Martin J. Landray

The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection) : a randomised placebo-controlled trial

Summary Background Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. Methods This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607. Findings 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11·3%] simvastatin plus ezetimibe vs 619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74–0·94; log-rank p=0·0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6%] vs 230 [5·0%]; RR 0·92, 95% CI 0·76–1·11; p=0·37) and there were significant reductions in non-haemorrhagic stroke (131 [2·8%] vs 174 [3·8%]; RR 0·75, 95% CI 0·60–0·94; p=0·01) and arterial revascularisation procedures (284 [6·1%] vs 352 [7·6%]; RR 0·79, 95% CI 0·68–0·93; p=0·0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0·2%] vs 5 [0·1%]). There was no evidence of excess risks of hepatitis (21 [0·5%] vs 18 [0·4%]), gallstones (106 [2·3%] vs 106 [2·3%]), or cancer (438 [9·4%] vs 439 [9·5%], p=0·89) and there was no significant excess of death from any non-vascular cause (668 [14·4%] vs 612 [13·2%], p=0·13). Interpretation Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease. Funding Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.

HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment.

Aims Niacin has potentially favourable effects on lipids, but its effect on cardiovascular outcomes is uncertain. HPS2-THRIVE is a large randomized trial assessing the effects of extended release (ER) niacin in patients at high risk of vascular events. Methods and results Prior to randomization, 42 424 patients with occlusive arterial disease were given simvastatin 40 mg plus, if required, ezetimibe 10 mg daily to standardize their low-density lipoprotein (LDL)-lowering therapy. The ability to remain compliant with ER niacin 2 g plus laropiprant 40 mg daily (ERN/LRPT) for ∼1 month was then assessed in 38 369 patients and about one-third were excluded (mainly due to niacin side effects). A total of 25 673 patients were randomized between ERN/LRPT daily vs. placebo and were followed for a median of 3.9 years. By the end of the study, 25% of participants allocated ERN/LRPT vs. 17% allocated placebo had stopped their study treatment. The most common medical reasons for stopping ERN/LRPT were related to skin, gastrointestinal, diabetes, and musculoskeletal side effects. When added to statin-based LDL-lowering therapy, allocation to ERN/LRPT increased the risk of definite myopathy [75 (0.16%/year) vs. 17 (0.04%/year): risk ratio 4.4; 95% CI 2.6–7.5; P < 0.0001]; 7 vs. 5 were rhabdomyolysis. Any myopathy (definite or incipient) was more common among participants in China [138 (0.66%/year) vs. 27 (0.13%/year)] than among those in Europe [17 (0.07%/year) vs. 11 (0.04%/year)]. Consecutive alanine transaminase >3× upper limit of normal, in the absence of muscle damage, was seen in 48 (0.10%/year) ERN/LRPT vs. 30 (0.06%/year) placebo allocated participants. Conclusion The risk of myopathy was increased by adding ERN/LRPT to simvastatin 40 mg daily (with or without ezetimibe), particularly in Chinese patients whose myopathy rates on simvastatin were higher. Despite the side effects of ERN/LRPT, among individuals who were able to tolerate it for ∼1 month, three-quarters continued to take it for ∼4 years.

Analyses of cancer data from three ezetimibe trials.

BACKGROUND Five years of statin therapy lowers low-density lipoprotein (LDL) cholesterol substantially and, over a 5-year period, results in reductions in the incidence of cardiovascular events. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (ClinicalTrials.gov number, NCT00092677) has raised the hypothesis that adding ezetimibe to statin therapy for larger LDL cholesterol reductions might increase the incidence of cancer. METHODS We compared the results of a hypothesis-generating analysis of the incidence of cancer in the SEAS trial of ezetimibe plus simvastatin in 1873 patients (mean follow-up after ezetimibe or matching placebo was begun, 4.1 years) with a hypothesis-testing analysis of cancer data from the two large ongoing trials of this regimen: the Study of Heart and Renal Protection (SHARP) (NCT00125593) with 9264 patients (mean follow-up, 2.7 years) and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (NCT00202878), currently with 11,353 patients (mean follow-up, 1.0 year). RESULTS In the SEAS trial, assignment to ezetimibe was associated with an increase in any new onset of cancer (101 patients in the active-treatment group vs. 65 in the control group) from several cancer sites. In SHARP and IMPROVE-IT combined, there was no overall excess of cancer (313 active-treatment vs. 326 control; risk ratio, 0.96; 95% confidence interval, 0.82 to 1.12; P=0.61) and no significant excess at any particular site. Among patients assigned to ezetimibe, there were more, albeit not significantly more, deaths from cancer (97, vs. 72 in the control group; P=0.07), but there were also fewer, although not significantly fewer, other cases of cancer (216, vs. 254 in the control group; P=0.08). There was no evidence of a trend in the risk ratio for incidence of or death from cancer with increasing duration of follow-up. CONCLUSIONS The available results from these three trials do not provide credible evidence of any adverse effect of ezetimibe on rates of cancer. Follow-up of longer duration will permit the balance of risks and benefits to be determined more reliably.

