ARTICLES
Pentoxifylline Decreases Dialysis Risk in Patients With Advanced Chronic Kidney Disease P-C Wu1,2, C-J Wu1,3,4, C-J Lin1,3,5, C-F Pan1, C-Y Chen1, T-M Huang6, C-H Wu7, S-L Lin8, Y-M Chen8, L Chen9, V-C Wu8 and the NSARF Group10 and the Kidney Consortium Few studies evaluated the effects of pentoxifylline on hard endpoints in patients with predialysis stage 5 chronic kidney disease (CKD). Thus, we tried to explore the effects of pentoxifylline and its interaction with renin-angiotensin-aldosterone system (RAAS) blockade on the development of endstage renal disease (ESRD) and mortality. This nationwide cohort study retrospectively included patients who had a serum creatinine level of >6 mg/dL and received erythropoiesis-stimulating agents (ESAs) between 2000 and 2010. We analyzed 7,366 pentoxifylline users and 7,366 propensity score-matched nonusers. Using Cox proportional hazard models, pentoxifylline reduced the risks of ESRD and the composite renal outcome but not that of mortality. In terms of the risks of developing ESRD, pentoxifylline alone exerted a comparable beneficial effect to combined therapy with an RAAS inhibitor and greater renoprotection than RAAS inhibitor monotherapy. This study suggests pentoxifylline is efficacious in slowing progression to ESRD in patients with predialysis stage 5 CKD. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? þ Limited evidence suggests pentoxifylline has an antiproteinuric effect and inconsistent ability to slow GFR decline in patients with different stages of CKD. Even fewer studies have evaluated the effects of pentoxifylline on hard endpoints, such as ESRD and mortality, in patients with predialysis advanced CKD. WHAT QUESTION DID THIS STUDY ADDRESS? þ This study was designed to assess the effects of pentoxifylline, and its interaction with RAAS blockade, on the occurrence of ESRD and death in predialysis patients with stage 5 CKD. WHAT THIS STUDY ADDS TO OUR KNOWLEDGE þ This study is the first to show in patients with predialysis stage 5 CKD that pentoxifylline reduces the risk of developing ESRD and one-fifth to one DDD of pentoxifylline is sufficient for renoprotection. Particularly, pentoxifylline monotherapy may exert a more prominent renoprotective effect than ACEI/ARB monotherapy in this population. HOW THIS MIGHT CHANGE CLINICAL PHARMACOLOGY AND THERAPEUTICS þ This study suggests pentoxifylline is a safe and efficacious alternative for slowing progression to ESRD in patients with stage 5 CKD, especially in those who cannot tolerate ACEI/ARB.
Chronic kidney disease (CKD) is increasingly recognized as a global health burden characterized by proteinuria and a gradual decline in glomerular filtration rate (GFR). Higher proteinuria and lower GFR are strongly associated with adverse outcomes, including endstage renal disease (ESRD),1 coronary events, and all-cause mortality.2 Inhibition of the renin-angiotensin-aldosterone system (RAAS) is the mainstream strategy against CKD progression.3,4 However, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor antagonists (ARBs) cannot completely prevent proteinuria, GFR decline, or the development of ESRD.5 Because the pathogenesis of CKD is complex,6 a multifactorial management plan may be required to halt or further retard kidney disease progression. Pentoxifylline, a methylxanthine derivative, is a nonselective phosphodiesterase inhibitor that exerts anti-inflammatory and
immunomodulatory effects with indiscernible toxicity.6,7 A number of studies have shown its renoprotective effects in the treatment of CKD.8 When combined with an RAAS inhibitor, pentoxifylline provides significant additive antiproteinuric effect in studies targeting patients with early-stage CKD using proteinuria and GFR decline as endpoints.9,10 Data focusing on the use of pentoxifylline in patients with advanced renal disease and using hard endpoints, such as doubling of serum creatinine, ESRD, and mortality, are limited. The purpose of this study was to examine the hypothesis that pentoxifylline is a drug of choice with renoprotective and long-term survival benefit in patients with advanced CKD. Specifically, we sought to evaluate the effects of pentoxifylline, and its interaction with ACEI/ARB, on ESRD and all-cause mortality.
