Effect of diuretics on plasma renin activity in primary hypertension: A systematic review and meta-analysis.

AIMS: Plasma renin activity (PRA) is regarded as a marker of sodium and fluid homeostasis in patients with primary hypertension. Whether effects of diuretics on PRA differ according to class of diuretic, whether diuretics lead to a sustained increase in PRA, and whether changes in PRA relate to those in blood pressure (BP) is unknown. We performed a systematic review and meta-analysis of trials investigating the antihypertensive effects of diuretic therapy in which PRA and/or other biomarkers of fluid homeostasis were measured before and after treatment. METHODS: Three databases were searched: MEDLINE, EMBASE and The Cochrane Central Register of Controlled Trials. Titles were firstly screened by title and abstract for relevancy before full-text articles were assessed for eligibility according to a predefined inclusion/exclusion criteria. RESULTS: A total of 1684 articles were retrieved of which 61 met the prespecified inclusion/exclusion criteria. PRA was measured in 30/61 studies. Diuretics led to a sustained increase in PRA which was similar for different classes of diuretic (standardised mean difference [95% confidence interval] 0.481 [0.362, 0.601], 0.729 [0.181, 1.28], 0.541 [0.253, 0.830] and 0.548 [0.159, 0.937] for thiazide, loop, mineralocorticoid receptor antagonists/potassium-sparing and combination diuretics respectively, Q = 0.897, P = .826), and did not relate to the average decrease in blood pressure. CONCLUSION: In antihypertensive drug trials, diuretics lead to a sustained increase in average PRA, which is similar across different classes of diuretic and unrelated to the average reduction in blood pressure.

Grapefruit juice enhances the systolic blood pressure-lowering effects of dietary nitrate-containing beetroot juice.

AIMS: Dietary nitrate from sources such as beetroot juice lowers blood pressure (BP) via the nitrate-nitrite-nitric oxide (NO) pathway. However, NO and nitrite are inactivated via reoxidation to nitrate, potentially limiting their activity. Cytochrome P450-3A4 inhibition with troleandomycin prevents nitrite re-oxidation to nitrate in rodent liver. Grapefruit juice contains the CYP3A4 inhibitor furanocoumarin. We therefore hypothesized that grapefruit juice would enhance BP-lowering with beetroot juice by maintaining circulating [nitrite]. METHODS: We performed a randomized, placebo-controlled, 7-hour crossover study in 11 healthy volunteers, attending on 3 occasions, receiving: a 70-mL shot of active beetroot juice (Beet-It) and either (i) 250 mL grapefruit juice (Active Beet+GFJ), or (ii) 250 mL water (Buxton, Active Beet+H2 O); or (iii) Placebo Beet+GFJ. RESULTS: The addition of grapefruit juice to active beetroot juice lowered systolic BP (SBP): Active Beet+GFJ vs Active Beet+H2 O (P = .02), and pulse pressure, PP (P = .0003). Peak mean differences in SBP and PP were seen at T = 5 hours: -3.3 mmHg (95% confidence interval [CI] -6.43 to -0.15) and at T = 2.5 hours: -4.2 mmHg (95% CI -0.3 to -8.2), respectively. Contrary to the hypothesis, plasma [nitrite] was lower with Active Beet+GFJ vs Active Beet+H2 O (P = .006), as was salivary nitrite production (P = .002) and saliva volume (-0.34 mL/min [95% CI -0.05 to -0.68]). The taste score of Beet+GFJ was 1.4/10 points higher than Beet+H2 O (P = .03). CONCLUSION: Grapefruit juice enhanced beetroot juice's effect on lowering SBP and PP despite decreasing plasma [nitrite]. Besides suggesting more complex mechanisms, there is potential for maximising the clinical benefit of dietary nitrate and targeting isolated systolic hypertension.

Reorganizing the treatment of cardiovascular disease in response to coronavirus disease 2019; time for the polypill?

PURPOSE OF REVIEW: The coronavirus disease 2019 (COVID-19) pandemic has forced a redesign of healthcare services. Resource reallocation will have consequences on the routine management of chronic diseases, including cardiovascular disease (CVD). We consider how to mitigate potential adverse effects. RECENT FINDINGS: Combination therapy is well established in hypertension. Many guidelines recommend dual antihypertensive therapy as the initial treatment step as this results in faster blood pressure control, albeit with limited evidence of improved outcomes. Control of CVD risk factors through multiclass combination therapy (the polypill) was proposed many years ago. This approach has not been adopted by Western healthcare systems despite improving surrogate outcomes. Recently, the PolyIran trials have demonstrated improved CVD outcomes without increased adverse events, in both primary and secondary prevention. SUMMARY: The COVID-19 pandemic allows models of chronic healthcare to be rethought. Current practices are resource-intensive and there is a need to simplify titration and monitoring protocols in CVD. Moving toward the use of polypill combinations allied with telehealth consultations may be one solution.

