Role of Arenesp and cinacalcet in protecting hearts of renal patients

Role of Arenesp and cinacalcet in protecting hearts of renal patients

Treatment of chronic kidney disease (CKD) is focussing increasingly on prevention of cardiovascular complications with the aim of reducing the cardiovascular mortality and morbidity to which many patients currently succumb. Recognition of the fact that it is heart disease rather than renal failure that kills most CKD patients, and that the risks start early in the disease process, was reinforced a couple of years ago when an analysis of the Kaiser Permanente Renal Registry of 1.1 million patients was published in the New England Journal of Medicine (1).  It showed that when kidney function drops, risk of CVD deaths and morbidity shoot up.  Compared to patients with a glomerular filtration rate (GFR) of at least 60ml per minute per 1.73m2, ie, approximately half the normal value, the increased risk of CV death ranged from 17 per cent for GFRs between 45 and 59 to a six-fold increase when GFR was below 15ml/min (1).

At the recent joint meeting of the European Renal Association and European Dialysis and Transplant Association (ERA-EDTA), conference-President Jorge Cannata Andia. Professor of Nephrology at University of Oviedo, Spain stressed the need for early detection of CKD which he pointed out was at epidemic levels in Europe.  “An estimated 30 million Europeans, at least, have CKD with reduced renal function and progressive renal damage that can ultimately lead to renal failure and the need for dialysis or transplantation.”  These patients are likely to already have experienced some vascular damage.  Although there are multiple causes of renal disease, the current epidemic can be attributed to rising levels of hypertension, type 2 diabetes and hyperlipidaemia in Europe’s ageing population.  Nephrosclerosis – atheroma in renal blood vessels – affects 40 per cent of the population, he estimates.

The increased risk of CV death in CKD stems from multiple complications  including anaemia, oxidative stress, inflammation, disordered calcium and phosphate regulation and factors promoting thrombogenesis.  Professor Cannata Andia believes serum creatinine testing should be performed more frequently in future to detect renal function problems among middle-aged and older adults during the lengthy asymptomatic phase of the disease.  “Creatinine is the cholesterol of the new millennium,” he said.  ‘”Cholesterol is widely checked because everyone knows the dangers of high levels but we haven’t appreciated in the past that creatinine can give just as much of a warning signal.”  Early detection and treatment may enable interventions to arrest and possibly even reverse progress of renal disease with new drugs in development.  But already, recently developed drugs could be used early in CKD to offer cardiovascular protection, he said.

Anaemia is common CKD complication

Anaemia is common as a result of failing kidneys no longer producing the natural hormone erythropoietin that stimulates production of red blood cells needed to transport oxygen via haemoglobin.  Anaemia starves the body of oxygen contributing to multiple organ dysfunction including heart and brain.  In the heart it can lead to left ventricular hypertrophy and heart failure. In the brain it causes cognitive dysfunction.  Before the arrival of recombinant human erythropoietin (rHuEpo) therapies, patients required frequent blood transfusions.      

Treatment with Aranesp (darbepoetin alfa) a recombinant erythropoiesis-stimulating agent is effective in correcting anaemia, producing haemoglobins (Hb) in the desired range of 12-14g/dL.  Used sufficiently early it may retard organ damage.  Two major cardiovascular outcome studies are currently investigating the potential of Aranesp to reduce mortality in anaemic patients. TREAT is comparing Aranesp with placebo in treatment of anaemia in 3,400 CKD patients with type 2 diabetes. The primary endpoint is a composite of all-cause mortality, myocardial infarction, myocardial ischaemia, congestive heart failure and stroke.   RED-HF is evaluating the effect of Aranesp on time to death or hospital admission for worsening heart failure in patients with left ventricular systolic dysfunction and anaemia.

Alternate week dosing

Two studies presented for the first time at ERA-EDTA, involving a total of 413 haemodialysis patients, show Aranesp iv dosing every two weeks with double the weekly dose, is as effective as once-weekly dosing with Aranesp or any other rHuEpo in maintaining Hb within the desired 10-13g/dl range (2,3). There was no evidence of over-reaching the Hb target, in fact patients receiving every-other-week dosing had fewer episodes where Hb rose above 14g/dL .  Nor did every-other-week dosing increase risks of adverse events, or raise the incidence of vascular disorders.  Switching from Aranesp administered weekly to an every-other-week regimen maintained efficacy in stabilising Hb levels without the need to increase the total amount used in dosing.  Switching resulted in no significant differences in mean Hb levels or in the mean weekly dose of Aranesp.

