Beta-adrenergic receptor blockers and liver cancer mortality in a national cohort of hepatocellular carcinoma patients

Figures & data

Table 1. Baseline characteristics of patients diagnosed with primary hepatocellular carcinoma in Sweden in 2006 to 2014 by β-blocker use at cancer diagnosis.

	Non-selective β–blocker (N = 242)		Selective β–blocker (N = 472)		No β–blocker (N = 1390)		p^a
	N	Col%	N	Col %	N	Col%
Age at diagnosis, years (mean, SD)	63.3	9.2	72.3	8.8	66.6	11.4	<.001^b
Male	197	81.4	346	73.3	1041	74.9	.050
Attained education							.023
Compulsory	91	37.6	233	49.4	619	44.5
Secondary	120	49.6	178	37.7	570	41.0
Post-secondary	31	12.8	61	12.9	201	14.5
Marital status at diagnosis							<.001
Unmarried	39	16.1	54	11.4	244	17.6
Married/cohabiting	125	51.7	253	53.6	655	47.1
Divorced/separated	61	25.2	83	17.6	337	24.2
Widowed	17	7.0	82	17.4	154	11.1
TNM stage							<.001
Stage 1	55	22.7	61	12.9	190	13.7
Stage 2	51	21.1	56	11.9	160	11.5
Stage 3A	13	5.4	47	10.0	149	10.7
Stage 3B	2	0.8	10	2.1	20	1.4
Stage 4A	10	4.1	23	4.9	55	4.0
Stage 4B	18	7.4	79	16.7	215	15.5
Recorded incompletely^d	57	23.6	82	17.4	351	25.3
Missing^e	36	14.9	114	24.2	250	18.0
No distant metastases (M stage = M0)	146	60.3	224	47.5	711	51.2	.002
Comorbidity score (median, IQR)^f	7	4–10	8	5-11	4	2-7	<.001^c
Comorbidity before HCC diagnosis
Varices without bleeding	176	72.7	16	3.4	138	9.9	<.001
Varices with bleeding	63	26.0	5	1.1	43	3.1	<.001
Viral hepatitis C	99	40.9	48	10.2	362	26.0	<.001
Viral hepatitis B, D	43	17.8	16	3.4	145	10.4	<.001
Various diseases of liver^g	203	83.9	94	19.9	466	33.5	<.001
Portal vein thrombosis	13	5.4	8	1.7	19	1.4	<.001
Diabetes	99	40.9	242	51.3	429	30.9	<.001
Cardiovascular disease^h	136	56.2	409	86.7	662	47.6	<.001
Moderate-severe renal disease	13	5.4	48	10.2	46	3.3	<.001
Other medications^i
Other anti-hypertensive medications^j	61	25.2	334	70.8	402	28.9	<.001
Lactulose^k	53	21.9	19	4.0	90	6.5	<.001
Spironolactone^l	94	38.8	47	10.0	109	7.8	<.001
Loop diuretics^m	88	36.4	140	29.7	176	12.7	<.001
NSAIDs	14	5.8	46	9.7	159	11.4	0.025
Aspirin	25	10.3	201	42.6	177	12.7	<.001
Statins	27	11.2	174	36.9	145	10.4	<.001

Patients were considered exposed to β-blocker use at cancer diagnosis if they collected at least one prescription during the 90-day period before cancer diagnosis, and unexposed otherwise. Patients using both selective and non-selective β-blockers (n = 14) are in the non-selective subgroup. TNM recording in the Cancer Register was introduced in 2004 and has improved over time. Diabetes and chronic lower respiratory diseases were defined using ICD codes from the Patient Register and medications (ATC: A10 and R03, respectively) from the Prescribed Drug Register; other comorbidities were defined using ICD codes in the Patient Register. Moderate-severe renal disease includes end stage renal disease.

ATC: Anatomic Therapeutic Chemical classification system; ICD: International Classification of Diseases; IQR: interquartile range; SD: standard deviation.

^a p Values are from a χ² test.

^b Robust one-way ANOVA.

^c Median test.

^d Either T, N or M stage was not specified.

^e Captured patients with either all T, N, M stages missing or recorded as TxNxMx.

^f Number of distinct medication classes (medications with the same initial five characters of ATC classification) within 90 days before cancer diagnosis were used to derive a comorbidity score.

