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Inclisiran, a small interfering RNA molecule, reduces low-density lipoprotein cholesterol (LDL-C) by inhibiting production of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the liver.To investigate the pharmacokinetics, pharmacodynamics, and safety of inclisiran in patients with mild or moderate hepatic impairment (HI) vs participants with normal hepatic function (NHF).In this single-center, open-label, parallel-group study, patients with mild (Child-Pugh A) or moderate (Child-Pugh B) HI and with NHF, matched by age, body mass index, sex, and race (if possible), received a single subcutaneous therapeutic dose of inclisiran (300 mg). Pharmacokinetic profiles, pharmacodynamic endpoints (PCSK9 and LDL-C), and safety were assessed.Twenty-eight participants completed the study (mild HI: n = 10; moderate HI: n = 6; NHF: n = 12). Inclisiran achieved maximum plasma concentration at 4-6 h and was undetectable in plasma at 48 h in most participants, irrespective of liver function. Inclisiran exposure was 1.24-fold higher in the mild HI vs NHF groups (90% confidence interval [CI] 1.01-1.53) and 2.03-fold higher in the moderate HI vs NHF groups (90% CI 1.60-2.58). LDL-C and PCSK9 plasma levels decreased from baseline up to the last assessment on Day 60 in all groups, with a similar response in NHF and mild HI groups but a less pronounced and more varied decrease in the moderate HI group. Inclisiran was generally safe and well tolerated.The pharmacokinetic exposure of inclisiran increased by up to two fold in patients with moderate HI compared with those with NHF, while pharmacodynamic effects remained relatively unchanged. Inclisiran is generally safe and well tolerated in patients with mild or moderate HI, with no dose adjustment needed. However, a larger, long-term clinical trial would help to further evaluate the long-term safety profile of inclisiran in patients with liver disease.

Acute kidney injury (AKI) is not uncommon in patients undergoing transcatheter aortic valve replacement (TAVR). We examined the incidence, predictors, and outcomes of AKI from the BRAVO 3 randomized trial. The BRAVO-3 trial included 802 patients undergoing transfemoral TAVR randomized to bivalirudin vs. unfractionated heparin (UFH). The primary endpoint of the trial was Bleeding Academic Research Consortium (BARC) type ≥ 3b bleeding at 48 h. Total follow-up was to 30 days. AKI was adjudicated using the modified RIFLE (Valve Academic Research Consortium, VARC 1) criteria through 30-day follow-up, and in a sensitivity analysis AKI was assessed at 7 days (modified VARC-2 criteria). We examined the incidence, predictors, and 30-day outcomes associated with diagnosis of AKI. We also examined the effect of procedural anticoagulant (bivalirudin or unfractionated heparin, UFH) on AKI within 48 h after TAVR. The trial population had a mean age of 82.3 ± 6.5 years including 48.8% women with mean EuroScore I 17.05 ± 10.3%. AKI occurred in 17.0% during 30-day follow-up and was associated with greater adjusted risk of 30-day death (13.0% vs. 3.5%, OR 5.84, 95% CI 2.62–12.99) and a trend for more BARC ≥ 3b bleeding (15.1% vs. 8.6%, OR 1.80, 95% CI 0.99–3.25). Predictors of 30-day AKI were baseline hemoglobin, body weight, and pre-existing coronary disease. AKI occurred in 10.7% at 7 days and was associated with significantly greater risk of 30-day death (OR 6.99, 95% CI 2.85–17.15). Independent predictors of AKI within 7 days included pre-existing coronary or cerebrovascular disease, chronic kidney disease (CKD), and transfusion which increased risk, whereas post-dilation was protective. The incidence of 48-h AKI was higher with bivalirudin compared to UFH in the intention to treat cohort (10.9% vs. 6.5%, p = 0.03), but not in the per-protocol assessment (10.7% vs. 7.1%, p = 0.08). In the BRAVO 3 trial, AKI occurred in 17% at 30 days and in 10.7% at 7 days. AKI was associated with a significantly greater adjusted risk for 30-day death. Multivariate predictors of AKI at 30 days included baseline hemoglobin, body weight, and prior coronary artery disease, and predictors at 7 days included pre-existing vascular disease, CKD, transfusion, and valve post-dilation. Bivalirudin was associated with greater AKI within 48 h in the intention to treat but not in the per-protocol analysis.

