Project Retrosight. Understanding the returns from cardiovascular and stroke research: Case Studies

Copyright @ 2011 RAND Europe. All rights reserved. The full text article is available via the link below.This project explores the impacts arising from cardiovascular and stroke research funded 15-20 years ago and attempts to draw out aspects of the research, researcher or environment that are associated with high or low impact. The project is a case study-based review of 29 cardiovascular and stroke research grants, funded in Australia, Canada and UK between 1989 and 1993. The case studies focused on the individual grants but considered the development of the investigators and ideas involved in the research projects from initiation to the present day. Grants were selected through a stratified random selection approach that aimed to include both high- and low-impact grants. The key messages are as follows: 1) The cases reveal that a large and diverse range of impacts arose from the 29 grants studied. 2) There are variations between the impacts derived from basic biomedical and clinical research. 3) There is no correlation between knowledge production and wider impacts 4) The majority of economic impacts identified come from a minority of projects. 5) We identified factors that appear to be associated with high and low impact. This report presents the key observations of the study and an overview of the methods involved. It has been written for funders of biomedical and health research and health services, health researchers, and policy makers in those fields. It will also be of interest to those involved in research and impact evaluation.This study was initiated with internal funding from RAND Europe and HERG, with continuing funding from the UK National Institute for Health Research, the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada and the National Heart Foundation of Australia. The UK Stroke Association and the British Heart Foundation provided support in kind through access to their archives

Personalized medicine—a modern approach for the diagnosis and management of hypertension

The main goal of treating hypertension is to reduce blood pressure to physiological levels and thereby prevent risk of cardiovascular disease and hypertension-associated target organ damage. Despite reductions in major risk factors and the availability of a plethora of effective antihypertensive drugs, the control of blood pressure to target values is still poor due to multiple factors including apparent drug resistance and lack of adherence. An explanation for this problem is related to the current reductionist and ‘trial-and-error’ approach in the management of hypertension, as we may oversimplify the complex nature of the disease and not pay enough attention to the heterogeneity of the pathophysiology and clinical presentation of the disorder. Taking into account specific risk factors, genetic phenotype, pharmacokinetic characteristics, and other particular features unique to each patient, would allow a personalized approach to managing the disease. Personalized medicine therefore represents the tailoring of medical approach and treatment to the individual characteristics of each patient and is expected to become the paradigm of future healthcare. The advancement of systems biology research and the rapid development of high-throughput technologies, as well as the characterization of different –omics, have contributed to a shift in modern biological and medical research from traditional hypothesis-driven designs toward data-driven studies and have facilitated the evolution of personalized or precision medicine for chronic diseases such as hypertension

Motivational Interviewing Impact on Cardiovascular Disease

abstract: Harm reduction in cardiovascular disease is a significant problem worldwide. Providers, families, and healthcare agencies are feeling the burdens imparted by these diseases. Not to mention missed days of work and caregiver strain, the losses are insurmountable. Motivational interviewing (MI) is gaining momentum as a method of stimulating change through intrinsic motivation by resolving ambivalence toward change (Ma, Zhou, Zhou, & Huang, 2014). If practitioners can find methods of educating the public in a culturally-appropriate and sensitive manner, and if they can work with community stakeholders to organize our resources to make them more accessible to the people, we may find that simple lifestyle changes can lead to risk reduction of cardiovascular diseases. By working with our community leaders and identifying barriers unique to each population, we can make positive impacts on a wide range of issues that markedly impact our healthcare systems

Profiling of cardio-metabolic risk factors and medication utilisation among Type II diabetes patients in Ghana: a prospective cohort study