Prediction of ESRD and Death Among People With CKD: The Chronic Renal Impairment in Birmingham (CRIB) Prospective Cohort Study

Background Validated prediction scores are required to assess the risks of end-stage renal disease (ESRD) and death in individuals with chronic kidney disease (CKD). Study Design Prospective cohort study with validation in a separate cohort. Setting & Participants Cox regression was used to assess the relevance of baseline characteristics to risk of ESRD (mean follow-up, 4.1 years) and death (mean follow-up, 6.0 years) in 382 patients with stages 3-5 CKD not initially on dialysis therapy in the Chronic Renal Impairment in Birmingham (CRIB) Study. Resultant risk prediction equations were tested in a separate cohort of 213 patients with CKD (the East Kent cohort). Factors 44 baseline characteristics (including 30 blood and urine assays). Outcomes ESRD and all-cause mortality. Results In the CRIB cohort, 190 patients reached ESRD (12.1%/y) and 150 died (6.5%/y). Each 30% lower baseline estimated glomerular filtration rate was associated with a 3-fold higher ESRD rate and a 1.3-fold higher death rate. After adjustment for each other, only baseline creatinine level, serum phosphate level, urinary albumin-creatinine ratio, and female sex remained strongly (P < 0.01) predictive of ESRD. For death, age, N-terminal pro-brain natriuretic peptide, troponin T level, and cigarette smoking remained strongly predictive of risk. Using these factors to predict outcomes in the East Kent cohort yielded an area under the receiver operating characteristic curve (ie, C statistic) of 0.91 (95% CI, 0.87-0.96) for ESRD and 0.82 (95% CI, 0.75-0.89) for death. Limitations Other important factors may have been missed because of limited study power. Conclusions Simple laboratory measures of kidney and cardiac function plus age, sex, and smoking history can be used to help identify patients with CKD at highest risk of ESRD and death. Larger cohort studies are required to further validate these results.

Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial.

BACKGROUND Calcineurin inhibitors (CNIs) reduce short-term kidney transplant failure, but might contribute to transplant failure in the long-term. The role of alemtuzumab (a potent lymphocyte-depleting antibody) as an induction treatment followed by an early reduction in CNI and mycophenolate exposure and steroid avoidance, after kidney transplantation is uncertain. We aimed to assess the efficacy and safety of alemtuzumab-based induction treatment compared with basiliximab-based induction treatment in patients receiving kidney transplants. METHODS For this randomised trial, we enrolled patients aged 18 years and older who were scheduled to receive a kidney transplant in the next 24 h from 18 transplant centres in the UK. Using minimised randomisation, we randomly assigned patients (1:1; minimised for age, sex, and immunological risk) to either alemtuzumab-based induction treatment (ie, alemtuzumab followed by low-dose tacrolimus and mycophenolate without steroids) or basiliximab-based induction treatment (basiliximab followed by standard-dose tacrolimus, mycophenolate, and prednisolone). Participants were reviewed at discharge from hospital and at 1, 3, 6, 9, and 12 months after transplantation. The primary outcome was biopsy-proven acute rejection at 6 months, analysed by intention to treat. The study is registered at ClinicalTrials.gov, number NCT01120028, and isrctn.org, number ISRCTN88894088. FINDINGS Between Oct 4, 2010, and Jan 21, 2013, we randomly assigned 852 participants to treatment: 426 to alemtuzumab-based treatment and 426 to basiliximab-based treatment. Overall, individuals allocated to alemtuzumab-based treatment had a 58% proportional reduction in biopsy-proven acute rejection compared with those allocated to basiliximab-based treatment (31 [7%] patients in the alemtuzumab group vs 68 [16%] patients in the basiliximab group; hazard ratio (HR) 0·42, 95% CI 0·28-0·64; log-rank p<0·0001). We detected no between-group difference in treatment effect on transplant failure during the first 6 months (16 [4%] patients vs 13 [3%] patients; HR 1·23, 0·59-2·55; p=0·58) or serious infection (135 [32%] patients vs 136 [32%] patients; HR 1·02, 0·80-1·29; p=0·88). During the first 6 months after transplantation, 11 (3%) patients given alemtuzumab-based treatment and six (1%) patients given basiliximab-based treatment died (HR 1·79, 95% CI 0·66-4·83; p=0·25). INTERPRETATION Compared with standard basiliximab-based treatment, alemtuzumab-based induction therapy followed by reduced CNI and mycophenolate exposure and steroid avoidance reduced the risk of biopsy-proven acute rejection in a broad range of patients receiving a kidney transplant. Long-term follow-up of this trial will assess whether these effects translate into differences in long-term transplant function and survival. FUNDING UK National Health Service Blood and Transplant Research and Development Programme, Pfizer, and Novartis UK.

Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials

BACKGROUND Statin therapy is effective for the prevention of coronary heart disease and stroke in patients with mild-to-moderate chronic kidney disease, but its effects in individuals with more advanced disease, particularly those undergoing dialysis, are uncertain. METHODS We did a meta-analysis of individual participant data from 28 trials (n=183 419), examining effects of statin-based therapy on major vascular events (major coronary event [non-fatal myocardial infarction or coronary death], stroke, or coronary revascularisation) and cause-specific mortality. Participants were subdivided into categories of estimated glomerular filtration rate (eGFR) at baseline. Treatment effects were estimated with rate ratio (RR) per mmol/L reduction in LDL cholesterol. FINDINGS Overall, statin-based therapy reduced the risk of a first major vascular event by 21% (RR 0·79, 95% CI 0·77-0·81; p<0·0001) per mmol/L reduction in LDL cholesterol. Smaller relative effects on major vascular events were observed as eGFR declined (p=0·008 for trend; RR 0·78, 99% CI 0·75-0·82 for eGFR ≥60 mL/min per 1·73 m(2); 0·76, 0·70-0·81 for eGFR 45 to <60 mL/min per 1·73 m(2); 0·85, 0·75-0·96 for eGFR 30 to <45 mL/min per 1·73 m(2); 0·85, 0·71-1·02 for eGFR <30 mL/min per 1·73 m(2) and not on dialysis; and 0·94, 0·79-1·11 for patients on dialysis). Analogous trends by baseline renal function were seen for major coronary events (p=0·01 for trend) and vascular mortality (p=0·03 for trend), but there was no significant trend for coronary revascularisation (p=0·90). Reducing LDL cholesterol with statin-based therapy had no effect on non-vascular mortality, irrespective of eGFR. INTERPRETATION Even after allowing for the smaller reductions in LDL cholesterol achieved by patients with more advanced chronic kidney disease, and for differences in outcome definitions between dialysis trials, the relative reductions in major vascular events observed with statin-based treatment became smaller as eGFR declined, with little evidence of benefit in patients on dialysis. In patients with chronic kidney disease, statin-based regimens should be chosen to maximise the absolute reduction in LDL cholesterol to achieve the largest treatment benefits. FUNDING UK Medical Research Council, British Heart Foundation, Cancer Research UK, European Community Biomed Programme, Australian National Health and Medical Research Council, Australian National Heart Foundation.

Estimated Glomerular Filtration Rate and the Risk of Major Vascular Events and All-Cause Mortality: A Meta-Analysis

Background Lower estimated glomerular filtration rate (eGFR) has been associated with an increased risk of major vascular events (MVEs) and death, but differences in methodology make between-study comparisons difficult. We used a novel method to summarise the published results. Methods and Findings Studies assessing the relationship between baseline eGFR and subsequent MVEs or all cause mortality were identified using Pubmed. Those which involved at least 500 individuals, planned at least 1 year of follow-up, reported age and sex adjusted relative risks, and provided the mean eGFR in each category (or sufficient information to allow its estimation) were included. To take account of differences in underlying risk between studies, proportional within-study differences in eGFR (rather than absolute eGFR values) were related to risk. Fifty studies (2 million participants) assessing MVEs and 67 studies (5 million participants) assessing all cause mortality were eligible. There was an inverse relationship between lower eGFR and the risk of MVEs and of death. In studies among people without prior vascular disease, a 30% lower eGFR level was on average associated with a 29% (SE 0.2%) increase in the risk of a MVE and a 31% (SE 0.2%) increase in the risk of death from any cause. In studies among people with prior vascular disease, these estimates were 26% (SE 1.0%) and 23% (SE 0.2%) respectively. While there was substantial statistical heterogeneity between the results of individual studies, a 30% lower eGFR was consistently associated with a 20-30% higher risk of both outcomes, irrespective of prior history of vascular disease or study design. Conclusions Lower eGFR was consistently associated with a moderate increase in the risk of death and MVEs. If these relationships are causal and continuous, then around one fifth of vascular events among those over 70 years might be attributable to renal impairment.

