Activation of GLP-1 receptor signalling by sacubitril/valsartan: Implications for patients with poor glycaemic control.

Sacubitril/valsartan is a first-in-class Angiotensin Receptor-Neprilysin inhibitor (ARNi) to be approved for the treatment of heart failure with reduced ejection fraction (HFrEF). The combination tablet has become a mainstay of treatment in the management of heart failure (HF) due to its composite inhibition of the neurohumoral system. There is growing support to show that sacubitril/valsartan may enhance glycaemic control through the augmentation of neprilysin substrates - in particular, glucagon-like peptide 1 (GLP-1). Given that HF and Diabetes Mellitus (DM) frequently coexist, with 44% of patients hospitalised with heart failure also having diabetes as a co-morbidity, it is plausible that sacubitril/valsartan may represent a novel way to address glucose intolerance in HF. However, the role of neprilysin in the degradation of GLP-1 raises important clinical considerations such as the risk of hypoglycaemia and potential drug-drug interactions in patients with and without concurrent DM. We review the current body of research addressing the effect of neprilysin inhibition on GLP-1 receptor signalling and discuss the implications for treatment of HF and DM.

Phase analysis, a novel SPECT technique for left ventricular dyssynchrony: Are degrees and milliseconds interchangeable?

BACKGROUND: Phase analysis of gated single photon emission computed tomography (SPECT) myocardial perfusion scintigraphy provides a measure of left ventricular dyssynchrony and may have applications for identifying patients suitable for cardiac resynchronisation therapy. Phase analysis is typically described in degrees of cardiac cycle, less intuitive to cardiologists familiar with ECGs. We assessed the relationship between time and degrees, to determine whether they are interchangeable. METHODS AND RESULTS: 399 patients underwent normal stress-only SPECT myocardial perfusion imaging using Technetium-99m-tetrofosmin. Data analysis used QGS software (Cedars Sinai) calculating bandwidth and standard deviation. Heart rate, age, gender, stress modality, and ejection fraction were analyzed for their relation to phase variables. 13 patients were excluded for conduction abnormalities including right and left bundle branch block and ventricular pacing. Heart rate was strongly correlated to bandwidth and standard deviation measured in time, but unrelated when measured in degrees. Although bandwidth measured by time and degrees were strongly correlated with each other this relationship was not perfect (correlation coefficient 0.87, P < .001). The addition of heart rate to the model explained most of the residual variation between the two. The results for standard deviation were similar. CONCLUSION: In patients with normal myocardial perfusion and QRS duration bandwidth measured by degrees is not directly interchangeable with time in milliseconds. However most of the variation is explainable by heart rate, which predominantly affects measures of time rather than degrees. We would propose that although the values are less intuitive to cardiologists, normal ranges for phase measured in degrees are potentially more robust.

Is it time to change? Portable echocardiography demonstrates high prevalence of abnormalities in self-presenting members of a rural community in Kyrgyzstan.

OBJECTIVES: Cardiovascular disease accounts for 42% of male and 51% of female mortality within Europe. Kyrgyzstan, population of almost 6 million, has amongst the highest rates within Europe, second only to Uzbekistan for female cardiovascular disease mortality (588 per 100,000). We attempted to identify established cardiovascular disease prevalence within a rural community in Kyrgyzstan using portable echocardiography. DESIGN: Free open access echocardiography (VIVID-I, GE, USA) was offered to all adults in Batken district. Routine echocardiographic views were obtained and analysis performed using EchoPac Clinical Workstation (GE, USA). Mild valvular regurgitation, mild LV hypertrophy, patent foramen ovales and mild atrial enlargement were considered mild abnormalities; compensated ischaemic or valvular heart disease - moderate abnormalities, and decompensated congenital, ischaemic or valvular disease - severe abnormalities. RESULTS: One hundred and twenty five adults (48 male, 77 female), mean age 53 ± 16 years, underwent echocardiography. Only 16% of participants had no significant abnormality, 46% had mild disease, 25% moderate, compensated disease and 13% had severe disease. Nine percent had congenital heart disease including one tetralogy of Fallot and one Ebstein's anomaly. Average LV function was normal, however, 19 participants had EF < 50%. Forty percent of participants had a new diagnosis warranting formal follow-up, 12% a new diagnosis of heart failure. CONCLUSION: Using portable echocardiography, we identify a higher than reported prevalence of cardiovascular disease in rural Kyrgyzstan. Absence of portable tools and specialists for early diagnosis might lead to presentation in an advanced stage of disease when little can be done to improve mortality. Embracing remote access diagnostics is essential for disease identification within rural communities.

