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Journal of Hypertension Nov 2023Cough caused by angiotensin-converting enzyme inhibitors (ACEIs) limits their clinical application and cardiovascular benefits. This randomized trial investigated... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Cough caused by angiotensin-converting enzyme inhibitors (ACEIs) limits their clinical application and cardiovascular benefits. This randomized trial investigated whether genotype-guided perindopril use could reduce drug-related cough in 20 to 79-year-old individuals with hypertension.
METHODS
After screening 120 patients and randomization, 68 were assigned to genotyping ( n = 41) and control ( n = 27) groups. NELL1 p.Arg382Trp (rs8176786) and intron (rs10766756) genotype information was used to subdivide the genotyping group into high-risk and low-risk subgroups with at least one or no risk alleles for ACEI-related cough, respectively. The high-risk subgroup received candesartan (8 mg/day) for 6 weeks, whereas the low-risk subgroup received perindopril (4 mg/day). The control group, which was not genotyped, received perindopril (4 mg/day). The primary outcome variables were cough and moderate/severe cough; the secondary outcome variable was any adverse event.
RESULTS
During the 6-week period, the risk of cough was lower in the genotyping group than in the control group [five (12.2%) and nine (33.3%) participants, respectively; hazard ratio: 0.25; log-rank P = 0.017]. The moderate/severe cough risk was also lower in the genotyping group [one (2.4%) and five (18.5%) participants, respectively; hazard ratio: 0.12; log-rank P = 0.025]. Differences in cough (hazard ratio: 0.56; log-rank P = 0.32) and moderate/severe cough risk (hazard ratio: 0.26; log-rank P = 0.19) between the low-risk and control groups were not significant. The risk of total adverse events was similar between any two groups.
CONCLUSION
Cough risk was lower during genotype-guided treatment than during conventional treatment. These results support the utility of NELL1 variant data in clinical decision making to personalize renin-angiotensin system blocker therapy use.
TRIAL REGISTRATION
ClinicalTrials.gov number: NCT05535595 (retrospectively registered at September 7, 2022).
Topics: Humans; Young Adult; Adult; Middle Aged; Aged; Perindopril; Cough; Angiotensin-Converting Enzyme Inhibitors; Hypertension; Genotype
PubMed: 37602458
DOI: 10.1097/HJH.0000000000003536 -
Journal of Hypertension Mar 2023The aim of this study was to assess the reduction in all-cause death and cardiovascular outcomes associated with the administration of the thiazide-like diuretic... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The aim of this study was to assess the reduction in all-cause death and cardiovascular outcomes associated with the administration of the thiazide-like diuretic indapamide monotherapy or in combination with perindopril as a blood pressure lowering drug in randomized controlled trials (RCTs).
METHOD
Aggregate data from four published RCTs conducted versus matching placebo were pooled: PATS, a 2-year study (indapamide), and PROGRESS, a 4-year study (indapamide and perindopril), both in patients with a history of stroke or transient ischemic attack; ADVANCE, a 4-year study in patients with type 2 diabetes and cardiovascular risk factor (single-pill combination perindopril/indapamide) and HYVET, a 2-year study in very elderly hypertensive individuals (indapamide and an option of perindopril). The pooled effect (fixed and random) estimate (hazard ratio) was reported with corresponding 95% confidence intervals and P values. Treatment discontinuations were also analysed to assess the net benefit of the treatment.
RESULTS
The population involved 24 194 patients (active: 12 113, placebo: 12 081). The fixed-effects meta-analysis of the three mortality endpoints found low statistical heterogeneity ( I2 = 0). Statistically significant risk reductions in the indapamide with or without perindopril-treated patients as compared to placebo were observed for all-cause death (-15%), cardiovascular death (-21%), fatal stroke (-36%) and all strokes (-27%). Other cardiovascular outcomes were improved (risk reduction, 22 to 36%). As expected, discontinuation rates for safety (two studies) were higher in the active group (6.4 vs. 3.9%), while they were similar when discontinuation for any reason is concerned (18.4 vs. 18.0%).
