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Archives of cardiovascular diseases
Volume 106, n° 3
pages 124-134 (mars 2013)
Doi : 10.1016/j.acvd.2012.11.006
Received : 3 May 2012 ;  accepted : 27 November 2012
Modelling of blood pressure outcomes in patients with and without established cardiovascular or renal disease following treatment with valsartan (the PREVIEW study)
Modélisation des résultats de pression artérielle chez les patients avec et sans maladie cardiovasculaire ou rénale établie traités par valsartan (l’étude PREVIEW)
 

Karen MacDonald a, Heidi Brié b, Stefaan Vancayzeele b, Christopher Lee a, c, d, John Bowles a, Kathleen Piotrowski a, Christine Hermans b, Ivo Abraham a, c,
a Matrix45, Tucson, AZ, USA 
b Novartis Pharma, Vilvoorde, Belgium 
c Center for Health Outcomes and PharmacoEconomic Research, University of Arizona College of Pharmacy, Tucson, AZ, USA 
d Oregon Health and Science University School of Nursing, Portland, OR, USA 

Corresponding author. Center for Health Outcomes and PharmacoEconomic Research, College of Pharmacy, University of Arizona, 6159 W Sunset Road, AZ 85721 Tucson, USA. Fax: +1 708 575 8504.
Summary
Background

Hypertensive patients with established cardiovascular or renal disease (ECVRD) have an added 10-year risk of cardiovascular events, classified by the European Society of Hypertension/European Society of Cardiology as ‘very high’.

Aims

To identify determinants of blood pressure (BP) outcomes in hypertensive patients with and without ECVRD treated in second-line with valsartan.

Methods

This was a subgroup analysis comparing patients with and without ECVRD who participated in the PREVIEW study, a 90-day observational prospective effectiveness study of valsartan, conducted in Belgium. Two-level (patients ‘nested’ under physicians) hierarchical linear and logistic modelling of BP values and BP control (140/90mmHg; 130/80mmHg for diabetics) at 90 days was applied to data from 1107 patients with and 2087 patients without ECVRD treated with valsartan by 504 general practitioners.

Results

Absolute reductions in BP were similar across subgroups, with minor variations in actual BP levels in general and by subgroup. Fewer patients with versus without ECVRD achieved targets for systolic BP, diastolic BP and combined systolic/diastolic BP control. Variability in BP values and control at 90 days attributable to a physician-level class effect ranged from 24.6% to 28.1% and 15.0% to 22.4%, respectively. Physician- and patient-related determinants of 90-day BP outcomes varied considerably between the two subgroups.

Conclusion

Several determinants of BP outcomes were identified comparing patients with and without ECVRD, including amenable physician-level and patient-level factors and warning signs for continued risk of uncontrolled BP. ECVRD patients present with differential characteristics, conditions and determinants that mandate individualized attention to complement general evidence-based antihypertensive treatment.

The full text of this article is available in PDF format.
Résumé
Justification

Les patients hypertendus ayant une atteinte cardiovasculaire ou rénale ont une augmentation du risque d’évènement cardiovasculaire à dix ans, considérée comme élevée dans la classification de l’European Society of Hypertension/European Society of Cardiology.

Objectifs

Identifier les déterminants de la pression artérielle chez les patients hypertendus, avec ou sans attente rénale ou cardiovasculaire, traités en seconde intention par valsartan.

Méthode

Cette étude est une analyse en sous-groupes de l’étude PREVIEW, comparant des patients avec et sans atteinte rénale et cardiovasculaire participant à cette étude, avec une période d’observation de 90 jours, effectuée en Belgique. Un modèle linéaire hiérarchisé a deux niveaux : patients et médecins ainsi qu’un modèle logistique de valeurs des pressions artérielles et de son contrôle (140/90 mmHg ; 130/80 mmHg chez les diabétiques) ont été appliqués à 90 jours, parmi les 1107 patients avec et 2087 patients sans atteinte rénale ou cardiovasculaire traités par valsartan par 504 médecins généralistes.

