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Cardiovascular disease is a leading cause of death globally. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), compared in the ONTARGET trial (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial), each prevent cardiovascular disease. However, trial results may not be generalizable, and their effectiveness in underrepresented groups is unclear. Using trial emulation methods within routine-care data to validate findings, we explored the generalizability of ONTARGET results. For people prescribed an ACEi/ARB in the UK Clinical Practice Research Datalink GOLD dataset from January 1, 2001, to July 31, 2019, we applied trial criteria and propensity-score methods to create an ONTARGET trial-eligible cohort. Comparing ARB with ACEi, we estimated hazard ratios for the primary composite trial outcome (cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure) and secondary outcomes. Because the prespecified criteria were met, confirming trial emulation, we then explored treatment heterogeneity among 3 trial-underrepresented subgroups: females, persons aged ≥75 years, and those with chronic kidney disease. In the trial-eligible population (n  = 137 155), results for the primary outcome demonstrated similar effects of ARB and ACEi (hazard ratio = 0.97; 95% CI, 0.93-1.01), meeting the prespecified validation criteria. When extending this outcome to trial-underrepresented groups, similar treatment effects were observed by sex, age, and chronic kidney disease. This suggests that ONTARGET trial findings are generalizable to trial-underrepresented subgroups. This article is part of a Special Collection on Pharmacoepidemiology. [ABSTRACT FROM AUTHOR]

Hypertension is common and is a cause of morbidity and mortality around the world. Many affected are unaware that they have a problem, and it is found opportunistically when their blood pressure is recorded during a consultation for another problem. If the disease is inadequately treated, it can have potentially fatal outcomes. Nurses and non-medical prescribers are likely to come across patients with raised blood pressure readings during routine clinic appointments. This article hopes to give them a better understanding of the condition, its treatment and complications, with the aim of reducing the risk of serious problems and improving outcomes for all those affected by this potentially dangerous condition. [ABSTRACT FROM AUTHOR]

The article focuses on the importance of early and accurate diagnosis and coding in managing Chronic Kidney Disease (CKD) to delay deterioration in kidney function and optimize cardiovascular risk reduction, aiming to review CKD pathophysiology, recognize diagnostic criteria, implement evidence-based recommendations, reflect on cardiovascular risk reduction, determine complications, support patient understanding, and consider timely referrals into secondary care.

Aims: To determine whether initiation of treatment with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers (ACEI/ARBs) is associated with a subsequent reduction in haemoglobin in the general population. Methods: We undertook a national cohort study over a 13‐year period (2004–2016), using routine primary healthcare data from the UK Clinical Practice Research Datalink. We compared ACEI/ARB initiation with calcium channel blocker (CCB) initiation, to minimise confounding by indication. We included all first ACEI/ARB or CCB prescriptions in adults with at least 1 haemoglobin result in the 12 months before and 6 months after drug initiation. Our primary outcome was a ≥1 g/dL haemoglobin reduction in the 6 months after drug initiation. Results: We examined 146 610 drug initiation events in 136 655 patients. Haemoglobin fell by ≥1 g/dL after drug initiation in 19.5% (16 936/86 652) of ACEI/ARB initiators and 15.9% (9521/59 958) of CCB initiators. The adjusted odds ratio of a ≥1 g/dL haemoglobin reduction in ACEI/ARB initiators vs CCB initiators was 1.15 (95% confidence interval 1.12–1.19). Conclusion: ACEI/ARBs are associated with a modest increase in the risk of a haemoglobin reduction. For every 100 patients in our study that initiated a CCB, 16 experienced a ≥1 g/dL haemoglobin decline. If the effect is causal, 3 additional patients would have experienced this outcome if they had received an ACEI/ARB. This may have implications for drug choice and monitoring for many patients in primary care. Further research could identify patients at higher risk of this outcome, who may benefit from closer monitoring. [ABSTRACT FROM AUTHOR]

