Improving prioritization processes for clinical practice guidelines: new methods and an evaluation from the National Heart Foundation of Australia.

BACKGROUND: Releasing timely and relevant clinical guidelines is challenging for organizations globally. Priority-setting is crucial, as guideline development is resource-intensive. Our aim, as a national organization responsible for developing cardiovascular clinical guidelines, was to develop a method for generating and prioritizing topics for future clinical guideline development in areas where guidance was most needed. METHODS: Several novel processes were developed, adopted and evaluated, including (1) initial public consultation for health professionals and the general public to generate topics; (2) thematic and qualitative analysis, according to the International Classification of Diseases (ICD-11), to aggregate topics; (3) adapting a criteria-based matrix tool to prioritize topics; (4) achieving consensus through a modified-nominal group technique and voting on priorities; and (5) process evaluation via survey of end-users. The latter comprised the organization's Expert Committee of 12 members with expertise across cardiology and public health, including two citizen representatives. RESULTS: Topics (n = 405; reduced to n = 278 when duplicates removed) were identified from public consultation responses (n = 107 respondents). Thematic analysis synthesized 127 topics that were then categorized into 37 themes using ICD-11 codes. Exclusion criteria were applied (n = 32 themes omitted), resulting in five short-listed topics: (1) congenital heart disease, (2) valvular heart disease, (3) hypercholesterolaemia, (4) hypertension and (5) ischaemic heart diseases and diseases of the coronary artery. The Expert Committee applied the prioritization matrix to all five short-listed topics during a consensus meeting and voted to prioritize topics. Unanimous consensus was reached for the topic voted the highest priority: ischaemic heart disease and diseases of the coronary arteries, resulting in the decision to update the organization's 2016 clinical guidelines for acute coronary syndromes. Evaluation indicated that initial public consultation was highly valued by the Expert Committee, and the matrix tool was easy to use and improved transparency in priority-setting. CONCLUSION: Developing a multistage, systematic process, incorporating public consultation and an international classification system led to improved transparency in our clinical guideline priority-setting processes and that topics chosen would have the greatest impact on health outcomes. These methods are potentially applicable to other national and international organizations responsible for developing clinical guidelines.

Effects of high- and low-dose aspirin on adaptive immunity and hypertension in the stroke-prone spontaneously hypertensive rat.

Despite its well-known antithrombotic properties, the effect of aspirin on blood pressure (BP) and hypertension pathology is unclear. The hugely varying doses used clinically have contributed to this confusion, with high-dose aspirin still commonly used due to concerns about the efficacy of low-dose aspirin. Because prostaglandins have been shown to both promote and inhibit T-cell activation, we also explored the immunomodulatory properties of aspirin in hypertension. Although the common preclinical high dose of 100 mg/kg/d improved vascular dysfunction and cardiac hypertrophy, this effect was accompanied by indices of elevated adaptive immunity, renal T-cell infiltration, renal fibrosis, and BP elevation in stroke-prone spontaneously hypertensive rats and in angiotensin II-induced hypertensive mice. The cardioprotective effects of aspirin were conserved with a lower dose (10 mg/kg/d) while circumventing heightened adaptive immunity and elevated BP. We also show that low-dose aspirin improves renal fibrosis. Differential inhibition of the COX-2 isoform may underlie the disparate effects of the 2 doses. Our results demonstrate the efficacy of low-dose aspirin in treating a vast array of cardiovascular parameters and suggest modulation of adaptive immunity as a novel mechanism underlying adverse cardiovascular profiles associated with COX-2 inhibitors. Clinical studies should identify the dose of aspirin that achieves maximal cardioprotection with a new awareness that higher doses of aspirin could trigger undesired autoimmunity in hypertensive individuals. This work also warrants an evaluation of high-dose aspirin and COX-2 inhibitor therapy in sufferers of inflammatory conditions who are already at increased risk for cardiovascular disease.-Khan, S. I., Shihata, W. A., Andrews, K. L., Lee, M. K. S., Moore, X.-L., Jefferis, A.-M., Vinh, A., Gaspari, T., Dragoljevic, D., Jennings, G. L., Murphy, A. J., Chin-Dusting, J. P. F. Effects of high- and low-dose aspirin on adaptive immunity and hypertension in the stroke-prone spontaneously hypertensive rat.