Résultats

La réduction absolue de la pression artérielle était similaire dans les différents sous-groupes avec des variations mineures de niveaux de pression artérielle, tant dans la population générale que dans l’analyse en sous-groupes. Un nombre moindre de patients, avec versus sans atteinte rénale ou cardiovasculaire, a atteint les objectifs cibles de niveau de pression artérielle systolique, diastolique ainsi que l’association des deux. La variabilité dans les valeurs de pression artérielle à 90 jours attribuable à l’effet médecin variait de 24,6 à 28,1 % et de 15 % à 22,4 %, respectivement. Les déterminants liés aux patients ou aux médecins de l’objectif de pression artérielle à 90 jours variaient de façon significative entre les deux sous-groupes.

Conclusion

De nombreux déterminants de l’évolution de la pression artérielle ont été identifiés chez des patients avec et sans atteinte rénale et cardiovasculaire prenant en considération des facteurs liés aux médecins et aux patients, ainsi que la prise en compte de signes d’alerte pour un contrôle des niveaux de pression artérielle. Les patients ayant une atteinte rénale ou cardiovasculaire avaient des caractéristiques différentes et des déterminants également différents, justifiant une approche individualisée pour compléter le traitement antihypertenseur en fonction de la présence ou de l’absence de ce retentissement rénal ou cardiovasculaire.

The full text of this article is available in PDF format.

Keywords : Effectiveness, Hypertension, Valsartan, Cardiovascular disease, Renal disease

Mots clés : Efficacité, Hypertension artérielle, Valsartan, Maladie cardiovasculaire, Pathologie rénale

Abbreviations : ACE, ARB, BP, CI, DBP, ECVRD, ESC, ESH, GP, ICC, SBP


Background

Cardiovascular disease resulting from poor blood pressure (BP) control is a leading cause of death globally [1, 2]. Up to 13.5% of premature deaths – or 7.6 million deaths worldwide annually – are attributed to suboptimal control of arterial hypertension [3, 4]. Europeans are among those with the highest systolic BP (SBP) in the world and thus are at higher risk of end-organ damage [5]. Achieving guideline-recommended BP targets [6, 7] is difficult in general [8, 9, 10] and an even greater challenge in patients with established cardiovascular and/or renal disease (ECVRD) [6, 7, 8]. The European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines for the management of hypertension [11, 12] classify patients with ECVRD as having a ‘very high added’ 10-year risk for (additional) cardiovascular events. Identifying determinants of BP outcomes in patients with ECVRD and how these may be different from those in patients without ECVRD is critical to effective hypertension management and prevention of further cardiovascular and renal disease.

We report here on subgroup analyses for 1107 patients with and 2087 patients without ECVRD who were included in the Belgian PREVIEW study by 504 general practitioners (GPs) [13]. PREVIEW was a prospective pharmacoepidemiological multicentre study that examined determinants and predictors of BP reduction and control following 90-day second-line treatment with the angiotensin II receptor blocker (ARB) valsartan. The purpose of the subgroup analyses was fourfold: to examine whether there were significant differences in patient characteristics, antihypertensive treatment and BP values and control at 90 days in patients with and without ECVRD; to quantify the proportions of variance in BP outcomes at 90 days attributable to physician-level versus patient-level factors; to identify the multilevel (patients ‘nested’) determinants of BP values at 90 days in these two subsamples; and to identify independent predictors of uncontrolled BP at 90 days in both subsamples.

Methods

The methodology of the PREVIEW study is described in detail in the article reporting the results for the entire sample, as are data on the physician sample, including knowledge of and practice according to evidence-based hypertension guidelines [13]. Elements of relevance are summarized below.

Design

PREVIEW was designed as a 90-day prospective multicentre multilevel (patients ‘nested’ under physicians) pharmacoepidemiological study of the effectiveness of valsartan-centric antihypertensive regimens and the determinants thereof, in patients in whom prior treatment had failed or was not tolerated. A total of 3194 hypertensive patients (SBP140mmHg and/or DBP90mmHg; SBP130mmHg and/or DBP80mmHg for diabetic patients) treated by 504 general practitioners in Belgium were started on a valsartan-centric regimen in accordance with their physician’s best clinical judgment and re-evaluated 90 days later.

