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The Cochrane Database of Systematic... Apr 2017Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. Renin is the enzyme responsible for converting angiotensinogen to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors are a new class of drugs that decrease blood pressure (BP) by preventing the formation of both angiotensin I and angiotensin II.
OBJECTIVES
To quantify the dose-related BP lowering efficacy of renin inhibitors compared to placebo in the treatment of primary hypertension.To determine the change in BP variability, pulse pressure, and heart rate and to evaluate adverse events (mortality, non-fatal serious adverse events, total adverse events, withdrawal due to adverse effects and specific adverse events such as dry cough, diarrhoea and angioedema).
SEARCH METHODS
The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to February 2017: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. There was no restriction by language or publication status. We also searched the European Medicines Agency (EMA) for clinical study reports, the Novartis Clinical Study Results Database, bibliographic citations from retrieved references, and contacted authors of relevant papers regarding further published and unpublished work.
SELECTION CRITERIA
We included randomized, double-blinded, placebo-controlled studies evaluating BP lowering efficacy of fixed-dose monotherapy with renin inhibitor compared with placebo for a minimum duration of three to 12 weeks in adult patients with primary hypertension.
DATA COLLECTION AND ANALYSIS
This systematic review is a comprehensive update which includes four additional studies and extensive detail from nine clinical study reports (CSRs) of previously included studies obtained from EMA. The remaining three CSRs are not available.Two review authors independently assessed study eligibility and extracted data. In all cases where there was a difference between the CSR and the published report, data from the CSR was used. Dichotomous outcomes were reported as risk ratio (RR) with 95% confidence intervals (CIs) and continuous outcomes as mean difference (MD) with 95% CIs.
MAIN RESULTS
12 studies (mean duration of eight weeks) in 7439 mostly Caucasian patients (mean age 54 years) with mild-to-moderate uncomplicated hypertension were eligible for inclusion in the review. Aliskiren was the only renin inhibitor evaluated. All included studies were assessed to have high likelihood of attrition, reporting and funding bias.Aliskiren has a dose-related systolic/diastolic blood pressure (SBP/DBP) lowering effect as compared with placebo MD with 95% CI: aliskiren 75 mg (MD -2.97, 95% CI -4.76 to -1.18)/(MD -2.05, 95% CI -3.13 to -0.96) mm Hg (moderate-quality evidence), aliskiren 150 mg (MD -5.95, 95% CI -6.85 to -5.06)/ (MD -3.16, 95% CI -3.74 to -2.58) mm Hg (moderate-quality evidence), aliskiren 300 mg (MD -7.88, 95% CI -8.94 to -6.82)/ (MD -4.49, 95% CI -5.17 to -3.82) mm Hg (moderate-quality evidence), aliskiren 600 mg (MD -11.35, 95% CI -14.43 to -8.27)/ (MD -5.86, 95% CI -7.73 to -3.99) mm Hg (low-quality evidence). There was a dose-dependent decrease in blood pressure for aliskiren 75 mg, 150 mg and 300 mg. The blood pressure lowering effect of aliskiren 600 mg was not different from 300 mg (MD -0.61, 95% CI -2.78 to 1.56)/(MD -0.68, 95% CI -2.03 to 0.67). Aliskiren had no effect on blood pressure variability. Due to very limited information available regarding change in heart rate and pulse pressure, it was not possible to meta-analyze these outcomes.Mortality and non-fatal serious adverse events were not increased. This review found that in studies of eight week duration aliskiren may not increase withdrawal due to adverse events (low-quality evidence). Diarrhoea was increased in a dose-dependent manner (RR 7.00, 95% CI 2.48 to 19.72) with aliskiren 600 mg (low-quality evidence). The most frequent adverse events reported were headache, nasopharyngitis, diarrhoea, dizziness and fatigue.
