1. © PPRNet, 2007 © PPRNet, 2008 The MS-TRIP 2 Indicator Set The Dissemination of the PPRNet Model for Improving Medication Safety in Primary Care Practice Project AHRQ Grant Number 1 R18HS019593

2. Purpose Define PPRNet Medication Safety indicatorsDefine PPRNet Medication Safety indicators Review available safety evidence behind each indicatorReview available safety evidence behind each indicator Illustrate use of decision support tools within McKesson-Practice Partner ® EHRIllustrate use of decision support tools within McKesson-Practice Partner ® EHR

3. Organization Measure descriptionMeasure description Safety evidenceSafety evidence ReferencesReferences Supplemental informationSupplemental information

4. General Definitions PPRNet reportsPPRNet reports –Active patient: progress note recorded within 1 year (not indicated as “Cancelled” or “No Show”) and not designated as deceased, transferred or inactive status –Active prescription: written within the last 365 days and lacks a discontinuation date If duration available, discontinuation date is calculatedIf duration available, discontinuation date is calculated © PPRNet, 2010.

5. Potentially Inappropriate Therapy Antibiotics within 3 days of an upper respiratory infectionAntibiotics within 3 days of an upper respiratory infection –Excluding patients with COPD exacerbation, otitis media, pneumonia, strep pharyngitis or sinusitis Rarely appropriate and inappropriate medications in the elderlyRarely appropriate and inappropriate medications in the elderly © PPRNet, 2010.

6. Antibiotics in URI Upper respiratory infection = the common cold, pharyngitis or bronchitisUpper respiratory infection = the common cold, pharyngitis or bronchitis Antibiotics are ineffective for viral URI and may lead to increased bacterial resistanceAntibiotics are ineffective for viral URI and may lead to increased bacterial resistance www.cdc.gov/getsmartwww.cdc.gov/getsmart; Annals of Internal Medicine. 2001;134(6):487-9; AHRQ National Healthcare Quality Report.

7. Defining Potentially Inappropriate Medication Use Beers Criteria 1991, 1992, 1997 Beers Criteria 1991, 1992, 1997 Expert Panel 1996 Expert Panel 1996 1996 Medical Expenditure Panel Survey Categories Inappropriate Rarely appropriate Appropriate for some indications but often misused 1996 Medical Expenditure Panel Survey Categories Inappropriate Rarely appropriate Appropriate for some indications but often misused JAMA 2001;286:2823-29; AHRQ National Healthcare Quality Report.

8. Potentially Inappropriate Medications in the Elderly BarbituratesBarbiturates Flurazepam (Dalmane)Flurazepam (Dalmane) Meprobamate (Miltown, Equanil)Meprobamate (Miltown, Equanil) Chlorpropamide (Diabinese)Chlorpropamide (Diabinese) Meperidine (Demerol)Meperidine (Demerol) Pentazocine (Talwin)Pentazocine (Talwin) Trimethobenzamide (Tigan)Trimethobenzamide (Tigan) Belladonna alkaloids (Donnatal and others)Belladonna alkaloids (Donnatal and others) Dicyclomine (Bentyl)Dicyclomine (Bentyl) Hyoscyamine (Levsin, Levsinex)Hyoscyamine (Levsin, Levsinex) Propantheline (Pro- Banthine)Propantheline (Pro- Banthine) JAMA 2001;286:2823-29; Amer J Geri Pharm 2008; 6(1):21-27.

9. Rarely Appropriate Medications in the Elderly Chlordiazopoxide (Librium)Chlordiazopoxide (Librium) Diazepam (Valium)Diazepam (Valium) Propoxyphene (Darvocet)Propoxyphene (Darvocet) Carisoprodol (Soma)Carisoprodol (Soma) Chlorzoxazone (Paraflex)Chlorzoxazone (Paraflex) Cyclobenzaprine (Flexeril)Cyclobenzaprine (Flexeril) Metaxalone (Skelaxin)Metaxalone (Skelaxin) Methocarbamol (Robaxin)Methocarbamol (Robaxin) JAMA 2001;286:2823-29; Amer J Geri Pharm 2008; 6(1):21-27.

