Effectiveness of Valsartan Alone vs Combination Therapy in Hypertensive Heart Disease (VALHCT-HHD)

Comparison of Effectiveness of Combination of Valsartan and Hydrochlorothiazide Versus Valsartan Alone in the Treatment of Hypertensive Heart Disease

Hypertension is a major global health problem, affecting about 30% of people and up to two-thirds of those over 60 years. Its prevalence has increased significantly, with over one billion adults affected worldwide and expected to reach 1.56 billion by 2025, especially in developing countries where early diagnosis and treatment are limited. Long-term hypertension can lead to hypertensive heart disease (HHD), which includes left ventricular hypertrophy and increases the risk of stroke, heart attack, heart failure, and kidney disease. Diagnosis is based on clinical assessment along with ECG, echocardiography, and cardiac MRI.

Management focuses on controlling blood pressure and preventing heart damage. Valsartan, an angiotensin receptor blocker, and hydrochlorothiazide, a thiazide diuretic, are commonly used treatments. Studies suggest that combining these drugs may be more effective than valsartan alone, with better outcomes and fewer side effects. However, local evidence in Pakistan is limited.

This study aims to compare valsartan plus hydrochlorothiazide versus valsartan alone in patients with HHD. A randomized controlled trial will be conducted at Sheikh Zayed Hospital, Lahore, including 118 patients aged 18-70 years diagnosed with HHD. Participants will be divided into two groups: one receiving combination therapy and the other valsartan alone for eight weeks, with dose adjustments as needed.

Effectiveness will be classified as effective or ineffective. Patient data, including age, gender, BMI, and disease duration, will be analyzed using SPSS version 26. Results will be compared using the chi-square test, with further analysis to control confounding factors.

This study will help determine the better treatment option and support improved management of hypertension in Pakistan.

Study Overview

• Status: Completed
• Conditions: Heart Diseases; Hypertension
• Intervention / Treatment: Drug: Valsartan + Hydrochlorothiazide

Detailed Description

Background and Rationale:

Hypertension (HTN) is a chronic medical condition characterized by persistently elevated blood pressure, which poses significant health risks worldwide. The global burden of hypertension has been steadily increasing, with current estimates indicating a prevalence of approximately 30% in the general population and up to two-thirds in individuals over 60 years of age. Epidemiological studies have demonstrated that between 1990 and 2019, the number of adults aged 30-79 years with hypertension doubled globally, reaching more than one billion affected individuals in 2019. The prevalence is projected to rise to 1.56 billion by 2025, particularly in rapidly developing countries with limited access to early detection, screening, and healthcare resources.1,2

Hypertension is a major risk factor for cardiovascular morbidity and mortality. Prolonged uncontrolled hypertension can result in hypertensive heart disease (HHD), a condition characterized by structural and functional cardiac alterations due to chronic pressure overload. HHD encompasses a spectrum of cardiac changes, including left ventricular hypertrophy (LVH), diastolic dysfunction, and, in advanced stages, heart failure with preserved or reduced ejection fraction.3 The pathological mechanisms of HHD are multifactorial, involving neurohormonal activation, vascular remodeling, myocardial fibrosis, and cellular-level changes in cardiomyocytes. These structural and functional abnormalities predispose patients to serious cardiovascular events, including stroke, myocardial infarction, heart failure, and renal failure.4,5

Diagnosis of HHD relies on a combination of clinical, electrocardiographic, and imaging criteria. Electrocardiography (ECG) findings indicative of HHD include LVH as defined by Cornell Voltage Criteria (R in aVL + S in V3 ≥ 28 mm for males and ≥ 20 mm for females) and significant ST-segment changes. Echocardiography is the standard tool for assessing cardiac morphology and function, while cardiac magnetic resonance imaging (cMRI) offers enhanced tissue characterization and helps differentiate HHD from hypertrophic cardiomyopathy (HCM).6

Effective management of HHD requires both control of blood pressure and mitigation of myocardial remodeling. Pharmacological treatment is central to management, with angiotensin receptor blockers (ARBs) such as valsartan commonly prescribed due to their efficacy in reducing blood pressure and preventing left ventricular hypertrophy. Valsartan functions by inhibiting the angiotensin II receptor, reducing vasoconstriction, aldosterone secretion, and myocardial remodeling.7 Despite its proven efficacy, monotherapy may not always achieve optimal blood pressure control, necessitating consideration of combination therapy with other antihypertensive agents.

Hydrochlorothiazide, a thiazide diuretic, is widely used as a first-line treatment for hypertension worldwide. It reduces blood pressure by promoting renal sodium and water excretion, decreasing plasma volume, and lowering systemic vascular resistance. Extensive clinical evidence demonstrates the antihypertensive efficacy of hydrochlorothiazide both as monotherapy and in combination with other antihypertensive agents.8 Emerging studies suggest that the combination of valsartan and hydrochlorothiazide offers superior blood pressure reduction and improved cardiovascular outcomes compared to valsartan alone. Zhou et al. (2023) reported that patients receiving the combination therapy had higher treatment effectiveness (95.45% vs. 79.63%; p=0.007) and a lower incidence of adverse reactions (9.09% vs. 31.48%; p=0.001) compared to valsartan monotherapy.9

Despite these promising results, local evidence is lacking, particularly in countries like Pakistan, where healthcare resources are limited, and the cost-effectiveness of therapy is a critical consideration. Before recommending combination therapy as standard practice, it is essential to validate these findings in the local population. This study aims to address this gap by comparing the effectiveness and safety of valsartan combined with hydrochlorothiazide versus valsartan alone in patients with HHD in Pakistan.

