Secondary prevention of renal and cardiovascular disease: Results of a renal and cardiovascular treatment program in an Australian aboriginal community

Australian Aborigines are experiencing an epidemic of renal and cardiovascular disease. In late 1995 we introduced a treatment program into the Tiwi community, which has a three- to fivefold increase in death rates and a recent annual incidence of treated ESRD of 2760 per million. Eligible for treatment were people with hypertension, diabetics with micro or overt albuminuria, and all people with overt albuminuria. Treatment centered around use of perindopril (Coversyl, Servier), with other agents added to reach BP goals; attempts to control glucose and lipid levels; and health education. Thirty percent of the adult population, or 267 people, were enrolled, with a mean follow up of 3.39 yr. Clinical parameters were followed every 6 mo, and rates of terminal endpoints were compared with those of 327 historical controls matched for baseline disease severity, followed in the pretreatment program era. There was a dramatic reduction in BP in the treatment group, which was sustained through 3 yr of treatment. Albuminuria and GFR stabilized or improved. Rates of natural deaths were reduced by an estimated 50% (P = 0.012); renal deaths were reduced by 57% (P = 0.038); and nonrenal deaths by 46% (P = 0.085). Survival benefit was suggested at all levels of overt albuminuria, and regardless of diabetes status, baseline BP, or prior administration of angiotensin converting enzyme inhibitors (ACEI). No significant benefit was apparent among people without overt albuminuria, nor among those with GFR less than 60 ml/min. An estimated 13 renal deaths and 10 nonrenal deaths were prevented, with the number-needed-to-treat to avoid one terminal event of only 11.6. Falling deaths and renal failure in the whole community support these estimates. The program was extremely cost-effective. Programs like this should be introduced to all high-risk communities as a matter of urgency.

Achieving better in-hospital and after-hospital care of patients with acute cardiac disease

In patients hospitalised with acute coronary syndromes (ACS) and congestive heart failure (CHF), evidence suggests opportunities for improving in-hospital and after hospital care, patient self-care, and hospital-community integration. A multidisciplinary quality improvement program was designed and instigated in Brisbane in October 2000 involving 250 clinicians at three teaching hospitals, 1080 general practitioners (GPs) from five Divisions of General Practice, 1594 patients with ACS and 904 patients with CHF. Quality improvement interventions were implemented over 17 months after a 6-month baseline period and included: clinical decision support (clinical practice guidelines, reminders, checklists, clinical pathways); educational interventions (seminars, academic detailing); regular performance feedback; patient self-management strategies; and hospital-community integration (discharge referral summaries; community pharmacist liaison; patient prompts to attend GPs). Using a before-after study design to assess program impact, significantly more program patients compared with historical controls received: ACS: Angiotensin-converting enzyme (ACE) inhibitors and lipid-lowering agents at discharge, aspirin and beta-blockers at 3 months after discharge, inpatient cardiac counselling, and referral to outpatient cardiac rehabilitation. CHF. Assessment for reversible precipitants, use of prophylaxis for deep-venous thrombosis, beta-blockers at discharge, ACE inhibitors at 6 months after discharge, imaging of left ventricular function, and optimal management of blood pressure levels. Risk-adjusted mortality rates at 6 and 12 months decreased, respectively, from 9.8% to 7.4% (P=0.06) and from 13.4% to 10.1% (P= 0.06) for patients with ACS and from 22.8% to 15.2% (P < 0.001) and from 32.8% to 22.4% (P= 0.005) for patients with CHF. Quality improvement programs that feature multifaceted interventions across the continuum of care can change clinical culture, optimise care and improve clinical outcomes.

Multisite, quality-improvement collaboration to optimise cardiac care in Queensland public hospitals

Objective: To evaluate changes in quality of in-hospital care of patients with either acute coronary syndromes (ACS) or congestive heart failure (CHF) admitted to hospitals participating in a multisite quality improvement collaboration. Design: Before-and-after study of changes in quality indicators measured on representative patient samples between June 2001 and January 2003. Setting: Nine public hospitals in Queensland. Study populations: Consecutive or randomly selected patients admitted to study hospitals during the baseline period (June 2001 to January 2002; n = 807 for ACS, n = 357 for CHF) and post-intervention period (July 2002 to January 2003; n = 717 for ACS, n = 220 for CHF). Intervention: Provision of comparative baseline feedback at a facilitative workshop combined with hospital-specific quality-improvement interventions supported by on-site quality officers and a central program management group. Main outcome measure: Changes in process-of-care indicators between baseline and post-intervention periods. Results: Compared with baseline, more patients with ACS in the post-intervention period received therapeutic heparin regimens (84% v 72%; P < 0.001), angiotensin-converting enzyme inhibitors (64% v 56%; P = 0.02), lipid-lowering agents (72% v 62%; P < 0.001), early use of coronary angiography (52% v 39%; P < 0.001), in-hospital cardiac counselling (65% v 43%; P < 0.001), and referral to cardiac rehabilitation (15% v 5%; P < 0.001). The numbers of patients with CHF receiving β-blockers also increased (52% v 34%; P < 0.001), with fewer patients receiving deleterious agents (13% v 23%; P = 0.04). Same-cause 30-day readmission rate decreased from 7.2% to 2.4% (P = 0.02) in patients with CHF. Conclusion: Quality-improvement interventions conducted as multisite collaborations may improve in-hospital care of acute cardiac conditions within relatively short time frames.

