Clinical Controversies: Recent Updates for Medication Use in Chronic Kidney Disease - PowerPoint Presentation

1. Clinical Controversies: Recent Updates for Medication Use in Chronic Kidney DiseaseTracy Anderson-Haag, PharmD, BCPSClinical Pharmacy SpecialistHennepin HealthcareandClinical Assistant ProfessorUniversity of Minnesota, College of Pharmacy

2. ObjectivesDescribe recent changes to medication labeling, guidelines and practice patterns for use of controversial medications in patients with chronic kidney diseaseReview literature driving changes in labeling, guidelines and usageRecognize how described changes affect your daily management of the CKD patient

3. Clinical ControversiesWhat are YOU doing?

4. Urinary Tract InfectionsNitrofurantoin News: Old Dogs, New Tricks?

5. NitrofurantoinFDA approval: 1953Indicated for treatment of uncomplicated UTIsOnly effective for cystitis-very little systemic exposure*Bacteriocidal in urine; negligible prostate penetrationBroad spectrum of gm negative and gm positive bacteriaSome Klebsiella strains, Pseudomonas aeruginosa and Proteus, Morganella and Providencia sp. inherently resistant

6. NitrofurantoinMechanism of ActionInactive antiseptic; activated in the urineReaches urine through glomerular filtration, active proximal tubular secretion and tubular reabsorptionReduced by bacterial flavoproteins to reactive intermediates which inactivate or alter bacterial ribosomal proteins and other macromoleculesPatients with CrCl < 20 mL/min excrete no drugAntibacterial activity and urine concentration dependent on urine pH; optimal at 5.4-7

7. NitrofurantoinAdverse effects (associated most often with impaired kidney function or long term use) Nausea, vomiting, diarrheaPulmonary toxicityLiver toxicityPeripheral neuropathyHeadacheFlatulenceDiscolored urine (brown in most, can also be yellow..GASP!)

8. Nitrofurantoin: What WasContraindication with CrCl < 60 mL/minElimination of nitrofurantoin reduced with low kidney functionRisksEfficacy Inadequate drug levels in urineTreatment failuresSafetyElevated drug levels in bloodSupporting EvidenceSmall sample size ( 9-20 pts with “low” CrCl)Lack of clinical outcomesDespite these recommendations, nitrofurantoin is used frequently in patients with high potential for or known compromised kidney function

9. News on NitrofurantoinPrescribing Information: UnchangedClinical practice “guidelines” have become more permissive2015 Beer’s Criteria:“can be used with relative safety and efficacy in individuals with a creatinine clearance of 30 mL/min or greater”“long term use for suppression should still be avoided” related to safety concerns

10. Nitrofurantoin: What IsContraindication with CrCl < 30 mL/minGuidelines/Antibiotic resistance pushing practice toward use of nitrofurantoinLimited PO options, worth a try?Risk for lack of assessment of appropriateness of therapy Reassessment through systematic reviews and meta-analysisSupporting Evidence?

11. Nitrofurantoin: What IsSingh N et al (2015)Retrospective, database review women > 65 with relatively low (38 mL/min) or high estimated GFR (69 mL/min)No difference in clinical efficacy from other antibiotics between low or high groups Baines, et al (2009)Retrospective cohort study; control (92 mL/min) and renal impairment group (48 mL/min)Cure rates and ADRs similar between control and renal impairment group

12. Nitrofurantoin: What IsGeerts et al (2013) Retrospective studyeGFR 30-49 mL/min/1.73m2 not significantly associated with ineffective nitrifurantoin treatmenteGFR < 50 mL/min/1.73m2 higher risk of ADR (pulmonary toxicity)Santos JM et al (2016)Retrospective, matched cohort study; age > 65No difference in treatment efficacy between CrCl < 30, 30-60 or > 60 mL/minAcute exposure did not increase risk of pulmonary toxicityChronic exposure did increase risk of pulmonary toxicity, but so did chronic use of other antibiotics?No new “landmark” paper; more lack of evidence to support current restriction; where did 30 mL/min come from?

