- Top of page
- Study Limitations
The authors used pooled data from 6 valsartan-related studies including 3983 adherent and 10,663 nonadherent patients to evaluate blood pressure (BP) outcomes in both groups after 90 days of treatment, applying hierarchical linear and logistic regression to identify determinants of BP outcomes. The principal findings were that: (1) BP outcomes were consistently better in adherent patients; (2) approximately a quarter of the variance in 90-day BP values was attributable to a physician class effect; (3) common and unique patient- and physician-related variables were associated with BP outcomes in both groups; (4) physician vigilance was associated with better outcomes, especially in adherent patients; and (5) adherent patients were more likely to exhibit target organ damage and associated events while being prescribed more complex medication regimens. Adherence to antihypertensive medication may be a function of prior line treatment failure, severity of illness, and sequelae, and the ensuing patient resolution to change medication behavior.
The prevalence of nonadherence has been estimated at 25% in general, 23% among patients with cardiovascular disease and 50% among patients with hypertension.[2, 3] Nonadherence to antihypertensive medication is associated with a 30% loss of treatment effectiveness, while adherence is associated with a 38% decreased risk of cardiovascular events. While blood pressure (BP) control is a challenge in general,[6-10] achieving BP targets is particularly difficult in nonadherent patients. Prior studies have focused mainly on identifying patient variables associated with nonadherence to antihypertensive medication,[12, 13] even though the determinants of nonadherence are believed to be multifactorial and to include, among others, health care providers and treatment-related factors.
Adherence behavior was a consistent determinant of BP outcomes in multivariate analyses in a series of large observational studies on second-line treatment of hypertension with various valsartan regimens conducted in Belgium. We pooled the data of 6 of these studies to examine whether there were differences in BP outcomes between adherent and nonadherent patients after 90 days of treatment, the proportion of variance in BP outcomes attributable to a physician class effect, and the patient- and physician-related determinants of BP outcomes common across and unique in each of these groups. The 14,646 evaluable patients were classified as nonadherent if they recalled not having taken their medication at some time in the 4 weeks prior to the 90-day follow-up visit; if not, they were classified as adherent. While perhaps a crude criterion potentially subject to bias, we have reported elsewhere that such a simple query is highly predictive of BP outcomes.
- Top of page
- Study Limitations
The principal findings of this subanalysis comparing 3983 adherent and 10,663 nonadherent patients to valsartan-centric antihypertensive medication regimens are 5-fold. First, BP outcomes following 90 days of second-line treatment in patients in whom first-line treatment failed or was not tolerated were consistently better in adherent patients. While BP decreased in both the adherent and nonadherent group, reductions and control rates were higher among adherent patients. Significant differences were generally not noted between adherent and non-adherent patients with diabetes. Second, and understandably in line with related findings from each of the constituent studies, approximately a quarter of the variance in BP values at 90 days was attributable to a physician class effect. This affirms that patients seen by the same clinician are affected by that physician's knowledge, experience, treatment perspectives, and practice patterns, among other factors. Third, common and unique patient- and physician-related variables were associated with BP values and BP control in both groups (see Table 7 for a summary). These determinants centered on BP values at initial diagnosis of hypertension, risk factors and comorbid diseases, and treatment-related variables. Fourth, physician vigilance was associated with better outcomes. Although not measured directly, it is inferred from such seemingly paradoxical findings that cardiovascular disease and renal impairment improved but that complex antihypertensive medication regimens impaired BP outcomes, especially in adherent patients. Lastly, adherent patients were more likely to exhibit target organ damage and associated events, while being prescribed more complex medication regimens. This may suggest that adherence, whether in general or in relation to antihypertensive regimens, may be less of a behavioral trait but instead shaped by poor prior treatment outcomes if not prior adverse events. These are important findings considering the evidence that good antihypertensive therapy reduces morbidity and mortality and further corroborate that increasing the effectiveness of adherence interventions might have a far greater impact on the health of the population than any improvement in specific medical treatments.[21-24]
