Real-life effectiveness of sacubitril/valsartan in older Belgians with heart failure, reduced ejection fraction and most severe symptoms.

We assessed the real-world effectiveness of sacubitril/valsartan in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF) with an emphasis on those with older age (≥ 75 years) or with New York Heart Association (NYHA) class IV, for whom greater uncertainty existed regarding clinical outcomes. We conducted a retrospective cohort study based on patient-level linkage of electronic healthcare datasets. Data from all adults with HFrEF in Belgium receiving a prescription for sacubitril/valsartan between 01-November-2016 and 31-December-2018 were collected, with a follow-up of > 6 years. The total study population comprised 5446 patients, older than the PARADIGM-HF trial participants, and with higher NYHA class (all P < 0.0001). NYHA class improved following sacubitril/valsartan initiation (P < 0.0001 baseline vs. reassessment). Most concomitant medications were reduced. Remarkably, the risk of hospitalization for a cardiovascular reason and for HF was reduced by > 26% in the overall cohort, and in subgroups of patients ≥ 75 years, with NYHA class III/IV (all P < 0.0001) or with NYHA class IV (P < 0.05), vs. baseline. All-cause mortality did not increase in real-world patients with NYHA class III/IV. The results support the long-term beneficial effects of sacubitril/valsartan in older patients and in those experiencing the most severe symptoms.

Gender-stratified hierarchical modeling of patient and physician determinants of antihypertensive treatment outcomes: pooled analysis of seven prospective real-world studies with 17,044 patients.

OBJECTIVE: Seven prospective real-world studies conducted in general practices in Belgium of antihypertensive treatment with valsartan-centric regimens were pooled to examine similarities and differences in determinants of blood pressure (BP) values (mmHg) and BP control rates between female and male patients. METHODS: Pooled analysis of a total evaluable sample of 17,044 patients, including 8273 (48.5%) women and 8771 men (51.5%) treated over approximately 90 days with valsartan-centric regimens in second or later line. Hierarchical linear and logistic regressions were applied to identify patient- and physician-related determinants of BP outcomes and a potential physician class effect. RESULTS: Reductions in BP (mmHg) over 90 days were similar for women and men, and so were changes in BP control rates. Approximately a quarter of the variance in 90 day BP values was attributable to a physician class effect. Both gender groups shared some patient- and physician-related determinants of BP outcomes, though often varying in degree of influence. Analyses also revealed gender-specific determinants. Among others, modifiable/manageable patient-related determinants included BP at hypertension diagnosis (proxy for time of diagnosis), risk factors, antihypertensive treatment and adherence; while among the physician-related determinants clinical experience in hypertension treatment was modifiable/manageable. CONCLUSION: Valsartan-centric treatment regimens are associated with significant reductions in BP level and improvement in BP control in both women and men. The determinants revealed in modeling provide guidance to clinicians in the common and differential management of hypertension in female and male patients.

Hierarchical modeling of blood pressure determinants and outcomes following valsartan treatment in hypertensive patients with known comorbidities: pooled analysis of six prospective real-world studies including 11,999 patients.

AIMS: Six prospective real-world studies of antihypertensive treatment with valsartan-centric regimens were pooled to: (1) examine the effectiveness of ∼90 days of second- or later-line valsartan treatment in hypertensive patients with known comorbidities; and (2) identify physician- and patient-related determinants associated with systolic (SBP) and diastolic blood pressure (DBP) outcomes in these patients. METHODS AND MATERIALS: A pooled analysis was performed of an evaluable sample of 11,999 hypertensive patients with known comorbidities treated ∼90 days with valsartan-centric regimens. We applied hierarchical linear and logistic regression models to identify determinants of blood pressure (BP) outcomes and a potential physician class effect. RESULTS: Valsartan regimens resulted in mean (SD) SBP and DBP reductions of 18.0 (15.8) mmHg and 9.5 (10.1) mmHg, respectively, at ∼90 days, yielding SBP, DBP and combined SBP/DBP control rates of 44.0%, 67.2% and 39.3%, respectively. About a quarter of the variance in 90 day BP values was attributable to a physician class effect. BP outcomes declined with physicians' increasing years in practice and being male. At the patient level, BP outcomes declined with SBP and DBP at diagnosis; diabetes; higher cholesterol and BMI; lower valsartan and hydrochlorothiazide (HCTZ) doses; and concomitant anti-hypertensives. Older age was associated with improved DBP. A proxy of physician vigilance, cardiovascular disease history, was associated with improved BP outcomes, as were patient adherence and higher doses of valsartan in combination with HCTZ. CONCLUSIONS: Valsartan-centric regimens have significant BP lowering benefits in this pooled sample of patients with known comorbidities. Many observed determinants of BP outcomes are modifiable or manageable.

