Angiotensin converting enzyme inhibitor and angiotensin receptor blockade use in relation to outcomes in anticoagulated patients with atrial fibrillation

BACKGROUND: The renin-angiotensin-aldosterone-system (RAAS) plays an important role in atrial fibrillation (AF). Evidence shows that blocking the RAAS with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has a definite role in preventing new onset AF and in maintaining sinus rhythm in recurrent AF. Our aim was to determine if ACEI/ARB treatment was associated with clinical outcomes [stroke/systemic embolic events (SEE), mortality] in a controlled, anticoagulated AF population. METHODS: An ancillary retrospective cross-sectional and longitudinal analysis of participants in the Stroke Prevention using an ORal Thrombin Inhibitor in AF (SPORTIF) III and V trials, in relation to use (or nonuse) of ACEI/ARBs. RESULTS: Rates of stroke/SEEs, mortality or major bleeding were no different between users and nonusers in the whole cohort, or in relation to the presence/absence of hypertension, coronary artery disease and previous stroke/transient ischaemic attack, nor amongst those aged <75 years. Patients aged > or = 75 years taking ACEIs or ARBs had lower mortality (HR 0.71, 95% CI 0.52-0.95), but no significant influence on other end-points was noted. Diabetics and those with left ventricular dysfunction on ximelagatran had a higher odds ratio of abnormal liver enzyme levels. There was no apparent benefit of ACEIs or ARBs on other event rates. CONCLUSIONS: This analysis from two large randomized trials of anticoagulation has not demonstrated a significant benefit of ACEI or ARB use amongst AF patients, except amongst elderly subjects.     

Angiotensin-converting enzyme inhibitor induced cough compared with placebo,and other antihypertensives: A systematic review,and network meta-analysis

Studies have shown that angiotensin converting enzyme inhibitors (ACEIs) are superior in primary and secondary prevention for cardiac mortality and morbidity to angiotensin receptor blocker (ARBs). One of the common side effects from ACEI is dry cough. The aims of this systematic review, and network meta-analysis are to rank the risk of cough induced by different ACEIs and between ACEI and placebo, ARB or calcium channel blockers (CCB). We performed a systematic review, and network meta-analysis of randomized controlled trials to rank the risk of cough induced by each ACEI and between ACEI and placebo, ARB or CCB. A total of 135 RCTs with 45,420 patients treated with eleven ACEIs were included in the analyses. The pooled estimated relative risk (RR) between ACEI and placebo was 2.21 (95% CI: 2.05–2.39). ACEI had more incidences of cough than ARB (RR 3.2; 95% CI: 2.91, 3.51), and pooled estimated of RR between ACEI and CCB was 5.30 (95% CI: 4.32–6.50) Moexipril ranked as number one for inducing cough (SUCRA 80.4%) and spirapril ranked the least (SUCRA 12.3%). The order for the rest of the ACEIs are as follows: ramipril (SUCRA 76.4%), fosinopril (SUCRA 72.5%), lisinopril (SUCRA 64.7%), benazepril (SUCRA 58.6%), quinapril (SUCRA 56.5%), perindopril (SUCRA 54.1%), enalapril (SUCRA 49.7%), trandolapril (SUCRA 44.6%) and, captopril (SUCRA 13.7%). All ACEI has the similar risk of developing a cough. ACEI should be avoided in patients who have risk of developing cough, and an ARB or CCB is an alternative based on the patient's comorbidity.     

