Efficacy of Guideline-Directed Medical Therapy in Heart Failure Patients With and Without Chronic Kidney Disease: A Meta-Analysis of 63,677 Patients.

BACKGROUND: Chronic kidney disease (CKD) coexists in up to 50% of heart failure (HF) patients, affecting both those with reduced ejection fraction (HFrEF) and those with preserved ejection fraction (HFpEF). Although the efficacy of several guideline-directed medical therapies (GDMT) has been well established, the treatment recommendations are similar for those patients with HF with and without CKD. We aimed to investigate the efficacy of GDMT in patients with HF with versus those without CKD. METHOD: This systematic review and meta-analysis included randomised controlled trials that compared the efficacy of GDMT (angiotensin-converting enzyme inhibitor [ACE-I], beta blocker, sodium-glucose cotransporter-2 inhibitor, mineralocorticoid receptor antagonist, angiotensin receptor-neprilysin inhibitor) in patients with HF with and without CKD. The primary outcome was the composite of cardiovascular death and HF hospitalisation. Risk ratios (RR) were pooled using random-effects meta-analysis. RESULTS: A total of 19 trials (15 trials in HFrEF and four trials in HFpEF) enrolling 63,677 (38% had CKD) participants were included. Among HFrEF patients, GDMT reduced the primary endpoint in those with CKD (RR 0.77, 95% confidence interval [CI] 0.72-0.82) and without CKD (RR 0.79, 95% CI 0.74-0.84). Among HFpEF patients, the pooled summary RR for GDMT reducing the primary endpoint was 0.82 (95% CI 0.74-0.91) among those with CKD and 0.88 (95% CI 0.77-0.99) among those without CKD. There was no significant difference in the efficacy of GDMT in head-to-head comparisons between those with and without CKD in HFrEF (ratio of RR 0.97, 95% CI 0.88-1.06) and HFpEF (ratio of RR 0.94, 95% CI 0.80-1.11). CONCLUSIONS: Among patients with HF, GDMT had a consistent effect in reducing adverse cardiovascular events in those with and without CKD. Future studies should investigate the best strategy to ensure patients with HF with CKD receive and tolerate GDMT when indicated.

Sex-specific differences in the efficacy of heart failure therapies: a meta-analysis of 84,818 patients.

Women have been historically underrepresented in clinical trials of heart failure (HF). We aimed to assess for sex differences in patient characteristics and the efficacy of guideline-directed medical therapy (GDMT) in HF. Systematic literature search for randomized controlled trials (RCTs) of GDMT reporting cardiovascular outcomes by sex in patients with HF. The primary outcome was the composite of cardiovascular death and hospitalization for HF. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using inverse variance weighting and random effects meta-analysis. Twenty-six RCTs totaling 84,818 participants (27% women) were included. Women with HF were older, had higher New York Heart Association (NYHA) class, more hypertension and obesity, and higher mean left ventricular ejection fraction compared to men. There was evidence for most GDMT in reducing the primary outcome in women with HF with reduced ejection fraction (HFrEF) (angiotensin-converting enzyme inhibitors/angiotensin-receptor blocker [RR 0.86, 95% CI 0.75-0.97], angiotensin-receptor blocker/neprilysin inhibitor (ARNI) [RR 0.77, 95% CI 0.62-0.94], beta-blocker [RR 0.67, 95% CI 0.51-0.89], ivabradine [RR 0.74, 95% CI 0.60-0.91], and sodium-glucose cotransporter-2 (SGLT2) inhibitors [RR 0.66, 95% CI 0.54-0.81]) and a non-significant trend for benefit with mineralocorticoid-receptor-antagonist (MRA) [RR 0.77, 95% CI 0.52-1.16]). Compared to men with HFrEF, GDMT reduced the primary outcome in women to a similar degree across all drug classes (ratio of RR 1.05, 95% CI 0.96-1.14). Despite differences in baseline characteristics and an underrepresentation of women in HF clinical trials, GDMT are as efficacious in women as compared to men in reducing cardiovascular events in HF.

