Benefits Of Angiotensin-converting Enzyme Inhibitors Research Articles

Renin–angiotensin system inhibition and mortality in patients undergoing dialysis with coronary artery disease: insights from a multi-center observational study

ABSTRACT Background While the survival benefits of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are firmly established in the general population, their efficacy within patient undergoing dialysis with coronary artery disease (CAD) remains controversial. Methods Between January 2015 and June 2021, 1168 patients undergoing dialysis with CAD were assessed from 30 tertiary medical centers. The primary outcome was all-cause death, and the secondary outcome was cardiovascular death. Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were performed to account for between-group differences. Results Overall, ACEI or ARB were prescribed to 518 patients (44.3%) upon discharge. After a median follow-up of 22.2 months, 361 (30.9%) patients died, including 243 cardiovascular deaths. The use of ACEI or ARB was associated with a significantly lower risk of all-cause (25.3% vs 35.4%, hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.52–0.82, p < 0.001) and cardiovascular death (17.0% vs 23.8%; HR 0.64, 95% CI 0.48–0.83, p = 0.001). These findings remained consistent across IPTW and PSM analyses. Sensitivity analyses for ACEI and ARB use separately yielded similar results. Conclusions Our findings suggested that among patients undergoing dialysis with CAD, ACEI or ARB use was associated with a lower risk of all-cause and cardiovascular death.

Association of Hypertension with Different Cognitive Disorders.

This literature review explores the association between hypertension and major neurocognitive disorders, including delirium, Alzheimer's disease, vascular dementia, Lewy body dementia, and frontotemporal dementia, which contribute significantly to global mortality and morbidity. Hypertension is a potentially modifiable risk factor for cognitive decline, as it contributes to the progression of neurodegenerative pathologies via vascular damage, inflammation, and the disruption of the blood-brain barrier. Despite this, the effectiveness of antihypertensive treatments in preventing or alleviating cognitive decline remains contentious. While some research highlights the potential benefits of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, other studies show inconsistent results, complicated by variations in hypertension definitions, diagnostic criteria for cognitive disorders, and confounding factors like medication adherence. Furthermore, the complex bidirectional relationship between hypertension and major neurocognitive disorders warrants more investigation, as cognitive decline can exacerbate cardiovascular risks through heightened inflammatory responses and compromised autonomic regulation. This review underscores the need for prospective, long-term studies to elucidate the relationships between hypertension and cognitive disorders and to evaluate the potential therapeutic benefits of antihypertensive treatments.

Patients with Prior Exposure to a Combination of Statins & Angiotensin-Converting Enzyme Inhibitors (ACE-Is)/Angiotensin Receptor Blockers (ARBs) Have Better Outcomes after Carotid Revascularization than Patients with Prior Exposure to Statins Alone: A MultiCenter Analysis

Statin use has been studied and confirmed to have a beneficial impact on perioperative carotid endarterectomy (CEA) and carotid artery stenting (CAS) outcomes. The benefits of Angiotensin-converting enzyme inhibitors (ACE-I) in hypertension, ischemic heart disease, heart failure, diabetes mellitus, and renal disease are well-known; however, the impact of continuing or withholding ACE-Is/angiotensin receptor blockers (ARBs) on CEA and CAS outcomes is not addressed well in the literature. This study aimed to evaluate the impact of preoperative statin use combined with ACE-Is/ARBs in patients undergoing CEA or CAS on mortality and morbidity using a multi-institutional database. Using the data of all patients who underwent carotid artery revascularization, including CEA, transcarotid artery revascularization, and transfemoral carotid artery stenting from 2016 to 2021 in the Vascular Quality Initiative data, we determined as our primary outcome 30-day mortality/stroke after carotid revascularization based on periop exposure to statins alone, or the combination of statins and ACE-Is/ARBs. Secondary outcomes were postop myocardial infarction and postop congestive heart failure. Poisson regression with robust variance was used to determine postop outcomes comparing the combination of statin and ACE-Is/ARBs group with statins alone group. A total of 131,285 patients were included in the study, with 59,860 (46%) patients receiving statin only, and 71,425 (54%) receiving both statin and ACE-Is/ARBs preoperatively. Both patient groups differed significantly in preop clinical and demographic characteristics. After adjusting for potential confounders, the statins plus ACE-I/ARB group had a 12% lower risk of postop mortality/stroke (Incident Rate Ratio comparing Statin/ACE group to Statins Only group [IRR] 0.88, 95% confidence interval 0.81-0.95, P=0.001), 18% lower risk of postop congestive heart failure (IRR 0.82, 95% CI 0.68-0.98, P=0.029), and similar risk of postop myocardial infarction (IRR 1.05 95% confidence interval 0.91-1.20, P=0.54) compared to the statin-only group. Statins combined with ACE-Is/ARBs perioperatively offer better protection compared to statins alone in patients undergoing carotid revascularization surgery. We recommend the continuation of ACE-Is/ARBs use in patients undergoing carotid revascularization, especially if they have concurrent hypertension. Further prospective studies are needed to evaluate the benefit of adding ACE-Is/ARBs.

