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.

Ambulatory blood pressure after 12 weeks of quadruple combination of quarter doses of blood pressure medication vs. standard medication.

BACKGROUND: A combination of four ultra-low-dose blood pressure (BP) medications lowered office BP more effectively than initial monotherapy in the QUARTET trial. The effects on average ambulatory BP changes at 12 weeks have not yet been reported in detail. METHODS: Adults with hypertension who were untreated or on monotherapy were eligible for participation. Overall, 591 participants were randomized to either the quadpill (irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg) or monotherapy control (irbesartan 150 mg). The difference in 24-h, daytime, and night-time systolic and diastolic ambulatory BP at 12 weeks along further metrics were predefined secondary outcomes. RESULTS: Of 576 participants, 289 were randomized to the quadpill group and 287 to the monotherapy group. At 12 weeks, mean 24-h ambulatory SBP and DBP were 7.7 [95% confidence interval (95% CI) 9.6-5.8] and 5.3 (95% CI: 6.5-4.1) mmHg lower in the quadpill vs. monotherapy group ( P  < 0.001 for both). Similar reductions in the quadpill group were observed for daytime (8.1/5.7 mmHg lower) and night-time (6.3/4.0 mmHg lower) BP at 12 weeks (all P  < 0.001) compared to monotherapy. The rate of BP control (24-h average BP < 130/80 mmHg) at 12 weeks was higher in the quadpill group (77 vs. 50%; P  < 0.001). The reduction in BP load was also more pronounced with the quadpill. CONCLUSION: A quadruple quarter-dose combination compared with monotherapy resulted in greater ambulatory BP lowering across the entire 24-h period with higher ambulatory BP control rates and reduced BP variability at 12 weeks. These findings further substantiate the efficacy of an ultra-low-dose quadpill-based BP lowering strategy.

Scale-up of the Australian Fans in Training (Aussie-FIT) men's health behaviour change program: a protocol for a randomised controlled hybrid effectiveness-implementation trial.

INTRODUCTION: Improving physical activity (PA) and healthy eating is critical for primary and secondary prevention of cardiovascular disease (CVD). Behaviour change programmes delivered in sporting clubs can engage men in health behaviour change, but are rarely sustained or scaled-up post trial. Following the success of pilot studies of the Australian Fans in Training (Aussie-FIT) programme, a hybrid effectiveness-implementation trial protocol was developed. This protocol outlines methods to: (1) establish if Aussie-FIT is effective at supporting men with or at risk of CVD to sustain improvements in moderate-to-vigorous PA (primary outcome), diet and physical and psychological health and (2) examine the feasibility and utility of implementation strategies to support programme adoption, implementation and sustainment. METHODS AND ANALYSIS: A pragmatic multistate/territory hybrid type 2 effectiveness-implementation parallel group randomised controlled trial with a 6-month wait list control arm in Australia. 320 men aged 35-75 years with or at risk of CVD will be recruited. Aussie-FIT involves 12 weekly face-to-face sessions including coach-led interactive education workshops and PA delivered in Australian Football League (Western Australia, Northern Territory) and rugby (Queensland) sports club settings. Follow-up measures will be at 3 and 6 months (both groups) and at 12 months to assess maintenance (intervention group only). Implementation outcomes will be reported using the Reach, Effectiveness, Adoption, Implementation, Maintenance framework. ETHICS AND DISSEMINATION: This multisite study has been approved by the lead ethics committees in the lead site's jurisdiction, the South Metropolitan Health Service Human Research Ethics Committee (Reference RGS4254) and the West Australian Aboriginal Health Ethics Committee (HREC1221). Findings will be disseminated at academic conferences, peer-reviewed journals and via presentations and reports to stakeholders, including consumers. Findings will inform a blueprint to support the sustainment and scale-up of Aussie-FIT across diverse Australian settings and populations to benefit men's health. TRIAL REGISTRATION NUMBER: This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12623000437662).

Cost-effectiveness of ultra-low-dose quadruple combination therapy for high blood pressure.