Background: Type II diabetes mellitus (T2DM) is complicated by multiple cardio-metabolic risk factors. Controlling these factors requires lifestyle modifications alongside utilisation of anti-diabetic medications. Different glucose lowering [(biguanides (BIGs), sulfonylureas (SUAs), thiazolidinediones (TNZ)], lipid lowering (statins), and anti-hypertensive medicines [angiotensin converting enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), angiotensin II receptor blockers (ARBs) and central acting drugs (CADs)] have been approved for controlling hyperglycaemia, dyslipidaemia and hypertension respectively. Here, we examined factors that characterise T2DM and explored the response to medication therapy among T2DM patients. Methods: This prospective cohort study recruited 241 T2DM patients reporting at a clinic in Ghana, from January through to August, 2016. Each patient’s demographic, medications and anthropometric data was obtained while information on medication adherence was captured using Morisky adherence scale-8 (MMAS-8). Fasting blood samples were collected for biochemical analysis. Results: The mean age of participants was 57.82 years for baseline and six-month follow-up. Physical activity differed at baseline and follow up (p \u3c 0.05) but not body mass index (BMI). BIG alone, or in combination with SUA and TNZ did not improve glycaemic status at follow up (p \u3e 0.05). Many participants using either ACEI or ARB were able to control their blood pressures. Among dyslipidaemia patients under statin treatment, there was an improved lipid profile at follow-up. Conclusions: Statin medications are effective for reducing dyslipidaemia in T2DM patients. However, control of modifiable risk factors, particularly blood glucose and to a lesser degree blood pressure is suboptimal. Addressing these will require concomitant interventions including education on medication adherence and correct dietary plans, lifestyle modifications and physical activity

Characterisation of the pharmacological actions in humans of multiple vasoactive enzyme inhibitors with therapeutic potential in heart failure

Introduction The work described in this thesis looks particularly but not exclusively at two recently developed molecules which have dual enzyme inhibitor activity. Omapatrilat, a molecule which inhibits both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), and SLV 306 (active metabolite KC12615) a compound with both NEP and endothelin converting enzyme (ECE) inhibiting properties. Neurohumoral activation characterises the complex chronic heart failure syndrome. Clearly there is value in antagonizing neurohumoral systems likely to have detrimental effects in patients with heart failure, while simultaneously augmenting potentially desirable neurohumoral mediators. However enzyme inhibitors which act on multiple vasoactive mediators with complex interactions have unpredictable effects. Omapatrilat has received much attention following demonstration of a powerful hypotensive effect but a higher than expected incidence of angioedema in patients with hypertension or heart failure. GW660511X is another dual ACE/NEP inhibitor at an earlier stage in development. The pharmacodynamic profile of neither the ACE inhibitor activity nor the NEP inhibitor activity of GW 660511X has been fully described in humans. SLV 306 is the first orally available molecule of its kind and its NEP and ECE inhibitory properties have not previously been demonstrated in humans either in vitro or in vivo. The intention of this thesis is further characterisation of these molecules and their therapeutic potential while utilising their inhibitory properties in further investigation of the human neurohumoral system. I specifically consider the possible mediators of the impressive hypotensive effects of these molecules and of the unexpected and potentially life threatening side effects associated with them. Having demonstrated the complex neurohumoral substrate of these molecules I go on to report, for the first time in heart failure patients, the benefits of a more specific approach to neurohumoral manipulation using a recently developed renin inhibitor, aliskiren. Aliskiren has been shown to offer haemodynamic benefit in patients with hypertension but has not previously been given to patients with chronic heart failure. Methods 1) Small resistance arteries from patients (n=89) with coronary artery disease but normal left ventricular function were studied using wire myography. The vasopressor response to various neurohormones in the presence of omapatrilat, KC12615 (the active metabolite of SLV 306) and other vasoactive enzyme inhibitors is reported. 2) Following pilot studies of the pressor response to intravenous infusion of big ET-1 (n=6) and pharmacokinetic modeling of orally dosed SLV 306 in healthy volunteers (n=29), the effect of 3 doses of SLV 306 and placebo given at four separate visits one week apart, on the pressor and neurohumoral response to intravenous infusion of big endothelin-1 in healthy volunteers (n=15) is compared. 3) The effect of 2 oral doses of GW660511X and a single dose of the ACE inhibitor ramipril, given on three separate visits one week apart, on the pressor and neurohumoral response to an intravenous infusion of angiotensin I in healthy volunteers (n=16) is compared. 4) Finally, the neurohumoral and blood pressure response to aliskiren an orally active, long acting renin inhibitor is compared with placebo for one week and the ACE inhibitor ramipril for 6 weeks, in patients with left ventricular systolic dysfunction (n=27). Results 1) In patients with coronary artery disease but normal left ventricular systolic dysfunction; the vasodilator response to bradykinin was augmented by omapatrilat, KC 12615, phosphoramidon (NEP/ECE inhibitor), captopril (ACE inhibitor), and thiorphan (NEP inhibitor). Of note the augmentation is no greater with omapatrilat than captopril and in arteries taken from patients prescribed ACE inhibitor, KC 12615 does not augment the response. The vasodilator response to adrenomedullin was augmented by omapatrilat, KC 12615 and phosphoramidon. The vasoconstrictor response to angiotensin I was inhibited by omapatrilat and captopril and the vasoconstrictor response to endothelin-1 was inhibited by KC 12615 and phosphoramidon. 2) In healthy volunteers, SLV 306 caused a dose dependent attenuation of the hypertensive and reflex bradycardia response to big ET-1. There was also a dose dependent increase in ANP, big ET-1 and the ratio big ET-1: ET-1 but no increase in ET-1 following big ET-1 infusion. 3) In healthy volunteers, there was no notable change in blood pressure (pre angiotensin I infusion) and no significant inhibition of pressor response to angiotensin I following administration of GW660511X. Ramipril 10mg was associated with a reduction in blood pressure (pre angiotensin I infusion) and inhibition of the response to angiotensin I. There was significantly greater reduction in ACE activity with ramipril than GW660511X. GW660511X but not ramipril led to a dose dependent increase in plasma ANP concentration. 4) In patients with chronic heart failure, aliskiren suppressed plasma renin activity and reduced plasma angiotensin II. Ramipril in comparison caused an increase in renin activity and no change in angiotensin II. There were no significant changes in blood pressure with either treatment. Conclusion I have demonstrated the ACE and NEP inhibitory properties of omapatrilat and for the first time in humans, the ECE and NEP inhibitory properties of SLV 306, in vitro in patients with coronary artery disease but normal left ventricular dysfunction. I found no additional augmentation of bradykinin by omapatrilat or SLV 306 over and above that offered by ACE inhibition but significant augmentation by both dual inhibitors of adrenomedullin. This contradicts the suggestion that bradykinin has a role in the incidence of angioedema offers adrenomedullin as an alternative mediator. Adrenomedullin augmentation may also contribute significantly to the hypotensive effects of these molecules. I have demonstrated for the first time in humans the ECE and NEP inhibitory properties of SLV 306 in vivo. GW660511X is shown to inhibit NEP but to a much lesser extent ACE. Of note the comparison made is with full dose of a powerful pure ACE inhibitor. Any inhibition of ACE activity in contrast to the study of pure NEP inhibitors is consistent with the belief that dual inhibition offers additional benefit. Finally I have demonstrated for the first time in patients with chronic heart failure the renin inhibitor activity of aliskiren, confirming attenuation of the renin angiotensin aldosterone pathway consistently from its origin and in contrast the rise in renin activity seen with ACE inhibitors

Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib.

BackgroundEarly detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics.MethodsA nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of 1129 proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death.ResultsPlasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% (P=0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk.ConclusionsHeretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264

Torcetrapib impairs endothelial function in hypertension

Aims A marked increase in HDL notwithstanding, the cholesterol ester transfer protein (CETP) inhibitor torcetrapib was associated with an increase in all-cause mortality in the ILLUMINATE trial. As underlying mechanisms remain elusive, the present study was designed to delineate potential off-target effects of torcetrapib. Methods and results Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were treated with torcetrapib (100 mg/kg/day; SHR-T and WKY-T) or placebo (SHR-P and WKY-P) for 3 weeks. Blood pressure transiently increased during the first 3 days of torcetrapib administration in SHRs and returned to baseline thereafter despite continued drug administration. Acetylcholine-induced endothelium-dependent relaxations of aortic rings were markedly impaired, and endothelial nitric oxide synthase (eNOS) mRNA and protein were down-regulated after 3 weeks of torcetrapib treatment in SHR (P < 0.0001, <0.01, and <0.05, resp. vs. SHR-P). Torcetrapib reduced NO release in cultured aortic endothelial cells (P < 0.01 vs. vehicle-treated cells) and increased generation of reactive oxygen species in aortas of SHR-T (P < 0.05, vs. SHR-P). Vascular reactivity to endothelin-1 (ET-1) and aortic ET-1 tissue content were increased in SHR-T (P < 0.05 vs. SHR-P). Importantly, the ET-1 receptor A/B (ETA/B) antagonist bosentan normalized endothelial function in SHR-T (P < 0.05). Conclusion Torcetrapib induces a sustained impairment of endothelial function, decreases eNOS mRNA, protein as well as NO release, stimulates vascular ROS and ET production, an effect that is prevented by chronic ETA/B-receptor blockade. These unexpected off-target effects of torcetrapib need to be ruled out in the clinical development of novel CETP inhibitors, particularly before a large patient population at increased cardiovascular risk is exposed to these compound