Samples for subgroup analyses

Patients were considered to have ECVRD if they presented at baseline with at least one of the following cardiovascular and/or renal conditions comorbid to their arterial hypertension: myocardial infarction; angina pectoris; coronary revascularization; heart failure; ischaemic or haemorrhagic cerebrovascular accident; transient ischaemic attacks; intermittent claudication; peripheral bypass/stent or amputation; or diabetic nephropathy or any other nephropathies as evidenced by creatinine greater or equal to 1.5mg/dL and/or proteinuria. The subsamples consisted of patients whose treating physician had decided independently, according to best clinical judgment and within the approved label and reimbursement regulations, to prescribe one of three formulations of valsartan (80mg, 160mg or 80mg/12.5mg hydrochlorothiazide) as second-line monotherapy or combination therapy because first-line therapy had failed or was not tolerated. Patients with known sensitivity to ARBs or hydrochlorothiazide were excluded, as were patients concomitantly treated with an ARB other than valsartan.

Data model
Physician questionnaire

The physician questionnaire comprised: practice type, location/setting and patient mix; demographics; sources of information and knowledge related to hypertension; hypertension management practices; prescription patterns; management of adverse effects; SBP/DBP thresholds for treatment initiation and intensification; perceptions of patient adherence; and knowledge of practice guidelines.

Baseline patient data

The baseline patient data acquired were as follows: demographics; hypertension and cardiovascular history; comorbidities; lifestyle; prior antihypertensive medications; SBP and DBP; clinical data; starting valsartan dose; class of concomitant antihypertensives; and patient-reported number of days they had been non-adherent in the preceding 4 weeks.

Patient follow-up data

The patient follow-up data acquired after 90 days were as follows: SBP and DBP; concomitant drug(s) taken or changed since previous visit; clinical data; patient-reported number of days they had been non-adherent in the preceding 4 weeks; changes in valsartan dose since previous visit; and adverse effects over the past 90 days.

GPs were asked to measure BP three times at 1 to 2-min intervals in a sitting position after 5min of rest using a calibrated standard sphygmomanometer and appropriately-sized cuff placed at heart level [14]. The mean of the three sitting measurements without rounding was recorded as the SBP and DBP.

Statistical analysis

Standard descriptive statistics were used to describe the subsamples, including proportions and appropriate measures of central tendency and dispersion. Comparisons between subsamples were made using independent sample t tests, corrected as necessary for unequal variances, or Pearson’s or Yates’s χ2 tests (contingency corrected) or Fisher’s exact test where appropriate.

We hypothesized that BP outcomes in each subsample were related to physician- and patient-level variables. Each participating physician recruited several patients; therefore patients could not be considered independent but instead ‘nested’ under their treating physician. We assumed that the n j patients recruited by physician j might share some proportion of variance in BP values attributable to their common physician and that this physician’s influence might impact BP values prior to any patient-specific variables. Accordingly, we applied two-level hierarchical linear and logistic modelling for each subsample [15]. The intraclass correlation coefficient (ICC) quantified the variability in patient outcome attributable to within-physician variability before any patient-level determinants were considered. Likelihood-ratio tests were performed to determine if the physician-level ICC was significantly greater than zero. Adjusted slope coefficients or odds ratios and 95% confidence intervals (CI) were calculated to estimate the direction and strength of the relationship between individual factors and BP values and control. The ESH/ESC and Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) guidelines for BP control (140/90mmHg for non-diabetics; 130/80mmHg for diabetics) [6, 7] were used to determine controlled versus uncontrolled BP. Statistical significance was set at P <0.05, with corrections for multiplicity applied as necessary.

