Association Between Self‐Reported Medication Adherence and Therapeutic Inertia in Hypertension: A Secondary Analysis of SPRINT (Systolic Blood Pressure Intervention Trial)

Abstract

Background

Therapeutic inertia (TI), failure to intensify antihypertensive medication when blood pressure (BP) is above goal, remains prevalent in hypertension management. The degree to which self‐reported antihypertensive adherence is associated with TI with intensive BP goals remains unclear.

Methods and Results

Cross‐sectional analysis was performed of the 12‐month visit of participants in the intensive arm of SPRINT (Systolic Blood Pressure Intervention Trial), which randomized adults to intensive (<120 mm Hg) versus standard (<140 mm Hg) systolic BP goals. TI was defined as no increase in antihypertensive regimen intensity score, which incorporates medication number and dose, when systolic BP is ≥120 mm Hg. Self‐reported adherence was assessed using the 8‐Item Morisky Medication Adherence Scale (MMAS‐8) and categorized as low (MMAS‐8 score <6), medium (MMAS‐8 score 6 to <8), and high (MMAS‐8 score 8). Poisson regressions estimated prevalence ratios (PRs) and 95% CIs for TI associated with MMAS‐8. Among 1009 intensive arm participants with systolic BP >120 mm Hg at the 12‐month visit (mean age, 69.6 years; 35.2% female, 28.8% non‐Hispanic Black), TI occurred in 50.8% of participants. Participants with low adherence (versus high) were younger and more likely to be non‐Hispanic Black or smokers. The prevalence of TI among patients with low, medium, and high adherence was 45.0%, 53.5%, and 50.4%, respectively. After adjustment, neither low nor medium adherence (versus high) were associated with TI (PR, 1.11 [95% CI, 0.87–1.42]; PR, 1.08 [95% CI, 0.84–1.38], respectively).

Conclusions

Although clinician uncertainty about adherence is often cited as a reason for why antihypertensive intensification is withheld when above BP goals, we observed no evidence of an association between self‐reported adherence and TI.

Non standard Abbreviations and Acronyms

MMAS‐8

8‐Item Morisky Medication Adherence Scale

mTIS

modified therapeutic intensity score

NHLBI

National Heart, Lung, and Blood Institute

PR

prevalence ratio

SBP

systolic blood pressure

SPRINT

Systolic Blood Pressure Intervention Trial

TI

therapeutic inertia

Clinical Perspective.

What Is New?

• Among 1009 participants with blood pressure above the intensive target goal in SPRINT (Systolic Blood Pressure Intervention Trial) at the 12‐month visit, self‐reported adherence to antihypertensive medication was not associated with therapeutic inertia.

What Are the Clinical Implications?

• While uncertainty around medication adherence may be a common reason for therapeutic inertia, we found no evidence that self‐reported adherence was associated with therapeutic inertia when treating to intensive blood pressure goals in high‐risk individuals.

• Identification of causes of therapeutic inertia and how to overcome them in clinical practice are needed to reduce the significant burden of uncontrolled hypertension in the United States.

Hypertension remains the leading modifiable risk factor for cardiovascular disease and occurs in nearly 50% of US adults. ¹ , ² Barriers to achieving blood pressure (BP) control are multifactorial and include patient‐, clinician‐, and health care system–related factors. ³ Therapeutic inertia (TI) is a clinician‐related barrier defined as the failure to initiate or intensify antihypertensive therapy despite appropriate medical indication. ⁴ , ⁵ , ⁶ One of the most common reasons cited by clinicians for TI is uncertainty about patient medication adherence. ⁷ , ⁸ That is, if the reason for a patient's BP being above goal is low adherence to their current prescribed regimen, then intensifying their medication regimen is unlikely to improve their BP and may pose unnecessary risk. ⁵ TI may be classified as inappropriate TI when adherence is high but clinically appropriate inaction when adherence is low. ⁹

