Cardiovascular risk reduction in hypertension: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers. Where are we up to?

Previously, management of hypertension has concentrated on lowering elevated blood pressure. However, the target has shifted to reducing absolute cardiovascular (CV) risk. It is estimated that two in three Australian adults have three or more CV risk factors at the same time. Moderate reductions in several risk factors can, therefore, be more effective than major reductions in one. When managing hypertension, therapy should be focused on medications with the strongest evidence for CV event reduction, substituting alternatives only when a primary choice is not appropriate. Hypertension management guidelines categorise angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) interchangeably as first-line treatments in uncomplicated hypertension. These medications have different mechanisms of action and quite different evidence bases. They are not interchangeable and their prescription should be based on clinical evidence. Despite this, currently ARB prescriptions are increasing at a higher rate than those for ACEI and other antihypertensive classes. Evidence that ACEI therapy prevents CV events and death, in patients with coronary artery disease or multiple CV risk factors, emerged from the European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA) and Heart Outcomes Prevention Evaluation (HOPE) trials respectively. The consistent benefit has been demonstrated in meta-analyses. The clinical trial data for ARB are less consistent, particularly regarding CV outcomes and mortality benefit. The evidence supports the use of ACEI (Class 1a) compared with ARB despite current prescribing trends.

Test performance characteristics of quantitative nucleic acid testing for polyomaviruses in kidney and kidney-pancreas transplant recipients.

Screening for polyoma BK virus (BK) using nucleic testing (NAT) is recommended for kidney and kidney-pancreas transplant recipients, but the performance characteristics of quantitative BK NAT at different thresholds of plasma BK viral loads are unclear. We aim to evaluate the diagnostic accuracy of quantitative BK NAT as an add-on test to qualitative polyoma NAT for the diagnosis of BK virus-associated nephropathy (BKVAN) in kidney and kidney transplant recipients. We calculated the test sensitivity, specificity, and predictive values at the different thresholds of plasma BK viral load for BKVAN. At the recommended threshold of >1 × 10(3) serum BK copies/mL serum for test positivity, the sensitivity for BKVAN was 92.9% (95% confidence intervals [CI]: 66.1-99.8) and specificity 79.1% (95%: CI 67.4-88.1), with corresponding positive and negative predictive values of 42.0% (95% CI: 24.8-57.7%) and 98.6% (95% CI: 98.3-99.9%), respectively. The overall area under curve for the quantitative BK NAT was 0.92 (95% CI: 0.85-0.97). Quantitative BK NAT displays properties of high sensitivity and specificity that are fit for purpose as an add-on test to qualitative polyomavirus NAT for kidney and kidney-pancreas transplant recipients at risk of BKVAN.

Biosimilars: it's not as simple as cost alone.

BACKGROUND: Biosimilars or follow-on biologics (FoB) are biopharmaceuticals that, unlike small molecule generic products, are copies of larger, much more complex proteins. As such, data generated from one biopharmaceutical cannot be extrapolated to another. Unlike small molecule generics, FoB require a full developmental programme, albeit smaller than for an originator product. This has been recognized by European regulatory authorities and it is becoming clear that accelerated processes for FoB marketing approval are not feasible. OBJECTIVE: To determine the balance between costs surrounding FoB (including relatively extensive developmental programmes and subsequent price to the market) and the necessity to ensure efficacy and safety. PRINCIPAL FINDINGS: It is important that FoB are sufficiently tested to ensure patient safety is not compromised. Conducting such a development programme followed by sound pharmacovigilance is very challenging and costly. CONCLUSIONS: Cost-savings associated with FoB may be limited.

Extended administration of erythropoiesis-stimulating agents for optimising the management of renal anaemia: what is the evidence?

