Measuring adherence to antihypertensive medication using an objective test in older adults attending primary care: cross-sectional study.

Analysis of urine samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS) has previously revealed high rates of non-adherence to antihypertensive medication. It is unclear whether these rates represent those in the general population. This study aimed to investigate whether it is feasible to collect urine samples in a primary care setting and analyse them using LC-MS/MS to detect non-adherence to antihypertensive medication. This study used a prospective, observational cohort design. Consecutive patients were recruited opportunistically from five general practices in UK primary care. They were aged ≥65 years with hypertension and had at least one antihypertensive prescription. Participants were asked to provide a urine sample for analysis of medication adherence. Samples were sent to a laboratory via post and analysed using LC-MS/MS. Predictors of adherence to medication were explored with multivariable logistic regression. Of 349 consecutive patients approached for the study, 214 (61.3%) gave informed consent and 191 (54.7%) provided a valid urine sample for analysis. Participants were aged 76.2 ± 6.6 years and taking a median of 2 antihypertensive medications (IQR 1-3). A total of 27/191 participants (14.2%) reported not taking all of their medications on the day of urine sample collection. However, LC-MS/MS analysis of samples revealed only 4/27 (9/191 in total; 4.7%) were non-adherent to some of their medications. Patients prescribed more antihypertensive medications were less likely to be adherent (OR 0.24, 95%CI 0.09-0.65). Biochemical testing for antihypertensive medication adherence is feasible in routine primary care, although non-adherence to medication is generally low, and therefore widespread testing is not indicated.

Association between antihypertensive treatment and adverse events: systematic review and meta-analysis.

OBJECTIVE: To examine the association between antihypertensive treatment and specific adverse events. DESIGN: Systematic review and meta-analysis. ELIGIBILITY CRITERIA: Randomised controlled trials of adults receiving antihypertensives compared with placebo or no treatment, more antihypertensive drugs compared with fewer antihypertensive drugs, or higher blood pressure targets compared with lower targets. To avoid small early phase trials, studies were required to have at least 650 patient years of follow-up. INFORMATION SOURCES: Searches were conducted in Embase, Medline, CENTRAL, and the Science Citation Index databases from inception until 14 April 2020. MAIN OUTCOME MEASURES: The primary outcome was falls during trial follow-up. Secondary outcomes were acute kidney injury, fractures, gout, hyperkalaemia, hypokalaemia, hypotension, and syncope. Additional outcomes related to death and major cardiovascular events were extracted. Risk of bias was assessed using the Cochrane risk of bias tool, and random effects meta-analysis was used to pool rate ratios, odds ratios, and hazard ratios across studies, allowing for between study heterogeneity (τ2). RESULTS: Of 15 023 articles screened for inclusion, 58 randomised controlled trials were identified, including 280 638 participants followed up for a median of 3 (interquartile range 2-4) years. Most of the trials (n=40, 69%) had a low risk of bias. Among seven trials reporting data for falls, no evidence was found of an association with antihypertensive treatment (summary risk ratio 1.05, 95% confidence interval 0.89 to 1.24, τ2=0.009). Antihypertensives were associated with an increased risk of acute kidney injury (1.18, 95% confidence interval 1.01 to 1.39, τ2=0.037, n=15), hyperkalaemia (1.89, 1.56 to 2.30, τ2=0.122, n=26), hypotension (1.97, 1.67 to 2.32, τ2=0.132, n=35), and syncope (1.28, 1.03 to 1.59, τ2=0.050, n=16). The heterogeneity between studies assessing acute kidney injury and hyperkalaemia events was reduced when focusing on drugs that affect the renin angiotensin-aldosterone system. Results were robust to sensitivity analyses focusing on adverse events leading to withdrawal from each trial. Antihypertensive treatment was associated with a reduced risk of all cause mortality, cardiovascular death, and stroke, but not of myocardial infarction. CONCLUSIONS: This meta-analysis found no evidence to suggest that antihypertensive treatment is associated with falls but found evidence of an association with mild (hyperkalaemia, hypotension) and severe adverse events (acute kidney injury, syncope). These data could be used to inform shared decision making between doctors and patients about initiation and continuation of antihypertensive treatment, especially in patients at high risk of harm because of previous adverse events or poor renal function. REGISTRATION: PROSPERO CRD42018116860.

Impact of point-of-care tests in community pharmacies: a systematic review and meta-analysis.