Medication adherence is a major barrier to achieving BP control. Up to 20% to 40% of patients with hypertension discontinue newly prescribed medications within the first year. ¹⁰ , ¹¹ , ¹² Furthermore, 30% to 40% of patients do not achieve adherence levels ≥80% during the first year of antihypertensive therapy per pharmacy fill records. ¹¹ , ¹² , ¹³ Observational data suggest that both greater medication adherence and lower TI are associated with higher BP control. ⁶ , ¹⁴ , ¹⁵ Previous expert opinions infer that clinician knowledge of high medication adherence may reduce inappropriate TI. ⁸ , ¹⁶ However, the degree to which self‐reported adherence to antihypertensive medication is associated with TI, both clinically appropriate inaction and inappropriate TI, remains unclear. ¹⁷ , ¹⁸ , ¹⁹ SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized trial in which US adults with a high risk of cardiovascular disease were randomized to an intensive (systolic BP [SBP] <120 mm Hg) versus standard (SBP <140 mm Hg) treatment goal. ²⁰ We used data from the intensive treatment group of SPRINT to determine the association between self‐reported antihypertensive medication adherence and TI in the setting of intensive SBP treatment goals. We hypothesized that higher self‐reported medication adherence would be associated with lower TI in patients above the intensive SBP treatment goal.

Methods

Design of the Parent Study (SPRINT)

The rationale, design, and primary results of SPRINT have been previously published elsewhere. ²⁰ , ²¹ The protocol was approved by the institutional review board or ethics committee at each center and by an independent protocol review committee appointed by the National Heart, Lung, and Blood Institute (NHLBI), and participants provided written informed consent. SPRINT randomized 9361 US adults 50 years and older with an SBP ≥130 mm Hg and high risk of cardiovascular disease to an intensive (SBP goal <120 mm Hg) or standard (SBP goal <140 mm Hg) treatment goal between November 2010 and March 2013. ²⁰ When not at the randomized treatment goal, the study protocol encouraged study clinicians to initiate or uptitrate the antihypertensive medication regimen until the SBP goal was achieved. ²² In the intensive arm, milepost visits were performed every 6 months in which clinicians were mandated to escalate therapy for participants whose SBP was >120 mm Hg unless there was a compelling reason to not intensify or patient unwillingness. ²² In addition, the standard arm did not require escalation of therapy at every visit, therefore a cross‐sectional analysis would fail to accurately capture TI. At each visit, investigators provided a sufficient supply of antihypertensive medications at no cost to each participant. ²² The SPRINT protocol states preferred automated BP device measurements to reduce potential observer bias and decrease staffing demands, but allowed for further physical examination of the patient at the investigator's discretion.

Design of the Current Analysis

This was a cross‐sectional analysis of SPRINT at the 12‐month follow‐up visit. We limited the analysis to the 12‐month visit because the MMAS‐8 was only administered at the 12‐ and 48‐month visits. We did not analyze data from the 48‐month visit due to small sample size. We included only participants in the intensive treatment group where SBP was not at goal at the 12‐month postrandomization visit. TI could not be assessed at baseline because TI was defined based on information from the previous visit, therefore no protocolized previous visit was available prior to baseline. We restricted the current analysis to participants in the intensive treatment group because, unlike the standard arm, the intensive arm included the mandated milepost visits every 6 months to ensure that antihypertensive intensification was occurring if SBP was <120 mm Hg in concordance with SPRINT protocol. ²² We excluded participants who were not using antihypertensive medications before the 12‐month visit as adherence could not be assessed (n=17); the final sample included 1008 intensive arm participants (Figure 1). Data and methods from SPRINT are publicly available to researchers through the NHLBI's Biologic Specimen and Data Repository Information and Coordinating Center (http://www.biolincc.nhlbi.nih.gov/home). This analysis was approved by the University of Utah's institutional review board.

Figure 1. Flow diagram of inclusion and exclusion criteria.

BP indicates blood pressure; and SBP, systolic blood pressure.