AUTHORS' CONCLUSIONS
Compared to placebo, aliskiren lowered BP and this effect is dose-dependent. This magnitude of BP lowering effect is similar to that for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). There is no difference in mortality, nonfatal serious adverse events or withdrawal due to adverse effects with short term aliskiren monotherapy. Diarrhoea was considerably increased with aliskiren 600 mg.
Topics: Amides; Antihypertensive Agents; Blood Pressure; Diarrhea; Fumarates; Humans; Middle Aged; Randomized Controlled Trials as Topic; Renin
PubMed: 28379619
DOI: 10.1002/14651858.CD007066.pub3 -
Journal of Human Hypertension Aug 2016This systematic review investigates the high level of hypertension found among urban dwellers in West Africa and in the West African Diaspora in the Americas in relation... (Meta-Analysis)
Meta-Analysis Review
This systematic review investigates the high level of hypertension found among urban dwellers in West Africa and in the West African Diaspora in the Americas in relation to variants within the genes encoding the renin angiotensinogen system. For comparison, the results from the Caucasian populations are reviewed as well. Through a PubMed search, 1252 articles were identified and 28 eligible articles assessed in detail of which 13 included a Caucasian population. The results suggest that among the people of West African descent and among the people of Caucasian descent, hypertension is partly related to a number of single nucleotide polymorphisms (SNPs) and haplotypes in the renin gene, the angiotensinogen gene, the angiotensinogen I-converting enzyme gene and the angiotensinogen II type 1 receptor gene. Concordance between these two populations was found for some SNPs. However, for others, it was found that the SNPs associating with hypertension and the disease allele frequencies differed between these populations. Understanding the importance of these variants in a modern life setting may assist our understanding of the increased risk of developing hypertension among West Africans. Because of inconsistency in the results, low statistical power and methodological differences between studies, these results can only be taken as indicative of an association.
Topics: Africa, Western; Black People; Essential Hypertension; Gene Frequency; Genetic Predisposition to Disease; Humans; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Renin-Angiotensin System; Risk Assessment; Risk Factors
PubMed: 26607294
DOI: 10.1038/jhh.2015.114 -
Journal of Science and Medicine in Sport May 2016To meta-analyze candidate gene association studies on the change in blood pressure beyond the immediate post-exercise phase after versus before aerobic exercise. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To meta-analyze candidate gene association studies on the change in blood pressure beyond the immediate post-exercise phase after versus before aerobic exercise.
DESIGN
Meta-analysis.
METHODS
A systematic search was conducted. Studies retrieved included acute (short-term or postexercise hypotension) or chronic (long-term or training) aerobic exercise interventions; and blood pressure measured before and after aerobic exercise training, or before and after exercise or control under ambulatory conditions by genotype. Effect sizes were determined for genotype and adjusted for sample features.
RESULTS
Qualifying studies (k=17, n=3524) on average included middle-aged, overweight men (44.2%) and women (55.8%) with prehypertension (134.9±11.7/78.6±9.5mmHg). Training interventions (k=12) were performed at 60.4±12.9% of maximum oxygen consumption (VO2max) for 41.9±12.5minsession(-1), 3.6±1.2daysweek(-1) for 15.7±7.6week; and post-exercise hypotension interventions (k=5) were performed at 53.5±14.4% VO2max for 38.5±5.4minsession(-1). Sample characteristics explained 54.2-59.0% of the variability in the blood pressure change after versus before acute exercise or control under ambulatory conditions, and 57.4-67.1% of the variability in the blood pressure change after versus before training (p<0.001). Only angiotensinogen M235T (rs699) associated with the change in diastolic blood pressure after versus before training (R(2)=0.1%, p=0.05), but this association did not remain statistically significant after adjustment for multiple comparisons.
CONCLUSIONS
Sample characteristics explained most of the variability in the change of BP beyond the immediate post-exercise phase after versus before acute and chronic aerobic exercise. Angiotensinogen M235T (rs699) was the only genetic variant that associated with the change in diastolic blood pressure after versus before training, accounting for <1% of the variance.
