Use of histamine H₂ receptor antagonists and outcomes in patients with heart failure: a nationwide population-based cohort study

Figures & data

Table 1 Baseline characteristics of the two study cohorts (values are numbers (%) unless stated otherwise)

Baseline characteristics	Histamine H2 receptor antagonist initiators	Proton pump inhibitor initiators
Total study population	3,296 (100)	42,902 (100)
Median age, years (25th–75th percentile)	76 (68–83)	78 (69–85)
Age groups
<60 years	395 (12)	4,423 (10)
60–69 years	559 (17)	7,253 (17)
70–79 years	1,179 (36)	13,057 (30)
80+ years	1,163 (35)	18,169 (42)
Index-year groups
1995–1999	1,558 (47)	4,039 (9)
2000–2004	1,307 (40)	11,921 (28)
2005–2009	388 (12)	15,055 (35)
2010–2014	43 (1)	11,887 (28)
Female	1,593 (48)	19,721 (46)
Time from heart failure diagnosis to first prescription
Median, days (25th–75th percentile)	297 (71–801)	447 (62–1346)
<3 months	933 (28)	12,319 (29)
≥3 to <6 months	352 (11)	3,255 (8)
≥6 to <12 months	522 (16)	4,355 (10)
≥12 to <18 months	328 (10)	3,146 (7)
≥18 to <24 months	259 (8)	2,620 (6)
≥24 to <30 months	195 (6)	2,309 (5)
≥30 months	707 (21)	14,898 (35)
Heart failure risk factors and comorbidity
Coronary artery disease	1,659 (50)	23,090 (54)
Valvular heart disease	387 (12)	6,499 (15)
Hypertension	854 (26)	17,489 (41)
Atrial fibrillation or atrial flutter	930 (28)	15,966 (37)
Venous thromboembolism	129 (4)	1,783 (4)
Stroke	359 (11)	6,461 (15)
Intermittent claudication	74 (2)	2,089 (5)
Diabetes mellitus	581 (18)	9,761 (23)
Obesity	228 (7)	3,588 (8)
Cancer within 1 year	197 (6)	3,592 (8)
Chronic pulmonary disease	822 (25)	11,040 (26)
Chronic kidney disease	148 (5)	4,132 (10)
Dementia	82 (3)	1,652 (4)
Depression	834 (25)	14,525 (34)
Illicit drug abuse/alcohol abuse/smoking	131 (4)	2,611 (6)
Peptic ulcer disease	247 (7)	5,274 (12)
Gastroesophageal reflux disease	95 (3)	1,367 (3)
Anemia	311 (9)	7,392 (17)
Liver disease	68 (2)	1,091 (3)
Alcoholism-related disorders	91 (3)	1,399 (3)
Musculosketal disorders	1,168 (35)	19,552 (46)
Inflammatory bowel disease	25 (1)	545 (1)
Cardiac surgery within past 90 days
Coronary artery bypass grafting	177 (5)	947 (2)
Percutaneous coronary intervention	46 (1)	1,377 (3)
Comedication within past 90 days
Beta blockers	838 (25)	15,684 (37)
ACEI/ARBs	1,341 (41)	19,213 (45)
Diuretics	2,379 (72)	27,511 (64)
Statins	428 (13)	10,324 (24)
NSAIDs	602 (18)	7,504 (17)
Antithrombotics	1,564 (47)	23,889 (56)
Benzodiazepines	531 (16)	4,522 (11)
Opioids	632 (19)	9,952 (23)
Income
Low	1,591 (48)	9,946 (23)
Intermediate	687 (21)	10,851 (25)
High	504 (15)	11,031 (26)
Very high	508 (15)	11,032 (26)
Unknown	6 (0.18)	42 (0.10)
Employment
Employed	343 (10)	4,468 (10)
Early retirement, receiving sickness/incapacity/early retirement	41 (1)	554 (1)
Unemployed	440 (13)	4,852 (10)
State pensioner	2,468 (75)	32,952 (77)
Unknown	4 (0.12)	76 (0.18)

Note: All the abovementioned covariables were included in the regression models.

Abbreviations: ACEIs/ARBs, angiotensin-converting enzyme inhibitors/angiotensin receptor II blockers; NSAIDs, nonsteroidal anti-inflammatory drugs.