ACEI/ARB在心房颤动的预防治疗作用

心房颤动是临床上最常见的心律失常,并且很难治愈。目前,大家都把兴趣集中在针对发病机制的新治疗手段。近期研究提示,肾素-血管紧张素-醛固酮系统在心房颤动的发病机制中是一个非常重要的内分泌系统。因此,血管紧张素转换酶抑制剂和血管紧张素Ⅱ受体拮抗剂都成为了预防心房颤动的新型药物。现对血管紧张素转换酶抑制剂和血管紧张素Ⅱ受体拮抗剂在心房颤动治疗中所发挥的作用进行了讨论,并回顾了大量血管紧张素转换酶抑制剂和血管紧张素Ⅱ受体拮抗剂在高危心房颤动人群（如心力衰竭、高血压、心肌梗死等）的临床研究。     

Effects of initial antihypertensive drug class on patient persistence and compliance in a usual-care setting in the United States

Antihypertensive treatment regimen persistence and compliance were measured using a retrospective cohort study of pharmacy claims data. Newly treated patients receiving monotherapy with angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), beta-blockers (BBs), or diuretics were followed for 1 year (N=242,882). A higher proportion of ARB patients (51.9%) were persistent in taking prescribed medication compared with those in the ACEI (48.0%), BB (40.3%), CCB (38.3%), and diuretic groups (29.9%). Compared with patients receiving diuretics, those receiving ARBs (hazard ratio [HR], 0.593; P<.0001), ACEIs (HR, 0.640; P<.0001), CCBs (HR, 0.859; P<.0001), and BBs (HR, 0.819; P<.0001) were all less likely to discontinue therapy. Compliance was similar in ACEI and ARB patients, but patients receiving ARBs and ACEIs had better compliance than those receiving BBs, CCBs, or diuretics. The lesser degree of compliance and persistence observed in patients receiving diuretics compared with other antihypertensive medications may have public health as well as cost implications.     

A Nonpeptide,Piperidine Renin Inhibitor Provides Renal and Cardiac Protection in Double-Transgenic Mice Expressing Human Renin and Angiotensinogen Genes

Introduction  Controlling hypertension by angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), mechanisms that inhibit later pathway steps in the renin–angiotensin system (RAS), have clinically afforded protection against cardiac and renal disease. Materials and methods  In order to determine if blocking the RAS rate-limiting step of angiotensin II generation via renin inhibition could afford similar end organ protection in a human-relevant preclinical model, this study investigated the cardiac and renal effects of a nonpeptide, piperidine renin inhibitor (RI; 100 mg/kg/day PO) in double transgenic mice (dTGM) which express both human renin and angiotensinogen genes. RI was compared to the ARB, candesartan (3 mg/kg/day PO), and to the ACEI, enalapril (60 mg/kg/day PO) in a 4-week dosing paradigm. These doses of RI, ACEI and ARB were previously found to normalize mean blood pressure (MBP) to 110 + 3, 109 + 7 and 107 + 6 mmHg, respectively, after 1 day of treatment. Results and discussion  In the dTGM, PRA, plasma aldosterone, GFR, microalbuminuria and left ventricular free wall thickness (LVH) were higher than in the wild type C57BL/6 mice. Microalbuminuria and LVH were significantly reduced by 93% and 9% for the RI, 83% and 13% for enalapril and 73% and 6% for candesartan, respectively. PRA and aldosterone were reduced by the RI 56% and 23%, respectively. These results suggest that the RI provides protection against cardiac and renal disease, similar to ARB and ACEI.     

Ranolazine,ACE Inhibitors,and Angiotensin Receptor Blockers

BackgroundRanolazine is an anti-angina agent with many metabolites creating the potential for off-target effects. The U.S. Food and Drug Administration (FDA) reviews sometimes contain clinically relevant data not found in other sources.MethodsWe reanalyzed data in an FDA review of the placebo-controlled MERLIN trial of ranolazine to display differences in adverse event rates graphically.ResultsRates of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)-related adverse events (eg, angioedema, dry cough, renal impairment, hypotension, anemia, and serum potassium > 5.5 mmol/L) were higher in patients receiving ranolazine and an ACEI or ARB. Rates of adverse events that should be decreased by ACEI/ARBs (eg, hypokalemia, hypertension, and serum potassium < 3.5 mmol/L) were lower in patients receiving ranolazine and an ACEI or ARB compared to rates in patients receiving placebo and an ACEI or ARB.ConclusionsRanolazine potentiates the effects of ACEIs and ARBs. Clinicians should monitor for this potentiation when initiating treatment with ranolazine and an ACEI or ARB.     