Yung-Ming Chen and Vin-Cent Wu contributed equally to this work. 1 Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan; 2Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; 3Department of Medicine, Mackay Medical College, Taipei, Taiwan; 4Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan; 5Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan; 6Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Douliou City, Yunlin County, Taiwan; 7 Division of Nephrology, Taipei Buddhist Tzu Chi General Hospital, Buddhist Tzu Chi University, Taipei, Taiwan; 8Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 9Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan; 10 NSARF, the National Taiwan University Study Group on Acute Renal Failure. Correspondence: Y-M Chen ([email protected]) Received 17 February 2015; accepted 11 June 2015; advance online publication 16 June 2015. doi:10.1002/cpt.173 442
VOLUME 98 NUMBER 4 | OCTOBER 2015 | www.wileyonlinelibrary/cpt
ARTICLES
Figure 1 Detailed flowchart for patient enrollment.
RESULTS Patient characteristics
Among the 7,368 pentoxifylline users, 7,366 were matched with the same number of pentoxifylline nonusers as controls by propensity scores (Figure 1). The average age of the patients was 64 years, 47% were men, and the Charlson comorbidity index was 2.65 (Table 1). The proportions of patients with diabetes mellitus, hypertension, cardiovascular disease, moderate or severe liver disease, and malignancy were similar in both groups. ARB was prescribed more frequently in pentoxifylline users than nonusers. In the univariate analysis, the incidence of ESRD was higher and that of mortality was lower among the pentoxifylline users vs. nonusers (both P < 0.001). The median time from the first prescription of erythropoiesis-stimulating agent (ESA) to the initiation of dialysis and death was 1.05 years and 3.61 years, respectively. Risk factors for ESRD development
As shown in Table 2, in the multivariate Cox proportional hazard models with influential drugs as time-dependent variables, pentoxifylline (hazard ratio (HR), 0.64; 95% confidence interval (CI), 0.60–0.68), as well as RAAS inhibitors (HR, 0.68; 95% CI, 0.65–0.72), protected against ESRD development, whereas male gender, congestive heart failure, diabetes mellitus, hypertension, and diuretic use were predictive of ESRD (all P < 0.001). This model exhibited modest discrimination with a C statistic of 0.63 and an adjusted R2 of 0.11. When the ESRD endpoint was substituted by the composite renal outcome in the Cox regression model (Supplementary Table 1 online), pentoxifylline significantly decreased the risk of long-term dialysis or death (HR, 0.70; 95% CI, 0.66–0.74), but RAAS inhibitors did not (HR, 0.98; 95% CI, 0.94–1.02). After adjusting for competing mortality in the competing-risks regression model (Supplementary Table 2 online, Supplementary Figure 1 online), pentoxifylline CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 98 NUMBER 4 | OCTOBER 2015
(subhazard ratio, 0.67; 95% CI, 0.62–0.71) and RAAS inhibitors (subhazard ratio, 0.73; 95% CI, 0.69–0.77) remained protective from ESRD development. Furthermore, the renoprotective effect of pentoxifylline was consistent across the subgroups stratified by baseline comorbidities, and the effect was seemingly more prominent in patients with diabetes mellitus and hypertension (Figure 2). Next, we evaluated the dose-response relationship between pentoxifylline and ESRD. Targeting pentoxifylline users, we found the HR was 0.62 (95% CI, 0.54–0.71; P < 0.001) per defined daily dose (DDD) of pentoxifylline after adjustment for age, comorbidities, and influential drugs (C statistic, 0.63; adjusted R2, 0.11). However, the generalized additive model plot showed that the dose-response curve was nonlinear (Figure 3). One-fifth to one DDD of pentoxifylline was sufficient to prevent the initiation of long-term dialysis. This favorable effect increased in a dose-response manner up to one DDD, at which point a ceiling effect was reached. In the evaluation of the interaction between pentoxifylline and an RAAS inhibitor, taking pentoxifylline-only users as the reference, concurrent use of ACEI/ARB and pentoxifylline did not further diminish the risk of ESRD progression (Figure 4). Of note, pentoxifylline alone was associated with a lower risk for ESRD development than ACEI/ARB alone. Patients who were not taking pentoxifylline or ACEI/ARB had the highest risk for ESRD (C statistic, 0.61; adjusted R2, 0.09).
