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

The dual endothelin converting enzyme/neutral endopeptidase inhibitor SLV-306 (daglutril), inhibits systemic conversion of big endothelin-1 in humans

Aims - Inhibition of neutral endopeptidases (NEP) results in a beneficial increase in plasma concentrations of natriuretic peptides such as ANP. However NEP inhibitors were ineffective anti-hypertensives, probably because NEP also degrades vasoconstrictor peptides, including endothelin-1 (ET-1). Dual NEP and endothelin converting enzyme (ECE) inhibition may be more useful. The aim of the study was to determine whether SLV-306 (daglutril), a combined ECE/NEP inhibitor, reduced the systemic conversion of big ET-1 to the mature peptide. Secondly, to determine whether plasma ANP levels were increased. Main methods - Following oral administration of three increasing doses of SLV-306 (to reach an average target concentration of 75, 300, 1200 ng ml− 1 of the active metabolite KC-12615), in a randomised, double blinded regime, big ET-1 was infused into thirteen healthy male volunteers. Big ET-1 was administered at a rate of 8 and 12 pmol kg− 1 min− 1 (20 min each). Plasma samples were collected pre, during and post big ET-1 infusion. ET-1, C-terminal fragment (CTF), big ET-1, and atrial natriuretic peptide (ANP) were measured. Key findings - At the two highest concentrations tested, SLV-306 dose dependently attenuated the rise in blood pressure after big ET-1 infusion. There was a significant increase in circulating big ET-1 levels, compared with placebo, indicating that SLV-306 was inhibiting an increasing proportion of endogenous ECE activity. Plasma ANP concentrations also significantly increased, consistent with systemic NEP inhibition. Significance - SLV-306 leads to inhibition of both NEP and ECE in humans. Simultaneous augmentation of ANP and inhibition of ET-1 production is of potential therapeutic benefit in cardiovascular disease

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN):an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial

Background: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. Methods: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 μg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. Findings: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8–3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference –7·00% [95% CI –12·69 to –1·32]; p=0·016). Interpretation: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. Funding: British Heart Foundation and Pharmacosmos.</p

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN):an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial

Background: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. Methods: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 μg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. Findings: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8–3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference –7·00% [95% CI –12·69 to –1·32]; p=0·016). Interpretation: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. Funding: British Heart Foundation and Pharmacosmos.</p

Intravenous iron for heart failure, iron deficiency definitions, and clinical response:the IRONMAN trial

BACKGROUND AND AIMS: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure?METHODS: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin &lt; 100 µg/L or transferrin saturation (TSAT) &lt; 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death.RESULTS: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction &lt; .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT &lt; 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant.CONCLUSIONS: This hypothesis-generating analysis suggests that anaemia or TSAT &lt; 20% with ferritin &gt; 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.</p

Intravenous iron for heart failure, iron deficiency definitions, and clinical response:the IRONMAN trial

BACKGROUND AND AIMS: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure?METHODS: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin &lt; 100 µg/L or transferrin saturation (TSAT) &lt; 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death.RESULTS: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction &lt; .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT &lt; 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant.CONCLUSIONS: This hypothesis-generating analysis suggests that anaemia or TSAT &lt; 20% with ferritin &gt; 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.</p

Placental magnetic resonance imaging in chronic hypertension: A case-control study

Introduction We aimed to explore the use of magnetic resonance imaging (MRI) in vivo as a tool to elucidate the placental phenotype in women with chronic hypertension. Methods In case-control study, women with chronic hypertension and those with uncomplicated pregnancies were imaged using either a 3T Achieva or 1.5T Ingenia scanner. T2-weighted images, diffusion weighted and T1/T2* relaxometry data was acquired. Placental T2*, T1 and apparent diffusion coefficient (ADC) maps were calculated. Results 129 women (43 with chronic hypertension and 86 uncomplicated pregnancies) were imaged at a median of 27.7 weeks’ gestation (interquartile range (IQR) 23.9–32.1) and 28.9 (IQR 26.1–32.9) respectively. Visual analysis of T2-weighted imaging demonstrated placentae to be either appropriate for gestation or to have advanced lobulation in women with chronic hypertension, resulting in a greater range of placental mean T2* values for a given gestation, compared to gestation-matched controls. Both skew and kurtosis (derived from histograms of T2* values across the whole placenta) increased with advancing gestational age at imaging in healthy pregnancies; women with chronic hypertension had values overlapping those in the control group range. Upon visual assessment, the mean ADC declined in the third trimester, with a corresponding decline in placental mean T2* values and showed an overlap of values between women with chronic hypertension and the control group. Discussion A combined placental MR examination including T2 weighted imaging, T2*, T1 mapping and diffusion imaging demonstrates varying placental phenotypes in a cohort of women with chronic hypertension, showing overlap with the control group

HEART UK statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom

This consensus statement addresses the current three main modalities of treatment of homozygous familial hypercholesterolaemia (HoFH): pharmacotherapy, lipoprotein (Lp) apheresis and liver transplantation. HoFH may cause very premature atheromatous arterial disease and death, despite treatment with Lp apheresis combined with statin, ezetimibe and bile acid sequestrants. Two new classes of drug, effective in lowering cholesterol in HoFH, are now licensed in the United Kingdom. Lomitapide is restricted to use in HoFH but, may cause fatty liver and is very expensive. PCSK9 inhibitors are quite effective in receptor defective HoFH, are safe and are less expensive. Lower treatment targets for lipid lowering in HoFH, in line with those for the general FH population, have been proposed to improve cardiovascular outcomes. HEART UK presents a strategy combining Lp apheresis with pharmacological treatment to achieve these targets in the United Kingdom (UK). Improved provision of Lp apheresis by use of existing infrastructure for extracorporeal treatments such as renal dialysis is promoted. The clinical management of adults and children with HoFH including advice on pregnancy and contraception are addressed. A premise of the HEART UK strategy is that the risk of early use of drug treatments beyond their licensed age restriction may be balanced against risks of liver transplantation or ineffective treatment in severely affected patients. This may be of interest beyond the UK

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial

Background: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. Methods: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 μg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. Findings: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8–3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference –7·00% [95% CI –12·69 to –1·32]; p=0·016). Interpretation: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. Funding: British Heart Foundation and Pharmacosmos