Comparison of long‐term safety of fixed‐dose combinations azilsartan medoxomil/chlorthalidone vs olmesartan medoxomil/hydrochlorothiazide

This 52‐week, randomized, open‐label study evaluated long‐term safety/tolerability of fixed‐dose combination azilsartan medoxomil/chlorthalidone (AZL‐M/CLD) vs fixed‐dose combination olmesartan medoxomil/hydrochlorothiazide (OLM/HCTZ) in patients with essential hypertension (stage 2; clinic systolic blood pressure 160–190 mm Hg). Initial AZL‐M/CLD 40/12.5 mg/d (n=418) or OLM/HCTZ 20/12.5 mg/d (n=419) could be uptitrated during weeks 4 to 52 (AZL‐M/CLD to 80/25 mg; OLM/HCTZ to 40/25 mg [United States] or 20/25 mg [Europe]) to meet blood pressure targets. Treatment‐emergent adverse events/serious adverse events occurred in 78.5%/5.7% of patients taking AZL‐M/CLD vs 76.4%/6.2% taking OLM/HCTZ. The most frequent adverse events were dizziness (16.3% vs 12.6%), blood creatinine increase (21.5% vs 8.6%), headache (7.4% vs 11.0%), and nasopharyngitis (12.2% vs 11.5%). Hypokalemia was uncommon (1.0% vs 0.7%). Greater blood pressure reductions with AZL‐M/CLD by week 2 were maintained throughout the study, despite less uptitration (32.3% vs 48.9% with OLM/HCTZ). Fixed‐dose combination AZL‐M/CLD showed an encouraging benefit‐risk profile when used per standard clinical practice in a titrate‐to‐target strategy.     

Fixed‐dose vs free‐dose combinations for the management of hypertension—An analysis of 81 958 patients

Fixed‐dose combinations (FDC) have been developed to reduce the pill burden for hypertensive patients. Data on fixed‐dose or free‐dose (freeDC) ramipril/amlodipine (R/A) or candesartan/amlodipine (C/A) combination treatment initiation were assessed. 71 463 patients were prescribed R/A and 10 495 C/A. For both R/A and C/A, FDC patients were younger (both P < .001) and less comorbid. Prior MI (OR: 0.61 and 0.60), prior stroke (OR: 0.68 and 0.70) and CHD (OR: 0.68 and 0.64) were negatively associated with FDC use, whereas hyperlipidemia was positively associated (OR: 1.26 and 1.19). Use of antihypertensive comedication (OR: 0.78; OR: 0.55) and treatment discontinuation within 12 months (HR: 0.65 and 0.82) were less likely in FDC patients, who also showed superior adherence (mean MPR; both P < .001). Cost of the combination was higher for FDCs (both P < .001). FDCs improve persistence and adherence, although they are more commonly prescribed in patients with less cardiovascular disease.     

Combination Therapy of Olmesartan and Azelnidipine Inhibits Sympathetic Activity Associated with Reducing Oxidative Stress in the Brain of Hypertensive Rats

It has been demonstrated that the antihypertensive drugs with the antioxidant action on the brainstem inhibit the sympathetic activity and consequently decrease blood pressure and heart rate (HR) in hypertensive rats. Combination drugs of the angiotensin receptor blocker and calcium channel blocker, such as olmesartan (OLM)/azelnidipine (AZ) and candesartan (CAN)/amlodipine (AM), are widely used for treating hypertension in Japan. In this study, it was investigated whether there are differences in the antioxidant effect in the brain and the sympathoinhibitory effect between OLM/AZ and CAN/AM combination therapies in stroke-prone spontaneously hypertensive rats (SHRSP). OLM/AZ (10/8 mg kg^?1 day^?1), CAN/AM (4/2.5 mg kg^?1 day^?1), or vehicle was orally administered for 30 days to SHRSP. OLM/AZ and CAN/AM markedly decreased systolic blood pressure to the same extent. OLM/AZ decreased HR to a greater extent than CAN/AM. Urinary norepinephrine excretion as a marker of sympathetic activity was unchanged in the CAN/AM group, but reduced in the OLM/AZ group. Oxidative stress in the whole brain assessed using the in vivo electron spin resonance method was similarly decreased in both OLM/AZ and CAN/AM groups. Importantly, thiobarbituric acid reactive substance levels in the brainstem were significantly lower in the OLM/AZ group, but not in the CAN/AM group, than in the vehicle group. These results suggest that combination therapy of either OLM/AZ or CAN/AM does not induce reflex-mediated sympathetic activation despite the marked blood pressure reduction, which is associated with an antioxidant effect in the brain regions affecting the sympathetic activity. Furthermore, the antioxidant effect in the brainstem and the sympathoinhibitory effect of OLM/AZ combination may be greater than those of CAN/AM combination treatment.     

