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40th Annual Meeting and Scientific Exhibition of the American Society of Nephrology

San Francisco, California / October 31-November 5, 2007

Ultra-high doses of the angiotensin II receptor blocker (ARB) candesartan have shown to produce significantly greater reductions in proteinuria than either standard doses or very high-dose candesartan in chronic kidney disease (CKD) patients, according to results from the Supra Maximal Atacand Renal Trial (SMART).

Equally important, the supra-maximal doses of candesartan used in SMART were not associated with an increased risk of adverse events (AEs) and serum potassium levels remained within the normal range throughout the 30-week treatment trial.

As presented here by Dr. Ellen Burgess, Foothills Medical Centre and Professor of Medicine, University of Calgary, Alberta, SMART originally recruited 346 hypertensive patients with a history of proteinuria in excess of 1 g/24 h for over six months.

All patients were initially treated with standard-dose candesartan 16 mg, for eight weeks. Out of this cohort, 269 patients still had persistent proteinuria at eight weeks and these patients were then randomized to remain on 16 mg or to a carefully uptitrated dose at a maximum of either 64 mg/day or 128 mg/day. The cohort of 269 patients remained on therapy for 30 weeks. Median estimated glomerular filtration rate (eGFR) at baseline was 49.9 mL/min/1.73 m2 and the median urinary protein excretion rate was 2.66 g/24 h. Mean baseline blood pressure (BP) was 132.5/77.5 mm Hg, median serum creatinine was 130 µmol/L and median serum potassium was 4.5 mmol/L. Approximately one-third of patients had primary glomerular disease, some 12% had hypertensive nephrosclerosis and just over half had diabetic nephropathy.

At final assessment 30 weeks later, there was a mean 33% greater reduction in urinary protein excretion in the intent-to-treat population given 128 mg (including all participants who had received at least one dose of the agent) compared with the 16-mg group (P<0.0001).

In the per-protocol analysis (all doses taken for 30 weeks), there was a mean 44.3% reduction in proteinuria, again relative to the 16-mg group (P<0.0001). A non-significant 16.9% greater reduction in urinary protein excretion was also seen in the 64-mg group vs. the 16-mg group.

“Change in systolic BP was not different between the three groups at randomization or at study completion,” Dr. Burgess added, “and similarly, for diastolic BP, there were no significant differences across the three groups at randomization or at study end point.” As anticipated, serum creatinine rose modestly during the study but increases were not significantly different across the three groups. Most importantly, serum potassium “remained comfortably within normal limits” throughout the 30-week trial and was not significantly different across the three groups either at randomization or at study end point. Nor was the incidence of other AEs significantly different across the three dosage groups.

“BP is very important for preservation of kidney function but you also have to think about proteinuria,” Dr. Burgess commented, “and if you’ve got BP under control but you still have proteinuria on maximally recommended ARB therapy, you should consider a proven high-dose ARB, because if you are talking about other ARBs, you don’t know what doses of the other ARBs are going to give you the same effect. You have to choose a proven dose of an ARB, and the only proven high-dose ARB right now is candesartan.”

Antihypertensive Doses and Proteinuria

Commenting on SMART findings, Dr. Paul René de Cotret, Associate Professor of Medicine, Université Laval, Quebec City, Quebec, and a member of the SMART steering committee, noted that specialists have always assumed that antihypertensive doses of either an ARB or an ACE inhibitor would protect the kidney and decrease proteinuria. “There was no logic behind this, but this is what we’ve been assuming all along,” he commented. But as findings from the study suggest, blockade of the renin-angiotensin-aldosterone system (RAAS) with antihypertensive doses from either class of drugs is far from complete. Further, optimal doses of both drug classes—even when used together—do not always prevent the kidney from deteriorating into end-stage renal failure (ESRF). As Dr. René de Cotret noted, blocking the RAAS within tissues likely requires much higher doses of an ARB or an ACE inhibitor than those approved for hypertension control.

This is particularly true in the kidney, he added, where it is harder for any molecule to penetrate the tissue and where there is vastly more angiotensin II to block than there is in the circulation. Thus, as he suggested, the kidneys may well be a “prototypic tissue” and serve as a harbinger for the kind of end-organ protection that may be possible to achieve in other target organs. “It is at least plausible that what we saw in the kidney with ultra-high-dose candesartan may also be the case in the myocardium , and at least [SMART] questions the dogma that we should be using antihypertensive doses for end-organ protection,” he indicated.

Dr. René de Cotret also cautioned against extrapolating findings from SMART to other ARBs, as results have not necessarily been replicated in other very high or ultra-high dose studies. For example, in type 2 diabetes patients with microalbuminuria, Rossing et al. (Kidney Int 2005;68:1190-8) treated patients with irbesartan, 300 mg, 600 mg and 900 mg/day. Each dose significantly reduced the urinary albumin excretion rate but the ultra-high 900 mg/day dose only lowered urinary albumin excretion by an additional 15% compared with the 300-mg dose, as Dr. René de Cotret pointed out. Nevertheless, he emphasized that physicians need to be cautious about proceeding with supra-maximal-dose candesartan in general and avoid using it altogether in patients with a baseline serum potassium in excess of 5 mmol/L. “We also need to increase the dose of candesartan in a stepwise way, as we did in SMART, every two weeks, and check serum creatinine and potassium as we are inching upwards,” he told delegates.

Still, with the reductions in proteinuria observed in the supra-maximal dose arm in SMART, “we would predict that this [approach] will attenuate renal damage,” he concluded.

Questions and Answers

The following section is based on discussions with Nathalie Francoeur, BPharm, MSc, CHUQ-L'Hôtel-Dieu de Québec, Quebec City.

Q: When a patient receives a prescription for candesartan at a dose of 128 mg, what advice would you offer?

A: Counselling should always be individualized. With inpatients, we should focus on diet if serum potassium is close to the upper limit of normal or if it tends to increase. With a dose of 128 mg, it goes without saying that it is important to inform patients of potential adverse events. However, it is even more important to ensure that doses are increased gradually and patients are followed closely and that a complete blood count is done regularly.

Q: In your opinion, are findings from SMART an important advance in the potential prevention of ESRD in CKD patients?

A: Yes. From a pharmacological viewpoint, it is most interesting to see that complementary mechanisms may be involved when the dose is increased. Proteinuria is a clinically critical factor that we focus on to prevent progression of renal failure. That said, I remain convinced that it is impossible in practice to administer such high doses to many of our patients [as] they are often elderly patients who have a complex clinical profile and a low eGFR (£30 mL/min).

Q: Do you think pharmacists will embrace this new paradigm shift towards the use of ultra-high doses of candesartan, and not just as antihypertensive doses as a way to postpone disease progression in patients living with CKD?

A: It may still be a little early to answer that question. Under such conditions, pharmacists will of course need to carry out close pharmacotherapeutic follow-ups.