Effects of Nebivolol Versus Carvedilol on Cardiopulmonary Function at High Altitude in Healthy Subjects.
Condition: Hypoxia; Altitude; Heart Failure
MeSH terms: Heart Failure; Hypoxia
Study type: Interventional
Phase: Phase 4

Summary: 
      Exposure of healthy subjects to high altitude hypoxia elicits changes in cardiovascular,
      respiratory and metabolic features as weel as in exercise performance similar, for some
      aspects, to those observed in chronic heart failure. Exposure to high altitude hypoxia
      represents a suitable model to assess different treatments proposed for this pathological
      condition. Our aim was to evaluate the impact of two different third-generation beta-blockers
      used in heart failure (carvedilol and nebivolol) on cardiovascular, respiratory, metabolic
      profile and on exercise performance at high altitude.
    

Detailed description: 
      Methods. Study Subjects. Adults, males and females, non smoking healthy volunteers, sea-level
      residents not engaged in regular endurance exercise training, taking no medications will be
      recruited. As there are no studies comparing the effects of beta-blockers on exercise
      performance at high altitude, the sample size set for each treatment arm was defined on the
      basis of the sample size of previous investigations showing significant changes in exercise
      performance in normal subjects taking no medications.

      Study design. Time 0. Screening, enrollement and randomization. Subjects meeting the
      inclusion/exclusion criteria will undergo at sea-level, general laboratory investigations and
      physical examination. Eligible subjects will be double blindly randomized to either placebo
      (one tablet twice daily), carvedilol (one 25 mg tablets twice daily), or to nebivolol (one 5
      mg tablet in the morning and one placebo tablet in the evening).

      Time 1. Before starting the medications, at sea level after an overnight fast, subject will
      undergo: blood pressure and heart rate measurement, 24 hour ambulatory blood pressure
      monitoring, Doppler heart ultrasound, cardiopulmonary exercise test, resting energy
      expenditure measurement.

      Time 2. After three weeks of allocated treatment, at sea-level, after an overnight fast,
      subjects will undergo: blood pressure and heart rate measurement, 24 hour ambulatory blood
      pressure monitoring, Doppler heart ultrasound, cardiopulmonary exercise test, resting energy
      expenditure measurement.

      Time 3. Under treatment within the first two days of high altitude exposure (Regina
      Margherita hut, Monte Rosa, altitude 4559 m), subjects will undergo after an overnight fast
      to blood pressure and heart rate measurement, 24 hour ambulatory blood pressure monitoring,
      Doppler heart ultrasound, cardiopulmonary exercise test, resting energy expenditure
      measurement, acute mountain sickness quantification by the Lake Louise Score.

        -  Protocol for blood pressure and heart rate measurement. Blood pressure and heart rate
           were measured according to current European guidelines(Task Force for the Management of
           Arterial Hypertension of the European Society of Hypertension(ESH) and of the European
           Society of Cardiology (ESC). 2007 Guidelines for the Management of Arterial
           Hypertension. J Hypertens 2007; 25:1105-1187.

        -  Protocol for 24 hour ambulatory blood pressure monitoring. Ambulatory blood pressure
           monitoring was performed according to current European guidelines(O'Brien E, et al.
           Practice guidelines of the European Society of Hypertension for clinic, ambulatory and
           self blood pressure measurement. J Hypertens 2005; 23: 1697-701).

        -  Protocol for Doppler heart ultrasound. All echographic-Doppler examinations will be
           performed by the same two operators using a portable device (Vivid I, GE Ultrasound)
           according to current guidelines (Lang RM, et al. Recommendations for chamber
           quantification. Eur J Echocardiogr 2006; 7 : 79-108

        -  Protocol for cardiopulmonary exercise test. Tests will be performed and evaluated
           according to current European Society of Cardiology guidelines (Eur J Cardiovasc Prev
           Rehabil 13:150-164 2006; Eur J Cardiovasc Prev Rehabil 2006; 13:300-311). All tests will
           be performed using the same cyclo-ergometer (Ergometrics 100, Ergoline, Bitz,
           Germany)and metabolic cart (Oxycon Mobile software v. 4.6, VIASYS Healthcare GmbH,
           Wurburg, Germany). The exercise protocol will include 10 minutes of monitored sitting
           rest, followed by 3 minutes of unloaded pedalling and by 30 W load increments every 2
           minutes up to exhaustion. Breath-by-breath ventilation, respiratory gases, one-lead ECG
           and pulse oxymetry (SpO2) will be recorded throughout each test. Arterial blood pressure
           will be measured by a mercury sphygmomanometer in duplicate at the end of the resting
           phase and of each 30 W step, and at peak exercise. Cardiopulmonry exercise tests will be
           blindly and independently evaluated by two expert readers. The anaerobic threshold will
           be identified by the standard technique (Wasserman K. Breathing during exercise. N Engl
           J Med 1978; 298:780-785. VE/VCO2 slope will be calculated as the slope of the linear
           relationship between VE and VCO2 measured up to the respiratory compensation point.

        -  Protocol for resting energy expenditure measurement. The energy expenditure was
           calculated according to the abbreviated formula provided by Weir (Weir JB. New methods
           for calculating metabolic rate with special reference to protein metabolism. J Physiol
           Lond 1949; 55:14-21). O2 consumption and CO2 production (integrated over 1 min) were
           measured for 30 min. Baseline values were calculated by averaging the readings taken
           during the last 10 min.

        -  Protocol for assessment of acute mountain sickness. Acute mountain sickness (AMS) will
           be assessed by means of the Lake Louise AMS Scoring system (Roach RC, Bärtsch P et al.
           The Lake Louise AMS Scoring Consensus Committee. The Lake Louise acute mountain sickness
           scoring system. In: Sutton JR, Houtson CS, Coates G, eds. Hypoxia and Molecular
           Medicine. Burlington, VT: Queen City Printers; 1993:272-274).

        -  Statistical analysis. Data will be reported as means ± SD. Data management and analysis
           will be performed with SPSS version 13.0 (SPSS Inc, Chicago, IL, USA). Differences among
           groups, changes over time within each group (time effect), and any interaction
           (differing trends over time among groups), will be assessed by two-way repeated measures
           ANOVA with unpaired Student's t-test with Bonferroni correction whenever needed. For all
           parameters during cardiopulmonary exercise test, mean values will be computed over 20
           seconds. Spearman correlations will be used to assess the relationship between peak VO2
           and other respiratory and haemodynamic variables at altitude. A P level of < 0.05 was
           considered statistically significant.
    

Intervention name(s): placebo; Carvedilol; Nebivolol
Intervention type(s): Drug; Drug; Drug
Intervention description(s): placebo tablet BID; Carvedilol 25 mg tablets. One tablet twice daily.; nebivolol 5 mg tablets. One nebivolol tablet daily. One placebo tablet daily.
Intervention MeSH terms: Carvedilol; Nebivolol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: hypoxia; autonomic nervous system; blood pressure; heart rate; exercise; heart failure; receptors, adrenergic, beta.