OBJECTIVE: To determine the cost-effectiveness and cost-utility of a quadpill containing irbesartan 37.5 mg, amlodipine 1.25 mg, indapamide 0.625 mg and bisoprolol 2.5 mg in comparison with irbesartan 150 mg for people with hypertension who are either untreated or receiving monotherapy. METHODS: We conducted a within-trial and modelled economic evaluation of the Quadruple UltrA-low-dose tReaTment for hypErTension trial. The analysis was preplanned, and medications and health service use captured during the trial. The main outcomes were incremental cost-effectiveness ratios (ICERs) for cost per mm Hg systolic blood pressure (BP) reduction at 3 months, and modelled cost per quality-adjusted life year (QALY) over a lifetime. RESULTS: The within-trial analysis showed no clear difference in cost per mm Hg BP lowering between randomised treatments at 3 months ($A10 (95% uncertainty interval (UI) $A -18 to $A37) per mm Hg per person) for quadpill versus monotherapy. The modelled cost-utility over a lifetime projected a mean incremental cost of $A265 (95% UI $A166 to $A357) and a mean 0.02 QALYs gained (95% UI 0.01 to 0.03) per person with quadpill therapy compared with monotherapy. Quadpill therapy was cost-effective in the base case (ICER of $A14 006 per QALY), and the result was sensitive to the quadpill cost in one-way sensitivity analysis. CONCLUSIONS: Quadpill in comparison with monotherapy is comparably cost-effective for short-term BP lowering. In the long-term, quadpill therapy is likely to be cost-effective. TRIAL REGISTRATION NUMBER: ANZCTRN12616001144404.

Clinical outcomes and health care costs of transferring rural Western Australians for invasive coronary angiography, and a cost-effective alternative care model: a retrospective cross-sectional study.

OBJECTIVES: To examine the severity of coronary artery disease (CAD) in people from rural or remote Western Australia referred for invasive coronary angiography (ICA) in Perth and their subsequent management; to estimate the cost savings were computed tomography coronary angiography (CTCA) offered in rural centres as a first line investigation for people with suspected CAD. DESIGN: Retrospective cohort study. SETTING, PARTICIPANTS: Adults with stable symptoms in rural and remote WA referred to Perth public tertiary hospitals for ICA evaluation during the 2019 calendar year. MAIN OUTCOME MEASURES: Severity and management of CAD (medical management or revascularisation); health care costs by care model (standard care or a proposed alternative model with local CTCA assessment). RESULTS: The mean age of the 1017 people from rural and remote WA who underwent ICA in Perth was 62 years (standard deviation, 13 years); 680 were men (66.9%), 245 were Indigenous people (24.1%). Indications for referral were non-ST elevation myocardial infarction (438, 43.1%), chest pain with normal troponin level (394, 38.7%), and other (185, 18.2%). After ICA assessment, 619 people were medically managed (60.9%) and 398 underwent revascularisation (39.1%). None of the 365 patients (35.9%) without obstructed coronaries (< 50% stenosis) underwent revascularisation; nine patients with moderate CAD (50-69% stenosis; 7%) and 389 with severe CAD (≥ 70% stenosis or occluded vessel; 75.5%) underwent revascularisation. Were CTCA used locally to determine the need for referral, 527 referrals could have been averted (53%), the ICA:revascularisation ratio would have improved from 2.6 to 1.6, and 1757 metropolitan hospital bed-days (43% reduction) and $7.3 million in health care costs (36% reduction) would have been saved. CONCLUSION: Many rural and remote Western Australians transferred for ICA in Perth have non-obstructive CAD and are medically managed. Providing CTCA as a first line investigation in rural centres could avert half of these transfers and be a cost-effective strategy for risk stratification of people with suspected CAD.

Characteristics and Outcomes of Young Patients With ST-Elevation Myocardial Infarction Without Standard Modifiable Risk Factors.