Variability in total serum IgE over 1 year in severe asthmatics.

BACKGROUND: Immunoglobulin E (IgE) is the treatment target of omalizumab, a monoclonal antibody indicated in the treatment of severe allergic asthma. Long-term variability of serum total IgE (sIgEtot) in asthmatics remains poorly documented. METHODS: In this prospective study, sIgEtot levels were measured over 1 year at 7 time points in 41 severe asthmatics treated with high-dose of inhaled corticosteroids and long-acting ß2 agonists. 33 patients were atopic based on at least one positive RAST to common aeroallergens. Patients were divided into three groups according to their baseline sIgEtot level: low (< 76 IU/mL; n = 10), intermediate (76-700 IU/mL; n = 20) or high (> 700 IU/mL; n = 11). Patients also completed the six-item Juniper Asthma Control Questionnaire (ACQ6). The sIgEtot variability and factors predictive for this variability were studied, as well as ACQ6 outcomes. RESULTS: The variation in sIgEtot level was mostly the consequence of between patient-variability, which represented 96%, 71% and 96% of the total variability in the low, intermediate and high sIgEtot subgroups, respectively. The residual within-patient variability was therefore limited. In 10/41 patients, sIgEtot levels increased or decreased, for at least one visit, beyond the predefined range of the subgroups to which they were assigned (< 76 IU/mL; 76-700 IU/mL; > 700 IU/mL). There was a significant but weak correlation between sIgEtot and ACQ6 score over all time points (r = 0.15, p = 0.02), but sIgEtot failed to associate with severe exacerbation. sIgEtot decreased by 3% with any additional year of age for the whole group (p = 0.01) and increased by 5% per one unit of allergen exposure score in atopic patients (p = 0.002). CONCLUSION: In severe asthmatics, limited within-patient variability of sIgEtot levels was observed over 1 year as opposed to marked between-subject variability. sIgEtot decreases with age. Variation in sIgEtot weakly associates with asthma control but not with exacerbation.

Effectiveness and Tolerability of Vildagliptin and the Single Pill Combination of Vildagliptin and Metformin in "Real-World" Management of Type 2 Diabetes Mellitus: The G-FORCE Study.

INTRODUCTION: Randomized clinical trials showed that vildagliptin is well tolerated and leads to clinically meaningful decreases in glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) both in monotherapy and as add-on therapy in inadequately controlled type 2 diabetes mellitus (T2DM) patients. Nevertheless, there is an increased interest for real-life studies to confirm the clinical trial findings in the setting of a daily clinical practice. The aim of this study was to evaluate the effectiveness and tolerability of vildagliptin in a real-life clinical setting and to explore factors determining drug adherence and T2DM management. METHODS: G-FORCE was a prospective, observational, open-label, multi-center study in which T2DM patients were prescribed de novo vildagliptin. Clinical effectiveness was determined by changes in HbA1c and FPG and by the proportion of patients reaching glycemic goal. Data were collected at baseline, after 105 ± 15 days and after 180 ± 15 days. RESULTS: A total of 1230 patients were included in this analysis. Mean age was 63.9 ± 10.8 years, and mean HbA1c and FPG levels were 8.2 ± 1.3% and 171.0 ± 53.3 mg/dL, respectively. At 180 days of treatment, HbA1c and FPG levels decreased to 7.2 ± 1.0% and 141.1 ± 44.0 mg/dL, respectively, while the proportion of patients reaching HbA1c and FPG goals rose from 8.6 to 44.6% and from 14.2 to 42.8%, respectively. CONCLUSION: In this real-world study, vildagliptin was an effective and safe treatment for T2DM patients already treated with metformin, while the single pill combination of vildagliptin and metformin provides a convenient alternative while ensuring comparable effectiveness and tolerability. FUNDING: Novartis Pharma.