Risk factors for all-cause mortality
Table 3 shows the clinical predictors of death after applying the time-varying Cox proportional hazards model, whereas timevarying ESRD predicted a lower risk of death, age, male gender, and other baseline comorbidities all predicted mortality. 443
ARTICLES Table 1 Clinical characteristics and outcomes in pentoxifylline users and nonusers Pentoxifylline nonusers (n 5 7,366)
Pentoxifylline users (n 5 7,366)
P value
Male gender
3,458 (46.9%)
3,462 (47.0%)
0.96
Age, year
64.00 6 13.64
64.11 6 13.07
0.85
2.64 6 1.54
2.65 6 1.56
0.89
Myocardial infarction
111 (1.5%)
111 (1.5%)
0.99
Congestive heart failure
585 (7.9%)
587 (8.0%)
0.98
38 (0.5%)
38 (0.5%)
0.99
338 (4.6%)
351 (4.8%)
0.64
74 (1.0%)
74 (1.0%)
0.99
452 (6.1%)
431 (5.9%)
0.49
Rheumatologic disease
97 (1.3%)
110 (1.5%)
0.40
Hemiplegia
17 (0.2%)
19 (0.3%)
0.87
Malignancy
293 (4.0%)
299 (4.1%)
0.83
2,912 (39.5%)
2,920 (39.6%)
0.91
278 (3.8%)
287 (3.9%)
0.73
4,795 (65.1%)
4,803 (65.2%)
0.90
ACEI
1,633 (22.2%)
1,676 (22.8%)
0.40
ARB
2,987 (40.6%)
3,245 (44.1%)
< 0.001
Diuretic
5,495 (74.6%)
5,528 (75.0%)
0.54
ESRD
5,399 (73.3%)
5,754 (78.1%)
< 0.001
Mortality
2,855 (38.8%)
2,421 (32.9%)
< 0.001
Baseline comorbidities Charlson comorbidity index
Peripheral vascular disease Cerebrovascular disease Dementia COPD
Diabetes mellitus Moderate or severe liver disease Hypertension Antihypertensive agents
Outcomes
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor antagonist; COPD, chronic obstructive pulmonary disease; ESRD, endstage renal disease.
Pentoxifylline and RAAS blockade had no significant impact on survival (C statistic, 0.73; adjusted R2, 0.21).