Y-chromosome lineage determines cardiovascular organ T-cell infiltration in the stroke-prone spontaneously hypertensive rat.

The essential role of the Y chromosome in male sex determination has largely overshadowed the possibility that it may exert other biologic roles. Here, we show that Y-chromosome lineage is a strong determinant of perivascular and renal T-cell infiltration in the stroke-prone spontaneously hypertensive rat, which, in turn, may influence vascular function and blood pressure (BP). We also show, for the first time to our knowledge, that augmented perivascular T-cell levels can directly instigate vascular dysfunction, and that the production of reactive oxygen species that stimulate cyclo-oxygenase underlies this. We thus provide strong evidence for the consideration of Y-chromosome lineage in the diagnosis and treatment of male hypertension, and point to the modulation of cardiovascular organ T-cell infiltration as a possible mechanism that underpins Y- chromosome regulation of BP.-Khan, S. I., Andrews, K. L., Jackson, K. L., Memon, B., Jefferis, A.-M., Lee, M. K. S., Diep, H., Wei, Z., Drummond, G. R., Head, G. A., Jennings, G. L., Murphy, A. J., Vinh, A., Sampson, A. K., Chin-Dusting, J. P. F. Y-chromosome lineage determines cardiovascular organ T-cell infiltration in the stroke-prone spontaneously hypertensive rat.

Y Chromosome, Hypertension and Cardiovascular Disease: Is Inflammation the Answer?

It is now becomingly increasingly evident that the functions of the mammalian Y chromosome are not circumscribed to the induction of male sex. While animal studies have shown variations in the Y are strongly accountable for blood pressure (BP), this is yet to be confirmed in humans. We have recently shown modulation of adaptive immunity to be a significant mechanism underpinning Y-chromosome-dependent differences in BP in consomic strains. This is paralleled by studies in man showing Y chromosome haplogroup is a significant predictor for coronary artery disease through influencing pathways of immunity. Furthermore, recent studies in mice and humans have shown that Y chromosome lineage determines susceptibility to autoimmune disease. Here we review the evidence in animals and humans that Y chromosome lineage influences hypertension and cardiovascular disease risk, with a novel focus on pathways of immunity as a significant pathway involved.

Vascular dysfunction in the stroke-prone spontaneously hypertensive rat is dependent on constrictor prostanoid activity and Y chromosome lineage.

Vascular dysfunction is a hallmark of hypertension and the strongest risk factor to date for coronary artery disease. As Y chromosome lineage has emerged as one of the strongest genetic predictors of cardiovascular disease risk to date, we investigated if Y chromosome lineage modulated this important facet in the stroke-prone spontaneously hypertensive rat (SHRSP) using consomic strains. Here, we show that vascular dysfunction in the SHRSP is attributable to differential cyclooxygenase (COX) activity with nitric oxide (NO) levels playing a less significant role. Measurement of prostacyclin, the most abundant product of COX in the vasculature, confirmed the augmented COX activity in the SHRSP aorta. This was accompanied by functional impairment of the vasodilatory prostacyclin (IP) receptor, while inhibition of the thromboxane (TP) receptor significantly ameliorated vascular dysfunction in the SHRSP, suggesting this is the downstream target responsible for constrictor prostanoid activity. Importantly, Y chromosome lineage was shown to modulate vascular function in the SHRSP through influencing COX activity, prostacyclin levels and IP dysfunction. Vascular dysfunction in the renal and intrarenal arteries was also found to be prostanoid and Y chromosome dependent. Interestingly, despite no apparent differences in agonist-stimulated NO levels, basal NO levels were compromised in the SHRSP aorta, which was also Y chromosome dependent. Thus, in contrast with the widely held view that COX inhibition is deleterious for the vasculature due to inhibition of the vasodilator prostacyclin, we show that COX inhibition abolishes vascular dysfunction in three distinct vascular beds, with IP dysfunction likely being a key mechanism underlying this effect. We also delineate a novel role for Y chromosome lineage in regulating vascular function through modulation of COX and basal NO levels.

A New Guideline on Treatment of Hypertension in Those with Coronary Artery Disease: Scientific Statement From the American Heart Association, American College of Cardiology, and American Society of Hypertension About Treatment of Hypertension in Patients with Coronary Artery Disease.