Main Exposure

The 8‐Item Morisky Medication Adherence Scale (MMAS‐8) is a validated self‐reported questionnaire to assess antihypertensive medication adherence. ²³ , ²⁴ Lower scores indicate worse adherence (Table S1). ²³ , ²⁴ , ²⁵ , ²⁶ As in prior SPRINT and validated analyses, we categorized MMAS‐8 into low adherence (MMAS‐8 score <6), medium adherence (MMAS‐8 score 6 to <8), and high adherence (MMAS‐8 score 8). ²³ , ²⁷ Previous overall SPRINT analyses reported high adherence based on the MMAS‐8 in 44.4% of all participants and 47.0% reporting no change in MMAS‐8 from baseline to 12 months. ²⁵ At each visit, antihypertensive medication adherence was also assessed using a visual analog scale (VAS) as a single‐item adherence question: “Please circle the percentage below that shows your best guess about how many days you have taken all of your blood pressure medications as prescribed since your last visit”. The VAS was from 0% to 100% (by 10% increments). ²¹ In the SPRINT protocol, if participants were identified via the VAS at any visit or MMAS‐8 at the 12‐ or 48‐month visit to be of low adherence, investigators were encouraged to address the specific barriers to optimal adherence. ²² The distribution of responses to the VAS at the 12‐month visit revealed that 86.2% of participants reported no missed doses at 12 months, indicating the limitation of utility for a single‐item self‐reported adherence measurement (Figure S1). Therefore, we utilized the previously validated, multidimensional, self‐reported adherence MMAS‐8 measurement as the primary approach to classify adherence. ²³

Outcome

The primary outcome was TI at the 12‐month visit. To calculate the intensity of each participant's antihypertensive regimen at the beginning and end of the visit, we used the modified therapeutic intensity score (mTIS). ⁸ , ²⁸ The mTIS is a summary score of the medication regimen intensity based on the 2017 American College of Cardiology/American Heart Association BP guideline–defined maximum dose for each medication. ¹⁵ , ²⁸ The mTIS was calculated as follows:

$$\text{mTIS}={\Sigma }_i^n\frac{\text{Prescribed}{\text{medication dose}}_i}{\text{Guideline}-\text{defined maximum}{\text{daily dose}}_i}$$

where n is the number of antihypertensive medications in the regimen and i is each antihypertensive medication. For example, the mTIS for a participant who is taking losartan 25 mg daily (maximum daily dose 100 mg) and hydrochlorothiazide 25 mg daily (maximum daily dose 50 mg) would be calculated as follows:

$$\begin{array}{c}\text{mTIS}=\frac{\text{losartan}25\mathit{mg}}{\text{losartan}100\mathit{mg}}+\frac{\text{hydrochlorothiazide}25\mathrm{mg}}{\text{hydrochlorothiazide}50\mathrm{mg}}\hfill \\ =\frac{1}{4}+\frac{1}{2}=0.75\hfill \end{array}$$

TI was present when the beginning, and end‐of‐visit mTIS remained the same or decreased.

Covariates

Investigators collected data on clinical and sociodemographic variables at baseline. BP was measured by trained personnel using a standardized protocol and automated device (Omron‐HEM‐907 XL). ²⁹ We used clinical measurements at the 12‐month visit including vitals, body mass index, antihypertensive medication use, number of nonantihypertensive medications, laboratory values, and treatment‐related serious adverse events (SAEs). In the current analysis, we included SAEs if reported within the previous month (ie, month 11). The following SAEs were included in the current analysis: orthostatic hypotension with symptoms, electrolyte abnormalities, syncope, injurious fall, acute kidney injury, hypotension, and bradycardia. The proportion of previous visits where BP was controlled (ie, <120 mm Hg) was calculated by dividing the number of visits prior to the 12‐month visit where the SBP was <120 mm Hg, divided by the total number of visits preceding the 12‐month visit.

Statistical Analysis

We summarized and compared participant characteristics by low and medium (versus high) self‐reported medication adherence groups. We used multivariable modified Poisson regression models with robust error variance to calculate prevalence ratios (PRs) and 95% CIs for TI associated with MMAS‐8. ³⁰ Four nested models were assessed: (1) unadjusted; (2) adjusted for baseline sociodemographic and clinical measurements, visit‐level clinical measurements including number of antihypertensive medications, total mTIS, and whether treatment‐related SAE occurred within the previous month; (3) variables in model 2 plus degree (per 10 mm Hg) to which SBP was above 120 mm Hg; and (4) variables in model 3 plus the proportion of previous visits where the BP was controlled. ²⁸ All analyses were performed using R version 4.1.3 (R Project for Statistical Computing). Statistical significance was assessed at the 0.05 level, and all tests were 2‐tailed.

