Kristine Hommel

Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease

BACKGROUND Both atrial fibrillation and chronic kidney disease increase the risk of stroke and systemic thromboembolism. However, these risks, and the effects of antithrombotic treatment, have not been thoroughly investigated in patients with both conditions. METHODS Using Danish national registries, we identified all patients discharged from the hospital with a diagnosis of nonvalvular atrial fibrillation between 1997 and 2008. The risk of stroke or systemic thromboembolism and bleeding associated with non-end-stage chronic kidney disease and with end-stage chronic kidney disease (i.e., disease requiring renal-replacement therapy) was estimated with the use of time-dependent Cox regression analyses. In addition, the effects of treatment with warfarin, aspirin, or both in patients with chronic kidney disease were compared with the effects in patients with no renal disease. RESULTS Of 132,372 patients included in the analysis, 3587 (2.7%) had non-end-stage chronic kidney disease and 901 (0.7%) required renal-replacement therapy at the time of inclusion. As compared with patients who did not have renal disease, patients with non-end-stage chronic kidney disease had an increased risk of stroke or systemic thromboembolism (hazard ratio, 1.49; 95% confidence interval [CI], 1.38 to 1.59; P<0.001), as did those requiring renal-replacement therapy (hazard ratio, 1.83; 95% CI, 1.57 to 2.14; P<0.001); this risk was significantly decreased for both groups of patients with warfarin but not with aspirin. The risk of bleeding was also increased among patients who had non-end-stage chronic kidney disease or required renal-replacement therapy and was further increased with warfarin, aspirin, or both. CONCLUSIONS Chronic kidney disease was associated with an increased risk of stroke or systemic thromboembolism and bleeding among patients with atrial fibrillation. Warfarin treatment was associated with a decreased risk of stroke or systemic thromboembolism among patients with chronic kidney disease, whereas warfarin and aspirin were associated with an increased risk of bleeding. (Funded by the Lundbeck Foundation.).

Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study.

BACKGROUND The balance between stroke reduction and increased bleeding associated with antithrombotic therapy among patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is controversial. OBJECTIVES This study assessed the risk associated with CKD in individual CHA₂DS₂-VASc (Congestive heart failure; Hypertension; Age ≥75 years; Diabetes mellitus; previous Stroke, transient ischemic attack, or thromboembolism; Vascular disease; Age 65 to 74 years; Sex category) strata and the net clinical benefit of warfarin in patients with AF and CKD in a nationwide cohort. METHODS By individual-level linkage of nationwide Danish registries, we identified all patients discharged with nonvalvular AF from 1997 to 2011. The stroke risk associated with non-end-stage CKD and end-stage CKD (e.g., patients on renal replacement therapy [RRT]) was estimated using Cox regression analyses. The net clinical benefit of warfarin was assessed using 4 endpoints: a composite endpoint of death/hospitalization from stroke/bleeding; a composite endpoint of fatal stroke/fatal bleeding; cardiovascular death; and all-cause death. RESULTS From nonvalvular AF patients (n = 154,259), we identified 11,128 patients (7.2%) with non-end-stage CKD and 1,728 (1.1%) receiving RRT. In all CHA₂DS₂-VASc risk groups, RRT was independently associated with a higher risk of stroke/thromboembolism, from a 5.5-fold higher risk in patients with CHA₂DS₂-VASc score = 0 to a 1.6-fold higher risk in patients with CHA₂DS₂-VASc score ≥2. In patients receiving RRT with CHA₂DS₂-VASc score ≥2, warfarin was associated with lower risk of all-cause death (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.72 to 0.99). In non-end-stage CKD patients with CHA₂DS₂-VASc score ≥2, warfarin was associated with a lower risk of a composite outcome of fatal stroke/fatal bleeding (HR: 0.71, 95% CI: 0.57 to 0.88), a lower risk of cardiovascular death (HR: 0.80, 95% CI: 0.74 to 0.88), and a lower risk of all-cause death (HR: 0.64, 95% CI: 0.60 to 0.69). CONCLUSIONS CKD is associated with a higher risk of stroke/thromboembolism across stroke risk strata in AF patients. High-risk CKD patients (CHA₂DS₂-VASc ≥2) with AF benefit from warfarin treatment for stroke prevention.