Patients with ST-elevation myocardial infarction (STEMI) with no standard modifiable risk factors (SMuRFs: hypertension, diabetes mellitus, hypercholesterolemia, and smoking) have worse short-term mortality than those with SMuRFs. Whether this association extends to younger patients is unclear. A retrospective cohort study was performed of patients aged 18 to 45 years with STEMI at 3 Australian hospitals between 2010 and 2020. Nonatherosclerotic causes of STEMI were excluded. The primary outcome was 30-day all-cause mortality. Secondary outcomes included 1 and 2-year mortality. Cox proportional hazards analysis was used. Of 597 patients, the median age was 42 (interquartile range 38 to 44) years, 85.1% were men and 8.4% were SMuRF-less. Patients who are SMuRF-less were >2 times more likely to have cardiac arrest (28.0% vs 12.6%, p = 0.003); require vasopressors (16.0% vs 6.8%, p = 0.018), mechanical support (10.0% vs 2.3%, p = 0.046), or intensive care admission (20.0% vs 5.7%, p <0.001); and have higher rate of left anterior descending artery infarcts than those with SMuRFs (62.0% vs 47.2%, p = 0.045). No significant differences in thrombolysis or percutaneous intervention were observed. Guideline-directed medical therapy at discharge was high (>90%), and not different in the SMuRF-less. 30-day mortality was almost fivefold higher in the SMuRF-less (hazard ratio 4.70, 95% confidence interval 1.66 to 13.35, p = 0.004), remaining significant at 1 and 2 years. In conclusion, young patients who are SMuRF-less have a higher 30-day mortality after STEMI than their counterparts with SMuRFs. This may be partially mediated by higher rates of cardiac arrest and left anterior descending artery territory events. These findings further highlight the need for improved prevention and management of SMuRF-less STEMI.

Cardiovascular risk management in the peri-operative setting.

Peri-operative cardiovascular events occur in up to 3% of patients undergoing non-cardiac surgery. Accurate cardiovascular risk assessment is important in the peri-operative setting, as it allows informed and shared decisions regarding the appropriateness of proceeding with surgery, guides surgical and anaesthetic approaches, and may influence the use of preventive medications and post-operative cardiac monitoring. Quantitative risk assessment may also inform a reconsideration of choosing a more limited lower risk type of surgery, or conservative management. Pre-operative cardiovascular risk assessment starts with clinical assessment and should include an estimate of functional capacity. Specialised cardiac investigations are rarely indicated specifically to assess pre-operative cardiovascular risk. The decision regarding cardiac investigations is influenced by the nature, extent and urgency of surgery. The strategy of performing pre-operative revascularisation to improve post-operative outcomes is not evidence-based and recent international guidelines recommend against this.

Efficacy and safety of sodium glucose cotransporter 2 inhibitors plus standard care in diabetic kidney disease: A systematic review and meta-analysis.

INTRODUCTION: Many people with type 2 diabetes progress to end-stage diabetic kidney disease (DKD) despite blockade of the renin-angiotensin system, suggesting the need for innovative treatment options for DKD. To capture the findings of recent studies, we performed an updated systematic review and meta-analysis of the efficacy and safety of sodium glucose co-transporter 2 (SGLT2) inhibitors combined with standard care involving angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) on the development and progression of DKD in people with type 2 diabetes compared with standard care alone. METHODS: The Cochrane Library, MEDLINE, EMBASE, PubMed and clinical trials registers were systematically searched for randomized controlled trials published before 1 September 2022. Primary outcomes were urine albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). Secondary outcomes were glycated hemoglobin (HbA1c) and systolic blood pressure (SBP). Relative risk was calculated for adverse events. RESULTS: Eight studies enrolling 5512 participants were included. In the meta-analysis (n = 1327), SGLT2 inhibitors were associated with a statistically significant reduction in UACR (weighted mean difference [WMD] -105.61 mg/g, 95 % CI -197.25 to -13.98, I2 = 99 %, p = 0.02). There was no statistically significant difference in relation to eGFR (n = 1375; WMD -0.23 mL/min/1.73m2, 95 % CI -4.34 to 3.89, I2 = 94 %, p = 0.91). CONCLUSIONS: SGLT2 inhibitors in addition to standard care including ACE inhibitors and/or ARBs significantly reduced albuminuria, HbA1c and SBP when compared to standard care alone, supporting their routine use in people with type 2 diabetes.

Medical Therapy to Prevent or Slow Progression of Aortic Stenosis: Current Evidence and Future Directions.