Genetic determinants of genus-level glycan diversity in a bacterial protein glycosylation system.

The human pathogens N. gonorrhoeae and N. meningitidis display robust intra- and interstrain glycan diversity associated with their O-linked protein glycosylation (pgl) systems. In an effort to better understand the evolution and function of protein glycosylation operating there, we aimed to determine if other human-restricted, Neisseria species similarly glycosylate proteins and if so, to assess the levels of glycoform diversity. Comparative genomics revealed the conservation of a subset of genes minimally required for O-linked protein glycosylation glycan and established those pgl genes as core genome constituents of the genus. In conjunction with mass spectrometric-based glycan phenotyping, we found that extant glycoform repertoires in N. gonorrhoeae, N. meningitidis and the closely related species N. polysaccharea and N. lactamica reflect the functional replacement of a progenitor glycan biosynthetic pathway. This replacement involved loss of pgl gene components of the primordial pathway coincident with the acquisition of two exogenous glycosyltransferase genes. Critical to this discovery was the identification of a ubiquitous but previously unrecognized glycosyltransferase gene (pglP) that has uniquely undergone parallel but independent pseudogenization in N. gonorrhoeae and N. meningitidis. We suggest that the pseudogenization events are driven by processes of compositional epistasis leading to gene decay. Additionally, we documented instances where inter-species recombination influences pgl gene status and creates discordant genetic interactions due ostensibly to the multi-locus nature of pgl gene networks. In summary, these findings provide a novel perspective on the evolution of protein glycosylation systems and identify phylogenetically informative, genetic differences associated with Neisseria species.

Allelic polymorphisms in a glycosyltransferase gene shape glycan repertoire in the O-linked protein glycosylation system of Neisseria.

Glycosylation of multiple proteins via O-linkage is well documented in bacterial species of Neisseria of import to human disease. Recent studies of protein glycosylation (pgl) gene distribution established that related protein glycosylation systems occur throughout the genus including nonpathogenic species. However, there are inconsistencies between pgl gene status and observed glycan structures. One of these relates to the widespread distribution of pglG, encoding a glycosyltransferase that in Neisseria elongata subsp. glycolytica is responsible for the addition of di-N-acetyl glucuronic acid at the third position of a tetrasaccharide. Despite pglG residing in strains of N. gonorrhoeae, N. meningitidis and N. lactamica, no glycan structures have been correlated with its presence in these backgrounds. Moreover, PglG function in N. elongata subsp. glycolytica minimally requires UDP-glucuronic acid (GlcNAcA), and yet N. gonorrhoeae, N. meningitidis and N. lactamica lack pglJ, the gene whose product is essential for UDP-GlcNAcA synthesis. We examined the functionality of pglG alleles from species spanning the Neisseria genus by genetic complementation in N. elongata subsp. glycolytica. The results indicate that select pglG alleles from N. meningitidis and N. lactamica are associated with incorporation of an N-acetyl-hexosamine at the third position and reveal the potential for an expanded glycan repertoire in those species. Similar experiments using pglG from N. gonorrhoeae failed to find any evidence of function suggesting that those alleles are missense pseudogenes. Taken together, the results are emblematic of how allelic polymorphisms can shape bacterial glycosyltransferase function and demonstrate that such alterations may be constrained to distinct phylogenetic lineages.

Tricuspid regurgitation is associated with increased mortality independent of pulmonary pressures and right heart failure: a systematic review and meta-analysis.