Aims: The SARS-CoV-2 virus binds to the angiotensin-converting enzyme 2 (ACE2) receptor for cell entry. It has been suggested that angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB), which are commonly used in patients with hypertension or diabetes and may raise tissue ACE2 levels, could increase the risk of severe COVID-19 infection.Methods and Results: We evaluated this hypothesis in a consecutive cohort of 1200 acute inpatients with COVID-19 at two hospitals with a multi-ethnic catchment population in London (UK). The mean age was 68 ± 17 years (57% male) and 74% of patients had at least one comorbidity. Overall, 415 patients (34.6%) reached the primary endpoint of death or transfer to a critical care unit for organ support within 21 days of symptom onset. A total of 399 patients (33.3%) were taking ACEi or ARB. Patients on ACEi/ARB were significantly older and had more comorbidities. The odds ratio for the primary endpoint in patients on ACEi and ARB, after adjustment for age, sex and co-morbidities, was 0.63 (95% confidence interval 0.47-0.84, P < 0.01).Conclusions: There was no evidence for increased severity of COVID-19 in hospitalised patients on chronic treatment with ACEi or ARB. A trend towards a beneficial effect of ACEi/ARB requires further evaluation in larger meta-analyses and randomised clinical trials. [ABSTRACT FROM AUTHOR]

Just under 1 million people in the UK have symptomatic heart failure. Decompensated heart failure is associated with a particularly poor prognosis with in-hospital mortality at around 10%. Over the last 30 years renin-angiotensinaldosterone system antagonists have been shown to have incremental benefit on improved quality of life, reduced hospitalisation and mortality rates in those with heart failure with reduced ejection fraction. Concomitant chronic kidney disease and 'acute kidney injury' are common and associated with adverse outcomes. In patients with decompensated heart failure, congestion is a key driver of deterioration in renal function. Decongestion is fundamental to successful management. Yet it is not uncommon to see prognostically important medication (such as angiotensin converting enzyme inhibitors and mineralocorticoid antagonists) inappropriately stopped, along with under-diuresis of the patient. This leaves the patient still in a state of congestion without the prognostic medication at discharge, with resultant adverse outcome. The British Society for Heart Failure and the Renal Association have produced consensus guidance to help guide management in a more consistent fashion based on heart failure classification, whether the patient is congested and the degree of renal impairment. Early heart failure specialist review is associated with improved patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome.Methods: We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6-40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794.Findings: Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12-28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking β blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of -0·22 mm per year (-0·41 to -0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means -0·10 per year, 95% CI -0·19 to -0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events.Interpretation: Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications.Funding: British Heart Foundation, the UK Marfan Trust, the UK Marfan Association. [ABSTRACT FROM AUTHOR]

Background. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are the most commonly prescribed antihypertensive medications in higher-risk surgical patients. However, there is no clinical consensus on their use in the perioperative period, in part, due to an inconsistent evidence-base. To help inform the design of a large multi-centre randomized controlled trial (ISRCTN17251494), we undertook a questionnaire-based survey exploring variability in ACEi/ARB prescribing in perioperative practice. Methods. The online survey included perioperative scenarios to examine how consistent respondents were with their stated routine preoperative practice. Clinicians with an academic interest in perioperative medicine were primarily targeted between July and September 2017. STROBE guidelines for observational research and ANZCA Trials Group Survey Reporting recommendations were adhered to. Results. 194 responses were received, primarily from clinicians practicing in the UK. A similar minority of respondents continue ACEi (n = 57; 30%) and ARBs (n = 62; 32%) throughout the perioperative period. However, timing of preoperative cessation was highly variable, and rarely influenced by the pharmacokinetics of individual ACE-i/ARBs. Respondents' stated routine practice was frequently misaligned with their management of common pre- and postoperative scenarios involving continuation or restarting ACE-i/ARBs. Discussion. This survey highlights many inconsistencies amongst clinicians' practice in perioperative ACE-i/ARB management. Studies designed to reveal an enhanced understanding of perioperative mechanisms at play, coupled with randomised controlled trials, are required to rationally inform the clinical management of ACE-i/ARBs in patients most at risk of postoperative morbidity. [ABSTRACT FROM AUTHOR]