Results
Patient characteristics, medical history and clinical status at baseline

Of the 3194 patients with evaluable data, 1107 (35.9%) had ECVRD whereas 2087 (64.1%) did not. Compared with patients without ECVRD, patients with ECVRD tended to be older, male and living alone (Table 1). A larger proportion of patients with ECVRD had significant risk factors at baseline, including lack of physical exercise, dyslipidaemia, diabetes, elevated C-reactive protein and family history of early cardiovascular disease. These patients had been treated for hypertension longer, with more classes of antihypertensives and with more prior antihypertensive medication changes. Their SBP and DBP at the time of enrollment were slightly but significantly lower compared with patients without ECVRD. Both groups had statistically similar proportions of patients who admitted to having been non-adherent to their antihypertensive medication prior to enrolment in the study.

Evolution of BP from baseline to follow-up

At 90 days, mean SBP was not statistically different between the two groups, but mean DBP was lower among patients with ECVRD (Table 2). Mean SBP and DBP at follow-up were statistically similar between diabetic patients with and without ECVRD, but were higher among non-diabetic patients without ECVRD. Mean absolute changes in mmHg from baseline to follow-up were statistically similar among patients with and without ECVRD in general and stratified by diabetic status. BP control rates at baseline were not statistically different between the ECVRD and non-ECVRD groups in general and stratified by diabetic status. At follow-up, the proportions of patients with controlled SBP, DBP and combined SBP/DBP were higher among patients without ECVRD in general, although these differences were not evident when stratified by diabetic status.

Attribution of variance to physician class effect
Blood pressure values at 90 days

Among patients with ECVRD, 25.5% of the variance in SBP at follow-up was attributable to a physician class effect (ICC 0.255, 95% CI 0.189–0.331; P <0.001), similar to that observed for patients without ECVRD (ICC 0.257, 95% CI 0.212–0.306; P <0.001). The corresponding DBP percentages of attributable variance were 28.1% for patients with ECVRD (ICC 0.281, 95% CI 0.214–0.35; P <0.001) and 24.6% for patients without ECVRD (ICC 0.246, 95% CI 0.202–0.295; P <0.001).

Blood pressure control at 90 days

Among patients with ECVRD, a physician class effect accounted for 20.7% (ICC 0.207, 95% CI 0.123–0.329; P <0.001) and 19.8% (ICC 0.198, 95% CI 0.214–0.356; P <0.001) of the variance in SBP control among patients with and without ECVRD, respectively. The corresponding percentages for DBP were 15.0% for patients with ECVRD (ICC 0.150, 95% CI 0.144–0.265; P <0.001) and 15.3% for patients without ECVRD (ICC 0.153, 95% CI 0.102–0.224; P <0.001). For combined SBP/DBP control, the percentages were 22.4% (ICC 0.224, 95% CI 0.133–0.353; P <0.001) for patients with ECVRD and 19.8% (ICC 0.198, 95% CI 0.143–0.267; P <0.001) for patients without ECVRD.

Modelling of blood pressure values and control at follow-up

Table 3 presents the hierarchical linear models for SBP and DBP values at 90 days for the ECVRD and non-ECVRD groups. Table 4 summarizes the hierarchical logistic models for SBP, DBP and combined SBP/DBP control for patients with and without ECVRD. Table 5 summarizes the variables retained in the five models for each group, indicating whether a patient- or physician-related determinant increased or decreased SBP or DBP at 90 days or increased or decreased the odds of uncontrolled SBP, DBP and combined SBP/DBP at 90 days, stratified by ECVRD status.

Patient-related variables retained in three or more models included age, lack of regular physical exercise, being highly vulnerable to uncontrolled BP, concomitant treatment with a β-adrenergic blocker and non-adherent days in the past 4 weeks. Less frequently retained variables included living alone, obesity, family history of premature cardiovascular disease, days elapsed since most recent BP measurement, C-reactive protein greater or equal to 1mg/dL and being treated with 80mg valsartan (versus higher doses) and/or an angiotensin-converting enzyme inhibitor concomitantly. As to physician-related variables, years in practice and the number of clinical practices that were concordant with best practice guidelines were included in three or more models; this refers to hypertensive treatment practices reported by physicians that were in accordance with the prevailing ESH/ESC guidelines. Retained less frequently were the number of hypertension patients seen in the past 12 months, the median duration of the first visit with a newly-diagnosed hypertension patient or a visit for titrating antihypertensive medication and the median number of visits during the first 3 months following diagnosis of hypertension to achieve BP control.