elimination of pentoxifylline and its metabolites, lower starting doses and individualized dose titration are required. A daily dose of 400 mg in ESRD11 and 1,200 mg in stage 3–4 CKD12 has
DISCUSSION
Table 2 Risk factors for ESRD development
This study, including a total of 14,732 patients, is the largest to date and the first to show that pentoxifylline use reduces the risk of developing ESRD in patients with predialysis stage 5 CKD and anemia, with a greater effect in patients with diabetes mellitus and hypertension. The renoprotective effect of pentoxifylline was consistent in the Cox proportional hazard models with different endpoints and was not confounded by death before ESRD in the competing-risks analysis. One-fifth to one DDD of pentoxifylline was sufficient for ESRD risk reduction in the doseeffect analysis. In particular, pentoxifylline monotherapy could have a more prominent renoprotective effect than ACEI/ARB monotherapy in this population. We demonstrated that one-fifth to one DDD of pentoxifylline had a dose-dependent attenuating effect on the possibility of initiation of long-term dialysis. Because renal failure impairs the 444
Variables
HR (95% CI)
P value
Age, per year
0.99 (0.99–0.99)
Pentoxifylline Decreases Dialysis Risk in Patients With Advanced Chronic Kidney Disease P-C Wu1,2, C-J Wu1,3,4, C-J Lin1,3,5, C-F Pan1, C-Y Chen1, T-M Huang6, C-H Wu7, S-L Lin8, Y-M Chen8, L Chen9, V-C Wu8 and the NSARF Group10 and the Kidney Consortium Few studies evaluated the effects of pentoxifylline on hard endpoints in patients with predialysis stage 5 chronic kidney disease (CKD). Thus, we tried to explore the effects of pentoxifylline and its interaction with renin-angiotensin-aldosterone system (RAAS) blockade on the development of endstage renal disease (ESRD) and mortality. This nationwide cohort study retrospectively included patients who had a serum creatinine level of >6 mg/dL and received erythropoiesis-stimulating agents (ESAs) between 2000 and 2010. We analyzed 7,366 pentoxifylline users and 7,366 propensity score-matched nonusers. Using Cox proportional hazard models, pentoxifylline reduced the risks of ESRD and the composite renal outcome but not that of mortality. In terms of the risks of developing ESRD, pentoxifylline alone exerted a comparable beneficial effect to combined therapy with an RAAS inhibitor and greater renoprotection than RAAS inhibitor monotherapy. This study suggests pentoxifylline is efficacious in slowing progression to ESRD in patients with predialysis stage 5 CKD. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? þ Limited evidence suggests pentoxifylline has an antiproteinuric effect and inconsistent ability to slow GFR decline in patients with different stages of CKD. Even fewer studies have evaluated the effects of pentoxifylline on hard endpoints, such as ESRD and mortality, in patients with predialysis advanced CKD. WHAT QUESTION DID THIS STUDY ADDRESS? þ This study was designed to assess the effects of pentoxifylline, and its interaction with RAAS blockade, on the occurrence of ESRD and death in predialysis patients with stage 5 CKD. WHAT THIS STUDY ADDS TO OUR KNOWLEDGE þ This study is the first to show in patients with predialysis stage 5 CKD that pentoxifylline reduces the risk of developing ESRD and one-fifth to one DDD of pentoxifylline is sufficient for renoprotection. Particularly, pentoxifylline monotherapy may exert a more prominent renoprotective effect than ACEI/ARB monotherapy in this population. HOW THIS MIGHT CHANGE CLINICAL PHARMACOLOGY AND THERAPEUTICS þ This study suggests pentoxifylline is a safe and efficacious alternative for slowing progression to ESRD in patients with stage 5 CKD, especially in those who cannot tolerate ACEI/ARB.
Chronic kidney disease (CKD) is increasingly recognized as a global health burden characterized by proteinuria and a gradual decline in glomerular filtration rate (GFR). Higher proteinuria and lower GFR are strongly associated with adverse outcomes, including endstage renal disease (ESRD),1 coronary events, and all-cause mortality.2 Inhibition of the renin-angiotensin-aldosterone system (RAAS) is the mainstream strategy against CKD progression.3,4 However, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor antagonists (ARBs) cannot completely prevent proteinuria, GFR decline, or the development of ESRD.5 Because the pathogenesis of CKD is complex,6 a multifactorial management plan may be required to halt or further retard kidney disease progression. Pentoxifylline, a methylxanthine derivative, is a nonselective phosphodiesterase inhibitor that exerts anti-inflammatory and
immunomodulatory effects with indiscernible toxicity.6,7 A number of studies have shown its renoprotective effects in the treatment of CKD.8 When combined with an RAAS inhibitor, pentoxifylline provides significant additive antiproteinuric effect in studies targeting patients with early-stage CKD using proteinuria and GFR decline as endpoints.9,10 Data focusing on the use of pentoxifylline in patients with advanced renal disease and using hard endpoints, such as doubling of serum creatinine, ESRD, and mortality, are limited. The purpose of this study was to examine the hypothesis that pentoxifylline is a drug of choice with renoprotective and long-term survival benefit in patients with advanced CKD. Specifically, we sought to evaluate the effects of pentoxifylline, and its interaction with ACEI/ARB, on ESRD and all-cause mortality.
