ASN 2013 Quoi de neuf ? D.Guerrot - 10/12/2013

VA-NEPHRON Trial : IEC+ARA II … c’est re-fini N = 1448 Diabétiques DFGe 30-90 ml/min AlbU > 300 mg/j ARAII vs IEC+ARAII Obj. I : DDFGe/IRCT/† → p = NS Etude arrêtée pour ↑ EIG HyperK IRA Combination ACEI and ARB: ON TARGET showed a caution for harm.  ALTITUDE which was in DMII and was stopped for futility as well. Included CKD 2,3 and DMII with albuminuria >300mg/day.  All non diabetic were not included and uncontrolled HTN and DMII.  The primary end points  were eGFR changes and ESRD and death.  Safety outcomes were K, all cause mortality, AKI, and hospitalization. 1648 patients enrolled, 724 were assigned in both groups. Most of the patients were men as it was a VA study. 25% had CAD, 70% were on ACEI at the start, another 16% were on ARB at start and 5% on both at start. Median eGFR was 54 mL/min. Results: No significant benefit in primary Endpoint of ESRD and eGFR change.  No change in all cause mortality.  No subgroup benefitted in combination therapy (especially 1gm or more albuminuria).  eGFR was slightly lower in combined arm but overall in time, about the same.  Albuminuria is decreased as shown by prior studies.  No benefit in cardiovascular benefits either. A significant and early difference with hyperkalemia in combined group- and severe as well and peak levels and treatment required. Also significant AKI (serious events requiring being in ER).  In terms of overall safety outcomes, half of them had one serious adverse event. Combination therapy with an ACEI and ARB was associated with serious adverse events. Fried LF et al. NEJM 2013

HTA en Hémodialyse : Lisinopril vs Atenolol Quel ttt pour HTA non volodépendante en HMD ? Manque de RCT ! N = 200 Patients hémodialysés - Inclusion : HTA (MAPA) + HVG + HMD > 3 mois Exclusion : Obèses, événement CV < 3 mois Ttt habituel (sauf IEC/ARAII/B-) et PS « optimal » + Lisinopril vs + Atenolol Cible PA < 140/90 mm Hg (MAPA M0, M3, M6, M12) Objectifs : I: Evénements CV II: Régression HVG The late breaking trials continued with Rajiv Agarwal’s randomized controlled retrial of different blood pressure therapy in the dialysis unit. Agarwal has been out in front on this subject for awhile. He did some landmark work showing that blood pressure control was not another case of reverse epidemiology in the dialysis unit and also showed the utility of ambulatory and home blood pressure monitoring for dialysis pts. Agarwal discussed that most of the hypertension in dialysis patients is volume related, but that even after you correct this there is some residual hypertension. He designed a trial to see how to optimally treat that. This trial enrolled hypertensive dialysis patients; they used 48 hour ambulatory BP measurements to ensure hypertension for enrollment. The trial pitted atenolol against lisinopril against each other. Both of these drugs are renally excreted so Agarwal was able to dose them after each dialysis session only 3 days a week. Direct observational treatment, like tuberculosis but for hypertension. He randomized 200 patients. Only 104 completed the trial. They had heavy patient drop out, especially in the lisinopril group. They saw more BP lowering affect with atenolol, about 5.6 mmHg systolic. This was seen at 3 months and continued to the end of the trial. The improved blood pressure in the atenolol group was despite more weight loss (more aggressive UF I imagine) and more antihypertensive drugs with lisinopril. The real meat of the study was the CV event rate, which was more than double with lisinopril compared to atenolol, IRR = 2.36, P=0.001. Maybe the most important slide was titled “Nearly all SAEs more in lisinopril.” The details: CHF Hospitalization IRR 3.13 P=0.02 All cause Hospitalization IRR 1.61 P<0.01 All cause SAE IRR 1.47 P<0.001 Hypertensive Crisis IRR 3.81 P=0.03 Hyperkalemia IRR 3.38 P=0.05 Dr. Agarwal was unable to assess if this was due to harm from lisinopril or harm from a lack of beta-blocker. Overall, this was an interesting study and really lays bare the fact that we have almost no RCT data on what to do about blood pressure control in dialysis patients. Agarwal R et al. (Non publié)

