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

High Blood Pressure Clinical Trial

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT05275907
• Other study ID #: STU00215781
• Secondary ID: 1R56HL155093-01
• Status: Withdrawn
• Phase: Phase 4
• Start date: July 12, 2022
• Est. completion date: October 4, 2023

Study information

• Verified date: October 2023
• Source: Northwestern University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: October 4, 2023
• Est. primary completion date: October 2, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• High Blood Pressure
• Hypertension
• Liver Transplant
• Renal Function Abnormal

Intervention

Drug:
• Amlodipine Besylate
10 mg capsule once daily for 6 weeks
• Chlorthalidone
25mg capsule once daily for 6 weeks

Locations

Country	Name	City	State
United States	Northwestern University	Chicago	Illinois

Sponsors (3)

Lead Sponsor	Collaborator
Northwestern University	American Society for Transplantation, National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (11)

ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981-97. doi: 10.1001/jama.288.23.2981. Erratum In: JAMA 2003 Jan 8;289(2):178. JAMA. 2004 May 12;291(18):2196. — View Citation

Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005 Sep 10-16;366(9489):895-906. doi: 10.1016/S0140-6736(05)67185-1. — View Citation

Kwon BJ, Jang SW, Choi KY, Kim DB, Cho EJ, Ihm SH, Youn HJ, Kim JH. Comparison of the efficacy between hydrochlorothiazide and chlorthalidone on central aortic pressure when added on to candesartan in treatment-naive patients of hypertension. Hypertens Res. 2013 Jan;36(1):79-84. doi: 10.1038/hr.2012.143. Epub 2012 Oct 4. — View Citation

Levitsky J, O'Leary JG, Asrani S, Sharma P, Fung J, Wiseman A, Niemann CU. Protecting the Kidney in Liver Transplant Recipients: Practice-Based Recommendations From the American Society of Transplantation Liver and Intestine Community of Practice. Am J Transplant. 2016 Sep;16(9):2532-44. doi: 10.1111/ajt.13765. Epub 2016 Apr 22. — View Citation

Luscher TF, Yang Z, Kiowski W, Linder L, Dohi Y, Diederich D. Endothelin-induced vasoconstriction and calcium antagonists. J Hum Hypertens. 1992 Dec;6 Suppl 2:S3-8. — View Citation

Moes AD, Hesselink DA, van den Meiracker AH, Zietse R, Hoorn EJ. Chlorthalidone Versus Amlodipine for Hypertension in Kidney Transplant Recipients Treated With Tacrolimus: A Randomized Crossover Trial. Am J Kidney Dis. 2017 Jun;69(6):796-804. doi: 10.1053/j.ajkd.2016.12.017. Epub 2017 Mar 1. — View Citation

Neal DA, Brown MJ, Wilkinson IB, Byrne CD, Alexander GJ. Hemodynamic effects of amlodipine, bisoprolol, and lisinopril in hypertensive patients after liver transplantation. Transplantation. 2004 Mar 15;77(5):748-50. doi: 10.1097/01.tp.0000116418.78963.dc. — View Citation

Olde Engberink RH, Frenkel WJ, van den Bogaard B, Brewster LM, Vogt L, van den Born BJ. Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis. Hypertension. 2015 May;65(5):1033-40. doi: 10.1161/HYPERTENSIONAHA.114.05122. Epub 2015 Mar 2. — View Citation

Pareek A, Messerli FH, Saravia G, Mehta RT. Interamerican Society of Cardiology (IASC) position statement: Chlorthalidone vs. thiazide-type diuretics. Int J Cardiol Hypertens. 2020 Sep 19;7:100054. doi: 10.1016/j.ijchy.2020.100054. eCollection 2020 Dec. — View Citation

Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 May 15;71(19):e127-e248. doi: 10.1016/j.jacc.2017.11.006. Epub 2017 Nov 13. No abstract available. Erratum In: J Am Coll Cardiol. 2018 May 15;71(19):2275-2279. — View Citation

Wright JT Jr, Dunn JK, Cutler JA, Davis BR, Cushman WC, Ford CE, Haywood LJ, Leenen FH, Margolis KL, Papademetriou V, Probstfield JL, Whelton PK, Habib GB; ALLHAT Collaborative Research Group. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA. 2005 Apr 6;293(13):1595-608. doi: 10.1001/jama.293.13.1595. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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