CONCLUSION
Across medium to high cardiovascular risk population, long-term indapamide, mostly combined with perindopril-based treatment, provided evidence of benefit on mortality and morbidity.
Topics: Humans; Aged; Perindopril; Indapamide; Antihypertensive Agents; Hypertension; Stroke; Drug Combinations; Blood Pressure; Randomized Controlled Trials as Topic
PubMed: 36633311
DOI: 10.1097/HJH.0000000000003368 -
Journal of Physiology and Pharmacology... Jun 2023Thrombotic events are highly prevalent in coronavirus disease 2019 (COVID-19), especially in patients presenting with risk factors of adverse outcomes such as obesity....
Thrombotic events are highly prevalent in coronavirus disease 2019 (COVID-19), especially in patients presenting with risk factors of adverse outcomes such as obesity. Recently, the associations between the angiotensin converting enzyme 2 (ACE2) pathway and thrombosis have been reported. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARBs) are widely used cardiovascular pharmacologic agents that upregulate ACE2 levels. An observation of the alterations in pro-coagulation factors after exposure to ACEIs and ARBs may provide valuable insight into the thrombosis mechanism and how it may relate to ACE2. This study use adipose tissue harvested from an obese male donor was isolated and exposed to perindopril, losartan, and ACE2 recombinant as binding assay, following exposure with 10 nm of SARS-CoV-2 S1 spike protein. After 48 hours, tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) as pro-coagulation factors as well as ACE2 levels and binding evaluated. The results shows TF level was significantly reduced in Perindopril group compared to control (4.834; p=0.005), while a non-significant reduction was observed in Losartan group (5.624; p=0.111). However, Losartan group showed a better reduction of PAI-1 levels (2.633; p≤0.001) than Perindopril group (3.484; p=0.001). These findings were consistent with the observations in ACE2 recombinant group, suggesting that both drugs lowered the bindings of ACE2 and SARS-CoV-2 spike proteins. This study indicated that both perindopril and losartan may attenuate pro-coagulation factors in human adipocytes exposed to SARS-CoV-2 spike proteins, and therefore showcased a potential role of ACE2 in the mechanism of COVID-19-related thrombosis. Further investigation in non-COVID-19 populations should commence and may be of value to expanding this potential in general cardiovascular diseases.
Topics: Humans; Male; Perindopril; Spike Glycoprotein, Coronavirus; Losartan; Plasminogen Activator Inhibitor 1; Angiotensin-Converting Enzyme 2; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; COVID-19; SARS-CoV-2; Blood Coagulation Factors; Adipocytes; Thromboplastin; Cardiovascular Agents; Obesity
PubMed: 37661180
DOI: 10.26402/jpp.2023.3.03 -
High Blood Pressure & Cardiovascular... Nov 2022Hypertension represent the commonest cause of death in 2017. Hypertension is classified into two types which are primary or essential hypertension and secondary... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Hypertension represent the commonest cause of death in 2017. Hypertension is classified into two types which are primary or essential hypertension and secondary hypertension. The perindopril-amlodipine combination showed a significant effect in reduction of the elevated BP and the cardiovascular complications.
AIM
To evaluate the efficacy and safety of a fixed-dose single-pill combination of perindopril-amlodipine in hypertensive patients.
METHODS
We searched PubMed, Medline, SCOPUS, and Web of Science for relevant clinical trials. Quality appraisal was evaluated according to GRADE and we assessed the risk of bias using Cochrane's risk of bias tool. We included the following outcomes: systolic blood pressure, diastolic blood pressure, pulse pressure, mean blood pressure, heart rate, cough, dizziness, headache, and peripheral edema. We performed the analysis of homogeneous data under the fixed-effects model, while analysis of heterogeneous data was analyzed under the random-effects model. We conducted a meta-regression according to the dose.
