Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu
Trial record 5 of 7 for:    CYP11B2

Renin-angiotensin-aldosterone System Polymorphisms in Resistant Hypertension and Adverse Cardiovascular Events (GENHART)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01173029
Recruitment Status : Completed
First Posted : July 30, 2010
Results First Posted : March 6, 2013
Last Update Posted : April 22, 2013
Sponsor:
Collaborator:
Instituto Nacional de Cardiologia de Laranjeiras
Information provided by (Responsible Party):
Paulo Roberto Benchimol Barbosa, Universidade Gama Filho

Study Type Observational
Study Design Observational Model: Cohort;   Time Perspective: Prospective
Conditions Systemic Arterial Hypertension
Hypertension Resistant to Conventional Therapy
Myocardial Infarction
Stroke
Intervention Drug: Anti-hypertensive drug treatment
Enrollment 92
Recruitment Details Recruitment was carried out in outpatient clinics at Instituto Nacional de Cardiologia.
Pre-assignment Details Participants who have been diagnosed as secondary hypertension were excluded from the trial before assignment to resistant and pseudo-resistant groups.
Arm/Group Title Resistant Arterial Hypertension Pseudo-resistant Arterial Hypertension
Hide Arm/Group Description Subjects with systemic arterial hypertension in whom arterial pressure control was not achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure >/=130 mmHg and mean 24h diastolic pressure >/=80mmHg) by non-investigation specialized hypertensive unit care, in spite of appropriate drug treatment regimen with three or more anti-hypertensive drugs including a diuretic. Subjects with systemic arterial hypertension in whom arterial pressure control was achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure <130 mmHg and mean 24h diastolic pressure <80mmHg) by non-investigation specialized hypertensive unit care, with appropriate drug treatment regimen with three or more anti-hypertensive drugs including a diuretic.
Period Title: Overall Study
Started 61 31
Completed 61 31
Not Completed 0 0
Arm/Group Title Resistant Arterial Hypertension Pseudo-resistant Arterial Hypertension Total
Hide Arm/Group Description Subjects with systemic arterial hypertension in whom arterial pressure control was not achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure >/=130 mmHg and mean 24h diastolic pressure >/=80mmHg) by non-investigation specialized hypertensive unit care, in spite of appropriate drug treatment regimen with three or more anti-hypertensive drugs including a diuretic. Subjects with systemic arterial hypertension in whom arterial pressure control was achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure <130 mmHg and mean 24h diastolic pressure <80mmHg) by non-investigation specialized hypertensive unit care, with appropriate drug treatment regimen with three or more anti-hypertensive drugs including a diuretic. Total of all reporting groups
Overall Number of Baseline Participants 61 31 92
Hide Baseline Analysis Population Description
Subjects referred from primary care with diagnosis of resistant arterial hypertension. Each one had a clinical visit scheduled in the center within one week of referral. All were taking two AH drugs plus diuretic. ABP was measured in seated position, after 5 min of rest. If the highest average of two measures was >140/90mmHg, subject was admitted.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 61 participants 31 participants 92 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
50
  82.0%
20
  64.5%
70
  76.1%
>=65 years
11
  18.0%
11
  35.5%
22
  23.9%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 61 participants 31 participants 92 participants
52.3  (9.6) 56.8  (9.0) 54.4  (9.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 61 participants 31 participants 92 participants
Female
40
  65.6%
20
  64.5%
60
  65.2%
Male
21
  34.4%
11
  35.5%
32
  34.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Brazil Number Analyzed 61 participants 31 participants 92 participants
61 31 92
Renin-Angiotensin-Aldosterone System Polymorphism   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 61 participants 31 participants 92 participants
Renin (G1051A) GG 22 10 32
Renin (G1051A) GA 24 6 30
Renin (G1051A) AA 15 15 30
[1]
Measure Description: Genetic assessment was carried out using polymerase chain reaction assay amplification. The following single nucleotide polymorphisms were analyzed: renin (G1051A), angiotensinogen (M235T), ACE (I/D), angiotensin II type 1 receptor (A1166C), aldosterone synthase (C344T) and mineralocorticoid receptor (G3514C)
Renin-Angiotensin-Aldosterone System Polymorphism   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 61 participants 31 participants 92 participants
ACE (I/D) II 12 7 19
ACE (I/D) ID 29 13 42
ACE (I/D) DD 20 11 31
[1]
Measure Description: Genetic assessment was carried out using polymerase chain reaction assay amplification. The following single nucleotide polymorphisms were analyzed: renin (G1051A), angiotensinogen (M235T), ACE (I/D), angiotensin II type 1 receptor (A1166C), aldosterone synthase (C344T) and mineralocorticoid receptor (G3514C)
Renin-Angiotensin-Aldosterone System Polymorphism   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 61 participants 31 participants 92 participants
Angiotensin II type 1 receptor (A1166C) AA 36 26 62
Angiotensin II type 1 receptor (A1166C) AC 24 5 29
Angiotensin II type 1 receptor (A1166C) CC 1 0 1
[1]
Measure Description: Genetic assessment carried out using polymerase chain reaction assay amplification. The following single nucleotide polymorphisms were analyzed: renin (G1051A), angiotensinogen (M235T), ACE (I/D), angiotensin II type 1 receptor (A1166C), aldosterone synthase (C344T) and mineralocorticoid receptor (G3514C)
Renin-Angiotensin-Aldosterone System Polymorphism   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 61 participants 31 participants 92 participants
aldosterone synthase (C344T) CC 24 9 33
aldosterone synthase (C344T) TC 30 15 45
aldosterone synthase (C344T) TT 7 7 14
[1]
Measure Description: Genetic assessment was carried out using polymerase chain reaction assay amplification. The following single nucleotide polymorphisms were analyzed: renin (G1051A), angiotensinogen (M235T), ACE (I/D), angiotensin II type 1 receptor (A1166C), aldosterone synthase (C344T) and mineralocorticoid receptor (G3514C).
Renin-Angiotensin-Aldosterone System Polymorphism   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 61 participants 31 participants 92 participants
Angiotensinogen (M235T) TT 24 6 30
Angiotensinogen (M235T) MT 25 15 40
Angiotensinogen (M235T) MM 12 10 22
[1]
Measure Description: Genetic assessment was carried out using polymerase chain reaction assay amplification. The following single nucleotide polymorphisms were analyzed: renin (G1051A), angiotensinogen (M235T), ACE (I/D), angiotensin II type 1 receptor (A1166C), aldosterone synthase (C344T) and mineralocorticoid receptor (G3514C)
Anti-hypertensive treatment   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 61 participants 31 participants 92 participants
61 31 92
[1]
Measure Description: Anti-hypertensive treatment, including regimen, drug and the number of drugs prescribed, was left at discrtion of the physician who carried primary assiatnce.
1.Primary Outcome
Title Strokes, Either Fatal or Nonfatal
Hide Description