Aims: To undertake a systematic review and meta-analysis to determine the influence of tricuspid regurgitation (TR) severity on mortality. Methods and results: We performed a systematic search for studies reporting clinical outcomes of patients with TR. The primary endpoint was all-cause mortality and secondary endpoints were cardiac mortality and hospitalization for heart failure (HF). Overall risk ratios (RR) and 95% confidence intervals (CIs) were derived for each endpoint according to the severity of TR by meta-analysing the effect estimates of eligible studies. Seventy studies totalling 32 601 patients were included in the analysis, with a mean (±SD) follow-up of 3.2 ± 2.1 years. Moderate/severe TR was associated with a two-fold increased mortality risk compared to no/mild TR (RR 1.95, 95% CI 1.75-2.17). Moderate/severe TR remained associated with higher all-cause mortality among 13 studies which adjusted for systolic pulmonary arterial pressures (RR 1.85, 95% CI 1.44-2.39), and 15 studies, which adjusted for right ventricular (RV) dysfunction (RR 1.78, 95% CI 1.49-2.13). Moderate/severe TR was also associated with increased cardiac mortality (RR 2.56, 95% CI 1.84-3.55) and HF hospitalization (RR 1.73, 95% CI 1.14-2.62). Compared to patients with no TR, patients with mild, moderate, and severe TR had a progressively increased risk of all-cause mortality (RR 1.25, 1.61, and 3.44, respectively; P < 0.001 for trend). Conclusions: Moderate/severe TR is associated with an increased mortality risk, which appears to be independent of pulmonary pressures and RV dysfunction.

Disrupted Synthesis of a Di-N-acetylated Sugar Perturbs Mature Glycoform Structure and Microheterogeneity in the O-Linked Protein Glycosylation System of Neisseria elongata subsp. glycolytica.

The genus Neisseria includes three major species of importance to human health and disease (Neisseria gonorrhoeae, Neisseria meningitidis, and Neisseria lactamica) that express broad-spectrum O-linked protein glycosylation (Pgl) systems. The potential for related Pgl systems in other species in the genus, however, remains to be determined. Using a strain of Neisseria elongata subsp. glycolytica, a unique tetrasaccharide glycoform consisting of di-N-acetylbacillosamine and glucose as the first two sugars followed by a rare sugar whose mass spectrometric fragmentation profile was most consistent with di-N-acetyl hexuronic acid and a N-acetylhexosamine at the nonreducing end has been identified. Based on established mechanisms for UDP-di-N-acetyl hexuronic acid biosynthesis found in other microbes, we searched for genes encoding related pathway components in the N. elongata subsp. glycolytica genome. Here, we detail the identification of such genes and the ensuing glycosylation phenotypes engendered by their inactivation. While the findings extend the conservative nature of microbial UDP-di-N-acetyl hexuronic acid biosynthesis, mutant glycosylation phenotypes reveal unique, relaxed specificities of the glycosyltransferases and oligosaccharyltransferases to incorporate pathway intermediate UDP-sugars into mature glycoforms.IMPORTANCE Broad-spectrum protein glycosylation (Pgl) systems are well recognized in bacteria and archaea. Knowledge of how these systems relate structurally, biochemically, and evolutionarily to one another and to others associated with microbial surface glycoconjugate expression is still incomplete. Here, we detail reverse genetic efforts toward characterization of protein glycosylation mutants of N. elongata subsp. glycolytica that define the biosynthesis of a conserved but relatively rare UDP-sugar precursor. The results show both a significant degree of intra- and transkingdom conservation in the utilization of UDP-di-N-acetyl-glucuronic acid and singular properties related to the relaxed specificities of the N. elongata subsp. glycolytica system.

15-Year Trends in Patients Hospitalised With Heart Failure and Enrolled in an Australian Heart Failure Management Program.