Commenting on the studies, Dr Fernando Carrera of the Eurodial Clinic, Leiria, Portugal, an author of one of the studies, said:  “When compared with standard weekly dosing, fortnightly administration is just as effective but is much more convenient for both patients and staff.  It reduces the number of injections required so minimises the risk of needle-stick accidents. It saves time for nurses, allowing them to spend more time talking to patients.   Overall it simplifies anaemia management for healthcare providers as well as patients.”

Role of the parathyroid in heart disease among CKD patients

A more difficult-to-manage complication of CKD which can seriously affect the heart is secondary hyperparathyroidism (SHPT), said Dr Martin Wilkie, Consultant Renal Physician of Northern General Hospital, Sheffield, the first author of a poster on the OPTIMA study (4).   As kidney function declines, the parathyroid gland becomes overactive and loses the ability to regulate levels of calcium and phosphate, he explained. The normal calcium and phosphorous balance is thrown out of kilter triggering the parathyroid’s calcium-sensing receptor to generate more parathyroid hormone (PTH). “This has very deleterious effects on the bones and the soft tissues,” he noted.  Calcium leaches out of bones making them susceptible to fracture while excess calcium in the blood is deposited in the heart muscle, heart valves and arteries.  Calcification seriously damages the ability of these structures to function normally and at the extreme end of the spectrum, calciphylaxis may occur where blood- vessel damage results in extensive ulceration.”

A large proportion of dialysis patients develop SHPT to some degree and in a UK study, 37 per cent of an estimated 21,000 CKD patients on dialysis had signs of the complication including PTH levels well above recommended values of <32pmol/L or 304pg/ml. 

Treatment has been extremely limited in its scope to control PTH and minerals.  But the arrival of cinacalcet HCl – a calcimimetic marketed in Europe as Mimpara and in the US as Sensipar – has brought new hope, said Dr Wilkie.  “This is the first drug of its class;  it mimics calcium and has been shown to act directly on parathyroid cells decreasing output of PTH whilst simultaneously reducing calcium and phosphate levels.”  Introduction of cinacalcet HCl dramatically reduced the need for parathyroid surgery and halved the number of fractures occurring in long bones.

The OPTIMA study shows the importance of early treatment with cinacalcet HCl alongside vitamin D when PTH levels are low (4).  Treatment reduced all parameters and PTH reduction was maximised.  “Earlier intervention is undoubtedly better in making SHPT easier to control” he remarked.

Amgen is now launching a double-blind, placebo-controlled Phase III study of cinacalcet HCl.  The E.V.O.L.V.E (Evaluation of cinacalcet therapy to lower cardiovascular events) trial will enrol 3,800 patients with CKD and early SHPT on maintenance dialysis in 500 centres of 30 countries.  Patients already receiving traditional therapy for SHPT will be randomised to either additional placebo or cinacalcet HCl.  The primary endpoint is a composite of all cause mortality and cardiovascular (CV) morbidity including myocardial infarction, myocardial ischaemia, congestive heart failure and stroke.  Results should be available in 2011.

“Many patients with CKD die before they even start dialysis,” commented Dr William Sheridan, Vice President of Amgen International’s medical affairs.  This trial will be definitive in showing that cinacalcet HCl is significantly better than conventional therapy at reducing CV mortality and morbidity, he added

Olwen Glynn Owen

References

1. Go A et al.  CKD and the risks of death, cardiovascular events and hospitalisation. N Eng J Med 2004; 351:1296-1305.
2. Carrera F et al. Aranesp administered Q2W maintains recommended Hb in CKD patients on haemodialysis switched from QW dosing.  Nephrology, Dialysis, Transplantation 2006; 21: Supplt 4: 148-9 (poster SP401)
3. Locatelli F et al. Control of anaemia with Aranesp: Hb stability achieved with fewer patients requiring dose adjustments after switching to Aranesp every 2 weeks.  Nephrology, Dialysis, Transplantation 2006; 21: Supplt 4: 152 (poster SP411)
4. Wilkie M et al.  The OPTIMA study. Nephrology, Dialysis, Transplantation 2006; 21: Supplt 4:134 (poster SP358)

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