Original InvestigationNet Clinical Benefit of Antithrombotic Therapy in Patients With Atrial Fibrillation and Chronic Kidney Disease: A Nationwide Observational Cohort Study

BACKGROUND The balance between stroke reduction and increased bleeding associated with antithrombotic therapy among patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is controversial. OBJECTIVES This study assessed the risk associated with CKD in individual CHA₂DS₂-VASc (Congestive heart failure; Hypertension; Age ≥75 years; Diabetes mellitus; previous Stroke, transient ischemic attack, or thromboembolism; Vascular disease; Age 65 to 74 years; Sex category) strata and the net clinical benefit of warfarin in patients with AF and CKD in a nationwide cohort. METHODS By individual-level linkage of nationwide Danish registries, we identified all patients discharged with nonvalvular AF from 1997 to 2011. The stroke risk associated with non-end-stage CKD and end-stage CKD (e.g., patients on renal replacement therapy [RRT]) was estimated using Cox regression analyses. The net clinical benefit of warfarin was assessed using 4 endpoints: a composite endpoint of death/hospitalization from stroke/bleeding; a composite endpoint of fatal stroke/fatal bleeding; cardiovascular death; and all-cause death. RESULTS From nonvalvular AF patients (n = 154,259), we identified 11,128 patients (7.2%) with non-end-stage CKD and 1,728 (1.1%) receiving RRT. In all CHA₂DS₂-VASc risk groups, RRT was independently associated with a higher risk of stroke/thromboembolism, from a 5.5-fold higher risk in patients with CHA₂DS₂-VASc score = 0 to a 1.6-fold higher risk in patients with CHA₂DS₂-VASc score ≥2. In patients receiving RRT with CHA₂DS₂-VASc score ≥2, warfarin was associated with lower risk of all-cause death (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.72 to 0.99). In non-end-stage CKD patients with CHA₂DS₂-VASc score ≥2, warfarin was associated with a lower risk of a composite outcome of fatal stroke/fatal bleeding (HR: 0.71, 95% CI: 0.57 to 0.88), a lower risk of cardiovascular death (HR: 0.80, 95% CI: 0.74 to 0.88), and a lower risk of all-cause death (HR: 0.64, 95% CI: 0.60 to 0.69). CONCLUSIONS CKD is associated with a higher risk of stroke/thromboembolism across stroke risk strata in AF patients. High-risk CKD patients (CHA₂DS₂-VASc ≥2) with AF benefit from warfarin treatment for stroke prevention.

The Danish Registry on Regular Dialysis and Transplantation:completeness and validity of incident patient registration

BACKGROUND The Danish National Registry on Regular Dialysis and Transplantation (NRDT) provides systematic information on the epidemiology and treatment of end-stage chronic kidney disease in Denmark. It is therefore of major importance that the registry is valid and complete. The aim of the present study was to evaluate the registration of incident patients on chronic renal replacement therapy (RRT). METHODS Incident patients on chronic RRT in the period 2001-2004 were identified in NRDT and in the National Patient Registry, which contains information on hospital admissions and treatments. In the National Patient Registry, identification of patients was as follows: patients receiving the procedure of dialysis during a minimum of 90 days and for a minimum of 12 times or the procedure of renal transplantation. Only patients with at least 2 years of dialysis-free interval before and never being transplanted were included. The completeness of NRDT was calculated as the percentage of new patients on chronic RRT registered in the National Patient Registry also found in NRDT. Validity of data in NRDT was assessed by information from medical records and analysed using kappa statistics. RESULTS Completeness of NRDT: Of 3020 patients registered in the National Patient Registry as incident chronic RRT patients, 97.2% were found in NRDT but 22.5% with another year of entry. There were no differences in completeness between hospitals or regions. Validity of NRDT: Validity of common renal diagnoses and RRT modality was high: diabetic nephropathy (kappa = 0.98), adult polycystic kidney disease (kappa = 0.95), chronic glomerulonephritis (kappa = 0.78) and RRT modality (kappa = 0.94). The diagnosis CKD of unknown aetiology and type of diabetes were less valid (kappa = 0.62, 0.60 and 0.73, respectively). The date of RRT start had also high validity. CONCLUSIONS Completeness of incident patient registration in NRDT was highly acceptable. Validity of incident patient data was also good, except for type of diabetes.

