Stopping renin-angiotensin system inhibitors in patients with advanced CKD and risk of adverse outcomes: a nationwide study

Background It is unknown whether stopping renin-angiotensin system (RAS) inhibitor therapy in patients with advanced CKD affects outcomes.Methods We studied patients referred to nephrologist care, listed on the Swedish Renal Registry during 2007-2017, who developed advanced CKD (eGFR 30 ml/min per 1.73 m(2), 1553 (15%) stopped RAS inhibitor therapy within 6 months. Median eGFR was 23 ml/min per 1.73 m(2). Compared with continuing RAS inhibition, stopping this therapy was associated with a higher absolute 5-year risk of death (40.9% versus 54.5%) and major adverse cardiovascular events (47.6% versus 59.5%), but with a lower risk of KRT (36.1% versus 27.9%); these corresponded to absolute risk differences of 13.6 events per 100 patients, 11.9 events per 100 patients, and -8.3 events per 100 patients, respectively. Results were consistent whether patients stopped RAS inhibition at higher or lower eGFR, across prespecified subgroups, after adjustment and stratification for albuminuria and potassium, and when modeling RAS inhibition as a time-dependent exposure using a marginal structural model.Conclusions In this nationwide observational study of people with advanced CKD, stopping RAS inhibition was associated with higher absolute risks of mortality and major adverse cardiovascular events, but also with a lower absolute risk of initiating KRT.Clinical epidemiolog

Cardiorenal outcomes among patients with atrial fibrillation treated with oral anticoagulants

Rationale & Objective: Direct oral anticoagulants (DOACs) have progressively replaced vitamin K antagonists (VKAs) for stroke prevention in pa-tients with nonvalvular atrial fibrillation (AF). DOACs cause fewer bleeding complications, but their other advantages, particularly related to kid-ney outcomes, remain inconclusive. We studied the risks of chronic kidney disease (CKD) pro-gression and acute kidney injury (AKI) after DOAC and VKA administration for nonvalvular AF.Study Design: Retrospective cohort study. Setting & Participants: Cohort study of Swedish patients enrolled in the Stockholm Creatinine Measurements (SCREAM) project with a diag-nosis of nonvalvular AF during 2011-2018. Exposure: Initiation of DOAC or VKA treatment.Outcome: Primary outcomes were CKD pro-gression (composite of >30% estimated glomer-ular filtration rate [eGFR] decline and kidney failure) and AKI (by diagnosis or KDIGO-defined transient creatinine elevations). Secondary outcomes were death, major bleeding, and the composite of stroke and systemic embolism.Analytical Approach: Propensity score weighted Cox regression was used to balance 50 baseline confounders. Sensitivity analyses included falsification end points, subgroups, and estima-tion of per-protocol effects.Results: We included 32,699 patients (56% initiated DOAC) who were observed for a me-dian of 3.8 years. Their median age was 75 years, 45% were women, and 27% had an eGFR <60 mL/min/1.73 m2. The adjusted HRs for DOAC versus VKA were 0.87 (95% CI, 0.78-0.9 8) for the risk of CKD progression and 0.88 (95% CI, 0.80-0.97) for AKI. HRs were 0.77 (95% CI, 0.67-0.8 9) for major bleeding, 0.93 (95% CI, 0.78-1.11) for the composite of stroke and systemic embolism, and 1.04 (95% CI, 0.95-1.14) for death. The results were similar across subgroups of age, sex, and baseline eGFR when restricting to patients at high risk for thromboembolic events and when censoring follow up at treatment discontinuation or change in type of anticoagulation.Limitations: Missing information on time in ther-apeutic range and treatment dosages.Conclusions: Among patients with nonvalvular AF treated in routine clinical practice compared with VKA use, DOAC use was associated with a lower risk of CKD progression, AKI, and major bleeding but a similar risk of the composite of stroke, systemic embolism, or death.Clinical epidemiolog

Comparative effectiveness of renin-angiotensin system inhibitors and calcium channel blockers in individuals with advanced CKD: a nationwide observational cohort study

