials of patients exclusively treated with PCI. Furthermore, bleeding events were defined using the BARC criteria, known to be sensitive
Bleeding and mortality association
and to offer a detailed hierarchical system of quantification of bleeding severity that correlates closely with the risk of mortality [17]. By showing a significant association between bleeding and early and late mortality, the present study offers strong support for those studies that have reported a prolonged impact of bleeding after PCI on mortality. Estimation of the weight of the impact of bleeding relative to other markers of cardiovascular risk on early and late mortality is an important finding of this study. Bleeding was the strongest correlate of early mortality. Thus it outperformed all cardiovascular risk factors in terms of the strength of association with the risk of early (30-day) mortality. When it comes to the strength of association with late mortality, bleeding lost ground to traditional cardiovascular risk factors in terms of the strength of association with the late mortality. Based on the statistical indices (Wald Chi square values from multivariable analysis), bleeding was listed on the sixth place after age, diabetes, C-reactive protein level, creatinine level and platelet count in terms of the strength of association with late mortality. These findings may have implications. First, they show that the association between bleeding and mortality may attenuate with time depending on the degree of baseline cardiovascular risk and the length of time interval. Thus this study may help explain the discrepant results across the studies regarding sustenance of risk after bleeding. Second, the study may offer mechanistic information on the impact of bleeding on mortality. The strong association between bleeding and early mortality may be explained by a direct impact of bleeding itself or of measures aimed to correct bleeding, such as blood transfusion [18] and to a lesser extent by worse cardiovascular risk profile in patients with bleeding. Conversely, the association of bleeding with late mortality may be explained by the influence of cardiovascular risk factors and hidden comorbidities which tend to cluster in patients with bleeding [19]. Third, the findings of this study offer further support for the inclusion of bleeding in composite end points to assess short-term (30-day) efficacy of PCI adjunct therapies, as suggested [3] but not for the efficacy assessment at long-term ([30-day) follow-up. In conclusion, patients with bleeding continue to be at higher risk of early (30-day) and late (30-day–1 year) mortality after PCI compared to patients without bleeding. The weight of the impact of bleeding and cardiovascular risk factors on early and late mortality after PCI differs. Bleeding was the strongest associate of early mortality whereas the increased risk for late mortality was mostly mediated by cardiovascular risk factors clustered in patients with bleeding. Conflict of interest disclose.
The authors have no conflicts of interest to
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