Important Treatment Gaps in Vascular Protection for the Elderly After Type 2 Diabetes Therapy Initiation

Background

Canadian practice guidelines recommend the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) for vascular protection in individuals with diabetes who are at high risk of cardiovascular events, including those ≥ 65 years. We estimated the proportion of elderly persons who initiated an ACEI or an ARB in the year after beginning oral antidiabetes (OAD) treatment, and we identified factors associated with this initiation.

Methods

Using the Quebec Health Insurance Board (RAMQ) databases, we conducted a population-based cohort study of individuals ≥ 65 years recently prescribed an OAD. We excluded those who were already taking an ACEI or ARB. Factors associated with ACEI or ARB initiation were identified using multivariate logistic regression.

Results

Among 43,700 individuals, 13,621 (31.2%) initiated an ACEI or ARB in the year after beginning OAD. Individuals were more likely to begin an ACEI or an ARB if they initially received both metformin and a sulfonylurea, lived in a rural region, began OAD treatment between 2001 and 2006, were hospitalized, or had ≥ 22 medical visits in the year before OAD initiation. Individuals ≥ 75 years, those who were prescribed an OAD by a general practitioner, initially received a sulfonylurea, or received ≥ 4 different medications in the year before OAD initiation were less likely to begin an ACEI or ARB.

Conclusions

In the elderly not already taking ACEIs or ARBs, a low proportion of those undertaking OAD treatment are prescribed the recommended cardioprotection of an ACEI or ARB in the following year. Interventions are needed to close this treatment gap.     

Angiotensin Receptor Blockers Reduce Left Ventricular Hypertrophy in Dialysis Patients: A Meta-Analysis

IntroductionLeft ventricular hypertrophy (LVH) is a major cardiovascular complication and an important predictor of mortality in patients with end-stage renal disease. Angiotensin II blockades have been widely used in the treatment of hypertension; however, the influence of angiotensin receptor blockers (ARBs) on LVH in dialysis patients has not been thoroughly studied. In this meta-analysis, the authors analyzed the effect of ARBs on LVH and left ventricular function in patients on maintenance dialysis.MethodsThe authors did systematic search of PubMed, Embase and Cochrane Central Register of Controlled Trials, until November 2010. Data extracted from the literature were analyzed with the Review Manager.ResultsThe results of 6 randomized controlled trials (207 participants) reveal that ARB group had a greater regression of left ventricular mass index (LVMi) when compared with non-ARB group (P = 0.002) in dialysis patients while no significant difference for left ventricular ejection fraction (LVEF; P = 0.30). The ARB group had a nonsignificantly greater therapeutic value of LVMi or LVEF when compared with angiotensin-converting enzyme inhibitor (ACEI; P = 0.74 and 0.49, respectively). No significant alterations were observed in LVMi and LVEF between the combination of ARBs and ACEIs and ARBs group (P = 0.43 and 0.24, respectively).ConclusionsARBs are associated with a greater reduction in LVH in patients on dialysis. The ARB therapy tends to have a similar favorable effectiveness as ACEI; however, the combination of ARBs with ACEIs did not show additional benefit to LVH in patients on hemodialysis.     

Effect of angiotensin receptor blockers on the development of cancer: A nationwide cohort study in korea