^g Includes alcoholic liver disease (ICD-10: K70), toxic liver disease (K71), hepatic failure (K72), chronic hepatitis (K73), fibrosis and cirrhosis of liver (K74), other inflammatory liver diseases (K75), other diseases of liver (K76).

^h Other than varices and portal vein thrombosis.

ⁱ Medications (yes/no variables) are dispensed within 90 days before cancer diagnosis and are not mutually exclusive.

^j Include angiotensin-converting enzyme inhibitors (ATC: C09: A, BA, BB), angiotensin receptor blockers (C09: C, DA, DB), calcium channel blockers (C08) and thiazide diuretics (C03A).

^k Lactulose (ATC: A06AD11) is used for hepatic encephalopathy and as a laxative.

^l Spironolactone (ATC: C03DA01) is the drug of choice for cirrhotic ascites if there is no renal failure. Other indications include hypokalemia, idiopathic edema, and nephrotic syndrome.

^m Loop diuretics (ATC: C03CA): mainly (99%) furosemide (C03CA01), which complements the effect of spironolactone for edema caused by hepatic cirrhosis. Also indicated for the diuretic treatment of chronic heart failure and acute pulmonary edema.

Figure 1. Age-adjusted liver cancer survival curves by β-blocker use among patients with primary hepatocellular carcinoma diagnosed in 2006 to 2014 in Sweden. Survival curves were estimated using flexible parametric survival analysis. The adjusted curves show the survival we would expect to see in exposure groups if each had the age distribution of the study population as a whole (to compare like with like). Values on the plot are age-adjusted median survival estimates by β-blocker use.

Table 2. Cox proportional hazards regression analyses for the association between β-blocker use and liver cancer mortality in patients diagnosed with primary hepatocellular carcinoma (N = 2104) in Sweden in 2006–2014.

β-blockers^a	No. of events	HR^b (95% CI)	p	HR^c (95% CI)	p	HR^d (95% CI)	p
Any β-blocker	414	0.81 [0.72, 0.91]	<.001	0.84 [0.73,0.95]	.008	0.82 [0.72, 0.94]	.005
Non-selective^e	106	0.58 [0.48, 0.72]	<.001	0.74 [0.58, 0.95]	.017	0.71 [0.55, 0.91]	.006
β1-receptor selective^f	308	0.94 [0.82, 1.07]	.362	0.87 [0.75, 1.00]	.053	0.86 [0.75, 1.00]	.049
Lipophilic^g	327	0.76 [0.67, 0.86]	<.001	0.80 [0.69, 0.92]	.002	0.78 [0.67, 0.90]	.001
Hydrophilic^h	87	1.09 [0.88, 1.37]	.422	1.00 [0.80, 1.26]	.974	1.01 [0.80, 1.28]	.906

ATC: Anatomic therapeutic chemical classification system; CI: confidence interval; HR: hazard ratio; TNM: tumor–node–metastasis.

^a Exposed if collected at least one prescription during the 90-day period before liver cancer diagnosis, unexposed otherwise. Patients using both selective and non-selective β-blockers (n = 14) are in the non-selective subgroup, and patients using both lipophilic and hydrophilic β-blockers (n = 2) are in the lipophilic subgroup.

^b β-blocker use compared with non-use adjusting for age at diagnosis.

^c β-blocker use compared with non-use adjusting for age at diagnosis, sex, TNM stage, diagnosis year, healthcare/residence region, attained education, marital status, comorbidity score (number of distinct ATC classes prescribed during 90 days prior to diagnosis), diabetes, gastroesophageal varices with and without bleeding, viral hepatitis C and other, various liver diseases, portal vein thrombosis, other anti-hypertensive medications, NSAIDs, aspirin, statin, loop diuretics, lactulose, spironolactone.

^d Further adjusted for alcohol abuse related morbidity at diagnosis, as well as ablation, transarterial chemoembolization (TACE), liver transplantation, liver resection, and sorafenib use modeled as time-varying covariates. Portal vein thrombosis is also modeled as time-updated covariate in this model.

^e Includes pindolol, propranolol, sotalol, labetalol, carvedilol.

^f Includes metoprolol, atenolol, bisoprolol, metoprolol + felodipine.

^g Includes bisoprolol, carvedilol, labetalol, metoprolol, pindolol, propranolol, metoprolol + felodipine.