HTA en Hémodialyse : Lisinopril vs Atenolol

HTA en Hémodialyse : Lisinopril vs Atenolol Quel ttt pour HTA non volodépendante en HMD ? Manque de RCT ! N = 200 Patients hémodialysés - Inclusion : HTA (MAPA) + HVG + HMD > 3 mois Exclusion : Obèses, événement CV < 3 mois Ttt habituel (sauf IEC/ARAII/B-) et PS « optimal » + Lisinopril vs + Atenolol Cible PA < 140/90 mm Hg (MAPA M0, M3, M6, M12) Objectifs : Evénements CV, Régression HVG Résultats : - MAPA M3 : Lisinopril -14 mmHg vs Atenolol -20 mmHg - HVG réduite dans groupe Lisinopril (p = NS) - Etude arrêtée fin septembre pour ↑ EIG - Evénements CV : ↑ Lisinopril RR 2.36 vs Atenolol p < 0.001 - Hospitalisation pour ICC : ↑ Lisinopril RR 3.1 vs Atenolol p = 0.02 - Hospitalisation toute cause : ↑ Lisinopril RR 1.6 vs Atenolol p < 0.01 The late breaking trials continued with Rajiv Agarwal’s randomized controlled retrial of different blood pressure therapy in the dialysis unit. Agarwal has been out in front on this subject for awhile. He did some landmark work showing that blood pressure control was not another case of reverse epidemiology in the dialysis unit and also showed the utility of ambulatory and home blood pressure monitoring for dialysis patients. Agarwal discussed that most of the hypertension in dialysis patients is volume related, but that even after you correct this there is some residual hypertension. He designed a trial to see how to optimally treat that. This trial enrolled hypertensive dialysis patients; they used 48 hour ambulatory BP measurements to ensure hypertension for enrollment. The trial pitted atenolol against lisinopril against each other. Both of these drugs are renally excreted so Agarwal was able to dose them after each dialysis session only 3 days a week. Direct observational treatment, like tuberculosis but for hypertension. He randomized 200 patients. Only 104 completed the trial. They had heavy patient drop out, especially in the lisinopril group. They saw more BP lowering affect with atenolol, about 5.6 mmHg systolic. This was seen at 3 months and continued to the end of the trial. The improved blood pressure in the atenolol group was despite more weight loss (more aggressive UF I imagine) and more antihypertensive drugs with lisinopril. The real meat of the study was the CV event rate, which was more than double with lisinopril compared to atenolol, IRR = 2.36, P=0.001. Maybe the most important slide was titled “Nearly all SAEs more in lisinopril.” The details: CHF Hospitalization IRR 3.13 P=0.02 All cause Hospitalization IRR 1.61 P<0.01 All cause SAE IRR 1.47 P<0.001 Hypertensive Crisis IRR 3.81 P=0.03 Hyperkalemia IRR 3.38 P=0.05 Dr. Agarwal was unable to assess if this was due to harm from lisinopril or harm from a lack of beta-blocker. Overall, this was an interesting study and really lays bare the fact that we have almost no RCT data on what to do about blood pressure control in dialysis patients. Agarwal R et al. (Non publié)