The potential cancer risk associated with long‐term exposure to angiotensin receptor blockers (ARBs) is still unclear. We assessed the risk of incident cancer among hypertensive patients who were treated with ARBs compared with patients exposed to angiotensin‐converting enzyme inhibitors (ACEIs), which are known to have a neutral effect on cancer development. Using the Korean National Health Insurance Service database, we analyzed the data of patients diagnosed with essential hypertension from January 2005 to December 2012 who were aged ≥40 years, initially free of cancer, and were prescribed either ACEI or ARB (n = 293,962). Cox proportional hazard model adjusted for covariates was used to evaluate the risk of incident cancer. During a mean follow‐up of 10 years, 24,610 incident cancers were observed. ARB use was associated with a decreased risk of overall cancer compared with ACEI use (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.72‐0.80). Similar results were obtained for lung (HR 0.73, 95% CI 0.64‐0.82), hepatic (HR 0.56, 95% CI 0.48‐0.65), and gastric cancers (HR 0.74, 95% CI 0.66‐0.83). Regardless of the subgroup, greater reduction of cancer risk was seen among patients treated with ARB than that among patients treated with ACEIs. Particularly, the decreased risk of cancer among ARB users was more prominent among males and heavy drinkers (interaction P < .005). Dose‐response analyses demonstrated a gradual decrease in risk with prolonged ARB therapy than that with ACEI use. In conclusion, ARB use was associated with a decreased risk of overall cancer and several site‐specific cancers.     

Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: a meta-analysis.

AIMS: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) prevent the progression of diabetic nephropathy (DN). Studies suggest that combination renin-angiotensin-aldosterone system (RAAS)-inhibiting therapy provides additive benefit in DN. However, these studies are small in size. We performed a meta-analysis of studies investigating combination therapy for DN. METHODS: Studies were identified through a search of medline, embase, cinahl and the Cochrane Database. All trials involving combined ACEI and ARB for slowing progression of DN were included. The primary end point was 24-h urinary protein excretion. Blood pressure, serum potassium and glomerular filtration rate (GFR) were secondary end points. RESULTS: In the 10 included trials, 156 patients received ACEI + ARB and 159 received ACEI only. Most studies were 8-12 weeks in duration. Proteinuria was reduced with ACEI + ARB (P = 0.01). This was associated with significant statistical heterogeneity (P = 0.005). ACEI + ARB was associated with a reduction in GFR [3.87 ml/min (7.32-0.42); P = 0.03] and a trend towards an increase in serum creatinine (6.86 micromol/l 95% CI -0.76-13.73; P = 0.09). Potassium was increased by 0.2 (0.08-0.32) mmol/l (P < 0.01) with ACEI + ARB. Systolic and diastolic blood pressure were reduced by 5.2 (2.1-8.4) mmHg (P < 0.01) and 5.3 (2.2-8.4) mmHg (P < 0.01), respectively. CONCLUSIONS: This meta-analysis suggests that ACEI + ARB reduces 24-h proteinuria to a greater extent than ACEI alone. This benefit is associated with small effects on GFR, serum creatinine, potassium and blood pressure. These results should be interpreted cautiously as most of the included studies were of short duration and the few long-term studies (12 months) have not demonstrated benefit.     

Treatment of patients with heart failure and preserved ejection fraction

Opinion statement  Of the more than 5 million Americans who have heart failure (HF), 30% to 50% have HF with preserved ejection fraction (HF-PEF). HF-PEF commonly occurs in elderly patients, especially women, with comorbidities of hypertension, left ventricular hypertrophy, diabetes, myocardial ischemia, and obesity. HF-PEF is associated with high morbidity and mortality. Although two large multicenter randomized, placebo-controlled trials evaluating an angiotensin-converting enzyme inhibitor (ACEI) and an angiotensin receptor blocker (ARB) in patients with HFPEF did not demonstrate any statistically significant benefit in their primary end points, they did suggest that these agents may have a modest role in reducing HF hospitalizations. Although calcium channel blockers and β-blockers may be of benefit in patients with HF-PEF, large clinical trial data are not available to support their routine use in all patients with HF-PEF. Subgroup analysis does not support the use of digoxin in patients with HF-PEF in sinus rhythm. Current therapeutic recommendations for HF-PEF are aimed at 1) management of HF symptoms with sodium and fluid restriction along with diuretics for volume overload and 2) treatment of concomitant comorbidities, especially hypertension, rate and possibly rhythm control of atrial fibrillation, and evaluation and treatment of myocardial ischemia and anemia. ACEIs, ARBs, calcium channel blockers, and β-blockers are recommended for HF-PEF patients who have other established indications for their use. Results are awaited from ongoing clinical trials with another ARB, irbesartan, and an aldosterone blocker, spironolactone.     