Discussion

This subgroup analysis comparing 1107 patients with and 2087 patients without ECVRD yielded five principal findings. First, both groups had different profiles in terms of demographics, cardiovascular risk factors, hypertension history and past and current antihypertensive treatment, indicating that ECVRD is a clinically relevant differentiator of hypertensive patient mix. Second, as to BP outcomes, there were only slight differences between groups in BP values at 90 days and absolute change in BP from baseline to follow-up, suggesting that BP reduction can be achieved in patients with and without ECVRD. Third, fewer patients with ECVRD achieved BP targets than did patients without ECVRD; hence, ECVRD can be considered as a warning signal for antihypertensive treatment failure. Fourth, physician-level class effects explained between 15.0% and 28.1% of the variance in BP outcomes before patient-level factors were considered; this confirms percentages observed in other studies on valsartan that we have conducted [16]. Lastly, despite some convergence, the multilevel determinants of BP values and the logistic likelihood of BP control varied considerably between hypertensive patients with and without ECVRD; this underscores that antihypertensive treatment with valsartan should carefully consider patient- and physician-related variables that may influence differential outcomes in patients with ECVRD.

Considering that patients with ECVRD were older, more likely to be male, had a higher prevalence of most risk factors and all indices of advanced pathology, had been diagnosed with hypertension longer and had more complex prior antihypertensive treatment than patients without ECVRD, it is remarkable that only 5% fewer of them achieved 90-day SBP control (35.1% and 40.5%, respectively) and combined SBP and DBP control (31.4% and 36.0%, respectively) than patients without ECVRD. Thus, these data provide evidence of the effectiveness of valsartan as a second-line antihypertensive agent in patients with and without ECVRD. The results may also be due, partially, to the fact that more patients with ECVRD were treated with each class of concomitant antihypertensive agent in addition to valsartan than patients without ECVRD; this may reflect the greater antihypertensive treatment complexity for these patients than for patients with a lower global cardiovascular risk [6, 7, 11].

Several determinants of SBP and DBP values and predictors of lack of SBP, DBP and SBP/DBP control at 90 days merit further discussion. These determinants fall into three categories: non-modifiable variables, manageable conditions and modifiable risk factors. The non-modifiable variables serve an important alert function. In addition to older age being associated with higher SBP but lower DBP, hypertension management in older adults is characterized by an even greater sensitivity to severe diabetes (as evidenced by advanced retinopathy), a complexity of antihypertensive regimens used in attempts to bring BP under control, and cardiovascular risk [17]. Sex was not retained as a determinant despite other evidence that BP control may be more difficult to achieve in women and differences in determinants of BP outcomes between women and men [18]. Living alone was retained in one model and may refer more generally to a lack of social support [19]. The influence of a family history of premature cardiovascular disease on BP outcomes underscores the interaction between this risk factor and patients’ current ECVRD.

Diabetes had the single most influential impact on BP outcomes and severely compromises the likelihood of achieving BP control. Baseline variables as well as the variables retained in the models point more broadly at the negative impact of metabolic syndrome on BP values and BP control, especially among patients with ECVRD but also among patients without ECVRD. Diabetes and metabolic syndrome are manageable conditions and our findings underscore the importance of aggressive diabetes treatment but also, more comprehensively, the constituent elements of metabolic syndrome (weight, lipids and blood pressure) and their associated risk factors [20]. Relatedly, fitting the heuristic profile of high vulnerability to uncontrolled hypertension [21] was consistently associated with increased BP values and decreased BP control, the effects being more pronounced among patients with ECVRD.