Table 7. Summary of Determinants Retained in Hierarchical Linear and Logistic Regression Modeling (Any Occurrence of Determinant)
|BP Values||BP Control||BP Values||BP Control|
|Age, per 1 y|| ||+|| ||+|| || || || || || |
|Male sex|| || || || || || || || || || |
|SBP at diagnosis of HTN, per 1 mm Hg||−|| ||−|| ||−||−|| ||−|| ||−|
|DBP at diagnosis of HTN, per 1 mm Hg|| ||−|| ||−||+|| ||−|| ||−|| |
|Diabetes mellitus|| || ||−||−||−||−|| ||−||−||−|
|Renal impairment|| || || || || ||+||+|| || || |
|Cardiovascular diseasea||+||+||+||+||+|| || || || || |
|Body mass index, per 1 kg/m2|| ||−|| || || ||−||−|| || || |
|Total cholesterol, per 1 mg/dL||−||−||−||−||−||−|| ||−|| ||−|
|Treated for high cholesterol|| || || || || || || || || || |
|Smoker|| || || || || || || || || || |
|Valsartan regimen prescribed|
|Valsartan dose (0/80/160 mg)||−||−||−||−||−|| || || || || |
|HCTZ dose (0/12.5/25 mg)||−||−||−||−||−||−||−||−||−||−|
|Concomitant antihypertensive treatment|
|α-Blocker||−|| || || || || || || || || |
|β-Blocker||−||−|| || || || || || || || |
|Calcium channel blocker||−|| || || || || || || || || |
|ACE inhibitor||−||−|| || || || || || || || |
|Diuretic|| || || || || || || || || || |
|PREVIEW||−|| ||−||−||−|| || || || || |
|IMPROVE||−||+||−|| ||−|| || || ||+|| |
|INSIST|| ||+||+|| ||+||+||+||+||+|| |
|eNOVA|| || || || || || || || || || |
|BSCORE|| || || || || || || || || || |
|EXCELLENT|| || || || || || || || || || |
|Years in practice, per 1 y||−||−||−|| ||−|| || || || || |
|Medication visit duration for newly diagnosed HTN patient|| || || || || || || || || || |
|Experience with HTN|
|HTN patients in past year (per 1 patient)|| || || || || ||+|| || || || |
|Male sex|| ||−|| ||−||−||−|| || ||−|| |
|Knowledge test scoreb|| || || || || || || || || || |
|Notion of the ESC-ESH guidelines|| || || || || || || || || || |
|Hypertension education in past year|| || || || || || || || || || |
|Heard or read of ESC-ESH best practices|| || || || || || || || || || |
A physician class effect accounted for between 23% and 29% of the difference in BP after 90 days of treatment. The determinants identified through hierarchical linear modeling clarify potential sources of this variance. In adherent patients, the length of time a physician had been practicing was associated with higher SBP and DBP values and a lower likelihood of SBP and SBP/DBP control. This might indicate that younger physicians are more likely to intensify therapy when observing poor BP outcomes, whereas their older colleagues may exhibit more therapeutic inertia.[25, 26] In contrast, this variable was not a determinant of BP in nonadherent patients. In this group, physicians' volume in hypertensive patients in the preceding year was retained as an SBP-mitigating factor, pointing at the role of routine clinical experience with hypertension. In line with a recent study, patients seen by female general practitioners may have better outcomes than those seen by male general practitioners. Consistently, male physicians were associated with worse BP outcomes in both adherent and nonadherent patients. While modeling yielded some physician-related determinants, these are unlikely to fully explain the 23% to 29% of variance in BP values after 90 days of treatment accounted for by a physician class effect.
Concerning patient-related factors, modeling revealed that in both adherent and nonadherent patients, two factors were consistently associated with worse 90-day BP outcomes: higher BP at the time of diagnosis of hypertension and hydrochlorothiazide (HCTZ) dose. Both variables relate to the severity of hypertension and the need for combination therapy with at least HCTZ in second line if not in first line as well. Note that in adherent patients, valsartan dose followed the trend observed for HCTZ dose, underscoring the possible relationship with severity of disease and need for more aggressive treatment. Further, diabetes was confirmed as the single most powerful obstacle in achieving BP control, as evidenced by the ORs ranging from 0.053 to 0.156.[28, 29] Elevated total cholesterol was consistently related to worse BP outcomes, underscoring the influence of dyslipidemia in hypertension regardless of patients' medication behavior. Body mass index was confirmed to be a predictor of higher DBP values in both groups. Study-related DBP-lowering effects were noted in both the adherent and nonadherent groups in the INSIST study. As this study included a stronger valsartan formulation (Table 1), the effect was likely a proxy for treatment intensity.
