Abstract
Aims
REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major ...coronary events. We now report results from extended follow-up beyond the scheduled study treatment period.
Methods and results
A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% 95% confidence interval (CI) 3–15%; P = 0.004 proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10–29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7–17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0–2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants.
Conclusion
The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms.
Trial registration
International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.
Structured Graphical Abstract
Structured Graphical Abstract
Abstract
The exclusion of chronic kidney disease (CKD) patients from clinical trials—particularly cardiovascular trials—remains a long-standing, unsolved problem, which prevents the optimization of ...clinical care in these patients. The situation recalls the insufficient recruitment of women in cardiovascular trials until the 1980s, a problem that was only resolved following regulatory interventions. Regulatory agencies are in a unique position to promote recruitment of CKD patients in clinical trials. The main stakeholders, namely patients’ associations and scientific societies, should make major lobbying efforts to persuade these agencies that the issue is an absolute public health priority.
Background
Fabry disease (FD) is an X‐linked lysosomal storage and multi‐system disorder due to mutations in the α‐galactosidase A (α‐GalA) gene. We investigated the impact of individual amino acid ...exchanges in the α‐GalA 3D‐structure on the clinical phenotype of FD patients.
Patients and methods
We enrolled 80 adult FD patients with α‐GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α‐GalA 3D‐structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD‐specific treatment.
Results
Patients with active site or buried mutations showed a severe phenotype with multi‐organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α‐GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso‐Gb3 levels were higher (P < 0.01 in men; <0.05 in women).
Conclusions
The type of amino acid exchange location in the α‐GalA 3D‐structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.
Chronic kidney disease (CKD) is accompanied by coronary artery disease (CAD) in most patients. In this article we describe differences in the pathogenesis, diagnosis, and treatment of CAD compared ...with patients without kidney impairment. The histological phenotype as well as the clinical presentation of acute and chronic coronary syndromes differ from those of patients with normal kidney function. The risk of cardiovascular events including death is strikingly increased with higher stages of CKD. Traditional but even more nontraditional cardiovascular risk factors are contributing to this increase. Screening and diagnostic procedures show limited sensitivity and specificity. Lifestyle modification is important for reducing the progression of both CKD and CAD. A special emphasis should be placed on physical exercising. Equally important is a strict antihypertensive therapy due to the very high incidences of hypertension in CKD patients. Blockade of the renin–angiotensin–system is imperative providing that adverse effects can be managed. Target blood pressure should be at 130 mm Hg systolic. Antiglycemic treatment should be implemented with metformin and SGLT2-inhibitors as first-line therapy, and glomerular filtration rate thresholds must be respected for both drugs. The risk of hypoglycemia is increased with worsening kidney function. Statins are indicated for up to stage 5 CKD. When a revascularization procedure is indicated (percutaneous intervention or bypass grafting), higher rates or peri-interventional morbidity and mortality must be anticipated. Taken together, the available literature on patients with CKD and CAD is clearly restricted compared with that on CAD patients with preserved kidney function. Mechanisms of arteriosclerosis and atheromatosis in CKD deserve more attention in the future. One major innovation in the field is SGLT2-inhibitor treatment with its concordant advantages for kidney and cardiac protection.
BACKGROUND:Exploratory analyses of previous randomized trials generated a hypothesis that the clinical response to cholesteryl ester transfer protein (CETP) inhibitor therapy differs by ADCY9 ...genotype, prompting the ongoing dal-GenE trial in individuals with a particular genetic profile. The randomized placebo-controlled REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib through Lipid-Modification) demonstrated the clinical efficacy of the CETP inhibitor anacetrapib among patients with preexisting atherosclerotic vascular disease. In the present study, we examined the impact of ADCY9 genotype on response to anacetrapib in the REVEAL trial.
METHODS:Individuals with stable atherosclerotic vascular disease who were treated with intensive atorvastatin therapy received either anacetrapib 100 mg daily or matching placebo. Cox proportional hazards models, adjusted for the first 5 principal components of ancestry, were used to estimate the effects of allocation to anacetrapib on major vascular events (a composite of coronary death, myocardial infarction, coronary revascularization, or presumed ischemic stroke) and the interaction with ADCY9 rs1967309 genotype.
RESULTS:Among 19 210 genotyped individuals of European ancestry, 2504 (13.0%) had a first major vascular event during 4 years median follow-up1216 (12.6%) among anacetrapib-allocated participants and 1288 (13.4%) among placebo-allocated participants. Proportional reductions in the risk of major vascular events with anacetrapib did not differ significantly by ADCY9 genotypehazard ratio (HR) = 0.92 (95% CI, 0.81–1.05) for GG; HR = 0.94 (95% CI, 0.84–1.06) for AG; and HR = 0.93 (95% CI, 0.76–1.13) for AA genotype carriers, respectively; genotypic P for interaction = 0.96. Furthermore, there were no associations between ADCY9 genotype and the proportional reductions in the separate components of major vascular events or meaningful differences in lipid response to anacetrapib.