Effects of Bisoprolol and Losartan Treatment in the Hypertrophic and Failing Right Heart

BackgroundSympathetic adrenergic stimulation and the renin-angiotensin-aldosterone system are highly elevated in right heart failure. We evaluated if treatment with the adrenergic receptor blocker bisoprolol or the angiotensin II receptor blocker losartan could prevent the progression of right ventricular (RV) hypertrophy and failure in rats after pulmonary trunk banding (PTB).Methods and ResultsMale Wistar rats were randomized to severe PTB with a 0.5-mm banding clip (PTB0.5, n = 29), moderate PTB with a 0.6-mm banding clip (PTB0.6, n = 28), or sham operation (SHAM, n = 13). The PTB0.5 and PTB0.6 rats were randomized to 6 weeks of 10 mg/kg/d bisoprolol treatment, 20 mg/kg/d losartan treatment, or vehicle treatment. The PTB caused hypertrophy, dilation, and reduced function of the RV in all rats subjected to the procedure. Rats subjected to the more severe banding developed decompensated RV failure with extracardiac manifestations. Treatment with bisoprolol slowed the heart rate, and treatment with losartan lowered mean arterial pressure, confirming adequate dosing, but none of the treatments improved RV function or arrested the progression of RV hypertrophy and failure compared with vehicle.ConclusionsIn our PTB model of pressure overload–induced RV hypertrophy and failure, treatment with bisoprolol and losartan did not demonstrate any beneficial effects in compensated or decompensated RV failure.     

Targeting the renin−angiotensin signaling pathway in COVID-19: Unanswered questions,opportunities, and challenges

The role of the renin−angiotensin signaling (RAS) pathway in COVID-19 has received much attention. A central mechanism for COVID-19 pathophysiology has been proposed: imbalance of angiotensin converting enzymes (ACE)1 and ACE2 (ACE2 being the severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] virus “receptor”) that results in tissue injury from angiotensin II (Ang II)-mediated signaling. This mechanism provides a rationale for multiple therapeutic approaches. In parallel, clinical data from retrospective analysis of COVID-19 cohorts has revealed that ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may be beneficial in COVID-19. These findings have led to the initiation of clinical trials using approved drugs that target the generation (ACEIs) and actions (ARBs) of Ang II. However, treatment of COVID-19 with ACEIs/ARBs poses several challenges. These include choosing appropriate inclusion and exclusion criteria, dose optimization, risk of adverse effects and drug interactions, and verification of target engagement. Other approaches related to the RAS pathway might be considered, for example, inhalational administration of ACEIs/ARBs (to deliver drugs directly to the lungs) and use of compounds with other actions (e.g., activation of ACE2, agonism of MAS1 receptors, β-arrestin−based Angiotensin receptor agonists, and administration of soluble ACE2 or ACE2 peptides). Studies with animal models could test such approaches and assess therapeutic benefit. This Perspective highlights questions whose answers could advance RAS-targeting agents as mechanism-driven ways to blunt tissue injury, morbidity, and mortality of COVID-19.     

Molecular Mechanisms Involved in Intrarenal Renin-Angiotensin and Alternative Pathways in Diabetic Nephropathy - A Review

Uncontrolled or chronic hyperglycemia causes kidney failure induced by the dysfunction of biomolecules and upregulation of inflammatory cytokines and growth factors. The reninangiotensin system (RAS) is incorporated in the regulation of renal hemodynamics. In a healthy state, local RAS is independent of systemic RAS. However, in pathological conditions such as chronic hyperglycemia, angiotensin II (Ang II) increases locally and causes tissue damage, mainly through the induction of oxidative stress, inflammation, and upregulation of some growth factors and their receptors. Such tissue events may cause disruption of the glomerular filtration barrier, thickening and hypertrophy of the glomerular basement membrane, microvascular hyperpermeability, proteinuria, and finally decrease in the glomerular filtration rate (GFR). Reduced GFR causes the kidney to sense falsely a low blood pressure condition and respond to it by stimulating systemic and local RAS. Therefore, patients with diabetic nephropathy (DN) suffer from chronic hypertension. In contrast to local RAS, there are alternative pathways in the kidney that act protectively by reducing tissue Ang II. Such autoregulatory and protective mechanisms are weakened in chronic kidney disease. Previously, it was presumed that systemic RAS inhibitors such as ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) could prevent renal damage by controlling blood pressure and proteinuria. However, the progression of renal failure to end-stage renal disease (ESRD), despite such treatments, indicates the presence of factors other than Ang II. This review highlights the molecular mechanism in renal disease and discusses pharmaceutical and therapeutic approaches.     

