Association between NSAID use and mortality risk in patients with end-stage renal disease: a population-based cohort study

Figures & data

Figure 1 Flowchart of study sample selection.

Table 1 Characteristics of patients with end-stage renal disease according to NSAID use

Characteristics	Total		Any NSAID use				P-value
	(N=3,383)		Yes (N=2,623)		No (N=760)
	N (%)		N (%)		N (%)
Age, years							<0.001
<55	1,088	(32.2)	926	(35.3)	162	(21.3)
55–64	816	(24.1)	654	(24.9)	162	(21.3)
65–74	809	(23.9)	625	(23.8)	184	(24.2)
≥75	670	(19.8)	418	(15.9)	252	(33.2)
Sex							0.91
Male	1,720	(50.8)	1335	(50.9)	385	(50.7)
Female	1,663	(49.2)	1288	(49.1)	375	(49.3)
Residence area							0.18
Central city	1,893	(56.0)	1486	(56.7)	407	(53.6)
Suburban	1,091	(32.3)	840	(32.0)	251	(33.0)
Countryside	399	(11.8)	297	(11.3)	102	(13.4)
Dialysis							0.60
Hemodialysis	3,082	(91.1)	2386	(91.0)	696	(91.6)
Peritoneal dialysis	301	(8.9)	237	(9.0)	64	(8.4)
Comorbidity
Myocardial infarction	151	(4.5)	96	(3.7)	55	(7.2)	<0.001
Congestive heart failure	842	(24.9)	583	(22.2)	259	(34.1)	<0.001
Peripheral vascular disease	66	(2.0)	48	(1.8)	18	(2.4)	0.35
Cerebrovascular disease	495	(14.6)	314	(12.0)	181	(23.8)	<0.001
Chronic pulmonary disease	381	(11.3)	283	(10.8)	98	(1.9)	0.11
Liver disease	210	(6.2)	161	(6.1)	49	(6.5)	0.76
Dementia	88	(2.6)	43	(1.6)	45	(5.9)	<0.001
Rheumatoid disease	50	(1.5)	40	(1.5)	10	(1.3)	0.67
Peptic ulcer	704	(20.8)	529	(20.2)	175	(23.0)	0.09
Hypertension	2,906	(85.9)	2236	(85.3)	670	(88.2)	0.04
Diabetes mellitus	1,824	(53.9)	1357	(51.7)	467	(61.5)	<0.001
Opioid use	1,385	(40.9)	1240	(47.3)	145	(19.1)	<0.001

Table 2 Association between the use of NSAIDs and the risk of all-cause mortality in patients with end-stage renal disease

NSAID use	Number of mortality	Person-years	Incidence rate (95% CI) (per 100 person-years)		Crude HR(95% CI)		Adjusted HR (95% CI)
Any NSAIDs
No	372	4,994	7.4	(6.7–8.2)	1.00	(reference)	1.00	(reference)
Yes	1,143	11,711	9.8	(9.2–10.3)	1.40	(1.22–1.60)	1.39	(1.21–1.60)
Nonselective NSAIDs
No	400	5,241	7.6	(6.9–8.4)	1.00	(reference)	1.00	(reference)
Yes	1,115	11,464	9.7	(9.2–10.3)	1.34	(1.18–1.54)	1.36	(1.19–1.55)
Selective COX-2 inhibitors
No	1,111	13,835	8.0	(7.6–8.5)	1.00	(reference)	1.00	(reference)
Yes	404	2,870	14.1	(12.8–15.5)	1.81	(1.61–2.04)	1.61	(1.42–1.83)

Notes: Adjusted HRs were computed after adjustment of age, sex, residence area, types of dialysis, baseline comorbidities, and opioid use.

Abbreviation: COX, cyclooxygenase.