13. Nitrofurantoin & Clinical PracticeWhat should be?Still left with limited data to support appropriate use or CrCl/GFR “cut off”Appropriate risk:benefit assessment of useFollow up to assess efficacyContinue to discourage chronic use related to safety concerns

14. DiabetesIn with the Old, Out with the New?

15. In with the Old and Out with the New?Diabetes ManagementMetformin (April 2016)Sodium-glucose transporter 2 (SGLT2) inhibitors (June 2016)Canagliflozin, dapagliflozin, empagliflozinRecent FDA Drug Safety Communications regarding kidney disease

16. MetforminFirst line therapy for nearly all patients with DM2Historically contraindicated due to risk of lactic acidosisSCr ≥ 1.5 mg/dL for males, 1.4 mg/dL for females“Abnormal renal function”Recently has become clinical controversy as additional data demonstrating significant clinical benefits and minimizing safety concerns

17. Metformin Safety: Review Excreted renally; risk of accumulation with acute/chronic kidney diseaseIncreased risk of exposure dependent toxicity leading to lactic acidosisSmall studies show drug levels remain normal with CrCl > 30 mL/min/1.73m2Phenformin (removed from market): higher rate of lactic acidosisMore lipophilicMore slowly clearedIncreases muscle lactate release and inhibits lactate oxidation

18. Metformin Safety: Review Inzucci, S et al: “Frequency of lactic acidosis in the setting of metformin therapy is very low and numerically similar to what appears to be the background rate in the population with type 2 diabetes.”May be slightly higher risk of lactic acidosis with eGFR < 45-60 mL/min/1.73m2, but also significant clinical benefits (macrovascular), including reduced cardiac mortalityInzucci S, et al JAMA. Dec 2014; 312(24): 2668-2675.

19. MetforminWhat has changed?Dosing restrictions based on eGFR value instead of SCrBefore starting metformin, obtain eGFRContraindicated in patients with eGFR < 30 mL/min/1.73m2Not recommended to start with eGFR between 30-45 mL/min/1.73m2Annual eGFR; more frequent with higher risk (ie elderly)If eGFR falls to < 45 mL/min/1.73m2, consider risk/benefitD/C metformin if eGFR falls to < 30 mL/min/173m2

20. MetforminLazarus, et alCommunity-based cohort studyObjective: quantify association between metformin use and hospitalization with acidosis across range of eGFRsN=75,413Metformin associated with acidosis only at eGFR < 30 mL/min/1.73m2Events per 1000 patient yearseGFR > 60-89 mL/min/1.73m2 = 4eGFR 45-59 mL/min/1.73m2 = 7eGFR 30-44 mL/min/1.73m2 = 10eGFR < 30 mL/min/1.73m2 = 24Lazarus B, et al. JAMA Internal Medicine. 2018; 178(7): 903-910.

21. MetforminSuggested dosing in CKDLalau JD, et al. Diabetes Care. 2018; 41: 547-553.eGFR (mL/min/1.73m2)Metformin Dose45-59500 mg PO AM and 1000 mg PO PM30-44500 mg PO BID15-29500 mg PO Daily****NOT recommended for use with eGFR < 30 mLmin/1.73m2

22. Metformin in PracticeSick day educationClose monitoring of eGFR and communication to providers if eGFR approaching 30 mL/min/1.73m2Recent VA paper showing reduction in mortality for metformin over sulfonylurea, especially among pts with GFR 30-45 mL/min/1.73m2 –more to come!Marcum ZA, et al. Journal of General Internal Medicine. 2018; 33(2): 155-165.

23. SGLT2 InhibitorsCanagliflozin (Invokana®), dapagliflozin (Farxiga®), empagliflozin (Jardiance®)Sodium-glucose cotransporter 2 inhibitorDecrease reabsorption of renally-filtered glucose in the proximal tubules; increases urinary glucose excretionCarry warnings about risk of AKI

24. SGLT2 InhibitorsMarch 2013-October 2015, 101 cases of AKIHalf of cases within 1 month of initiation of medicationMost improved after d/c of agentSome required hospitalization or dialysisSome patients had additional risk factors for AKI

25. SGLT2 InhibitorsStrengthened warning for AKI riskAssess kidney function before initiation of therapy; monitor periodically thereafterConsider predisposing factors for AKIDecreased blood volumeCKDCHFDiuretics/ACEI/ARB/NSAIDs

26. SGLT2 InhibitorsContraindicatedCrCl < 30 mL/min/1.73m2Do not initiate if CrCl < 45 mL/min/1.73m2In generalCautions or Not Recommended for use if CrCl < 60 mL/min/1.73m2So…for us…just don’t do it. But then again…

27. Canagliflozin and CV and Renal Events in Type 2 Diabetes (CANVAS)Type 2 diabetes and high CV risk N=10,142Canagliflozin or placeboSodium-glucose cotransporter 2 inhibitorPrimary Outcome: composite of death from CV cause, nonfatal MI, nonfatal strokeSecondary Outcomes: CV, CHF, also renal outcomesNeal B, et al. NEJM. August 17, 2017; 377(7): 644-657.