Challenging Perceptions About Oncology Product Pricing in Breast and Colorectal Cancer.

Although significant progress has been made in the past decade in the treatment of both common and rare cancers, there has been significant concerns about the cost, and especially the value, of certain new oncology drugs. These concerns touch upon a number of issues regarding the price of these medicines, the value they deliver and the ability of healthcare systems to fund them. This paper looks at these perceptions and the extent to which they apply across different oncology products. Whilst it is acknowledged there is evidence that the launch price of pharmaceutical treatments for some forms of cancer has been rising in recent years, this is not uniformly the case; we find evidence to the contrary for some forms of cancer. This is illustrated by the cases of breast and colorectal cancer. We find cancer medicine prices depend on a number of factors, including pre-existing treatment options within a therapeutic class. Indeed, a number of studies have focused on the cost of treatment per month of overall survival gained as a simple (although partial) metric to judge value for money. Given the importance of oncology products being used in combination, developing similar approaches to capturing the overall cost of treatment will be crucial.

Oxygen Uptake Efficiency Slope and Breathing Reserve, Not Anaerobic Threshold, Discriminate Between Patients With Cardiovascular Disease Over Chronic Obstructive Pulmonary Disease.

OBJECTIVES: The study sought to compare the relative discrimination of various cardiopulmonary exercise testing (CPX) variables between cardiac and respiratory disease. BACKGROUND: CPX testing is used in many cardiorespiratory diseases. However, discrimination of cardiac and respiratory dysfunction can be problematic. Anaerobic threshold (AT) and oxygen-uptake to work-rate relationship (VO2/WR slope) have been proposed as diagnostic of cardiac dysfunction, but multiple variables have not been compared. METHODS: A total of 73 patients with chronic obstructive pulmonary disease (COPD) (n = 25), heart failure with reduced ejection fraction (HFrEF) (n = 40), or combined COPD and HFrEF (n = 8) were recruited and underwent CPX testing on a bicycle ergometer. Following a familiarization test, each patient underwent a personalized second test aiming for maximal exercise after ∼10 min. Measurements from this test were used to calculate area under the receiver-operator characteristic curve (AUC). RESULTS: Peak VO2 was similar between the 2 principal groups (COPD 17.1 ± 4.6 ml/min/kg; HFrEF 16.4 ± 3.6 ml/min/kg). Breathing reserve (AUC: 0.91) and percent predicted oxygen uptake efficiency slope (OUES) (AUC: 0.87) had the greatest ability to discriminate between COPD and HFrEF. VO2/WR slope performed significantly worse (AUC: 0.68). VO2 at the AT did not discriminate (AUC for AT as percent predicted peak VO2: 0.56). OUES and breathing reserve remained strong discriminators when compared with an external cohort of healthy matched controls, and were comparable to B-type natriuretic peptide. CONCLUSIONS: Breathing reserve and OUES discriminate heart failure from COPD. Despite it being considered an important determinant of cardiac dysfunction, the AT could not discriminate these typical clinical populations while the VO2/WR slope showed poor to moderate discriminant ability. (Identifying an Ideal Cardiopulmonary Exercise Test Parameter [PVA]; NCT01162083).

Physiology of oxygen uptake kinetics: Insights from incremental cardiopulmonary exercise testing in the Study of Health in Pomerania.