Hierarchical Modeling of Patient and Physician Determinants of Blood Pressure Outcomes in Hypertensive Patients with and without Diabetes: Pooled Analysis of Six Observational Valsartan Studies with 15,282 Evaluable Patients.

We pooled data from 6 valsartan-related studies including 3,658 diabetic and 11,624 nondiabetic patients to evaluate blood pressure (BP) outcomes after approximately 90 days of second- or later-line valsartan treatment. Hierarchical linear and logistic regressions were applied to identify determinants of BP outcomes. Similar reductions in BP values and similar BP control rates were achieved in both groups after approximately 90 days of therapy. The modeling analyses identified several common and different patient- and physician-related determinants of BP outcomes for both groups, many of which are modifiable or clinically manageable. Through varying in terms of association and influence between the diabetic and nondiabetic groups, patient-related determinants included age, BP at diagnosis of hypertension, risk factors, valsartan regimen, concomitant antihypertensive treatment, and adherence; and physician-related determinants included gender, years in practice, and hypertension management. In summary, in both diabetic and nondiabetic patients, the use of valsartan-centric treatment regimens in second- or later-line antihypertensive treatment is associated with significant reductions in BP level and improvement in BP control. The determinants identified in modeling provide guidance to clinicians in the common and differential management of hypertension in diabetic and nondiabetic patients.

Six-year outcomes in neovascular age-related macular degeneration with ranibizumab.

AIM: To evaluate the outcomes of ≥6y ranibizumab therapy in neovascular age-related macular degeneration (AMD). METHODS: HELIX was a retrospective, observational effectiveness study using medical records of patients treated in three clinics in Belgium. Patients had neovascular AMD and were initially treated with intravitreal ranibizumab (0.5 mg) between November 1, 2007 and October 31, 2008, had ≥6y of data available, and were treated on an ongoing, as-needed basis. Outcomes included best-corrected visual acuity (BCVA) and central retinal thickness (CRT). RESULTS: The sample consisted of 88 eyes from 69 patients. Mean age was 76.4±6.5y, most patients were female (62.3%). Most eyes (62.5%) were treatment-naive, 33 previously treated eyes had received predominantly other anti-vascular endothelial growth factor agents and verteporfin. Mean baseline BCVA was 57.4±12.7 ETDRS letters and CRT was 291.5±86.1 µm. On average, patients received 20.6±11.9 ranibizumab injections over the ≥6y. Intervals between injections were on average 12.7±16.1wk. Mean change in BCVA from baseline to last observation for the sample was less than one letter (-0.9±17.3 letters), with an average loss of -3.2±15.6 letters in previously treated eyes versus a gain of 0.6±18.4 letters in treatment-naïve eyes. When considering a loss of <15 letters over 6y as stabilization of disease, 75.9% of all eyes showed a positive (improvement or stabilization) outcome. Mean change in CRT from baseline to last observation for the sample was -26.9±148.4 µm with the greatest reduction observed in treatment-naive eyes. CONCLUSION: This retrospective study of 69 neovascular AMD patients treated for ≥6y with ranibizumab demonstrates long-term visual stabilization. In light of the natural evolution of the disease, these data confirm that ranibizumab is effective long-term under real-world conditions of heterogeneity of patients, clinicians, and centers.

Patient engagement impacts glycemic management with vildagliptin and vildagliptin/metformin (single pill) regimens in type 2 diabetes mellitus (the GLORIOUS study).