Background: Many patients with bronchiectasis have recurrent hospitalisations for infective exacerbations. Acute kidney injury (AKI) is known to be associated with increased in-hospital mortality. This study examined the frequency of AKI, associated risk-factors, and the association of AKI with in-hospital mortality among patients with bronchiectasis.Methods: Anonymised data of patients with non-cystic fibrosis bronchiectasis from the UK Clinical Practice Research Datalink, linked to Hospital Episode Statistics, were used to identify hospitalisations with a primary diagnosis of lower respiratory tract infection (LRTI), from 2004 to 2013. After estimating the proportion of AKI diagnoses, a multivariable logistic regression model was constructed to investigate which background factors were associated with AKI. In-hospital mortality was compared between hospitalisations with and without an AKI diagnosis, with subsequent logistic regression analyses carried out for the association between AKI and in-hospital mortality.Results: Of 7804 hospitalisations due to LRTI observed in 3477 patients with bronchiectasis, 230 hospitalisations involved an AKI diagnosis, an average of 2.9%. However, the percentage increased from less than 2% in 2004 to nearly 5% in 2013. After taking this temporal change into account, AKI was independently associated with older age, male sex, decreased baseline kidney function, previous history of AKI, and a diagnosis of sepsis. In-hospital mortality was 33.0% (76/230) and 6.8% (516/7574), in hospitalisations with and without AKI, respectively (P < 0.001). After adjustment for confounding factors, diagnosis of AKI remained associated with in-hospital mortality (Odds ratio 5.52, 95% confidence interval: 3.62-8.42).Conclusions: Among people with bronchiectasis hospitalised for infective exacerbations, there is an important subgroup of patients who develop AKI. These patients have substantially increased in-hospital mortality and therefore greater awareness is needed. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure and preserved ejection fraction (HFpEF) have a poor prognosis, and no therapies have been proven to improve outcomes. It has been proposed that heart failure, including HFpEF, represents overlapping syndromes that may have different prognoses. We present an exploratory study of patients enrolled in the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) using latent class analysis (LCA) with validation using the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved study to identify HFpEF subgroups.Methods and Results: In total, 4113 HFpEF patients randomized to irbesartan or placebo were characterized according to 11 clinical features. The HFpEF subgroups were identified using LCA. Event-free survival and effect of irbesartan on the composite of all-cause mortality and cardiovascular hospitalization were determined for each subgroup. Subgroup definitions were applied to 3203 patients enrolled in CHARM-Preserved to validate observations regarding prognosis and treatment response. Six subgroups were identified with significant differences in event-free survival (P < 0.001). Clinical profiles and prognoses of the six subgroups were similar in CHARM-Preserved. The two subgroups with the worst event-free survival in both studies were characterized by a high prevalence of obesity, hyperlipidaemia, diabetes mellitus, anaemia, and renal insufficiency (Subgroup C) and by female predominance, advanced age, lower body mass index, and high rates of atrial fibrillation, valvular disease, renal insufficiency, and anaemia (Subgroup F).Conclusion: Using a data-driven approach, we identified HFpEF subgroups with significantly different prognoses. Further development of this approach for characterizing HFpEF subgroups is warranted. [ABSTRACT FROM AUTHOR]