BACKGROUND: Cardiopulmonary exercise testing allows for assessment of cardiac and respiratory limitation, but is often affected by patient effort. Indices of oxygen kinetics, including the oxygen uptake efficiency slope (OUES), oxygen uptake-work-rate slope (VO2-WR slope) and the heart rate-oxygen uptake slope (HR-VO2 slope) are relatively effort independent but may be affected by patient characteristics. The objective of this study is to identify the impact of factors, such as age, gender, body size, respiratory function, smoking and beta-blockade on these parameters, as well as generate predictive equations. METHODS: 1708 volunteers from the population-based Study of Health in Pomerania underwent an incremental bicycle exercise protocol. Markers of oxygen kinetics were calculated. Participants with structural heart disease, echocardiographic or lung function pathology were excluded, leaving 577 males and 625 females. Age, height, weight, smoking, forced expiratory volume in 1 s (FEV1) and beta-blockers were analysed for their influencing power by gender. Quantile regression analysis determined the reference equations for each parameter. RESULTS: Age, gender, height, weight and FEV1 (but not percent predicted FEV1) are strongly related to OUES. Participants using beta-blockers and male smokers had significantly lower OUES values. VO2-WR slope was minimally affected by age, gender, weight and FEV1. Gender, height, weight and beta-blocker use, but not FEV1 and smoking status, were related to the HR-VO2 slope whilst age was only related in females. CONCLUSIONS: Markers of oxygen kinetics are differentially affected by patient characteristics. This study provides normal reference values for these variables thereby facilitating interpretation of oxygen uptake kinetics in health and disease.

The effect of duration of follow-up and presence of competing risk on lifespan-gain from implantable cardioverter defibrillator therapy: who benefits the most?

BACKGROUND: In at-risk patients with left ventricular dysfunction, implantable cardioverter defibrillators (ICDs) prolong life. Implantable cardioverter defibrillators are increasingly implanted for primary prevention and therefore into lower risk patients. Trial data have demonstrated the benefit of these devices but does not provide an estimate of potential lifespan-gain over longer time periods, e.g. a patient's lifespan. METHODS: Using data from landmark ICD trials, lifespan-gain was plotted against baseline annual mortality in the individual trials. Lifespan-gain was then extrapolated to a time-horizon of >20 years while adjusting for increasing 'competing' risk from ageing and non-sudden cardiac death (pump failure). RESULTS: At 3 years, directly observed lifespan-gain was strongly dependent on baseline event rate (r = 0.94, P < 0.001). However, projecting beyond the duration of the trial, lifespan-gain increases rapidly and non-linearly with time. At 3 years, it averages 1.7 months, but by 10 years up to 9-fold more. Lifespan-gain over time horizons >20 years were greatest in lower risk patients (∼5 life-years for 5% baseline mortality, ∼2 life-years for 15% baseline mortality). Increased competing risks significantly reduce lifespan-gain from ICD implantation. CONCLUSION: While high-risk patients may show the greatest short-term gain, the dramatic growth of lifespan-gain over time means that it is the lower risk patients, e.g. primary prevention ICD implantation, who gain the most life-years over their lifetime. Benefit is underestimated when only trial data are assessed as trials can only maintain randomization over limited periods. Lifespan-gain may be further increased through advances in ICD device programming.

A regulatory governance perspective on health technology assessment (HTA) in France: the contextual mediation of common functional pressures.

The new regulatory governance perspective has introduced several insights to the study of health technology assessment (HTA): it has broadened the scope for the analysis of HTA; it has provided a more sophisticated account of national diversity and the potential for cross-border policy learning; and, it has dissolved the distinction between HTA assessment and appraisal processes. In this paper, we undertake a qualitative study of the French process for HTA with a view to introducing a fourth insight: that the emergence and continuing function of national agencies for HTA follows a broadly evolutionary pattern in which contextual factors play an important mediating role. We demonstrate that the French process for HTA is characterised by distinctive institutions, processes and evidential requirements. Consistent with the mediating role of this divergent policy context, we argue that even initiatives for the harmonisation of national approaches to HTA are likely to meet with divergent national policy responses.

"Triple therapy" of heart failure with angiotensin-converting enzyme inhibitor, beta-blocker, and aldosterone antagonist may triple survival time: shouldn't we tell patients?