Patient-Reported Barriers to Adherence Among ACEI/ARB Users from a Motivational Interviewing Telephonic Intervention.

PurposeHypertension is a common comorbidity among type 2 diabetes mellitus (T2DM) patients, which increases the risk of cardiovascular diseases. Despite the proven benefit of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in this population, poor medication adherence is prevalent, resulting in higher complications and mortality rate. Motivational interviewing (MoI) has demonstrated effectiveness in improving medication adherence and identifying barriers. This study aimed to assess and identify patient-reported barriers to adherence to ACEI/ARB from an MoI telephonic intervention conducted by student pharmacist interns.Patients and MethodsThis retrospective study was conducted within an MoI intervention customized by past ACEI/ARB adherence trajectories for nonadherent patients with T2DM and hypertension enrolled in a Medicare Advantage Plan. Adherence barriers were extracted from the interviewers’ notes by two independent researchers. Descriptive analysis was performed to summarize the overall frequency of barriers as well as across trajectory groups, identified from the initial and follow-up calls.ResultsIn total, 247 patients received the initial MoI call from which 41% did not communicate any barrier for ACEI/ARB use despite having low adherence. About 59% of the patients reported at least one barrier during the initial call. The most common barriers included forgetfulness, discontinuation by physicians, side effects, multiple comorbidities, polypharmacy, lack of knowledge about disease/medication, and cost issues. The follow-up calls helped with uncovering at least one new barrier for 28 patients who previously communicated a different issue with their medication during the first call. Additionally, 18 patients with initial denial for having any barrier to adherence reported at least one barrier throughout the follow-up calls.ConclusionThis study summarized patient-reported barriers to ACEI/ARB adherence from an MoI telephonic intervention performed among nonadherent patients. Identifying specific barriers for patients may help to further design tailored interventions that address the barriers and improve adherence.

Effect of ACE Inhibitor Therapy on Mortality in COVID-19 Patients with Hypertension: Meta-Analysis

Background: Acute respiratory syndrome Corona Virus 2 (SARS-CoV-2) can trigger the occurrence of respiratory infectious disease Coronavirus Disease 2019 (COVID-19). Patients who have comorbid health problems such as hypertension, chronic liver, cardiovascular and diabetes mellitus are more likely to experience deterioration and death. ACE inhibitor therapy in patients with hypertension has a therapeutic effect in lowering blood pressure and is able to reduce mortality rates in COVID-19 patients, but the benefits of ACE inhibitors in patients with COVID-19 are still uncertain. This study aims to determine how much influence ACE inhibitors have on COVID-19 patients with hypertension on mortality rates.Subjects and Method: This study is a systematic review and meta-analysis with the following PICO, population: COVID-19 patients with hypertension. Intervention: administration of ACE inhibitor therapy. Comparison: therapy other than ACE inhibitors. Outcome: mortality. The articles used in this study were obtained from several online databases, including Science Direct, PubMed and Google Scholar. The keywords used in the article search were: “ACE inhibitor” AND “COVID-19” AND “Hypertension” AND “mortality”. The articles included are full-text English with a cohort study design from 2020 to 2021 and report the odds ratio in multivariate analysis. The selection of articles was carried out using the PRISMA flow chart. The articles were analyzed using the Review Manager 5.4. application.Results: A total of 4 cohort studies involving 4,998 COVID-19 patients from America, China and Italy were selected for systematic review and meta-analysis. The data collected yielded information that COVID-19 patients with hypertension who were given ACE inhibitors reduced the risk of mortality 0.67 times compared to COVID-19 patients with hypertension who were not treated with ACE inhibitors (aOR= 0.67; 95% CI= 0.36 to 1.26; p= 0.210).Conclusion: ACE inhibitors can reduce the risk of mortality in COVID-19 patients with hypertension. Keywords: COVID-19, hypertension, ACE inhibitors, mortality. Correspondence:Dwi Trisnawati Zainal. Social Security Administrator for Health, Madiun, East Java. Jl. Timor 6 Madiun, East Java, Indonesia. Email: dwitrisnawatiz@gmail.com. Mobile: 081331282009.

