Abstract
Aims
The use of an erythropoetic stimulating agent, darbepoetin alfa (DA), to treat anaemia in patients with diabetes mellitus and chronic kidney disease was associated with a heightened risk of stroke and neutral efficacy in The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT), despite epidemiologic data suggesting the contrary. However, this association has not been evaluated in another randomized, placebo controlled trial.
Methods and results
Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) was a randomized placebo controlled trial of DA in 2,278 patients with systolic heart failure and anaemia, enrolled from 2006-2012 and followed for a median of 28 months. Within RED-HF, 816 patients had diabetes mellitus and chronic kidney disease (eGFR 20-60 mL/min/1.73 m2) and met inclusion criteria for TREAT. TREAT-like RED-HF patient data was analyzed alone and combined at the patient level with the 4,038 TREAT patients. In RED-HF the annualized event rate of stroke was 2.3 in patients on DA and 1.1 in patients randomized to placebo (p=0.051). Analysis of the combined group (n=4,854) confirmed a nearly two-fold increase in stroke risk [HR 1.94, (95% CI 1.43-2.63)] and an overall neutral effect on mortality [1.00 (0.89-1.12)] of raising hemoglobin with DA.
Conclusion
The placebo controlled cohort of heart failure patients with anaemia, diabetes mellitus, and chronic kidney disease from RED-HF provides confirmation of the increased stroke risk associated with DA use identified in TREAT.
Keywords: heart failure, stroke, anaemia, diabetes mellitus, erythropoetic stimulating agent, renal dysfunction
INTRODUCTION
Anaemia is a common co-morbidity in patients with diabetes and chronic kidney disease (CKD).1 Whereas the presence of anaemia or CKD alone is associated with increased risk of cardiovascular morbidity and mortality in patients with diabetes mellitus, the presence of all three conditions appears to have a synergistic effect on adverse outcomes.2 Likewise, anaemia is common in patients with heart failure and is associated with worse long-term outcomes.3 The strength and consistency of epidemiologic data showing this increased risk associated with anaemia led to the hypothesis that treating anaemia would improve patient outcomes 4.
Erythropoetic stimulating agents (ESAs) are effective in raising hemoglobin (Hb) and until recently there was a widespread belief that their use would improve quality of life and prognosis in patients with anaemia. This concept was so pervasive that even in individuals with mild to moderate anaemia, clinical trials were designed to test the strategy of achieving high versus low target hemoglobin levels with ESAs rather than testing their effect against placebo.5 In Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT),6 the only large randomized trial of darbepoetin alfa (DA) versus placebo, the DA group exhibited a nearly two fold increased risk of stroke. This increased stroke risk has not subsequently been confirmed or refuted.
Since stroke was not a primary endpoint of TREAT, this finding could not be considered definitive, although it clearly raised an important safety concern. The Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF)7 trial presented an opportunity to examine this issue in another large randomized, placebo controlled trial of DA.
METHODS
Patients
RED-HF (NCT00358215) was a prospective, randomized, double-blind, placebo-controlled trial of DA for the treatment of systolic heart failure in 2,278 patients New York Heart Association (NYHA) functional class II, III, or IV heart failure, left ventricular ejection fraction ≤40%, hemoglobin 9.0-12.0 g/dL and transferrin saturation ≥15%. Exclusion criteria included: blood pressure >160/100 mmHg, active bleeding or a correctible etiology of anaemia, and serum creatinine > 3mg/dL. The primary outcome for the study was time to the composite outcome of death or hospitalization for heart failure. Secondary outcomes were all-cause mortality, composite of cardiovascular death or heart failure hospitalization and change in quality of life on the Kansas City Cardiomyopathy Questionnaire (KCCQ). Other adjudicated outcomes included fatal and nonfatal myocardial infarction, unstable angina, fatal and nonfatal stroke. All endpoints were adjudicated by a clinical endpoints committee masked to treatment assignment. The detailed study design, entry criteria and main results have been previously described.7-9
TREAT (NCT00093015) was a prospective, randomized, double-blind, placebo-controlled trial of DA for the treatment of anaemia in 4,038 patients with type 2 diabetes mellitus, impaired renal function (eGFR 20-60 mL/min/1.73 m2 by 4 component MDRD), hemoglobin ≤11.0 g/dL, and transferrin saturation ≥15%. Exclusion criteria included: uncontrolled hypertension, previous kidney transplantation or scheduled receipt of a kidney transplant from a living related donor, cancer, active bleeding, and pregnancy. The primary endpoints for the study were time to the composite outcome of death or cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and time to the composite outcome of death or end-stage renal disease. All endpoints, including end stage renal disease (ESRD) were adjudicated by a clinical endpoints committee masked to treatment assignment. The detailed study design, entry criteria and main results have been previously described.6,10,11
To provide a more reliable estimate of the effect of DA on the risk of stroke, the 816 RED-HF patients that met enrollment criteria for TREAT (diabetes mellitus and eGFR <60 mL/min/1.73m2) were analyzed alone and in combination with all 4,038 patients from TREAT. Race/ethnicity was self-reported by the participants. “The investigation conforms with the principles outlined in the Declaration of Helsinki” (Br Med J 1964; ii: 177). All patients gave written informed consent for participation in the primary trials. The clinical trials were approved by local institutional review boards at all participating centers.