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) have transformed the management of anaemia in patients with chronic kidney disease (CKD), reducing transfusion requirements and leading to improved quality of life. However, effective anaemia management with current ESAs is labour-intensive and time-consuming. Approaches are required to simplify anaemia management and reduce the burden on healthcare systems. There is increasing interest in extending the administration interval of ESAs. This would result in considerable time-savings, reducing the workload of healthcare providers and potentially reducing healthcare system costs. Time saved could be utilised in improving other aspects of patient care, such as implementation of guidelines, or treating more patients. Potential benefits of extended administration intervals for patients include a less demanding regimen and fewer injections, which could lead to improved adherence to treatment. AIM: This article reviews studies of the efficacy of current ESAs in maintaining stable haemoglobin (Hb) levels when used at extended administration intervals of up to once monthly. SUMMARY OF FINDING: Patients who are already stable on more frequent ESA therapy and who respond well to treatment may be able to maintain stable Hb with extended dosing regimens with established ESAs. However, few patients with CKD currently receive ESAs once-monthly in clinical practice. New agents with long half-lives offer the potential for extended dosing regimens in all patients with CKD.

Contribution of anaemia to progression of renal disease: a debate.

It is hypothesized that anaemia contributes to the progression of renal disease via hypoxia and oxidative stress. These effects may stimulate the production of extracellular matrix by fibroblasts, increasing interstitial fibrosis and leading to tubular destruction. Recombinant human erythropoietin (r-HuEPO, epoetin) has antioxidative and anti-apoptotic properties, though these effects have yet to be demonstrated in renal cells. In theory, epoetin treatment might slow the progression of renal failure, not only by correcting anaemia but also via direct effects on tubular and vascular cell survival. Alternative hypotheses suggest, however, that epoetin could have negative effects on the kidney because of its vasoconstrictive action, which is independent of haemoglobin levels. Retrospective and prospective clinical studies clearly show that epoetin does not accelerate progression of renal disease, provided that blood pressure is well controlled. Some studies suggest that epoetin slows the progression of renal failure, although this remains a controversial issue, as all these studies have methodological limitations. Larger randomized controlled trials and meta-analysis of the existing trials are required to establish whether treatment of anaemia with epoetin can indeed slow the progression of renal disease.

Recombinant erythropoietin increases blood pressure in experimental hypertension and uraemia without change in vascular cytosolic calcium.

The mechanism of erythropoietin-induced hypertension in dialysis patients is unclear. Intracellular calcium ([Ca2+]i) may be altered in both hypertension and uraemia, and the effects of both uraemia and r-HuEPO on vascular smooth muscle [Ca2+]i and blood pressure (BP) in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were therefore studied. Male WKY and SHR underwent partial nephrectomy or sham operation. Three weeks later a 28-day period of treatment with either r-HuEPO 100 U/kg, s.c., 3 times/week or buffer was commenced (n = 10-12 for each subgroup). BP was measured weekly, by noninvasive Doppler tail-cuff assessment. [Ca2+]i was measured following loading with fura-2 in pooled, primary aortic vascular smooth muscle cells (VSMC). Serum urea and creatinine rose 3- to 4-fold after partial nephrectomy. Treatment with r-HuEPO did not change renal function further in either uraemic or control WKY or SHR. Haemoglobin increased in both non-uraemic WKY (16.2-20.3 g/dl) and SHR (16.4-20.5 g/dl) and uraemic animals (WKY 13.9-20.9; SHR 13.8-18.8 g/dl; p < 0.01 for all changes) following 4 weeks of r-HuEPO treatment. BP was unaffected by r-HuEPO in WKY but increased in nonuraemic SHR (210-250; p < 0.01) and in uraemic SHR (224-251 mm Hg; p < 0.001) at 4 weeks. VSMC [Ca2+]i was higher in SHR than WKY (121 vs. 83 nmol/l; MANOVA p < 0.05) but no effect of uraemia or r-HuEPO on [Ca2+]i was detected. In conclusion, the hypertensive effects of r-HuEPO are augmented both in a genetic model of hypertension and in uraemia. Although VSMC [Ca2+]i was elevated in SHR, the further increase in BP induced by r-HuEPO was not associated with alterations in VSMC cytosolic calcium.

Modulation of platelet cytosolic calcium during erythropoietin therapy in uraemia.