Degenerative aortic stenosis is a growing clinical problem owing to the high incidence in an aging population and its significant morbidity and mortality. Currently, aortic valve replacement remains the only treatment. Despite promising observational data, pharmacological management to slow or halt progression of aortic stenosis has remained elusive. Nevertheless, with a greater understanding of the mechanisms which underpin aortic stenosis, research has begun to explore novel treatment strategies. This review will explore the historical agents used to manage aortic stenosis and the emerging agents that are currently under investigation.

Primary care Adherence To Heart Failure guidelines IN Diagnosis, Evaluation and Routine management (PATHFINDER): a randomised controlled trial protocol.

INTRODUCTION: General practitioners (GPs) routinely provide care for patients with heart failure (HF); however, adherence to management guidelines, including titrating medication to optimal dose, can be challenging in this setting. This study will evaluate the effectiveness of a multifaceted intervention to support adherence to HF management guidelines in primary care. METHODS AND ANALYSIS: We will undertake a multicentre, parallel-group, randomised controlled trial of 200 participants with HF with reduced ejection fraction. Participants will be recruited during a hospital admission due to HF. Following hospital discharge, the intervention group will have follow-up with their GP scheduled at 1 week, 4 weeks and 3 months with the provision of a medication titration plan approved by a specialist HF cardiologist. The control group will receive usual care. The primary endpoint, assessed at 6 months, will be the difference between groups in the proportion of participants being prescribed five guideline-recommended treatments; (1) ACE inhibitor/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor at least 50% of target dose, (2) beta-blocker at least 50% of target dose, (3) mineralocorticoid receptor antagonist at any dose, (4) anticoagulation for patients diagnosed with atrial fibrillation, (5) referral to cardiac rehabilitation. Secondary outcomes will include functional capacity (6-minute walk test); quality of life (Kansas City Cardiomyopathy Questionnaire); depressive symptoms (Patient Health Questionnaire-2); self-care behaviour (Self-Care of Heart Failure Index). Resource utilisation will also be assessed. ETHICS AND DISSEMINATION: Ethical approval was granted by the South Metropolitan Health Service Ethics Committee (RGS3531), with reciprocal approval at Curtin University (HRE2020-0322). Results will be disseminated via peer-reviewed publications and conferences. TRIAL REGISTRATION NUMBER: ACTRN12620001069943.

Developing community pharmacists' role in the management of type 2 diabetes and related microvascular complications: a nationwide survey in Australia.

Background: Community pharmacists have regular interactions with people living with type 2 diabetes to supply medications, and have a potential role in supporting other primary care professionals in the screening, management, monitoring and facilitation of timely referral of microvascular complications. This study aimed to investigate the contemporary and future roles of community pharmacists in diabetes-related microvascular complication management. Methods: This study involved an online Australian nation-wide survey of pharmacists administered via Qualtrics® and distributed through social media platforms, state and national pharmacy organisations, and via major banner groups. Descriptive analyses were undertaken using SPSS. Results: Among 77 valid responses, 72% of pharmacists already provided blood pressure and blood glucose monitoring services for the management of type 2 diabetes. Only 14% reported providing specific microvascular complication services. Over 80% identified a need for a comprehensive microvascular complication monitoring and referral service, and agreed it is feasible and within the scope of practice of a pharmacist. Almost all respondents agreed that they would implement and provide a monitoring and referral service if provided with appropriate training and resources. Potential barriers to service implementation were competing demands and lack of remuneration and awareness among consumers and health professionals. Conclusions: Type 2 diabetes services in Australian community pharmacies do not currently focus on microvascular complication management. There appears to be strong support for implementing a novel screening, monitoring and referral service via community pharmacy to facilitate timely access to care. Successful implementation would require additional pharmacist training, and identification of efficient pathways for service integration and remuneration.