Prescription and adherence to medical therapy for heart failure are disappointing despite convincing randomized controlled trial (RCT) evidence for angiotensin-converting enzyme inhibition, beta-blockade, and aldosterone antagonism. In this study, we report an imbalanced approach amongst clinicians, who describe focusing during patient consultations on perceived risks of therapy rather than survival benefits. Only one-half of clinicians mention increased lifespan, and very few suggest to the patient how large this gain might be. We calculate from the available RCT data that, for patients whose lifespan is limited by heart failure, triple therapy triples lifespan.

Serum albumin changes and multivariate dynamic risk modelling in chronic heart failure.

BACKGROUND: We examined the prognostic utility of rate of change in serum albumin over time in chronic heart failure (CHF), as well as the utility of multivariate dynamic risk modelling. METHODS AND RESULTS: The survival implication of ∆albumin was analysed in 232 systolic CHF patients and validated in 212 patients. A multivariate dynamic risk score predicated on the rate of change in 6 simple indices including albumin was calculated and related to mortality. In derivation patients, 50 (22%) deaths occurred over 13 months. Greater rates of decline in albumin related to higher mortality (HR 0.55, 95% CI 0.41-0.73, P<0.0001) independently, incrementally and more accurately than other covariates including baseline albumin. A rate of attenuation >0.4 g/dL/month optimally forecasted death and was associated with a 5-fold escalated risk of mortality (HR 5.13, 95% CI 2.92-9.00, P<0.0001). Similar results were seen in the validation cohort. On multivariate dynamic risk modelling, survival at 1-year worsened with higher scores-a score ≥ 3 was associated with a 12-fold greater risk of death than a score of 0, a 6-fold higher risk of death than a score of 1, and a 4-fold enhanced risk of mortality than a score of 2. CONCLUSION: Attenuations in serum albumin over time relate to increased mortality in CHF, and a risk model predicated on the rate of change in 6 simple indices can identify patients at a 12-fold enhanced risk of death over the coming year.

What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice.

OBJECTIVE: Discussions about statin efficacy in cardiovascular prevention are always based on data from blinded randomized controlled trials (RCTs) comparing statin to placebo; however, discussion of side effects is not. Clinicians often assume symptoms occurring with statins are caused by statins, encouraging discontinuation. We test this assumption and calculate an evidence-based estimate of the probability of a symptom being genuinely attributable to the statin itself. METHODS: We identified RCTs comparing statin to placebo for cardiovascular prevention that reported side effects separately in the two arms. RESULTS: Among 14 primary prevention trials (46,262 participants), statin therapy increased diabetes by absolute risk of 0.5% (95% CI 0.1-1%, p = 0.012), meanwhile reducing death by a similar extent: -0.5% (-0.9 to -0.2%, p = 0.003). In the 15 secondary prevention RCTs (37,618 participants), statins decreased death by 1.4% (-2.1 to -0.7%, p < 0.001). There were no other statin-attributable symptoms, although asymptomatic liver transaminase elevation was 0.4% more frequent with statins across all trials. Serious adverse events and withdrawals were similar in both arms. CONCLUSIONS: Only a small minority of symptoms reported on statins are genuinely due to the statins: almost all would occur just as frequently on placebo. Only development of new-onset diabetes mellitus was significantly higher on statins than placebo; nevertheless only 1 in 5 of new cases were actually caused by statins. Higher statin doses produce a detectable effect, but even still the proportion attributable to statins is variable: for asymptomatic liver enzyme elevation, the majority are attributable to the higher dose; in contrast for muscle aches, the majority are not.

A regulatory governance perspective on Health Technology Assessment (HTA) in Sweden.

Independent regulatory agencies (IRAs) for Health Technology Assessment (HTA) are a key means by which national governments have responded to the challenge of ensuring equitable public access to a new range of medicines and treatment options within the context of limited national budgets for healthcare. In this paper, we apply a regulatory governance frame to the study of the Swedish process for HTA. Based on qualitative interviews with key institutional stakeholders, we suggest that the major challenge for Swedish IRAs for HTA is successfully communicating nationally produced research outputs to the regional authorities responsible for the delivery of health services. We conclude that a regulatory governance approach to the analysis of national processes for HTA has the capacity to draw attention to a new range of challenges and issues which have direct relevance to improving the conduct of HTA within national regulatory spaces.