Erythropoietin therapy for uraemic anaemia is associated with a high rate of hypertensive and thrombotic complications. The mechanism is unknown, but a change in cellular calcium control may be relevant to changes in blood pressure and thrombosis. Platelets were utilized as a model of vascular smooth muscle cells. The effects of erythropoietin therapy on platelet cellular calcium, assessed by fura-2, were measured in 25 patients receiving renal replacement therapy during a 6-month treatment period. Three patients failed to reach a target haemoglobin and were excluded from the analysis. Blood pressure increased in 11 of the remaining 22 subjects, eight requiring an increase in antihypertensive medication. There were no differences in cellular calcium control between the group in whom blood pressure rose and patients with stable blood pressure. Overall there was a fall of 24% in resting cytosolic calcium (baseline 69.2 +/- 5.1 to 52.5 +/- 3.0 nmol/l, P < 0.05) after 3 months of erythropoietin therapy. There was no change in the thrombin-stimulated peak response in the presence of extracellular calcium during therapy, although thrombin-stimulated intracellular release also fell at 3 months (baseline 769 +/- 61 versus 3 months 559 +/- 49 nmol/l, P < 0.01). This study suggests that intracellular free calcium control within platelets improves in response to erythropoietin therapy. However these changes appear not to be related to the development of hypertension.

What is the value of measuring renal parenchymal thickness before renal biopsy?

Reduced renal length is widely used to diagnose chronicity in patients with renal impairment. A length of 9 cm or less measured ultrasonographically is considered to indicate irreversible disease. However, some patients with normal renal length have thin parenchyma. The aim of this study was to determine the relationship between ultrasonographically measured parenchymal thickness and renal length and to correlate parenchymal thickness with the histology obtained at renal biopsy. Sixty-four patients, aged 16-74 years, who had had a renal biopsy were evaluated retrospectively. Histology was considered in five categories: I, interstitial nephritis (n = 13); II, glomerulonephritis (28); III, diabetes mellitus/metabolic/other (8); IV, chronic renal disease (CRD) (11); V, hypertension/vascular disease (4). There was a good linear correlation between renal length and renal parenchymal thickness (r = 0.64, P < 0.001). Both were reduced most in patients with CRD. Sixty-four per cent of patients with CRD had renal parenchymal thickness 1.5 cm or less, compared to 38% in group I, 25% in groups II and V, and 7% in group II. Although 11/37 (30%) of patients whose serum creatinine had increased 3 months post-biopsy had parenchymal thickness 1.5 cm or less, so did 6/27 (23%) whose creatinine decreased. Like renal length, parenchymal thickness gives an indication of the chronicity of renal failure. However, some patients with parenchymal thickness 1.5 cm or less still have potential for improvement. This measurement alone should not be used to obviate renal biopsy.

Autonomic dysfunction and the development of hypertension in patients treated with recombinant human erythropoietin (r-HuEPO).

Hypertension is the most common complication of r-HuEPO therapy in dialysis patients. The aim of this study was to test the hypothesis that hypertension develops in patients who fail to autoregulate adequately their hemodynamic response to correction of anemia. Twenty-five dialysis patients (17-71 yrs, 13 male, 13 CAPD) initially received r-HuEPO 50 U/kg 3 times/week intravenously or subcutaneously. Hypertension, defined as a rise in mean blood pressure (BP) of greater than 15 mmHg during therapy developed in 44% (Group 1: stable BP; Group 2: rise in BP). There was no difference in sex, age, mode of dialysis or route of administration of r-HuEPO between the groups. Before commencement and after 6-12 months of r-HuEPO therapy, assessment of the baroreflex arc was performed using the Valsalva ratio and orthostatic BP testing, sympathetic efferent nerve function was assessed by the cold pressor test and afferent parasympathetic function by the 30:15 ratio and heart rate variation (HRV). No difference was detected prior to r-HuEPO therapy between the two groups in Valsalva ratio (Group 1: 1.26 +/- 0.06 vs Group 2: 1.23 +/- 0.06, mean +/- SEM); 30:15 ratio (1.06 +/- 0.02 vs 1.03 +/- 0.01), or systolic, diastolic, mean BP or pulse rate after standing for 3 minutes or following hand immersion in ice slush. Both groups had a fall in systolic and diastolic BP (p < 0.05) and a rise in pulse rate (p < 0.05) on standing. HRV during deep respiration between the 2 groups was not different (9.6 +/- 2.3 vs 7.1 +/- 1.4 beats/minute).(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced platelet reactivity with erythropoietin but not following transfusion in dialysis patients.