Rationale & Objective: It is unknown whether initiating renin-angiotensin system (RAS) inhibitor therapy in patients with advanced chronic kidney disease (CKD) is superior to alternative antihypertensive agents such as calcium channel blockers (CCBs). We compared the risks for kidney replacement therapy (KRT), mortality, and major adverse cardiovascular events (MACE) in patients with advanced CKD in routine nephrology practice who were initiating either RAS inhibitor or CCB therapy.Study Design: Observational study in the Swedish Renal Registry, 2007 to 2017.Settings & Participants: 2,458 new users of RAS inhibitors and 2,345 CCB users with estimated glomerular filtration rates < 30 mL/min/1.73 m(2) (CKD G4-G5 without KRT) who were being followed up by a nephrologist. As a positive control cohort, new users of the same drugs with CKD G3 (estimated glomerular filtration rate, 30-60 mL/min/1.73 m(2)) were evaluated.Exposures: RAS inhibitor versus CCB therapy initiation.Outcome: Initiation of KRT (maintenance dialysis or transplantation), all-cause mortality, and MACE (composite of cardiovascular death, myocardial infarction, or stroke).Analytical Approach: HRs with 95% CIs were estimated using propensity score-weighted Cox proportional hazards regression adjusting for demographic, clinical, and laboratory covariates.Results: Median age was 74 years, 38% were women, and median follow-up was 4.1 years. After propensity score weighting, there was significantly lower risk for KRT after new use of RAS inhibitors compared with new use of CCBs (adjusted HR, 0.79 [95% CI, 0.69-0.89]) but similar risks for mortality (adjusted HR, 0.97 [95% CI, 0.88-1.07]) and MACE (adjusted HR, 1.00 [95% CI, 0.88-1.15]). Results were consistent across subgroups and in as-treated analyses. The positive control cohort of patients with CKD G3 showed similar KRT risk reduction (adjusted HR, 0.67 [95% CI, 0.56-0.80]) with RAS inhibitor therapy compared with CCBs.Limitations: Potential confounding by indication.Conclusions: Our findings provide evidence from real-world clinical practice that initiation of RAS inhibitor therapy compared with CCBs may confer kidney benefits among patients with advanced CKD, with similar cardiovascular protection.Clinical epidemiolog

Timing of dialysis initiation to reduce mortality and cardiovascular events in advanced chronic kidney disease: nationwide cohort study

OBJECTIVE To identify the optimal estimated glomerular filtration rate (eGFR) at which to initiate dialysis in people with advanced chronic kidney disease.DESIGNNationwide observational cohort study.SETTINGNational Swedish Renal Registry of patients referred to nephrologists.PARTICIPANTSPatients had a baseline eGFR between 10 and 20 mL/min/1.73 m(2) and were included between 1 January 2007 and 31 December 2016, with follow-up until 1 June 2017.MAIN OUTCOME MEASURESThe strict design criteria of a clinical trial were mimicked by using the cloning, censoring, and weighting method to eliminate immortal time bias, lead time bias, and survivor bias. A dynamic marginal structural model was used to estimate adjusted hazard ratios and absolute risks for five year all cause mortality and major adverse cardiovascular events (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) for 15 dialysis initiation strategies with eGFR values between 4 and 19 mL/min/1.73 m(2) in increments of 1 mL/min/1.73 m(2). An eGFR between 6 and 7 mL/min/1.73 m(2) (eGFR(6-7)) was taken as the reference.RESULTSAmong 10 290 incident patients with advanced chronic kidney disease (median age 73 years; 3739 (36%) women; median eGFR 16.8 mL/min/1.73 m(2)), 3822 started dialysis, 4160 died, and 2446 had a major adverse cardiovascular event. A parabolic relation was observed for mortality, with the lowest risk for eGFR(15-16). Compared with dialysis initiation at eGFR(6-7), initiation at eGFR(15-16) was associated with a 5.1% (95% confidence interval 2.5% to 6.9%) lower absolute five year mortality risk and 2.9% (0.2% to 5.5%) lower risk of a major adverse cardiovascular event, corresponding to hazard ratios of 0.89 (95% confidence interval 0.87 to 0.92) and 0.94 (0.91 to 0.98), respectively. This 5.1% absolute risk difference corresponded to a mean postponement of death of 1.6 months over five years of follow-up. However, dialysis would need to be started four years earlier. When emulating the intended strategies of the Initiating Dialysis Early and Late (IDEAL) trial (eGFR(10-14)v eGFR(5-7)) and the achieved eGFRs in IDEAL (eGFR(7-10)v eGFR(5-7)), hazard ratios for all cause mortality were 0.96 (0.94 to 0.99) and 0.97 (0.94 to 1.00), respectively, which are congruent with the findings of the randomised IDEAL trial.CONCLUSIONSVery early initiation of dialysis was associated with a modest reduction in mortality and cardiovascular events. For most patients, such a reduction may not outweigh the burden of a substantially longer period spent on dialysis.Clinical epidemiolog