Test-retest repeatability of cardiopulmonary exercise test variables in patients with cardiac or respiratory disease.

BACKGROUND: The test-retest reliability for multiple cardiopulmonary exercise test (CPX) variables has not been compared in a single study and the influence of different diseases on test-retest reliability has not been examined. We investigated different measures of test-retest reliability for multiple variables and compared them by category of cardiac or respiratory disease. METHODS: Patients with chronic obstructive airways disease (n = 24), heart failure (n = 43), or severe mitral valve disease (n = 26) were recruited into a prospective study. Each patient underwent two bicycle ergometer tests; the first, a familiarization test, with a 10 W/min ramp, and the second a personalized ramp based on the results of the familiarization test to elicit maximal effort within 8-10 min. Intraclass correlation coefficients (ICC) and coefficients of variation between the two tests were calculated. Influence of potential modifiers was assessed using repeated measures analysis of variance. RESULTS: Peak VO2 (ICC 0.95, 95% CI 0.94-0.97), oxygen uptake efficiency slope (ICC 0.93, 95% CI 0.90-0.95), O2 pulse (ICC 0.96, 95% CI 0.94-0.97), and the VE/VCO2 ratio at the nadir (ICC 0.92, 95% CI 0.89-0.95) all showed excellent test-retest reliability, with within-subject coefficients of variation <0.12. VO2 at the anaerobic threshold (ICC 0.84, 95% CI 0.78-0.89) and the VE/VCO2 slope (ICC 0.88, 95% CI 0.79-0.93) showed good test-retest reliability, although inferior to peak VO2. Age, gender, body mass index, disease aetiology, protocol change, and intertest interval did not affect the reliability of most variables. CONCLUSIONS: CPX showed high test-retest reliability; certain variables such as peak VO2 and oxygen uptake efficiency slope outperform others. These results identify which variables are most suitable for serial testing of patients with three common disease aetiologies owing to their superior reproducibility.

Long-term antihypertensive treatment fails to improve E/e' despite regression of left ventricular mass: an Anglo-Scandinavian cardiac outcomes trial substudy.

Antihypertensive treatment can improve tissue Doppler indices of left ventricular diastolic function in the short term, but little is known about the longer-term effect of different antihypertensive treatments on progression of left ventricular diastolic function and left ventricular hypertrophy. We hypothesized that long-term treatment of hypertension will lead to improvements in left ventricular hypertrophy and diastolic function. We collected detailed cardiovascular phenotypic data on 1006 participants from a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial. Patients randomized to either an amlodipine±perindopril-based or an atenolol±bendroflumethiazide-based regimen underwent conventional and tissue Doppler echocardiography at time of control of blood pressure after randomization (≈1.5 years; phase 1) and after a further 2 years of antihypertensive treatment (phase 2). There were no prerandomization data. Five hundred thirty-six patients had complete data collection at both phases. Left ventricular mass index regressed from phase 1 to 2 with no significant difference between treatment groups (amlodipine: 119.5-116.8; atenolol: 122.9-117.5; P<0.001 for both). Conversely, tissue Doppler diastolic indices did not change in the amlodipine±perindopril-based regimen (E/e', 7.5-7.6 cm/s; P=not significant), but deteriorated in the atenolol±bendroflumethiazide-based regimen (E/e', 8.0-8.5 cm/s; P<0.01). Despite regression of left ventricular hypertrophy, there was no associated improvement in diastolic function. In fact, long-term treatment with atenolol±bendroflumethiazide resulted in a progressive deterioration in E/e'. This may be a factor contributing to the previously described worse clinical outcome in patients treated with atenolol±bendroflumethiazide compared with amlodipine±perindopril.

Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information.