The importance of early referral for the treatment of chronic kidney disease: a Danish nationwide cohort study

BackgroundMany patients with advanced chronic kidney disease are referred late to renal units. This is associated with negative aspects. The purpose of the present study was to characterize late versus early referrals for renal replacement therapy including their renal disease, health care contacts and medical treatment before renal replacement therapy (RRT) and the consequences for RRT modality and mortality.MethodsNationwide cohort study including 4495 RRT patients identified in the Danish Nephrology Registry 1999–2006. The cohort was followed to end 2007 by linkage to other national registries. Late referral: follow-up ≤16 weeks in renal unit before RRT start. Cox proportional hazards models were used to estimate the relative risk of mortality or waiting list status within 365 days in late referrals versus early referrals.ResultsA total of 1727 (38%) incident RRT patients were referred late. Among these, 72% were treated in non-nephrology hospital departments and 91% in general practice 2 years to 16 weeks before RRT start. Fewer late referrals received recommended pre-RRT treatment as judged by renin-angiotensin-system blockade: 32% versus 57% or the D-vitamin analogue alfacalcidol: 5% versus 30% (P < .001). Primary RRT modality was peritoneal dialysis: 18% in late versus 32% in early referrals (P < .001), 7% versus 30%, respectively, had an arteriovenous dialysis-fistula (P < .001) and 0.2% versus 6% were on the waiting-list for renal transplantation (P < .001) before RRT start. One-year-mortality was higher in late referrals: hazard ratio 1.55 (CI 95% 1.35–1.78). In a subgroup, 30% (CI 95% 25–35%) late and 9% (CI 95% 6–12%) early referrals had plasma creatinine ≤150% of upper reference limit within 1 to 2 years before RRT start (P < .001).ConclusionsLate nephrology referrals were well-known to the healthcare system before referral for RRT start and more often had near normal plasma creatinine levels within 2 years before RRT start. They infrequently received available treatment or optimal first RRT modality. An increased effort to identify these patients in the healthcare system in time for proper pre-dialysis care including preparation for RRT is needed.

Does nociceptin play a role in pain disorders in man

Nociceptin-immunoreactive cellbodies were detected in the human trigeminal ganglion, while no such fibers were identified in the temporal artery or in dermal tissue from the neck region. In four healthy subjects receiving nociceptin into the temporal muscle in an open labeled design no pain was detected. In 10 healthy subjects who received 200pmol of nociceptin into tender non-dominant trapezius muscles in a placebo-controlled, randomized, balanced, and double-blinded design local tenderness increased (P=0.025) while no pain was noted. Thus, the action of nociceptin should be searched for in the trigeminal ganglion and/or in the central nervous system (CNS).

Benefit of Clopidogrel Therapy in Patients With Myocardial Infarction and Chronic Kidney Disease—A Danish Nation-Wide Cohort Study

Background The aim of the present study was to evaluate clopidogrel treatment after incident myocardial infarction (MI) in patients with and without chronic kidney disease (CKD). Methods and Results By linking nation‐wide registries, information about patients admitted with incident MI was found. Primary endpoints were all‐cause and cardiovascular (CV) mortality, a composite of all‐cause mortality and recurrent MI, and a composite of fatal and nonfatal bleedings. Effect of clopidogrel use versus clopidogrel nonuse was estimated using an adjusted Coxs regression model stratified according to percutaneous coronary intervention (PCI) treatment. A total of 69 082 incident MI patients in the period 2002–2011 were included. Clopidogrel treatment was associated with hazard ratios (HRs) for the combined endpoint of all‐cause mortality and recurrent MI in PCI‐treated patients of 0.90 (95% confidence interval [CI], 0.47 to 1.72) in renal replacement therapy (RRT) patients, 0.59 (95% CI: 0.40 to 0.88) in non‐end‐stage CKD patients and 0.69 (95% CI, 0.61 to 0.77) in patients without kidney disease (P for interaction=0.60). In patients not treated with PCI, HRs were 0.90 (95% CI, 0.68 to 1.21) in RRT patients, 0.86 (95% CI, 0.75 to 0.99) in non‐end‐stage CKD patients, and 0.91 (95% CI, 0.87 to 0.95) in patients without kidney disease (P for interaction=0.74). An increase in bleeding events (not significant) was noted for clopidogrel‐treated patients not undergoing PCI and for non‐end‐stage CKD patients undergoing PCI, whereas clopidogrel was associated with less bleedings in PCI‐treated RRT patients and patients without kidney disease. Conclusions During a 1‐year follow‐up, after MI, clopidogrel was associated with improved outcomes in patients with non‐end‐stage CKD. Even though no effect difference, compared to patients without CKD, was observed, the benefit associated with the use of clopidogrel after MI in patients requiring RRT is less clear.

