Valsartan Intensified Primary Care Reduction of Blood Pressure Study

Study Overview
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Brief Summary
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This study will assess the efficacy of an intensive blood pressure management strategy compared to usual care in a primary care (general practice) setting.

Official Title
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A Phase IV Clinical Trial of Intensified Blood Pressure Management in Primary Care Using Valsartan Alone and as Combination Anti-Hypertensive Therapy

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Valsartan and hydrochlorothiazide (HCTZ) - monotherapy
* Drug: Valsartan and amlodipine
* Drug: Usual care
* Drug: Valsartan
* Drug: Valsartan and hydrochlorothiazide (HCTZ) - combination arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: newly diagnosed or currently treated hypertensive patients who have not attained their blood pressure target and require active pharmacological treatment as recommended by the local guidelines as judged by the general practitioner Exclusion Criteria: significantly elevated blood pressure (severe hypertension) requiring 3 or more antihypertensive drugs severe kidney disease or dialyses clinical diagnosis requiring concomitant therapy with antihypertensive treatment that would be outside the therapies allowed under study protocol Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Usual care<br>Physicians applied their usual pattern of patient visits and treatment strategies to achieve individualized blood pressure target | Drug: Usual care<br>* As directed by investigator<br>|
| Experimental: Monotherapy (initial monotherapy arm)<br>Physicians utilized valsartan 160mg per day for 6 weeks, followed by (if required) dose titrations every 4 weeks thereafter until week 14 (valsartan 320mg per day, then valsartan 320mg plus hydrochlorothiazide (HCTZ) 12.5mg per day, then valsartan 320mg plus HCTZ 25mg per day (maximal dose)). For patients not at blood pressure target at week 18, physicians were requested to consider triple or alternative therapy at their own discretion for the remainder of the study. | Drug: Valsartan and hydrochlorothiazide (HCTZ) - monotherapy<br>* Monotherapy arm - if monotherapy valsartan 320mg per day orally was not sufficient, then could add HCTZ up to 25 mg per day orally<br>Drug: Valsartan<br>* Valsartan 160mg per day to 320mg per day orally<br>|
| Experimental: Combination (initial combination therapy arm)<br>Physicians initially utilized single tablet combination products of either valsartan plus hydrochlorothiazide (HCTZ) or valsartan plus amlodipine for an initial 6 weeks of therapy (based on the treating physician's preference), with dose titrations (if required) every 4 weeks thereafter until week 10. The maximum dose for the HCTZ combination was valsartan 160mg plus HCTZ 25mg per day. The maximum dose for the amlodipine combination was valsartan 160mg plus amlodipine 10mg per day. For patients who were not at blood pressure target at week 14, physicians were requested to consider triple or alternative therapy at their own discretion for the remainder of the study. | Drug: Valsartan and amlodipine<br>* From valsartan 80mg/amlodipine 5mg per day to valsartan 160mg/amlodipine 10mg per day orally<br>Drug: Valsartan and hydrochlorothiazide (HCTZ) - combination arm<br>* Combination arm - from valsartan 80mg/hydrochlorothiazide 12.5mg per day to valsartan 160mg/hydrochlorothiazide 25mg per day orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Who Have Achieved Their Pre-specified (Individualized National Heart Foundation of Australia Criteria) Blood Pressure (BP) Target | BP target groups were: <= 125/75mmHg, <= 130/80mmHg and <= 140/90mmHg. The BP target was based on the patient's clinical risk profile as specified by National Heart Foundation of Australia guidelines. | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Sitting Systolic Blood Pressure | The visit window was from 22 to 36 weeks. If more than one blood pressure measure was available within the specified window, then the one closest to the scheduled visit was used for analysis. If no measure was available within this window, then the last recorded BP post-randomization was used for the endpoint. Analysis of covariance model was used with the factors: baseline blood pressure, treatment and blood pressure target group at randomization. | Baseline and 26 weeks | 
| Change in Mean Sitting Diastolic Blood Pressure | The visit window was from 22 to 36 weeks. If more than one blood pressure measure was available within the specified window, then the one closest to the scheduled visit was used for analysis. If no measure was available within this window, then the last recorded BP post-randomization was used for the endpoint. Analysis of covariance model was used with the factors: baseline blood pressure, treatment and blood pressure target group at randomization. | Baseline and 26 weeks | 