Chronic use of renin–angiotensin–aldosterone inhibitors in hypertensive COVID-19 patients: Results from a Spanish registry and meta-analysis

BackgroundHypertension is a prevalent condition among SARS-CoV-2 infected patients. Whether renin–angiotensin–aldosterone system (RAAS) inhibitors are beneficial or harmful is controversial. MethodsWe have performed a national retrospective, nonexperimental comparative study from two tertiary hospitals to evaluate the impact of chronic use of RAAS inhibitors in hypertensive COVID-19 patients. A meta-analysis was performed to strengthen our findings. ResultsOf 849 patients, 422 (49.7%) patients were hypertensive and 310 (73.5%) were taking RAAS inhibitors at baseline. Hypertensive patients were older, had more comorbidities, and a greater incidence of respiratory failure (−0.151 [95% CI −0.218, −0.084]). Overall mortality in hypertensive patients was 28.4%, but smaller among those with prescribed RAAS inhibitors before (−0.167 [95% CI −0.220, −0.114]) and during hospitalization (0.090 [−0.008,0.188]). Similar findings were observed after two propensity score matches that evaluated the benefit of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers among hypertensive patients. Multivariate logistic regression analysis of hypertensive patients found that age, diabetes mellitus, C-reactive protein, and renal failure were independently associated with all-cause mortality. On the contrary, ACEIs decreased the risk of death (OR 0.444 [95% CI 0.224–0.881]). Meta-analysis suggested a protective benefit of RAAS inhibitors (OR 0.6 [95% CI 0.42–0.8]) among hypertensive COVID-19. ConclusionOur data suggest that RAAS inhibitors may play a protective role in hypertensive COVID-19 patients. This finding was supported by a meta-analysis of the current evidence. Maintaining these medications during hospital stay may not negatively affect COVID-19 outcomes.

Old and new therapeutic strategies in systemic sclerosis (Review).

Systemic sclerosis (SSc) is a chronic inflammatory disease with autoimmune determinism having an incompletely known pathogenesis. Although not all links in the pathogenic chain are known, studies have shown that vasculopathy is the initial event and is followed by extensive fibrosis of the skin and internal organs. New therapeutic strategies have been developed in recent years, thanks to innovative research which has increased understanding of the disease mechanisms. No curative treatment for SSc is currently known. Therefore, the therapeutic target in SSc is its symptomatology. Peripheral vasculopathy can be improved by administering vasodilators. Endothelin receptor antagonists and 5-phosphodiesterase inhibitors have a double benefit, both on peripheral and on pulmonary vasculopathy. Several molecules with antifibrotic effects are currently available; however, further studies are needed to confirm their beneficial effects. Immunosuppressants manage to control the cutaneous and visceral fibrotic process, thereby remaining as first-line drugs in the treatment of SSc. Although biological therapy using rituximab and tocilizumab has shown promising results in pulmonary fibrosis, ongoing studies are needed to determine their exact impact. The authors have differing views on the triggering role of glucocorticoids and the benefits of angiotensin-converting enzyme inhibitors in renal scleroderma. Some aspects of this disease such as calcinosis and pruritus, asthenia, or joint and muscle damage, remain difficult to manage.

Two Opposing Functions of Angiotensin-Converting Enzyme (ACE) That Links Hypertension, Dementia, and Aging.