Endoscopic thoracic sympathectomy for hyperhidrosis: Technique and results

Outline: We review the clinical features of hyperhidrosis and the range of treatments used for this condition. We describe in detail the technique of endoscopic sympathectomy. We summarize studies that have reported results of endoscopic sympathectomy. We present new data highlighting the difference in quality of life between patients with hyperhidrosis and controls

Comparative effectiveness of SGLT2i versus GLP1-RA on cardiovascular outcomes in routine clinical practice

Background: To investigate the comparative effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1-RA) on cardiovascular outcomes in routine clinical practice, which have never been directly compared in head-to-head outcome trials.Methods: We compared outcomes of adults who newly started SGLT2i or GLP1-RA therapy in Stockholm, Sweden, during 2013-2019. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular (CV) death, myocardial infarction and stroke. Secondary outcomes included the individual MACE components and hospitalization for heart failure. Cox regression with propensity score overlap weighting was used to estimate hazard ratios (HRs) with 95% confidence intervals and adjust for 57 covariates.Results: We included 12,375 individuals, of which 5489 initiated SGLT2i and 6886 GLP1-RA therapy, followed for median 1.6 years. Mean age was 61 years and 37.6% were women. Compared with GLP1-RA, SGLT2i new users had similar risk of MACE risk (adjusted HR 1.04; 95% CI 0.83-1.31). The adjusted HRs (95% CI) for SGLT2i vs. GLP1-RA were 0.80 (0.59-1.09) for heart failure hospitalization, 0.95 (0.58-1.55) for cardiovascular death, 0.91 (0.67-1.24) for myocardial infarction and 1.71 (1.14-2.59) for ischemic stroke (5-year absolute risk dif-ference for stroke 1.9% [95% CI 0.8-3.0]).Conclusions: In a largely primary-prevention population of people undergoing routine care, no differences were observed in MACE risk among initiators of SGLT2i and GLP1-RA. However, compared with GLP1RA, the use of SGLT2i was associated with an increased risk of ischemic stroke that was small in absolute magnitude.Clinical epidemiolog

Comparative effectiveness of SGLT2i versus GLP1-RA on cardiovascular outcomes in routine clinical practice

Background: To investigate the comparative effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1-RA) on cardiovascular outcomes in routine clinical practice, which have never been directly compared in head-to-head outcome trials.Methods: We compared outcomes of adults who newly started SGLT2i or GLP1-RA therapy in Stockholm, Sweden, during 2013-2019. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular (CV) death, myocardial infarction and stroke. Secondary outcomes included the individual MACE components and hospitalization for heart failure. Cox regression with propensity score overlap weighting was used to estimate hazard ratios (HRs) with 95% confidence intervals and adjust for 57 covariates.Results: We included 12,375 individuals, of which 5489 initiated SGLT2i and 6886 GLP1-RA therapy, followed for median 1.6 years. Mean age was 61 years and 37.6% were women. Compared with GLP1-RA, SGLT2i new users had similar risk of MACE risk (adjusted HR 1.04; 95% CI 0.83-1.31). The adjusted HRs (95% CI) for SGLT2i vs. GLP1-RA were 0.80 (0.59-1.09) for heart failure hospitalization, 0.95 (0.58-1.55) for cardiovascular death, 0.91 (0.67-1.24) for myocardial infarction and 1.71 (1.14-2.59) for ischemic stroke (5-year absolute risk dif-ference for stroke 1.9% [95% CI 0.8-3.0]).Conclusions: In a largely primary-prevention population of people undergoing routine care, no differences were observed in MACE risk among initiators of SGLT2i and GLP1-RA. However, compared with GLP1RA, the use of SGLT2i was associated with an increased risk of ischemic stroke that was small in absolute magnitude

Stopping mineralocorticoid receptor antagonists after hyperkalaemia: trial emulation in data from routine care