Statistical Analysis
Baseline characteristics of the 816 TREAT-like patients in RED-HF were compared to the 1,459 non-TREAT-like RED-HF patients (without CKD and diabetes mellitus), and also to all TREAT patients. Categorical variables were compared using Pearson's X2 tests and continuous variables were compared using Student's t-tests. Hazard ratios and corresponding 95% confidence intervals by treatment arm in both the TREAT-like RED-HF group and the combined group were estimated with the use of stratified Cox proportional hazards models for all endpoints. We used the Kaplan-Meier approach and two-sided stratified log rank test to perform time to event analyses. The assumption of proportionality for the Cox analysis was tested and the criteria were met.
Patients in the combined group of TREAT-like RED-HF and TREAT were stratified according to stroke outcome. Univariate analysis of baseline characteristics associated with stroke was performed using a Cox proportional hazards model. A multivariable model was then created using forward selection with alpha=0.05 as the level of stringency for significance. All tests were two sided, and a p-value <0.05 was considered statistically significant. SAS version 9.2 (SAS, Cary, NC) was used for all analyses.
RESULTS
Baseline Characteristics of TREAT-like RED-HF Patients compared to Non-TREAT-like RED-HF Patients
There were 816 RED-HF patients who met the criteria for TREAT. TREAT-like RED-HF patients had higher levels of glycated hemoglobin (7.3% vs. 6.0%, p<0.001) and lower eGFR (39 vs. 56 mL/min/1.73m2, p<0.001), though they were of similar age, sex, and racial background as the RED-HF patients who did not meet the TREAT criteria (n=1459) (Table 1). They also had a greater burden of cardiovascular disease with more prior myocardial infarction and a higher prevalence of hypertension, though rates of prior stroke and atrial fibrillation were the same in both groups. Within the 816 TREAT-like RED-HF patients, there were no baseline differences between those assigned to DA versus placebo (Table 2).
Table 1.