A 2018 report from the American Heart Association shows that over 103 million American adults have hypertension. The angiotensin-converting enzyme (ACE) (EC 3.4.15.1) is a dipeptidyl carboxylase that, when inhibited, can reduce blood pressure through the renin–angiotensin system. ACE inhibitors are used as a first-line medication to be prescribed to treat hypertension, chronic kidney disease, and heart failure, among others. It has been suggested that ACE inhibitors can alleviate the symptoms in mouse models. Despite the benefits of ACE inhibitors, previous studies also have suggested that genetic variants of the ACE gene are risk factors for Alzheimer’s disease (AD) and other neurological diseases, while other variants are associated with reduced risk of AD. In mice, ACE overexpression in the brain reduces symptoms of the AD model systems. Thus, we find two opposing effects of ACE on health. To clarify the effects, we dissect the functions of ACE as follows: (1) angiotensin-converting enzyme that hydrolyzes angiotensin I to make angiotensin II in the renin–angiotensin system; (2) amyloid-degrading enzyme that hydrolyzes beta-amyloid, reducing amyloid toxicity. The efficacy of the ACE inhibitors is well established in humans, while the knowledge specific to AD remains to be open for further research. We provide an overview of ACE and inhibitors that link a wide variety of age-related comorbidities from hypertension to AD to aging. ACE also serves as an example of the middle-life crisis theory that assumes deleterious events during midlife, leading to age-related later events.

Chronic use of renin–angiotensin–aldosterone inhibitors in hypertensive COVID-19 patients: Results from a Spanish registry and meta-analysis

BackgroundHypertension is a prevalent condition among SARS-CoV-2 infected patients. Whether renin–angiotensin–aldosterone system (RAAS) inhibitors are beneficial or harmful is controversial. MethodsWe have performed a national retrospective, nonexperimental comparative study from two tertiary hospitals to evaluate the impact of chronic use of RAAS inhibitors in hypertensive COVID-19 patients. A meta-analysis was performed to strengthen our findings. ResultsOf 849 patients, 422 (49.7%) patients were hypertensive and 310 (73.5%) were taking RAAS inhibitors at baseline. Hypertensive patients were older, had more comorbidities, and a greater incidence of respiratory failure (−0.151 [95% CI −0.218, −0.084]). Overall mortality in hypertensive patients was 28.4%, but smaller among those with prescribed RAAS inhibitors before (−0.167 [95% CI −0.220, −0.114]) and during hospitalization (0.090 [−0.008,0.188]). Similar findings were observed after two propensity score matches that evaluated the benefit of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers among hypertensive patients. Multivariate logistic regression analysis of hypertensive patients found that age, diabetes mellitus, C-reactive protein, and renal failure were independently associated with all-cause mortality. On the contrary, ACEIs decreased the risk of death (OR 0.444 [95% CI 0.224–0.881]). Meta-analysis suggested a protective benefit of RAAS inhibitors (OR 0.6 [95% CI 0.42–0.8]) among hypertensive COVID-19. ConclusionOur data suggest that RAAS inhibitors may play a protective role in hypertensive COVID-19 patients. This finding was supported by a meta-analysis of the current evidence. Maintaining these medications during hospital stay may not negatively affect COVID-19 outcomes.

Effects of Angiotensin Receptor Blockers (ARBs) on In-Hospital Outcomes of Patients With Hypertension and Confirmed or Clinically Suspected COVID-19.