Evidence of clinically definite stroke (focal neurological deficits persisting for more than 24 hours) confirmed or not by non-investigational computerized tomography.

Death was considered to be related to the event if occurring up to 30 days after the acute event.

Assessment twice an year by active and direct contact to patients or relatives and review of medical records.

Time Frame up to 10 years
Hide Outcome Measure Data
Hide Analysis Population Description

Number of participants was based on input demand at outpatient clinics. Those who provided provided consent for genetic testing were included.

A post-hoc sampling procedure (power calculation) validated sample size.

Arm/Group Title Resistant Arterial Hypertension Pseudo-resistant Arterial Hypertension
Hide Arm/Group Description:
Subjects with systemic arterial hypertension in whom arterial pressure control was not achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure >/=130 mmHg and mean 24h diastolic pressure >/=80mmHg) by non-investigation specialized hypertensive unit care, in spite of appropriate drug treatment regimen with three or more anti-hypertensive drugs including a diuretic.
Subjects with systemic arterial hypertension in whom arterial pressure control was achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure <130 mmHg and mean 24h diastolic pressure <80mmHg) by non-investigation specialized hypertensive unit care, with appropriate drug treatment regimen with three or more anti-hypertensive drugs including a diuretic.
Overall Number of Participants Analyzed 61 31
Measure Type: Number
Unit of Measure: participants
24 7
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Resistant Arterial Hypertension, Pseudo-resistant Arterial Hypertension
Comments