The modifiable variables found to impact on BP outcomes, especially among patients with ECVRD, are behavioural. Exercise regimens must be developed for patients under consideration of whether or not they have ECVRD, to optimize the BP-lowering effect of physical activity [22, 23, 24]. Low adherence decreases the outcomes of medication treatment by 26%. Our subanalyses underscore how BP values rise and BP control declines for every day of non-adherence in the preceding 4 weeks. GPs must be provided with rapid if not intuitive methods of assessing adherence that can be integrated seamlessly into the clinical visit and patients must be counselled to be adherent and provided with tools enabling better medication behaviour. A known determinant of non-adherence is the complexity of the medication regimen and our findings confirm this, in particular among patients with ECVRD [25].

Focusing on these three categories of determinants of BP outcomes may go a long way towards overcoming the ‘hypertension paradox’ identified by Chobanian [26], which states that despite therapeutic advances, rates of uncontrolled BP keep rising. Our studies continue to underscore the influence of clinicians in successful hypertension management and this may be an integral part of the solution to the hypertension paradox [16]. Physician-level factors improved BP outcomes in general but especially among patients with ECVRD. Managing hypertension in congruence with evidence-based guidelines is critical, as is exposure to a high volume of patients with hypertension. Yet, so is physician vigilance – although this was not demonstrated directly but, as in our prior studies, paradoxically, in terms of number, type and duration of visits and interval of BP measurement [16]. On the other hand, how long one has been practicing tends to lead to poorer BP outcomes [16, 25]. Hence, it is not surprising that up to 28.1% of BP outcomes were attributable to the treating physician, confirming similar proportions observed in other analyses [16].

The limitations of the PREVIEW study, its subanalyses and related studies have been identified elsewhere [13, 16, 27], as have directions for future research. Limitations include the study being conducted in only one country, not being population-based, focusing only on valsartan and not other ARBs and not being an effectiveness randomized controlled trial but an effectiveness observational study. The subanalyses here employed a post hoc-defined binary measure of ECVRD; future studies are needed to evaluate the role of an a priori operationalized ECVRD gradient on BP outcomes following antihypertensive treatment. In this regard, it might be helpful to examine the interaction of established cardiovascular and established renal disease, not just as singular or joint presences.

Conclusion

We examined the multilevel determinants of 90-day BP values and control in 1107 hypertensive patients with ECVRD and 2087 without ECVRD being treated with valsartan as part of the Belgian PREVIEW study. A greater proportion of patients without ECVRD had controlled SBP and DBP at 90 days compared with patients with ECVRD. Many of the patient- and physician-level determinants of BP by ECVRD subpopulation are amenable to intervention and the remainder can serve as warning signs that patients may remain vulnerable to poor outcomes associated with suboptimal BP control. ECVRD patients present with differential characteristics, conditions and determinants that mandate individualized attention to complement general evidence-based antihypertensive treatment.

Disclosure of interest

I. Abraham, K. MacDonald, J. Bowles, K. Piotrowski and C. Lee are or were employees of Matrix45. Company policy prohibits employees from owning equity in client organizations of Matrix45. Matrix45 performs similar studies for other pharmaceutical companies on a non-exclusivity basis. H. Brié, C. Hermans and S. Vancayzeele are employees of Novartis.


Acknowledgments

The PREVIEW study was supported by grants and contracts from Novartis Pharma. The work reported here was outside the scope of this prior support and authors contributed pro bono. Any issues related to results or manuscripts were addressed by the external authors. The sponsor had right to review and comment.

Ivo Abraham was supported in part as the Director of the Arizona Postdoctoral/Academic Fellowship Program in Clinical Outcomes and Comparative Effectiveness Research in Primary Care, funded by the Bureau of Health Professions, US Department of Health and Human Services. Christopher Lee was supported in part by a postdoctoral fellowship in cardiovascular clinical outcomes and effectiveness research at the University of Arizona, funded by Matrix45.

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