BackgroundThere is an ongoing controversy about harms and benefits of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in hypertensive patients with coronavirus disease 2019 (COVID-19). Given the unresolved debate, we investigated the association of ARBs with in-hospital outcomes of these patients.MethodsIn this retrospective observational study, we studied patients with COVID-19 who referred to Sina Hospital in Tehran, Iran, from February 20 to May 29, 2020. Patients with either positive real-time reverse-transcriptase polymerase-chain-reaction test of swab specimens, or high clinical suspicion according to the World Health Organization's interim guidance were included. We followed-up patients for incurring death, severe COVID-19, and in-hospital complications.ResultsWe evaluated 681 patients with COVID-19 of whom 37 patients were excluded due to incomplete medical records and 8 patients who used ACEIs which left 636 patients in the analysis. In this cohort, 108 (17.0%) patients expired and 407 (64.0%) patients incurred severe COVID-19. Of 254 (39.9%) patients with hypertension, 122 (48.0%) patients were receiving an ARB. After adjustment for possible confounders, we found no independent association between taking ARBs and in-hospital outcomes except for acute kidney injury (AKI), in patients with confirmed or clinically suspected COVID-19, either hypertensive or not-hypertensive. We found that discontinuation of ARBs during hospitalization was associated with a greater risk of mortality, invasive ventilation, and AKI (All P˂0.002).ConclusionsWe found that taking ARBs by patients with hypertension and confirmed or clinically suspected COVID-19 is not associated with poorer in-hospital outcomes after adjustment for possible confounders.

The benefits of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers combined with calcium channel blockers on metabolic, renal, and cardiovascular outcomes in hypertensive patients: a meta-analysis.

The prevalence of hypertension and its associated complications are markedly growing. Most patients need more than one drug to achieve blood pressure (BP) target. However, most guidelines only focus on the first-line treatment. We conducted a meta-analysis to explore the benefits of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) combined with calcium channel blockers (CCBs) on metabolic, renal, and cardiovascular outcomes in hypertensive patients. A systematic literature search was conducted in MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, and Clinical Trials.gov (until April 7, 2016) to identify randomized controlled trials (RCTs) comparing the benefits of ACEIs/ARBs combined with CCBs versus other dual or triple combinations on clinical outcomes in hypertensive patients. Random effects models were used to compute the weighted mean difference (WMD) for continuous variables. Sixty RCTs (48,913 patients) were identified. When compared with other combinations, the combination of ACEIs/ARBs and CCBs had comparable WMD of systolic as well as diastolic BP (73 study arms) but provided better benefits on metabolic parameters, such as HDL, FBS, HbA1C, and serum uric acid; renal functions, including serum creatinine and estimated glomerular filtration rate; and cardiovascular diseases, including reduction of all cardiovascular events, myocardial infarction, and syncope/hypotension. A significant increase of serum potassium was observed. The combination of ACEIs/ARBs with CCBs has superior benefits on metabolic, renal, and cardiovascular outcomes in hypertensive patients. Therefore, this combination should be considered whenever monotherapy does not achieve the guideline target.

Prevention of Trastuzumab and Anthracycline-induced Cardiotoxicity Using Angiotensin-converting Enzyme Inhibitors or β-blockers in Older Adults With Breast Cancer.

Although clinical trials have provided some data on the benefit of angiotensin-converting enzyme inhibitors (ACEIs) or β-blockers (BBs) in patients with chemotherapy-induced cardiotoxicity, evidence of ACEIs/BBs on prevention of trastuzumab and/or anthracycline-induced cardiotoxicity outside trials is limited. A cohort study of 142,990 women (66 y and above) newly diagnosed with breast cancer from 2001 to 2009 was conducted using the Surveillance, Epidemiology, and End Results-Medicare-linked database. The ACEI/BB exposure was defined as filled prescription(s) before or after the initiation of trastuzumab/anthracyclines. The nonexposed group was defined as those who had never been prescribed ACEIs/BBs. Cumulative rates of cardiotoxicity and all-cause mortality were estimated and marginal structural Cox models were used to determine factors associated with cardiotoxicity and all-cause mortality adjusting for baseline covariates and use of chemotherapy. All statistical tests were 2 sided. The final sample included 6542 women. Adjusted hazard ratio for cardiotoxicity and all-cause mortality for the ACEI/BB exposed group were 0.77 (95% confidence interval, 0.62-0.95) and 0.79 (95% confidence interval, 0.70-0.90) compared with the nonexposed group, respectively. Starting ACEIs/BBs≤6 months after the initiation of trastuzumab/anthracyclines and having exposed duration≥6 months were also associated with decreased risk of cardiotoxicity and all-cause mortality. Baseline characteristics, including age, non-Hispanic black, advanced cancer, region, comorbidity, preexisting cardiovascular conditions, lower socioeconomic status, and concomitant treatment were significantly associated with an elevated risk of all-cause mortality and/or cardiotoxicity (all P<0.05). ACEIs/BBs show favorable effects on preventing cardiotoxicity and improving survival in female breast cancer patients undergoing trastuzumab/anthracycline treatment.