Hypertension is a major risk factor for coronary artery disease (CAD) and the two frequently coexist. The peak cardiology and hypertension societies of the United States recently published new guidelines on the treatment of hypertension in people with CAD. The guidelines update those previously issued eight years previously in the light of new trial data. However, for the most part they will validate what cardiologists are already doing in these patients. The major change is resetting of the blood pressure general treatment target for most people with hypertension and CAD from 130/80mm Hg to 140/90mm Hg. It is arguable that the evidence supporting the new target is any stronger than that supporting the old. While this will remain controversial in the absence of good data on the relative benefits of different treatment targets in hypertension it is in line with trends from a number of other general hypertension guidelines.

A strategy for translating evidence into policy and practice to close the gap - developing essential service standards for Aboriginal and Torres Strait Islander cardiovascular care.

The development and application of essential standards for cardiovascular care for Aboriginal and Torres Strait Islander people creates a strategic platform on which to systematically close the gap in the health outcomes and life expectancy between Aboriginal and Torres Strait Islander and non-Indigenous people in Australia. We outline six developmental stages that can be used to enhance the effective translation of evidence into practice that reduces life expectancy differentials. Focussing efforts where the biggest gain can be made; considering how to make a policy-relevant difference with an emphasis on translation into policy and practice; establishing a foundation for action by engaging with stakeholders throughout the process; developing a framework to guide action; drafting policy-relevant and framework-appropriate essential service standards; and defining standards that help policy decision makers achieve current priority policy targets.

Essential service standards for equitable national cardiovascular care for Aboriginal and Torres Strait Islander people.

Cardiovascular diseases (CVD) constitute the largest cause of death for Aboriginal and Torres Strait Islander people and remain the primary contributor to life expectancy differentials between Aboriginal and Torres Strait Islander and non-Indigenous Australians. As such, CVD remains the most critical target for reducing the life expectancy gap. The Essential Service Standards for Equitable National Cardiovascular Care for Aboriginal and Torres Strait Islander people (ESSENCE) outline elements of care that are necessary to reduce disparity in access and outcomes for five critical cardiovascular conditions. The ESSENCE approach builds a foundation on which the gap in life expectancy between Aboriginal and Torres Strait Islander and non-Indigenous Australians can be reduced. The standards purposefully focus on the prevention and management of CVD extending across the continuum of risk and disease. Each of the agreed essential service standards are presented alongside the most critical targets for policy development and health system reform aimed at mitigating population disparity in CVD and related conditions.

Plasma lipidomic analysis of stable and unstable coronary artery disease.

OBJECTIVE: Traditional risk factors for coronary artery disease (CAD) fail to adequately distinguish patients who have atherosclerotic plaques susceptible to instability from those who have more benign forms. Using plasma lipid profiling, this study aimed to provide insight into disease pathogenesis and evaluate the potential of lipid profiles to assess risk of future plaque instability. METHODS AND RESULTS: Plasma lipid profiles containing 305 lipids were measured on 220 individuals (matched healthy controls, n=80; stable angina, n=60; unstable coronary syndrome, n=80) using electrospray-ionisation tandem mass spectrometry. ReliefF feature selection coupled with an L2-regularized logistic regression based classifier was used to create multivariate classification models which were verified via 3-fold cross-validation (1000 repeats). Models incorporating both lipids and traditional risk factors provided improved classification of unstable CAD from stable CAD (C-statistic=0.875, 95% CI 0.874-0.877) compared with models containing only traditional risk factors (C-statistic=0.796, 95% CI 0.795-0.798). Many of the lipids identified as discriminatory for unstable CAD displayed an association with disease acuity (severity), suggesting that they are antecedents to the onset of acute coronary syndrome. CONCLUSION: Plasma lipid profiling may contribute to a new approach to risk stratification for unstable CAD.

Assessing cardiovascular risk in regional areas: the Healthy Hearts Beyond City Limits program.