Long-term intention-to-treat data analysis:

Student 't' tests Yates's corrected Chi-squared or Fisher's exact test, when appropriate Relative risk estimation Cox proportional-hazard model Hardy-Weinberg equilibrium

Type of Statistical Test Non-Inferiority or Equivalence
Comments Study power calculation was post-hoc based on composite end-point achieved. Number of exposed: 62 Non-exposed to exposed ratio: 0.5 Relative risk worth detecting: 2.5 Attack rate among non-exposed: 23% Alpha risk: 0.05 Calculated power: 89.8%
Statistical Test of Hypothesis P-Value 0.19
Comments not adjusted
Method Chi-squared, Corrected
Comments 1 degree-of-freedom
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.7
Confidence Interval (2-Sided) 95%
0.7 to 4.1
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Composite of Acute Myocardial Infarctions and/or Strokes Either Fatal or Nonfatal
Hide Description

Evidence of clinically definite stroke (focal neurological deficits persisting for more than 24 hours) confirmed or not by non-investigational computerized tomography.

Evidence of clinically definite acute myocardial infarction (prolonged > 20min chest pain, not relieved by sublingual nitrate, ST-T segment deviation on 12-lead surface ECG, elevation of plasma troponin >0.2 ng/dL 6h following chest pain episode).

Death was considered to be related to the event if occurring up to 30 days after the acute event.

Assessment twice an year by active and direct contact to patients or relatives and review of medical records.

Time Frame up to 10 years
Hide Outcome Measure Data
Hide Analysis Population Description

Number of participants was based on input demand at outpatient clinics. Those who provided provided consent for genetic testing were included.

A post-hoc sampling procedure (power calculation) validated sample size.

Arm/Group Title Resistant Arterial Hypertension Pseudo-resistant Arterial Hypertension
Hide Arm/Group Description:
Subjects with systemic arterial hypertension in whom arterial pressure control was not achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure >/=130 mmHg and mean 24h diastolic pressure >/=80mmHg) by non-investigation specialized hypertensive unit care, in spite of appropriate drug treatment regimen with three or more anti-hypertensive drugs including a diuretic.
Subjects with systemic arterial hypertension in whom arterial pressure control was achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure <130 mmHg and mean 24h diastolic pressure <80mmHg) by non-investigation specialized hypertensive unit care, with appropriate drug treatment regimen with three or more anti-hypertensive drugs including a diuretic.
Overall Number of Participants Analyzed 61 31
Measure Type: Number
Unit of Measure: participants
34 9
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Resistant Arterial Hypertension, Pseudo-resistant Arterial Hypertension
Comments

Long-term intention-to-treat data analysis:

Student 't' test Yates' corrected Chi-squared or Fisher's exact test Relative risk estimation Cox proportional-hazard model Hardy-Weinberg equilibrium

Type of Statistical Test Non-Inferiority or Equivalence
Comments Study power calculation was post-hoc based on composite end-point achieved. Number of exposed: 62 Non-exposed to exposed ratio: 0.5 Relative risk worth detecting: 2.5 Attack rate among non-exposed: 23% Alpha risk: 0.05 Calculated power: 89.8%
Statistical Test of Hypothesis P-Value 0.01
Comments not adjusted
Method Chi-squared, Corrected
Comments 1 degree-of-freedom
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 2.6
Confidence Interval (2-Sided) 95%
1.01 to 7.3
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Resistant Arterial Hypertension, Pseudo-resistant Arterial Hypertension
Comments Cox proportional hazard model for the composite endpoint (stroke + myocardial infarction) was assessed. By taking pseudo-resistant arterial hypertension as baseline reference, the hazard ratio for the composite endpoint was calculated.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Proportional-risk hypothesis was tested using the correlation between Schoenfeld's residuals and time (Schoenfeld's global test). The correlation rho was -0.08, Chi-squared was 0.12, and p was 0.73. Therefore, the hypothesis of proportional risk was accepted, validating the correct application model.
Statistical Test of Hypothesis P-Value 0.04
Comments The p-value was adjusted for confounders: Framingham risk score, body mass index, ethnic groups
Method Regression, Cox
Comments The actuarial function of events per time since the first diagnosis of arterial hypertension was plotted for both groups.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 2.2
Confidence Interval (2-Sided) 95%
1.1 to 4.8
Estimation Comments [Not Specified]
3.Post-Hoc Outcome
Title Polygenic Risk Score
Hide Description

Among all analyzed, four renin-angiotensin-aldosterone polymorphisms had statistical significance relating to composite endpoint.