Medication compliance and clinical outcomes of fixed‐dose combinations vs free combinations of an angiotensin II receptor blocker and a calcium channel blocker in hypertension treatment

Using the National Health Insurance Research Database of Taiwan, the authors identified 1136 patients taking fixed‐dose combination and 4544 patients taking free combinations of an angiotensin II receptor blocker and a dihydropyridine calcium channel blocker from January 2009 to December 2012. At a mean follow‐up of 2.1 years, the fixed‐dose combination was associated with improved medication adherence and persistence and better survival free from major adverse cardiac events and hospitalization for heart failure compared with the free combination regimens.     

Influence of angiotensin converting enzyme inhibitors/angiotensin receptor blockers on the risk of all‐cause mortality and other clinical outcomes in patients with confirmed COVID‐19: A systemic review and meta‐analysis

Since the COVID‐19 pandemic, physicians concerned about the potential adverse effects of angiotensin converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs). To explore the relationship between ACEIs/ARBs and the risk of mortality and other clinical outcomes in COVID‐19 patients, the authors conducted a systemic review and meta‐analysis. An electronic search was performed from inception to November 12, 2020 in PubMed, Medline, EMBASE, ClinicalTrials, TRIP, the Cochrane Library, CNKI, Wanfang, and CBM database. Risk of bias was assessed using the Risk Of Bias In Non‐randomized Studies of Interventions tool. The primary outcome was in‐hospital all‐cause mortality. Secondary outcomes included all‐cause mortality measured at 30‐day or longer term, mechanical ventilation, length of hospital stay, readmission, and cardiac adverse events. A total of 28 studies with 73 465 patients was included. Twenty‐two studies with 19 871 patients reported the incidence of all‐cause mortality. Results showed no association between using ACEIs/ARBs and risk of mortality crude odds ratio （OR） of 1.02, 95% CI 0.71–1.46, p = .90, I ² = 88%, adjusted OR in 6260 patients of 0.96, 95% CI 0.77–1.18, p = .68, I ² = 0%. While six studies with 10 030 patients reported a lower risk of mortality in ACEIs/ARBs group hazard ratio (HR) of 0.53, 95% CI 0.34–0.84, p = .007, I ² = 68%. Similar association (for HR) was found in hypertension subgroup. There was no significant association for the secondary outcomes. Based on the available data, we concluded that ACEIs/ARBs is not associated with the risk of in‐hospital all‐cause mortality in COVID‐19 patients, but may be associated with a decreased risk of 30‐day all‐cause mortality. Patients with hypertension may benefit from using ACEIs/ARBs.     

Worsening Renal Function and Outcome in Heart Failure Patients With Preserved Ejection Fraction and the Impact of Angiotensin Receptor Blocker Treatment

Background

Worsening renal function (WRF) associated with renin-angiotensin-aldosterone system (RAAS) inhibition does not confer excess risk in heart failure patients with reduced ejection fraction (HFrEF).

Objectives

The goal of this study was to investigate the relationship between WRF and outcomes in heart failure patients with preserved ejection fraction (HFpEF) and the interaction with RAAS blockade.

Methods

In 3,595 patients included in the I-PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction) trial, change in estimated glomerular filtration rate (eGFR) and development of WRF after initiation of irbesartan or placebo were examined. We examined the association between WRF and the first occurrence of cardiovascular death or heart failure hospitalization (primary outcome in this analysis) and the interaction with randomized treatment.

Results

Estimated GFR decreased early with irbesartan treatment and remained significantly lower than in the placebo group. WRF developed in 229 (6.4%) patients and occurred more frequently with irbesartan treatment (8% vs. 4%). Overall, WRF was associated with an increased risk of the primary outcome (adjusted hazard ratio [HR]: 1.43; 95% confidence interval [CI]: 1.10 to 1.85; p = 0.008). Although the risk related to WRF was greater in the irbesartan group (HR: 1.66; 95% CI: 1.21 to 2.28; p = 0.002) than with placebo (HR: 1.09; 95% CI: 0.66 to 1.79; p = 0.73), the interaction between treatment and WRF on outcome was not significant in an adjusted analysis.