Aims Patients with diabetes (DM) and metabolic syndrome (MS) have elevated risks for atherosclerotic cardiovascular disease (ASCVD). Aggressive LDL-C lowering reduces risks. Inclisiran, a new siRNA, lowers LDL-C and was evaluated in patients with Type 2 diabetes (DM), metabolic syndrome (MS) without DM or neither (N) in the ORION-10 trial. Methods ORION-10 was a double-blind, randomized, placebo controlled trial evaluating inclisiran in 1561 patients with ASCVD on maximally tolerated therapy for lowering LDL-C. 781 inclisiran (INC) participants and 780 placebo (P) patients received 1.5 mL SQ tx at Days 1, 90, then every 6 months until Day 540. We evaluated the time adjusted change in LDL-C from baseline after Days 90–540 in DM (n = 702), MS (n = 455) and N participants (n = 404). Results There were no differences in baseline demographics and background therapies between INC and P. Statins were utilized in 89.8% INC and 88.7% of P. High intensity statins were utilized in 67.2% of INC and 68.8% of P; ezetimibe in 10.2% of NC and 9.5% of P participants. INC reduced LDL-C by − 54.4% (−58.3, −50.6 95% CI) in DM, (P Conclusions Inclisiran potently and durably reduces LDL-C across patients with DM, MS and those with neither, demonstrating potent efficacy and durability across glycaemic categories. Inclisiran may also represent a potent LDL-C lowering treatment for those with DM and MS.

Background: Inclisiran is a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin–kexin type 9 (PCSK9) translation in the liver, leading to sustained reductions in low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins with twice-yearly dosing. Objectives: The purpose of this study was to conduct a patient-level pooled analysis from 3 phase 3 studies of inclisiran. Methods: Participants with heterozygous familial hypercholesterolemia (ORION-9 [Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)]), atherosclerotic cardiovascular disease (ASCVD) (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]), or ASCVD and ASCVD risk equivalents (ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]) taking maximally tolerated statin therapy, with or without other LDL-C–lowering agents, were randomly assigned in a 1:1 ratio to receive either inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter for 540 days. The coprimary endpoints were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 to day 540. Levels of other atherogenic lipoproteins and treatment-emergent adverse events were also assessed. Results: A total of 3,660 participants (n = 482, n = 1,561, and n = 1,617 from ORION-9, -10, and -11, respectively) underwent randomization. The placebo-corrected change in LDL-C with inclisiran at day 510 was −50.7% (95% confidence interval: −52.9% to −48.4%; p < 0.0001). The corresponding time-adjusted change in LDL-C was −50.5% (95% confidence interval: −52.1% to −48.9%; p < 0.0001). Safety was similar in both groups. Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups. Conclusions: These pooled safety and efficacy data show that inclisiran, given twice yearly in addition to maximally tolerated statin therapy with or without other LDL-C lowering agents, is an effective, safe, and well-tolerated treatment to lower LDL-C in adults with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk equivalents.

Introduction: Despite a later onset in life than males, ASCVD is the leading cause of death in females, additionally mortality is higher compared to males. Disparities in the diagnosis and treatment of CVD risk factors may contribute to this difference. Inclisiran is a novel siRNA that inhibits PCSK9 synthesis and lowers LDL-C. Three Phase III placebo-controlled trials evaluated efficacy and safety of inclisiran in patients with HeFH (ORION-9), ASCVD (ORION-10, -11) and ASCVD risk equivalents (ORION-11). Objective: To assess the impact of sex on the efficacy and safety profile of inclisiran. Methods: Patients from each trial were categorized by sex. The co-primary endpoints were percentage change in LDL-C from baseline to Day 510 and time-adjusted percentage change in LDL-C from baseline after Day 90 up to Day 540. Secondary efficacy and safety parameters were assessed over 18 months. Results: Of a total 3660 patients, 1190 (32.5%) were females and 2470 (67.5%) were males. At baseline, females were less likely to receive statins [high-intensity statins] (90% [70%] vs 93% [76%]), or have ASCVD (73.6% vs 90.3%), were more likely to have ASCVD-risk equivalent (26.4% vs 9.7%) vs males. The efficacy of inclisiran vs placebo in both co-primary endpoints was similar in both sexes. Females had higher LDL-C at baseline (122.9 mg/dL vs 105.8 mg/dL) and (secondary endpoints) placebo-corrected mean absolute reduction in LDL-C at Day 510 (62.6 vs 54.0 mg/dL, P vs 51.5 mg/dL, P vs placebo for both sexes except for injection-site AEs that were higher in the inclisiran arm than placebo (females 9.4% vs 0.2%, males 2.8% vs 0.9%; Table). Conclusions: The efficacy and safety profile of inclisiran was generally similar in both sexes, except for more inclisiran injection-site AEs (mainly mild) vs placebo, which were more frequent in females.