BACKGROUND: Cardiovascular disease (CVD) is more prevalent in regional and remote Australia compared to metropolitan areas. The aim of Healthy Hearts was to determine age and sex specific CVD risk factor levels and the potential value of national risk clinics. METHODS: Healthy Hearts was an observational research study conducted in four purposefully selected higher risk communities in regional Victoria, Australia. The main outcome measures were the proportion of participants with CVD risk factors with group comparisons to determine the adjusted likelihood of elevated risk factor levels. Trained personnel used a standardized protocol over four weeks per community to measure CVD risk factor levels, estimate absolute CVD risk and provide feedback and advice. RESULTS: A total of 2125 self-selected participants were assessed (mean age 58 ± 15 years, 57% women). Overall, CVD risk factors were highly prevalent. More men than women had ≥ 2 modifiable CVD risk factors (76% vs. 68%, p < .001), pre-existing CVD (20 vs. 15%, p < .01) and a major ECG abnormality requiring follow-up (15% vs. 7%, p < .001) . Less men reported depressive symptoms compared to women (28% vs. 22%, p < .01). A higher proportion of women were obese (adjusted OR 1.36, 95% CI 1.13 to 1.63), and physically inactive (adjusted OR 1.32, 95% CI 1.07 to 1.63). CONCLUSIONS: High CVD risk factor levels were confirmed for regional Victoria. Close engagement with individuals and communities provides scope for the application of regional risk management clinics to reduce the burden of CVD risk in regional Australia.

Erectile dysfunction predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both: The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) Trials.

BACKGROUND: Although erectile dysfunction (ED) is associated with cardiovascular risk factors and atherosclerosis, it is not known whether the presence of ED is predictive of future events in individuals with cardiovascular disease. We evaluated whether ED is predictive of mortality and cardiovascular outcomes, and because inhibition of the renin-angiotensin system in high-risk patients reduces cardiovascular events, we also tested the effects on ED of randomized treatments with telmisartan, ramipril, and the combination of the 2 drugs (ONTARGET), as well as with telmisartan or placebo in patients who were intolerant of angiotensin-converting enzyme inhibitors (TRANSCEND). METHODS AND RESULTS: In a prespecified substudy, 1549 patients underwent double-blind randomization, with 400 participants assigned to receive ramipril, 395 telmisartan, and 381 the combination thereof (ONTARGET), as well as 171 participants assigned to receive telmisartan and 202 placebo (TRANSCEND). ED was evaluated at baseline, at 2-year follow-up, and at the penultimate visit before closeout. ED was predictive of all-cause death (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.21 to 2.81, P=0.005) and the composite primary outcome (HR 1.42, 95% CI 1.04 to 1.94, P=0.029), which consisted of cardiovascular death (HR 1.93, 95% CI 1.13 to 3.29, P=0.016), myocardial infarction (HR 2.02, 95% CI 1.13 to 3.58, P=0.017), hospitalization for heart failure (HR 1.2, 95% CI 0.64 to 2.26, P=0.563), and stroke (HR 1.1, 95% CI 0.64 to 1.9, P=0.742). The study medications did not influence the course or development of ED. CONCLUSIONS: ED is a potent predictor of all-cause death and the composite of cardiovascular death, myocardial infarction, stroke, and heart failure in men with cardiovascular disease. Trial treatment did not significantly improve or worsen ED. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00153101.

High intraluminal pressure promotes vascular inflammation via caveolin-1.

The aetiology and progression of hypertension involves various endogenous systems, such as the renin angiotensin system, the sympathetic nervous system, and endothelial dysfunction. Recent data suggest that vascular inflammation may also play a key role in the pathogenesis of hypertension. This study sought to determine whether high intraluminal pressure results in vascular inflammation. Leukocyte adhesion was assessed in rat carotid arteries exposed to 1 h of high intraluminal pressure. The effect of intraluminal pressure on signaling mechanisms including reactive oxygen species production (ROS), arginase expression, and NFĸB translocation was monitored. 1 h exposure to high intraluminal pressure (120 mmHg) resulted in increased leukocyte adhesion and inflammatory gene expression in rat carotid arteries. High intraluminal pressure also resulted in a downstream signaling cascade of ROS production, arginase expression, and NFĸB translocation. This process was found to be angiotensin II-independent and mediated by the mechanosensor caveolae, as caveolin-1 (Cav1)-deficient endothelial cells and mice were protected from pressure-induced vascular inflammatory signaling and leukocyte adhesion. Cav1 deficiency also resulted in a reduction in pressure-induced glomerular macrophage infiltration in vivo. These findings demonstrate Cav1 is an important mechanosensor in pressure-induced vascular and renal inflammation.

Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments. A limited understanding of the molecular mechanisms responsible for the development of AF has hindered treatment strategies. The purpose of this study was to assess whether reduced activation of phosphoinositide 3-kinase (PI3K, p110alpha) makes the compromised heart susceptible to AF. Risk factors for AF, including aging, obesity, and diabetes, have been associated with insulin resistance that leads to depressed/defective PI3K signaling. However, to date, there has been no link between PI3K(p110alpha) and AF. To address this question, we crossed a cardiac-specific transgenic mouse model of dilated cardiomyopathy (DCM) with a cardiac-specific transgenic mouse expressing a dominant negative mutant of PI3K (dnPI3K; reduces PI3K activity). Adult ( approximately 4.5 months) double-transgenic (dnPI3K-DCM), single-transgenic (DCM-Tg, dnPI3K-Tg), and nontransgenic mice were subjected to morphological, functional/ECG, microarray, and biochemical analyses. dnPI3K-DCM mice developed AF and had depressed cardiac function as well as greater atrial enlargement and fibrosis than DCM-Tg mice. AF was not detected in other groups. Aged DCM-Tg mice ( approximately 15 months) with a similar phenotype to dnPI3K-DCM mice (4.5 months) did not develop AF, suggesting loss of PI3K activity directly contributed to the AF phenotype. Furthermore, increasing PI3K activity reduced atrial fibrosis and improved cardiac conduction in DCM-Tg mice. Finally, in atrial appendages from patients with AF, PI3K activation was lower compared with tissue from patients in sinus rhythm. These results suggest a link between PI3K(p110alpha) and AF.

Cholesterol complacency in Australia: time to revisit the basics of cardiovascular disease prevention.

AIMS AND OBJECTIVES: Community awareness of the importance of hypercholesterolemia and the need for appropriate therapy is an important part of global efforts to reduce the population burden of cardiovascular disease. The aim of this study was to assess the knowledge and attitudes about cholesterol and to determine adherence to taking cholesterol-lowering medication among patients at high risk for cardiovascular events. BACKGROUND: In spite of the availability of lifestyle and medical treatments for lipid management, an estimated 50% of adult Australians (6.4 million) remain at risk for a cardiovascular-related event because they have total blood cholesterol levels which exceed recommended limits. It is within this context that a significant gap remains in meeting cholesterol goals, despite easy to meet targets with readily available therapeutic options. DESIGN: A two-page national self-report postal survey was conducted from August-October 2006. METHODS: A total of 508 Australian adults previously treated for hypercholesterolemia were surveyed to determine their understanding about cholesterol and their adherence to treatment. The mean age of participants was 67 (SD 10) years (72% male). Many participants (72%) were at risk of a cardiovascular event based on a prior history and 18% had type II diabetes. RESULTS: Participants had been prescribed lipid-lowering therapy (94% statin therapy) for an average of 10 years and visited their general practitioner on average three times per year. For those who knew their most recent cholesterol reading (67%), the total cholesterol was on average 4.5 (SD 1.1) mmol/l. This level was above the recommended limits for 40% of participants. Overall, 85% of participants reported knowing that there was high- and low-density lipoprotein forms of cholesterol, but only 56% and 38%, respectively, said that they understood or showed signs of clearly understanding the different types of cholesterol when their knowledge was assessed further. On the whole, therefore, participants had a limited understanding about cholesterol and its potential impact on cardiovascular events. Moreover, 25% of participants admitted to being non-compliant in taking their medication and only 51% correctly identified modifiable risk factors as most important for heart disease. Encouragingly, despite 85% of participants finding lifestyle changes challenging, most still identified their potential benefits. CONCLUSIONS: This study highlights that there are many unresolved issues in relation to educating high-risk patients who regularly visit their general practitioner to learn about and optimise their cholesterol levels via appropriate treatment and monitoring. RELEVANCE TO CLINICAL PRACTICE: There is a need for urgent public education and management by individuals and the health community. Strategies to address 'cholesterol complacency', in the sense of a willingness to accept sub-optimal standards of cholesterol control at both the patient and healthcare system levels (general practitioners in particular), are urgently needed to truncate an anticipated rising tide of cardiovascular disease in Australia.