AIMS: To evaluate the real-world effectiveness of vildagliptin and vildagliptin/metformin, combined with patient engagement, on glycemic outcomes. Patient engagement included both clinicians' engaging patients through education and counseling; and patients' self-engagement through disease awareness, lifestyle changes, and medication adherence. METHODS: Prospective, observational, open-label, multi-center, pharmacoepidemiologic study of type 2 diabetes mellitus (T2DM) patients treated de novo with vildagliptin or vildagliptin/metformin. Data were collected at baseline (treatment initiation), 105±15d, and ≥145d. RESULTS: The evaluable sample included 896 mainly male (58%), overweight (mean±SD BMI=30.3±5.4kg/m2), in later middle age (mean±SD age=64±11years) patients. Over the three visits, mean(±SD) HbA1c levels declined from 8.1%(±1.0) to 7.3%(±1.0) to 7.2%(±0.9); HbA1c control rates rose from 7% to 36% to 43%. Mean±SD FPG levels decreased from 170(±49) to 141(±41) to 139(±42)mg/dL; control rates increased from 12% to 39% to 43% (all p<0.0001). Weight decreased nominally by 2kg (p=0.0290) and BMI by 0.8kg/m2 (p<0.0001). Modeling showed patient engagement activities by clinicians and by patients to be major determinants of glycemic outcomes. No unknown safety signals were detected. CONCLUSIONS: Vildagliptin and vildagliptin/metformin are effective and safe oral agents in the management of T2DM, especially if part of a treatment program with active patient engagement by clinicians and empowered patients.

Predicting blood pressure outcomes using single-item physician-administered measures: a retrospective pooled analysis of observational studies in Belgium.

BACKGROUND: Patient adherence is often not monitored because existing methods of evaluating adherence are either burdensome or do not accurately predict treatment outcomes. AIM: To examine whether two simple, single-item physician-administered measures of patient adherence to antihypertensive medication are predictive of blood pressure outcomes. DESIGN AND SETTING: Retrospective database analysis of patients with hypertension treated in Belgian primary care. METHOD: Using pooled data from five observational studies, a sample was identified of 9725 patients who were assessed using two single-item physician-administered measures of adherence to antihypertensive medication: the first item of the Basel Assessment of Adherence Scale (BAAS) and the Visual Analogue Scale (VAS). These two assessment tools were administered by GPs during regular appointments with patients. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and combined SBP/DBP were measured at baseline and at 90 days. RESULTS: BAAS-identified adherent patients achieved lower mean SBP and DBP compared with non-adherent patients at 90 days (P<0.001), and had odds ratios of achieving blood pressure control of 0.66 (95% confidence intervals (CI) = 0.61 to 0.73, P<0.001) for SBP, 0.69 (95% CI = 0.62 to 0.76, P<0.001) for DBP, and 0.65 (95% CI = 0.59 to 0.72, P<0.001) for combined SBP/DBP. For VAS-identified adherent patients, the odds ratios of achieving blood pressure control were 0.93 (95% CI = 0.86 to 1.00, P<0.001) for SBP, 0.79 (95% CI = 0.73 to 0.85, P<0.001) for DBP, and 0.91 (95% CI = 0.84 to 0.99, P<0.001) for combined SBP/DBP. CONCLUSIONS: The first item of the BAAS and the VAS are independent predictors of blood pressure control. These methods can be integrated seamlessly into routine clinical practice by allowing GPs to quickly evaluate a patient's adherence and tailor treatment recommendations accordingly.

Remission over 3 years in patients with Paget disease of bone treated with a single intravenous infusion of 5 mg zoledronic acid.

Using data from the Belgian Paget's Disease Registry of 142 patients treated with a 5 mg intravenous infusion of zoledronic acid, we examined disease remission over 3 years in 98 patients with Paget disease of bone (PDB) seen in routine practice. Median age was 76 years, most patients (60.2 %) were male, and all were Caucasian. Median time since PDB diagnosis was 11.5 years, few patients (5.1 %) had a family history of PDB, and 32.6 % had received prior bisphosphonate and/or other treatments. The most common pagetic locations were pelvis, spine, femur, tibia, and skull. The most common symptoms included pain, impaired mobility, bone deformities, and joint disease: 36.7 % of patients had comorbid osteoarthritis and 16.3 % comorbid osteoporosis. Response rates were 93.3 % at 1 year, 89.5 % at 2 years, and 91.6 % at 3 years, statistically similar to an extension study of the original zoledronic acid trials. Twenty-one patients experienced a relapse over the 3-year period at a median of 20.7 months posttreatment; of these, 13 regained remission by the end of the observation period. Relapse was not associated with osteoarthritis, osteoporosis, or other comorbidities. Safety data were similar to those reported elsewhere. In summary, in this somewhat frailer sample of patients with PDB, effectiveness and safety data were similar to those observed in the original trial populations. These findings, which are the first on the use of zoledronic acid for PDB in routine clinical practice, underscore the therapeutic benefits and relative safety of zoledronic acid in the management of PDB in "real-world" clinical settings.