4061One year survival benefit of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in acute coronary syndrome undergoing PCI according to left ventricular ejection fraction

4061One year survival benefit of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in acute coronary syndrome undergoing PCI according to left ventricular ejection fraction

Effects of adding Rheum officinale to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on renal function in patients with chronic renal failure: Ameta-analysis of randomized controlled trials .

<italic>Rheum officinale</italic> is a traditional medicinal herb used widely in China to treat chronic renal failure, but the proof of evidence-based medicine is poor. This meta-analysis aims to assess the benefits of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) supplemented with <italic>Rheum officinale</italic> for delaying the progression of chronic renal failure. The MEDLINE, EMBASE, Cochrane Library, SinoMed, Chinese National Knowledge Infrastructure, Wanfang, and VIP databases were searched to identify studies published before September 2016 that investigated the effects of ACEI/ARB plus the Chinese patented medicine Rheum (CPM-Rheum) compared to ACEI/ARB alone in lowering serum creatinine (SCr) and blood urea nitrogen (BUN) levels in chronic renal failure patients. Review Manager 5.3 was used to perform the meta-analysis. Fixed- and random-effects models were used to analyze the data. The meta-analysis included nine clinical trials. Comparisons of patients before and after treatment with ACEI/ARB plus CPM-Rheum or ACEI/ARB alone revealed that ACEI/ARB plus CPM-Rheum resulted in significantly greater reductions in SCr (short-term: weighted mean difference (WMD): 17.26, 95% confidence interval (CI): 7.28-27.24; long-term: WMD: 63.71, 95% CI: 51.01-76.41) and BUN (short-term: WMD: 1.70, 95% CI: 1.27-2.12; long-term: WMD: 3.98, 95% CI: 3.14-4.82) than ACEI/ARB alone. In patients with chronic renal failure, the addition of CPM-Rheum to ACEI/ARB significantly lowered both SCr and BUN, particularly after long-term administration. Thus, the combination of ACEI/ARB and CPM-Rheum may improve the treatment of patients with impaired renal function. .

Abstract 265: Angiotensin-Converting-Enzyme Inhibition in Stable Coronary Artery Disease and Cardiomyopathy With Mid-range Ejection Fraction: Insights From the PEACE Trial

Background: There have been significant advances in the treatment of patients with cardiomyopathy with reduced ejection fraction (EF &lt;40%). However, there is a dearth of information in the treatment of patients with cardiomyopathy and mid-range ejection fraction (EF 40 to 50%). Current guidelines state to treat these patients as patients with cardiomyopathy and preserved ejection fraction. The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial was conducted on patients with stable coronary artery disease and normal or slightly reduced left ventricular function to evaluate the benefit of an ACE inhibitor, trandolapril, versus modern conventional therapy. This trial did not show any advantage from treating these subjects with an ACE inhibitor. Our goal is to elucidate further whether ACE inhibitors reduce death in patients with cardiomyopathy and mid-range ejection fraction. Methods: PEACE Trial data was used to evaluate the effect of ACE inhibitors in a subgroup of patients with cardiomyopathy and mid-range ejection fraction (40-50%). A chi-square test and a t-test were used to examine and compare the binary and continuous variables of demographic and health characteristics between experimental and comparison groups. A chi-square test was used to compare the difference in outcomes between the two groups. The statistical analyses were performed using SAS version 9.4. All tests were conducted using an α=0.05 as the probability of a Type I error. Results: We studied a subgroup of subjects from the PEACE trial with cardiomyopathy and mid-range ejection fraction (n=2512 of 8290 total subjects). Subjects were randomly assigned to the interventional group (n=1247) and the placebo group (n=1265). There were no significant differences in baseline demographic and health characteristics between the two groups. The risks of composite outcomes (death from cardiovascular causes, death from noncardiovascular causes, nonfatal myocardial infarction, and stroke) (RR 0.88, 95% CI 0.78-0.99; P=0.03) and death from any causes (RR 0.85, 95% CI 0.73-0.99; P=0.03) were lower in subjects treated with trandolapril. Conclusion: This study unveiled the benefit of ACE inhibitors among patients with cardiomyopathy and mid-range EF.