^h Includes: sotalol, atenolol.

Table 3. Cox proportional hazards regression analyses for the association between selected β-blockers and liver cancer mortality in patients diagnosed with primary hepatocellular carcinoma (N = 2104) in Sweden in 2006–2014.

β-blockers^a	β-receptor selectivity ratio	Solubility	No. of events	HR^b (95% CI)	p	HR^c (95% CI)	p
Non-selective	β2 vs. β1
Propranolol	8.3	Highly lipophilic	88	0.74 [0.56, 0.97]	.032	0.72 [0.55, 0.95]	.021
Carvedilol	4.5	Moderately lipophilic	12	0.63 [0.35, 1.13]	.120	0.52 [0.29, 0.94]	.031
Selective	β1 vs. β2
Metoprolol	2.3	Highly lipophilic	177	0.84 [0.70, 1.00]	.053	0.81 [0.68, 0.97]	.021
Atenolol	4.7	Hydrophilic	84	1.00 [0.79, 1.27]	.973	1.01 [0.80, 1.28]	.928
Bisoprolol	13.5	Moderately lipophilic	49	0.82 [0.61, 1.11]	.195	0.90 [0.67, 1.22]	.513

Note: Selectivity ratio means, e.g., that the affinity of bisoprolol is 13.5-fold more at the β1- than β2-receptor, while the affinity of propranolol is 8.3-fold more at the β2- than β1-receptor. Carvedilol is a non-selective β-blocker that blocks β1 and β2 adrenergic receptors as well as α1 adrenergic receptors.

ATC: Anatomic therapeutic chemical classification system; CI: confidence interval; HR: hazard ratio.

^a Exposed if collected at least one prescription during the 90-day period before liver cancer diagnosis, unexposed otherwise.

^b β-blocker use compared with non-use adjusting for age at diagnosis, sex, TNM stage, diagnosis year, healthcare/residence region, attained education, marital status, comorbidity score (number of distinct ATC classes prescribed during 90 days prior to diagnosis), diabetes, gastroesophageal varices with and without bleeding, viral hepatitis C and other, various liver diseases, portal vein thrombosis, other anti-hypertensive medications, NSAIDs, aspirin, statin, loop diuretics, lactulose, spironolactone.

^c Further adjusted for alcohol abuse related morbidity at diagnosis, as well as ablation, transarterial chemoembolization (TACE), liver transplantation, liver resection, and sorafenib use modeled as time-varying covariates. Portal vein thrombosis is also modeled as time-updated covariate in this model.

Table 4. Cox proportional hazards regression analyses for the association between antihypertensive medications and liver cancer mortality in patients diagnosed with primary hepatocellular carcinoma in Sweden between 1 July 2006 and 31 December 2014 (N = 1479).

Antihypertensive medications dispensed for hypertension^a	No. of events	HR^b (95% CI)	p
Selective β-blockers	178	0.82 [0.68, 0.98]	.030
ACEi	155	0.96 [0.79, 1.17]	.703
ARBs	122	1.16 [0.94, 1.43]	.162
CCB	160	0.95 [0.79, 1.15]	.589
Thiazide diuretics	36	0.91 [0.65, 1.30]	.615

ACEi: angiotensin-converting enzyme inhibitors; ARBs: angiotensin receptor blockers; ATC: Anatomic therapeutic chemical classification system; CCB: calcium channel blockers; CI: confidence interval; HR: hazard ratio.

^a Exposed if collected at least one prescription during the 90-day period before liver cancer diagnosis dispensed for no other indication but hypertension. Prior prescriptions dispensed during 1 year before cancer diagnosis also had to be for no other indication but hypertension.

^b Antihypertensive medication use compared with non-use adjusting for age at diagnosis, sex, TNM stage, diagnosis year, healthcare/residence region, attained education, marital status, comorbidity score (number of distinct ATC classes prescribed during 90 days prior to diagnosis), diabetes, gastroesophageal varices with and without bleeding, viral hepatitis C and other, various liver diseases, NSAIDs, aspirin, statin, loop diuretics, lactulose, spironolactone, alcohol abuse related morbidity, as well as ablation, transarterial chemoembolization (TACE), liver transplantation, liver resection, sorafenib use, and portal vein thrombosis modeled as time-updated covariates.