Real-world variability in ranibizumab treatment and associated clinical, quality of life, and safety outcomes over 24 months in patients with neovascular age-related macular degeneration: the HELIOS study.

INTRODUCTION: The aim of this study was to examine ranibizumab treatment patterns in "real-world" practice and clinical settings, as well as to assess quality of life outcomes over a 24-month period. MATERIALS AND METHODS: This was a prospective, observational, multicenter, open-label study of 0.5 mg of ranibizumab administered intravitreally. Patients were followed over 24 ± 3 months with intermediate data points at 6 ± 2 months and 12 ± 2 months, and a limited data point at 2.5 ± 1 month that coincided with the end of the loading phase. Outcomes included visual acuity (Early Treatment Diabetic Retinopathy Study), visual function (National Eye Institute Visual Function Questionnaire-25 [NEI VFQ-25]), quality of life (Health Utilities Index Mark III [HUI3]), and safety. RESULTS: A total of 267 patients with wet age-related macular degeneration (mean ± standard deviation [SD] age = 78.5 ± 7.3 years; 62.4% were female; 34.5% with dual eye involvement; 74.9% were treatment-naïve) were treated (309 eyes were treated). The mean ± SD Early Treatment Diabetic Retinopathy Study score at baseline was 56.3 ± 14.3 letters. The mean ± SD number of injections over 24 months was 7.6 ± 4.1, including 2.5 ± 0.7 and 5.9 ± 3.6 during the loading and maintenance phases, respectively, with corresponding treatment intervals of 4.8 ± 1.4 weeks and 11.5 ± 9.5 weeks, respectively. Improvements in visual acuity over baseline were reached at 2.5 months and maintained at 6 months (both P < 0.0001). The mean visual acuity increase over baseline at 12 months was not significant (P = 0.08); the decline over baseline at 24 months statistically significant (P = 0.02). Overall, 94.3% of patients showed stable or improved disease at 6 months and 81.5% of patients showed stable or improved disease at 24 months. At 6 months, improvements over baseline were significant for VFQ-25 (P = 0.03) and HUI3 (P = 0.02), but not at 12 months and 24 months. Improvements in VFQ-25 and HUI3 were maintained at 24 months in 38% and 34% of patients, respectively. In total 78 serious adverse events were reported in 40 patients and 77 nonserious adverse events in 34 patients. Nine serious adverse events and nine nonserious adverse events in 14 patients were suspected to be related to ranibizumab treatment. CONCLUSION: The "real-world" clinical effectiveness of ranibizumab was evidenced by the initial improvements over baseline in visual acuity and quality of life, as well as the maintenance of these outcomes at baseline levels at 24 months, and this was observed under variable treatment conditions. The findings underscore the need for individualized treatment with regular monitoring to achieve optimal vision and quality of life outcomes.

Hierarchical modeling of patient and physician determinants of blood pressure outcomes in adherent vs nonadherent hypertensive patients: pooled analysis of 6 studies with 14,646 evaluable patients.

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.

Modelling of blood pressure outcomes in patients with and without established cardiovascular or renal disease following treatment with valsartan (the PREVIEW study).

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 (140/90 mmHg; 130/80 mmHg 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.

Clinical, Quality of Life, Patient Adherence, and Safety Outcomes of Short-Course (12 Weeks) Treatment with Cyclosporine in Patients with Severe Psoriasis (the Practice Study).