BACKGROUND: Heart failure (HF) is associated with high morbidity and mortality, and is a major contributor to health care costs. Since the area continues to be rapidly evolving, the aim of this study was to examine 15-year trends in demographics, precipitants, symptoms and outcomes of patients hospitalised with HF, and consider the individual and societal implications. METHODS: Data were prospectively collected by Heart Failure nurses from patients enrolled in the Management of Cardiac Function program (MACARF) in Northern Sydney, Australia. Analyses of trends were performed using Mantel-Hanzel tests and one-way analysis of variance. Multivariate Cox proportional hazard models were used to determine changes in readmission and mortality rates. RESULTS: From 2001 to 2015, 5,588 patients were hospitalised with HF and enrolled in the MACARF program. Over the 15-year period, the average age of enrolled patients increased by a decade (from 74 to 84 years), with an increase in hypertension (52% to 67%), chronic kidney disease (11% to 21%), atrial fibrillation/flutter (29% to 44%), and HF with preserved ejection fraction (24% to 35%) but a decrease in ischaemic heart disease (62% to 47%). Infection and atrial arrhythmias were the two most common precipitants of admission (27% and 18% of patients in 2013-15 respectively), while acute ischaemia became less common, and "unknown" precipitant increased to 35%. While increased exertional dyspnoea and peripheral oedema remained the most common presenting symptoms, weight gain, fatigue and chest pain were less frequently identified. Medication trends included an increase in spironolactone use and a decrease in angiotensin converting enzyme inhibitors. Average length of stay reduced while 1- and 3-year mortality rates improved to 11.3% and 26.6% respectively. In contrast, readmission rates have not improved, with current 30-day and 1-year rates of 9.9% and 42.6%. CONCLUSIONS: Significant temporal changes have occurred in the characteristics and outcome of patients with HF, which pose a challenge and opportunity to improve management. Although length of stay and mortality have improved, unchanged readmission rates highlight the importance of addressing the implications of the changing nature of patients with HF.

Predictors of Frequent Readmissions in Patients With Heart Failure.

BACKGROUND: Patients with heart failure (HF) have a high incidence of hospital readmissions. However risk models that explore predictors of a single readmission may be less useful at identifying the patients with frequent readmissions who contribute to a disproportionately large proportion of morbidity and health care costs. METHODS: A total of 6252 patients enrolled in the Management of Cardiac Failure Program (MACARF) in Northern Sydney Area Hospitals between 1998 and 2015 were randomly divided into derivation and validation cohorts to create and test a risk model for predictors of ≥2 readmissions or death within 1year of initial hospitalisation for HF. RESULTS: Multivariate predictors of frequent (≥2) readmissions or death were a history of ischaemic heart disease and chronic kidney disease, being unmarried, having anaemia, low serum albumin, elevated creatinine, prolonged hospital stay (>7 days), and not receiving beta blockers on discharge. Event rates increased with a higher risk score (p<0.001) and the prediction was similar in the validation and derivation cohorts (p=0.588). The C-statistic was 0.65. CONCLUSIONS: Our risk score may assist in focussing health care resources and interventions by identifying the subset of HF patients at increased risk for a disproportionately high burden of disease.

Major Abdominal and Perianal Surgery in Crohn's Disease: Long-term Follow-up of Australian Patients With Crohn's Disease.

