Cost-effectiveness of Simvastatin plus Ezetimibe for Cardiovascular Prevention in CKD: Results of the Study of Heart and Renal Protection (SHARP).

BACKGROUND: Simvastatin, 20mg, plus ezetimibe, 10mg, daily (simvastatin plus ezetimibe) reduced major atherosclerotic events in patients with moderate to severe chronic kidney disease (CKD) in the Study of Heart and Renal Protection (SHARP), but its cost-effectiveness is unknown. STUDY DESIGN: Cost-effectiveness of simvastatin plus ezetimibe in SHARP, a randomized controlled trial. SETTING & POPULATION: 9,270 patients with CKD randomly assigned to simvastatin plus ezetimibe versus placebo; participants in categories by 5-year cardiovascular risk (low, <10%; medium, 10%-<20%; or high, ≥20%) and CKD stage (3, 4, 5 not on dialysis, or on dialysis therapy). MODEL, PERSPECTIVE, & TIMELINE: Assessment during SHARP follow-up from the UK perspective; long-term projections. INTERVENTION: Simvastatin plus ezetimibe (2015 UK £1.19 per day) during 4.9 years' median follow-up in SHARP; scenario analyses with high-intensity statin regimens (2015 UK £0.05-£1.06 per day). OUTCOMES: Additional health care costs per major atherosclerotic event avoided and per quality-adjusted life-year (QALY) gained. RESULTS: In SHARP, the proportional reductions per 1mmol/L of low-density lipoprotein (LDL) cholesterol reduction with simvastatin plus ezetimibe in all major atherosclerotic events of 20% (95% CI, 6%-32%) and in the costs of vascular hospital episodes of 17% (95% CI, 4%-28%) were similar across participant categories by cardiovascular risk and CKD stage. The 5-year reduction in major atherosclerotic events per 1,000 participants ranged from 10 in low-risk to 58 in high-risk patients and from 28 in CKD stage 3 to 36 in patients on dialysis therapy. The net cost per major atherosclerotic event avoided with simvastatin plus ezetimibe compared to no LDL-lowering regimen ranged from £157,060 in patients at low risk to £15,230 in those at high risk (£30,500-£39,600 per QALY); and from £47,280 in CKD stage 3 to £28,180 in patients on dialysis therapy (£13,000-£43,300 per QALY). In scenario analyses, generic high-intensity statin regimens were estimated to yield similar benefits at substantially lower cost. LIMITATIONS: High-intensity statin-alone regimens were not studied in SHARP. CONCLUSIONS: Simvastatin plus ezetimibe prevented atherosclerotic events in SHARP, but other less costly statin regimens are likely to be more cost-effective for reducing cardiovascular risk in CKD.

What is the impact of chronic kidney disease stage and cardiovascular disease on the annual cost of hospital care in moderate-to-severe kidney disease?

BACKGROUND: Reliable estimates of the impacts of chronic kidney disease (CKD) stage, with and without cardiovascular disease, on hospital costs are needed to inform health policy. METHODS: The Study of Heart and Renal Protection (SHARP) randomized trial prospectively collected information on kidney disease progression, serious adverse events and hospital care use in a cohort of patients with moderate-to-severe CKD. In a secondary analysis of SHARP data, the impact of participants' CKD stage, non-fatal cardiovascular events and deaths on annual hospital costs (i.e. all hospital admissions, routine dialysis treatments and recorded outpatient/day-case attendances in United Kingdom 2011 prices) were estimated using linear regression. RESULTS: 7,246 SHARP patients (2,498 on dialysis at baseline) from Europe, North America, and Australasia contributed 28,261 years of data. CKD patients without diabetes or vascular disease incurred annual hospital care costs ranging from £403 (95% confidence interval: 345-462) in CKD stages 1-3B to £525 (449-602) in CKD stage 5 (not on dialysis). Patients in receipt of maintenance dialysis incurred annual hospital costs of £18,986 (18,620-19,352) in the year of initiation and £23,326 (23,231-23,421) annually thereafter. Patients with a functioning kidney transplant incurred £24,602 (24,027-25,178) in hospital care costs in the year of transplantation and £1,148 (978-1,318) annually thereafter. Non-fatal major vascular events increased annual costs in the year of the event by £6,133 (5,608-6,658) for patients on dialysis and by £4,350 (3,819-4,880) for patients not on dialysis, and were associated with increased costs, though to a lesser extent, in subsequent years. CONCLUSIONS: Renal replacement therapy and major vascular events are the main contributors to the high hospital care costs in moderate-to-severe CKD. These estimates of hospital costs can be used to inform health policy in moderate-to-severe CKD.

Genetic variation I148M in patatin-like phospholipase 3 gene and risk of non-alcoholic fatty liver disease among Filipinos.

