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American Society of Nephrology: Renal Week 2010
The 43rd annual meeting, which took place from November 16 to 21, 2010, in Denver, Colorado, hosted more than 13,000 nephrologists and other health care professionals from around the world. Most prominent among the presentations was the SHARP trial results, whose positive primary outcomes were greeted by audience applause, spurred possibly by a sense of an end to the drought for statin trials in patients with chronic kidney disease. Of all the new drug research presented, the data on bardoxolone were felt to be the most promising. Although trials of eculizumab (Soliris) are small because of the rarity of the diseases it treats, the life-saving effects in atypical hemolytic uremic syndrome created a constant stir among researchers streaming past a poster displaying these results.
Ezetimibe/Simvastatin (Vytorin) In Heart and Renal Protection: The SHARP Trial
- Colin Gaigent, MD, University of Oxford, United Kingdom
- Martin Landray, MD, University of Oxford, United Kingdom
Although the risk of vascular events is high among patients with chronic kidney disease (CKD), evidence of a clear association between cholesterol levels and vascular disease risk is lacking. In CKD patients, the pattern of vascular disease is atypical, with a large proportion being non-atherosclerotic. Furthermore, prior trials of reducing low-density lipoprotein-cholesterol (LDL-C) in CKD have been inconclusive.
In the completed SHARP trial (Study of Heart And Renal Protection), investigators recruited patients 40 years of age or older with a history of CKD. One group was not on dialysis, but the patients had had elevated creatinine levels on two occasions (men, 1.7 mg/dL or higher; women, 1.5 mg/dL or higher). The other group was receiving dialysis, but those patients had no history of myocardial infarction (MI) or coronary revascularization. The key criterion for entry into the study was that the physician had to be unsure about initiating LDL-lowering treatment.
Patients (N = 9,438) were randomly assigned to receive ezetimibe (Zetia, Merck), simvastatin (Zocor, Merck), or placebo for one year. The patients then received ezetimibe/simvastatin (Vytorin, Merck/Schering-Plough) (N = 4,650) or placebo (N = 4,620). Median follow-up was 4.9 years. The main outcome was major atherosclerotic events, namely coronary death, MI, non-hemorrhagic stroke, or any revascularization.
Mean age was 62 years (63% were men). Compliance with LDL-C–reducing therapy was approximately 65% in the two groups. Of the placebo patients, 8% were taking lipid-lowering therapy. There was a reduction of 32 mg/dL in LDL despite the two-thirds compliance. Had patients been fully compliant, Dr. Gaigent pointed out, the reduction would have been 50 mg/dL.
After five years of follow-up, the primary outcome measure of major atherosclerotic events was reduced by 17% in the ezetimibe/simvastatin group, compared with the placebo group (risk ratio, 0.83; logrank2P = 0.0022). For those using ezetimibe/simvastatin, event rates were lower for each of the endpoint components. Reductions in major atherosclerotic events were similar in non-dialysis patients (15% with ezetimibe/simvastatin vs. 16.5% with placebo) and for the dialysis patients (9.5% vs. 11.9% with placebo).
Mortality rates were similar between groups, with no differences noted in the subgroups (24.6% with ezetimibe/simvastatin; 24.1% with placebo). There were no differences in rates of end-stage renal disease (33.9% with ezetimibe/simvastatin, 34.6% with placebo) or combined end-stage kidney disease or death (47.4% and 48.3%, respectively).
The incidence of cancer was similar between groups (9.4% with ezetimibe/simvastatin vs. 9.5% with placebo). No significant differences were observed among specific subtypes. Myopathy rates were also similar.
Dr. Landry concluded, “In this trial, ezetimibe/simvastatin reduced the risk of major atherosclerotic events by a highly statistically and clinically significant 17%—despite the fact that only two-thirds of subjects were compliant.”
He noted that the results were entirely consistent with prior findings with lipid-lowering agents in other statin trials in other populations. He commented further:
Over the last couple of decades we’ve become increasingly aware that even moderate CKD is associated with a high risk of cardiovascular complications . . .What we have failed to do is to identify reliably any treatments that are active and safe in reducing that risk—until today.
The SHARP results, he said, provide clear evidence that “lowering cholesterol with ezetimibe/simvastatin safely reduces the risk of major atherosclerotic events.”
In response to a question from the audience about the lack of a mortality benefit, Dr. Landry answered that with two-thirds of deaths having nothing to do with vascular disease, the trial was not powered to detect a difference in deaths from vascular disease. Decisions about starting therapy in CKD patients, he suggested, should be based on cardiovascular risk, not absolute cholesterol levels.
Eculizumab (Soliris) in Atypical Hemolytic Uremic Syndrome Refractory to Plasma Therapy: Analysis from a Phase 2 Trial
- Christophe Legendre, MD, Université Paris Descartes, Paris, France
According to interim results among adults and adolescents, sustained therapy with eculizumab (Soliris, Alexion) rapidly stops thrombotic microangiopathy (TMA) in atypical hemolytic uremic syndrome (aHUS), restoring renal function and ending the need for plasma therapy. This syndrome, in which complement inhibitor deficiencies lead to chronic uncontrolled complement activation, is a rapidly progressing, life-threatening condition that affects children and adults. The result is chronic inflammation, TMA-induced platelet consumption, renal failure, and hemolytic anemia. Beyond progressive kidney destruction, systemic TMA leads to cerebral, cardiac, and other ischemic events. Despite standard treatment with plasma therapy, about 60% of patients develop end-stage renal disease or die within a year of diagnosis. This syndrome is rare, affecting only 1 in 1,000 people (approximately 3,000 individuals) in the U.S.