CONCLUSIONS:The REVEAL trial is the single largest study to date evaluating the ADCY9 pharmacogenetic interaction. It provides no support for the hypothesis that ADCY9 genotype is materially relevant to the clinical effects of the CETP inhibitor anacetrapib. The ongoing dal-GenE study will provide direct evidence as to whether there is any specific pharmacogenetic interaction with dalcetrapib.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT01252953. URLhttp://www.isrctn.com. Unique identifierISRCTN48678192. URLhttps://www.clinicaltrialsregister.eu. Unique identifier2010-023467-18.
Homoarginine is an amino acid which may play a role in nitric oxide and energy metabolism. Low homoarginine concentrations have previously been linked to increased mortality, but the underlying ...mechanisms remain unknown.
To investigate whether serum homoarginine concentrations are associated with myocardial function, energy metabolism and fatal events.
Serum homoarginine concentrations were measured in 3305 Caucasian patients who were referred for coronary angiography at a tertiary care centre in Germany. After baseline examinations (1997-2000), patients were followed-up with respect to specific causes of death.
Homoarginine concentration correlated positively with angiographic ejection fraction and was inversely associated with N-terminal pro-B-type natriuretic peptide (p<0.001 for both). Variables of energy metabolism (guanidinoacetate and creatine) were significantly associated with homoarginine concentration (p<0.001 for both). Over a median follow-up time of 9.9 years, 991 patients died, including 258 sudden cardiac deaths, 148 heart failure deaths and 105 fatal myocardial infarctions. Multivariable adjusted Cox proportional HRs (with 95% CI) for the first versus the fourth homoarginine quartile were 2.44 (1.60 to 3.73) for sudden cardiac deaths, 3.44 (1.89 to 6.24) for heart failure deaths, and 3.78 (1.77 to 8.06) for fatal myocardial infarctions.
Homoarginine deficiency is associated with myocardial dysfunction and significantly increased risk of fatal cardiovascular events and may be related to poor energy metabolism. Further studies are warranted to explore the significance of homoarginine metabolism in risk stratification and treatment of heart diseases.
Background. The accumulation of larger and protein-bound toxins is involved in the uraemic syndrome but their elimination by dialysis therapy remains difficult. In the present study, the impact of ...the albumin permeability of recently introduced advanced high-flux dialysis membranes on the removal of such substances was tested in haemodialysis and online post-dilution haemodiafiltration. Methods. Two types of polyethersulfone membranes only differing in albumin permeability (referred as PU− and PU+) were compared in eight patients on maintenance dialysis in a prospective cross-over manner. Treatment settings were identical for individual patients: time 229 ± 22 min; blood flow rate 378 ± 33 mL/min; dialysate flow rate 500 mL/min; substitution flow rate in haemodiafiltration 94 ± 9 mL/min. Removal of the protein-bound compounds p-cresyl sulfate (pCS) and indoxyl sulfate (IS) was determined by reduction ratios (RRs), dialytic clearances and mass in continuously collected dialysate. In addition, the elimination of the low-molecular weight (LMW) proteins beta2-microglobulin, cystatin c, myoglobin (myo), free retinol-binding protein (rbp) and albumin was measured. Results. Plasma levels of the protein-bound toxins were significantly decreased by all treatment forms. However, the decreases were comparable between dialysis membranes and between haemodialysis and haemodiafiltration. The RRs of total pCS ranged between 40.4 ± 25.3 and 47.8 ± 10.3% and of total IS between 50.4 ± 2.6 and 54.6 ± 8.7%. Elimination of free protein-bound toxins as assessed by their mass in dialysate closely correlated positively with the pre-treatment plasma concentrations being r = 0.920 (P < 0.001) for total pCS and r = 0.906 (P < 0.001) for total IS, respectively. Compared to haemodialysis, much higher removal of all LMW proteins was found in haemodiafiltration. Dialysis membrane differences were only obvious in haemodialysis for the larger LMW proteins myo and rbp yielding significantly higher RRs for PU+ (myo 46 ± 9 versus 37 ± 9%; rbp 18 ± 5 versus 15 ± 5%; P < 0.05). Additionally, the albumin loss varied between membranes and treatment modes being undetectable with PU− in haemodialysis and highest with PU+ in haemodiafiltration (1430 ± 566 mg). Conclusions. The elimination of protein-bound compounds into dialysate is predicted by the level of pre-treatment plasma concentrations and depends particularly on diffusion. Lacking enhanced removal in online post-dilution haemodiafiltration emphasizes the minor significance of convection for the clearance of these solutes. Compared to LMW proteins, the highly protein-bound toxins pCS and IS are less effectively eliminated with all treatment forms. For a sustained decrease of pCS and IS plasma levels, alternative strategies promise to be more efficient therapy forms.