Sensitivity Analyses

Two sensitivity analyses were performed. First, we recategorized the MMAS‐8 measurement to assess high versus not high self‐reported adherence by collapsing low and medium adherence together. This was to potentially assess the difference in types of TI, clinically appropriate inaction versus inappropriate TI. We hypothesized that by collapsing groups, TI, presumably inappropriate TI, would be lower in those with high adherence and the inverse with clinically appropriate inaction for those without high adherence. In addition, we assessed the association of self‐reported adherence via the VAS at each participant visit for the first 48 months using a generalized estimating equation with the same covariates from model 4. The generalized estimating equation model was used to account for clustering with repeated measurements of VAS. ³¹ VAS was categorized as high adherence (VAS of 100%) versus not high adherence (VAS <100%).

Results

Participant Characteristics

Among the 1009 participants at month 12 in the intensive treatment group with SBP >120 mm Hg, 140 mm Hg (13.9%), 391 mm Hg (38.8%), and 478 mm Hg (47.4%) reported low, medium, and high self‐reported adherence, respectively. At baseline, low, medium, and high MMAS‐8 were 21.3%, 39.3%, and 39.4%, respectively. The mean age was 69.6 years (SD, 9.4 years), 35.2% were women, 28.8% were non‐Hispanic Black, and participants were taking a median of 2 (interquartile range [IQR], 1–3) antihypertensive medications with a median mTIS of 2.00 (IQR, 1.25–2.63). The median proportion of previous controlled visits was 27.3% (IQR, 11.1%–42.9%). Participants with low (versus high) adherence were more likely to be younger, non‐Hispanic Black, retired, current smokers, have higher SBP, take a lower number of nonantihypertensive medications, and have depression (Table 1). The median SBP was 130 mm Hg (IQR, 125–137 mm Hg) with 132 mm Hg (IQR, 126–142 mm Hg) for participants with low adherence, 130 mm Hg (IQR, 125–136 mm Hg) for those with medium adherence, and 129 mm Hg (IQR, 124–136 mm Hg) for those with high adherence (P=0.01). During the first 12 months, the included participants had 19 171 total visits with an average of 4.23 visits per participant. Of these, TI occurred at 7838 (40.9%), and 1889 (9.9%) had a reduction in mTIS. The number of visits in the first 12 months was similar between participants with SBP ≥120 mm Hg and <120 mm Hg (8.8±1.6 versus 8.1±1.3, respectively).

Table 1.

Participant Characteristics by Self‐Reported Medication Adherence Groups at Month 12

Variable	Low adherence (MMAS‐8 score <6), n=140	Medium adherence (MMAS‐8 score 6 to <8), n=391	High adherence (MMAS‐8 score 8), n=478	P value (low vs high adherence)*	P value (medium vs high adherence)*
Age, y, median (IQR)	65 (59–75)	70 (62–77)	71 (63–77)	<0.001	0.65
Sex, n (%)
Male	97 (69)	249 (64)	308 (64)	0.31	0.83
Female	43 (31)	142 (36)	170 (36)
Race and ethnicity, n (%)
Non‐Hispanic White	63 (45)	250 (64)	309 (65)	<0.001	0.99
Non‐Hispanic Black	65 (46)	102 (26)	124 (26)
Hispanic	9 (6.4)	30 (7.7)	34 (7.1)
High school level of education or less, n (%)	46 (33)	107 (27)	118 (25)	0.06	0.39
Retired, n (%)	74 (53)	258 (66)	329 (69)	<0.001	0.38
Lives with others, n (%)	96 (69)	276 (71)	324 (68)	0.92	0.38
Health insurance status, n (%)
Medicare/Medicaid	75 (54)	253 (65)	309 (65)	0.07	0.51
Private	56 (40)	178 (46)	209 (44)
Usual source of care, n (%)
No usual source	117 (84)	341 (87)	416 (87)	0.28	0.69
Hospital/clinic	14 (10)	39 (10)	45 (9.4)
Community health center	9 (6.4)	10 (2.6)	17 (3.6)
Current smoker, n (%)	26 (19)	44 (11)	51 (11)	0.03	0.80
BMI, kg/m2, median (IQR)	28.7 (25.7–32.6)	28.6 (25.5–32.6)	28.2 (25.5–31.7)	0.44	0.63
SBP, mm Hg, median (IQR)	132 (126–142)	130 (125–136)	129 (124–136)	0.004	0.75
eGFR, mL/min per 1.73 m2, median (IQR)	70.2 (57.0–81.8)	67.8 (55.0–83.1)	66.4 (50.9–79.4)	0.11	0.08
Serum potassium, mmol/L, median (IQR)	4.1 (3.8–4.4)	4.1 (3.8–4.4)	4.2 (3.8–4.5)	0.59	0.18
Serum sodium, mEq/L, median (IQR)	140 (139–142)	140 (138–141)	140 (138–141)	0.03	0.29
Comorbid conditions, n (%)
Prediabetes	59 (42)	145 (37)	197 (41)	0.85	0.24
Coronary heart disease	27 (19)	94 (24)	100 (21)	0.72	0.29
Chronic kidney disease	41 (29)	113 (29)	170 (36)	0.19	0.04
Depression	30 (21)	76 (19)	68 (14)	0.05	0.04
No. of antihypertensive medications, median (IQR)	2 (1–3)	2 (1–3)	2 (1–3)	0.51	0.76
mTIS, median (IQR)	2.0 (1.3–3.0)	2.0 (1.3–2.5)	2.0 (1.3–2.6)	0.15	0.93
No. of nonantihypertensive medications, median (IQR)	2 (0–5)	3 (1–5)	3 (1–6)	<0.001	0.21