While these various determinants were common to both the adherent and nonadherent groups, there was differentiation between them in terms of the determinants' relative impact—certainly in the linear models but also in the logistic models. For instance, the slope estimates of the determinants on BP for the nonadherent cohort obtained from the linear analyses were consistently greater than those for the adherent cohort, denoting a stronger negative impact on BP values after 90 days of treatment. This suggests that nonadherence amplifies the effect of variables known to be associated with poor BP outcomes. In contrast, adherence might mitigate the effect of these variables. Hence, it is not because a given determinant was retained in both the adherent and nonadherent models that its effect is constant. On the contrary, our findings reveal that the effect is expressed as a function of medication behavior: “bad” in nonadherent patients and “less bad” in adherent patients.
In addition to these common determinants, several determinants unique to each group were identified. In adherent patients, most determinants of BP after 90 days were related to medication (valsartan and concomitant antihypertensive agents) or to study-related effects differentiating studies with weaker valsartan formulations (such as PREVIEW and IMPROVE) from those including also stronger formulations, singularly or in single-pill combinations with HCTZ. This validates that complex treatment regimens with several antihypertensive agents are needed in patients in whom prior-line treatment failed and that treatment resistance should be considered. Yet, this also confirms that, while an essential behavior, patient adherence to less-intensive and less-effective treatment regimens is insufficient to achieve targets.
Adherence behavior indeed may not necessarily be a trait but also a positive behavioral response shaped by patients' realization that hypertensive disease has progressed and that major clinical events either have occurred or are more likely. Note in this regard that the adherent group comprised proportionately more patients with microalbuminuria, left ventricular hypertrophy, cerebrovascular accident, claudicatio intermittens, and elevated low-density lipoprotein cholesterol, and that cardiovascular disease was retained as a determinant in nearly all models for adherent patients. The adherent group included indeed more patients with evidence of (advanced) target organ damage.
It is striking that the models for the nonadherent subsample comprised fewer unique determinants. In fact, except for study effects of the INSIST and IMPROVE studies, there were none in the logistic models; only differences in the magnitude of the ORs. Renal impairment was retained as a determinant in some of the models for the nonadherent patients, but with a BP-lowering effect, so was cardiovascular disease (specifically, a myocardial infarction or coronary disease) in adherent patients. These results may seem paradoxical, as their impact would be expected to be negative. We believe that these variables are proxies of physician vigilance and that the general practitioners in the 6 pooled studies ended up paying closer clinical attention to patients with evident advanced target organ damage.
- Top of page
- Study Limitations
Physicians should closely follow up patients that present with higher BP values at the diagnosis of hypertension and with well-known risk factors, such as diabetes as they will be more likely to experience uncontrolled BP despite being treated for it. As the factors influencing BP vary in adherent and nonadherent patients, physicians need to differentiate between them in the management of hypertension. Simple self-report measures are practically feasible and indicative of patients' actual intake behavior. In adherent patients with persistent uncontrolled BP additional antihypertensive medications or hygienic measures are to be considered. In nonadherent patients the first aim should be to improve intake behavior, as nonadherence severely attenuates optimum clinical benefit and results in poorer outcomes. Further, it is important for physicians to realize that they too influence BP. When experiencing difficulties in controlling BP, after tackling possible patient-related factors and after intensifying treatment, referral should be considered.
This pooled analysis of 6 observational effectiveness studies of valsartan regimens in second-line antihypertensive treatment comparing outcomes and determinants in adherent vs nonadherent patients confirms some prior findings with regard to differential outcomes, but, in particular, sheds light on the behavioral dynamics of adherence and nonadherence to medication therapy. Adherent patients were more likely to exhibit target organ damage and associated events while being prescribed more complex medication regimens, whereas nonadherent patients presented with singular risk conditions but without manifest sequelae. Adherence behavior indeed may not necessarily (only) be a trait but (also) a positive behavioral response shaped by patients' realization that hypertensive disease has progressed and that major clinical events either have occurred or are more likely.