Topics: Adult; Blood Pressure; Exercise; Female; Humans; Male; Middle Aged; Regression Analysis
PubMed: 26122461
DOI: 10.1016/j.jsams.2015.05.009 -
Journal of Research in Medical Sciences... Nov 2014The renin angiotensin aldosterone system (RAAS) plays a vital role in regulating glucose metabolism and blood pressure, electrolyte and fluid homeostasis. The aim of... (Review)
Review
BACKGROUND
The renin angiotensin aldosterone system (RAAS) plays a vital role in regulating glucose metabolism and blood pressure, electrolyte and fluid homeostasis. The aim of this systematic review is to assess the association of the RAAS genes with diabetes mellitus (DM) and its complications of retinopathy, neuropathy and cardiovascular disease (CVD).
MATERIALS AND METHODS
The relevant English-language studies were identified using the key words of DM, type 1 diabetes mellitus (T1DM), T2DM, renin angiotensin aldosterone polymorphisms or genotypes and RAAS from the search engines of MEDLINE/PubMed, and Scopus from January 1, 1995 to July 30, 2014. Inclusion criteria for selecting relevant studies were reporting the role of RAAS gene variants in the pathogenesis of T1DM or T2DM, diabetic retinopathy (DR), diabetic neuropathy and cardiovascular complication of DM.
RESULTS
The reviewers identified 204 studies of which 73 were eligible for inclusion in the present systematic review. The review indicates the angiotensinogen (AGT) M235T polymorphism might not affect the risk of DM. The role of angiotensin converting enzyme insertion/deletion (ACE I/D) and angiotensin II type 1 receptor gene (AT1R) A1166C polymorphisms in the pathogenesis of DM could not be established. Studies indicate the absence of an association between three polymorphisms of AGT M235T, ACE I/D and AT1R A1166C and DR in DM patients. A protective role for ACE II genotype against diabetic peripheral neuropathy has been suggested. Also, the ACE I/D polymorphism might be associated with the risk of CVD in DM patients.
CONCLUSION
More studies with adequate sample size that investigate the influence of all RAAS gene variants together on the risk of DM and its complications are necessary to provide a more clear picture of the RAAS genes polymorphisms involvement in the pathogenesis of DM and its complications.
PubMed: 25657757
DOI: No ID Found -
Progres En Urologie : Journal de... Feb 2014A controversy animates the literature on the potential role of the renin-angiotensin system (RAS) in tumorogenesis. The objective of this review was to determine the... (Review)
Review
INTRODUCTION
A controversy animates the literature on the potential role of the renin-angiotensin system (RAS) in tumorogenesis. The objective of this review was to determine the involvement of this pathway in cancer, and more specifically in urological cancers.
MATERIAL AND METHOD
We made a systematic review of articles referenced in Pubmed, using the following keywords alone or combined: cancer, renin, angiotensin, VEGF, AT1R, antagonists of angiotensin-2 receptors, inhibitors of angiotensinogen converting.
RESULTS
Many types of cancers overexpress AT1-R in their tumoral tissues (breast, stomach, bladder, astrocytoma, glioblastoma, ovary, uterus, pancreas, kidney, prostate, adrenal gland). Ang-II can induce VEGF-A expression and promote neoangiogenesis, but also can trigger different molecular pathways involved in cell proliferation or inhibit apoptosis. Several xenograft murin models demonstrated anti-tumoral efficacy of RAS blockers, alone or using combined therapies, targeting angiogenesis and slowing down tumor growth. Retrospective studies in patients have also revealed a better progression-free survival and a better response to therapies in those treated with RAS blockers.
CONCLUSION
Many data seem to demonstrate the involvement of the RAS in carcinogenesis, as well as anti-tumoral effect of RAS blockers in addition to anti-cancer treatments. Clinical data are now expected to confirm these experimental findings.