BACKGROUND: Most patients with Crohn's disease still require surgery despite significant advances in medical therapy, surveillance, and management strategies. OBJECTIVE: The purpose of this study was to assess surgical strategies and outcomes in Crohn's disease, including surgical recurrence and emergency surgery. DESIGN: This was a multicenter, retrospective review of a prospectively collected database. SETTINGS: A specialist-referred cohort of patients with Crohn's disease between 1970 and 2009 was studied. PATIENTS: Included were 972 patients with Crohn's disease who were referred to the Sydney Inflammatory Bowel Disease cohort database. MAIN OUTCOME MEASURES: Main outcomes of interest were the rates of major abdominal and perianal surgery between decades (1970-1979, 1980-1989, 1990-1999, and 2000-2009), indications for surgery, types of procedure performed, rate of elective and emergency surgery, risk of surgical recurrence, and predictive factors for surgery. RESULTS: Between 1970 and 2009, the overall risks of surgery within 5, 10, and 15 years of diagnosis were 31.7%, 43.3%, and 48.4%. The median time to first surgery from time of diagnosis was 2 years (range, 0-31 years). A total of 6.7% of patients required emergency surgery within 5 years of diagnosis. In total, 8.8% of patients required emergency surgery within 15 years. The overall risk of surgical recurrence was 35.9%. The risk of major abdominal surgery significantly decreased between 2000 and 2009 when compared with the 1970 to 1979 period (OR = 0.49 (95% CI, 0.34-0.70). However, the rate of perianal surgery significantly increased (OR = 5.76 (95% CI, 2.54-13.06)). The main indications for surgery were enteric stricture or obstruction, perianal disease, and intra-abdominal fistulas/abscess. Of the 972 patients over 4 decades, only 11 patients (1.1%) were diagnosed with colorectal cancer. LIMITATIONS: This was a specialist-referred cohort, not a population-based study. CONCLUSIONS: The rate of major abdominal surgery has decreased, with surgery reserved for more severe and complicated disease. The natural history of patients with more complicated Crohn's disease and severe phenotypes puts them at higher risk of surgical recurrence and emergency surgery. There has been no reduction in emergency surgery rates and there has been an increase in surgical recurrence despite the reduction in surgical rate morbidity. See Video Abstract at http://links.lww.com/DCR/A483.

Adenosine Testing After Atrial Fibrillation Ablation: Systematic Review and Meta-Analysis.

BACKGROUND: Adenosine can be used to reveal dormant pulmonary vein (PV) conduction after pulmonary vein isolation (PVI) for the treatment of atrial fibrillation (AF). We performed a systematic review and meta-analysis to assess the impact of adenosine administration in patients undergoing PVI for AF. METHODS: Meta-analysis of 22 studies was performed to assess the rates of freedom from AF in 1) patients with dormant PV conduction versus patients without dormant PV conduction, and 2) patients given routine adenosine post PVI versus patients not given adenosine. Relative-risks (RR) were calculated using random effects modelling. RESULTS: In 18 studies, 3038 patients received adenosine and freedom from AF in those patients with dormant PV reconnection was significantly lower (62.9%) compared to patients without PV reconnection (67.2%) (RR 0.87; 95% CI: 0.78-0.98). In seven studies with 3049 patients, the freedom from AF was significantly higher in patients who received adenosine (67%) versus those patients who did not receive adenosine (63%) (RR: 1.11; 95% CI: 1.01-1.22). CONCLUSIONS: The present study showed clear benefits of adenosine testing for freedom from AF recurrence. Adenosine-guided dormant conduction is associated with higher AF recurrence despite further ablation. Future studies should investigate the optimal methodology, including dosage and waiting time between PVI and adenosine administration.

Post-dilation in transcatheter aortic valve replacement: A systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to perform a meta-analysis to compare the outcomes of patients undergoing TAVR with and without balloon post-dilation (PD). BACKGROUND: PD is a commonly used technique in TAVR to minimize paravalvular regurgitation (PVR), albeit supported by little evidence. METHODS: Systematic review and meta-analysis of 6 studies comparing 889 patients who had PD compared to 4118 patients without PD. RESULTS: Patients undergoing PD were more likely male (OR 1.92; 95% CI, 1.41-2.61; P < 0.001) and to have coronary artery disease (OR 1.31; 95% CI, 1.03-1.68; P = 0.03) than those patients not requiring PD. There were no significant differences in 30-day mortality (OR 1.24; 95% CI, 0.88-1.74; P = 0.22) and myocardial infarction (OR 0.93; 95% CI, 0.46-1.90; P = 0.85). Patients undergoing TAVR did not have higher 1-year mortality rates (OR 0.98; 95% CI, 0.61-1.56; P = 0.92). The incidence of stroke was significantly greater in patients with PD (OR, 1.71; 95% CI, 1.10-2.66). PD was able to reduce the incidence of moderate-severe PVR by 15 fold (OR 15.0; 95% CI, 4.2-54.5; P < 0.001), although rates of moderate-severe PVR were still higher after PD than patients who did not require PD (OR 3.64; 95% CI, 1.96-6.75; P < 0.001). CONCLUSIONS: PD significantly improves rates of PVR, however careful patient selection is needed to minimize increased risk of strokes.

