Hypertension Resistant to Conventional Therapy, Myocardial Infarction, Stroke, Systemic Arterial Hypertension
Conditions
Keywords
Systemic arterial hypertension, Hypertension Resistant to Conventional Therapy, Genetic polymorphisms, Renin-angiotensin-aldosterone system genetic polymorphism, Risk markers, Adverse events, Acute myocardial infarction, Stroke
Brief summary
Renin-angiotensin-aldosterone system (RAAS) polymorphisms influence 24h arterial pressure fluctuation. Resistant systemic arterial hypertension (RSAH) has an increased risk of end organ damage and unfavourable prognosis, whereas pseudo-RSAH usually respond favourably to drug therapy. To prospectively investigate, in subjects with RSAH in a tropical South American city: 1) Adverse cardiovascular events defined as fatal and non-fatal stroke or acute myocardial infarction (AMI); and 2) the association of RAAS polymorphisms and adverse cardiovascular events in this population. Study population: 212 hypertensives recruited from primary care assistance (time since first diagnosis of hypertension: 16.5±8.1 years) and without appropriate pressure control, between 2001 and 2006, corresponding to 0.48% of all hypertensives under care (18 new cases/year), 57±10 years old, 66% females. Under drug treatment schedule: three or more drugs including a diuretic. Ninety two randomly selected hypertensives basis had renin-angiotensin-aldosterone system genetic profile determined. Genetic assessment was carried out using a polymerase chain reaction assay amplification technique. The following single nucleotide polymorphisms were analyzed: renin (G1051A), angiotensinogen (M235T), angiotensin converting enzyme-ACE (I/D), angiotensin II type 1 receptor (A1166C), aldosterone synthase (C344T) and mineralocorticoid receptor (G3514C).
Interventions
DRUGAnti-hypertensive drug treatment
Anti-hypertensive drug treatment was non-investigational. Drug regimen, including which drug and the number of drugs prescribed, was left at discretion of the physician who carried primary assistance.
Sponsors
Instituto Nacional de Cardiologia de Laranjeiras
Universidade Gama Filho
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with uncontrolled systemic arterial hypertension despite use of three anti-hypertensive drugs, including one diuretic
Exclusion criteria
* Secondary causes of systemic arterial hypertension
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Strokes, Either Fatal or Nonfatal | up to 10 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Acute Myocardial Infarctions and/or Strokes Either Fatal or Nonfatal | up to 10 years | 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. |
Countries
Brazil
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Resistant Arterial Hypertension 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. | 61 |
| Pseudo-resistant Arterial Hypertension 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. | 31 |
| Total | 92 |
Baseline characteristics
| Characteristic | Resistant Arterial Hypertension | Pseudo-resistant Arterial Hypertension | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 11 Participants | 11 Participants | 22 Participants |
| Age, Categorical Between 18 and 65 years | 50 Participants | 20 Participants | 70 Participants |
| Age Continuous | 52.3 years STANDARD_DEVIATION 9.6 | 56.8 years STANDARD_DEVIATION 9 | 54.4 years STANDARD_DEVIATION 9.4 |
| Anti-hypertensive treatment | 61 participants | 31 participants | 92 participants |
| Region of Enrollment Brazil | 61 participants | 31 participants | 92 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism ACE (I/D) DD | 20 participants | 11 participants | 31 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism ACE (I/D) ID | 29 participants | 13 participants | 42 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism ACE (I/D) II | 12 participants | 7 participants | 19 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism aldosterone synthase (C344T) CC | 24 participants | 9 participants | 33 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism aldosterone synthase (C344T) TC | 30 participants | 15 participants | 45 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism aldosterone synthase (C344T) TT | 7 participants | 7 participants | 14 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism Angiotensin II type 1 receptor (A1166C) AA | 36 participants | 26 participants | 62 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism Angiotensin II type 1 receptor (A1166C) AC | 24 participants | 5 participants | 29 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism Angiotensin II type 1 receptor (A1166C) CC | 1 participants | 0 participants | 1 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism Angiotensinogen (M235T) MM | 12 participants | 10 participants | 22 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism Angiotensinogen (M235T) MT | 25 participants | 15 participants | 40 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism Angiotensinogen (M235T) TT | 24 participants | 6 participants | 30 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism Renin (G1051A) AA | 15 participants | 15 participants | 30 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism Renin (G1051A) GA | 24 participants | 6 participants | 30 participants |
| Renin-Angiotensin-Aldosterone System Polymorphism Renin (G1051A) GG | 22 participants | 10 participants | 32 participants |
| Sex: Female, Male Female | 40 Participants | 20 Participants | 60 Participants |
| Sex: Female, Male Male | 21 Participants | 11 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 62 | 0 / 31 |
| serious Total, serious adverse events | 0 / 62 | 0 / 31 |
Outcome results
Primary
Strokes, Either Fatal or Nonfatal
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Resistant Arterial Hypertension | Strokes, Either Fatal or Nonfatal | 24 participants |
| Pseudo-resistant Arterial Hypertension | Strokes, Either Fatal or Nonfatal | 7 participants |
Comparison: 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 equilibriump-value: 0.1995% CI: [0.7, 4.1]Chi-squared, Corrected
Secondary
Composite of Acute Myocardial Infarctions and/or Strokes Either Fatal or Nonfatal
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Resistant Arterial Hypertension | Composite of Acute Myocardial Infarctions and/or Strokes Either Fatal or Nonfatal | 34 participants |
| Pseudo-resistant Arterial Hypertension | Composite of Acute Myocardial Infarctions and/or Strokes Either Fatal or Nonfatal | 9 participants |
Comparison: 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 equilibriump-value: 0.0195% CI: [1.01, 7.3]Chi-squared, Corrected
Comparison: 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.p-value: 0.0495% CI: [1.1, 4.8]Regression, Cox
Post Hoc
Polygenic Risk Score
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Resistant Arterial Hypertension | Polygenic Risk Score | 0 composite enpoint events |
| Pseudo-resistant Arterial Hypertension | Polygenic Risk Score | 0 composite enpoint events |
| Polygenic Score: Two | Polygenic Risk Score | 1 composite enpoint events |
| Polygenic Score: Three | Polygenic Risk Score | 3 composite enpoint events |
| Polygenic Score: Four | Polygenic Risk Score | 17 composite enpoint events |
| Polygenic Score: Five | Polygenic Risk Score | 10 composite enpoint events |
| Polygenic Score: Six | Polygenic Risk Score | 8 composite enpoint events |
| Polygenic Score: Seven | Polygenic Risk Score | 3 composite enpoint events |
| Polygenic Score: Eight | Polygenic Risk Score | 2 composite enpoint events |
Comparison: Receiver operating characteristic curve analysis for the polygenic score as predictor of composite endpoint (stroke + myocardial infarction)p-value: <0.0195% CI: [0.56, 0.76]z test
Comparison: 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 .p-value: 0.0495% CI: [1.2, 9.2]Regression, Cox