Yung-Ming Chen and Vin-Cent Wu contributed equally to this work. 1 Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan; 2Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; 3Department of Medicine, Mackay Medical College, Taipei, Taiwan; 4Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan; 5Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan; 6Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Douliou City, Yunlin County, Taiwan; 7 Division of Nephrology, Taipei Buddhist Tzu Chi General Hospital, Buddhist Tzu Chi University, Taipei, Taiwan; 8Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 9Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan; 10 NSARF, the National Taiwan University Study Group on Acute Renal Failure. Correspondence: Y-M Chen ([email protected]) Received 17 February 2015; accepted 11 June 2015; advance online publication 16 June 2015. doi:10.1002/cpt.173 442
VOLUME 98 NUMBER 4 | OCTOBER 2015 | www.wileyonlinelibrary/cpt
ARTICLES
Figure 1 Detailed flowchart for patient enrollment.
RESULTS Patient characteristics
Among the 7,368 pentoxifylline users, 7,366 were matched with the same number of pentoxifylline nonusers as controls by propensity scores (Figure 1). The average age of the patients was 64 years, 47% were men, and the Charlson comorbidity index was 2.65 (Table 1). The proportions of patients with diabetes mellitus, hypertension, cardiovascular disease, moderate or severe liver disease, and malignancy were similar in both groups. ARB was prescribed more frequently in pentoxifylline users than nonusers. In the univariate analysis, the incidence of ESRD was higher and that of mortality was lower among the pentoxifylline users vs. nonusers (both P < 0.001). The median time from the first prescription of erythropoiesis-stimulating agent (ESA) to the initiation of dialysis and death was 1.05 years and 3.61 years, respectively. Risk factors for ESRD development
As shown in Table 2, in the multivariate Cox proportional hazard models with influential drugs as time-dependent variables, pentoxifylline (hazard ratio (HR), 0.64; 95% confidence interval (CI), 0.60–0.68), as well as RAAS inhibitors (HR, 0.68; 95% CI, 0.65–0.72), protected against ESRD development, whereas male gender, congestive heart failure, diabetes mellitus, hypertension, and diuretic use were predictive of ESRD (all P < 0.001). This model exhibited modest discrimination with a C statistic of 0.63 and an adjusted R2 of 0.11. When the ESRD endpoint was substituted by the composite renal outcome in the Cox regression model (Supplementary Table 1 online), pentoxifylline significantly decreased the risk of long-term dialysis or death (HR, 0.70; 95% CI, 0.66–0.74), but RAAS inhibitors did not (HR, 0.98; 95% CI, 0.94–1.02). After adjusting for competing mortality in the competing-risks regression model (Supplementary Table 2 online, Supplementary Figure 1 online), pentoxifylline CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 98 NUMBER 4 | OCTOBER 2015
(subhazard ratio, 0.67; 95% CI, 0.62–0.71) and RAAS inhibitors (subhazard ratio, 0.73; 95% CI, 0.69–0.77) remained protective from ESRD development. Furthermore, the renoprotective effect of pentoxifylline was consistent across the subgroups stratified by baseline comorbidities, and the effect was seemingly more prominent in patients with diabetes mellitus and hypertension (Figure 2). Next, we evaluated the dose-response relationship between pentoxifylline and ESRD. Targeting pentoxifylline users, we found the HR was 0.62 (95% CI, 0.54–0.71; P < 0.001) per defined daily dose (DDD) of pentoxifylline after adjustment for age, comorbidities, and influential drugs (C statistic, 0.63; adjusted R2, 0.11). However, the generalized additive model plot showed that the dose-response curve was nonlinear (Figure 3). One-fifth to one DDD of pentoxifylline was sufficient to prevent the initiation of long-term dialysis. This favorable effect increased in a dose-response manner up to one DDD, at which point a ceiling effect was reached. In the evaluation of the interaction between pentoxifylline and an RAAS inhibitor, taking pentoxifylline-only users as the reference, concurrent use of ACEI/ARB and pentoxifylline did not further diminish the risk of ESRD progression (Figure 4). Of note, pentoxifylline alone was associated with a lower risk for ESRD development than ACEI/ARB alone. Patients who were not taking pentoxifylline or ACEI/ARB had the highest risk for ESRD (C statistic, 0.61; adjusted R2, 0.09).