Approaching Regulatory Approval of Cardiovascular Regenerative Therapy.

> For the race is not always to the swift …. > > —Aesop (600–564 BC) After 25 years of research and well over a decade after the first randomized blinded clinical trials suggested benefit of stem cell therapy on cardiac performance, the field seems no closer to clinical approval of a product, and skepticism exists about the viability of the idea that myocardial regeneration can be effected. What has kept the field from crossing the finish line of clinical approval and is the goal in site? From a regulatory perspective, the efficacy and safety of regenerative approaches remain unproven.1 Despite significant expenditures of time and funding, definitive adequately powered trials have yet to be completed. Many of the challenges in the field of myocardial regeneration reflect obstacles in cardiovascular drug development as a whole. Improvements in the treatment of cardiovascular disease have resulted in dramatic reductions in cardiovascular mortality and have extended the life span of patients with cardiovascular disease but have also resulted in an increased prevalence of chronic conditions like congestive heart failure and refractory angina. These improvements in care have paradoxically increased the burden of disease and need for new therapies while exponentially increasing the number of patients required to demonstrate effectiveness. Recent estimates indicate that the cost of bringing a new drug to market increased from $140 million in the 1970s to >$2.5 billion in 2014 and tripled in the past decade alone.2 The implications of this can be seen in an example from the field of heart failure: although the CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study; published in 1987) proved a mortality benefit of angiotensin-converting enzyme inhibition after following up 253 patients for 6 months, the benefit of sacubitril/valsartan in 2014 required enrollment of >8000 patients and 27-month follow-up to demonstrate an effect on …

Combined blockade of renin-angiotensin-aldosterone system reduced all-cause but not cardiovascular mortality in dialysis patients: A mediation analysis and systematic review

Background and aimsFull blockade of renin-angiotensin-aldosterone system (RAAS) is believed to decrease morbidity and mortality of patients with chronic kidney disease. In non-dialysis patients, combined RAAS blockade with two different RAAS blockers causes more adverse events without improving survival, but its role in maintenance dialysis patients is still unclear. We conducted a systematic review and mediation analysis to investigate the efficacy and safety of combined RAAS blockade in dialysis patients. MethodsComprehensive search was conducted in PubMed, EMBASE, Web of Science and Cochrane Library database to June 2017 to identify relevant studies. Studies comparing combined with single RAAS blockade and reporting all-cause death, cardiovascular death, hypotension or hyperkalemia in dialysis patients were included. Effect sizes were calculated with randomized effects model and summarized as odd ratios (OR). ResultsA total of 9 studies with 13,050 dialysis patients were included. Compared with single blockade, combined blockade significantly reduced all-cause mortality (OR 0.71, 95% confidence interval 0.54–0.93, p = 0.01), while cardiovascular mortality remained unchanged (0.85, 0.45–1.59, p = 0.61). Combined blockade tended to increase odd of hypotension but not odd of hyperkalemia (1.54, 1.00–2.38, p = 0.05; 0.89, 0.76–1.05, p = 0.17). Further mediation analysis indicated that hypotension might exert a suppression effect on the survival benefit of angiotensin-converting enzyme inhibitor plus angiotensin receptor blocker treatment on cardiovascular mortality. ConclusionsCombined RAAS blockade might be a promising treatment in dialysis patients to further reduce mortality if blood pressure was well controlled.

The effect of angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) on cancer recurrence and survival: a meta-analysis.