BACKGROUND: Apart from clinical outcomes, the "real-world" outcomes of intermittent short-course cyclosporine treatment remain poorly documented. OBJECTIVE: To evaluate various outcomes of short-course cyclosporine treatment for severe psoriasis; and to describe dermatologists' use of the Rule of Tens. METHODS: A 12-week pharmacoepidemiological study; 112 evaluable patients recruited by 43 dermatologists. RESULTS: The mean initial cyclosporine dose was 2.88±0.74 mg/kg/day. At 12 weeks, 64.3% of patients were continued beyond the study period at mean dose of 2.51±0.91 mg/kg/day. Percent body surface affected, Psoriasis Area Severity Index score, and patient and physician rating of psoriasis severity decreased significantly, while quality of life (QoL) improved significantly. Median patient satisfaction at 12 weeks was 85 (0~100 scale). Patient-reported non-adherence was 43.9% and 56.1%, respectively at both the time points (p=0.18). In modeling on logarithmized outcomes variables, living along was consistently the single most important (negative) determinant of therapeutic and patient outcomes. Safety and tolerance parameters were similar to the ones reported in the literature. Only 7.3% of physicians correctly identified the measures included in the Rule of Tens and the Rule's criterion for inferring severe psoriasis. CONCLUSION: With adequate monitoring and patient adherence, cyclosporine treatment reduces the severity of severe psoriasis, improves QoL, and is appropriately tolerated; leading to high patient satisfaction. Social support is a key determinant of therapeutic and patient outcomes and patients living along may require clinical attention. The relevance of the Rule of Tens was not evident.

Modelling of blood pressure and total cardiovascular risk outcomes after second-line valsartan therapy: the BSCORE study.

BACKGROUND: European guidelines recommend that antihypertensive management should be graded as a function of total cardiovascular risk. AIMS: To examine the multilevel (patient- and physician-level) determinants of blood pressure and residual total cardiovascular risk outcomes associated with second-line valsartan therapy. METHODS: The BSCORE study was a prospective, multi-centre, pharmacoepidemiological study of the "real-world" effectiveness of second-line valsartan with or without hydrochlorothiazide. RESULTS: A total of 3497 patients were recruited by 354 physicians. Mean age was 63.8±12.0 years; 52.3% were male; 20.9% were smokers; 47.7% were dyslipidaemic; and 23.6% had diabetes. On average, reductions in blood pressure and increases in the proportions of patients with controlled blood pressure after 90 days were statistically significant (all P<0.001). Twenty-one percent of systolic blood pressure and 25.6% of diastolic blood pressure variability at follow-up was attributable to physician-level characteristics. Significant reductions in total cardiovascular risk were observed (P<0.001); with 12.5% of the variability in total cardiovascular risk change attributable to physician-level characteristics. Several independent determinants of blood pressure outcomes were identified, many of which are modifiable. CONCLUSIONS: Second-line valsartan therapy improves blood pressure outcomes under variable real-world conditions, and is associated with a decrease in total cardiovascular risk. Optimizing antihypertensive effectiveness, including the reduction of residual cardiovascular risk, involves managing concomitant conditions and risk factors, improving adherence, and identifying physician-level factors amenable to intervention.

Effectiveness of amlodipine-valsartan single-pill combinations: hierarchical modeling of blood pressure and total cardiovascular disease risk outcomes (the EXCELLENT study).

BACKGROUND: Both patient- and physician-related factors have been shown to explain variability in the outcomes of antihypertensive treatment. Total cardiovascular risk (TCVR) is increasingly used as a determinant of treatment effectiveness but has also been proposed as a treatment outcome. To our knowledge, no studies have reported how antihypertensive treatment impacts blood pressure and TCVR outcomes. OBJECTIVE: To examine in patients treated with a regimen including single-pill combinations (SPCs) of amlodipine/valsartan (1) blood pressure (BP) reduction and control, total cardiovascular risk (TCVR) change, and TCVR reduction of 1 class or more; (2) hierarchical patient- and physician-level determinants of these outcomes; and (3) predictors of uncontrolled BP and improved TCVR classification. METHODS: A prospective (90 days), multicenter, multilevel pharmacoepidemiologic study was conducted in 3546 patients with hypertension treated with SPC amlodipine/valsartan by 698 general practitioners. Statistical analysis included hierarchical linear and logistic modeling of BP and TCVR outcomes. RESULTS: Mean (SD) systolic BP (SBP) reductions were 20.1 (15.5) mm Hg and diastolic BP (DBP) reductions were 9.8 (10.3) mm Hg, with higher reductions among high-risk patients. SBP, DBP, and SBP/DBP control rates were 33.3%, 45.3%, and 25.5%, respectively, with lower rates among high-risk patients. Mean TCVR improvement was a reduction of 0.73 (0.96) classes (-4 [best] to +4 [worst]), with higher reductions for high-risk patients; 58.2% of patients achieved a TCVR reduction of 1 or more classes, with lower percentages for high-risk patients. Twenty-two percent of systolic variability and 26% of diastolic variability in 90-day BP values were attributable to a physician class effect, as was 16% of TCVR change. CONCLUSIONS: Regimens that include SPC amlodipine/valsartan formulations are effective in reducing BP and TCVR in a real-world observational setting. Hierarchical modeling identified patient- and physician-related determinants of BP values and TCVR change, as well as independent predictors of uncontrolled BP and reduced TCVR. TCVR is a scientifically feasible and clinically relevant effectiveness outcome of antihypertensive treatment.