They were: Angiotensinogen, renin, angiotensin II type 1 receptor and aldosterone synthase. Each polymorphism was arbitrarily weighted according to respective presentation in both alleles as follows: zero (low risk homozygosis), one (heterozygosis) and two (high risk homozygosis). In a following step, they were summed up for each subject, thus, creating a polygenic risk score.

The weights of the polymorphisms were, thus, defined:

  1. Angiotensinogen: MM - zero, MT - one, TT - two
  2. Renin: AA - zero, GA - one, GG - two
  3. Angiotensin II type 1 receptor: CC - zero, AC - one, AA - two
  4. Aldosterone synthase: CC - zero, TC - one, TT - two

The polygenic risk score value ranges from zero (all low risk polymorphisms in homozygosis) to eight (all high risk polymorphisms in homozygosis).

Time Frame up to 10 years
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects in both resistant systemic arterial hypertension and pseudo-resistant systemic arterial hypertension groups had their respective genetic background scored according to present rule.
Arm/Group Title Polygenic Score: Zero Polygenic Score: One Polygenic Score: Two Polygenic Score: Three Polygenic Score: Four Polygenic Score: Five Polygenic Score: Six Polygenic Score: Seven Polygenic Score: Eight
Hide Arm/Group Description:
Sum of the weights for analyzing polymorphisms equal to zero.
Sum of the weights for analyzing polymorphisms equal to one.
Sum of the weights for analyzing polymorphisms equal to two.
Sum of the weights for analyzing polymorphisms equal to three.
Sum of the weights for analyzing polymorphisms equal to four.
Sum of the weights for analyzing polymorphisms equal to five.
Sum of the weights for analyzing polymorphisms equal to six.
Sum of the weights for analyzing polymorphisms equal to seven.
Sum of the weights for analyzing polymorphisms equal to eight.
Overall Number of Participants Analyzed 1 1 7 14 28 21 14 5 2
Measure Type: Number
Unit of Measure: composite enpoint events
0 0 1 3 17 10 8 3 2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Polygenic Score: Zero, Polygenic Score: One, Polygenic Score: Two, Polygenic Score: Three, Polygenic Score: Four, Polygenic Score: Five, Polygenic Score: Six, Polygenic Score: Seven, Polygenic Score: Eight
Comments Receiver operating characteristic curve analysis for the polygenic score as predictor of composite endpoint (stroke + myocardial infarction)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.01
Comments At an optimal value of >3, polygenic risk score yielded 90% sensitivity and 40% specificity for composite endpoint.
Method z test
Comments Area under receiver operating characteristic curve.
Method of Estimation Estimation Parameter C-statistic
Estimated Value 0.66
Confidence Interval (2-Sided) 95%
0.56 to 0.76
Estimation Comments The optimal cutoff value for polygenic risk score was set to >3.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Polygenic Score: Zero, Polygenic Score: One, Polygenic Score: Two, Polygenic Score: Three, Polygenic Score: Four, Polygenic Score: Five, Polygenic Score: Six, Polygenic Score: Seven, Polygenic Score: Eight
Comments Cox proportional hazard model of the polygenic risk score<=3 and > 3 for the composite endpoint (stroke + myocardial infarction). By taking polygenic risk score<=3, the hazard ratio for the composite endpoint was calculated for polygenic risk score>3 .
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.04
Comments The p-value was adjusted for confounders: Framingham risk score, body mass index, ethnic group
Method Regression, Cox
Comments The actuarial function of events per time since the first diagnosis of arterial hypertension was plotted for polygenic risk score<=3 and >3.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 2.9
Confidence Interval (2-Sided) 95%
1.2 to 9.2
Estimation Comments [Not Specified]