ZS-9 : Du nouveau dans l’hyperK Propriétés : KXL/Resikali : Résines polymériques ZS-9 : Cristal inorganique Fixe spécifiquement cations monovalents (3.5 mmol K / g) Non absorbé Ne gonfle pas Aucun goût ZS-9, a first-in-class selective monovalent cation trap under development by ZS Pharma, is safe and effective for patients with chronic kidney disease, preliminary results suggest. "ZS-9 shows promise as a novel, safe, well-tolerated, predictable, fast-acting, and effective drug for the rapid and sustained removal of serum potassium," said senior investigator Stephen Ash, MD, from Indiana University in Lafayette. Despite the fact that hyperkalemia causes significant mortality in patients with kidney disease or cardiovascular disease, effective treatments are lacking. The only currently approved therapy in the United States — sodium polystyrene sulfonate — has been associated with adverse drug reactions and sometimes fatal gastrointestinal events. Unlike sodium polystyrene sulfonate, ZS-9 is an inorganic exchanger that preferentially entraps monovalent cations, specifically excess potassium ions, over divalent cations in the gastrointestinal tract. Because the drug is not systemically absorbed, it minimizes the risk for systemic toxicity. Dr. Ash presented the results from the first in-human phase 2 safety and efficacy study and preliminary results from a phase 3 trial of nearly 800 patients here at Kidney Week 2013. "We believe the phase 3 trial is the largest of any potassium-reducing drug," he noted. First In-Human Results In the multicenter double-blind phase 2 study, patients with stage 3 kidney disease and mild to moderate hyperkalemia were randomized to receive placebo (n = 30) or 1 of 3 ZS-9 doses: 0.3 g (n = 12), 3 g (n = 24), 10 g (n = 24). Investigators assessed the primary end point at 48 hours, and patients with potassium levels below 5 mEq/L proceeded to observation. Those with levels above 5 mEq/L received the drug for another day or 2 and then went on to observation. A total of 43% of patients in the treatment groups and 37% in the placebo group were receiving concomitant angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). ZS-9 was well tolerated and there were no serious adverse events, including no significant gastrointestinal issues or cases of hypokalemia, hypomagnesemia, or hypocalcemia. "The most frequent adverse events were nausea, vomiting, or urinary tract infection, and they were all mild to moderate. The majority were transient and did not require treatment," Dr. Ash said. There were no serum and urine sodium effects from the drug. There were dose-dependent reductions in serum potassium from baseline, compared with the placebo group, in the 10 g group (P < .0001) and in the 3 g group (P = .048). In the 10 g group, serum potassium decreased 1.0 mEg/L or more in the first 48 hours of treatment in 63% of patients; it decreased only 17% in the placebo group. Significant decreases in serum potassium levels were seen much faster in the 10 g group — as soon as 1 hour after the initial dose — than in the placebo group (P = .022). The decrease from baseline was 0.92 mEq/L after 38 hours of treatment with 10 g (P < .001). Potassium levels in the 10 g group remained significantly lower than in the placebo group for another 3.5 days after the final dose (P = .016). The decreases in serum potassium levels in patients in the 10 g and placebo groups who were taking concomitant ACE inhibitors or ARBs were consistent with the entire 10 g and placebo cohorts. Preliminary results from the phase 3 trial have shown similar success, Dr. Ash reported. Phase 3 Results The phase 3 trial involved 753 patients with chronic kidney disease who were not on dialysis. Investigators randomized patients to receive placebo or 1 of 4 doses of ZS-9: 1.25 g, 2.5 g, 5 g, or 10 g. Patients received treatment 3 times daily over a 48-hour acute phase and, if their potassium was below 5 mmol/L, they went into the subacute maintenance phase of once-daily dosing and were evaluated in a 12-day subacute maintenance phase. The primary efficacy end point of a difference in the rate of change in serum potassium over 48 hours was reached in the 10 g, 5 g, and 2.5 g groups, which all had highly significant decreases. In the 10 g group, the decrease in serum potassium was 0.73 mEq/L at 48 hours (P < .0001); in the 5 g group, it was 0.54 mEq/L (P < .0001); and in the 2.5 g group, it was 0.46 mEq/L (P < .0009). As in the phase 2 study, the drug was well tolerated, and gastrointestinal effects were reported more often in the placebo group than in the ZS-9 groups (3.5% vs 5.1%). "This is important because sodium polystyrene sulfonate has some significant gastrointestinal effects," Dr. Ash noted. He reported that more extensive results from the phase 3 trial will be presented in coming months. Session comoderator Orlando Gutierrez, MD, a nephrologist from the University of Alabama in Birmingham, said the field could benefit from a new drug to treat hyperkalemia. "It is a common problem in the outpatient and inpatient settings, and we have few effective therapeutics beyond sodium polystyrene sulfonate, which has a number of undesirable side effects," he told Medscape Medical News. ZS-9 could be particularly beneficial for patients requiring ACE inhibitors or ARBs, he added. "If additional studies can establish the long-term safety and efficacy of ZS-9, it could have a role in the control of hyperkalemia in patients who would benefit from therapies such as ACE inhibitors, ARBs, and mineralocorticoid-receptor blockers but who can't take them due to hyperkalemia." Ash SR et al. (Non publié)

