Tadalafil Effects in Left Ventricle Diastolic Dysfunction in Resistant Hypertensive Patients

Phosphodiesterase-5 Inhibitor (Tadalafil) Two Weeks Administration Period Effects in Left Ventricle Diastolic Dysfunction and BNP Levels in Resistant Hypertensive Patients

Left ventricle diastolic dysfunction (LVDD) is associated with resistant hypertension. In addition, brain natriuretic peptide (BNP) levels are elevated when LVDD is present. It has been shown that phosphodiesterase-5 (PDE5) inhibition improves left ventricle diastolic function in hypertensive rats, despite any difference in blood pressure levels. Also, left ventricle diastolic function enhancement reduces BNP concentration in hypertensive patients. However, it is unknown if these effects exists in humans with resistant hypertension. Therefore, this study was developed to evaluate if the use of a PDE5 inhibitor (tadalafil) for 2 weeks improves LVDD and its effects in BNP levels in resistant hypertensive patients.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Other: sugar pill; Drug: Tadalafil

Detailed Description

Resistant hypertensive patients have a high incidence of left ventricle diastolic dysfunction (LVDD). Lowering blood pressure levels improves diastolic function, however, there is no proved effective treatment specifically for this disease. Studies in hypertensive rats have shown presence of phosphodiesterase-5 in cardiac cells and an improvement in left ventricle diastolic function using a phosphodiesterase-5 (PDE5) inhibitor, the sildenafil. PDE5 has also been demonstrated in human heart cells with cardiac disease. In addition, LVDD is associated with high levels of brain natriuretic peptide (BNP), which reduces with diastolic function improvement. Therefore, it is reasonable to suppose that PDE-5 inhibitor use in humans with LVDD and resistant hypertension could improve diastolic function. Objective: Evaluate the chronic effect of a PDE-5 inhibitor on LVDD and BNP levels in resistant hypertensive patients. Casuistic and methods: 20 resistant hypertensive patients with LVDD types I and II will be evaluated with echocardiography study, ambulatory blood pressure monitoring (ABPM), office blood pressure measurements, endothelial function analysis using the brachial artery flow mediation dilation technique (FMD) and BNP plasma levels. Then, the subjects will receive oral placebo for 2 weeks. After this period, the same exams will be repeated. Two weeks later, the protocol will be performed again to the same 20 patients, using tadalafil (the longest half-life PDE-5 inhibitor) 20mg orally instead of the placebo. Hypothesis: investigators hypothesize that the use of tadalafil will improve left ventricle diastolic function with BNP reduced levels and this effect will be independent of blood pressure decrease or endothelial function improvement.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Brazil
  • São Paulo
    • Campinas, São Paulo, Brazil, 13083-970
      • Laboratory of Cardiovascular Pharmacology - FCM - Unicamp

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 33 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• resistant hypertension (according to Resistant Hypertension - American Heart Association Statement - 2008);
• compliance with antihypertensive treatment;
• age >35 years;
• left ventricle diastolic dysfunction types I and II

Exclusion Criteria:

• valvulopathy
• decompensated heart failure
• important cardiac arrhythmias
• nephropathy
• hepatopathy
• autoimmune disease
• tabagism
• decompensated diabetes
• uncontrolled dislipidemia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: sugar pill; Intervention: sugar pill	Other: sugar pill; Sugar pills: 20mg orally, once a day for 2 weeks; Other Names: No brand name.
Active Comparator: tadalafil; Intervention: tadalafil	Drug: Tadalafil; Tadalafil pills: 20mg orally, once a day for 2 weeks.; Other Names: Cialis, Lilly, USA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Left Ventricle Diastolic Dysfunction	Outcome measurement assessed by Echocardiogram before and after a 2-week tadalafil administration period.	Baseline and 2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in endothelial function	Outcome measure assessed by flow-mediated dilation before and after a 2-week tadalafil administration period.	baseline and 2 weeks
Change in blood pressure levels	Blood pressure measurements assessed before and after a 2-week tadalafil administration period.	Baseline and 2 weeks
Change in B-type Natriuretic Peptide (BNP-32) levels	Plasma brain natriuretic peptide (BNP-32)assessed before and after a 2-week tadalafil administration period	Baseline and 2 weeks
Change in cyclic guanosine monophosphate (cGMP) levels	Cyclic guanosine monophosphate (cGMP) levels assessed before and after a 2-week tadalafil administration period	Baseline and 2 weeks
Change in nitrite levels	Nitrite levels assessed before and after a 2-week tadalafil administration period.	Baseline and 2 weeks

Collaborators and Investigators

• Sponsor: University of Campinas, Brazil
• Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo
• Investigators: Principal Investigator: Heitor Moreno-Junior, MD, PhD, Faculty of Medical Sciences - Unicamp

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): April 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: November 30, 2012
• First Submitted That Met QC Criteria: December 4, 2012
• First Posted (Estimate): December 6, 2012

Study Record Updates

• Last Update Posted (Estimate): December 6, 2012
• Last Update Submitted That Met QC Criteria: December 4, 2012
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Keywords: Resistant Hypertension; Tadalafil; Left Ventricle Diastolic Dysfunction; Brain natriuretic peptide
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Tadalafil
• Other Study ID Numbers: CAAE 0044.0.146.000-09; [2009/53430-7] (Other Identifier: FAPESP)