Introduction: The risk of major atherosclerotic CV events increases with age, as do comorbidities, polypharmacy, and greater vulnerability to adverse drug reactions/events, posing challenges in the treatment of dyslipidemia. Three Phase III placebo-controlled trials evaluated the efficacy and safety of inclisiran according to age. Objective: To assess the efficacy and safety of inclisiran in patients across age categories. Methods: Patients were categorized according to age: Results: Of a total 3660 patients, 1737 [47.5%] were not old, 1431 [39.1%] were old, and 492 [13.4%] were very old. At baseline, the prevalence of comorbidities increased with age (not old, old, very old): stage 3 CKD (8.4%, 19.9%, 31.2%), hypertension (72.9%, 85.2%, 88.1%) and diabetes mellitus (32.2%, 40.0%, 38.0%), respectively. The placebo-corrected percentage change in LDL-C with inclisiran was similar across all ages: from baseline to Day 510 [–51.3% (not old), –49.9% (old), –51.0% (very old); P P 5x ULN were more frequently elevated in the not old category (Table). Conclusion: Inclisiran lowered LDL-C similarly across all ages with an acceptable safety profile. Inclisiran added to maximally tolerated statin therapy could be a safe option for older patients with ASCVD who need more intensive lipid-lowering treatment.

Background: Prior studies have suggested that patients with atrial fibrillation (AF) undergoing transcatheter aortic valve replacement (TAVR) are at higher risk for adverse cardiovascular events. Whether procedural bivalirudin compared to unfractionated heparin (UFH) has a beneficial effect on early outcomes in these patients is unknown. We examined for the effect of baseline or new-onset AF within 30 days of TAVR and explored for the effect of bivalirudin vs. UFH by AF status, on 30-day outcomes from the BRAVO 3 trial. Methods: The BRAVO-3 trial multicenter randomized trial included 802 patients undergoing transfemoral TAVR randomized to bivalirudin or UFH. We compared AF and no-AF groups and examined for 30-day Bleeding Academic Research Consortium (BARC) type ≥3b bleeding, major vascular complications and all ischemic endpoints. Adjusted outcomes were analyzed using logistic regression methods. Results: Of the study population, 41.4% (n=332) patients had baseline or new-onset AF within 30 days of TAVR, whereas 58.6% (n= 470) had no AF. Patients with AF had greater prevalence of renal dysfunction, lower left ventricular ejection fraction and higher euroSCORE I compared to their counterparts without AF. Among AF and no-AF patients, there were no significant baseline differences between bivalirudin and UFH groups. At 30 days the incidence of death (6.0% vs. 4.5%, p = 0.324) and stroke (3.9% vs. 2.6%, p = 0.274) was similar in AF vs. no-AF patients. However, new-onset AF (n=38) was associated with significantly greater crude risk of 30-day stroke compared to no AF (HR 4.49, 95% CI 1.37-14.67). Regardless of AF status, there were no differences in 30-day death (p-int = 0.652) or stroke (p-int= 0.066) by anticoagulation type. Conclusions: Prior or new-onset AF within 30 days of transfemoral TAVR is noted in more than one-third of patients. Despite greater baseline comorbidities than non-AF patients, AF was not associated with greater risk of adjusted 30-day outcomes. In the BRAVO 3 trial, early outcomes were similar regardless of anticoagulant strategy in each group. This article is protected by copyright. All rights reserved.