ZS-9 : Du nouveau dans l’hyperK Etude Phase 3, n = 753, IRC stade 3, K 5-6 mM Placebo vs 1.25gx3/j vs 2.5gx3/j vs 5gx3/j vs 10gx3/j Pleine dose 48h, puis dose d’entretien si K<5 Obj I = ↓ K à 48h : OK pour 2.5g (-0.46mM), 5g (-0.54mM), 10g (-0.73mM) Tolérance : ZS-9 = Placebo (EI dig 3.5% vs 5.1%) A suivre… ZS-9, a first-in-class selective monovalent cation trap under development by ZS Pharma, is safe and effective for patients with chronic kidney disease, preliminary results suggest. "ZS-9 shows promise as a novel, safe, well-tolerated, predictable, fast-acting, and effective drug for the rapid and sustained removal of serum potassium," said senior investigator Stephen Ash, MD, from Indiana University in Lafayette. Despite the fact that hyperkalemia causes significant mortality in patients with kidney disease or cardiovascular disease, effective treatments are lacking. The only currently approved therapy in the United States — sodium polystyrene sulfonate — has been associated with adverse drug reactions and sometimes fatal gastrointestinal events. Unlike sodium polystyrene sulfonate, ZS-9 is an inorganic exchanger that preferentially entraps monovalent cations, specifically excess potassium ions, over divalent cations in the gastrointestinal tract. Because the drug is not systemically absorbed, it minimizes the risk for systemic toxicity. Dr. Ash presented the results from the first in-human phase 2 safety and efficacy study and preliminary results from a phase 3 trial of nearly 800 patients here at Kidney Week 2013. "We believe the phase 3 trial is the largest of any potassium-reducing drug," he noted. First In-Human Results In the multicenter double-blind phase 2 study, patients with stage 3 kidney disease and mild to moderate hyperkalemia were randomized to receive placebo (n = 30) or 1 of 3 ZS-9 doses: 0.3 g (n = 12), 3 g (n = 24), 10 g (n = 24). Investigators assessed the primary end point at 48 hours, and patients with potassium levels below 5 mEq/L proceeded to observation. Those with levels above 5 mEq/L received the drug for another day or 2 and then went on to observation. A total of 43% of patients in the treatment groups and 37% in the placebo group were receiving concomitant angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). ZS-9 was well tolerated and there were no serious adverse events, including no significant gastrointestinal issues or cases of hypokalemia, hypomagnesemia, or hypocalcemia. "The most frequent adverse events were nausea, vomiting, or urinary tract infection, and they were all mild to moderate. The majority were transient and did not require treatment," Dr. Ash said. There were no serum and urine sodium effects from the drug. There were dose-dependent reductions in serum potassium from baseline, compared with the placebo group, in the 10 g group (P < .0001) and in the 3 g group (P = .048). In the 10 g group, serum potassium decreased 1.0 mEg/L or more in the first 48 hours of treatment in 63% of patients; it decreased only 17% in the placebo group. Significant decreases in serum potassium levels were seen much faster in the 10 g group — as soon as 1 hour after the initial dose — than in the placebo group (P = .022). The decrease from baseline was 0.92 mEq/L after 38 hours of treatment with 10 g (P < .001). Potassium levels in the 10 g group remained significantly lower than in the placebo group for another 3.5 days after the final dose (P = .016). The decreases in serum potassium levels in patients in the 10 g and placebo groups who were taking concomitant ACE inhibitors or ARBs were consistent with the entire 10 g and placebo cohorts. Preliminary results from the phase 3 trial have shown similar success, Dr. Ash reported. Phase 3 Results The phase 3 trial involved 753 patients with chronic kidney disease who were not on dialysis. Investigators randomized patients to receive placebo or 1 of 4 doses of ZS-9: 1.25 g, 2.5 g, 5 g, or 10 g. Patients received treatment 3 times daily over a 48-hour acute phase and, if their potassium was below 5 mmol/L, they went into the subacute maintenance phase of once-daily dosing and were evaluated in a 12-day subacute maintenance phase. The primary efficacy end point of a difference in the rate of change in serum potassium over 48 hours was reached in the 10 g, 5 g, and 2.5 g groups, which all had highly significant decreases. In the 10 g group, the decrease in serum potassium was 0.73 mEq/L at 48 hours (P < .0001); in the 5 g group, it was 0.54 mEq/L (P < .0001); and in the 2.5 g group, it was 0.46 mEq/L (P < .0009). As in the phase 2 study, the drug was well tolerated, and gastrointestinal effects were reported more often in the placebo group than in the ZS-9 groups (3.5% vs 5.1%). "This is important because sodium polystyrene sulfonate has some significant gastrointestinal effects," Dr. Ash noted. He reported that more extensive results from the phase 3 trial will be presented in coming months. Session comoderator Orlando Gutierrez, MD, a nephrologist from the University of Alabama in Birmingham, said the field could benefit from a new drug to treat hyperkalemia. "It is a common problem in the outpatient and inpatient settings, and we have few effective therapeutics beyond sodium polystyrene sulfonate, which has a number of undesirable side effects," he told Medscape Medical News. ZS-9 could be particularly beneficial for patients requiring ACE inhibitors or ARBs, he added. "If additional studies can establish the long-term safety and efficacy of ZS-9, it could have a role in the control of hyperkalemia in patients who would benefit from therapies such as ACE inhibitors, ARBs, and mineralocorticoid-receptor blockers but who can't take them due to hyperkalemia." Ash SR et al. (Non publié)