Background: In April/2009, the UK National Health Service initiated four Better Care Better Value (BCBV) prescribing indicators, one of which encouraged the prescribing of cheaper angiotensin-converting enzyme inhibitors (ACEIs) instead of expensive angiotensin receptor blockers (ARBs), with 80 % ACEIs/20 % ARBs as a proposed, and achievable target. The policy was intended to save costs without affecting patient outcomes. However, little is known about the actual impact of the BCBV indicator on ACEIs/ARBs utilisation and cost-savings. Therefore, this study aimed to evaluate the impact of BCBV policy on ACEIs/ARBs utilisation and cost-savings, including exploration of regional variations of the policy's impact.Methods: This cross-sectional study used data from the UK Clinical Practice Research Datalink. Segmented time-series analysis was applied to monthly ACEIs prescription proportion, adjusted number of ACEIs/ARBs prescriptions and costs.Results: Overall, the proportion of ACEIs prescription decreased during the study period from 71.2% in April/2006 to 70.7% in March/2012, with a small but a statistically significant pre-policy reduction in its monthly trend of 0.02% (p < 0.001). Instantly after its initiation, the policy was associated with a sudden reduction in the proportion of ACEIs prescription; however, it resulted in a statistically significant increase in the post-policy monthly trend of ACEIs prescription proportion of 0.013% (p < 0.001), resulting in an overall post-policy slope of -0.007%. Despite this post-policy induced increment, the policy failed to achieve the 80% target, which resulted in missing a potential cost-saving opportunity. The pre-policy trend of the adjusted number of ACEIs/ARBs prescriptions was increasing; however, their trends declined after the policy implementation. The policy affected neither total ACEIs/ARBs cost nor individual ACEIs or ARBs costs.Conclusions: ACEIs/ARBs utilisation was not affected by the BCBV policy. The small increase in post-policy ACEIs prescription proportion was not associated with any savings. This study represents a case study of a failed or ineffective policy and thus provides key learning lessons for other healthcare authorities. Given the existing opportunity of potential cost-savings from achieving the 80 % target, specific measures would be needed to enhance the policy implementation and uptake; however, this must be balanced against other cost-saving policies in other high-priority areas. [ABSTRACT FROM AUTHOR]

Aims This was a cohort study to evaluate whether individuals exposed to angiotensin receptor blockers have a reduced risk of dementia compared with those exposed to angiotensin-converting enzyme inhibitors. Methods The study included new users of angiotensin receptor blockers or angiotensin-converting enzyme inhibitors (from 1995 to 2010) from UK primary care practices contributing to the Clinical Research Practice Datalink. The association between exposure to angiotensin receptor blockers and the risk of incident dementia was analysed using a Cox model, adjusting for age, sex, body mass index, diabetes, hypertension, heart failure, statin use, socioeconomic status, alcohol, smoking, number of consultations and calendar year. Results A total of 426 089 persons were included in the primary analysis, with 45 541 persons exposed to angiotensin receptor blockers and the remainder to angiotensin-converting enzyme inhibitors. The total number of new diagnoses of dementia was 6517. There was weak evidence of a decreased risk of dementia with exposure to angiotensin receptor blockers, with follow-up beginning at 1 year after the start of treatment (adjusted hazard ratio 0.92, 95% confidence interval 0.85-1.00). An analysis restricted to the first 12 months after the index date showed a larger effect on dementia risk (adjusted hazard ratio 0.60, 95% confidence interval 0.50-0.72). Conclusions A small reduction in dementia risk was seen with angiotensin receptor blockers in comparison to angiotensin-converting enzyme inhibitors. However, the strongest association was seen in early follow-up, suggesting that the inverse association is unlikely to be causal, but instead reflects other important but unmeasured differences between angiotensin receptor blocker and angiotensin-converting enzyme inhibitor users. [ABSTRACT FROM AUTHOR]

Abstract: Poor outcomes and poor uptake of evidence based therapies persist for patients with heart failure in the United Kingdom. We offer a strategic analysis of services, defining the context, organization and objectives of the service, before focusing on implementation and performance. Critical flaws in past service development and performance are apparent, a consequence of failed performance management, policy and political initiative. The barriers to change and potential solutions are common to many health care systems. Integration, information, financing, incentives, innovation and values: all must be challenged and improved if heart failure services are to succeed. Modern healthcare requires open adaptive systems, continually learning and improving. The system also needs controls. Performance indicators should be simple, clinically relevant, and outcome focused. Heart failure presents one of the greatest opportunities to improve symptoms and survival with existing technology. To do so, heart failure services require radical reorganization. [Copyright &y& Elsevier]