Objectives:

Primary Objective: To compare the effectiveness of valsartan combined with hydrochlorothiazide versus valsartan monotherapy in the treatment of hypertensive heart disease.

Secondary Objective: To assess the safety profile of combination therapy and monitor the incidence of adverse reactions.

Hypothesis: There is a significant difference in treatment effectiveness between valsartan combined with hydrochlorothiazide and valsartan alone in patients with hypertensive heart disease.

Operational Definitions:

Hypertensive Heart Disease (HHD): Diagnosed by sustained high blood pressure (systolic ≥140 mmHg or diastolic ≥90 mmHg, confirmed as the average of two readings) and ECG criteria: LVH as per Cornell Voltage Criteria (R in aVL + S in V3 ≥28 mm in males, ≥20 mm in females), ST-segment changes ≥1 mm, or left atrial enlargement (P wave duration >120 ms or amplitude >0.2 mV in lead V1).

Effectiveness: Categorized as markedly effective, effective, or ineffective (see Appendix-I). Both markedly effective and effective are considered clinically beneficial.

Study Design:

This study is a randomized controlled trial conducted over a six-month period following synopsis approval. The trial will enroll 118 patients meeting inclusion criteria and randomize them into two equal groups:

Group A: Valsartan (80 mg) plus hydrochlorothiazide (25 mg) daily for eight weeks, with initial dose adjustments (6.5 mg/day, titrated to 13 mg/day based on clinical response).

Group B: Valsartan alone (80 mg/day) for eight weeks.

Study Setting:

Department of Cardiology, Sheikh Zayed Hospital, Lahore.

Sample Size and Sampling Technique:

Sample Size: 118 patients (59 per group), calculated to achieve 80% power and 5% significance, assuming treatment efficacy of 95.4% for combination therapy and 79.6% for monotherapy.

Sampling Technique: Non-probability, consecutive sampling.

Inclusion Criteria:

Adults aged 18-70 years of both genders with HHD diagnosed per operational criteria.

Patients willing to provide written informed consent.

Exclusion Criteria:

Drug allergies or contraindications to valsartan or hydrochlorothiazide.

Emergency presentations with hypertension, poor compliance, or incompatible health status.

Presence of other endocrine disorders, coagulation dysfunction, infectious or immune diseases.

Mental disorders affecting adherence or safety.

Data Collection Procedure:

Following ethical approval, eligible patients presenting to the outpatient cardiology clinic will be enrolled after informed consent. Baseline demographic and clinical data (age, gender, BMI, duration of disease) will be collected. Patients will be randomized into two groups using a computer-generated randomization schedule. Treatment effectiveness will be assessed after eight weeks based on operational criteria. Adverse reactions (headache, vertigo, nausea, vomiting, dry cough, edema) will be recorded, and standard hospital protocols will be followed for management. All assessments will be performed by a senior consultant, while the resident investigator will record findings to minimize bias.

Data Analysis:

All data will be entered and analyzed using SPSS version 26. Continuous variables (age, BMI, disease duration) will be reported as mean ± standard deviation, while categorical variables (gender, treatment effectiveness, adverse reactions) will be expressed as frequency and percentages. Chi-square tests will compare effectiveness and adverse events between groups, with p ≤0.05 considered statistically significant. Stratified analysis will address potential effect modifiers, including age, gender, BMI, and disease duration.

Ethical Considerations:

The study will adhere to the Declaration of Helsinki. Written informed consent will be obtained from all participants. Confidentiality will be maintained, participation will be voluntary, and patients may withdraw at any time without penalty. Any adverse events will be managed promptly and free of cost. The trial protocol has been submitted for approval to the hospital's Ethical Review Board.

Significance:

This study will provide locally relevant evidence regarding the comparative effectiveness and safety of valsartan plus hydrochlorothiazide versus valsartan monotherapy in HHD. Positive results may support adoption of combination therapy to achieve better blood pressure control, mitigate left ventricular hypertrophy, and reduce adverse cardiovascular outcomes. Conversely, if no benefit is observed, the study will prevent unnecessary healthcare expenditure and guide rational antihypertensive use in resource-limited settings.

Expected Outcomes:

Determine whether combination therapy is more effective than monotherapy in managing hypertensive heart disease.

Assess the safety and tolerability of the combination therapy.

Provide evidence to inform clinical guidelines and optimize resource allocation in Pakistan.