Real-world effectiveness of valsartan on hypertension and total cardiovascular risk: review and implications of a translational research program.

The pharmacological efficacy of various monotherapy, single pill, and combination therapies of the angiotensin II receptor blocker valsartan have been established, mainly through randomized controlled trials that used similar methodological and statistical platforms and thus enabled synthesis of evidence. The real world effectiveness of valsartan has been studied extensively, but the relative lack of scientific and technical congruence of these studies render synthesis virtually impossible. To date, all have focused on blood pressure outcomes, despite evidence-based calls to grade antihypertensive treatment to patients' total cardiovascular risk. We review a T3 translational research program of seven studies involving valsartan monotherapy as well as single and separate pill combinations, and the determinants and effect on blood pressure and total cardiovascular risk outcomes. All seven studies examined not only the impact of valsartan-based regimens on blood pressure values and control, but also, within a statistical hierarchical approach, the physician- and patient-related determinants of these blood pressure outcomes. Two studies also investigated the determinants and outcomes of valsartan-based treatment on total cardiovascular risk - among the first studies to use this risk coefficient as an outcome rather than only a determinant. These seven studies included a total of 19,533 patients, contributed by 3434 physician-investigators in Belgium - a country particularly well-suited for observational effectiveness studies because of demographics and epidemiology. Each study used the same methodological and statistical platform. We summarize the impact of various valsartan regimens on such outcomes as blood pressure values and control, change in total cardiovascular risk, and reduction in risk by at least one category. We also review the results of statistical multilevel and logistic modeling of physician- and patient-related determinants on these outcomes, including the proportion of variance attributable to a physician class effect before patients enter the equation. In its different formulations, valsartan has major real-world benefits in lowering blood pressure and total cardiovascular risk within a 90-day period. It is essential to understand the physician- and patient-related determinants of blood pressure and total cardiovascular risk outcomes associated with valsartan treatment. Antihypertensive research should expand its historical focus on lowering blood pressure with an emphasis on lowering total cardiovascular research.

"Later, lazier, and unluckier": a heuristic profile of high vulnerability is an independent predictor of uncontrolled blood pressure (the PREVIEW study).

OBJECTIVE: Vulnerability profiling, an alternative to deterministic risk assessment, offers clinicians a more intuitive but empirically-grounded assessment of patient risk. This study aimed to determine whether a heuristic profile of high vulnerability is an independent predictor of uncontrolled hypertension. METHODS: Secondary analysis of prospective observational study data on 2999 hypertensive patients treated with valsartan. Predictive validity of vulnerability profiling for first-line, second-line, and first-or-second-line antihypertensive treatment was inferred from 1) logistic regression models with adequate statistical fit, 2) statistically significant odds ratios for uncontrolled BP for the high-vulnerability cluster exceeding 1.00, and 3) correct classification rates for patients' BP control status. RESULTS: All models of uncontrolled BP were significant (P < 0.001); all odds ratios for the high-vulnerability cluster were greater than 1.00 and significant (P < 0.001). Correct classification rates for the highly-vulnerability cluster on uncontrolled BP after first-line, second-line, or either treatment were 91.1%, 61.2%, and 93.5% for systolic BP; 74.5%, 65.8%, and 76.7% for diastolic BP; and 92.8%, 65.3%, and 94.6% for combined systolic and diastolic BP. CONCLUSION: The heuristic profile of "later, lazier, and unluckier" is an intuitive and valid tool to help identify patients at greater risk for poor BP control seen in general practice.

