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

BACKGROUND: A limited number of studies have been conducted to test the magnitudes of the association between apparent treatment resistant hypertension (aTRH) and risk of cardiovascular disease (CVD). AIM: To investigate the association between aTRH and risk of CVD and examine whether sex and age modify this association. METHODS: We applied an observational analysis study design using data from the United States Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT recruited participants (n = 25516) from 625 primary care settings throughout the United States, Canada, Puerto Rico, and United States Virgin Islands, aged 55 and older with hypertension and at least one additional risk factor for heart disease. aTRH was assessed from the year 2 visit. CVD event was defined as one of the following from the year 2 follow-up visit: Fatal or non-fatal myocardial infarction, coronary revascularization, angina, stroke, heart failure, or peripheral artery disease. Cox proportional hazards regression was used to examine the effect of aTRH on CVD risk. Potential modifications of sex and age on this association were examined on the multiplicative scale by interaction term and additive scale by joint effects and relative excess risk for interaction. RESULTS: Of the total study participants (n = 25516), 5030 experienced a CVD event during a mean of 4.7 years follow-up. aTRH was associated with a 30% increase in risk of CVD compared to non-aTRH [hazards ratio (HR) = 1.3, 95%CI: 1.19-1.42]. Sex and age modified this relationship on both multiplicative and additive scales independently. Stratified by sex, aTRH was associated with a 64% increase in risk of CVD (HR = 1.64, 95%CI: 1.43–1.88) in women, and a 13% increase in risk of CVD (HR = 1.13, 95%CI: 1.01–1.27) in men. Stratified by age, aTRH had a stronger impact on the risk of CVD in participants aged < 65 (HR = 1.53, 95%CI: 1.32–1.77) than it did in those aged ≥ 65 (HR = 1.18, 95%CI: 1.05–1.32). Significant two-way interactions of sex and aTRH, and age and aTRH on risk of CVD were observed (P < 0.05). The observed joint effect of aTRH and ages ≥ 65 years (HR = 1.85, 95%CI: 1.22–2.48) in males was less than what was expected for both additive and multiplicative models (HR = 4.10, 95%CI: 3.63–4.57 and 4.88, 95%CI: 3.66–6.31), although three-way interaction of sex, age, and aTRH on the risk of CVD and coronary heart disease did not reach a statistical significance (P > 0.05). CONCLUSION: aTRH was significantly associated with an increased risk of CVD and this association was modified by both sex and age. Further studies are warranted to test these mechanisms.