Impact of Apparent Treatment Resistant Hypertension on Cardiovascular Disease and Potential Biological and Pharmaceutical Interactions

Abstract

Apparent Treatment Resistant Hypertension (ATRH) is a growing and serious concern in the U.S. affecting approximately 13% of hypertensive adults. Uncontrolled blood pressure has been connected to adverse health outcomes; however, little has been researched on long-term prognosis of individuals with ATRH. It is unclear how the relationship between ATRH and CVD would be modified by differing biological/demographic factors (age, sex, obesity, and diabetes), and first-line antihypertensive medications (diuretic, calcium channel blocker, and ACE inhibitor). Data was obtained from the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial (ALLHAT, N = 25,516) was used and ATRH was assessed from the year 2 follow-up visit (N = 2,329). Cox Proportional Hazards models were used to analyze the relationship between ATRH and CVD. Two-way interactions were analyzed (modifier*ATRH) and results suggested which three-way interactions to test (modifier*modifier*ATRH). Effect modification on the multiplicative scale and additive scale was assessed through use of product terms in the Cox model, heterogeneity of effects, and joint effects. CVD event was the outcome (N=5,030) of interest. ATRH was associated with a 30% increase in risk of CVD (HR 1.3 95% CI 1.19-1.42). Sex and age were found to modify the relationship of ATRH and CVD on both scales. Among women, ATRH was associated with a 62% increase in risk of CVD event (95% CI 1.41 - 1.86) while among men, ATRH was associated with a 14% increase in risk of CVD (95% CI 1.01 - 1.28). ATRH had a stronger impact on risk of CVD among younger subjects than it did among older (HR 1.55, 95% CI 1.33 - 1.79 and HR 1.18, 95% CI 1.05 - 1.32 respectively). No significant two-way effect modification by drug class was observed on either the multiplicative or additive scale. Potential three-way interaction was observed for both ATRH*Sex*Age and ATRH*Sex*Drug. The observed joint effect of being male, with ATRH, and on Lisinopril or Amlodipine on CVD risk (HR 1.39, 95% CI 0.73 - 2.06 and HR 1.55, 95% CI 0.87 - 2.22 respectively) was less than what was expected for both the multiplicative and additive models. The observed joint effect of being male, with ATRH and 65 years or older (HR 1.85, 95% CI 1.22 - 2.48) was less than what was expected for both additive and multiplicative models (HRs 4.10, 95% CI 3.63 - 4.57 and 4.88, 95% CI 3.66 - 6.31 respectively). The sub-multiplicative two-way interaction with ATRH*sex was a main driver in both observed three-way interactions. Our findings indicate that patient sex should be taken into consideration when considering ways to improve awareness, diagnosis, treatment, and management of ATRH. Future research should focus on these observed gender differences in patient outcomes with ATRH with specific focus on the underlying mechanisms at play in this relationship.%%%%Ph.D., Epidemiology – Drexel University, 2018