Acute kidney injury (AKI) is not uncommon in patients undergoing transcatheter aortic valve replacement (TAVR).We examined the incidence, predictors, and outcomes of AKI from the BRAVO 3 randomized trial.The BRAVO-3 trial included 802 patients undergoing transfemoral TAVR randomized to bivalirudin vs. unfractionated heparin (UFH). The primary endpoint of the trial was Bleeding Academic Research Consortium (BARC) type ≥ 3b bleeding at 48 h. Total follow-up was to 30 days. AKI was adjudicated using the modified RIFLE (Valve Academic Research Consortium, VARC 1) criteria through 30-day follow-up, and in a sensitivity analysis AKI was assessed at 7 days (modified VARC-2 criteria). We examined the incidence, predictors, and 30-day outcomes associated with diagnosis of AKI. We also examined the effect of procedural anticoagulant (bivalirudin or unfractionated heparin, UFH) on AKI within 48 h after TAVR.The trial population had a mean age of 82.3 ± 6.5 years including 48.8% women with mean EuroScore I 17.05 ± 10.3%. AKI occurred in 17.0% during 30-day follow-up and was associated with greater adjusted risk of 30-day death (13.0% vs. 3.5%, OR 5.84, 95% CI 2.62-12.99) and a trend for more BARC ≥ 3b bleeding (15.1% vs. 8.6%, OR 1.80, 95% CI 0.99-3.25). Predictors of 30-day AKI were baseline hemoglobin, body weight, and pre-existing coronary disease. AKI occurred in 10.7% at 7 days and was associated with significantly greater risk of 30-day death (OR 6.99, 95% CI 2.85-17.15). Independent predictors of AKI within 7 days included pre-existing coronary or cerebrovascular disease, chronic kidney disease (CKD), and transfusion which increased risk, whereas post-dilation was protective. The incidence of 48-h AKI was higher with bivalirudin compared to UFH in the intention to treat cohort (10.9% vs. 6.5%, p = 0.03), but not in the per-protocol assessment (10.7% vs. 7.1%, p = 0.08).In the BRAVO 3 trial, AKI occurred in 17% at 30 days and in 10.7% at 7 days. AKI was associated with a significantly greater adjusted risk for 30-day death. Multivariate predictors of AKI at 30 days included baseline hemoglobin, body weight, and prior coronary artery disease, and predictors at 7 days included pre-existing vascular disease, CKD, transfusion, and valve post-dilation. Bivalirudin was associated with greater AKI within 48 h in the intention to treat but not in the per-protocol analysis.

Background/Objective: Prostar XL (PS) and ProGlide (PG) are common vascular closure devices (VCD) used in TAVR via transfemoral vascular approach. The impact of these VCD on vascular and bleeding complications remains unclear. Methods: The BRAVO-3 trial randomized 802 patients undergoing transfemoral TAVR. We stratified patients according to type of VCD used and examined the 30-day incidence of major or minor vascular complications, major bleeding (BARC ≥3b), AKI and major adverse cardiac and cerebrovascular events (MACCE; death, myocardial infarction or stroke). Results: A total of 746 (93%) patients were treated with either PS (n = 352, 47%) or PG (n = 394, 53%) VCD, without significant differences in successful deployment rate (PS 322 [91.2%] vs. PG 373 [94.2%] respectively, p =.20). PG was associated with a significantly lower incidence of major or minor vascular complications, compared to PS (adjusted OR: 0.54; 95% CI: 0.37–0.80; p

Patients with diabetes (DM) and metabolic syndrome (MS) have elevated risks for atherosclerotic cardiovascular disease. Aggressive LDL-C lowering reduces risks. Inclisiran, a new siRNA, lowers LDL-C and was evaluated in patients with type 2 diabetes (DM), metabolic syndrome (MS) without DM or

Lipid lowering therapies (LLT) increase PCSK9. Inclisiran reduces hepatic PCSK9 synthesis and LDL-C. The effect of inclisiran on LDL-C by background LLT status is unknown. ORION-11 randomized 1617 subjects with stable ASCVD or ASCVD-risk equivalent and elevated LDL-C despite maximum tolerated