Genome-wide association studies have shown that a non-synonymous single nucleotide polymorphism characterized by a C-to-G change encoding an isoleucine-to-methionine substitution at amino acid position 148 in the human patatin-like phospholipase 3 (PNPLA3) gene was found to be associated with non-alcoholic fatty liver disease (NAFLD) and advanced liver damage. A hospital-based study was conducted to determine the distribution of PNPLA3 genotypes among patients clinically diagnosed and histologically confirmed with NAFLD and among normal controls. We also compared the allelic frequencies of PNPLA3 with different ethnic populations. More importantly, we evaluated the association between PNPLA3 genetic variation and risk of developing NAFLD among Filipinos. Real-time PCR was performed using the Taqman SNP genotyping assay for rs738409. Nucleotide sequencing was performed to confirm the PNPLA3 genotypes. Allelic frequencies among normal controls were 0.83 and 0.17 for the PNPLA3 C and PNPLA3 G alleles, respectively. Calculated frequencies in Hardy Weinberg Equilibrium were 72% for PNPLA3 C/C, 22% for PNPLA3 C/G, and 6% for PNPLA3 G/G genotype. There is a significant difference in the distribution of PNPLA3 genotypes between normal controls and NAFLD patients (p = 0.0172). However, there was no significant association found between PNPLA3 genotypes and risk of developing NAFLD after controlling for possible confounding effects (p = 0.0574). Allelic frequencies of PNPLA3 among Filipinos were statistically different from Hispanics, Japanese, and Han Chinese. In conclusion, genetic variation in PNPLA3 rs738409 C>G seems to be associated with NAFLD among Filipinos. Further studies are needed to replicate our observations in an independent larger population.

Allelic and genotype frequencies of catechol-O-methyltransferase (Val158Met) and CYP2D6*10 (Pro34Ser) single nucleotide polymorphisms in the Philippines.

A hospital-based cross-sectional study was conducted to determine the allelic and genotype frequencies in the genes encoding for catechol-O-methyltransferase and CYP2D6*10 among healthy volunteers and patients clinically diagnosed with cancer pain. PCR-RFLP was used to identify COMT and CYP2D6*10 genotypes. Allelic frequencies among healthy volunteer Filipinos were 0.83 and 0.17 for the COMT Val and COMT Met alleles, respectively. Calculated frequencies in Hardy-Weinberg equilibrium (HWE) were 73% for COMT Val/Val, 26% for COMT Val/Met, and 1% for COMT Met/Met genotype. For CYP2D6*10, allelic frequencies in HWE among volunteers were 0.46 for the C allele and 0.54 for the T allele. Twenty percent were identified as homozygous for the wild-type C/C genotype, 56% were identified as heterozygous for the C/T genotype, and 24% were identified as homozygous for the T/T variant genotype. No significant differences in COMT and CYP2D6*10 allele frequencies between cancer patients and healthy volunteers were noted. Our data demonstrated that the allele frequencies of COMT and CYP2D6*10 in the Filipino healthy volunteers were similar with other Asians but markedly different from Caucasian populations.

Association of glutathione S-transferase T1 and M1 genotypes with chronic liver diseases among Filipinos.

The glutathione S-transferase (GST) supergene family is made up of four gene families responsible for the biotransformation of drugs and other xenobiotics. Genetic variations in this supergene family influence individual detoxification levels and may contribute to the development of cancer. A hospital-based case-control study was conducted to evaluate the association between GST polymorphism among Filipino patients positive for hepatitis B virus (HBV DNA) and clinically diagnosed as either with chronic active hepatitis, liver cirrhosis, and hepatocellular carcinoma as well as normal individuals negative for HBV infection. Multiplex PCR was used to detect the presence or absence of the GSTT1 and GSTM1 polymorphisms in peripheral blood. DNA sequencing of the S gene region of the virus was used to determine the predominant genotype found among HBV-infected patients. Our results showed that the odds of having a chronic liver disease is only 0.95 (95% CI 0.58-1.57) among those with GSTT1 null genotype compared to those with GSTT1+ genotype. On the other hand, the odds of chronic liver disease is 17.85 times (95% CI 7.34-43.45) for those with GSTM1 null genotype compared to those with GSTM1+ genotype. Using the GSTT1+/GSTM1+ genotype as the reference, both GSTT1+/GSTM1- (OR 16.61; 95% CI 6.69-41.22) and GSTT1-/GSTM1- (OR 11.91; 95% CI 4.48-31.66) genotypes seem to be risk factors for chronic liver disease. From our observations, we conclude that polymorphism in GSTM1 null genotype (OR 17.85; 95% CI 7.34-43.45) seem to be associated with an increased risk of chronic liver disease among Filipinos.