Baseline characteristics of the 816 TREAT-like RED-HF patients compared to the Non-TREAT-like RED-HF patients
| TREAT-like RED-HF N=816 | Non-TREAT-like RED-HF N=1459 | p-value | |
|---|---|---|---|
| Age (years) | 70 ± 10 | 70 ± 12 | 0.15 |
| Female | 41% | 42% | 0.56 |
| Race | |||
| White | 68% | 68% | 0.787 |
| Black | 8% | 9% | 0.252 |
| Other | 24% | 22% | 0.284 |
| BMI (kg/m2) | 29 ± 6 | 26 ± 5 | <0.001 |
| Current smoker | 4% | 4% | 0.86 |
| History of CVD: | |||
| Coronary artery disease | 76% | 68% | <0.001 |
| Heart failure | 100% | 100% | -- |
| Myocardial infarction | 58% | 52% | 0.007 |
| Stroke | 9% | 7% | 0.15 |
| Peripheral arterial disease | 17% | 10% | <0.001 |
| Hypertension | 82% | 69% | <0.001 |
| Atrial fibrillation | 32% | 33% | 0.43 |
| Blood Pressure (mmHg) | |||
| Systolic blood pressure | 122 ± 18 | 119 ± 18 | <0.001 |
| Diastolic blood pressure | 69 ± 11 | 70 ± 11 | 0.34 |
| Heart rate (beats/minute) | 72 ± 11 | 72 ± 11 | 0.65 |
| eGFR (mL/min/1.73m2) | 39 ± 11 | 56 ± 23 | <0.001 |
| Glycated hemoglobin (%) | 7.3 ± 1.6 | 6.0 ± 1.1 | <0.001 |
| Hemoglobin (g/dL) | 11.0 ± 0.8 | 11.1 ± 0.7 | 0.002 |
| Platelets (109/L) | 231 ± 77 | 232 ± 80 | 0.74 |
| Medications: | |||
| Insulin | 46% | 5% | <0.001 |
| ACE or ARB | 88% | 89% | 0.25 |
| B-blocker | 85% | 85% | 0.97 |
| Statin | 69% | 58% | <0.001 |
| Aspirin | 61% | 56% | 0.02 |
| Dual antiplatelet therapy | 15% | 12% | 0.02 |
| Vitamin k antagonist | 26% | 27% | 0.58 |
ACE, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate;
Table 2.
Baseline characteristics of the TREAT-like RED-HF patients compared to TREAT patients
| TREAT-like RED-HF |
|||||
|---|---|---|---|---|---|
| DA N=404 | Placebo N=412 | Overall N=816 | TREAT N=4038 | p-value* | |
| Age (years) | 71 ± 10 | 70 ± 10 | 70 ± 10 | 67 ± 11 | <0.001 |
| Female | 42% | 39% | 41% | 57% | <0.001 |
| Race | |||||
| White | 69% | 67% | 68% | 64% | 0.03 |
| Black | 7% | 9% | 8% | 20% | <0.001 |
| Other | 25% | 24% | 24% | 16% | <0.001 |
| BMI (kg/m2) | 29 ± 6 | 29 ± 6 | 29 ± 6 | 32 ± 7 | <0.001 |
| Current smoker | 4% | 4% | 4% | 5% | 0.29 |
| History of CVD: | |||||
| Coronary artery disease | 77% | 76% | 76% | 43% | <0.001 |
| Heart failure | 100% | 100% | 100% | 33% | <0.001 |
| Myocardial infarction | 57% | 59% | 58% | 18% | <0.001 |
| Stroke | 10% | 8.0 | 9% | 11% | 0.07 |
| Hypertension | 83% | 81% | 82% | 92% | <0.001 |
| Atrial fibrillation | 32% | 32% | 32% | 11% | <0.001 |
| Blood Pressure (mmHg) | |||||
| Systolic blood pressure | 123 ± 19 | 120 ± 18 | 122 ± 18 | 136 ± 19 | <0.001 |
| Diastolic blood pressure | 70 ± 12 | 69 ± 11 | 69 ± 11 | 72 ± 11 | <0.001 |
| Heart rate (beats/minute) | 72 ± 11 | 72 ± 12 | 72 ± 11 | 72 ± 11 | <0.001 |
| eGFR (mL/min/1.73m2) | 38 ± 11 | 39 ± 11 | 39 ± 11 | 35 ± 12 | <0.001 |
| Glycated hemoglobin (%) | 7.3 ± 1.6 | 7.3 ± 1.6 | 7.3 ± 1.6 | 7.3 ± 1.5 | 0.30 |
| Hemoglobin (g/dL) | 11.0 ± 0.7 | 11.0 ± 0.8 | 11.0 ± 0.8 | 10.4 ± 1.0 | <0.001 |
| Platelets (109/L) | 230 ± 80 | 232 ± 75 | 231 ± 77 | 250 ± 79 | <0.001 |
| Medications: | |||||
| Insulin | 46% | 46% | 46% | 49% | 0.06 |
| ACE or ARB | 87% | 89% | 88% | 80% | <0.001 |
| B-blocker | 85% | 85% | 85% | 49% | <0.001 |
| Statin | 68% | 71% | 69% | 59% | <0.001 |
| Aspirin | 64% | 59% | 61% | 42% | <0.001 |
| Dual antiplatelet | 13% | 17% | 15% | 48% | <0.001 |
| Vitamin k antagonist | 25% | 28% | 26% | 7% | <0.001 |
P-value is for the overall comparison between TREAT-like RED-HF patients and TREAT patients. ACE, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate;
Baseline Characteristics of TREAT-like RED-HF Patients Compared to TREAT Patients
In comparison to the TREAT patients, TREAT-like RED-HF patients had similar rates of insulin use and HbA1c levels (Table 2). eGFR was lower in TREAT (33 ml/min/1.73m2 vs. 39 ml/min/1.73m2, p<0.001) though on average both groups had National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Stage 3 CKD. Hemoglobin levels were slightly lower in TREAT patients compared to the TREAT-like RED-HF patients (Hb 10.4 vs. 11.0 g/dL, p<0.001).