Robot-assisted Hybrid Coronary Revascularisation: Systematic Review.

BACKGROUND: Hybrid coronary revascularisation (HCR) for multi-vessel coronary artery disease combines surgical bypass grafting for the left anterior descending (LAD) coronary artery and percutaneous coronary intervention (PCI) for non-LAD coronary arteries. The present systematic review was conducted to assess the available evidence on robotic-assisted HCR and explore the potential advantages and disadvantages it proposes. METHODS: A comprehensive search from six electronic databases was performed for studies reporting outcomes for robotic-assisted hybrid coronary revascularisation. Eight studies were identified from six electronic databases amenable for qualitative assessment and pooled quantitative analysis. RESULTS: There were no in-hospital deaths reported. Pooled myocardial infarction rates was 1.2% (range 0-3.7%), pooled strokes was 0.8% (range: 0-1.7%), freedom from reintervention was 92.5% (range 70.4-100%), and freedom from angina was 92.9% (range 74.3-100%). LITA patency ranged from 89-100%, while hospital stay ranged from 4-8.1 days. CONCLUSIONS: The current data suggests potentially acceptable mortality and complication rates, when patients are carefully selected and operated on by expert cardiovascular teams. However, due to the heterogeneous nature of the evidence and lack of long-term outcomes, this promising technique warrants future comparative and randomised studies before becoming a part of mainstay coronary interventions.

The contribution of cumulative blood pressure load to dementia, cognitive function and mortality in older adults.

BACKGROUND: Few studies evaluated the contribution of long-term elevated blood pressure (BP) towards dementia and deaths. We examined the association between cumulative BP (cBP) load and dementia, cognitive decline, all-cause and cardiovascular deaths in older Australians. We also explored whether seated versus standing BP were associated with these outcomes. METHODS: The Sydney Memory and Aging Study included 1037 community-dwelling individuals aged 70-90 years, recruited from Sydney, Australia. Baseline data was collected in 2005-2007 and the cohort was followed for seven waves until 2021. cSBP load was calculated as the area under the curve (AUC) for SBP ≥140 mmHg divided by the AUC for all SBP values. Cumulative diastolic BP (cDBP) and pulse pressure (cPP) load were calculated using thresholds of 90 mmHg and 60 mmHg. Cox and mixed linear models were used to assess associations. RESULTS: Of 527 participants with both seated and standing BP data (47.7% men, median age 77), 152 (28.8%) developed dementia over a mean follow-up of 10.5 years. Higher cPP load was associated with a higher risk of all-cause deaths, and cSBP load was associated with a higher risk of cardiovascular deaths in multivariate models (P for trend < 0.05). Associations between cPP load, dementia and cognitive decline lost statistical significance after adjustment for age. Differences between sitting and standing BP load were not associated with the outcomes. CONCLUSION: Long-term cPP load was associated with a higher risk of all-cause deaths and cSBP load associated with a higher risk of cardiovascular deaths in older Australians.

Echocardiographic predictors of cardiovascular outcome in heart failure with preserved ejection fraction.