Antithrombotic dose: Some observations from published clinical trials.

The clinical doses of antithrombotics-antiplatelet and anticoagulant agents-need to balance efficacy and safety. It is not clear from the published literature how the doses currently used in clinical practice have been derived from preclinical and clinical data. There are few large randomised controlled trials (RCTs) that compare outcomes with different doses vs placebo. For newer antithrombotics, RCT doses appear to have been chosen to maximise the probability of demonstrating noninferiority when compared to established agents such as warfarin or clopidogrel. Data from RCTs show that aspirin is an effective antithrombotic at doses below 75 mg daily, and that direct oral anticoagulants reduce the risk of stroke in patients with coronary disease at doses 1/4 of those recommended in atrial fibrillation. Lower doses than those currently recommended are safer and still maintain substantial efficacy.

Acute interaction between oral glucose (75 g as Lucozade) and inorganic nitrate: Decreased insulin clearance, but lack of blood pressure-lowering.

AIMS: Dietary inorganic nitrate (NO3- ) lowers peripheral blood pressure (BP) in healthy volunteers, but lacks such effect in individuals with, or at risk of, type 2 diabetes mellitus (T2DM). Whilst this is commonly assumed to be a consequence of chronic hyperglycaemia/hyperinsulinaemia, we hypothesized that acute physiological elevations in plasma [glucose]/[insulin] blunt the haemodynamic responses to NO3- , a pertinent question for carbohydrate-rich Western diets. METHODS: We conducted an acute, randomized, placebo-controlled, double-blind, crossover study on the haemodynamic and metabolic effects of potassium nitrate (8 or 24 mmol KNO3 ) vs. potassium chloride (KCl; placebo) administered 1 hour prior to an oral glucose tolerance test in 33 healthy volunteers. RESULTS: Compared to placebo, there were no significant differences in systolic or diastolic BP (P = 0.27 and P = 0.30 on ANOVA, respectively) with KNO3 , nor in pulse wave velocity or central systolic BP (P = 0.99 and P = 0.54 on ANOVA, respectively). Whilst there were significant elevations from baseline for plasma [glucose] and [C-peptide], no differences between interventions were observed. A significant increase in plasma [insulin] was observed with KNO3 vs. KCl (n = 33; P = 0.014 on ANOVA) with the effect driven by the high-dose cohort (24 mmol, n = 13; P < 0.001 on ANOVA; at T = 0.75 h mean difference 210.4 pmol/L (95% CI 28.5 to 392.3), P = 0.012). CONCLUSIONS: In healthy adults, acute physiological elevations of plasma [glucose] and [insulin] result in a lack of BP-lowering with dietary nitrate. The increase in plasma [insulin] without a corresponding change in [C-peptide] or [glucose] suggests that high-dose NO3- decreases insulin clearance. A likely mechanism is via NO-dependent inhibition of insulin-degrading enzyme.

Baclofen in gamma-hydroxybutyrate withdrawal: patterns of use and online availability.

PURPOSE: Gamma-hydroxybutyrate (GHB) withdrawal is a life-threatening condition that does not always respond to standard treatment with benzodiazepines. Baclofen has potential utility as a pharmacological adjunct and anecdotal reports suggest that it is being used by drug users to self-manage GHB withdrawal symptoms. Here, we investigate current patterns of use and the online availably of baclofen. METHODS: Data triangulation techniques were applied to published scientific literature and publicly accessible Internet resources (grey literature) to assess the use of baclofen in GHB withdrawal. An Internet snapshot survey was performed to identify the availability of baclofen for online purchase and the compliance of retailers with the UK regulations. Data were collected according to pre-defined criteria. RESULTS: A total of 37 cases of baclofen use in GHB withdrawal were identified in the scientific literature, as well as 51 relevant discussion threads across eight Internet forums in the grey literature. Baclofen was available to purchase from 38 online pharmacies, of which only one conformed to the UK regulations. CONCLUSIONS: There is limited published evidence on the use of baclofen in GHB withdrawal, but both scientific and grey literature suggests clinical utility. Online pharmacies are readily offering prescription-only-medication without prescription and due to inadequate regulation, pose a danger to the public.