Association entre l’hypertension artérielle,les traitements inhibiteurs du système rénine angiotensine et les formes graves de COVID-19. Étude prospective monocentrique française

Background and aimAngiotensin converting enzyme (ACE) type 2 is the receptor of SARSCoV-2 for cell entry into lung cells. Because ACE-2 may be modulated by ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), there are concern that patients treated with ACEIs and ARBs are at higher risk for COVID-19 infection or severity. This study sought to analyse the association of severe forms of COVID-19 and mortality with hypertension and a previous treatment with ACEI and ARB.MethodsProspective follow-up of 433 consecutive patients hospitalised for COVID-19 pneumonia confirmed by PCR or highly probable on clinical, biological, and radiological findings, and included in the COVHYP study. Mortality and severe COVID-19 (criteria: death, intensive care unit, or hospitalisation > 30 days) were compared in patients receiving or not ACEIs and ARBs. Follow-up was 100% at hospital discharge, and 96.5% at > 1 month.ResultsAge was 63.6 ± 18.7 years, and 40%) were female. At follow-up (mean 78 ± 50 days), 136 (31%) patients had severity criteria (death, 64 ; intensive care unit, 73; hospital stay > 30 days, 49). Hypertension (55.1% vs 36.7%, P < 0.001) and antihypertensive treatment were associated with severe COVID-19 and mortality. The association between ACEI/ARB treatment and COVID-19 severity criteria found in univariate analysis (Odds Ratio 1.74, 95%CI [1.14–2.64], P = 0.01) was not confirmed when adjusted on age, gender, and hypertension (adjusted OR1.13 [0.59–2.15], P = 0.72). Diabetes and hypothyroidism were associated with severe COVID-19, whereas history of asthma was not.ConclusionThis study suggests that previous treatment with ACEI and ARB is not associated with hospital mortality, 1- and 2-month mortality, and severity criteria in patients hospitalised for COVID-19. No protective effect of ACEIs and ARBs on severe pneumonia related to COVID-19 was demonstrated.     

Comparative effectiveness of antihypertensive drugs in nondiabetic patients with hypertension: A population‐based study

The authors compared the effectiveness of thiazide diuretic (TD), angiotensin‐converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), and calcium channel blocker (CCB) monotherapies for the treatment of nondiabetic hypertension using MarketScan Databases 2010–2014. Multivariable Cox regression models assessed whether the addition of a new antihypertensive drug, treatment discontinuation, or switch and major cardiovascular or cerebrovascular events varied across groups. A total of 565 009 patients started monotherapy with ACEIs (43.6%), CCBs (23.6%), TDs (18.8%), or ARBs (14.0%). Patients who took TDs had a higher risk for either drug addition or discontinuation than patients who took ACEIs (hazard ratio [HR], 0.69 [95% CI, 0.68–0.70] vs HR, 0.81 [95% CI, 0.80–0.81]), ARBs (HR, 0.67 [95% CI, 0.66–0.68] vs HR, 0.66 [95% CI, 0.65–0.67]), and CCBs (HR, 0.85 [95% CI, 0.84–0.87] vs HR, 0.94 [95% CI, 0.93–0.95]). Conversely, patients who took TDs experienced a lower risk of clinical events compared with patients who took ACEIs (HR, 1.24 [95% CI, 1.15–1.33]), ARBs (HR, 1.28 [95% CI, 1.18–1.39]), and CCBs (HR, 1.35 [95% CI, 1.25–1.46]). Our results provide a strong rationale for choosing TDs as first‐line monotherapy for the control of hypertension.     

Effects of monotherapy of temocapril or candesartan with dose increments or combination therapy with both drugs on the suppression of diabetic nephropathy.