AIMS: The optimal echocardiographic predictors of cardiovascular outcome in heart failure (HF) with preserved ejection fraction (HFpEF) are unknown. We aimed to identify independent echocardiographic predictors of cardiovascular outcome in patients with HFpEF. METHODS AND RESULTS: Systematic literature search of three electronic databases was conducted from date of inception until November 2022. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for echocardiographic variables from multivariate prediction models for the composite primary endpoint of cardiovascular death and HF hospitalization were pooled using a random effects meta-analysis. Specific subgroup analyses were conducted for studies that enrolled patients with acute versus chronic HF, and for those studies that included E/e', pulmonary artery systolic pressure (PASP), renal function, natriuretic peptides and diuretic use in multivariate models. Forty-six studies totalling 20 056 patients with HFpEF were included. Three echocardiographic parameters emerged as independent predictors in all subgroup analyses: decreased left ventricular (LV) global longitudinal strain (HR 1.24, 95% CI 1.10-1.39 per 5% decrease), decreased left atrial (LA) reservoir strain (HR 1.30, 95% CI 1.13-1.1.50 per 5% decrease) and lower tricuspid annular plane systolic excursion (TAPSE) to PASP ratio (HR 1.17, 95% CI 1.07-1.25 per 0.1 unit decrease). Other independent echocardiographic predictors of the primary endpoint were a higher E/e', moderate to severe tricuspid regurgitation, LV mass index and LA ejection fraction, although these variables were less robust. CONCLUSIONS: Impaired LV global longitudinal strain, lower LA reservoir strain and lower TAPSE/PASP ratio predict cardiovascular death and HF hospitalization in HFpEF and are independent of filling pressures, clinical characteristics and natriuretic peptides. These echocardiographic parameters reflect key functional changes in HFpEF, and should be incorporated in future prospective risk prediction models.

Therapeutic Inertia With Initial Low-Dose Quadruple Combination Therapy for Hypertension: Results From the QUARTET Trial.

BACKGROUND: Low-dose combinations are a promising intervention for improving blood pressure (BP) control but their effects on therapeutic inertia are uncertain. METHODS: Analysis of 591 patients randomized to an ultra-low-dose quadruple pill or initial monotherapy. The episode of therapeutic inertia was defined as a patient visit with a BP of >140/90 mm Hg without intensification of antihypertensive treatment. We compared the frequency of therapeutic inertia episodes between Quadpill and initial monotherapy as a proportion of the total population (intention-to-treat analysis with the denominator being all participants randomized) and as a proportion of people with uncontrolled BP (with the denominator being participants with uncontrolled BP). RESULTS: Therapeutic inertia occurred in fewer participants randomized to Quadpill compared with monotherapy. For example, among the 390 participants with a 6-month follow-up, therapeutic inertia according to unattended BP was 21/192 (11%) versus 45/192 (23%), P=0.002. There were similar rates of therapeutic inertia among those with uncontrolled unattended BP in each group (all P>0.4). Consistent observations were seen with the use of attended office BP measures. The major determinants of not intensifying treatment during follow-up were BP readings that were close to target and large improvements in BP compared with the previous visit. CONCLUSIONS: Among all treated individuals, low-dose Quadpill reduced the number of therapeutic inertia episodes compared with initial monotherapy. After the first follow-up visit, most high BP values did not lead to treatment intensification in both groups. Education is needed about the importance of treatment intensification despite a significant improvement in BP or BP being close to target. REGISTRATION: URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12616001144404; Unique identifier: ACTRN12616001144404.

Under-representation of ethnic and regional minorities in lipid-lowering randomized clinical trials: a systematic review and meta-analysis.

AIMS: The efficacy of lipid-lowering therapies (LLT) amongst different ethnicities and regions remains unclear. We aimed to assess cardiovascular event reductions associated with LLT according to ethnicity and region in previously published randomized clinical trials (RCTs). METHODS AND RESULTS: Medline, EMBASE, and Cochrane CENTRAL were searched for RCTs of statins, ezetimibe, or proprotein convertase subtilisin/kexin type 9 inhibitors comparing intensive vs. less-intensive low-density lipoprotein cholesterol (LDL-C) lowering. The primary endpoint was major adverse cardiovascular events (MACE) defined as the composite of cardiovascular mortality, myocardial infarction, stroke, and revascularization. Random-effects meta-analysis was used to pool risk ratios (RRs) with 95% confidence intervals (CI) adjusted per mmol/L reduction in LDL-C. Fifty-three trials with 329 897 participants were included. Amongst participants, 39.5% were from Europe, 16.0% from North America, 9.0% from Japan, 2.8% from Australasia, 1.8% from South America, 1.1% from Asia, 0.6% from South Africa, and 29.2% were unspecified. Amongst trials reporting ethnicities, there were 60.3% White, 20.2% Japanese, 9.4% Asian, 5.5% Black, and 4.7% Latin American. There was reduction in MACE with LLT in regions including Australasia (RR 0.75, 95% CI 0.67-0.85), North America (RR 0.75, 95% CI 0.69-0.83), Europe (RR 0.78, 95% CI 0.71-0.86), and Japan (RR 0.73, 95% CI 0.63-0.85) and in Black ethnicity (RR 0.55, 95% CI 0.37-0.82). Head-to-head comparisons between regions and ethnicities revealed no significant differences in MACE reduction. CONCLUSION: Despite under-representation in clinical trials, regional and ethnic minority groups such as Australasia and Blacks appear to derive at least as much cardiovascular benefit from LLT.