To assess the current evidence on the potential benefit of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) on cancer recurrence and survival, we comprehensively searched PubMed, Embase, and the Cochrane Library from their inception to April 2013. Two authors screened out duplicates and independently reviewed the eligibility of each study. We included comparative studies comparing the use and nonuse of ACEIs or ARBs in cancer patients. Primary outcomes were disease-free survival (DFS) and overall survival. We included 11 studies with 4964 participants in the final analysis. The meta-analysis showed that the use of ACEIs or ARBs resulted in a significant improvement in DFS [hazard ratio (HR) 0.60; 95% confidence interval (CI) 0.41-0.87; P=0.007)] and overall survival (HR 0.75; 95% CI 0.57-0.99; P=0.04). Even when cancer stage was classified into low (I/II) or high (III/IV), DFS improvement was applied to both low stage (HR 0.56; 95% CI 0.32-0.96; P=0.04) and high stage (HR 0.59; 95% CI 0.37-0.94; P=0.03). Analysis according to cancer type showed benefits in urinary tract cancer (HR 0.22), colorectal cancer (HR 0.22), pancreatic cancer (HR 0.58), and prostate cancer (HR 0.14), but not in breast cancer and hepatocellular cancer. This meta-analysis provides evidence that the use of ACEIs or ARBs in cancer patients can lead to a 40 and 25% reduction in the risk of cancer recurrence and mortality.

Newer Therapies for Amyloid Cardiomyopathy.

The heart and the kidneys are the most commonly involved organs in systemic amyloidosis. Cardiac involvement is associated with an increased morbidity, treatment intolerance, and poorer overall survival. The most common types of amyloidosis that are associated with cardiac involvement include light chain (AL) amyloidosis and transthyretin (TTR) amyloidosis (both mutant and wild type). The traditional first-line treatment for AL amyloidosis includes alkylator-based chemotherapy or high-dose melphalan followed by autologous stem cell transplantation (ASCT). Novel agents, including proteasome inhibitors, immunomodulators, and monoclonal antibodies, have shown promising activity in both frontline and relapsed settings. Orthotopic heart transplantation (OHT) followed by ASCT has led to superior outcomes compared to OHT alone. Orthotopic liver transplantation (OLT) is the first-line treatment for TTR amyloidosis. However, progression of cardiac amyloidosis after OLT is often noted due to deposition of wild TTR. Combined OLT and OHT also has a role in treatment and leads to superior outcomes in carefully selected candidates. Pharmacologic agents, including diflunisal, tafamidis, small interfering ribonucleic acid, and doxycycline, have shown promising activity in stabilizing TTR from misfolding into fibrils and are being actively investigated. Best supportive care and management of heart failure symptoms with diuretics are a mainstay of treatment in all cardiac amyloidosis subtypes. Robust data on the benefit of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta blockers in amyloid cardiomyopathy is lacking.

Pharmacologic management of types 1 and 2 diabetes mellitus and their complications in women of childbearing age.

The numbers of women of childbearing age with pregestational diabetes mellitus (diabetes existing before pregnancy) are increasing, primarily because more patients are developing type 2 diabetes at younger ages. The teratogenicity associated with hyperglycemia in early pregnancy is well documented, and tight glucose control minimizes the risk of congenital malformation. Preconception planning is essential; thus contraception that does not worsen complications of diabetes is desirable. In addition, because contraceptives are not 100% effective, the treatment of elevated blood glucose levels, hypertension, and dyslipidemia in these women requires consideration of unplanned pregnancy. We summarized the literature to aid clinicians in choosing individualized treatment that minimizes risk in case pregnancy occurs and maximizes benefit in preventing the complications of diabetes. In women with well-controlled diabetes without vascular disease, all contraceptive methods are safe. Intrauterine devices are recommended due to their minimal effects on risk factors for diabetic complications and their lack of reliance on patient adherence for efficacy. Among insulins, the insulin analogs-insulin lispro, insulin aspart, and insulin detemir-offer patients greater convenience than regular insulin and NPH insulin, and they are safe in case of unplanned pregnancy. Of the noninsulin agents, glyburide and metformin are the safest during pregnancy, but many of the other agents pose minimal risk as long as they are withdrawn during early pregnancy. The risks and benefits of angiotensin-converting enzyme inhibitors in women with compelling indications must be weighed individually. In hypertensive patients at a high risk for unplanned pregnancy, nifedipine should be considered due to literature supporting its safety during early pregnancy. Pravastatin is recommended for women with dyslipidemia who are using effective contraception because there have been no reports of birth defects with this statin when used during early pregnancy in humans and animals.