BMI indicates body mass index; eGFR, estimated glomerular filtration rate; IQR, interquartile range; MMAS‐8, 8‐Item Morisky Medication Adherence Score; mTIS, modified therapeutic intensity score; and SBP, systolic blood pressure.

^* P values calculated via Wilcoxon rank sum test for continuous variables, and χ² test or Fisher exact test for categorical variables.

Outcomes

Overall, TI was present in 513 (50.8%) of 1009 participants at the 12‐month visit. Among those with low, medium, and high self‐reported adherence, TI was present in 63 of 140 (45.0%), 209 of 391 (53.5%), and 241 of 478 (50.4%), respectively (Table 2). The PRs for medium versus high adherence ranged from 1.09 to 1.19, and for low versus high between 1.05 and 1.12. In the fully adjusted model 4, low and medium (versus high) self‐reported adherence was not associated with TI (PR, 1.08 [95% CI, 0.84–1.38]; PR, 1.11 [95% CI, 0.87–1.42], respectively).

Table 2.

PRs for TI by Self‐Reported Medication Adherence Level at Month 12

	High adherence (MMAS‐8 score 8)	Medium adherence (MMAS‐8 score 6 to <8)	Low adherence (MMAS‐8 score <6)
Prevalence, n (%)	241 of 478 (50.4)	209 of 391 (53.5)	63 of 140 (45.0)
Model 1 (unadjusted)	1 (Reference)	1.19 (0.97–1.46)	1.12 (0.91–1.38)
Model 2	1 (Reference)	1.14 (0.91–1.42)	1.09 (0.88–1.36)
Model 3	1 (Reference)	1.09 (0.88–1.36)	1.05 (0.85–1.32)
Model 4	1 (Reference)	1.11 (0.87–1.42)	1.08 (0.84–1.38)

Data are represented as PRs (95% CIs) unless otherwise stated.

Model 1 is unadjusted.

Model 2 includes baseline sociodemographic and baseline clinical measurements (included in Table 1), visit‐level clinical measurements, and whether a treatment‐related serious adverse event occurred within the previous month.

Model 3 includes variables in model 2 and degree above systolic blood pressure goal.

Model 4 includes variables in model 3 and percent of previously controlled visits.

MMAS‐8 indicates 8‐Item Morisky Medication Adherence Scale; PR, prevalence ratio; and TI, therapeutic inertia.

Factors Associated With TI

At 12 months, after full adjustment, participants without insurance versus Medicare/Medicaid (PR, 0.62 [95% CI, 0.42–0.91]; P=0.01), taking a loop diuretic (PR, 0.72 [95% CI, 0.53–0.98]; P=0.04), and the amount by which SBP exceeded goal (per 10 mm Hg; PR, 0.90 [95% CI, 0.83–0.98]; P=0.01) had a lower likelihood of TI (Figure 2; see Table S2 for results from all models). No additional factors were associated with TI.

Figure 2. Factors associated with therapeutic inertia at 12 months in the fully adjusted model.

No serious adverse events within the previous month occurred at month 12 for any participant; therefore, the variable was omitted from the model. ACEI indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; mTIS, modified therapeutic intensity score; PR, prevalence ratio; SBP, systolic blood pressure; TI, therapeutic inertia; and VA, Veterans Affairs.