Cross-sectional analysis of abnormalities of mineral homeostasis, vitamin D and parathyroid hormone in a cohort of pre-dialysis patients. The chronic renal impairment in Birmingham (CRIB) study.

Background: Disturbances in mineral and vitamin D metabolism, which affect parathyroid hormone (PTH) synthesis, are well recognized in patients receiving dialysis. However, it is unclear at what stage of chronic kidney disease (CKD) these abnormalities develop. Methods: The associations between CKD stages 3 and 5, and alterations of calcium, phosphate, vitamin D and PTH concentrations were assessed in 249 patients (mean age 61 years, 66% male) and 79 age- and sex-matched healthy controls. Results: As compared to controls, serum phosphate concentrations were elevated among CKD patients (1.40 vs. 1.11 mmol/l; p < 0.0001). And levels of both 25-hydroxyvitamin D (42.1 vs. 60.4 nmol/l; p < 0.0001) and 1,25-dihydroxyvitamin D (58.2 vs. 119.5 pmol/l; p < 0.0001) were lower among patients with CKD, even among those with only stage 3 CKD and despite 73% of patients receiving vitamin D supplements. The ratio of 1,25-dihydroxy- to 25-hydroxyvitamin D was lower than controls, even among patients with stage 3 CKD (p = 0.0001), and this ratio diminished with advancing renal impairment. Concomitant elevations were observed in intact PTH (13.8 vs. 4.2 pmol/l; p < 0.0001) and whole PTH (7.9 vs. 2.7 pmol/l; p < 0.0001). Conclusion: Impaired conversion of 25-hydroxy- to 1,25-dihydroxyvitamin D is an early feature of renal disease, and progresses as renal function deteriorates.

Neprilysin inhibition in chronic kidney disease

Despite current practice, patients with chronic kidney disease (CKD) are at increased risk of progression to end-stage renal disease and cardiovascular events. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. NEPi enhances the activity of natriuretic peptide systems leading to natriuresis, diuresis and inhibition of the renin–angiotensin system (RAS), which could act as a potentially beneficial counter-regulatory system in states of RAS activation such as chronic heart failure (HF) and CKD. Early NEPi drugs were combined with angiotensin-converting enzyme inhibitors but were associated with unacceptable rates of angioedema and, therefore, withdrawn. However, one such agent (omapatrilat) showed promise of NEP/RAS inhibition in treating CKD in animal models, producing greater reductions in proteinuria, glomerulosclerosis and tubulointerstitial fibrosis compared with isolated RAS inhibition. A new class of drug called angiotensin receptor neprilysin inhibitor (ARNi) has been developed. One such drug, LCZ696, has shown substantial benefits in trials in hypertension and HF. In CKD, HF is common due to a range of mechanisms including hypertension and structural heart disease (including left ventricular hypertrophy), suggesting that ARNi could benefit patients with CKD by both retarding the progression of CKD (hence delaying the need for renal replacement therapy) and reducing the risk of cardiovascular disease. LCZ696 is now being studied in a CKD population.

Serum Free Light Chains and the Risk of ESRD and Death in CKD

BACKGROUND AND OBJECTIVES Associations between inflammation and ESRD and death in chronic kidney disease are well established. However, the potential role of the adaptive immune system is uncertain. We aimed to prospectively study the relevance of the adaptive immune system to ESRD and mortality by measuring monoclonal and polyclonal excesses of highly sensitive serum free light chains (sFLCs). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Three hundred sixty-four patients selected from a nephrology outpatient clinic had kappa and lambda sFLCs concentrations and serum immunofixation electrophoresis measured. Cox regression was used to assess the relevance of monoclonal and polyclonal excess of sFLCs to the incidence of ESRD and death (mean follow-up for death 6.0 years). RESULTS After adjustment for baseline eGFR, there was no significant association between monoclonal excess of sFLCs and risk of ESRD or mortality. Baseline log κ and log λ concentrations were positively associated with ESRD risk, but these associations seemed to be due to correlations with eGFR (per 1 SD higher concentration: adjusted hazard ratio 1.05 [95% confidence interval 0.88 to 1.26] and 0.99 [0.83 to 1.19], respectively). For mortality, after adjustment for eGFR plus markers of cardiac damage, there was weak evidence of an association with λ, but not κ, sFLC concentration (fully adjusted hazard ratio 1.33 [95% confidence interval 1.05 to 1.67] per 1 SD higher concentration). CONCLUSIONS Associations between monoclonal and polyclonal excess of sFLCs and risk of ESRD are explained by the correlation between these measures and renal function. We found only weak evidence of an association between polyclonal excess of λ sFLC concentration and mortality.