Lipoprotein(a) Is Associated with Thrombus Burden in Culprit Arteries of Younger Patients with ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Lipoprotein(a) (Lp[a]) is a risk factor for cardiovascular disease. The burden of thrombus in ST-segment elevation myocardial infarction (STEMI) has implications on treatment and outcomes. However, the association between Lp(a) and atherothrombosis in STEMI remains unclear. OBJECTIVES: The aim of the study was to determine the association between Lp(a) and culprit artery thrombus burden in younger patients with STEMI. METHODS: This was a single-center study of 83 patients aged <65 years with STEMI between 2016-2018 who underwent percutaneous coronary intervention and measurement of Lp(a); those receiving thrombolytic therapy were excluded. Thrombus burden in the culprit artery was determined angiographically using the Thrombolysis In Myocardial Infarction score and classified as absent-to-small, moderate, or large. Elevated Lp(a) was defined as plasma mass concentration >30 mg/dL. Multivariate analysis was performed adjusting for cardiovascular risk factors. RESULTS: The mean age was 48.0 ± 8.4 years, and 78.3% were male. Thirteen (16%), 9 (11%), and 61 (73%) patients had small, moderate, or large thrombus burden, respectively, and 34 (41%) had elevated Lp(a). Elevated Lp(a) was associated with greater thrombus burden compared to normal Lp(a) (large burden 85% vs. 65%; p = 0.024). Elevated Lp(a) was associated with moderate or large thrombus in univariate (OR 10.70 [95% CI 1.32-86.82]; p = 0.026) and multivariate analysis (OR 10.33 [95% CI 1.19-89.52]; p = 0.034). Lp(a) was not associated with culprit artery or stenosis location according to culprit artery. CONCLUSIONS: Elevated Lp(a) is associated with greater thrombus burden in younger patients with STEMI. The finding of this observational study accords with the thrombotic and anti-fibrinolytic properties of Lp(a). A causal relationship requires verification.

Contemporary Chest Pain Evaluation: The Australian Case for Cardiac CT.

Computed tomography coronary angiography (CTCA) is a non-invasive diagnostic modality that provides a comprehensive anatomical assessment of the coronary arteries and coronary atherosclerosis, including plaque burden, composition and morphology. The past decade has witnessed an increase in the role of CTCA for evaluating patients with both stable and acute chest pain, and recent international guidelines have provided increasing support for a first line CTCA diagnostic strategy in select patients. CTCA offers some advantages over current functional tests in the detection of obstructive and non-obstructive coronary artery disease, as well as for ruling out obstructive coronary artery disease. Recent randomised trials have also shown that CTCA improves prognostication and guides the use of guideline-directed preventive therapies, leading to improved clinical outcomes. CTCA technology advances such as fractional flow reserve, plaque quantification and perivascular fat inflammation potentially allow for more personalised risk assessment and targeted therapies. Further studies evaluating demand, supply, and cost-effectiveness of CTCA for evaluating chest pain are required in Australia. This discussion paper revisits the evidence supporting the use of CTCA, provides an overview of its implications and limitations, and considers its potential role for chest pain evaluation pathways in Australia.

Unravelling the role of macrophages in cardiovascular inflammation through imaging: a state-of-the-art review.

Cardiovascular disease remains the leading cause of death and disability for patients across the world. Our understanding of atherosclerosis as a primary cholesterol issue has diversified, with a significant dysregulated inflammatory component that largely remains untreated and continues to drive persistent cardiovascular risk. Macrophages are central to atherosclerotic inflammation, and they exist along a functional spectrum between pro-inflammatory and anti-inflammatory extremes. Recent clinical trials have demonstrated a reduction in major cardiovascular events with some, but not all, anti-inflammatory therapies. The recent addition of colchicine to societal guidelines for the prevention of recurrent cardiovascular events in high-risk patients with chronic coronary syndromes highlights the real-world utility of this class of therapies. A highly targeted approach to modification of interleukin-1-dependent pathways shows promise with several novel agents in development, although excessive immunosuppression and resulting serious infection have proven a barrier to implementation into clinical practice. Current risk stratification tools to identify high-risk patients for secondary prevention are either inadequately robust or prohibitively expensive and invasive. A non-invasive and relatively inexpensive method to identify patients who will benefit most from novel anti-inflammatory therapies is required, a role likely to be fulfilled by functional imaging methods. This review article outlines our current understanding of the inflammatory biology of atherosclerosis, upcoming therapies and recent landmark clinical trials, imaging modalities (both invasive and non-invasive) and the current landscape surrounding functional imaging including through targeted nuclear and nanobody tracer development and their application.