Less use of standard guideline-based treatment of myocardial infarction in patients with chronic kidney disease: a Danish nation-wide cohort study

AIMS The aim of this Danish nationwide study was to evaluate the treatment of myocardial infarction (MI) in patients with non-end-stage chronic kidney disease (CKD) and in patients requiring renal replacement therapy (RRT). Upgraded guidelines for the management of MI were implemented around 2004; hence, the treatment of MI in the time periods before and after 2004 was compared in order to evaluate the impact for patients with CKD. METHODS AND RESULTS By linking nationwide registries by the personal registration number, we identified patients admitted to Danish hospitals with first time MI in the period 2000-09 (79 585 with no renal disease, 3144 with non-end-stage CKD, and 725 requiring RRT). Cox proportional hazards model was used to estimate the chance of invasive treatment within 60 days after MI and the chance of filling prescriptions on recommended post-MI drugs within 90 days before and after 2004. Significantly less use of relevant MI treatment in patients with non-end-stage CKD and patients requiring RRT compared with patients with no renal disease were seen; however, the absolute frequencies of invasive procedures and filled prescriptions on post-MI drugs increased after 2004 in all patients. CONCLUSIONS After 2004, invasive and pharmacological treatment of first-time MI improved in patients with non-end-stage CKD and patients requiring RRT; however, all CKD patients were less treated with standard MI care compared with patients with no renal disease.

Use of nonsteroidal anti-inflammatory drugs prior to chronic renal replacement therapy initiation: a nationwide study

Nonsteroidal anti‐inflammatory drugs (NSAIDs) may be associated with severe renal complications, including acute renal failure, reduced glomerular filtration rate and interstitial nephritis. Caution against NSAIDs is therefore recommended in advanced chronic kidney disease. In this study, we examined NSAID use, aetiology and comorbidity among a national cohort of patients before the initiation of chronic renal replacement therapy (RRT).

Regional and social inequalities in chronic renal replacement therapy in Denmark

BACKGROUND The incidence of chronic renal replacement therapy (RRT) varies markedly between Danish nephrology centres. The aim of the present study was to establish if there is regional and social variation in the incidence of chronic RRT in Denmark when analysed according to patient residence. The importance of diabetic nephropathy and patients aged 70 years or older was also studied. METHODS Incident patients on chronic RRT in the period 1995-2006 were identified in the Danish National Registry on Regular Dialysis and Transplantation. Information on residence, income, educational status and ethnic origin was obtained from Statistics Denmark. Rates of incident RRT patients were standardized for regional differences of sex and age as well as income, educational status and ethnic origin. Poisson regression was used when comparing rates. RESULTS Age- and sex-standardized incident chronic RRT rates among individuals with low income or short educational level were higher (P < 0.0001) compared to other groups. Also, standardized rates of patients in total and patients aged 70 years or older were higher in the catchment areas of the nephrology centres located in the two largest cities than for patients with residence in other areas of the country (P < 0.0001). Standardizing for regional differences of ethnic origin did not change the rates. The incident chronic RRT rate caused by diabetic nephropathy was higher for patients with residence in the catchment area of the nephrology centre in the largest city [49 per million people (p.m.p.) (95% CI = 40-57 p.m.p.)] compared to the catchment area of the nephrology centre located in the second largest city [31 (95% CI = 26-37 p.m.p.)] and other areas [29 p.m.p. (95% CI = 26-31 p.m.p.)] in 2001-06. When standardizing for differences in income among the 30-69-year-old persons, the rate of patients with residence in the catchment area of the nephrology centre located in the largest city decreased but was still higher than in other regions (P = 0.0003). CONCLUSIONS There are marked socio-economic and regional differences in rates of incident RRT patients. The rates of incident RRT patients are highest in the catchment areas of the two largest nephrology centres and this may be partly explained by a higher frequency of end-stage diabetic nephropathy and a new treatment programme targeting frail, mainly elderly, patients.