In patients with paroxysmal nocturnal hemoglobinuria (PNH), another complement-mediated disease, eculizumab, a terminal complement inhibitor, has been shown to decrease thrombosis, reduce renal impairment, and improve quality of life.
In a prospective, controlled, single-arm study, eculizumab intravenous (IV) infusions were given to adults and adolescents with aHUS who had evidence of ongoing TMA despite plasma therapy. Treatment consisted of 900 mg/week during weeks 1 to 5 and 1,200 mg every two weeks to week 26.
The median age among 17 patients was 28 years (29% were men). The primary endpoint was the change in platelet count.
Dr. Legendre reported an immediate, significant, and sustained increase in platelets (P < 0.0001). The mean change from baseline at week 26 was 96 ± 21 x 109/L, with 13 of 17 of patients (77%) achieving normal platelet levels. TMA event-free status was achieved in 15 of 17 patients (88%), and platelet levels remained stable or increased for at least 12 weeks with no need for plasma therapy or new dialysis.
The pre-treatment rate of intervention per patient per day had been 0.51. No intervention was needed with treatment. Sixty-five percent of patients had at least a one-stage improvement in CKD status, and estimated glomerular filtration rate (eGFR) improved in 15 of the 17 patients (88%).
Of seven patients on dialysis at baseline, five became dialysis-free. Mean creatinine levels were reduced by 48% within the entire population, and renal function continued to improve with sustained eculizumab therapy.
Clinically meaningful benefits in quality of life, as measured by the EuroQol EQ-5D self-reporting health questionnaire, were noted in 87% of patients (P < 0.0001). Eculizumab was well tolerated. The most commonly reported adverse events were anemia (35%; severe in one patient), headache (41%; severe in one patient), and diarrhea (35%). One patient withdrew from treatment because of an adverse event considered to be unrelated to the study drug.
Dr. Legendre concluded, “Eculizumab is a potential new standard of care in aHUS patients.”
He pointed out that with plasma exchanges, getting transplants is difficult because “you know that the likelihood of getting a recurrence in the transplant is very high.” Recurrences can come on suddenly and destroy the kidneys within a few days.
The important unresolved question concerning the costly eculizumab regimen is whether it might be possible for some patients to stop therapy. Some individuals, he said, have been receiving treatment for nearly 10 years. An extension trial among these patients is ongoing.
Bardoxolone Methyl in Kidney Disease And Type-2 Diabetes
- Pablo E. Pergola, MD, PhD, University of Texas Health Science Center, San Antonio, Tex.
The persistent metabolic inflammation associated with chronic kidney disease (CKD) leads to a decline in the glomerular filtration rate (GFR) and, ultimately, may lead to dialysis, cardiac events, and death. Currently available treatments slow CKD progression, but they do not reverse it. CKD affects 26 million Americans.
Bardoxolone methyl (Reata Pharmaceuticals), also called RTA 402 and CDDO-methyl ester, is an antioxidant inflammation modulator targeting Nrf2, a novel pathway. It has been shown to improve eGFR and to reduce blood urea nitrogen (BUN), serum phosphorus, and serum uric acid, all markers of impaired renal function in patients with moderate-to-severe CKD.
In an ongoing, 52-week, multicenter, phase 2b double-blind trial, 227 adults with CKD (eGFR 20–45 mL/minute) and type-2 diabetes mellitus were enrolled. They were receiving standard-of-care therapy at entry, with 98% given an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). Patients were randomly assigned to receive either placebo or bardoxolone at three titrated doses of 25, 75, and 150 mg once daily. The primary outcome was the change in kidney function after 24 weeks of treatment.
At week 24, the bardoxolone groups experienced a large, mean dose-dependent increase in eGFR (10.1 mL/minute/1.73 m2) and the placebo group, a 0.1-mL/minute/1.73 m2 change (P < 0.0001). Improvements in eGFR of 10% or more were reported in about 75% of patients receiving the study drug, and 25% experienced improvements of 50% or more, compared with fewer than 2% of the placebo patients (P < 0.001). Of those patients receiving bardoxolone, 59% experienced a reduction in disease severity, compared with 16% in the placebo group.
Only 4% of patients in each bardoxolone group experienced a worsening of CKD stage, compared with 14% in the placebo group. Bardoxolone treatment resulted in a reduced number of patients with stage 3 CKD (by 50%) compared with baseline values. Significant reductions were also observed in other kidney function markers, including BUN, serum phosphorus, and uric acid, which correlated inversely with increased eGFR.
Bardoxolone was generally well tolerated, although treated patients experienced more adverse events than the placebo group. Muscle spasm was the most frequently reported event (in 49%).
Noting that the study met its primary endpoint, Dr. Pergola concluded, “These results merit follow-up in a phase 3 study.” The BEACON study, he said, is being initiated.