Study Overview
Objective. To determine the association between antihypertensive medication adherence and visit-to-visit variability of blood pressure (BP).
Design. Post hoc analysis of ALLHAT, a randomized, double-blind, multicenter trial to determine whether treatment with calcium-channel blockers, angiotensin-converting enzyme inhibitors, or α-adrenergic blockers, all newer antihypertensive classes at the time of the study, was superior to treatment with a thiazide diuretic for lowering risk for fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) (primary outcomes), with secondary outcomes including all-cause mortality, stroke, and combined cardiovascular disease (CHD death, nonfatal MI, stroke, angina, coronary revascularization, congestive heart failure, and peripheral arterial disease).
Setting and participants. Participants who had BP and medication adherence data from at least 5 of the 7 study visits conducted 6 to 28 months after randomization. Only patients who had no outcome events within the 28 months were included in the analysis (ie, no fatal CHD or nonfatal MI, stroke, all-cause mortality, or heart failure). In a secondary analysis, participants who had data from 5 of the 7 study visits between 32 to 56 months after randomization were included.
Measures. Adherence to medication was assessed at each visit by a study clinician using the Adherence Survival Kit developed for ALLHAT. Participants were asked whether they had taken at least 80% of their assigned study drug since the last follow-up visit. For primary analyses, participants were categorized as nonadherent if they reported having taken < 80% of their assigned antihypertensive medication at ≥ 1 visits during the 6- to 28-month time period after randomization. For secondary analyses, participants were categorized as nonadherent if they reported having taken < 80% of their assigned medication at ≥ 1 visits during the 32 to 56 months after randomization. In a sensitivity analysis, participants were categorized as nonadherent if they reported taking < 80% of the prescribed antihypertensive medication at ≥ 2 visits during the 6 to 28 months post-randomization time period. Visit-to-visit variability of BP was calculated using 3 metrics based on each ALLHAT participants’ BP measurements: standard deviation independent of mean (SDIM), SD, and average real variability. The BP used for these calculations was the mean of 2 measurements taken during each follow-up study visit according to a standardized BP measurement protocol. Participants were followed from the end of the visit-to-visit variability of BP assessment period to the date of each outcome, their date of death, or end of active ALLHAT follow-up.
Results. Of 33,357 participants randomized, 19,970 participants met eligibility criteria for primary analyses. Of these, 2912 participants (15%) were considered nonadherent. Compared with adherent participants, nonadherent participants were slightly older and more likely to be Hispanic or black. Nonadherent participants were more likely to have evidence of end-organ damage as signified by major ST segment depression or T wave inversion or left ventricular hypertrophy on electrocardiogram but were less likely to have a history of MI, stroke, or coronary revascularization. Nonadherent participants were also less likely to have used BP medications before randomization and less likely to use statins during follow-up. Nonadherent participants were more likely to have changes in BP medication classes during follow-up, were more likely to have uncontrolled BP between 6 and 28 months after randomization, and had higher mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) at the visits. The association between nonadherence and higher BP remained statistically significant in adjusted analyses.
SDIM of SBP was higher among those who were nonadherent (11.4 ± 4.9 versus 10.5 ± 4.5; P < 0.001). After full adjustment, nonadherent participants had 0.8 (95% CI, 0.7–1.0; P < 0.001) higher SDIM of SBP than adherent participants. In addition, compared with adherent participants, nonadherent participants had higher SD and average real variability of SBP. Researcher found the same pattern when the sample was restricted to 11,290 participants without antihypertensive medication changes. The association between adherence status and visit-to-visit variability of SBP was consistent across antihypertensive drug randomization assignment for interaction term for all definitions of visit-to-visit variability of SBP ( P > 0.8). Nonadherent participants also had higher visit-to-visit variability of DBP.
Overall, 4.6% of participants had ≥ 2 visits with < 80% adherence. SDIM of SBP was higher among nonadherent participants versus adherent participants according to this more stringent categorization of nonadherence (11.0 ± 4.6 vs. 10.6 ± 4.6; P = 0.01). After full multivariable adjustment, SDIM of SBP was 0.5 (95% CI, 0.2–0.9; P = 0.001) higher among nonadherent than among adherent participants. Participants who were nonadherent in both the early and late study periods had higher SDIMs of SBP than those who were adherent in both study periods. Minimal changes were found in the SDIM of SBP between the early and late study periods for participants who were adherent in both study periods and nonadherent in both study periods. However, a significant number of participants, had a change in adherence between the early and late study period, with 6.5% switching from adherent to nonadherent and 10.0% switching from nonadherent to adherent. Compared with participants who were adherent in both time periods, participants who changed from adherent to non-adherent had an increase in SDIM of SBP (0.9; 95% CI, 0.5–1.3; P < 0.001), whereas participants who changed from nonadherent to adherent had a decrease in SDIM of SBP (−0.7; 95% CI, −1.0 to −0.3; P < 0.001). Among participants in the primary analysis without a cardiovascular event before the 28-month visit (n = 18 442), being in the highest versus lowest quintile of SDIM of SBP was associated with increased risk of fatal CHD or nonfatal MI, stroke, heart failure, and all-cause mortality after multivariable adjustment. In a mediation analysis, further adjustment for adherence status did not explain the association between SDIM of SBP and any of our cardiovascular or mortality outcomes.
Conclusion. The study provided significant evidence that medication adherence reduces visit-to-visit variability of BP. However, visit-to-visit variability of BP is associated with cardiovascular outcomes independent of medication adherence. Further work is needed to examine both the mechanisms underlying the association between visit-to-visit variability of BP and cardiovascular outcomes and whether decreasing visit-to-visit variability of BP can improve health outcomes.
Commentary
Hypertension remains one of the most important preventable contributors to disease and death [1]. Health care providers continue to reinforce the importance of adherence to medication treatment in conjunction with the adoption of healthy lifestyle habits, which have been shown to be effective interventions [2]. Low adherence to antihypertensive medication has been hypothesized to increase visit-to-visit variability of BP. Literature has shown that visit-to-visit variability of BP is associated with increased risk for stroke, CHD, and mortality [3]. In this post hoc analysis of ALLHAT, the researchers found that nonadherence was associated with increased visit-to-visit variability of BP. The study extended the findings of only a few studies that have tested this association.
Efforts to improve adherence could impact the occurrence of visit-to-visit variability of BP. Current methods of improving medication adherence for chronic health problems are mostly complex and not very effective. Awareness and commitment are essential to promote and ensure adherence in the treatment of disease [4]. Advances in this field of research are needed, including improved design of feasible long-term interventions, objective adherence measures, and sufficient study power to detect improvements outcomes that patients care about [4].
However, in this study, medication nonadherence did not explain the association between visit-to-visit variability of BP levels and cardiovascular risk. The researchers posit that in light of this, improving adherence is unlikely to offset the increased risk associated with visit-to-visit variability of BP found in treated patients with hypertension.
Limitations of this study include the use of self-report for adherence measurement, use of a summary measure for adherence, and the exclusion of a substantial number of participants who had < 5 visits in which adherence was assessed.
Applications for Clinical Practice
Although nonadherence to medication treatment contributed to visit-to-visit variability of BP, nonadherence did not explain why individuals with higher visit-to-visit of BP were at increased cardiovascular risk. Additional research is suggested in order to better understand how visit-to-visit variability of BP levels influences prognosis of hypertension.
—Paloma Cesar de Sales, BS, RN, MS