28. Canagliflozin and CV and Renal Events in Type 2 Diabetes (CANVAS)ResultsRate of primary outcome lower with canagliflozin than placebo26.9 vs 31.5 patients per 1000 patient-yearsHazard ratio 0.86 [CI 0.75-0.97]; p< 0.001 for noninferiority, 0.02 for superiorityPotential benefit for progression of albuminuria and renal composite outcomeCREDENCE (Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation Trial)Hot off the press- July 18, 2018: CREDENCE study has been stopped due to positive efficacy findings (composite endpoint of ESKD, doubling of SCr and renal or CV death)

29. Canagliflozin and CV and Renal Events in Type 2 Diabetes (CANVAS)SafetyIncreased risk of amputations6.3 vs 3.4 patients per 1000 patient-years, HR 1.97 [CI 1.41-2.75]Primarily toe or metatarsal

30. Empagliflozin (EMPA-REG) StudyIncluded stage 3 CKD patientsCV benefit in T2DM patients

31. SGLT2 Inhibitors in PracticeMay see this used cautiously in CKD patientsSick day education essential due to risk of dehydration/AKI

32. Added Bonus Diabetes Pearls LEADER Study (liraglutide)Included patients with CKD stage 3 and higherSubgroup analysis showed CV benefit in patient with GFR 30-60 mL/min/1.73m2Also demonstrated positive renal outcomes (lower rate of nephropathy events)Remember: this is injectable productDPP-4 inhibitors (-gliptins) all require dose modification for eGFR < 45 mL/min except linagliptinMarso S, et al. NEJM. 2016; 375: 311-22.

33. GERDBye Bye PPI?

34. GERDProton Pump InhibitorsOmeprazole, lansoprazole, esomeprazole, dexlansoprazole, pantoprazole, rabeprazoleInitially prescription only25-70% of prescriptions have no appropriate indicationOTC useJune 20, 2003

35. PPI and SafetyGeneral Hip fractureCommunity acquired pneumoniaClostridium difficile infectionHypomagnesemia Kidney Acute interstitial nephritisAcute kidney injuryRisk of CKD?

36. PPI and CKDObjective: Quantify association between PPI use and incident CKDPopulation10,482 participants; ARIC StudySelf-reported PPI use N=322Self-reported H2-antagonist use N=956Non-users N= 9204248,751 participants, Geisinger Health SystemOutpatient PPI prescription N=16,900H2-antagonist use N=6640Non-users N=225,221Lazarus B, et al. Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA Internal Medicine. 2016; 176(2): 238-246.

37. PPI and CKDPPI users more likely to have higher BMI, take antihypertensive medication, aspirin or statinH2-antagonist users similar to PPI usersBaseline use of PPI independently associated with 20-50% higher risk of incident CKDAlso higher risk of AKI in usersUse of H2-antagonists not independently associated with CKD or AKILazarus B, et al. Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA Internal Medicine. 2016; 176(2): 238-246.

38. Bye Bye PPI?ConsiderationsObservational study cannot provide evidence of causalityMany adjustments made and results were persistentLimitationsOTC use captured consistently?, surveillance bias (discharge codes, outpatient labs), adherence to therapy (PRN v daily v twice daily)Ultimately need to consider risk:benefit

39. What to tell Patients?No data to support that appropriate use of PPI (short term treatment) is problematicStep 1: Define IndicationMany patients likely have no ongoing indication for long-term PPI use (70% of prescriptions with no indication, OTC?!)sShort term with indication, benefit may outweigh risk

40. What to tell Patients?Step 2: Provide Plan for DiscontinuationLifestyle modifications!!!DietBehaviorCan try “cold turkey”; may have rebound symptomsH2-antagonist (ranitidine, famotidine, avoid cimetidine)TUMS, antacids (if able considering calcium, magnesium, aluminum contents)Taper scheduleBID Daily Every other day

41. Non-vitamin K dependent Oral Anticoagulants (NOACs)How Low can we Go?

42. NOACInhibit factor Xa (Apix/Edox/Rivarox) or thrombin (dabigatran only)Indications include atrial fibrillation and VTEPros: fixed dosing, no routine monitoringAll agents rely on renal eliminationDabigatran 80% > Rivaroxaban 66% > Edoxaban 50% > Apixaban 27%Reversal agents are now FDA approved; may have limited availability

43. NOACs and CKDCKD Stage 1-3All NOACs non-inferior to warfarin for efficacy; dabigatran achieved superiority endpointApixaban and edoxaban demonstrated superior (lower risk of) bleeding profileCKD Stage 4 and 5DVery little data supporting recommendationsSmall numbersSingle doseUse of anticoagulation for NVAF controversial in 5D; risk v benefit Shroff GR, Stoecker R, Hart A. AJKD. 2018; Online ahead of print.