Lowering PCSK9 with monoclonal antibodies reduces LDL-C and cardiovascular events. Inclisiran, a small interfering RNA (siRNA) targeting hepatic PCSK9 synthesis reduced LDL-C by over 50% in the ORION 11 trial. Whether this approach might reduce cardiovascular events is unknown. ORION-11 was a Phase

BACKGROUND Anticoagulation is required during transcatheter aortic valve replacement (TAVR) procedures. Although an optimal regimen has not been determined, heparin is mainly used. Direct thrombin inhibition with bivalirudin may be an effective alternative to heparin as the procedural anticoagulant agent in this setting. OBJECTIVES The goal of this study was to determine whether bivalirudin offers an alternative to heparin as the procedural anticoagulant agent in patients undergoing TAVR. METHODS A total of 802 patients with aortic stenosis were randomized to undergo transfemoral TAVR with bivalirudin versus unfractionated heparin during the procedure. The 2 primary endpoints were major bleeding within 48 h or before hospital discharge (whichever occurred first) and 30-day net adverse clinical events, defined as the combination of major adverse cardiovascular events (all-cause mortality, myocardial infarction, or stroke) and major bleeding. RESULTS Anticoagulation with bivalirudin versus heparin did not meet superiority because it did not result in significantly lower rates of major bleeding at 48 h (6.9% vs. 9.0%; relative risk: 0.77; 95% confidence interval [CI]: 0.48 to 1.23; p = 0.27) or net adverse cardiovascular events at 30 days (14.4% vs. 16.1%; relative risk: 0.89; 95% CI: 0.64 to 1.24; risk difference: -1.72; 95% CI: -6.70 to 3.25; p = 0.50); regarding the latter, the prespecified noninferiority hypothesis was met (pnoninferiority < 0.01). Rates of major adverse cardiovascular events at 48 h were not significantly different (3.5% vs. 4.8%; relative risk: 0.73; 95% CI: 0.37 to 1.43; p = 0.35). At 48 h, the bivalirudin group had significantly fewer myocardial infarctions but more acute kidney injury events than the heparin group; at 30 days, these differences were no longer significant. CONCLUSIONS In this randomized trial of TAVR procedural pharmacotherapy, bivalirudin did not reduce rates of major bleeding at 48 h or net adverse cardiovascular events within 30 days compared with heparin. Although superiority was not shown, the noninferiority hypothesis was met with respect to the latter factor. Given the lower cost, heparin should remain the standard of care, and bivalirudin can be an alternative anticoagulant option in patients unable to receive heparin in TAVR. (International, Multi-center, Open-label, Randomized Controlled Trial in Patients Undergoing TAVR to Determine the Treatment Effect [Both Safety and Efficacy] of Using Bivalirudin Instead of UFH [BRAVO-2/3]; NCT01651780).

Cangrelor is an intravenous P2Y12 inhibitor under investigation as an antiplatelet drug in the setting of acute coronary syndromes. To determine the electrophysiologic safety of parenteral cangrelor, cardiac repolarization effects were measured in 67 healthy volunteers (aged 18-45 years) in a randomized crossover design, including 4 treatment sequences of therapeutic cangrelor, supratherapeutic cangrelor, placebo, and moxifloxacin (positive control). Triplicate electrocardiogram measurements and pharmacokinetic samples were collected at baseline and 9 time points postdose on day 1. For both cangrelor and moxifloxacin, time-matched, placebo-adjusted change in QT from baseline was evaluated using an individual (QTcI) heart rate correction. After cangrelor dosing, change in QTcI was5 ms at all times points and all corresponding upper 2-sided 90% confidence intervals (CIs) were10 ms. Although moxifloxacin failed to show a lower CI5 ms, expected time trends and lower CI4.0 ms demonstrate assay sensitivity. QTcI was not affected by plasma concentrations of cangrelor metabolites, and cangrelor had no other adverse effects on electrocardiographic parameters. Clinically, cangrelor exposure was well tolerated. Thus, this thorough QT study demonstrated that therapeutic and supratherapeutic cangrelor doses do not adversely affect cardiac repolarization in normal volunteers (clinicaltrials.gov; identifier NCT00699504).