OBJECTIVES: To summarise the literature regarding the use of point-of-care test (POCT) in pharmacies versus control/usual care. DESIGN AND SETTING: Systematic review and random-effects meta-analysis in community pharmacy. DATA SOURCES: MEDLINE, Cochrane Central Register of Controlled Trials, Embase, ClinicalTrial.gov and Web of Science databases were searched. ELIGIBILITY CRITERIA: Articles were included if they: involved a POCT conducted by a community pharmacist, member of pharmacy staff or local equivalent; measured a clinically relevant outcome for example, clinical parameter monitoring. No clinical condition or language limits were set. PATIENT AND PUBLIC INVOLVEMENT: No patient involvement. DATA EXTRACTION AND SYNTHESIS: Data were independently extracted by two members of the review team to capture changes in clinical care that resulted from the use of the POCTs. The methodological quality of included studies was assessed, using the Cochrane Risk of Bias tool and Newcastle-Ottawa scale. RESULTS: Thirteen of the 1584 articles found were included in the meta-analyses. Studies covered four therapeutic areas: targeted anti-malarial therapy (n=3 studies), glycated haemoglobin (HbA1c) in diabetes (n=2 studies), lipid control (n=3 studies) and international normalised ratio (INR) control in patients taking warfarin (n=5 studies). POCT in pharmacies reduced the risk of receiving antimalarial treatment when not clinically indicated (risk ratio 0.34, 95% CI 0.31 to 0.37). Lipid and HbA1c control appeared largely unaffected by pharmacy POCTs, and the impact on INR time-in-therapeutic-range was inconclusive. CONCLUSIONS: Only 4 out of 13 included studies used a gold-standard randomised controlled trial (RCT) design, limiting our ability to conclusively determine the clinical utility of POCT conducted in pharmacies. Further RCTs are needed, particularly in areas such as upper respiratory tract infections, which have gathered momentum among service commissioners in recent years. PROSPERO REGISTRATION NUMBER: CRD42017048578.

Currently prescribed drugs in the UK that could upregulate or downregulate ACE2 in COVID-19 disease: a systematic review.

OBJECTIVE: To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. DESIGN: Systematic review. DATA SOURCE: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. STUDY SELECTION: Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. DATA EXTRACTION AND SYNTHESIS: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. RESULTS: We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). CONCLUSIONS: There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.

Drug treatments affecting ACE2 in COVID-19 infection: a systematic review protocol.

BACKGROUND: The SARS-CoV-2 virus causing COVID-19 binds human angiotensin-converting enzyme 2 (ACE2) receptors in human tissues. ACE2 expression may be associated with COVID-19 infection and mortality rates. Routinely prescribed drugs that up- or down-regulate ACE2 expression are, therefore, of critical research interest as agents that might promote or reduce risk of COVID-19 infection in a susceptible population. AIM: To collate evidence on routinely prescribed drug treatments in the UK that could up- or down-regulate ACE2, and thus potentially affect COVID-19 infection. DESIGN & SETTING: Systematic review of studies published in MEDLINE, Embase, CINAHL (Cumulative Index to Nursing and Allied Health Literature), the Cochrane Library, and Web of Science from inception to 1 April 2020. METHOD: A systematic review will be conducted in line with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Inclusion criteria will be: (1) assesses the effect of drug exposure on ACE2 level of expression or activity; (2) the drug is included in the British National Formulary (BNF) and, therefore, available to prescribe in the UK; and (3) a control, placebo, or sham group is included as comparator. Exclusion criteria will be: (1) ACE2 measurement in utero; (2) ACE2 measurement in children aged <18 years; (3) drug not in the BNF; and (4) review article. Quality will be assessed using the Cochrane risk of bias tool for human studies, and the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) risk of bias tool for animal studies. RESULTS: Data will be reported in summary tables and narrative synthesis. CONCLUSION: This systematic review will identify drug therapies that may increase or decrease ACE2 expression. This might identify medications increasing risk of COVID-19 transmission, or as targets for intervention in mitigating transmission.

Defining the relationship between arm and leg blood pressure readings: a systematic review and meta-analysis.

OBJECTIVES: To define the relationship between arm and leg blood pressure (BP) to inform the interpretation of leg BP readings in routine clinical practice where arm readings are not available. METHODS: Systematic review of all existing studies comparing arm and leg BP measurements. A search strategy was designed in MEDLINE and adapted to be run across six further databases. Articles were deemed eligible for inclusion if they measured and reported arm and leg BP taken in the supine position and/or the difference between the two. Mean values for arm-leg BP difference and measures of precision [95% confidence intervals (CIs) or SD] were extracted and entered into a random-effects meta-analysis. RESULTS: A total of 887 articles were screened and 44 were included in the descriptive analyses, including 9771 patients. In the general population, ankle SBP was 17.0 mmHg (95% CI 15.4-21.3 mmHg) higher than arm BP in the supine position. For DBP, there was no difference between arm and ankle BP (-0.3 mmHg, 95% CI -1.5-1.0 mmHg). In patients with vascular disease, SBP was -33.3 mmHg (95% CI -59.1 to -7.6 mmHg) lower in the ankle compared with the arm. CONCLUSION: This is the first review to provide empirical data defining the difference between BP in the arm and leg in the general population. Findings suggest a diagnostic threshold of 155/90 mmHg could be used for diagnosing hypertension when only ankle measurements are available in routine practice.

Hypertension referrals from community pharmacy to general practice: multivariate logistic regression analysis of 131 419 patients.