RESULTS
We included ten clinical trials. The pooled analysis showed that there was a significant reduction of the systolic blood pressure, diastolic blood pressure, pulse plessure, mean blood pressure, and heart rate after the the perindopril-amlodipine combination (MD = 18.96 [14.32, 23.60], P < 0.0001), (MD = 11.90 [8.45, 15.35], P < 0.0001), (MD = 8.44 [6.91, 9.97], P = 0.0001), (MD = 13.07 [5.86, 20.29], P = 0.0004), and (MD = 2.93 [0.89, 4.96], P = 0.005), respectively. The results of the meta-regression revealed that the efficacy is increased by increasing the dose (P < 0.001) CONCLUSION: The use of the perindopril-amlodipine combination had a significant effect on the reduction of SBP, DBP, mean blood pressure, pulse pressure, and HR.
Topics: Humans; Perindopril; Amlodipine; Antihypertensive Agents; Drug Combinations; Hypertension; Blood Pressure; Treatment Outcome
PubMed: 36287359
DOI: 10.1007/s40292-022-00544-3 -
Current Medical Research and Opinion Sep 2018Much of the chronic care of patients with type 2 diabetes mellitus and hypertension involves the prevention of diabetic complications. Renin-angiotensin system... (Review)
Review
OBJECTIVES
Much of the chronic care of patients with type 2 diabetes mellitus and hypertension involves the prevention of diabetic complications. Renin-angiotensin system inhibitors are recommended as first-line therapies because of their nephroprotective properties. Their combination with metabolically neutral diuretics is recommended to reduce blood pressure, morbidity and mortality. Our objective was to review the mechanisms by which the combination of the angiotensin-converting enzyme inhibitor, perindopril, and metabolically neutral thiazide-like diuretic, indapamide, targets the pathways involved in microvascular and macrovascular diabetic complications.
METHODS
For this narrative review, extensive literature searches were performed using PubMed/Medline. Articles published in English describing clinical trials and mechanism of action studies that were relevant to the treatment of patients with perindopril and/or indapamide were included.
RESULTS
Perindopril/indapamide treatment has been shown to reduce blood pressure and to have significant beneficial effects on arterial distensibility, kidney structure and function, and endothelial function. Recent data also suggests that perindopril may reduce the deleterious accumulation of advanced glycation end products in diabetic tissue. In the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation diabetes trial, perindopril/indapamide treatment significantly reduced the relative risk of microvascular and macrovascular events by 9%, cardiovascular mortality by 18%, and all-cause mortality by 14%. Interestingly, 6 years after the end of the double-blind period, follow-up data showed that the beneficial effects on mortality continued to be significant even though differences in blood pressure and glycated hemoglobin levels had not been significant for several years. Together this data suggests that treatment with perindopril/indapamide has microvascular and macrovascular effects that extend beyond blood pressure lowering and that this treatment might confer a long-lasting beneficial vascular legacy.
CONCLUSION
Moving forward, understanding the pathophysiological bases of the effects that extend beyond those of blood pressure control will help us differentiate between anti-hypertensive choices.
Topics: Antihypertensive Agents; Blood Circulation; Diabetes Mellitus, Type 2; Drug Combinations; Humans; Hypertension; Indapamide; Perindopril
PubMed: 29307229
DOI: 10.1080/03007995.2018.1425674 -
Evidence-based Complementary and... 2021Excessive activation of the nod-like receptor family pyrin domain containing 3(NLRP3) inflammasome plays a significant role in the progression of cardiac injury. In...
BACKGROUND
Excessive activation of the nod-like receptor family pyrin domain containing 3(NLRP3) inflammasome plays a significant role in the progression of cardiac injury. In China, it has been well recognized that Chinese herbal medicine is markedly effective in treating cardiovascular diseases (CVDs). LuQi Formula (LQF) has been used clinically for more than 10 years and confirmed to be effective in improving cardiac function and inhibiting apoptosis. However, the specific mechanisms underlying its efficacy are mostly unknown. This study aimed to evaluate whether LQF could alleviate cardiac injury and apoptosis by regulating the NLRP3 inflammasome and the caspase-3/Bax pathway.