Lipid-lowering therapy (LLT) can effectively reduce cardiovascular disease across different ethnicities and regions, reinforcing the importance of their widespread use in at-risk populations. There is under-representation of several minority groups such as those from South Africa, South America, and Asia, as well as Black, Latin American, and Asian ethnicities. Furthermore, amongst included populations, the benefits of LLT appear to be consistent across regions and ethnicities.The findings of this study highlight the importance of ensuring at-risk patients have access to LLT regardless of ethnicity or region. Future trials should ensure adequate representation of all patient groups.

Benefits of intensified reductions in blood glucose and in blood pressure for patients with type 2 diabetes.

Adequate blood glucose and blood pressure control is paramount for the prevention of microvascular and macrovascular complications in patients with type 2 diabetes (T2D). This review article summarises the important advances in blood glucose and blood pressure lowering from the last three decades, with a focus on the evidence from large scale randomized clinical trials and meta-analyses. This paper focuses on evidence supporting specific blood glucose and blood pressure targets, and the importance of long-term sustained risk factor control. Novel therapies including the glucagon-like peptide-1 receptor agonists (GLP1-RA) and the sodium glucose co-transporter 2 inhibitors (SGLT2i) have revolutionized the treatment of type 2 diabetes and highlighted the importance of approaches that deliver benefits beyond glucose or blood pressure lowering. This article provides an overview of contemporary management of T2D with an emphasis on tailoring treatment plans to the individual.

Association between systolic blood pressure and low-density lipoprotein cholesterol with coronary heart disease according to age.

BACKGROUND: The impact of elevated systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) at different stages of life is unclear. We aimed to investigate whether genetically mediated SBP/LDL-C is associated with the risk of CHD throughout life. METHODS AND FINDINGS: We conducted a three-sample Mendelian randomization analysis using data from the UK Biobank including 136,648 participants for LDL-C, 135,431 participants for SBP, and 24,052 cases for CHD to assess the effect of duration of exposure to the risk factors on risk of CHD. Analyses were stratified by age at enrolment. In univariable analyses, there was a consistent association between exposure to higher LDL-C and SBP with increased odds of incident CHD in individuals aged ≤55 years, ≤60 years, and ≤65 years (p-value for heterogeneity = 1.00 for LDL-C and 0.67 for SBP, respectively). In multivariable Mendelian randomization analyses, exposure to elevated LDL-C/SBP early in life (age ≤55 years) was associated with a higher risk of CHD independent of later life levels (age >55 years) (odds ratio 1.68, 95% CI 1.20-2.34 per 1 mmol/L LDL-C, and odds ratio 1.33, 95% CI 1.18-1.51 per 10 mmHg SBP). CONCLUSIONS: Genetically predicted SBP and LDL-C increase the risk of CHD independent of age. Elevated SBP and LDL-C in early to middle life is associated with increased CHD risk independent of later-life SBP and LDL-C levels. These findings support the importance of lifelong risk factor control in young individuals, whose risk of CHD accumulates throughout life.