Sensitivity Analysis

In sensitivity analyses, changing the exposure groups to high versus not high adherence, the association between self‐reported adherence and TI did not significantly change whether assessed with the MMAS‐8 at 12 months (PR, 1.01 [95% CI, 0.88–1.16]) (Table S3). Having no insurance, taking a loop diuretic, and each 10 mm Hg SBP above goal remained significant factors associated with TI in the high versus not high MMAS‐8 sensitivity analysis.

The sensitivity analysis using VAS as the self‐reported medication adherence measurement included 41 796 participant visits (Figure S2). TI was prevalent in 22 990 (55.0%) of participant visits overall with 18 882 of 35 759 (52.8%) in participant visits with high adherence visits and 4108 of 6037 (68.0%) participants visits without high adherence (PR, 1.47 [95% CI, 1.43–1.51]) (Table S4). Overall, a reduction in mTIS occurred in 4590 (11.0%) of participant visits. Factors associated with TI via the VAS analysis also demonstrated inverse associations with uninsured status (PR, 0.89 [95% CI, 0.84–0.93]) and each 10 mm Hg SBP above goal and TI (PR, 0.85 [95% CI, 0.84–0.87]). Furthermore, being Hispanic, having less than a high school education, being retired, having a higher serum sodium, taking a calcium channel blocker, and taking a β‐blocker were associated with lower TI, whereas higher age, being female, being a race or ethnicity other than non‐Hispanic White, Non‐Hispanic Black, or Hispanic, having higher serum potassium, mTIS, percent of previously controlled visits, and having an SAE in the previous month were associated with higher TI.

Discussion

In this cross‐sectional analysis of SPRINT, self‐reported medication adherence, assessed using the MMAS‐8, was not associated with TI at the 12‐month visit in participants targeting an intensive SBP treatment goal of <120 mm Hg. The prevalence of TI was high at 50.8% of visits, with no significant differences between low, medium, and high medication MMAS‐8 adherence groups. Despite adherence to antihypertensive medication being a largely cited contributor to TI by clinicians, the current analysis suggests that self‐reported adherence assessed via the MMAS‐8 may not play a significant role in the clinician's decision to intensify an antihypertensive medication regimen in the context of a protocolized treatment algorithm in a randomized clinical trial.

At least 2 factors related to antihypertensive medication adherence are believed to contribute to TI in hypertension. The first factor is the clinician's uncertainty regarding the patient's actual adherence to their prescribed regimens, while the second factor is the variability in the accuracy of adherence measurements (eg, self‐report and refill history). Both of these factors are frequently suggested as common reasons for withholding appropriate medication intensification across a range of diseases. ⁷ , ⁸ , ³²

Accurately assessing and utilizing medication adherence data for clinical decision‐making poses challenges for clinicians. While direct observed therapy is the gold standard, it is impractical for daily medication regimens. ³ Although measuring metabolites of antihypertensive medications in the blood or urine is a developing approach for objectively assessing medication adherence in hypertension, it is not currently readily used in clinical use. ³³ Due to the lack of practical and objective assessments of medication adherence at the point of care, clinicians often rely on self‐report, which is known to have poor correlation with actual adherence. ¹⁷ Validated self‐reported questionnaires exist, such as the MMAS‐8 and VAS, but even in SPRINT, MMAS‐8 and VAS are only modestly associated with true medication adherence. ³⁴ , ³⁵ In our data, VAS and MMAS‐8 were weakly correlated (r ² =0.104), which is supported by a previous analysis demonstrating a likelihood ratio of 0.55 (95% CI, 0.35–0.85) for high adherence based on MMAS‐8 and 0.76 (95% CI, 0.57–1.01) for a VAS of 100 versus actual adherence as measured by electronic pillpox. ³⁴ In a secondary analysis, a significant association was found between higher self‐reported adherence and lower TI when using the VAS as the measure of adherence. Notably, the VAS was administered at every visit, whereas the MMAS‐8 was only performed at months 12 and 48, leading to a substantially larger sample size for the VAS‐based analysis. This discrepancy in results might arise from several factors: differential sample size limited power; repeated adherence measurements might have bolstered clinician trust, regardless of measurement quality; or it could be a result of the standardized protocol in which clinicians were consistently made aware of medication adherence levels throughout all study visits. In contrast, it remains unclear whether the SPRINT investigators were informed of MMAS‐8 results at the time they made prescribing decisions.