Risk factors for all-cause mortality
Table 3 shows the clinical predictors of death after applying the time-varying Cox proportional hazards model, whereas timevarying ESRD predicted a lower risk of death, age, male gender, and other baseline comorbidities all predicted mortality. 443
ARTICLES Table 1 Clinical characteristics and outcomes in pentoxifylline users and nonusers Pentoxifylline nonusers (n 5 7,366)
Pentoxifylline users (n 5 7,366)
P value
Male gender
3,458 (46.9%)
3,462 (47.0%)
0.96
Age, year
64.00 6 13.64
64.11 6 13.07
0.85
2.64 6 1.54
2.65 6 1.56
0.89
Myocardial infarction
111 (1.5%)
111 (1.5%)
0.99
Congestive heart failure
585 (7.9%)
587 (8.0%)
0.98
38 (0.5%)
38 (0.5%)
0.99
338 (4.6%)
351 (4.8%)
0.64
74 (1.0%)
74 (1.0%)
0.99
452 (6.1%)
431 (5.9%)
0.49
Rheumatologic disease
97 (1.3%)
110 (1.5%)
0.40
Hemiplegia
17 (0.2%)
19 (0.3%)
0.87
Malignancy
293 (4.0%)
299 (4.1%)
0.83
2,912 (39.5%)
2,920 (39.6%)
0.91
278 (3.8%)
287 (3.9%)
0.73
4,795 (65.1%)
4,803 (65.2%)
0.90
ACEI
1,633 (22.2%)
1,676 (22.8%)
0.40
ARB
2,987 (40.6%)
3,245 (44.1%)
< 0.001
Diuretic
5,495 (74.6%)
5,528 (75.0%)
0.54
ESRD
5,399 (73.3%)
5,754 (78.1%)
< 0.001
Mortality
2,855 (38.8%)
2,421 (32.9%)
< 0.001
Baseline comorbidities Charlson comorbidity index
Peripheral vascular disease Cerebrovascular disease Dementia COPD
Diabetes mellitus Moderate or severe liver disease Hypertension Antihypertensive agents
Outcomes
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor antagonist; COPD, chronic obstructive pulmonary disease; ESRD, endstage renal disease.
Pentoxifylline and RAAS blockade had no significant impact on survival (C statistic, 0.73; adjusted R2, 0.21).
elimination of pentoxifylline and its metabolites, lower starting doses and individualized dose titration are required. A daily dose of 400 mg in ESRD11 and 1,200 mg in stage 3–4 CKD12 has
DISCUSSION
Table 2 Risk factors for ESRD development
This study, including a total of 14,732 patients, is the largest to date and the first to show that pentoxifylline use reduces the risk of developing ESRD in patients with predialysis stage 5 CKD and anemia, with a greater effect in patients with diabetes mellitus and hypertension. The renoprotective effect of pentoxifylline was consistent in the Cox proportional hazard models with different endpoints and was not confounded by death before ESRD in the competing-risks analysis. One-fifth to one DDD of pentoxifylline was sufficient for ESRD risk reduction in the doseeffect analysis. In particular, pentoxifylline monotherapy could have a more prominent renoprotective effect than ACEI/ARB monotherapy in this population. We demonstrated that one-fifth to one DDD of pentoxifylline had a dose-dependent attenuating effect on the possibility of initiation of long-term dialysis. Because renal failure impairs the 444
Variables
HR (95% CI)
P value
Age, per year
0.99 (0.99–0.99)