Hierarchical linear and logistic modeling of outcomes of antihypertensive treatment in elderly patients: findings from the PREVIEW study.

Achieving guideline-recommended blood pressure targets is difficult in older adults with hypertension. We completed a subgroup analysis of patients 65 years of age or older enrolled in PREVIEW, a prospective, multicenter, pharmacoepidemiological study of the determinants and outcomes of second-line antihypertensive treatment with valsartan in Belgium. Multilevel modeling was used to identify physician- and patient-level determinants of blood pressure values and practice guideline-derived definitions of blood pressure control. Data on 1560 patients and 504 physicians were used in this analysis. Blood pressure control rates for patients age 65 and over were lower for systolic (34.2% vs. 38.6%) and combined systolic/diastolic blood pressure (31.2% vs. 34.4%) compared to the entire PREVIEW sample. Twenty-seven percent of the variability in systolic, and 32% in diastolic pressure after 90 days of treatment were attributable to such variables as physicians' knowledge and adherence to evidence-based guidelines, practice patterns, and experience; with the remaining variance attributable to various demographic, behavioral, and clinical patient-related factors. Several independent predictors of uncontrolled blood pressure after 90 days of treatment were identified, largely confirming factors identified as determinants of blood pressure values. Recommendations for managing hypertension in the elderly are made in view of these findings.

Effectiveness of valsartan for treatment of hypertension: patient profiling and hierarchical modeling of determinants and outcomes (the PREVIEW study).

BACKGROUND: Patient- and clinician-related factors may explain variability in blood pressure (BP) outcomes and the differences between real-world effectiveness and efficacy seen in randomized trials of antihypertensive agents. OBJECTIVE: To examine the effectiveness of 90 days of second-line valsartan treatment and identify patient- and physician-level determinants that impact BP outcomes. METHODS: A prospective, multicenter, multilevel pharmaco-epidemiological study was conducted in 3194 hypertensive patients (systolic BP [SBP] > or =140 mm Hg, diastolic BP [DBP] > or =90 mm Hg; for diabetic patients, > or =130 and > or =80 mm Hg, respectively) treated by 504 general practitioners (GPs). Statistical analysis included heuristic data mining, and hierarchical linear and logistic modeling. RESULTS: With valsartan treatment, mean +/- SD SBP decreased from 154.4 +/- 15.5 mm Hg to 139.0 +/- 12.0 mm Hg and mean DBP decreased from 91.3 +/- 9.2 mm Hg to 82.6 +/- 7.4 mm Hg. SBP control rates increased from 9.0% to 38.6%, DBP from 25.5% to 65.5%, and combined SBP/DBP from 7.3% to 34.4%. A highly vulnerable cohort (n = 1063; 35.4%) of patients was identified. Twenty-four percent of variability in SBP and 25% of variability in DBP at 90 days were attributable to physician-related variables: guideline-compliant BP management, hypertension, practice patterns, hypertensive patient volume, and years in practice. The remaining 76% and 75% of variability in SBP and DBP, respectively, were due to patient factors, notably diabetes and related complications, vulnerability to uncontrolled BP, nonadherence, cardiovascular risk, and age. Similar factors increased the odds of treatment nonresponse, with diabetes being the single largest determinant of uncontrolled SBP (OR 8.99), DBP (OR 20.35), and combined SBP/DBP (OR = 18.64). CONCLUSIONS: Valsartan is effective and well tolerated in a broad range of patients in whom first-line antihypertensive treatment failed or was not tolerated. Mitigating the impact of BP-elevating variables and optimizing the effect of BP-lowering factors provides therapeutic benefits incremental to valsartan's pharmacologic effect. Improving outcomes in hypertensive patients involves 3 steps: (1) identifying, intuitively rather than formally, patients less likely to achieve BP control; (2) targeting modifiable or manageable patient- and physician-level determinants with BP-elevating or BP-lowering effects; and (3) managing variables that increase the odds and optimizing those that lower the odds of uncontrolled BP.