Although the haemostatic defects that occur in uraemia are complex, a major factor is the anaemia of renal failure. This may now be corrected by recombinant human erythropoietin (rHuEpo) therapy rather than by repeated blood transfusion. Platelet reactivity to shear stress and collagen was measured using non-anticoagulated blood to study the effect of erythropoietin or blood transfusion on platelet function. Twenty dialysis patients were commenced on 25-50 U/kg rHuEpo twice weekly. The dose was adjusted after 3 months to maintain target Hb 10-10.5 g/dl. A further 15 patients were studied before and 10-12 days after receiving blood transfusion. Baseline platelet reactivity was subnormal in both groups versus control (P < 0.0001). In the rHuEpo group, a significant increase in platelet reactivity was observed at 2 months (P < 0.005) which disappeared at 3 months. This was not related to the increase in Hb (7.3 +/- 0.3 to 10.2 +/- 0.3 g/dl, P < 0.0001). There was no change in platelet reactivity after transfusion, despite an increase in Hb (6.2 +/- 0.2 to 8.8 +/- 0.2 g/dl, P < 0.0001) similar to that occurring in the rHuEpo group. We conclude that after rHuEpo therapy but not after transfusion a transient increase in platelet reactivity occurs which is dissociated from changes in platelet and red cell numbers.

Effects of oxygen breathing and erythropoietin on hypoxic vasodilation in uremic anemia.

Loss of hypoxic vasodilation has been proposed as a causative factor in the development of hypertension in dialysis patients treated with recombinant human erythropoietin (rHuEPO). Venous occlusion plethysmography was therefore performed on 22 dialysis patients (aged 23 to 71 years, dialysis duration 6 to 260 months, 8 males) before and after correction of anemia with rHuEPO, 50 U/kg 3x/week (Hb: 7.4 +/- 0.3 vs. 10.8 +2- 0.3 g/dl, P less than 0.0001). Hypertension (greater than 15 mm Hg rise in mean BP) occurred in 11 patients. The study was performed while breathing room air and repeated after breathing 60% O2 for 10 to 12 minutes. Before rHuEPO therapy, total blood O2 content increased from 10.01 +/- 0.39 to 10.32 +/- 0.29 ml O2/100 ml blood with breathing 60% O2 (P less than 0.01). After correction of anemia it was 14.65 +/- 0.40 ml O2/100 ml blood on room air (P less than 0.001). There was a significant decrease in forearm blood flow (7.9 +/- 0.5 vs. 6.5 +/- 0.6 ml/min/100 ml tissue, P less than 0.05) and increase in forearm vascular resistance (12.8 +/- 0.1 vs. 16.8 +/- 0.2 mm Hg/ml/min/100 ml tissue, P less than 0.05) with O2 breathing prior to rHuEPO therapy in the blood pressure responders, but no change in these parameters in the group in which blood pressure remained unchanged. When all patients were studied on room air, forearm vascular resistance rose significantly after correction of anemia (13.0 +/- 0.8 vs. 16.3 +/- 0.8 mm Hg/ml/min/100 ml tissue, P less than 0.05), compared with that prior to rHuEPO therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of haemostatic activity in haemodialysis and peritoneal dialysis patients with a novel technique, haemostatometry.