Optimising care of acute coronary syndromes in three Australian hospitals

Objective. To improve quality of in-hospital care of patients with acute coronary syndromes using a multifaceted quality improvement program. Design. Prospective, before and after study of the effects of quality improvement interventions between October 2000 and August 2002. Quality of care of patients admitted between 1 October 2000 and 16 April 2001 (baseline) was compared with that of those admitted between 15 February 2002 and 31 August 2002 (post-intervention). Setting. Three teaching hospitals in Brisbane, Australia. Study participants. Consecutive patients (n = 1594) admitted to hospital with acute coronary syndrome [mean age 68 years (SD 14 years); 65% males]. Interventions. Clinical guidelines, reminder tools, and educational interventions; 6-monthly performance feedback; pharmacist-mediated patient education program; and facilitation of multidisciplinary review of work practices. Main outcome measures. Changes in key quality indicators relating to timing of electrocardiogram (ECG) and thrombolysis in emergency departments, serum lipid measurement, prescription of adjunctive drugs, and secondary prevention. Results. Comparing post-intervention with baseline patients, increases occurred in the proportions of eligible patients: (i) undergoing timely ECG (70% versus 61%; P = 0.04); (ii) prescribed angiotensin-converting enzyme inhibitors (70% versus 60%; P = 0.002) and lipid-lowering agents (77% versus 68%; P = 0.005); (iii) receiving cardiac counselling in hospital (57% versus 48%; P = 0.009); and (iv) referred to cardiac rehabilitation (17% versus 8%; P < 0.001). Conclusions. Multifaceted approaches can improve care processes for patients hospitalized with acute coronary syndromes. Care processes under direct clinician control changed more quickly than those reliant on complex system factors. Identifying and overcoming organizational impediments to quality improvement deserves greater attention.

Tissue Doppler imaging for evaluation of myocardial function in patients with diabetes mellitus

Purpose of review Heart failure and diabetes mellitus are frequently associated, and diabetes appears to potentiate the clinical presentation of heart failure related to other causes. The purpose of this review is to examine recent advances in the application of tissue Doppler imaging for the assessment of diabetic heart disease. Recent findings Recent studies have documented that both myocardial systolic and diastolic abnormalities can be identified in apparently healthy patients with diabetes and no overt cardiac dysfunction. Interestingly, these are disturbances of longitudinal function, with compensatory increases of radial function-suggesting primary involvement of the subendocardium, which is a hallmark of myocardial ischemia. Despite this, there is limited evidence that diabetic microangiopathy is responsible-with reduced myocardial blood volume rather than reduced resting flow, and at least some evidence suggesting a normal increment of tissue velocity with stress. Finally, a few correlative studies have shown association of diabetic myocardial disease with poor glycemic control, while angiotensin converting enzyme inhibition may be protective. Summary Tissue Doppler imaging (and the related technique of strain rate imaging) appears to be extremely effective for the identification of subclinical LV dysfunction in diabetic patients It is hoped that the recognition of this condition will prompt specific therapy to prevent the development of overt LV dysfunction.

Benefits of ACE inhibitors with tissue-active levels in the cardiac-compromised patient

Angiotensin converting enzyme inhibitors (ACEI) have been proven beneficial to the cardiac-compromised patient, but whether there is an advantage associated with using a tissue-active or systemically-active ACEI is debatable. An investigation into the clinical benefits of tissue ACEI for veterinary patients was undertaken by comparing enalapril with ramipril. Results obtained concluded that although there is much evidence to prove that tissue ACEIs are superior over systemic ACEIs at the cellular level, this does not correlate in the clinical sense. Both enalapril and ramipril provided similar clinical benefits to the cardiac-compromised patient.