PURPOSE
In this study, we investigated the effects of LQF on cardiac remodeling in a mouse model of myocardial infarction (MI) in vivo.
METHODS
Forty male C57BL/6 mice were randomly divided into four groups: the sham group, the model group, the LQF group, and the perindopril group, with a sample size () of 10 mice in each group. Except the sham group, the other groups received left anterior descending (LAD) coronary artery ligation to induce MI and then treated with LQF, perindopril, or saline. Six weeks after MI, echocardiography was used to evaluate cardiac structure and function. Myocardial tissue morphology was observed by haematoxylin and eosin (H&E) staining, and heart samples were stained with Masson's trichrome to analyse myocardial fibrosis. Myocardial hypertrophy was observed by fluorescent wheat germ agglutinin (WGA) staining. The expressions of NLRP3, ASC, Cle-caspase-1, IL-1, TXNIP, Cle-caspase-3, Bcl-2, and Bax in heart tissues were assessed by western blot analysis. mRNA expressions of ANP and BNP in heart tissues were measured by RT-PCR. The expression of reactive oxygen species in myocardial tissue was detected by using a DCFH-DA probe.
RESULTS
Echocardiographic analysis showed that compared with the model group, the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) in the LQF and perindopril group were increased ( < 0.05), left ventricular internal diameter end diastole (LVIDd) and left ventricular internal diameter end-systole (LVIDs) were reduced ( < 0.05), and H&E and Masson's trichrome staining of cardiac tissues showed that LQF and perindopril could partially reverse ventricular remodeling and alleviate myocardial fibrosis ( < 0.05). WGA fluorescence results showed that compared with the model group, myocardial hypertrophy was significantly reduced in the LQF and perindopril group. We also found that LQF and perindopril reduce the oxidative stress response in the heart of MI mice. The protein expression of NLRP3, ASC, Cle-caspase-1, IL-1, TXNIP, Cle-caspase-3, and Bax was downregulated in the LHF and perindopril treatment group, and Bcl-2 expression was upregulated.
CONCLUSION
LQF and perindopril significantly attenuated cardiac injury and apoptosis in the MI model. In addition, we found that LQF effectively inhibited the activation of the NLRP3/ASC/caspase-1/IL-1 cascade, decreased inflammatory infiltration, delayed ventricular remodeling, and downregulated caspase-3/Bax signaling, which can effectively reduce the apoptosis of cardiomyocytes. Perindopril showed the same mechanism.
PubMed: 34257682
DOI: 10.1155/2021/5518083 -
Current Medical Research and Opinion 2015Treatment of hypertension remains challenging in clinical practice. One major problem is incorrect utilization of the principal drug classes. Drugs from each class are... (Review)
Review
OBJECTIVE
Treatment of hypertension remains challenging in clinical practice. One major problem is incorrect utilization of the principal drug classes. Drugs from each class are currently used in accordance with an assumption that the blood pressure (BP) lowering effect is dose dependent. While this is true for most drugs, it is not appropriate for all drugs that block the renin-angiotensin system (RAS).
METHODS
This review is based on a PubMed/Cochrane database search for articles on the dose-dependent effect of RAS blockers on BP and cardiovascular protection.
RESULTS
Of the RAS blockers, most angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have a flat dose-response curve for BP decrease, meaning an increase in dose prolongs duration of action, but does not yield greater potency. Perindopril is the only ACE inhibitor to show a real dose-response curve for BP decrease. While the effectiveness of RAS blockers on target organ damage is dose dependent and at least partially unrelated to BP control, there is evidence that the only way to obtain a beneficial effect is to use them at full dose. Thus, RAS blockers need to be used at the correct dose, based on the results of controlled clinical trials and meta-analysis. Furthermore, for all-cause mortality, ACE inhibitors have been shown to be better than ARBs, a specific efficacy supported by perindopril-based studies including ASCOT-BPLA (the Anglo-Scandinavian Cardiac Outcomes Trial-BP Lowering Arm), ADVANCE (the Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation trial) and HYVET (HYpertension in the Very Elderly Trial).