Figure 1 Kaplan–Meier survival curve for initiators of proton pump inhibitors and histamine H₂ receptor antagonists.

Abbreviations: H2RA, histamine H₂ receptor antagonist; PPI, proton pump inhibitor.

Table 2 Association between histamine H₂ receptor antagonists and all-cause mortality by follow-up interval

Follow-up interval	No. of events	Mortality risk, % (95% CI)	Unadjusted HR (95% CI)	Adjusted HR (95% CI)*	HR after propensity score matching (95% CI)
1 year
PPI	13,190	30.8 (30.4–31.3)	Reference	Reference	Reference
H2RA	843	25.6 (24.1–27.1)	0.80 (0.74–0.85)	0.80 (0.74–0.86)	0.78 (0.71–0.86)
3 years
PPI	21,403	51.9 (51.4–52.4)	Reference	Reference	Reference
H2RA	1,552	47.2 (45.5–48.9)	0.86 (0.81–0.90)	0.85 (0.80–0.89)	0.85 (0.79–0.92)
5 years
PPI	25,835	65.6 (65.1–66.1)	Reference	Reference	Reference
H2RA	1,964	59.8 (58.1–61.5)	0.85 (0.81–0.89)	0.84 (0.80–0.88)	0.86 (0.79–0.92)

Notes:

* Adjusted by age group, sex, index-year categories, time from heart failure diagnosis until first prescription for PPI or H2RA, coronary artery disease, valvular heart disease, hypertension, atrial fibrillation or atrial flutter, venous thromboembolism, stroke, intermittent claudication, diabetes mellitus, obesity, cancer within 1 year, chronic pulmonary disease, chronic kidney disease, dementia, depression, illicit drug abuse/alcohol abuse/smoking, peptic ulcer disease, gastroesophageal reflux disease, anemia, chronic liver disease, alcoholism-related disorders, musculoskeletal disorders, inflammatory bowel disease, cardiac surgery within past 90 days (coronary artery bypass graft surgery and percutaneous coronary intervention), comedication within past 90 days (beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor II blockers, diuretics, statins, NSAIDs, antithrombotics, benzodiazepines, and opioids), income, and employment.

Abbreviations: CI, confidence interval; HR, hazard ratio; H2RAs, histamine H₂ receptor antagonists; PPIs, proton pump inhibitors; NSAIDs, nonsteroidal anti-inflammatory drugs.

Table 3 Association between histamine H₂ receptor antagonists and cause-specific mortality by follow-up interval

Follow-up interval	Cardiovascular mortality			HR after propensity score matching (95% CI)	Noncardiovascular mortality			HR after propensity score matching (95% CI)
	Rate per 1,000 person-years (95% CI)	Unadjusted HR (95% CI)	Adjusted HR (95% CI)*		Rate per 1,000 person-years (95% CI)	Unadjusted HR (95% CI)	Adjusted HR (95% CI)*
1 year
PPI	125 (121–129)	Reference	Reference	Reference	232 (227–238)	Reference	Reference	Reference
H2RA	99 (88–112)	0.81 (0.72–0.92)	0.76 (0.67–0.87)	0.80 (0.68–0.96)	142 (129–157)	0.63 (0.57–0.69)	0.75 (0.67–0.84)	0.70 (0.61–0.82)
3 years
PPI	88 (86–90)	Reference	Reference	Reference	165 (162–168)	Reference	Reference	Reference
H2RA	73 (67–79)	0.86 (0.79–0.95)	0.83 (0.75–0.91)	0.82 (0.71–0.95)	109 (101–117)	0.69 (0.64–0.74)	0.81 (0.75–0.87)	0.78 (0.69–0.88)
5 years
PPI	80 (78–81)	Reference	Reference	Reference	151 (148–153)	Reference	Reference	Reference
H2RA	65 (60–70)	0.87 (0.80–0.94)	0.82 (0.75–0.89)	0.81 (0.71–0.93)	99 (93–106)	0.70 (0.65–0.74)	0.80 (0.75–0.86)	0.79 (0.71–0.0.89)

Notes:

* Adjusted by age group, sex, index-year categories, time from heart failure diagnosis until first prescription for PPI or H2RA, coronary artery disease, valvular heart disease, hypertension, atrial fibrillation or atrial flutter, venous thromboembolism, stroke, intermittent claudication, diabetes mellitus, obesity, cancer within 1 year, chronic pulmonary disease, chronic kidney disease, dementia, depression, illicit drug abuse/alcohol abuse/smoking, peptic ulcer disease, gastroesophageal reflux disease, anemia, chronic liver disease, alcoholism-related disorders, musculoskeletal disorders, inflammatory bowel disease, cardiac surgery within past 90 days (coronary artery bypass graft surgery and percutaneous coronary intervention), comedication within past 90 days (beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor II blockers, diuretics, statins, NSAIDs, antithrombotics, benzodiazepines, and opioids), income, and employment.

Abbreviations: CI, confidence interval; HR, hazard ratio; H2RAs, histamine H₂ receptor antagonists; PPIs, proton pump inhibitors; NSAIDs, nonsteroidal anti-inflammatory drugs.

Figure 2 One-year all-cause mortality in subgroups of heart failure patients, comparing new users of H2RA and new users of PPIs.

Notes: Adjusted by age group, sex, index-year categories, time from heart failure diagnosis until first prescription for PPI or H2RA, coronary artery disease, valvular heart disease, hypertension, atrial fibrillation or atrial flutter, venous thromboembolism, stroke, intermittent claudication, diabetes mellitus, obesity, cancer within 1 year, chronic pulmonary disease, chronic kidney disease, dementia, depression, illicit drug abuse/alcohol abuse/smoking, peptic ulcer disease, gastroesophageal reflux disease, anemia, chronic liver disease, alcoholism-related disorders, musculoskeletal disorders, inflammatory bowel disease, cardiac surgery within past 90 days (coronary artery bypass graft surgery and percutaneous coronary intervention), comedication within past 90 days (beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor II blockers, diuretics, statins, NSAIDs, antithrombotics, benzodiazepines, and opioids), income, and employment (except the stratifying variable).
Abbreviations: ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor II blocker; H2RA, histamine H₂ receptor antagonist; PPI, proton pump inhibitor; NSAIDs, nonsteroidal anti-inflammatory drugs.

Table 4 Association between H2RA and hospitalization due to worsening of heart failure by follow-up interval

Follow-up interval	No. of events	Rate per 1,000 person-years (95% CI)	Unadjusted HR (95% CI)	Adjusted HR (95% CI)*	HR after propensity score matching (95% CI)
1 year
PPI	1775	144 (140–148)	Reference	Reference	Reference
H2RA	138	139 (126–154)	0.98 (0.88–1.10)	0.86 (0.76–0.96)	0.85 (0.73–1.00)
3 years
PPI	4171	94 (92–96)	Reference	Reference	Reference
H2RA	296	88 (80–95)	0.97 (0.89–1.06)	0.85 (0.77–0.93)	0.86 (0.75–0.98)
5 years
PPI	5821	82 (80–84)	Reference	Reference	Reference
H2RA	422	74 (69–80)	0.97 (0.89–1.05)	0.85 (0.78–0.93)	0.84 (0.74–0.96)

Note:

* Adjusted by age group, sex, index-year categories, time from heart failure diagnosis until first prescription for PPI or H2RA, coronary artery disease, valvular heart disease, hypertension, atrial fibrillation or atrial flutter, venous thromboembolism, stroke, intermittent claudication, diabetes mellitus, obesity, cancer within 1 year, chronic pulmonary disease, chronic kidney disease, dementia, depression, illicit drug abuse/alcohol abuse/smoking, peptic ulcer disease, gastroesophageal reflux disease, anemia, chronic liver disease, alcoholism-related disorders, musculoskeletal disorders, inflammatory bowel disease, cardiac surgery within past 90 days (coronary artery bypass graft surgery and percutaneous coronary intervention), comedication within past 90 days (beta blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor II blockers, diuretics, statins, NSAIDs, antithrombotics, benzodiazepines, and opioids), income, and employment.

Abbreviations: CI, confidence interval; HR, hazard ratio; H2RAs, histamine H₂ receptor antagonists; PPIs, proton pump inhibitors; NSAIDs, nonsteroidal anti-inflammatory drugs.