BACKGROUND: The burden of hypertension in primary care is high, and alternative models of care, such as pharmacist management, have shown promise. However, data describing outcomes from routine consultations between pharmacists and patients with hypertension are lacking. AIM: To identify factors associated with referral of patients from pharmacies to general practice within the first 2 weeks of starting a new antihypertensive medication. DESIGN AND SETTING: Multivariate logistic regression conducted on data from community pharmacies in England. METHOD: Data were obtained from the New Medicine Service between 2011 and 2012. Analyses were conducted on 131 419 patients. In all, 15 predictors were included in the model, grouped into three categories: patient-reported factors, demographic factors, and medication-related factors. RESULTS: Mean patient age was 65 years (±13 years), and 85% of patients were of white ethnicity. A total of 5895 (4.5%) patients were referred by a pharmacist to a GP within the first 2 weeks of starting a new antihypertensive medication. Patients reporting side effects (adjusted odds ratio [OR] 11.60, 95% confidence interval [CI] = 10.85 to 12.41) were most likely to be referred. Prescriptions for alpha-blockers were associated with referral (adjusted OR 1.28, 95% CI = 1.12 to 1.47), whereas patients receiving angiotensin-II receptor blockers were less likely to be referred (adjusted OR 0.89, 95% CI = 0.80 to 0.99). CONCLUSION: Most patients were followed up by pharmacists without the need for referral. Patient-reported side effects, medication-related concerns, and the medication class prescribed influenced referral. These data are reassuring, in that additional pharmacist involvement does not increase medical workload appreciably, and support further development of pharmacist-led hypertension interventions.

Overtesting and undertesting in primary care: a systematic review and meta-analysis.

BACKGROUND: Health systems are currently subject to unprecedented financial strains. Inappropriate test use wastes finite health resources (overuse) and delays diagnoses and treatment (underuse). As most patient care is provided in primary care, it represents an ideal setting to mitigate waste. OBJECTIVE: To identify overuse and underuse of diagnostic tests in primary care. DESIGN: Systematic review and meta-analysis. DATA SOURCES AND ELIGIBILITY CRITERIA: We searched MEDLINE and Embase from January 1999 to October 2017 for studies that measured the inappropriateness of any diagnostic test (measured against a national or international guideline) ordered for adult patients in primary care. RESULTS: We included 357 171 patients from 63 studies in 15 countries. We extracted 103 measures of inappropriateness (41 underuse and 62 overuse) from included studies for 47 different diagnostic tests.The overall rate of inappropriate diagnostic test ordering varied substantially (0.2%-100%)%).17 tests were underused >50% of the time. Of these, echocardiography (n=4 measures) was consistently underused (between 54% and 89%, n=4). There was large variation in the rate of inappropriate underuse of pulmonary function tests (38%-78%, n=8).Eleven tests were inappropriately overused >50% of the time. Echocardiography was consistently overused (77%-92%), whereas inappropriate overuse of urinary cultures, upper endoscopy and colonoscopy varied widely, from 36% to 77% (n=3), 10%-54% (n=10) and 8%-52% (n=2), respectively. CONCLUSIONS: There is marked variation in the appropriate use of diagnostic tests in primary care. Specifically, the use of echocardiography (both underuse and overuse) is consistently poor. There is substantial variation in the rate of inappropriate underuse of pulmonary function tests and the overuse of upper endoscopy, urinary cultures and colonoscopy. PROSPERO REGISTRATION NUMBER: CRD42016048832.

A comparison of blood pressure in community pharmacies with ambulatory, home and general practitioner office readings: systematic review and meta-analysis.

BACKGROUND: Blood pressure (BP) readings are traditionally taken in a clinic setting, with treatment recommendations based on these measurements. The clinical interpretation of BP readings taken in community pharmacies is currently unclear. This study aimed to systematically review all literature comparing community pharmacy BP (CPBP) readings with ambulatory BP monitoring (ABPM), home BP monitoring and general practitioner clinic readings. METHOD: Studies were included if they compared CPBP with at least one other measurement modality used for the diagnosis or management of hypertension. Mean CPBP readings were compared with other measurement modalities and summarized using random-effects meta-analyses. The primary outcome was to compare CPBP with gold standard ABPM readings. RESULTS: Searches generated 3815 studies of which eight were included in the meta-analyses. The mean systolic CPBP-daytime ABPM difference was small [+1.6 mmHg (95% confidence interval -1.2 to 4.3) three studies, n = 319]. CPBP was significantly higher than 24-h ABPM [+7.8 mmHg (95% confidence interval 1.5-14.1) three studies n = 429]. Comparisons with general practitioner clinic readings (six studies, n = 2100) were inconclusive with significant heterogeneity between studies. CPBP and home BP monitoring readings (five studies, n = 1848) were nonsignificantly different. Diastolic comparisons mirrored systolic comparisons in all but the CPBP-daytime ABPM comparison, where CPBP was significantly higher. CONCLUSION: Current evidence around the clinical interpretation of CPBP is inconclusive. Although this review suggests that adopting the 135/85 mmHg threshold for hypertension might be reasonable and potentially result in a higher sensitivity for detecting patients with truly raised BP in pharmacies, the impact of this lower threshold on increased referrals to general practice clinics must be considered.