Antiplatelet therapy as a modulator of stroke aetiology: a meta-analysis.

AIMS: Antiplatelet therapy reduces the incidence of ischaemic stroke. Platelet-mediated thrombosis contributes variably to the major subtypes of stroke as defined by the TOAST criteria: large artery atherosclerosis (LAA), cardioembolic (CE) and small vessel occlusion (SVO). The effect of antiplatelet therapy on the incidence of each subtype is unknown and is the subject of this meta-analysis. METHODS: Electronic databases were searched for articles comparing the effect of antiplatelet therapy on the incidence of stroke according to aetiological subtype. Studies containing subjects prescribed anticoagulant therapy or solely investigating subjects with atrial fibrillation were excluded. Pooled odds ratios (ORs) were calculated using a fixed effects model. RESULTS: Nine studies were included (n = 5739). In patients who had an ischaemic stroke, pre-event antiplatelet therapy was associated with significantly decreased incidence of LAA (OR 0.88, 95% CI 0.79, 0.99; P = 0.026), increased incidence of CE (OR 1.23, 95% CI 1.08, 1.41; P = 0.002) and no effect on SVO (OR 0.99, 95% CI 0.88, 1.11; P = 0.806). Concordant non-significant trends were observed in primary prevention populations (n = 751): LAA (OR 0.81, 95% CI 0.57, 1.15; P = 0.240), CE (OR 1.29, 95% CI 0.89, 1.87; P = 0.179) and SVO (OR 0.99, 95% CI 0.73, 1.36; P = 0.970). Subgroup analysis of aspirin monotherapy (n = 3786) demonstrated a significant reduction in LAA (OR 0.87, 95% CI 0.76, 1.00; P = 0.046), but non-significant effects on the incidence of CE (OR 1.17, 95% CI 0.99, 1.39; P = 0.068) and SVO (OR 1.04, 95% CI 0.91, 1.20; P = 0.570). Probability of publication bias was low (P > 0.05). CONCLUSIONS: Antiplatelet therapy preferentially reduces the incidence of LAA stroke compared with CE and SVO subtypes.

Antiplatelet drug resistance: Molecular insights and clinical implications.

Antiplatelet drugs are prescribed to patients with cardiovascular disease in order to reduce their risk of clinically important atherothrombotic events. However, a proportion of patients fail to appropriately respond to these drugs in a heterogeneous phenomenon known as 'antiplatelet drug resistance'. Individuals who are identified as being resistant have a higher cardiovascular risk, but currently there is no clinically validated approach to identify and treat these individuals. Large randomised control trials have attempted to personalise antiplatelet therapy based on platelet function testing, but these have failed to demonstrate improved clinical outcomes. An alternative approach to this non-specific assessment of platelet function is to consider whether antiplatelet therapy may be personalised based on the identification of molecular mechanisms that are known to confer resistance. Here we present molecular insights into the mechanisms for aspirin and clopidogrel resistance, with a discussion of their clinical implications.

The PlA1/A2 polymorphism of glycoprotein IIIa in relation to efficacy of antiplatelet drugs: a systematic review and meta-analysis.

AIM: The PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been associated with both antiplatelet drug resistance and increased cardiovascular events. The aim of this study was to conduct the first meta-analysis investigating the association between carriage of the PlA2 allele and resistance to currently licensed antiplatelet drugs. METHODS: Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating genetic polymorphisms of GPIIIa. For studies where antiplatelet resistance was measured using validated techniques, pooled odds ratios (ORs) were calculated using fixed effects and random effects models. RESULTS: Sixteen studies were eligible for statistical analysis and included 1650 PlA1 homozygous subjects and 668 carriers of the PlA2 allele. For carriers of the PlA2 allele, OR 0.924 (n = 2318; 95% CI 0.743, 1.151; P = 0.481) was observed for resistance to any antiplatelet drug, OR 0.862 (n = 2085; 95% CI 0.685, 1.086; P = 0.208) for resistance to aspirin and OR 1.429 (n = 233; 95% CI 0.791, 2.582; P = 0.237) for resistance to clopidogrel. In the aspirin cohort, sub-group analysis revealed no statistical association in either healthy subjects or those with cardiovascular disease. PlA2 carriage was marginally associated with aspirin sensitivity using the fixed effects model when identified by the PFA-100 assay (n = 1151; OR 0.743, 95% CI 0.558, 0.989; P = 0.041) but with significant heterogeneity (I(2) = 55%; P = 0.002). Significance was lost with analysis using a random effects model. CONCLUSIONS: The totality of published data does not support an association between carriage of the PlA2 allele and antiplatelet drug resistance. Significant heterogeneity indicates the need for larger studies using validated and standardized assays.