The TREAT-like RED-HF and TREAT patients differ in multiple ways (Table 2). Because RED-HF was a heart failure trial, all TREAT-like RED-HF patients had systolic heart failure versus one third of those in TREAT. TREAT-like RED-HF patients were older, more likely to be male, white, and had lower body mass index. Current smoking and prior stroke rates were not significantly different between trials. Hypertension was less common and blood pressure was lower than in TREAT, though all patients had well controlled blood pressure. Atrial fibrillation and the use of a vitamin K antagonist were much more prevalent in the HF population, though dual antiplatelet use was more common in TREAT.
Cardiorenal Events in TREAT-like RED-HF Patients alone and in combination with TREAT patients
The numbers of events and incidence rates per 100 patient years experienced in the TREAT-like RED-HF group and the combined group is displayed in Table 3. During a median follow-up of 28 months, 367 (45%) of the 816 patients died and 4% experienced a stroke. Figure 1 displays the hazard ratios and 95% confidence intervals for all-cause mortality, hospitalizations for HF and myocardial infarction in TREAT-like RED-HF patients, TREAT patients and the combination. In RED-HF patients the majority of events were death, followed by heart failure hospitalizations and myocardial infarction, while the combined group was dominated by renal rather than cardiovascular events (Table 3).
Table 3.
Events experienced in TREAT-like RED-HF and in combination with TREAT
| TREAT-like RED-HF |
TREAT-like RED-HF + TREAT |
|||||
|---|---|---|---|---|---|---|
| DA N=404 | Placebo N=412 | DA N=2416 | Placebo N=2438 | |||
| Number and % of Patients with Event, and Incidence Rate per-100 person-year (95% CI) | HR (95% CI) | Number and % of Patients with Event, and Incidence Rate per-100 person-year (95% CI) | HR (95% CI) | |||
| Death | 175 (43.3%) | 192 (46.6%) | 0.89 (0.73-1.09) | 587 (24.3%) | 587 (24.1%) | 1.00 (0.89-1.12) |
| 16.5 (14.1-19.2) | 18.6 (16.0-21.4) | 9.7 (9.0-10.6) | 9.8 (9.0-10.6) | |||
| Hospitalization for Heart Failure | 129 (31.9%) | 126 (30.6%) | 1.00 (0.79-1.28) | 334 (13.8%) | 355 (14.6%) | 0.93 (0.80-1.08) |
| 15.9 (13.3, 18.9) | 16.0 (13.3, 19.1) | 6.2 (5.5, 6.9) | 6.7 (6.0, 7.4) | |||
| Myocardial Infarction | 27 (6.7%) | 37 (9.0%) | 0.68 (0.41-1.12) | 151 (6.3%) | 166 (6.8%) | 0.89 (0.71-1.11) |
| 2.8 (1.9, 4.1) | 4.2 (2.9, 5.7) | 2.7 (2.3, 3.1) | 3.0 (2.6, 3.5) | |||
| Stroke | 22 (5.4%) | 10 (2.4%) | 2.07 (0.98-4.38) | 123 (5.1%) | 63 (2.6%) | 1.94 (1.43-2.63) |
| 2.3 (1.4-3.4) | 1.1 (0.5-2.0) | 2.2 (1.8-2.6) | 1.1 (0.9-1.4) | |||
| Renal Composite | 185 (45.8%) | 204 (49.5%) | 0.87 (0.71-1.06) | 837 (34.6%) | 822 (33.7%) | 1.01 (0.92-1.11) |
| 19.1 (16.5, 22.1) | 22.4 (19.4, 25.7) | 15.0 (14.0, 16.1) | 14.9 (13.9, 16.0) | |||
| ESRD | 12 (3.0%) | 19 (4.6%) | 0.57 (0.28-1.17) | 350 (14.5%) | 349 (14.3%) | 0.98 (0.85-1.14) |
| 1.5 (0.8, 2.6) | 2.6 (1.5, 4.0) | 6.5 (5.9, 7.2) | 6.6 (6.0, 7.4) | |||
Figure 1.