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 1

Contacts and Locations

Study Locations

• Pakistan
  • Punjab Province
    • Lahore, Punjab Province, Pakistan
      • Department of Cardiology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Patients of both the genders diagnosed with hypertensive heart disease as per operational definition.
• Age18-70 years

Exclusion Criteria:

• Patients with drug allergies or contraindications to the medications used in this study.
• Patients attending emergency unit with hypertension, those with poor compatibility and compliance.
• Patients with other endocrine diseases, those with coagulation dysfunction.
• Patients with mental disorders, and patients whose health conditions will be complicated by infectious or immune diseases.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A (Combination Therapy): Valsartan 80 mg + Hydrochlorothiazide 25 mg Daily; Group A (Experimental Arm - Valsartan + Hydrochlorothiazide): Participants receive Valsartan 80 mg plus Hydrochlorothiazide 25 mg orally once daily for 8 weeks. Initial Hydrochlorothiazide dose is 6.5 mg/day, titrated to 13 mg/day based on response. Effectiveness is assessed via blood pressure reduction, ECG evidence of left ventricular hypertrophy, and symptom improvement. Adverse events (headache, vertigo, nausea, dry cough, edema) are monitored and managed per hospital protocol. This arm tests whether combination therapy is more effective than Valsartan alone in hypertensive heart disease.	Drug: Valsartan + Hydrochlorothiazide; Group A (Experimental Arm - Valsartan + Hydrochlorothiazide): Participants receive Valsartan 80 mg plus Hydrochlorothiazide 25 mg orally once daily for 8 weeks. Hydrochlorothiazide starts at 6.5 mg/day and may be titrated to 13 mg/day based on response. Effectiveness is assessed via blood pressure reduction, ECG evidence of left ventricular hypertrophy, and symptom improvement. Adverse events such as headache, vertigo, nausea, dry cough, and edema are monitored and managed according to hospital protocol. This arm evaluates whether combination therapy provides superior outcomes compared to monotherapy. Group B (Active Comparator Arm - Valsartan Alone): Participants receive Valsartan 80 mg orally once daily for 8 weeks. Effectiveness and safety are monitored using the same criteria as Group A. This arm serves as the standard-of-care comparator to assess the added benefit of combination therapy.
Active Comparator: Active Comparator Arm (Group B): Valsartan (80 mg) once daily (Monotherapy); Group B (Active Comparator - Valsartan Alone): Participants receive Valsartan 80 mg orally once daily for 8 weeks. Clinical effectiveness and safety are monitored using the same criteria as Group A. This arm represents standard-of-care therapy and serves as a comparator to evaluate the incremental benefit of combination therapy.	Drug: Valsartan + Hydrochlorothiazide; Group A (Experimental Arm - Valsartan + Hydrochlorothiazide): Participants receive Valsartan 80 mg plus Hydrochlorothiazide 25 mg orally once daily for 8 weeks. Hydrochlorothiazide starts at 6.5 mg/day and may be titrated to 13 mg/day based on response. Effectiveness is assessed via blood pressure reduction, ECG evidence of left ventricular hypertrophy, and symptom improvement. Adverse events such as headache, vertigo, nausea, dry cough, and edema are monitored and managed according to hospital protocol. This arm evaluates whether combination therapy provides superior outcomes compared to monotherapy. Group B (Active Comparator Arm - Valsartan Alone): Participants receive Valsartan 80 mg orally once daily for 8 weeks. Effectiveness and safety are monitored using the same criteria as Group A. This arm serves as the standard-of-care comparator to assess the added benefit of combination therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effectiveness	It will be labelled as per Appendix-I as markedly effective, effective and ineffective. Both markedly effective and effective will be labelled as effective.	At 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Headache	It will be measured as Yes or No	At 8 weeks
Vertigo	It will be measured as Yes or No	At 8 weeks
Nausea	It will be measured as Yes or No	At 8 weeks
Vomiting	It will be measured as Yes or No	At 8 weeks
Dry Cough	It will be measured as Yes or No	At 8 weeks
odema	It will be measured as Yes or No	At 8 weeks

Collaborators and Investigators

• Sponsor: Shaikh Zayed Hospital, Lahore

Publications and helpful links

General Publications

• 1. Ismail TF, Frey S, Kaufmann BA, Winkel DJ, Boll DT, Zellweger MJ, et al. Hypertensive Heart Disease-The Imaging Perspective. J Clin Med 2023;12(9):3122-6.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2025
• Primary Completion (Actual): March 1, 2026
• Study Completion (Actual): March 1, 2026

Study Registration Dates

• First Submitted: March 14, 2026
• First Submitted That Met QC Criteria: April 18, 2026
• First Posted (Actual): April 22, 2026

Study Record Updates

• Last Update Posted (Actual): April 22, 2026
• Last Update Submitted That Met QC Criteria: April 18, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Hypertension; Heart Diseases; Amino Acids, Peptides, and Proteins; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Azoles; Amino Acids; Amino Acids, Essential; Sulfonamides; Sulfones; Tetrazoles; Chlorothiazide; Benzothiadiazines; Thiazides; Valine; Amino Acids, Branched-Chain; Valsartan; Hydrochlorothiazide
• Other Study ID Numbers: Shaikh Zayed Hospital Lahore; No grant or funding (Other Grant/Funding Number: No grant)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Secrecy of keeping individual disclosure has been put in informed consent form. So will not be shared with other researchers

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No