Email is standard way of communication in our daily life and in projects. But email traffic becomes more and more cumbersome. More than 25 percent of a working day is spend on email related tasks. Email is misused, and can create crisis in project teams. Nowadays the current generation of project team members is more used to using social media and social collaboration to communicate. To take advantage of that and to limit the use of email, the Zero email program was introduced within Atos. Limiting the use of emails with project teams can be achieved by introducing the right set of tools, a thorough management of change program, using early adaptors, starting small and acting – as a project manager – as a good example. Completely get rid of all email is still not possible; only when all parties are working with the same social media and collaboration tooling, a 80% result can be achieved. But in the current global world of project management with all its different stakeholders and parties, there is still a long way to go.

Maintenance immunosuppression with cyclosporine (CsA) is associated with nephrotoxicity, hyperlipidemia, and hypertension. This long-term study (core study + 4 yr of follow-up) investigated the long-term efficacy and safety of CsA withdrawal from a mycophenolate mofetil (MMF)-based regimen. Seventy-seven patients were maintained on CsA, MMF, and steroids (CsA-MMF group), and 74 were given a CsA-free regimen of MMF and steroids (MMF group). Serum creatinine and creatinine clearance were measured at 6-month intervals. Patient and graft survival, acute rejection episodes, malignancies, BP, and lipid profile were also recorded. At 5 yr, patient and graft survival was 93 and 88%, respectively, for the MMF group and 95 and 92%, respectively, for the CsA-MMF group. During follow-up, seven MMF patients experienced acute rejection episodes compared with one CsA-MMF patient (P = 0.0283). Nine grafts were lost to chronic rejection in the MMF group versus three in the CsA-MMF group. No demographic or immunologic characteristics were associated with acute or chronic rejection in the MMF group, but the doses of both MMF and steroids decreased significantly between 1 and 5 yr. The MMF group showed a trend toward improved creatinine clearance (67.4 versus 61.7 ml/min; P = 0.0500). Withdrawal of CsA from an MMF-containing immunosuppressive regimen resulted in an increased risk for acute rejection episodes and graft loss as a result of rejection throughout the 5-yr study period. The creatinine clearance-confirmed improvement in renal function observed at year 1 was maintained at 5 yr BP and cholesterol levels were well controlled in both groups.

Background. This study determined whether cyclosporine A (CsA)-treated renal allograft recipients with deteriorating renal function (“creeping creatinine”) secondary to chronic allograft nephropathy (CAN) benefit from the addition of mycophenolate mofetil (MMF) to their immunosuppressive regimen, followed by withdrawal of CsA. Methods. In a controlled, open, multicenter study, CsA-treated renal allograft recipients with progressively deteriorating renal function were randomized to have their CsA discontinued with the concomitant addition of MMF to their regimen (group A) or to continue treatment with CsA (group B). The primary endpoint was the response rate over the 6-month period after withdrawal of CsA in group A or the equivalent time in group B. Response was defined as a stabilization or reduction of serum creatinine (SCr), as evidenced by a flattening or positive slope of the 1/SCr plot and no graft loss. Secondary endpoints included the incidence of acute rejection, graft and patient survival, and changes in selected metabolic parameters. Results. The response rate in the primary intent-to-treat population (n=122) was 58% (36/62) in group A versus 32% (19/60) in group B (P=0.0060). The corresponding percentages of responders in the per-protocol population (n=107) were 60% (36/60) and 26% (12/47), respectively (P=0.0008). There were no acute rejections in group A during the study period. Patients in this group also experienced a significant decrease in total cholesterol. Conclusions. In patients with progressively deteriorating renal function secondary to CAN, addition of MMF followed by withdrawal of CsA results in a significant improvement in transplant function without the risk of acute rejection.

