HIGH Altitude CArdiovascular REsearch in the ANDES (HIGHCARE-A)

This study is aimed to assess the efficacy of combined treatment with two antihypertensive agents (telmisartan and nifedipine) in subjects with mild hypertension exposed to high altitude.

Study Overview

• Status: Completed
• Conditions: Hypertension; High Altitude
• Intervention / Treatment: Drug: Telmisartan; Drug: Nifedipine; Drug: placebo

Detailed Description

This is a parallel group, prospective, double-blind, placebo controlled randomized trial, comparing the effects of combination of two antihypertensive agents (telmisartan/nifedipine)with placebo in hypertensive subjects exposed to high altitude. The principal objectives are:

1. to assess the response of BP to high altitude exposure in hypertensive subjects residing at sea level
2. To assess the efficacy and safety of combination of telmisartan 80 mg with nifedipine GITS 30 mg in preventing a possible excessive BP increase in hypertensive subjects exposed to high altitude.

The following data will be collected during the study at the different steps:

• Clinical history
• Symptoms and adverse events questionnaire
• Conventional BP and heart rate (HR) measurement - seated measurements with a validated oscillometric device will be performed after at least 5 minutes rest on non-dominant arm; two measurements will be performed 1-2 minutes apart and their average will be used in the analyses
• Vital signs:

respiratory rate - will be measured manually over 60 seconds body height and weight, waist circumference blood oxygen saturation (SpO2)

• Lake Louise Score
• 24 h ambulatory blood pressure monitoring (ABPM; AND TM2430, AND, Japan)
• Echocardiography
• Arterial properties assessment
• Six minute walking test (6MWT)
• Cardiopulmonary Exercise Test (CPET) in a subgroup of subjects
• Polysomnography with a portable device
• Pulmonary function tests (only at sea level baseline visit)
• Fluid balance chart
• Blood and urine analyses: Visit 1: electrolytes, creatinine, estimated glomerular filtration rate (eGFR), glycemia, renin, angiotensin, aldosterone, plasma catecholamines, 24 h urinary sodium excretion, carbonic anhydrase activity and isoenzyme expression (in 50 randomly selected subjects), samples for genetic studies. Visit 2: electrolytes, creatinine, eGFR. Visit 3: complete blood count, electrolytes, creatinine, eGFR, glycemia, insulin, renin, angiotensin, aldosterone, plasma catecholamines, classic urinalysis, microalbuminuria, 24 h urinary sodium excretion, carbonic anhydrase activity and isoenzyme expression (in 50 subjects selected at Visit 1). Visit 4: electrolytes, creatinine, eGFR, glycemia, insulin, renin, angiotensin, aldosterone, plasma catecholamines, 24 h urinary sodium excretion, carbonic anhydrase activity and isoenzyme expression (in 50 subjects selected at Visit 1)

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• Peru
  • Lima, Peru
    • Universidad Peruana Cayetano Heredia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Permanent residence at low (<500 m) altitude
• Conventional systolic BP (average of two measurements) 140-159 mmHg or conventional diastolic BP 90-99 mmHg in subjects untreated or after 4 weeks of washout
• Mean daytime systolic BP ≥135 and <150 mmHg and/or mean daytime diastolic BP ≥85 and <95 mmHg in subjects untreated or after 4 weeks of washout
• Written informed consent to participate in the study

Exclusion Criteria:

• Conventional systolic BP (average of two measurements) ≥150 mmHg and conventional diastolic BP ≥95 mmHg in treated subjects
• Regular use of two or more antihypertensive drugs (with the exception of subjects on two antihypertensive drugs in low doses)
• Treated antihypertensive subjects in whom withdrawal of treatment is deemed unethical by the investigator (e.g. because of the existence of compelling indications other than hypertension for continuous use of previously used antihypertensive agent)
• Contraindications (including a history of adverse reactions) to angiotensin receptor blockers or calcium antagonists
• History of serious mountain sickness
• Subjects who over 3 months preceding inclusion in the study spent considerable (> 1 week) amount of time at altitudes above 2500 m.
• Cardiovascular diseases other than hypertension (coronary heart disease, heart failure, atrial fibrillation, valvular or congenital heart disease, cardiomyopathies, cerebrovascular disease, peripheral artery disease, aortic aneurysm)
• Suspected or confirmed secondary hypertension
• Diabetes mellitus
• Serious respiratory disorders
• Other conditions deemed relevant by the investigator (including liver disease, renal disease, thyroid disorders)
• BMI ≥35 kg/m2
• Upper arm circumference >32 cm
• known severe obstructive sleep apnea (apnea-hypopnea index > 30 or use of CPAP) or excessive daytime sleepiness (Epworth Sleepiness Scale > 10)
• Pregnancy
• Premenopausal women not using effective contraceptive methods
• Elevated probability of noncompliance with the study procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Telmisartan/nifedipine; Subjects treated with telmisartan 80 mg (1 capsule daily in the morning) plus nifedipine slow release 30 mg (1 capsule daily in the morning) combination	Drug: Telmisartan; Subjects treated with telmisartan 80 mg (1 capsule daily in the morning) plus nifedipine slow release 30 mg (1 capsule daily in the morning) combination; Other Names: Micardis; Pritor; Drug: Nifedipine; Subjects treated with telmisartan 80 mg (1 capsule daily in the morning) plus nifedipine slow release 30 mg (1 capsule daily in the morning) combination; Other Names: Adalat
Placebo Comparator: Placebo; Two tablets containing placebo daily in the morning	Drug: placebo; two tablets daily in the morning