Conclusions

The incidence of WRF in HFpEF was similar to that previously reported in HFrEF but more frequent with irbesartan than with placebo. WRF after initiation of irbesartan treatment in HFpEF was associated with excess risk, in contrast to WRF occurring with RAAS blockade in HFrEF.     

Antiarrhythmic effects of losartan and enalapril in canine pulmonary vein sleeve preparations

Antiarrhythmic Effect of Losartan and Enalapril. Introduction: Angiotensin‐converting enzyme (ACE) inhibitors and angiotensin II‐receptor blockers (ARBs) are prototypes of “upstream” therapy for the management of atrial fibrillation (AF). Ectopic activity arising from the PV sleeves plays a prominent role in the development of AF. Methods: Transmembrane action potentials were recorded from canine superfused left superior or inferior PV sleeves using standard microelectrode techniques. Acetylcholine (ACh, 1 μM), isoproterenol (1 μM), high calcium ([Ca²⁺]_o= 5.4 mM) or a combination was used to induce early or delayed afterdepolarizations (EADs or DADs) and triggered activity. Results: The ARB losartan (1 μM, n = 5) and the ACE inhibitor enalapril (10 μM, n = 5) produced no significant change in action potential duration, maximum rate of rise of action potential upstroke (V_max), action potential amplitude or take‐off potential at basic cycle lengths of 200 to 2000 ms. Losartan (1 μM) and enalapril (10–20 μM) markedly attenuated or suppressed EADs and DAD‐induced triggered activity elicited by exposure of the PV sleeves to ACh, isoproterenol or high calcium following rapid pacing in 6 of 6 (losartan) and 4 of 5 (enalapril) PV sleeve preparations. Neither losartan nor enalapril altered Ca²⁺ or K⁺ channel currents in enzymatically‐dissociated atrial myocytes at these concentrations. Conclusions: Our data suggest that in addition to their “upstream” effects to reduce atrial structural remodeling, ACE inhibitors and ARBs exert a “direct” antiarrhythmic effect by suppressing triggers responsible for the genesis of AF and other atrial arrhythmias. (J Cardiovasc Electrophysiol, Vol. 22, pp. 698‐705, June 2011)     

Central blood pressure lowering effect of telmisartan‐rosuvastatin single‐pill combination in hypertensive patients combined with dyslipidemia: A pilot study

This multicenter, phase 4, Prospective Randomized Open, Blinded End‐point (PROBE) study aimed to evaluate safety and efficacy of telmisartan/rosuvastatin single‐pill combination (SPC) therapy on lowering central blood pressure (BP) compared with telmisartan monotherapy in hypertensive patients with dyslipidemia in Korea. Study was terminated earlier than planned due to COVID‐19 pandemic, thus should be considered as a pilot study. Among 125 patients who met the inclusion criteria of hypertension and dyslipidemia (defined as 10‐year Atherosclerotic Cardiovascular Disease risk score over 5%), 80 patients went through 4‐week single‐group run‐in period with telmisartan 40–80 mg, then randomized to telmisartan 80 mg + rosuvastatin (10 or 20 mg) SPC group or telmisartan 80 mg monotherapy group. The central/brachial BP, brachial‐ankle pulse wave velocity (baPWV), and augmentation index (AIx) were assessed at baseline and 16 weeks later. Mean brachial SBP changed from 135.80 ± 14.22 mmHg to 130.69 ± 13.23 mmHg in telmisartan/rosuvastatin group and from 134.37 ± 12.50 mmHg to 133.75 ± 12.30 mmHg in telmisartan monotherapy group without significant difference (between‐group difference p = .149). Mean central SBP were reduced significantly in the telmisartan/rosuvastatin group with change from 126.72 ± 14.44 mmHg to 121.56 ± 14.56 mmHg while telmisartan monotherapy group showed no significant change (between‐group difference p = .028). BaPWV changed from 1672.57 ± 371.72 m/s to 1591.75 ± 272.16 m/s in telmisartan/rosuvastatin group and from 1542.85 ± 263.70 m/s to 1586.12 ± 297.45 m/s in telmisartan group with no significance (between‐group difference p = .078). Change of AIx had no significant difference (between‐group difference p = .314). Both groups showed excellent compliance rate of 96.9 ± 4.5% with no significant difference in adverse rate. Telmisartan/rosuvastatin SPC therapy was more effective in lowering central BP compared with the telmisartan monotherapy. The results of this study showed benefit of additive statin therapy in hypertensive patients combined with dyslipidemia.