Bleeding due to impaired primary haemostasis is common in uraemia. However, thrombo-embolic episodes are also a clinical problem in dialysis patients. Platelet reactivity to shear stress (haemostasis, H1 and H2), exposure to collagen fibre (thrombus growth) and coagulation of flowing blood (clotting time, CT1 and CT2) were measured in non-anticoagulated blood samples taken immediately before and 18-24 h after haemodialysis (n = 26) and from patients maintained on continuous ambulatory peritoneal dialysis (CAPD, n = 30). H1 (p < 0.001), H2 (p < 0.01), percent thrombus growth rate (p < 0.03), CT1 (p < 0.01 and CT2 (p < 0.05) were restored towards normal after haemodialysis. Results obtained in the CAPD patients demonstrated that the mean values for formation of the haemostatic plug lay between the pre- and posthaemodialysis values; however, CT1 (p < 0.01) and CT2 (p < 0.05) were prolonged in CAPD compared with values after haemodialysis. These data, which indicate platelet function from non-anticoagulated blood and coagulation under flow conditions, (1) confirm that there is impaired haemostasis in uraemia; (2) demonstrate an improvement in haemostasis after haemodialysis; (3) show that peritoneal dialysis results in a haemostatic profile which falls between the pre- and posthaemodialysis pattern, and (4) show that neither dialysis modality returns haemostasis to normal.

Effects of erythropoietin on blood pressure.

Increased blood pressure (BP) has been the most commonly reported side effect in trials of treatment of the anemia of chronic renal failure with recombinant human erythropoietin (rHuEPO). An increase in BP develops in one third of patients, in most cases necessitating initiation or increase of antihypertensive therapy. Elevated BP is not related to dose of rHuEPO, nor to the final hematocrit level achieved or the rate of increase of hematocrit. Increases in BP arise particularly during the first 4 months of therapy, and BP usually stabilizes thereafter. rHuEPO therapy does not appear to affect BP in patients with normal renal function. The mechanism of hypertension related to rHuEPO remains uncertain. An increase in systemic vascular resistance occurs in all patients, whether or not BP increases. This is due largely to increased blood viscosity and reversal of hypoxic vasodilatation, but other factors may also contribute. A lack of adequate reduction in cardiac output distinguishes patients in whom BP increases, and this in turn may be due to abnormal cardiovascular autoregulation in these patients. Acute elevation in BP during rHuEPO therapy occasionally results in hypertensive encephalopathy and seizures. This complication is unrelated to the extent or rate of increase in hematocrit, but is associated with a rapid increase in BP, and may occur in previously normotensive patients. Hypertension developing during rHuEPO therapy should be controlled by conventional antihypertensive therapy. If hypertension persists, the rHuEPO dose should be reduced or therapy temporarily discontinued. Frequent BP monitoring during the first 4 months of treatment is mandatory.(ABSTRACT TRUNCATED AT 250 WORDS)

Low dose erythropoietin in maintenance haemodialysis: improvement in quality of life and reduction in true cost of haemodialysis.

Human recombinant erythropoietin (r-HuEPO) improves quality of life in patients on maintenance haemodialysis, but the haemoglobin (Hb) level necessary to achieve this improvement is unknown. In this study, quality of life, functional capacity and symptoms of 28 haemodialysis patients with an initial Hb of 67 +/- 2 (mean +/- SEM) g/L were assessed after 0, 6 and 12 months of r-HuEPO, the dose of which was titrated to achieve a stable Hb of between 90 and 100 g/L. At six and 12 months Hb was 97 +/- 2 and 93 +/- 2 g/L, and mean r-HuEPO dose between three and six, and between nine and 12 months was 88 +/- 6 and 62 +/- 9 U/kg/week intravenously respectively. There was a significant improvement in level of activity and satisfaction with various aspects of life, and a reduction in fatigue, weakness, dyspnoea, angina and restless legs. Patients were able to walk 50% further in six minutes. The improvement in quality of life and function was similar to that reported from other centres whose target Hb was between 100 and 120 g/L, and where the r-HuEPO dose was 75% higher than in this study. Costs of r-HuEPO therapy were assessed. The drug itself costs +A3681/yr/patient, to which was added the estimated cost of additional dialyses and medications, bringing the total to +A5177/yr/patient. There was, however, a reduction in both hospitalisation by 8.3 days/yr/patient and medical consultation by 3.9 hours/yr/patient. Five patients commenced full-time work, one took up full-time study aimed at finding work, three transferred to home haemodialysis and six fewer patients drew social security benefits. The net cost saving from using low dose r-HuEPO was more than +A1,000/yr/patient.