The Impact of a Health Education Program on the Attitudes of African-American Hypertensive Clients Regarding Adherence to a Prescribed Medical Regimen

This quasi-experimental study examined the effect of an educational program on the attitudes of hypertensive African-American clients regarding their adherence to a prescribed medical regimen. Despite increased public awareness and improved treatment in hypertension, poorly controlled hypertension continues to be a significant problem especially among blacks and other minority populations in the United States (Shea, Misra, Ehlich, Field, & Francis, 1991). On the basis of different experiences, people may form different beliefs and, therefore different attitudes about the consequences of performing or not performing a behavior (Ajzen & Fishbein, 1980). Studies have indicated that a variety of factors such as health beliefs contribute to behaviors that may ultimately decrease the patient\u27s adherence to therapy (Hershey, Morton, Davis, & Reichgott, 1980). Therefore, the effective use of educational strategies should influence beliefs and attitudes, thereby increasing the probability that an individual will acquire behaviors critical for the management of their disease. This quasi-experimental study examined the effect of an educational program on the attitudes of hypertensive African-American clients regarding their adherence to a prescribed medical regimen. Using a one group pretest-posttest design, the Miller Attitude Scale measured favorable and unfavorable attitudes toward performing regimen prescriptions for taking medications, following a prescribed diet, engaging in activity, modifying response to stress, and quitting smoking. Data analysis of a paired t-test between pretest mean scores and posttest mean scores, indicated an overall increase in favorable attitudes toward regimen prescriptions for medication, diet, activity, and stress, but not smoking.The results of this study suggest that health education programs aimed at increasing awareness and knowledge of hypertension may influence attitudes about intentions to follow a prescribed medical regimen. Therefore, in planning education programs, health care providers must focus on individualized assessments of beliefs and attitudes that may be of particular concern for the client in order to increase their likelihood of adhering to therapy

Beyond the Evidence of the New Hypertension Guidelines. Blood pressure measurement – is it good enough for accurate diagnosis of hypertension? Time might be in, for a paradigm shift (I)

Despite widespread availability of a large body of evidence in the area of hypertension, the translation of that evidence into viable recommendations aimed at improving the quality of health care is very difficult, sometimes to the point of questionable acceptability and overall credibility of the guidelines advocating those recommendations. The scientific community world-wide and especially professionals interested in the topic of hypertension are witnessing currently an unprecedented debate over the issue of appropriateness of using different drugs/drug classes for the treatment of hypertension. An endless supply of recent and less recent "drug-news", some in support of, others against the current guidelines, justifying the use of selected types of drug treatment or criticising other, are coming out in the scientific literature on an almost weekly basis. The latest of such debate (at the time of writing this paper) pertains the safety profile of ARBs vs ACE inhibitors. To great extent, the factual situation has been fuelled by the new hypertension guidelines (different for USA, Europe, New Zeeland and UK) through, apparently small inconsistencies and conflicting messages, that might have generated substantial and perpetuating confusion among both prescribing physicians and their patients, regardless of their country of origin. The overwhelming message conveyed by most guidelines and opinion leaders is the widespread use of diuretics as first-line agents in all patients with blood pressure above a certain cut-off level and the increasingly aggressive approach towards diagnosis and treatment of hypertension. This, apparently well-justified, logical and easily comprehensible message is unfortunately miss-obeyed by most physicians, on both parts of the Atlantic. Amazingly, the message assumes a universal simplicity of both diagnosis and treatment of hypertension, while ignoring several hypertension-specific variables, commonly known to have high level of complexity, such as: - accuracy of recorded blood pressure and the great inter-observer variability, - diversity in the competency and training of diagnosing physician, - individual patient/disease profile with highly subjective preferences, - difficulty in reaching consensus among opinion leaders, - pharmaceutical industry's influence, and, nonetheless, - the large variability in the efficacy and safety of the antihypertensive drugs. The present 2-series article attempts to identify and review possible causes that might have, at least in part, generated the current healthcare anachronism (I); to highlight the current trend to account for the uncertainties related to the fixed blood pressure cut-off point and the possible solutions to improve accuracy of diagnosis and treatment of hypertension (II)