Pharmacoepidemiologic study of association between apparent treatment resistant hypertension, cardiovascular disease and interaction effect by sex and age

Table 1 Baseline characteristics overall and by apparent treatment resistant hypertension status, n (%)

	Overall	Resistant hypertension
		Yes	No	P value
Total	25516	2329 (9.1)	23187 (90.9)
Treatment group				< 0.001
Chlorthalidone	11808 (46.3)	853 (36.6)	10955 (47.3)
Amlodipine	6955 (27.3)	554 (23.8)	6401 (27.6)
Lisinopril	6753 (26.5)	922 (39.6)	5831 (25.2)
Race				< 0.001
White	15397 (60.3)	1272 (54.6)	14125 (60.9)
African American	8808 (34.5)	953 (40.9)	7855 (33.9)
Am. Indian/Alaskan Native	58 (0.2)	3 (0.1)	55 (0.2)
Asian/Pacific Islander	312 (1.2)	26 (1.1)	286 (1.2)
Other	941 (3.7)	75 (3.2)	866 (3.7)
Hispanic	4485 (17.6)	204 (8.8)	4281 (18.5)	< 0.001
Sex				< 0.001
Male	13597 (53.3)	1333 (57.2)	12264 (52.9)
Female	11919 (46.7)	996 (42.8)	10923 (47.1)
Geographic region				< 0.001
East	3917 (15.4)	337 (14.5)	3580 (15.4)
Midwest	4736 (18.6)	449 (19.3)	4287 (18.5)
South	10603 (41.6)	1165 (50.0)	9438 (40.7)
West	2635 (10.3)	254 (10.9)	2381 (10.3)
Canada	461 (1.8)	33 (1.4)	428 (1.9)
PR/VI	3164 (12.4)	91 (3.9)	3073 (13.3)
Preventive HTN treat	23033 (90.3)	2242 (96.3)	20791 (89.7)	< 0.001
Obese	10604 (41.6)	1085 (46.6)	9519 (41.1)	< 0.001
History of MI or stroke	5499 (21.6)	498 (21.4)	5001 (21.6)	0.84
History of coronary revascularization	3016 (11.8)	327 (14.0)	2689 (11.6)	< 0.001
Type 2 diabetes	8975 (35.2)	1061 (45.6)	7914 (34.1)	< 0.001
left ventricular hypertrophy	5110 (20.0)	551 (23.7)	4559 (19.7)	< 0.001
History of CHD	5981 (23.6)	534 (23.2)	5447 (23.7)	0.61
Smoking status				< 0.001
Current	5491 (21.5)	423 (18.2)	5068 (21.9)
Past	10394 (40.7)	992 (42.6)	9402 (40.6)
Never	9631 (37.7)	914 (39.2)	8717 (37.6)
Aspirin use	9084 (35.6)	922 (39.6)	8162 (35.2)	< 0.001
Estrogen use (in women)	2230 (18.7)	182 (18.3)	2048 (18.8)	0.84
Age (years) (mean ± SD)	66.6 ± 7.5	67 ± 7.5	67 ± 7.5	0.78
BMI (kg/m2) (mean ± SD)	29.7 ± 5.9	30 ± 5.9	30 ± 5.9	< 0.001
SBP (mm Hg) (mean ± SD)	146.0 ± 15.6	152 ± 15.1	145 ± 15.5	< 0.001
DBP (mm Hg) (mean ± SD)	84.0 ± 10.0	85 ± 10.6	84 ± 9.9	0.001
Cholesterol (mean ± SD)	215.7 ± 42.5	216 ± 44.8	216 ± 42.2	0.79
GFR	78.0 ± 19.3	75 ± 20.6	78 ± 19.2	< 0.001

HTN: Hypertension; MI: Myocardial infarction; CHD: Coronary heart disease; BMI: Body mass index; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; GFR: Growth factor receptor; PR: Puerto Rico; VI: United States Virgin Islands.