We investigated whether angiotensin II receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACE-Is) are more strongly associated with Alzheimer's disease (AD), vascular dementia (VaD), and other dementias, than other anti-hypertensive drugs. We conducted a nested case-control analysis within the UK general practice research database, with prospectively recorded anti-hypertensive prescribing data. We sampled cases aged ≥60 years and diagnosed between 1997-2008 (5,797 with AD, 2,186 with VaD, 1,214 with unspecified/other dementia) which were matched to up to four controls by age, general practice and gender. We computed odds-ratios and dose response effects for AD, vascular and unspecified/other dementia, comparing those prescribed ARBs or ACE-Is for at least six months with patients prescribed other anti-hypertensives. We controlled for matching factors, co-morbidities, smoking status, an area measure of socioeconomic status, consultation rate and blood pressure and accounted for reverse causality by introducing time-lags of up to eight years prior to diagnosis/index date. Patients diagnosed with AD, vascular and unspecified/other dementia had fewer prescriptions for ARBs and ACE-Is. Inverse associations with AD were strongest for ARBs (odds-ratio; 0.47, 95%CI, 0.37-0.58) compared with ACE-Is (odds-ratio; 0.76, 95%CI, 0.69-0.84) (p(difference) < 0.001). Associations of ARBs with AD were stronger than for vascular dementia (p(difference) = 0.01) and unspecified/other dementia (p(difference) = 0.23). There were inverse dose-response relationships between ARBs and ACE-Is with AD (both p(trend) < 0.01). The inverse association of ACE-Is with AD diminished when using longer time lags but the ARB-AD association persisted. Patients with AD were around half as likely to be prescribed ARBs. Further randomized controlled trial evidence is required to rigorously test these findings. [ABSTRACT FROM AUTHOR]

Heart failure (HF) remains a significant healthcare burden in the UK, both in terms of high mortality for patients and financial cost to the NHS. Depending on the definition applied, 1-2 million people in the UK suffer from HF; this figure is continuing to rise, in part due to an ageing population and improved survival rates following a heart attack.1 Sacubitril/valsartan (Entresto), the first angiotensin receptor-neprilysin inhibitor (ARNI), is a recently licensed medication that has been shown to improve outcomes for patients with symptomatic chronic HF with reduced ejection fraction (HF-REF) compared with current gold-standard treatment with an ACE inhibitor. [ABSTRACT FROM AUTHOR]

In the UK, heart failure (HF) remains a leading cause of disability, hospitalisation, readmissions and death (30-40% of patients die within 12 months of diagnosis). Since the availability of specialist HF services varies across the country, many HF patients rely on practice nurses to monitor their care.3 Indeed, this multidisciplinary team (MDT) integrated, community approach has been endorsed by NICE guidelines in recognition of its necessity when delivering HF care.4 When any new drug is introduced into primary care, practice nurses need to know about the condition it is used to treat, current treatment guidelines, and the new treatment itself. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2) was previously engineered into a high affinity tetravalent format (ACE2-Fc-TD) that is a potential decoy protein in SARS-CoV-2 infection.We report that this protein shows greatly enhanced binding to SARS-CoV-2 spike proteins of the SARS-CoV-2 variants of concern B.1.1.7 (alpha variant, originally isolated in the United Kingdom) and B.1.351 (beta variant, originally isolated in South Africa) with picomolar compared with nanomolar Kd values. In addition, ACE2-Fc-TD displays greater neutralization of SARS-CoV-2 pseudotype viruses compared to a dimeric ACE2-Fc, with enhanced activity on variant B.1.351. This tetrameric decoy protein would be a valuable addition to SARS-CoV-2 therapeutic approaches, especially where vaccination cannot be used but also should there be any future coronavirus pandemics. • Soluble ACE2 coronavirus receptor neutralizes SARS-CoV-2 infection. • SARS-CoV-2 neutralization is enhanced by tetramerization of ACE2. • Tetrameric ACE2 is more potent than a dimeric form. • SARS-CoV-2 variants of concern are neutralized by tetrameric ACE2. • Tetrameric ACE2 decoy protein could be used in future, new coronavirus pandemics. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a complex clinical syndrome resulting from any structural or functional cardiac or non-cardiac disorder that impairs the ability of the heart to effectively pump blood around the body. Around 550,000 people in the UK have HF and almost as many have cardiac damage but without symptoms.1,2 The average general practice already cares for 30 patients with HF and can expect to diagnose the condition in about 10 patients each year,2 but prevalence is expected to rise with the ageing population and improved treatment. HF is always an essential topic for GPs and practice nurses, but the introduction of a first-in-class oral treatment makes the publication of this special issue particularly timely. [ABSTRACT FROM AUTHOR]