Mechanism of Hypertension Treatments in Liver Transplant Recipients (BLOCK LTR-HTN)

Study Overview
=================
Brief Summary
-----------------
Liver transplantation is a high risk, high-cost intervention that extends life in over 8,000 patients in the US each year. Of those that receive transplants, 1 in 3 will have a complication related to their heart after transplant. Research has been done to attempt to reduce the risk of these complications from occurring. High blood pressure, otherwise known as hypertension, is an important risk factor for heart complications. Hypertension is found in 92% of liver transplant recipients within 6 years of their procedure. However, using data from our transplant patients at Northwestern we recently showed that having a normal blood pressure in the first year following liver transplant lowered the risk of heart complications and the risk of death by over half. However, there are no studies investigating the best medications to lower blood pressure in liver transplant recipients. There are several types of medications that can be used to treat high blood pressure. Currently, most transplant providers use a class of medications called calcium channel blockers as the first medications for hypertension in liver transplant patients. However, there is little data to support this recommendation. There is some new evidence suggesting that another class of medications, called thiazide-like diuretics, might be beneficial to lower blood pressure in liver transplant recipients. The current study will use two different medications: the calcium channel blocker called amlodipine besylate (at dose of 10mg) and the thiazide-like diuretic known as chlorthalidone (25mg). Both medications are taken once per day by mouth and are FDA approved for the treatment of high blood pressure in the general population. The main purpose of this study is to determine how well these two medications lower blood pressure and how they may improve markers of heart function and kidney function in liver transplant recipients. The long-term goal of this research is to improve heart outcomes in those that have undergone liver transplant by addressing risk factors that can be modified, including blood pressure. This study will help determine the size of the needed group for further studies to ensure proper investigation of which of these two medications may most benefit liver transplant patients.

Detailed Description
-----------------
The study will involve a randomized crossover trial of two medications: amlodipine besylate 10mg and chlorthalidone 25mg daily by mouth. Amlodipine was selected as the dihydropyridine calcium channel blocker (CCB) due to extensive trial evidence demonstrating its efficacy in hypertension (HTN) in the general population and established safety and efficacy for calcineurin inhibitor (CNI)-induce HTN in kidney transplant recipients. Chlorthalidone was chosen amongst other thiazides due to its favorable safety profile, superior effectiveness in reducing cardiovascular events (CVEs) in the general population, stronger reduction in central pressure, and prior evidence of efficacy in kidney transplant recipients with CNI-induced HTN. Dosing for either medication was determined based on the median and maximum recommended doses for each medication when used for the treatment of stage II HTN BP ≥140/≥90 and previous trial evidence demonstrating similar blood pressure-lowering effects of amlodipine and chlorthalidone at these doses. We recognize that several prior studies have used a starting dose of chlorthalidone 12.5mg; however, this dose is no longer available in the U.S. and tablets are not scored to allow for accurate trial dosing. We specifically selected a relatively short duration of follow up (six weeks per intervention) due to several factors, including 1) the time to peak hemodynamic effects and durations of action of the trial interventions, balanced with 2) optimizing adherence to the study protocols to be able to measure key mechanistic factors, and 3) minimizing dropout. Given the well-described half-life elimination of the two medications, we do not anticipate issues with crossover effects in the second phase outcome assessments occurring six weeks following the washout period. Nonetheless, exploratory analyses will account for potential period or crossover effects using mixed effects models.

Official Title
-----------------
Pilot Study to Assess Blockade of Calcium Channels and Sodium Chloride Cotransporters for Physiologic Abnormalities in Liver Transplant Associated Hypertension

Conditions
-----------------
High Blood Pressure, Liver Transplant, Renal Function Abnormal

Intervention / Treatment
-----------------
* Drug: Amlodipine Besylate
* Drug: Chlorthalidone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Liver transplant alone recipient At least 90 days from transplant Average daytime systolic blood pressure (SBP)>140mmHG with 24h ambulatory blood pressure monitoring. Patients will be enrolled in 24h ambulatory blood pressure monitoring (ABPM) if they have hypertension (HTN) defined by diagnostic codes, treatment with antihypertensive medications for ≥ 2 months, and a history of office blood pressure readings ≥140/90 mmHg at two separate office visits. Stable antihypertensive medical therapy (e.g., no change in current antihypertensive medications within 30d of screening) No acute cellular rejection within 30d of screening Exclusion Criteria: Contraindication to withholding calcium channel blockers (CCB) or beta-blocker (e.g., atrial fibrillation/flutter) Treatment with other diuretics that cannot be held Acute coronary syndrome or revascularization within 60d Serum potassium < 3.5 mEq/L Serum sodium < 135 mg/dL Allergy to sulfa drugs Estimated Glomerular Filtration Rate (eGFR) < 30 mL/min/1.73 m2 or on dialysis Pregnant women

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A first, then B<br>6 weeks of drug A followed by a 2-week washout period completed with 6 weeks of drug B | Drug: Amlodipine Besylate<br>* 10 mg capsule once daily for 6 weeks<br>Drug: Chlorthalidone<br>* 25mg capsule once daily for 6 weeks<br>|
| Active Comparator: B first, then A<br>6 weeks of drug B followed by a 2-week washout period completed with 6 weeks of drug A | Drug: Amlodipine Besylate<br>* 10 mg capsule once daily for 6 weeks<br>Drug: Chlorthalidone<br>* 25mg capsule once daily for 6 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in central aortic pressure at 6 weeks of therapy compared to baseline values | Carotid-femoral pulse wave velocity (PWV), the gold standard measure of large artery stiffness, will be measured using a SphygmoCor XCEL device (Atcor Medical). | Endpoints will be measured before the first dose of either amlodipine or chlorthalidone and at the end of each six-week double-blinded treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with improvement in diastolic function (E/e' ratio) | We will perform comprehensive echo to assess diastolic function using E/e' ratio on all participants using a GE Vivid T8 ultrasound machine and a systematic echo protocol. | Endpoints will be measured before the first dose of either amlodipine or chlorthalidone and at the end of each six-week double-blinded treatment period | 
| Number of patients with improvement in systolic function (absolute global longitudinal strain, %) | We will perform comprehensive echo to assess systolic function using absolute global longitudinal strain (%) on all participants using a GE Vivid T8 ultrasound machine and a systematic echo protocol. | Endpoints will be measured before the first dose of either amlodipine or chlorthalidone and at the end of each six-week double-blinded treatment period | 
| Change in Blood pressure | 24-hour ambulatory blood pressure (BP) monitoring will be performed in addition to office BP to determine Mean home systolic and diastolic BP, office systolic and diastolic BP and nocturnal BP readings | Endpoints will be measured before the first dose of either amlodipine or chlorthalidone and at the end of each six-week double-blinded treatment period | 
| Change in Renal function | Renal function will be primarily assessed by 24-hour creatinine clearance which is the most accurate measure of GFR after liver transplant. | Endpoints will be measured before the first dose of either amlodipine or chlorthalidone and at the end of each six-week double-blinded treatment period | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
liver transplant, hypertension, cardiac function, kidney function, treatment