Increased platelet expression of glycoprotein IIIa following aspirin treatment in aspirin-resistant but not aspirin-sensitive subjects.

AIMS: Aspirin is widely used as an anti-platelet agent for cardiovascular prophylaxis. Despite aspirin treatment, many patients experience recurrent thrombotic events, and aspirin resistance may contribute to this. We examined the prevalence of aspirin resistance in a healthy population, and investigated whether the platelet proteome differed in aspirin-resistant subjects. METHODS: Ninety-three healthy subjects received aspirin 300 mg daily for 28 days. Before and at the end of treatment, urine was taken to determine 11-dehydrothromboxane B2 , and blood was taken to measure arachidonic acid (AA)-induced aggregation of platelet-rich plasma and to interrogate the platelet proteome by mass spectrometric analysis with further confirmation of findings using Western blotting. RESULTS: In two of the 93 subjects, neither AA-induced aggregation nor urinary 11-dehydrothromboxane B2 was effectively suppressed by aspirin, despite measurable plasma salicylate concentrations, suggesting the presence of true aspirin resistance. Despite no detectable differences in the platelet proteome at baseline, following aspirin a marked increase was seen in platelet glycoprotein IIIa expression in the aspirin-resistant but not aspirin-sensitive subjects. An increase in platelet glycoprotein IIIa expression with aspirin resistance was confirmed in a separate cohort of 17 patients with stable coronary artery disease on long term aspirin treatment, four of whom exhibited aspirin resistance. CONCLUSIONS: In a healthy population, true aspirin resistance is uncommon but exists. Resistance is associated with an increase in platelet glycoprotein IIIa expression in response to aspirin. These data shed new light on the mechanism of aspirin resistance, and provide the potential to identify aspirin-resistant subjects using a novel biomarker.

Influence of Blood Pressure Reduction on Pulse Wave Velocity in Primary Hypertension: A Meta-Analysis and Comparison With an Acute Modulation of Transmural Pressure.

BACKGROUND: Increased arterial stiffness and pulse wave velocity (PWV) of the aorta and large arteries impose adverse hemodynamic effects on the heart and other organs. Antihypertensive treatment reduces PWV, but it is unknown whether this results from an unloading of stiffer elements in the arterial wall or is due to an alternate functional or structural change that might differ according to class of antihypertensive drug. METHODS: We performed a systematic review and meta-analysis of the effects of different antihypertensive drug classes and duration of treatment on PWV with and without adjustment for change in mean arterial blood pressure (BP; study 1) and compared this to the change in PWV after an acute change in transmural pressure, simulating an acute change in BP (study 2). RESULTS: A total of 83 studies involving 6200 subjects were identified. For all drug classes combined, the reduction of PWV was 0.65 (95% CI, 0.46-0.83) m/s per 10 mm Hg reduction in mean arterial BP, a change similar to that induced by an acute change in transmural pressure in a group of hypertensive subjects. When adjusted for change in mean arterial BP, the reduction in PWV after treatment with beta-blockers or diuretics was less than that after treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists or calcium channel antagonists. CONCLUSIONS: Reduction in PWV after antihypertensive treatment is largely explained by the reduction in BP, but there are some BP-independent effects. These might increase over time and contribute to better outcomes over the long term, but this remains to be demonstrated in long-term clinical trials.

Reproducibility of sequential ambulatory blood pressure and pulse wave velocity measurements in normotensive and hypertensive individuals.