CONCLUSION
In hypertensive patients, a strategy based on ACE inhibitors with dose-dependent efficacy such as perindopril as optimal treatment should lead both to improved BP control and to a better protection from target organ damage, thereby reducing the incidence of cardiovascular events.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Humans; Hypertension; Renin-Angiotensin System
PubMed: 25985327
DOI: 10.1185/03007995.2015.1053047 -
Cardiovascular & Hematological... 2017Heart failure with preserved ejection fraction (HFpEF) makes up half of diagnosed heart failure (HF) cases and has similar outcomes compared to heart failure with... (Review)
Review
BACKGROUND
Heart failure with preserved ejection fraction (HFpEF) makes up half of diagnosed heart failure (HF) cases and has similar outcomes compared to heart failure with reduced ejection fraction (HFrEF) but a discrepancy in knowledge and approach to treatment. HFpEF is diagnosed using the following criteria: symptoms, preserved ejection fraction (greater than 50%), and evidence of abnormal left ventricular filling or relaxation, or diastolic distensibility or stiffness. Studies conducted to examine the efficacy of angiotensin receptor blockers (ARB) (irbesartan and candesartan), thiazide diuretics (chlorthalidone), and angiotensin converting enzyme inhibitors (ACEI) (perindopril) in the treatment of HFpEF, showed moderate efficacy but no clear benefit. Recently, the FDA has approved a novel drug, which combines an angiotensin receptor neprilysin inhibitor and ARB (valsartan) named LCZ696 (entresto) for possible treatment of HFrEF.
CONCLUSION
In this article, we will discuss the failure of previous treatment modalities and the promise that LCZ696 (entresto) may hold for treating patients with HFpEF.
Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Clinical Trials as Topic; Drug Combinations; Heart; Heart Failure; Humans; Irbesartan; Perindopril; Tetrazoles; Valsartan
PubMed: 28676030
DOI: 10.2174/1871529X17666170703120237 -
Expert Opinion on Investigational Drugs Oct 2017Currently, available therapies for Parkinson's disease (PD) are symptomatic. Therefore, the search for neuroprotective drugs remains a top priority. Areas covered: In... (Review)
Review
Currently, available therapies for Parkinson's disease (PD) are symptomatic. Therefore, the search for neuroprotective drugs remains a top priority. Areas covered: In this review, the potential symptomatic or disease-modifying effect of drugs targeting the Renin-Angiotensin System (RAS) in PD will be explored. Expert opinion: The importance of nigrostriatal local RAS has only begun to be unraveled in the last decades. On one hand, there is a complex feedback cycle between RAS and dopamine (DA). On the other hand, RAS affects dopaminergic neurons vulnerability. Neuroprotective effects in animal PD models have been shown for the angiotensin-converting enzyme (ACE) inhibitors captopril and perindopril, and the AT1 receptor antagonists losartan, candesartan and telmisartan. These effects appear to be mediated by a reduction in the overproduction of reactive oxygen species. In a proof-of-concept, randomized, double-blind, crossover study in PD patients, perindopril enhanced the effect of levodopa without inducing dyskinesias. There has not been any clinical trial exploring the neuroprotective effect of RAS drugs, but one cohort study in hypertensive patients suggested a protective effect of ACE inhibitors on PD risk. RAS is a promising target for symptomatic and neuroprotective therapies in PD. Further studies in PD animal models and patients are warranted.
Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antiparkinson Agents; Dopamine; Drug Design; Humans; Molecular Targeted Therapy; Neuroprotective Agents; Parkinson Disease; Randomized Controlled Trials as Topic; Reactive Oxygen Species; Renin-Angiotensin System
PubMed: 28836869
DOI: 10.1080/13543784.2017.1371133