Table 2 Hazard ratios of apparent treatment resistant hypertension for cardiovascular disease risk and sensitivity analyses

	Model 1			Model 2			Model 3
	HR	95%CI		HR	95%CI		HR	95%CI
aTRH	1.51	1.39	1.64	1.49	1.37	1.62	1.3	1.19	1.42
Sensitivity analyses
Propensity score							1.33	1.20	1.48
Multiple imputation sensitivity analysis							1.24	1.16	1.33
CHD							1.56	1.29	1.89
Without uncontrolled on < 3 drugs							1.3	1.18	1.44

aTRH: Apparent treatment resistant hypertension; HR: Hazards ratio; Model 1: Crude; Model 2: Adjusted for age and sex; Model 3: Adjusted for age, sex, region, race, body mass index, diabetes; GFR: Growth factor receptor, history of CHD, history of myocardial infarction (MI)/Stroke, history of coronary revascularization, baseline systolic blood pressure (BP), baseline diastolic BP, left ventricular hypertrophy, smoking status, baseline BP medication use, aspirin, lipid lowering trial. Propensity score weighting sensitivity analysis (model 3). Multiple imputation sensitivity analysis (model 3); CHD: Coronary heart disease-outcome CHD (fatal CHD or nonfatal MI, coronary revascularization, or hospitalized angina) (model 3).

Table 3 Joint effects for interaction of sex and apparent treatment resistant hypertension, and age and apparent treatment resistant hypertension on cardiovascular disease risk

		aTRH (No)		aTRH (Yes)
		HR	(95%CI)	HR	(95%CI)	HR (95%CI) by sex
Sex	Female	Reference		1.67	(1.45, 1.91)	1.64 (1.43, 1.88)
	Male	1.25	(1.16, 1.34)	1.39	(1.12, 1.56)	1.13 (1.01, 1.27)
HR (95%CI) (M vs F)		1.25	(1.16, 1.35)	0.80	(0.66, 0.97)
RERI (95%CI)		-0.52	(-0.75, 0.25)
Interaction of sex and aTRH on CVD: P < 0.0001
						HR (95%CI) by age
Age	< 65	Reference		1.56	(1.42, 1.71)	1.53 (1.32, 1.77)
	≥ 65	1.38	(1.31, 1.45)	1.61	(1.48, 1.73)	1.18 (1.05, 1.32)
	≥ 65 vs < 65	1.37	(1.28, 1.47)	1.05	(0.87, 1.27)
RERI (95%CI)		-0.339	(-0.61, 0.06)
Interaction of age and aTRH on CVD: P = 0.0326

CVD: Cardiovascular disease; HR: Hazards ratio; aTRH: Apparent treatment resistant hypertension; F: Female; M: Male; RERI: Relative excess risk for interaction.

Table 4 Joint impact of age, sex, and apparent treatment resistant hypertension on cardiovascular disease and coronary heart disease risk

	Sex	Age	HR	(95%CI)
Risk for CVD
aTRH
No	Female	< 65	Reference
No	Male	< 65	1.55	(1.43-1.67)
No	Female	65+	1.68	(1.56-1.79)
No	Male	65+	1.95	1.70-2.20)
Yes	Male	65+	1.85	(1.22-2.48)
Yes	Female	< 65	1.88	(1.64-2.11)
Yes	Male	< 65	2.17	(1.76-2.58)
Yes	Female	65+	2.61	(2.20-3.01)
Three-way interaction of sex, age, and aTRH on CVD, P = 0.2841
Risk for CHD
aTRH
No	Female	< 65	Reference
No	Male	< 65	1.72	(1.57-1.86)
No	Female	65+	1.59	(1.44-1.74)
No	Male	65+	2.1	(1.77-2.42)
Yes	Male	65+	2.12	(1.28-2.97)
Yes	Female	< 65	1.79	(1.47-2.11)
Yes	Male	< 65	2.37	(1.82-2.92)
Yes	Female	65+	2.53	(1.98-3.08)
Three-way interaction of sex, age, and aTRH on CHD, P = 0.4246

CVD: Cardiovascular disease; HR: Hazards ratio; aTRH: Apparent treatment resistant hypertension; CHD: Coronary heart disease.