| Change in Absolute Cardiovascular Risk Score | The absolute cardiovascular risk assessment uses the Framingham Risk Equation to predict risk of a cardiovascular event over the next 5 years. A score of <10% is a low risk, 10 to 15% is a moderate risk, and >15% is a high risk. A decrease indicates improvement. | Baseline and 26 weeks | 
| Number of Patients With at Least One Adverse Events Attributable to Anti-hypertensive Therapy | The rate of all adverse events by preferred terms as determined by the General Practice investigators to be related to study intervention therapy was reported. Percentage of adverse events was calculated based on the number of participants analyzed. 41 adverse events were not reported as inadequate information was supplied to allow determination of drug treatment at onset. | 26 weeks | 
| Number of 'Early Responder' Patients Who Achieve Individualized Blood Pressure Control After 1 or 2 Adjustments | A comparison of the early responders was made based on the blood pressure measurements taken at the week 6 visit window according to gender and guideline targets. The guideline targets were: patients with renal impairment: 125/75 mmHg; patients with end-organ damage/cardiovascular disease: 130/80 mmHg; others: 140/90 mmHg. | 26 weeks | 
| Change in the EQ-5D Score | The EQ-5D total indexed score (AUS) measures self-reported quality of life with the following 5 dimensions: mobility (range 1,2,3), self-care (range 1,2,3), usual activity (range 1,2,3), pain/discomfort (range 1,2,3) and anxiety/depression (range 1,2,3), where a 1 indicates no problems, a 2 indicates moderate problems, and a 3 indicates severe problems. The range of possible utility scores are between -0.217 (derived from worse responses from all 5 dimensions with severe problems ie 3,3,3,3,3) and 1.000 (no problems for all 5 dimensions) for each dimension. An increase in EQ-5D indexed score (AUS) indicates improvement. | Baseline and 26 weeks | 
| Number of Patients With Depression | Patients with depression refers to potential depressive symptoms, not clinically diagnosed depression. The 2 question Arrol screening tool was used to determine if the patient had potential depressive symptoms. The 2 questions are: During the last month have you often been bothered by feeling down, depressed or hopeless? During the past month have you often been bothered by little interest or pleasure in doing things? The presence of potential depressive symptoms was determined by a 'yes' answer to either of these questions. | Baseline and week 26 | 
| Change in Center for Epidemiologic Studies Depression (CES-D) Score From Baseline to Week 26 | The CES-D score was from 0 to 30, with a higher score indicating a higher level of depression. The categories for the score are: 0 to 9 suggests no depression; 10 to 15 suggests mild depression; 16 to 24 suggests moderate depression; 24 or above suggests severe depression. | Baseline and week 26 | 
| Participants With End Organ Disease at Baseline and Week 26 | A patient was considered to have end organ damage with either of the following: 1) proteinuria (dipstick = 1+ or more or protein/creatinine ratio > 30mg/mol or 24h urine protein > 0.3g); 2) no proteinuria, but presence of microalbuminuria (urine albumin/creatinine ratio 3.6 to 25mg/mol(male) or 3.6 to 35mg/mol (female) detected; 3) no proteinuria or microalbuminuria, but presence of macroalbuminuria (urine albumin/creatinine ratio > 25mg/mol(male) or >35mg/mol (female) detected OR 4) ECG evidence of LVH (Sokolow-Lyon voltage criteria values >= 38mm). Baseline potential for end organ damage was calculated in all 1562 randomised patients based on the criteria outlined above. If no investigation/data available, assumed no end-organ damage. It is important to note that given the limited number of ECGs at 26 weeks, between group comparisons should be limited to the two time points (baseline and 26 weeks). | Baseline and week 26 | 
| Change in Self-care Behavior Score From Baseline to Week 26 | A modified self-care behavior tool (questionnaire) was used to calculate 2 domain scales: maintenance and confidence. Each domain has a standardized score between 0 and 100. Self-care is best represented by maintenance. Confidence is an important process that moderates the relationship between self-care and outcomes. Higher index score suggests better self-care. A score of 70 or greater can be used as the cut-point to judge self-care adequacy. | Baseline and week 26 | 
| Rate of Treatment Compliance | The rate of compliance was planned to be estimated from the quantity of unused medication returned at each scheduled visit over the entire follow-up period. Rate of compliance = (tablets supplied - tablets returned)/(tablets for 100% compliance). | 26 weeks | 
| Number of Patients With Major Clinical Endpoints | Major clinical endpoints measured were all-cause mortality and fatal and non-fatal cardiovascular events (e.g. acute myocardial infarction, stroke and heart failure). | 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, valsartan