Time Frame Adverse events data were collected every 1 year. Study subjects were actively contacted either by telephone or by visit to their home places.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Resistant Arterial Hypertension Pseudo-resistant Arterial Hypertension
Hide Arm/Group Description Subjects with systemic arterial hypertension in whom arterial pressure control was not achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure >/=130 mmHg and mean 24h diastolic pressure >/=80mmHg) by non-investigation specialized hypertensive unit care, in spite of appropriate drug treatment regimen with three or more anti-hypertensive drugs including a diuretic. Subjects with systemic arterial hypertension in whom arterial pressure control was achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure <130 mmHg and mean 24h diastolic pressure <80mmHg) by non-investigation specialized hypertensive unit care, with appropriate drug treatment regimen with three or more anti-hypertensive drugs including a diuretic.
All-Cause Mortality
Resistant Arterial Hypertension Pseudo-resistant Arterial Hypertension
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Resistant Arterial Hypertension Pseudo-resistant Arterial Hypertension
Affected / at Risk (%) Affected / at Risk (%)
Total   0/62 (0.00%)   0/31 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Resistant Arterial Hypertension Pseudo-resistant Arterial Hypertension
Affected / at Risk (%) Affected / at Risk (%)
Total   0/62 (0.00%)   0/31 (0.00%) 
Drugs prescribed were at the discretion of attending physician. The impact of anti-hypertensive drugs on the outcomes was not assessed.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Paulo Robeto Benchimol Barbosa
Organization: Universidade Gama Filho
Phone: +55-21-95320182
EMail: ecgar@yahoo.com
Publications of Results:
Benchimol Barbosa PR, Silva PC, Cordovil I, Barbosa-Filho J. Renin-angiotensin-aldosterone system polymorphisms in resistant hypertension and adverse cardiovascular events: GENHART-RIO Study. Eur Heart J 2010;31(suppl 1):243-243.
Benchimol-Barbosa PR, Silva PC, Cordovil I, Barbosa-Filho J. Renin-angiotensin-aldosterone system polymorphisms in resistant arterial hypertension: a genetic risk score for adverse cardiovascular events - GENHART-RIO study. Eur Heart J (2011) 32 (suppl 1): 103-103.
Campos PS, Benchimol-Barbosa PR, Cordovil I, Gomes-Filho JB, Tura BR. Polimorfismos do sistema renina-angiotensina-aldosterona na hipertensão arterial resistente e desfechos cardiovasculares adversos: Estudo GENHART-RIO. Arq Bras Cardiol; 2010. 95(3 supl. 1): 59-59
Campos FV, Benchimol-Barbosa PR, Vilela FD, Miranda CS, Gobbi GN, Barbosa-Filho J, Gondar AF, Barros MV, Lima AB, Cordovil I. Evaluation on the risk of target organ damage based on the genetic profile of AGT 235MT, mineralocorticoid receptor GCC5GG4C and ACE I/D in subjects with resistant hypertension. Circulation. 2008; 118:e223-e223.
Vilela FD, Benchimol-Barbosa PR, Zeno CC, Lima AB, Barros M, Campos FV, Miranda CS, Gobbi GN, Barbosa-Filho J, Cordovil I. The resistant hypertension genotypes of the population resident in Rio de Janeiro. Circulation. 2008; 118:e356-e357.
Benchimol-Barbosa PR, Varanda-Rosario AD, Rollin-Ornelas M, Vilela FD, Miranda CS, Gobbi GN, Barbosa-Filho J, Cordovil I. Aldosterone synthase C344T polymorphisms determine circadian arterial blood pressure variation in resistant systemic arterial hypertension. Circulation. 2008; 118:e398-e398.
Layout table for additonal information
Responsible Party: Paulo Roberto Benchimol Barbosa, Universidade Gama Filho
ClinicalTrials.gov Identifier: NCT01173029     History of Changes
Other Study ID Numbers: 0204/21.07.08
First Submitted: July 29, 2010
First Posted: July 30, 2010
Results First Submitted: April 21, 2011
Results First Posted: March 6, 2013
Last Update Posted: April 22, 2013