Sclérostine Synthétisé par ostéocytes Inhibiteur de Wnt/bCat Diminue la synthèse osseuse Impliqué dans calcifications vasculaires Concentration ↗ dans l’IRC Pelletier S et al. (Non publié)

Sclérostine & Kaupilla Inhibiteur de Wnt synthétisé par ostéocyte Impliqué dans calcification vasc Taux augm ds IRC Obj: Scl/Kaupilla N = 53 HMD Pelletier S et al. (Non publié)

Sclérostine & Kaupilla Inhibiteur de Wnt synthétisé par ostéocyte Impliqué dans calcification vasc Taux augm ds IRC Obj: Scl/Kaupilla N = 53 HMD r=0,46 p<0,001 Pelletier S et al. (Non publié)

Sclérostine & Kaupilla Inhibiteur de Wnt synthétisé par ostéocyte Impliqué dans calcification vasc Taux augm ds IRC Obj: Scl/Kaupilla N = 53 HMD Pelletier S et al. (Non publié)

BEACON Trial : Bardoxolone ↓ progression IRC ? + Bardoxolone Methyl (BM) is most potent for known activators of Nrf2 pathway that help decrease oxidative stress. A stage 2 study had showed a decrease in crt in CKD in DMII. AIM: Reduction of ESRD and cardiovascular death in CKD IV with this agent. This was a Phase 3 randomized controlled trial, multi center. Stage IV stable ACEI/ ARB and some exclusion criteria including severe HTN and poorly controlled DMII. Primary outcome was ESRD, and or cardiovascular death. 3 secondary outcomes: Change in eGFR, hospitalization for death and due to heart failure and composite heart and stroke risk. Mean eGFR was 22.5 ml/min in both groups. Majority of patients had albuminuria. Many patients had retinopathy, neuropathy in both sides. There were 70 outcomes in 69 patients in the BM group and 70 outcomes in 69 patients in placebo groups. No statistical difference in ESRD events and cardiovascular deaths.  Secondary outcomes significant hazard with BM group. More heart failure in BM arm that was significant. In conclusions, in DMII and CKD, BM did not reduce the risk of death and ESRD events. Significant cardiovascular events and CHF had to halt the trail in the BM side. Patient with hx of CHD and elevated BNP concentrations were at the highest risk. Why??- Stage IV CKD and albuminuria are a high risk group for CV disease. BEAM trial was smaller and CKD was more advanced. Why so prominent here and not in BEAM is unclear per Dr. Chertow. Number of lessons to be learned: CAUTION is always wise. In high risk population, vigilance might be needed in early phases of clinical trials.  We need to explore new and innovative ways to prevent ESRD. A good start nevertheless.

BEACON Trial : Bardoxolone … c’est fini ! N = 2185 Diabétiques DFGe 15-30 ml/min Bardoloxone vs Placebo Obj. I : IRCT / †CV Etude arrêtée pour ↑ EIG I Cardiaque Critère composite CV Bardoxolone Methyl (BM) is most potent for known activators of Nrf2 pathway that help decrease oxidative stress. A stage 2 study had showed a decrease in crt in CKD in DMII. AIM: Reduction of ESRD and cardiovascular death in CKD IV with this agent. This was a Phase 3 randomized controlled trial, multi center. Stage IV stable ACEI/ ARB and some exclusion criteria including severe HTN and poorly controlled DMII. Primary outcome was ESRD, and or cardiovascular death. 3 secondary outcomes: Change in eGFR, hospitalization for death and due to heart failure and composite heart and stroke risk. Mean eGFR was 22.5 ml/min in both groups. Majority of patients had albuminuria. Many patients had retinopathy, neuropathy in both sides. There were 70 outcomes in 69 patients in the BM group and 70 outcomes in 69 patients in placebo groups. No statistical difference in ESRD events and cardiovascular deaths.  Secondary outcomes significant hazard with BM group. More heart failure in BM arm that was significant. In conclusions, in DMII and CKD, BM did not reduce the risk of death and ESRD events. Significant cardiovascular events and CHF had to halt the trail in the BM side. Patient with hx of CHD and elevated BNP concentrations were at the highest risk. Why??- Stage IV CKD and albuminuria are a high risk group for CV disease. BEAM trial was smaller and CKD was more advanced. Why so prominent here and not in BEAM is unclear per Dr. Chertow. Number of lessons to be learned: CAUTION is always wise. In high risk population, vigilance might be needed in early phases of clinical trials.  We need to explore new and innovative ways to prevent ESRD. A good start nevertheless. De Zeeuw D et al. NEJM 2013

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