Hazard ratios and 95% CI for events in TREAT-like RED-HF, TREAT, and the combined group
DA had an overall neutral effect on the outcomes of all-cause death, heart failure hospitalization and myocardial infarction in the three groups. The hazard ratio for stroke in TREAT-like RED-HF (2.07, 95% CI 0.98-4.38) was consistent with the findings in TREAT. The Kaplan Meier curves show the time to death (Figure 2A) and stroke (Figure 2B) in the combined TREAT-like RED-HF and TREAT group. Similar to the findings of the parent trials DA had a neutral effect on all-cause mortality but doubled the risk of stroke (HR 1.94, 95% CI 1.42-2.63, p<0.001).
Figure 2.
Kaplan Meier Curves in TREAT + TREAT-like RED-HF for: A. Death from any cause B. Stroke
Univariable and Multivariable Analysis Showing Baseline Variables Related to the Risk of Stroke in TREAT-like RED-HF + TREAT Combined Group
In the combined TREAT-like RED-HF and TREAT trial data 186 patients (3.8%) experienced a stroke. Univariate analysis revealed DA use, age, white or black race, prior history of stroke, baseline albumin level, history of atrial fibrillation and use of insulin or a vitamin K antagonist were independently associated with an increased risk of stroke. In multivariate analysis, the two strongest predictors of stroke within the trials were randomization to DA and history of prior stroke (Table 4).
Table 4.
Univariate and multivariate analysis of selected baseline characteristics for stroke risk in the combined trials
| Univariate | Multivariate | |||||
|---|---|---|---|---|---|---|
| Characteristic | HR | 95% CI | HR | 95% CI | p-value | Chi-square |
| Darbepoetin alfa | 1.94 | 1.43, 2.63 | 1.84 | 1.35, 2.52 | <0.001 | 14.67 |
| History of prior stroke | 2.43 | 1.71, 3.44 | 2.08 | 1.43, 3.04 | <0.001 | 14.41 |
| Age (per year) | 1.02 | 1.00, 1.03 | 1.03 | 1.01, 1.04 | 0.001 | 10.1 |
| Insulin use | 1.53 | 1.14, 2.04 | 1.61 | 1.18, 2.19 | 0.003 | 8.98 |
| Serum Albumin (per g/dL) | 0.59 | 0.44, 0.80 | 0.63 | 0.45, 0.89 | 0.008 | 6.94 |
| Heart rate (per bpm) | 1.01 | 1.00, 1.02 | 1.02 | 1.00, 1.03 | 0.024 | 5.11 |
| Hemoglobin (per g/dL) | 0.89 | 0.77, 1.03 | 0.85 | 0.73, 0.99 | 0.034 | 4.47 |
| Vitamin k antagonist use | 1.54 | 1.02, 2.33 | 1.55 | 1.02, 2.37 | 0.042 | 4.13 |
| White Race | 1.93 | 1.17, 3.21 | - | - | - | - |
| Black Race | 1.99 | 1.13, 3.52 | - | - | - | - |
| Atrial Fibrillation | 1.59 | 1.11, 2.29 | - | - | - | - |
DISCUSSION
The robustness of any outcome depends on its ability to be replicated, and the strength of evidence-based recommendations for patient care in quality improvement tools such as clinical practice guidelines depends on such replication.12,13 In this study, the observation originally made in the TREAT trial that treatment of anaemia in patients with diabetes mellitus and chronic kidney disease with an ESA does not improve clinical outcomes but is associated with an increased risk of stroke is confirmed in the TREAT-like patients enrolled in the RED-HF study. This finding highlights that although epidemiologic data can suggest associations between an exposure such as anaemia and poor outcomes, randomized trials (ideally comparing an intervention to placebo) are needed to prove causality and identify unanticipated and “off-target” effects.