Table 3 Dose–response associations between the use of NSAIDs and the risk of all-cause mortality in patients with end-stage renal disease

Cumulative NSAID use (DDDs)	Number of mortality	Person-years	Incidence rate (95% CI) (per 100 person-years)		Crude HR (95% CI)		Adjusted HR (95% CI)
Any NSAIDs
0	372	4,994	7.4	(6.7–8.2)	1.00	(reference)	1.00	(reference)
1−30	620	6,767	9.2	(8.5–9.9)	1.33	(1.15–1.53)	1.32	(1.15–1.53)
31−90	283	2,849	9.9	(8.8–11.2)	1.49	(1.25–1.78)	1.57	(1.31–1.88)
>90	240	2,095	11.5	(10.1–13.0)	1.78	(1.47–2.16)	1.65	(1.35–2.01)
Non-selective NSAIDs
0	400	5,241	7.6	(6.9–8.4)	1.00	(reference)	1.00	(reference)
1−30	676	7,103	9.5	(8.8–10.3)	1.32	(1.15–1.51)	1.32	(1.15–1.51)
31−90	268	2,766	9.7	(8.6–10.9)	1.37	(1.15–1.64)	1.47	(1.23–1.76)
>90	171	1,595	10.7	(9.2–12.5)	1.57	(1.27–1.93)	1.62	(1.31–2.01)
Selective COX-2 inhibitors
0	1,111	13,835	8.0	(7.6–8.5)	1.00	(reference)	1.00	(reference)
1−30	245	1,748	14.0	(12.4–15.9)	1.80	(1.56–2.07)	1.70	(1.47–1.96)
31−90	98	599	16.4	(13.4–19.9)	2.09	(1.69–2.58)	1.61	(1.29–1.99)
>90	61	523	11.7	(9.1–15.0)	1.53	(1.17–1.99)	1.31	(1.00–1.71)

Notes: Adjusted HRs were computed after adjustment of age, sex, residence area, types of dialysis, baseline comorbidities, and opioid use.

Abbreviations: DDD, defined daily dose; COX, cyclooxygenase.

Table 4 Association between the usage of frequently used individual NSAIDs and the risk of all-cause mortality in patients with end-stage renal disease

NSAID use	Number of mortality	Person-years	Incidence rate (95% CI) (per 100 person-years)		Crude HR (95% CI)		Adjusted HR (95% CI)
Non-selective NSAIDs
Diclofenac
No	810	9,967	8.1	(7.6–8.7)	1.00	(reference)	1.00	(reference)
Yes	705	6,738	10.5	(9.7–11.3)	1.33	(1.19–1.49)	1.44	(1.28–1.61)
Mefenamic acid
No	1,017	1,1004	9.2	(8.7–9.8)	1.00	(reference)	1.00	(reference)
Yes	498	5,701	8.7	(8.0–9.5)	0.91	(0.81–1.03)	1.00	(0.89–1.13)
Ibuprofen
No	1,255	13,718	9.1	(8.7–9.7)	1.00	(reference)	1.00	(reference)
Yes	260	2,987	8.7	(7.7–9.8)	0.93	(0.81–1.07)	1.13	(0.98–1.30)
Selective COX-2 inhibitors
Celecoxib
No	1,170	14,267	8.2	(7.7–8.7)	1.00	(reference)	1.00	(reference)
Yes	345	2,438	14.2	(12.7–15.7)	1.77	(1.56–2.01)	1.57	(1.38–1.79)
Etoricoxib
No	1,442	16,321	8.8	(8.4–9.3)	1.00	(reference)	1.00	(reference)
Yes	73	384	19.0	(15.1–23.9)	2.17	(1.71–2.75)	1.69	(1.33–2.16)
Rofecoxib
No	1,453	16,103	9.0	(8.6–9.5)	1.00	(reference)	1.00	(reference)
Yes	62	602	10.3	(8.0–13.2)	1.13	(0.87–1.46)	1.17	(0.91–1.52)

Notes: Adjusted HRs were computed after adjustment of age, sex, residence area, types of dialysis, baseline comorbidities, and opioid use.

Abbreviation: COX, cyclooxygenase.