Background Long-term maintenance immunosuppression with cyclosporine (CsA) is associated with chronic transplant nephropathy and adverse effects on blood pressure and lipid profile. Several nonrandomized studies suggest that CsA might safely be withdrawn from immunosuppressive regimens containing mycophenolate mofetil (MMF; CellCept). Methods A randomized, controlled study with 187 patients enrolled from 21 centers was conducted to compare CsA withdrawal with ongoing CsA therapy in stable renal transplant recipients receiving a triple-drug immunosuppressive regimen of MMF (2 g/day), CsA (Neoral), and corticosteroids. The primary endpoint was creatinine clearance at 6 months after complete withdrawal. Results In the intent-to-treat population, CsA withdrawal was associated with lower total cholesterol and low-density lipoprotein cholesterol (-0.3 mmol/L, P=0.02; -0.4 mmol/L, P=0.015). There was a trend toward improved creatinine clearance (4.5 mL/min, P=0.16) and serum creatinine (-1 vs. +4 micromol/L, P=0.34). In the per-protocol population, which excluded patients with acute rejections, the improvements in creatinine clearance and serum creatinine were statistically significant (7.5 mL/min, P=0.02; -11 vs. +4 micromol/L, P=0.0003). Reversible acute rejections, the majority of which were mild, occurred in nine CsA withdrawal versus two CsA continuation patients (10.6% vs. 2.4% of each group, P=0.03), with no graft loss. Conclusion Withdrawal of CsA from an MMF-containing triple-drug immunosuppressive regimen improves renal function and lipid profile at the cost of a modest increase in acute rejections, without graft loss.

This study determined whether cyclosporine A (CsA)-treated renal allograft recipients with deteriorating renal function ("creeping creatinine") secondary to chronic allograft nephropathy (CAN) benefit from the addition of mycophenolate mofetil (MMF) to their immunosuppressive regimen, followed by withdrawal of CsA.In a controlled, open, multicenter study, CsA-treated renal allograft recipients with progressively deteriorating renal function were randomized to have their CsA discontinued with the concomitant addition of MMF to their regimen (group A) or to continue treatment with CsA (group B). The primary endpoint was the response rate over the 6-month period after withdrawal of CsA in group A or the equivalent time in group B. Response was defined as a stabilization or reduction of serum creatinine (SCr), as evidenced by a flattening or positive slope of the 1/SCr plot and no graft loss. Secondary endpoints included the incidence of acute rejection, graft and patient survival, and changes in selected metabolic parameters.The response rate in the primary intent-to-treat population (n=122) was 58% (36/62) in group A versus 32% (19/60) in group B (P=0.0060). The corresponding percentages of responders in the per-protocol population (n=107) were 60% (36/60) and 26% (12/47), respectively (P=0.0008). There were no acute rejections in group A during the study period. Patients in this group also experienced a significant decrease in total cholesterol.In patients with progressively deteriorating renal function secondary to CAN, addition of MMF followed by withdrawal of CsA results in a significant improvement in transplant function without the risk of acute rejection.

Long-term maintenance immunosuppression with cyclosporine (CsA) is associated with chronic transplant nephropathy and adverse effects on blood pressure and lipid profile. Several nonrandomized studies suggest that CsA might safely be withdrawn from immunosuppressive regimens containing mycophenolate mofetil (MMF; CellCept).A randomized, controlled study with 187 patients enrolled from 21 centers was conducted to compare CsA withdrawal with ongoing CsA therapy in stable renal transplant recipients receiving a triple-drug immunosuppressive regimen of MMF (2 g/day), CsA (Neoral), and corticosteroids. The primary endpoint was creatinine clearance at 6 months after complete withdrawal.In the intent-to-treat population, CsA withdrawal was associated with lower total cholesterol and low-density lipoprotein cholesterol (-0.3 mmol/L, P=0.02; -0.4 mmol/L, P=0.015). There was a trend toward improved creatinine clearance (4.5 mL/min, P=0.16) and serum creatinine (-1 vs. +4 micromol/L, P=0.34). In the per-protocol population, which excluded patients with acute rejections, the improvements in creatinine clearance and serum creatinine were statistically significant (7.5 mL/min, P=0.02; -11 vs. +4 micromol/L, P=0.0003). Reversible acute rejections, the majority of which were mild, occurred in nine CsA withdrawal versus two CsA continuation patients (10.6% vs. 2.4% of each group, P=0.03), with no graft loss.Withdrawal of CsA from an MMF-containing triple-drug immunosuppressive regimen improves renal function and lipid profile at the cost of a modest increase in acute rejections, without graft loss.