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of study treatment on 24 h ambulatory systolic blood pressure at high altitude	Difference in 24 h ambulatory systolic BP at high altitude (Visit 4) between combination therapy group and placebo group	After 6 weeks of study treatment, during high altitude visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of study treatment on ambulatory blood pressure at high altitude (other variables)	Differences in other ambulatory blood pressure (BP) variables (including 24 h diastolic BP, daytime and night-time BP, nocturnal fall of BP) at high altitude (V4) between combination therapy and placebo groups	After 6 weeks of study treatment, during high altitude visit
Lake Louise Score	Differences in Lake Louise Score (score of acute mountain sickness severity) between groups	After 6 weeks of study treatment, during high altitude visit
Effect of high altitude on ambulatory blood pressure	Change in ambulatory blood pressure between sea level condition and high altitude in both treatment groups	After 6 weeks of study treatment, during high altitude visit
Effect of high altitude on conventional blood pressure	Change in conventional blood pressure between sea level condition and high altitude in both groups	After 6 weeks of study treatment, during high altitude visit
Effect of study treatment on conventional blood pressure at high altitude.	Difference in conventional systolic and diastolic blood pressure at high altitude (Visit 4) between combination therapy group and placebo group	After 6 weeks of study treatment, during high altitude visit
Rate of adverse events	Differences in rate of adverse events between groups.	After 6 weeks of treatment plus up to 1 additional week of treatment needed for high altitude visit (study end).
Effect of study treatment on ambulatory heart rate at high altitude	Differences in ambulatory heart rate (HR) variables (including 24 h, daytime and night-time HR, and nocturnal fall of HR) at high altitude (V4) between combination therapy and placebo groups	After 6 weeks of study treatment, during high altitude visit

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in other variables assessed in the study at high altitude between treatment groups	Differences between treatment groups in polysomnographic data, arterial stiffness, blood tests, echocardiography data assessed at high altitude	high altitude visit ( Visit 4)
blood pressure response at sea level	Changes in polysomnographic data, arterial stiffness, blood tests, echocardiography data between sea level condition and high altitude	Sea level visit (3) and high altitude visit (4)

Collaborators and Investigators

• Sponsor: Istituto Auxologico Italiano
• Collaborators: Bayer
• Investigators: Principal Investigator: Gianfranco Parati, MD, PhD, Istituto Auxologico Italiano

Publications and helpful links

General Publications

• Caravita S, Faini A, Baratto C, Bilo G, Macarlupu JL, Lang M, Revera M, Lombardi C, Villafuerte FC, Agostoni P, Parati G. Upward Shift and Steepening of the Blood Pressure Response to Exercise in Hypertensive Subjects at High Altitude. J Am Heart Assoc. 2018 Jun 9;7(12):e008506. doi: 10.1161/JAHA.117.008506.
• Bilo G, Villafuerte FC, Faini A, Anza-Ramirez C, Revera M, Giuliano A, Caravita S, Gregorini F, Lombardi C, Salvioni E, Macarlupu JL, Ossoli D, Landaveri L, Lang M, Agostoni P, Sosa JM, Mancia G, Parati G. Ambulatory blood pressure in untreated and treated hypertensive patients at high altitude: the High Altitude Cardiovascular Research-Andes study. Hypertension. 2015 Jun;65(6):1266-72. doi: 10.1161/HYPERTENSIONAHA.114.05003. Epub 2015 Apr 20.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: February 18, 2013
• First Submitted That Met QC Criteria: April 9, 2013
• First Posted (Estimate): April 12, 2013

Study Record Updates

• Last Update Posted (Estimate): April 12, 2013
• Last Update Submitted That Met QC Criteria: April 9, 2013
• Last Verified: February 1, 2013

More Information

Terms related to this study

• Keywords: arterial hypertension; combination treatment; hypobaric hypoxia; angiotensin receptor blocker; high altitude; calcium antagonist
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Respiration Disorders; Hypertension; Altitude Sickness; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Reproductive Control Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Tocolytic Agents; Nifedipine; Telmisartan
• Other Study ID Numbers: 09F102