Figure 2 Subgroup analysis of association between NSAID use and all-cause mortality. The reference group was NSAID nonusers. Cardiovascular disease included myocardial infarction, congestive heart failure, peripheral vascular disease, and cerebrovascular disease.

Table S1 All analyzed nonsteroidal anti-inflammatory drugs (NSAIDs) in this study

Classification of NSAIDs	ATC code	Drug name
Traditional NSAIDs	M01AB01	Indometacin
	M01AB02	Sulindac
	M01AB03	Tolmetin
	M01AB05	Diclofenac
	M01AB06	Alclofenac
	M01AB08	Etodolac
	M01AB11	Acemetacin
	M01AB15	Ketorolac
	M01AB16	Aceclofenac
	M01AC01	Piroxicam
	M01AC02	Tenoxicam
	M01AC06	Meloxicam
	M01AE01	Ibuprofen
	M01AE02	Naproxen
	M01AE03	Ketoprofen
	M01AE04	Fenoprofen
	M01AE05	Fenbufen
	M01AE09	Flurbiprofen
	M01AE11	Tiaprofenic acid
	M01AG01	Mefenamic acid
	M01AG02	Tolfenamic acid
	M01AG03	Flufenamic acid
	M01AX01	Nabumetone
	M01AX02	Niflumic acid
	M01AX17	Nimesulide
Selective COX-2 inhibitors	M01AH01	Celecoxib
	M01AH02	Rofecoxib
	M01AH05	Etoricoxib

Abbreviations: ATC, Anatomical Therapeutic Chemical; COX, cyclooxygenase.

Table S2 Dose–response associations between the use of individual NSAIDs and the risk of all-cause mortality in patients with end-stage renal disease

Cumulative NSAID use	Number of mortality	Person-years	Incidence rate (95% CI) (per 100 person-years)		Crude HR(95% CI)		Adjusted HR (95% CI)
Diclofenac
0 DDDs (0 g)	810	9967	8.1	(7.6–8.7)	1.00	(reference)	1.00	(reference)
1−30 DDDs (0.1−3 g)	599	5656	10.6	(9.8–11.5)	1.34	(1.19–1.50)	1.44	(1.29–1.62)
31−90 DDDs (3.1−9 g)	77	851	9.1	(7.2–11.3)	1.17	(0.92–1.50)	1.28	(1.00–1.64)
>90 DDDs (>9 g)	29	231	12.6	(8.7–18.1)	1.68	(1.15–2.45)	1.95	(1.33–2.86)
Celecoxib
0 DDDs (0 g)	1170	14267	8.2	(7.7–8.7)	1.00	(reference)	1.00	(reference)
1−30 DDDs (0.2−6 g)	222	1565	14.2	(12.4–16.2)	1.77	(1.53–2.05)	1.68	(1.44–1.95)
31−90 DDDs (6.1−18 g)	76	474	16.0	(12.8–20.1)	1.99	(1.58–2.52)	1.56	(1.22–1.98)
>90 DDDs (>18 g)	47	399	11.8	(8.9–15.7)	1.50	(1.11–2.02)	1.18	(0.88–1.60)
Etoricoxib
0 DDDs (0 g)	1442	16321	8.8	(8.4–9.3)	1.00	(reference)	1.00	(reference)
1−30 DDDs (0.06−1.8 g)	53	237	22.4	(17.1–29.3)	2.53	(1.92–3.34)	1.95	(1.47–2.57)
31−90 DDDs (1.9−5.4 g)	13	93	14.0	(8.1–24.1)	1.60	(0.93–2.78)	1.19	(0.69–2.07)
>90 DDDs (>5.4 g)	7	54	13.0	(6.2–27.2)	1.48	(0.70–3.11)	1.40	(0.66–2.96)

Notes: Adjusted HRs were computed after adjustment of age, sex, residence area, types of dialysis, baseline comorbidities, and opioid use.

Abbreviations: DDD, defined daily dose.