The findings from the current analysis are consistent with 2 previous large analyses assessing medication adherence using the proportion of days covered metric over the previous year among veterans with hypertension, which also found no association between adherence and TI. ¹⁷ , ¹⁸ The results of the current analysis, combined with prior evidence, suggests the existence of other factors apart from antihypertensive medication adherence that drive TI, such as severity of BP elevation above range, type of antihypertensive agents, and markers of health care access such as medical insurance. Alternatively, there may be a disconnect between clinician perception, trust in self‐reported adherence measurements, and clinician behavior. Gaining a better understanding of the real drivers of TI may aid in designing and implementing pragmatic implementation strategies to improve appropriate antihypertensive medication intensification.

TI can be clinically appropriate or inappropriate. ⁶ , ¹⁵ The presence of patient nonadherence is a key factor in determining whether TI is clinically appropriate or inappropriate. ⁶ , ¹⁵ Clinically appropriate inaction occurs when a clinician does not intensify the regimen in a nonadherent patient. Conversely, maintaining a suboptimal regimen in an adherent patient would be considered clinically inappropriate in most cases. In a sensitivity analysis, we combined the low and medium MMAS‐8 categories to differentiate between types of TI: clinically appropriate inaction in cases of low adherence and inappropriate TI in cases of high adherence. In this sensitivity analysis, there was no association between the binary categorization of MMAS‐8 and TI. However, in our main analysis, we did account for potential reasons for clinically appropriate TI in our adjusted models, such as the occurrence of an SAE in the previous month and laboratory measurements. Practically, clinically appropriate TI reflects patient‐centered care, and specific interventions are needed to reduce clinically inappropriate TI. For example, when a validated adherence measurement such as electronic pillbox data were available to clinicians, inappropriate TI decreased and clinically appropriate inaction increased. ³⁶ Electronic pillbox data are not the norm, however, and more generalizable interventions are needed. Furthermore, our results demonstrate that repeated measurements of a low‐quality adherence tool, such as the VAS, may also influence TI.

There are notable strengths and limitations to the present study. SPRINT used validated, high‐quality assessments of self‐reported adherence, medication use, and BP measurements. ²² In practice, validated self‐reported adherence measurements are not widely available or utilized and the variability in SBP does not resemble that of a clinical trial. ¹⁰ , ³⁷ Furthermore, the MMAS‐8 was only measured at 2 points of follow‐up (months 12 and 48), which may have limited clinician confidence in its accuracy. In addition, the mean SBP in the intensive arm of SPRINT was above target at 121.5 mm Hg at 3.3 years, making the intensive arm of SPRINT an ideal source for identifying TI. ²⁰ However, this study assumes that the clinician used the collected adherence information at the point of the study visit, which may not have been the case as SPRINT protocol only dictated the investigator to address specific barriers to adherence if low adherence was identified; adherence measurements may not have been used in the clinician decision‐making. ²² Therefore, we recommend caution in interpretation of these results on the relationship between clinician awareness of adherence and TI. While this post hoc analysis accounted for clinically appropriate reasons for TI (eg, SAE in the previous month and renal function), the presence of important unmeasured confounders in the relationship between adherence and TI (eg, previous medication intolerances or drug–drug interactions) or low power may have impacted the findings.

Conclusion

In the setting of a randomized clinical trial with a standardized approach to intensive BP management and a validated self‐reported adherence measurement, antihypertensive medication adherence was not associated with TI at the 12‐month follow‐up visit. Given the contribution of TI to low rates of BP control, there is a need to identify and intervene on preventable causes of TI to reduce the burden of cardiovascular disease in the United States.

Sources of Funding

I.M.K. received support from the National Heart, Lung, and Blood Institute (R01 HL152699). A.P.B. received support from the National Institute on Aging (1K24AG080168‐01 and R01AG065805‐04).

Disclosures

D.E.M. is the developer and owner of the copyrighted and trademarked MMAS‐8 diagnostic adherence assessment instrument and receives license fees for the use of the MMAS‐8 scale. He was not involved in evaluating the data from the scales he developed. Licenses can be obtained through MMAR, LLC, donald.morisky@moriskyscale.com.

The remaining authors have no disclosures to report.

Supporting information

Tables S1–S4

Figures S1–S2