ESAs are effective in raising hemoglobin levels, decreasing the need for blood transfusions, and improving the quality of life in patients with severe anaemia due to end-stage renal disease.14-17 On the other hand, their use a similar group of patients who also have diabetes mellitus is associated with an increased risk of thromboembolic stroke.6 Prior to TREAT the total experience of stroke risk associated with the use of ESAs was based on 50 strokes occurring in 3016 individuals randomized to high versus low hemoglobin target rather than placebo.18,19 This inclusion of 816 patients from the heart failure trial RED-HF adds 32 additional strokes to the 154 events in the 4038 patient TREAT experience and provides greater power to further confirm the increased stroke risk seen in patients with diabetes and CKD who receive an ESA. Despite RED-HF comprising patients with heart failure and experiencing very different annualized event rates for heart failure hospitalization, ESRD, and mortality compared to TREAT, a remarkably similar increase in stroke rate with a neutral effect on the other clinical events was detected in RED-HF patients with the combination of diabetes, anaemia, and CKD treated with DA.
Traditional risk factors for stroke include hypertension, diabetes mellitus, smoking, dyslipidemia, atrial fibrillation and prior stroke.20 In our patients with diabetes, CKD, and anaemia we found the strongest predictors of stroke were the use of an ESA and prior stroke. As has been shown in a previous multivariate analysis of baseline and post-randomization clinical variables in TREAT, the two-fold risk of stroke seen with DA appears to be intrinsic to the ESA use.21 Among the many adjudicated outcomes, the only increased hazard associated with DA use in TREAT-like RED-HF patients was stroke despite differences in baseline patient characteristics and event rates between RED-HF and TREAT.
Several limitations of our analysis merit consideration. First, the RED-HF trial was not designed to test the current hypothesis and we lacked power in the subgroup of patients with diabetes and chronic kidney disease to show a statistically significantly elevated stroke risk, though the trends in all endpoints were consistent with the findings in TREAT. Second, although hemoglobin and platelet levels were not associated with incident stroke, we do not have objective measures of blood viscosity or platelet reactivity. Greater viscosity and increased sheer stress on the vascular endothelium could exacerbate the risk for thrombotic events in the cerebral vasculature, as could elevated platelet reactivity. Treatment with ESAs has been shown to increase rates of thromboembolism in other vascular beds as well, though the exact mechanisms remain elusive.6,7 Despite a robust effort, iron supplementation may not have been optimal, and iron deficiency has also been associated with increased thromboembolic risk during ESA use. 22 Lastly, it is possible that some unmeasured confounder led to a spurious finding of increased stroke risk, though this pooled analysis of the only two major randomized placebo-controlled trials in this patient population and the consistency of their hazard ratios should minimize this risk
We conclude that an increased risk of stroke associated with ESA use has now been demonstrated in two independent, placebo-controlled trials in patients with diabetes and CKD. This hazard must be considered when deciding whether or not to use ESAs to treat anemic patients with diabetes and CKD. Although the epidemiologic data suggests that anaemia might be a modifiable mediator of cardiovascular risk, these data show that it may be just a marker of the severity of the disease.
Acknowledgments
FUNDING
This work was supported by the National Heart Lung and Blood Institute at the National Institutes of Health [grant number 5T32HL007374-34 (Dr. Bello)]. TREAT and RED-HF were funded by Amgen.
Footnotes
CONFLICT OF INTEREST
Drs. Lewis, Desai, Anand, Krum, McMurray, Solomon, Swedberg, van Veldhuisen, Young and Pfeffer have received research support and/or consulting fees or honoraria from Amgen. Mr. Olson is an employee of Amgen. Dr. Bello reports no conflicts.
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