Topics: Humans; Renin-Angiotensin System; Urologic Neoplasms
PubMed: 24485075
DOI: 10.1016/j.purol.2013.09.010 -
Stroke Jun 2009White matter hyperintensities (WMH) are highly heritable and associated with small artery ischemic stroke, so they may be a useful trait for studying the genetics of... (Review)
Review
BACKGROUND AND PURPOSE
White matter hyperintensities (WMH) are highly heritable and associated with small artery ischemic stroke, so they may be a useful trait for studying the genetics of small vessel disease. Many studies have attempted to find associations between polymorphisms in various candidate genes and WMH. We aimed to evaluate the evidence for these associations by performing a systematic review and series of meta-analyses.
METHODS
We used a comprehensive search strategy to identify studies of the association between any genetic polymorphism and WMH. For all polymorphisms in genes studied in >2000 subjects we performed meta-analyses, calculating pooled odds ratios or standardized mean differences.
RESULTS
We identified 46 studies of polymorphisms in 19 genes in approximately 19 000 subjects. Most genes were involved in lipid metabolism, control of vascular tone, or blood pressure regulation. Polymorphisms in the apolipoprotein E, angiotensin-converting enzyme, methylenetetrahydrofolate reductase, and angiotensinogen genes had been studied in >2000 subjects and were evaluated by meta-analysis. There was no evidence for an association between apolipoprotein E (epsilon 4+/-), methylenetetrahydrofolate reductase (677 cytosine/thymine polymorphism [C/T]), or angiotensinogen (Met235Thr) and WMH. For the angiotensin-converting enzyme insertion/deletion polymorphism (I/D) there appeared to be a significant association (OR, 1.95; 95% CI, 1.09-3.48), but this may be partly attributable to the small study (mainly publication) and other biases.
CONCLUSIONS
No genetic polymorphism has yet shown convincing evidence for an association with WMH. Much larger studies will be needed to detect and confirm genetic associations with this promising trait in the era of genome-wide association studies.
Topics: Apolipoproteins E; Brain; Brain Ischemia; Gene Frequency; Genotype; Humans; Methylenetetrahydrofolate Reductase (NADPH2); O(6)-Methylguanine-DNA Methyltransferase; Odds Ratio; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Stroke
PubMed: 19407234
DOI: 10.1161/STROKEAHA.108.542050 -
The Cochrane Database of Systematic... Oct 2008Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. The renin-angiotensin-aldosterone system is an important target site... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. The renin-angiotensin-aldosterone system is an important target site for five antihypertensive drug classes: beta blockers, renin inhibitors, ACE inhibitors, angiotensin receptor blockers (ARBs) and aldosterone inhibitors. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors prevent the formation of both angiotensin I and angiotensin II . Renin inhibitors do not affect kinin metabolism and may produce fewer adverse effects than ACE inhibitors such as dry cough or angioedema.
OBJECTIVES
To quantify the dose-related blood pressure lowering efficacy of renin inhibitors versus placebo in the treatment of primary hypertension.
SEARCH STRATEGY
We searched the following databases for randomised, double blind, placebo-controlled trials of renin inhibitors: Medline (1966-March 2008), EMBASE (1988-March 2008), Cochrane CENTRAL, and bibliographic citations from retrieved references. No language restrictions were applied.
SELECTION CRITERIA
Study design had to meet the following criteria: double-blinded, placebo-controlled; random allocation to a specific dose of renin inhibitor group and parallel placebo group; duration of follow-up of at least three weeks.
DATA COLLECTION AND ANALYSIS
Two reviewers independently extracted data and assessed trial quality using risk of bias tables. Disagreements were resolved by discussion or a third reviewer. Data synthesis and analyses were done using the Cochrane Review Manager software, RevMan 5. Data for continuous variables were combined using a weighted mean difference method. Dichotomous variables were analysed using relative risk.