BACKGROUND: Patients trying life-preserving agents such as beta-blockers may be discouraged by listings of harmful effects provided in good faith by doctors, drug information sheets, and media. We systematically review the world experience of side-effect information in blinded, placebo-controlled beta-blockade in heart failure. We present information for a physician advising a patient experiencing an unwanted symptom and suspecting the drug. METHODS: We searched Medline for double-blinded randomized trials of beta-blocker versus placebo in heart failure reporting side-effects. We calculated, per 100 patients reporting the symptom on beta-blockade, how many would have experienced it on placebo: the "proportion of symptoms non-pharmacological". RESULTS: 28 of the 33 classically-described side-effects are not significantly more common on beta-blockers than placebo. Of the 100 patients developing dizziness on beta-blockers, 81 (95% CI 73-89) would have developed it on placebo. For diarrhoea this proportion is 82/100 (70-95), and hyperglycaemia 83/100 (68-98). For only two side-effects is this under half (i.e. predominantly due to beta-blocker): bradycardia (33/100, CI 21-44) and intermittent claudication (41/100, 2-81). At least 6 so-called side-effects are less common on beta-blocker than placebo, including depression (reduced by 35%, p<0.01) and insomnia (by 27%, p=0.01). CONCLUSIONS: Clinicians might reconsider whether it is scientifically and ethically correct to warn a patient that a drug might cause them a certain side-effect, when randomized controlled trials show no significant increase, or indeed a significant reduction. A better informed consultation could, in patients taking beta-blockers, alleviate suffering. In patients who might otherwise not take the drug, it might prevent deaths.

Regulatory space and the contextual mediation of common functional pressures: analyzing the factors that led to the German Efficiency Frontier approach.

There are no automatic links between the functional advantages and pressures associated with delegation to independent agencies for Health Technology Assessment (HTA) and their emergence in national regulatory spaces. We argue that the rise of these organizations is mediated by contextual factors, which must be explained. Accordingly, we analyze the German 'regulatory space' for health policy decision-making, identifying contextual factors relevant to the adoption of the Efficiency Frontier approach. Based on qualitative interviews with key stakeholders, we argue that the development of the Efficiency Frontier can be associated with cultural reluctance to frame healthcare prioritization decisions around cost based valuations of human health and related doubts about the validity of metrics for human health gain. Based on this finding, we conclude that the delegation of authority to independent HTA agencies follows a broadly evolutionary pattern, in which contextual factors allow for significant variation in institutional and methodological responses to the functional pressures and advantages leading to their establishment.

First-in-man safety evaluation of renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study.

BACKGROUND: Sympathetic overactivation, is reduced by renal denervation in drug-resistant hypertension. A similar role for renal denervation in heart failure remains unstudied, partly due to the concern about potential concomitant deleterious blood pressure reductions. This pilot study evaluated the safety of renal denervation for heart failure using an intensive follow-up protocol. METHOD: 7 patients (mean age 69 years) with chronic systolic heart failure (mean BP on referral 112/65 mmHg) on maximal tolerated heart failure therapy underwent bilateral renal denervation May-July 2011. Patients were admitted for pre-procedure baseline assessments and in-patient observation for 5 days following denervation. Follow-up was weekly for 4 weeks, and then monthly for 6 months. RESULTS: No significant haemodynamic disturbances were noted during the acute phase post renal denervation. Over 6 months there was a non-significant trend to blood pressure reduction (Δsystolic -7.1 ± 6.9 mmHg, p=0.35; Δdiastolic -0.6 ± 4.0 mmHg, p=0.88). No hypotensive or syncopal episodes were reported. Renal function remained stable (Δcreatinine -5.7 ± 8.4 µmol/l, p=0.52 and Δurea -1.0 ± 1.0 mmol/l, p=0.33). All 7 patients described themselves as symptomatically improved. The six minute walk distance at six months was significantly increased (Δ=27.1 ± 9.7 m, p=0.03), with each patient showing an increase. CONCLUSIONS: This study found no procedural or post procedural complications following renal denervation in patients with chronic systolic heart failure in 6 months of intensive follow-up. Results suggested improvements in both symptoms and exercise capacity, but further randomised, blinded sham-controlled clinical trials are required to determine the impact of renal denervation on morbidity and mortality in systolic heart failure. These data suggest such trials will be safe. ClinicalTrial.gov NCT01584700