The majority of dialysis patients suffer from vitamin D deficiency, which might contribute to an adverse health outcome. We aimed to elucidate whether European dialysis patients with low ...25-hydroxyvitamin D (25(OH)D) levels are at increased risk of mortality and specific fatal events.
This was a prospective cohort study of incident dialysis patients in the Netherlands (the NECOSAD). We selected all patients with measured 25(OH)D at 12 months after the start of dialysis, the baseline for our study. By Cox regression analyses, we assessed the impact of 25(OH)D levels on short-term (6 months of follow-up) as well as longer-term mortality (3 years of follow-up). Associations of 25(OH)D levels with cardiovascular and non-cardiovascular mortality were also determined.
The data from 762 patients (39% females, age 59 ± 15 years, 25(OH)D = 18 ± 11 ng/mL) were available. Fifty-one and 213 patients died during a follow-up of 6 months and 3 years, respectively. After adjustments for possible confounders, the hazard ratio (HR) (with 95% CI) for mortality was 2.0 (1.0-3.8) for short-term and 1.5 (1.0-2.1) for longer-term mortality when comparing patients with 25(OH)D levels ≤ 10 ng/mL with those presenting with 25(OH)D levels > 10 ng/mL. Adjusted HRs for cardiovascular mortality were 2.7 (1.1-6.5) and 1.7 (1.1-2.7) for short- and longer-term mortality, respectively. For non-cardiovascular mortality, we observed no relevant association overall. The impact of 25(OH)D levels on clinical events was modified by parathyroid hormone (PTH) status, with low 25(OH)D levels meaningfully affecting outcomes only in patients with PTH levels above the median of 123 pmol/L.
Vitamin D deficiency in dialysis patients is associated with an adverse health outcome, in particular with short-term cardiovascular mortality. Intervention studies are urgently needed to evaluate whether vitamin D supplementation improves health outcomes of dialysis patients.
Considerable variation in grading systems used to rate the strength of guideline recommendations and the quality of the supporting evidence in Nephrology highlights the need for a uniform, ...internationally accepted, rigorous system. In 2004, Kidney Disease: Improving Global Outcomes (KDIGO) commissioned a methods expert group to recommend an approach for grading in future nephrology guidelines. This position statement by KDIGO recommends adopting the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach for the grading of evidence and guidelines on interventions. The GRADE approach appraises systematic reviews of the benefits and harms of an intervention to determine its net health benefit. The system considers the design, quality, and quantity of studies as well as the consistency and directness of findings when grading the quality of evidence. The strength of the recommendation builds on the quality of the evidence and additional considerations including costs. Adaptations of the GRADE approach are presented to address some issues pertinent to the field of nephrology, including (1) the need to extrapolate from studies performed predominantly in patients without kidney disease, and (2) the need to use qualitative summaries of effects when it is not feasible to quantitatively summarize them. Further refinement of the system will be required for grading of evidence on questions other than those related to intervention effects, such as diagnostic accuracy and prognosis.
Ocular sarcoidosis Springer-Wanner, C; Brauns, T
Zeitschrift für Rheumatologie
76, Številka:
5
Journal Article
Recenzirano
Ocular manifestation of sarcoidosis occurs in up to 60% of patients with confirmed systemic sarcoidosis and represents one of the most common forms of noninfectious uveitis. In known pulmonary ...sarcoidosis, ocular involvement can occur in up to 80% of cases. Sarcoidosis can also present only in the eye, without a systemic manifestation (ocular sarcoidosis). Typically, ocular sarcoidosis shows bilateral granulomatous uveitis and can involve all parts of the eye. Apart from an acute anterior uveitis, chronic intermediate or posterior uveitis can be found. In order to prevent a severe reduction of visual acuity leading to blindness, early diagnosis and treatment is essential. For diagnosis, specific clinical signs involving the eye (bilateral granulomatous changes in all parts of the eye) and typical laboratory investigations (angiotensin-converting enzyme, ACE; lysozyme; soluble interleukin 2 receptor, sIL2R; chest X‑ray; chest CT) have to be taken into account, since biopsy to prove noncaseating granulomas is not performed with changes restricted to the eye due to the high risk of vision loss. Ocular sarcoidosis mostly responds well to local or systemic steroid treatment. If the therapeutic effect is insufficient, immunosuppressive agents and biologics can be applied.
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