MAIN RESULTS
Six trials (N=3694) met the inclusion criteria for this review. Aliskiren was the only renin inhibitor studied in these studies. The meta-analysis shows that aliskiren has a dose-related both systolic/diastolic blood pressure lowering effect as compared to placebo: aliskiren 75 mg -2.9/-2.3 mmHg, aliskiren 150 mg -5.5/-3.0 mmHg, aliskiren 300 mg -8.7/-5.0, aliskiren 600 mg -11.4/-6.6 mmHg. Aliskiren 300 mg significantly lowered both SBP and DBP as compared to aliskiren 150 mg (SBP:-2.97 (95% CI -3.99, -1.95) and DBP: -1.66 (95% CI -2.32, -1.0). Aliskiren has no effect on blood pressure variability. No data was available to assess the effect of aliskiren on heart rate and pulse pressure. This review found weak evidence that with short- term use, aliskiren does not increase withdrawals due to adverse effects as compared to placebo.
AUTHORS' CONCLUSIONS
Aliskiren has a dose-related blood pressure lowering effect better than placebo. This effect is similar to that determined for ACE inhibitors and ARBs.
Topics: Amides; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Randomized Controlled Trials as Topic; Renin
PubMed: 18843743
DOI: 10.1002/14651858.CD007066.pub2 -
PloS One Jun 2008The M235T polymorphism in the AGT gene has been related to an increased risk of hypertension. This finding may also suggest an increased risk of coronary heart disease... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The M235T polymorphism in the AGT gene has been related to an increased risk of hypertension. This finding may also suggest an increased risk of coronary heart disease (CHD).
METHODOLOGY/PRINCIPAL FINDINGS
A case-cohort study was conducted in 1,732 unrelated middle-age women (210 CHD cases and 1,522 controls) from a prospective cohort of 15,236 initially healthy Dutch women. We applied a Cox proportional hazards model to study the association of the polymorphism with acute myocardial infarction (AMI) (n = 71) and CHD. In the case-cohort study, no increased risk for CHD was found under the additive genetic model (hazard ratio [HR] = 1.20; 95% confidence interval [CI], 0.86 to 1.68; P = 0.28). This result was not changed by adjustment (HR = 1.17; 95% CI, 0.83 to 1.64; P = 0.38) nor by using dominant, recessive and pairwise genetic models. Analyses for AMI risk under the additive genetic model also did not show any statistically significant association (crude HR = 1.14; 95% CI, 0.93 to 1.39; P = 0.20). To evaluate the association, a comprehensive systematic review and meta-analysis were undertaken of all studies published up to February 2007 (searched through PubMed/MEDLINE, Web of Science and EMBASE). The meta-analysis (38 studies with 13284 cases and 18722 controls) showed a per-allele odds ratio (OR) of 1.08 (95% CI, 1.01 to 1.15; P = 0.02). Moderate to large levels of heterogeneity were identified between studies. Hardy-Weinberg equilibrium (HWE) violation and the mean age of cases were statistically significant sources of the observed variation. In a stratum of non-HWE violation studies, there was no effect. An asymmetric funnel plot, the Egger's test (P = 0.066), and the Begg-Mazumdar test (P = 0.074) were all suggestive of the presence of publication bias.
CONCLUSIONS/SIGNIFICANCE
The pooled OR of the present meta-analysis, including our own data, presented evidence that there is an increase in the risk of CHD conferred by the M235T variant of the AGT gene. However, the relevance of this weakly positive overall association remains uncertain because it may be due to various residual biases, including HWE-violation and publication biases.
Topics: Angiotensinogen; Case-Control Studies; Cohort Studies; Coronary Disease; Female; Genetic Predisposition to Disease; Humans; Middle Aged; Polymorphism, Genetic; Proportional Hazards Models; Risk Factors
PubMed: 18575631
DOI: 10.1371/journal.pone.0002533 -
Journal of Hypertension Jul 2004To assess the role of genetic polymorphisms in salt sensitivity of blood pressure. (Review)
Review
PURPOSE
To assess the role of genetic polymorphisms in salt sensitivity of blood pressure.
DATA IDENTIFICATION
We conducted a systematic review by searching the Medline literature from March 1993 to June 2003. Each paper was scrutinized and data concerning study population, method of salt sensitivity testing, blood pressure measurement, definition of salt sensitivity, and effects were extracted.