44. NOACRecent literature identifying inappropriate dosing of DOACsBoth over- and under-dosingSignificant risks associated with both43% of patients who required dose reductions for renal compromise were receiving full dose13.3% of patients on reduced dose with no indicationYao X, Noseworthy PA, et al. Journal of the American College of Cardiology. June 2017.

45. NOACStroke rate higher (2.32 vs 1.85 per 100 patient years) in those on inappropriately high doseMajor bleeding rate higher (11.29 v 5.06 per 100 patient years) in those on inappropriately high doseStroke rate higher (1.7 v 1.43 per 100 patient years) in those on inappropriately low doseMajor bleeding rate slightly higher (5.43 v 5.03) in those in inappropriately low doseSome sign apixaban results for stroke drove effectYao X, Noseworthy PA, et al. Journal of the American College of Cardiology. June 2017.

46. DOAC Dosing in CKDNon-Valvular Atrial FibrillationDVT/PE TreatmentDVT/PE ProphylaxisDabigatranCrClDoseCrClDoseCrClDose>3015-30<15/HD150mg BID75mg BIDND>3015-30<15/HD150mg BIDNDND>3015-30<15/HD150mg BIDNDNDRivaroxaban> 5015-5020mg qPM15mg qPM> 30< 3015mg BID*Avoid> 30< 3010 mg qPMAvoidEdoxaban>95 50-9415-50<15Avoid60mg Daily30mg DailyAvoid>5015-50<1560mg Daily30mg DailyAvoid>15<1530mg DailyAvoidApixabanSCrDoseSCrDoseSCrDose< 1.5>1.5 & ≥ 80 yo or ≤60 kgHD5mg BID2.5mg BID2.5mg BIDNo adjustment for CKD or HD10mg BID x 7 days, then 5mg BIDNo adjustment for CKD or HD2.5mg BID

47. NOAC: Pre-Op H&PTiming of Dabitatran Dose Prior to Surgery or Invasive ProcedureTiming of Last DoseCrCl (mL/min)T1/2 (hr)Standard Bleed riskHigh Bleed Risk> 80 13≥ 24 hrs prior≥48 hrs prior50-80 15≥ 36 hrs prior≥ 72 hrs prior30-5018≥ 48 hrs prior≥ 96 hrs prior< 3027≥ 72 hrs prior≥ 120 hrs priorIf CrCl < 15 mL/min, no data. Consider measuring thrombin time and/or withholding ≥ 96 hoursShroff GR, Stoecker R, Hart A. AJKD. 2018; Online ahead of print.

48. NOAC: Pre-Op H&PApixiban, edoxaban, rivaroxabanLow Bleed Risk ProcedureCrCl ≥ 30 mL/min: d/c ≥ 24 hours priorCrCl 15-29 mL/min: d/c ≥ 36 hours priorCrCl < 15 mL/min: No data; consider measuring agent specific anti-Xa level and/or withholding ≥ 48 hoursUncertain, intermediate or high bleed riskCrCl ≥ 30 mL/min: d/c ≥ 48 hours priorCrCl 15-29 mL/min or < 15 mL/min: No data; consider measuring agent specific anti-Xa level and/or withholding ≥ 72 hoursShroff GR, Stoecker R, Hart A. AJKD. 2018; Online ahead of print.

49. NOACs in PracticeReassess prescribed dose, based on CrCl (Cockcroft-Gault) calculation to ensure appropriateMust also think about age and size!HOLD temporarily during episodes acute kidney injury; consider bridging if appropriateClinical pearlsRivaroxaban must be taken with foodDabigatran cannot be stored in pillboxes; must remain in original bottle

50. NOAC: Select Drug Interactions AbirateroneAmiodaroneDiltiazemDronedaroneErythromycinVerapamilRitonavirCarbamazepineQuinidineAzithromycinClarithromycinItraconazoleKetaconazoleCyclosporine/tacrolimusRifampinPhenytoinCaution: Check for dose modification!

51. ConclusionGuidelines and clinical practice patterns with high risk medications are a moving targetCareful consideration of medication usage and dose with regard to kidney function is imperative to ensure efficacy and safetyNephrology providers are essential to assist with provindg appropriate kidney function estimations and projections to ensure efficacious and safe use of controversial agentsDo not hesitate to consult your friendly pharmacist!