Influence of socioeconomic deprivation on the primary care burden and treatment of patients with a diagnosis of heart failure in general practice in Scotland: population based study

Objectives To examine whether there are socioeconomic gradients in die incidence, prevalence, treatment, and follow up of patients with heart failure in primary care. Design Population based study. Setting 53 general practices (307741 patients) participating in the Scottish continuous morbidity recording project between 1 April 1999 and 31 March 2000. Participants 2186 adults with heart failure. Main outcome measures Comorbid diagnoses, frequency of visits to general practitioner, and prescribed drugs. Results 2186 patients with heart failure were seen (prevalence 7.1 per 1000 population, incidence 2.0 per 1000 population). The age and sex standardised incidence of heart failure increased with greater socioeconomic deprivation, from 1.8 per 1000 population in the most affluent stratum to 2.6 per 1000 population in the most deprived stratum (odds ratio 1.44, P=0.0003). On average, patients were seen 2.4 times yearly, but follow up rates were less frequent with increasing socioeconomic deprivation (from 2.6 yearly in the most affluent subgroup to 2.0 yearly in the most deprived subgroup, P=0.00009). Overall, 812 (80.6%) patients were prescribed diuretics, 396 (39.3%) angiotensin converting enzyme inhibitors, 216 (21.4%) beta blockers, 208 (20.7%) digoxin, and 86 (8.5%) spironolactone. The wide discrepancies in prescribing between different general practices disappeared after adjustment for patient age and sex. Prescribing patterns did not vary by deprivation categories on univariate or multivariate analyses. Conclusions Compared with affluent patients, socioeconomically deprived patients were 44% more likely to develop heart failure but 23% less likely to see their general practitioner on an ongoing basis. Prescribed treatment did not differ across socioeconomic gradients.

Cardiac chymase: pathophysiological role and therapeutic potential of chymase inhibitors

On release from cardiac mast cells, alpha-chymase converts angiotensin I (Ang I) to Ang II. In addition to Ang II formation, alpha-chymase is capable of activating TGF-beta 1 and IL-1 beta, forming endothelins consisting of 31 amino acids, degrading endothelin-1, altering lipid metabolism, and degrading the extracellular matrix. Under physiological conditions the role of chymase in the mast cells of the heart is uncertain. In pathological situations, chymase may be secreted and have important effects on the heart. Thus, in animal models of cardiomyopathy, pressure overload, and myocardial infarction, there are increases in both chymase mRNA levels and chymase activity in the heart. In human diseased heart homogenates, alterations in chymase activity have also been reported. These findings have raised the possibility that inhibition of chymase may have a role in the therapy of cardiac disease. The selective chymase inhibitors developed to date include TY-51076, SUN-C8257, BCEAB, NK320, and TEI-E548. These have yet to be tested in humans, but promising results have been obtained in animal models of myocardial infarction, cardiomyopathy, and tachycardia-induced heart failure. It seems likely that orally active inhibitors of chymase could have a place in the treatment of cardiac diseases where injury-induced mast cell degranulation contributes to the pathology.

Cost-effectiveness analysis of a kidney and cardiovascular disease treatment program in an Australian aboriginal population

The objective of the study was to assess, from a health service perspective, whether a systematic program to modify kidney and cardiovascular disease reduced the costs of treating end-stage kidney failure. The participants in the study were 1,800 aboriginal adults with hypertension, diabetes with microalbuminuria or overt albuminuria, and overt albuminuria, living on two islands in the Northern Territory of Australia during 1995 to 2000. Perindopril was the primary treatment agent, and other medications were also used to control blood pressure. Control of glucose and lipid levels were attempted, and health education was offered. Evaluation of program resource use and costs for follow-up periods was done at 3 and 4.7 years. On an intention-to-treat basis, the number of dialysis starts and dialysis-years avoided were estimated by comparing the fate of the treatment group with that of historical control subjects, matched for disease severity, who were followed in the before the treatment program began. For the first three years, an estimated 11.6 person-years of dialysis were avoided, and over 4.7 years, 27.7 person-years of dialysis were avoided. The net cost of the program was $1,210 more per person per year than status quo care, and dialyses avoided gave net savings of $1.0 million at 3 years and $3.4 million at 4.6 years. The treatment program provided significant health benefit and impressive cost savings in dialysis avoided. (C) 2005 by the National Kidney Foundation, Inc.

Cloning and characterization of natriuretic peptides from the venom glands of Australian elapids

The venom from Australian elapid snakes contains a complex mixture of polypeptide toxins that adversely affect multiple homeostatic systems within their prey in a highly specific and targeted manner. Included in these toxin families are the recently described venom natriuretic peptides, which display similar structure and vasoactive functions to mammalian natriuretic peptides. This paper describes the identification and detailed comparative analysis of the cDNA transcripts coding for the mature natriuretic peptide from a total of nine Australian elapid snake species. Multiple isoforms were identified in a number of species and represent the first description of a natriuretic peptide from the venom gland for most of these snakes. Two distinct natriuretic peptide isoforms were selected from the common brown snake (Pseudonaja textilis), PtNP-a, and the mulga (Pseudechis australis), PaNP-c, for recombinant protein expression and functional analysis. Only one of these peptides, PtNP-a, displayed cGMP stimulation indicative of normal natriuretic peptide activity. Interestingly, both recombinant peptides demonstrated a dose-dependent inhibition of angiotensin converting enzyme (ACE) activity, which is predictive of the vasoactive effects of the toxin. The natriuretic peptides, however, did not possess any coagulopathic activity, nor did they inhibit or potentiate thrombin, adenosine diphosphate or arachidonic acid induced platelet aggregation. The data presented in this study represent a significant resource for understanding the role of various natriuretic peptides isoforms during the envenomation process by Australian elapid snakes. (c) 2006 Published by Elsevier Masson SAS.