STUDY SELECTION AND DATA EXTRACTION
A total of 23 studies met the inclusion criteria. There was considerable heterogeneity in the method of salt sensitivity testing among the studies. Due to these differences, it was impossible to perform pooled analyses by genetic variants. Detailed investigation was done on the alpha-adducin Gly460Trp, ACE I/D, angiotensinogen M235T, G protein beta 3 C825T, aldosterone synthase gene and 11 beta-hydroxysteroid dehydrogenase type 2 G534A polymorphism.
RESULTS AND CONCLUSIONS
Our analysis shows that the 460Trp variant of the alpha-adducin polymorphism is probably associated with a sodium-sensitive form of hypertension, while the polymorphisms of the angiotensin II type 1 receptor gene and the -344C/T variant of the aldosterone synthase gene are not associated with this phenotype. In view of the lack of standardization in salt sensitivity testing, we propose uniformity in study design in these type of studies.
Topics: Genetic Predisposition to Disease; Humans; Hypertension; Polymorphism, Genetic; Sodium Chloride
PubMed: 15201536
DOI: 10.1097/01.hjh.0000125443.28861.0d -
Journal of Cardiovascular Risk 1997Variants of the human genes coding for renin, angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and the angiotensin II type-I receptor (AT1R) are inconsistently... (Review)
Review
BACKGROUND
Variants of the human genes coding for renin, angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and the angiotensin II type-I receptor (AT1R) are inconsistently associated with cardiovascular-renal disease, possibly because of genetic differences in the background populations.
METHODS
This systematic review of the literature investigated genetic variation in the renin system according to race, sex and age. Across studies with relevant information, multivariate analyses also accounted for the methods of genotyping and the enrollment of subjects as controls, cases or groups studied cross-sectionally.
RESULTS
The 185 reviewed reports included 64978 subjects. In five studies (n=989) on the renin gene, the Hind III and Taq I polymorphisms varied with the groups' average age, whereas the Bg I, Bg II and Hind III but not Taq I sites differed according to race. Among 135 studies (n=44697) on the deletion/insertion (D/I) polymorphism of the ACE gene, the frequency of the D allele was 54.0%. Its prevalence was not related to sex and black race, was 49.9% lower in Asians, 10.0% lower in studies relying on I-specific primers, 4.9% higher for each 25-year increment in the average age of the groups studied, and 16.7% higher in cases than controls. Among 12 studies (n=4952) on the T174-->M variant of the AGT gene, the M174 frequency was 11.0%, did not vary according to sex and enrollment group, was 56.7% lower in blacks and 39.5% lower for each 25-year increase in the groups' mean age. Across 44 studies (n=16713) on the M235-->T substitution in the AGT gene, the T235 prevalence was 51.6%. Its frequency was not related to sex and the method of genotyping, tended to be 7.5% lower for each 25-year increase in average age, was from 4.6 to 6.6 times higher in nonwhites than whites and 13.2% higher in cases than controls. Among 13 studies (n=4332) on the A1166-->C variant of the AT1R gene, the C1166 allelic frequency was 25.7%. Its prevalence was independent of the enrollment group, 77.4% lower in Asians, and nearly doubled for each 25-year increment in age.
CONCLUSION
With adjustments applied for the subjects' enrollment group and the methods of genotyping, genetic polymorphism in the renin system varies according to race and age, but not sex. One possible application of the present results is to provide allelic and genotypic frequencies, which could be used to assess power, to perform sample size calculations, or to predict selection bias in future studies.
Topics: Age Factors; Analysis of Variance; Cardiovascular Diseases; Case-Control Studies; Cross-Sectional Studies; Female; Gene Frequency; Genetic Variation; Genotype; Humans; Kidney Diseases; Male; Racial Groups; Renin-Angiotensin System; Risk Factors; Sex Factors
PubMed: 9865673
DOI: No ID Found