We examined the effects of increasing the recommended initial doses of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), or of switching to combination therapy with both drugs, on diabetic nephropathy. Hypertensive type 2 diabetic patients with urinary albumin excretion (ACR) between 100 and 300 mg/g creatinine (Cre) were assigned to the following five groups in which an antihypertensive drug was administered at a recommended initial dose for 48 weeks, and then either the dose was doubled or an additional drugs was added to regimen for the following 48 weeks: N, nifedipine-CR (N) 20 mg/day (initial dose); T, ACEI temocapril (T) 2 mg/day; C, ARB candesartan (C) 4 mg/day; T+C, T first and then addition of C; C+T, C first and then addition of C. ACR decreased in the T (n=34), C (n=40), T+C (n=37) and C+T (n=35) groups, but not in the N group (n=18). However, the anti-proteinuric effect was less in the T than in the C, T+C or C+T groups, while no differences existed among the latter three. In each group, there were significant linear relationships between attained BP and ACR; however, the regression lines were shifted toward lower ACR level in the renin-angiotensin system-inhibition groups compared with the N group. These results indicate that an ACEI and/or ARB is superior to a CCB in retarding diabetic nephropathy, while the combination of low doses of ACEI and ARB has effects similar to those of high-dose ARB. Even among patients treated with an ACEI and/or ARB, lowering BP is important.     

Comparative Effectiveness of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Terms of Major Cardiovascular Disease Outcomes in Elderly Patients: A Nationwide Population-Based Cohort Study

Renin and aldosterone activity levels are low in elderly patients, raising concerns about the benefits and risks of angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARB) use. However, data from direct comparisons of the effects of ACEIs on ARBs in the elderly population remain inconclusive.In this nationwide study, all patients aged ≥ 70 years were retrieved from the Taiwan National Health Insurance database for the period 2000 to 2009 and were followed up until the end of 2010. The ARB cohort (12,347 patients who continuously used ARBs for ≥ 90 days) was matched to ACEI cohort using high-dimensional propensity score (hdPS). Intention-to-treat (ITT) and as-treated (AT) analyses were conducted.In the ITT analysis, after considering death as a competing risk, the ACEI cohort had similar risks of myocardial infarction (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.79–1.06), ischemic stroke (HR 0.98, 95% CI 0.90–1.07), and heart failure (HR 0.93, 95% CI 0.83–1.04) compared with the ARB cohort. No difference in adverse effects, such as acute kidney injury (HR 0.99, 95% CI 0.89–1.09) and hyperkalemia (HR 1.02, 95% CI 0.87–1.20), was observed between cohorts. AT analysis produced similar results to those of ITT analysis. We were unable to demonstrate a survival difference between cohorts (HR 1.03, 95% CI 0.88–1.21) after considering drug discontinuation as a competing risk in AT analysis.Our study supports the notion that ACEI and ARB users have similar risks of major adverse cardiovascular events (MACE), even in elderly populations.     

Target‐organ protection with combination renin‐angiotensin‐system blockade

Pharmacologic blockade of the renin‐angiotensin‐aldosterone system (RAS) has antihypertensive, anti‐atherogenic, antioxidant, and anti‐inflammatory effects. Treatment with angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been demonstrated to prevent atrial fibrillation and new‐onset diabetes, and provide cardiac, cerebral, and renal protection. Combination therapy with ACEIs and ARBs, compared with monotherapy, provides enhanced reno‐ and cardioprotection, although available data indicate that combination RAS blockade may be beneficial only in select patient groups, such as those with diabetes mellitus, chronic kidney disease, or heart failure (HF). In certain high‐risk patients, the use of ARBs provides comparable efficacy to that observed with ACEIs. The efficacy of these agents may stem from pleiotropic effects beyond blood pressure (BP) reduction. Several studies demonstrate achievement of clinical endpoints without significant effects on BP. Copyright © 2009 Wiley Periodicals, Inc.