The role of BNP testing in heart failure

Brain natriuretic peptide (BNP) levels are simple and objective measures of cardiac function. These measurements can be used to diagnose heart failure, including diastolic dysfunction, and using them has been shown to save money in the emergency department setting. The high negative predictive value of BNP tests is particularly helpful for ruling out heart failure. Treatment with angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, spironolactone, and diuretics reduces BNP levels, suggesting that BNP testing may have a role in monitoring patients with heart failure. However, patients with treated chronic stable heart failure may have levels in the normal range (i.e., BNP less than 100 pg per mL and N-terminal proBNP less than 125 pg per mL in patients younger than 75 years). Increases in BNP levels may be caused by intrinsic cardiac dysfunction or may be secondary to other causes such as pulmonary or renal diseases (e.g., chronic hypoxia). BNP tests are correlated with other measures of cardiac status such as New York Heart Association classification. BNP level is a strong predictor of risk of death and cardiovascular events in patients previously diagnosed with heart failure or cardiac dysfunction.

Mouse embryo culture induces changes in postnatal phenotype including raised systolic blood pressure

A key factor in the use of assisted reproductive technologies (ART) for diverse species is the safety of procedures for long-term health. By using a mouse model, we have investigated the effect of in vitro culture and embryo transfer (ET) of superovulated embryos on postnatal growth and physiological activity compared with that of embryos developing in vivo. Embryo culture from two-cell to blastocyst stages in T6 medium either with or without a protein source reduced blastocyst trophectoderm and inner cell mass cell number compared with that of embryos developing in vivo. Embryo culture and ET had minimal effects on postnatal growth when compared with in vivo development with an equivalent litter size. However, embryo culture, and to a lesser extent ET, led to an enhanced systolic blood pressure at 21 weeks compared with in vivo development independent of litter size, maternal origin, or body weight. Moreover, activity of enzymatic regulators of cardiovascular and metabolic physiology, namely, serum angiotensin-converting enzyme and the gluconeogenesis controller, hepatic phosphoeno/pyruvate carboxykinase, were significantly elevated in response to embryo culture and/or ET in female offspring at 27 weeks, independent of maternal factors and postnatal growth. These animal data indicate that postnatal physiological criteria important in cardiovascular and metabolic health may be more sensitive to routine ART procedures than growth. © 2007 by The National Academy of Sciences of the USA.

Paediatric drug development:reformulation, in vitro, genomic and in vivo evaluation

Angiotensin converting enzyme (ACE) inhibitors lisinopril and ramipril were selected from EMA/480197/2010 and the potassium-sparing diuretic spironolactone was selected from the NHS specials list for November 2011 drug tariff with the view to produce oral liquid formulations providing dosage forms targeting paediatrics. Lisinopril, ramipril and spironolactone were chosen for their interaction with transporter proteins in the small intestine. Formulation limitations such as poor solubility or pH sensitivity needed consideration. Lisinopril was formulated without extensive development as drug and excipients were water soluble. Ramipril and spironolactone are both insoluble in water and strategies combating this were employed. Ramipril was successfully solubilised using low concentrations of acetic acid in a co-solvent system and also via complexation with hydroxypropyl-β-cyclodextrin. A ramipril suspension was produced to take formulation development in a third direction. Spironolactone dosages were too high for solubilisation techniques to be effective so suspensions were developed. A buffer controlled pH for the sensitive drug whilst a precisely balanced surfactant and suspending agent mix provided excellent physical stability. Characterisation, stability profiling and permeability assessment were performed following formulation development. The formulation process highlighted current shortcomings in techniques for taste assessment of pharmaceutical preparations resulting in early stage research into a novel in vitro cell based assay. The formulations developed in the initial phase of the research were used as model formulations investigating microarray application in an in vitro-in vivo correlation for carrier mediated drug absorption. Caco-2 cells were assessed following transport studies for changes in genetic expression of the ATP-binding cassette and solute carrier transporter superfamilies. Findings of which were compared to in vitro and in vivo permeability findings. It was not possible to ascertain a correlation between in vivo drug absorption and the expression of individual genes or even gene families, however there was a correlation (R2 = 0.9934) between the total number of genes with significantly changed expression levels and the predicted human absorption.