OBJECTIVE: Errors in blood pressure (BP) measurement account for a large proportion of misclassified hypertension diagnoses. Ambulatory blood pressure monitoring (ABPM) is often considered to be the gold standard for measurement of BP, but uncertainty remains regarding the degree of measurement error. The aim of this study was to determine reproducibility of sequential ABPM in a population of normotensive and well controlled hypertensive individuals. METHODS: Individual participant data from three randomized controlled trials, which had recorded ABPM and carotid-femoral pulse wave velocity (PWV) at least twice were combined ( n  = 501). We calculated within-individual variability of daytime and night-time BP and compared the variability between normotensive ( n  = 324) and hypertensive ( n  = 177) individuals. As a secondary analysis, variability of PWV measurements was also calculated, and multivariable linear regression was used to assess characteristics associated with blood pressure variability (BPV). RESULTS: Within-individual coefficient of variation (CoV) for systolic BP was 5.4% (day) and 7.0% (night). Equivalent values for diastolic BP were 6.1% and 8.4%, respectively. No statistically significant difference in CoV was demonstrated between measurements for normotensive and hypertensive individuals. Within-individual CoV for PWV exceeded that of BP measurements (10.7%). BPV was associated with mean pressures, and BMI for night-time measurements. PWV was not independently associated with BPV. CONCLUSION: The variability of single ABPM measurements will still yield considerable uncertainty regarding true average pressures, potentially resulting in misclassification of hypertensive status and incorrect treatment regimes. Repeated ABPM may be necessary to refine antihypertensive therapy.

The role of pharmacogenomics in contemporary cardiovascular therapy: a position statement from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.

There is a strong and ever-growing body of evidence regarding the use of pharmacogenomics to inform cardiovascular pharmacology. However, there is no common position taken by international cardiovascular societies to unite diverse availability, interpretation, and application of such data, nor is there recognition of the challenges of variation in clinical practice between countries within Europe. Aside from the considerable barriers to implementing pharmacogenomic testing and the complexities of clinically actioning results, there are differences in the availability of resources and expertise internationally within Europe. Diverse legal and ethical approaches to genomic testing and clinical therapeutic application also require serious thought. As direct-to-consumer genomic testing becomes more common, it can be anticipated that data may be brought in by patients themselves, which will require critical assessment by the clinical cardiovascular prescriber. In a modern, pluralistic and multi-ethnic Europe, self-identified race/ethnicity may not be concordant with genetically detected ancestry and thus may not accurately convey polymorphism prevalence. Given the broad relevance of pharmacogenomics to areas, such as thrombosis and coagulation, interventional cardiology, heart failure, arrhythmias, clinical trials, and policy/regulatory activity within cardiovascular medicine, as well as to genomic and pharmacology subspecialists, this position statement attempts to address these issues at a wide-ranging level.

Challenges in cardiovascular pharmacogenomics implementation: a viewpoint from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy.

Pharmacogenomics promises to advance cardiovascular therapy, but there remain pragmatic barriers to implementation. These are particularly important to explore within Europe, as there are differences in the populations, availability of resources, and expertise, as well as in ethico-legal frameworks. Differences in healthcare delivery across Europe present a challenge, but also opportunities to collaborate on pharmacogenomics implementation. Clinical workforce upskilling is already in progress but will require substantial input. Digital infrastructure and clinical support tools are likely to prove crucial. It is important that widespread implementation serves to narrow rather than widen any existing gaps in health equality between populations. This viewpoint supplements the working group position paper on cardiovascular pharmacogenomics to address these important themes.

Cost-Effectiveness of Initiating Pharmacological Treatment in Stage One Hypertension Based on 10-Year Cardiovascular Disease Risk: A Markov Modeling Study.

Antihypertensive drug treatment is cost-effective for adults at high risk of developing cardiovascular disease (CVD). However, the cost-effectiveness in people with stage 1 hypertension (140-159 mm Hg systolic blood pressure) at lower CVD risk remains unclear. The objective was to establish the 10-year CVD risk threshold where initiating antihypertensive drug treatment for primary prevention in adults, with stage 1 hypertension, becomes cost-effective. A lifetime horizon Markov model compared antihypertensive drug versus no treatment, using a UK National Health Service perspective. Analyses were conducted for groups ranging between 5% and 20% 10-year CVD risk. Health states included no CVD event, CVD and non-CVD death, and 6 nonfatal CVD morbidities. Interventions were compared using cost-per-quality-adjusted life-years. The base-case age was 60, with analyses repeated between ages 40 and 75. The model was run separately for men and women, and threshold CVD risk assessed against the minimum plausible risk for each group. Treatment was cost-effective at 10% CVD risk for both sexes (incremental cost-effectiveness ratio £10 017/quality-adjusted life-year [$14 542] men, £8635/QALY [$12 536] women) in the base-case. The result was robust in probabilistic and deterministic sensitivity analyses but was sensitive to treatment effects. Treatment was cost-effective for men regardless of age and women aged >60. Initiating treatment in stage 1 hypertension for people aged 60 is cost-effective regardless of 10-year CVD risk. For other age groups, it is also cost-effective to treat regardless of risk, except in younger women.