Aims Whether to continue or stop mineralocorticoid receptor antagonists (MRA) after an episode of hyperkalaemia is a challenge in clinical practice. While stopping MRA may prevent recurrent hyperkalaemias, it deprives patients of their cardioprotection. We here assessed the association between stopping vs. continuingMRA therapy after hyperkalaemia and the subsequent risks of adverse health events.Methods and results Observational study from the Stockholm CREAtinine Measurements (SCREAM) project 2006- 2018. We identified patients initiating MRA and surviving a first-detected episode of hyperkalaemia (plasma potassium >5.0 mmol/L). Using target trial emulation methods, we assessed the association between stopping vs. continuing MRA within 6months after hyperkalaemia and subsequent outcomes. The primary outcome was the composite of hospital admission with heart failure, stroke, myocardial infarction, or death. The secondary outcome was occurrence of another hyperkalaemia event. Among 39 518 patients initiating MRA, we identified 7366 who developed hyperkalaemia. Median age was 76 years, 45% were women and 69% had a history of heart failure. Following hyperkalaemia, 2222 (30%) discontinued treatment. Compared with continuing MRA, stopping therapy was associated with a lower 2-year risk of recurrent hyperkalaemia [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.72-0.79], but a higher risk of the primary outcome (HR 1.10, 95% CI 1.06-1.14). Similar results were observed in patients with heart failure, after censoring when treatment decision was changed, and across pre-specified subgroups.Conclusions Stopping MRA after an episode of hyperkalaemia was associated with reduced risk for recurrent hyperkalaemia, but higher risk of death or cardiovascular events. Recurrent hyperkalaemia was common in either strategy.Clinical epidemiolog

Association of Acute Increases in Plasma Creatinine after Renin-Angiotensin Blockade with Subsequent Outcomes

Background and objectives Data from observational and interventional studies provide discordant results regarding the relationship between creatinine increase after renin-angiotensin system inhibition (RASi) and adverse outcomes. We compared health outcomes among patients with different categories of increase in creatinine upon initiation of RASi in a large population-based cohort.Design, setting, participants, & measurements We performed a retrospective analysis of the Stockholm CREAtinine Measurements database, which contains complete information on diagnoses, medication dispensation claims, and laboratory test results for all Stockholm citizens accessing health care. Included were 31,951 adults initiating RASi during 2007-2011 with available pre- and postinitiation creatinine monitoring. Multivariable Cox regression was used to compare mortality, cardiovascular and ESKD events among individuals with different ranges of creatinine increases within 2 months after starting treatment.Results In a median follow-up of 3.5 years, acute increases in creatinine were associated with mortality (3202 events) in a graded manner: compared with creatinine increases = 30%. Similar graded associations were present for heart failure (2275 events, P10%) after initiation of RASi are associated with worse health outcomes. These results do not address the issue of discontinuation of RASi when plasma creatinine increases but do suggest that patients with increases in creatinine have higher subsequent risk of cardiovascular and kidney outcomes.Nephrolog

Removing race from the CKD-EPI equation and its impact on prognosis in a predominantly White European population

Background While American nephrology societies recommend using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) equation without a Black race coefficient, it is unknown how this would impact disease distribution, prognosis and kidney failure risk prediction in predominantly White non-US populations. Methods We studied 1.6 million Stockholm adults with serum/plasma creatinine measurements between 2007 and 2019. We calculated changes in eGFR and reclassification across KDIGO GFR categories when changing from the 2009 to 2021 CKD-EPI equation; estimated associations between eGFR and the clinical outcomes kidney failure with replacement therapy (KFRT), (cardiovascular) mortality and major adverse cardiovascular events using Cox regression; and investigated prognostic accuracy (discrimination and calibration) of both equations within the Kidney Failure Risk Equation. Results Compared with the 2009 equation, the 2021 equation yielded a higher eGFR by a median [interquartile range (IQR)] of 3.9 (2.9-4.8) mL/min/1.73 m(2), which was larger at older age and for men. Consequently, 9.9% of the total population and 36.2% of the population with CKD G3a-G5 was reclassified to a higher eGFR category. Reclassified individuals exhibited a lower risk of KFRT, but higher risks of all-cause/cardiovascular death and major adverse cardiovascular events, compared with non-reclassified participants of similar eGFR. eGFR by both equations strongly predicted study outcomes, with equal discrimination and calibration for the Kidney Failure Risk Equation. Conclusions Implementing the 2021 CKD-EPI equation in predominantly White European populations would raise eGFR by a modest amount (larger at older age and in men) and shift a major proportion of CKD patients to a higher eGFR category. eGFR by both equations strongly predicted outcomes.Clinical epidemiolog