10. © PPRNet, 2010.

11. Potentially Inappropriate Dosages Allopurinol based on renal functionAllopurinol based on renal function Short-acting benzodiazepines in the elderlyShort-acting benzodiazepines in the elderly Digoxin in the elderly with CHFDigoxin in the elderly with CHF H-2 blockers based on renal functionH-2 blockers based on renal function © PPRNet, 2010.

12. How is renal function defined in MS-TRIP? For pts w/Serum Creatinine recorded in the last year: Calculated CrCl/GFR by Cockcroft-Gault estimate (140 – age) * wt (kg) *0.85 females (140 – age) * wt (kg) *0.85 females 72 * SCr (mg/dl) 72 * SCr (mg/dl) Same estimate used in PP Dose AdvisorSame estimate used in PP Dose Advisor Limitations: Overweight patients, SCr < 0.7 mg/dl, fluctuating SCrLimitations: Overweight patients, SCr < 0.7 mg/dl, fluctuating SCr

13. What about eGFR from the lab? Estimated GFR by MDRD Study EquationEstimated GFR by MDRD Study Equation 170 * (SCr -0.999 ) * (Age -0.176 ) * Sex (0.762 if female) 170 * (SCr -0.999 ) * (Age -0.176 ) * Sex (0.762 if female) * Race (1.18 if black) * (BUN -0.170 ) * (Albumin 0.318 ) * Race (1.18 if black) * (BUN -0.170 ) * (Albumin 0.318 ) Recommended by National Kidney Foundation for CKD evaluation/stagingRecommended by National Kidney Foundation for CKD evaluation/staging Limitations: Young patients w/o kidney disease, age > 85 yrs, pregnant women, Hispanic subgroupsLimitations: Young patients w/o kidney disease, age > 85 yrs, pregnant women, Hispanic subgroups National Kidney Foundation, www.kdoqi.org.

14. GFR estimates: Which is better for drug dosing? No evidence-based answerNo evidence-based answer C-G is recommended if differences exist since this estimate is used in standardized dosing recommendationsC-G is recommended if differences exist since this estimate is used in standardized dosing recommendations Bottom line: Use ‘Dose advisor’ calculations instead of eGFR to estimate renal function and medication adjustmentsBottom line: Use ‘Dose advisor’ calculations instead of eGFR to estimate renal function and medication adjustments © PPRNet, 2010.

15. Allopurinol in Renal Impairment Avoidance of daily dose over 200 mg for GFR 20-60 ml/min, over 100 mg for < 20 ml/minAvoidance of daily dose over 200 mg for GFR 20-60 ml/min, over 100 mg for < 20 ml/min Safety concernSafety concern –Potential toxicity due to accumulation of metabolite Skin rash, fever, hepatotoxicity, worsening renal functionSkin rash, fever, hepatotoxicity, worsening renal function Reduced doses are effective for most patientsReduced doses are effective for most patients Newer agents should also be used cautiouslyNewer agents should also be used cautiously American Journal of Medicine 1984;76(1):47-56.

16. Benzodiazepines in the Elderly Avoidance of daily dose over 2 mg alprazolam, 3 mg lorazepam (Ativan), 60 mg oxazepam (Serax), 15 mg temazepam (Restoril), 0.25 mg triazolam (Halcion) in patients > 65 yrsAvoidance of daily dose over 2 mg alprazolam, 3 mg lorazepam (Ativan), 60 mg oxazepam (Serax), 15 mg temazepam (Restoril), 0.25 mg triazolam (Halcion) in patients > 65 yrs Safety concernSafety concern –Greater sensitivity to effects and adverse reactions –Increased risk of falls, memory impairment and cognitive decline Archives of Internal Medicine. 2003;163(22):2716-24; Journal of the American Geriatrics Society 2007;55(s2):S373-S82.

17. Digoxin in the Elderly with CHF Avoidance of daily dose >0.125 mg/day in patients > 65 yrs with CHFAvoidance of daily dose >0.125 mg/day in patients > 65 yrs with CHF Safety concernsSafety concerns –Adverse reactions from decreased renal clearance: nausea, vomiting, anorexia Efficacy in CHF established with low dosesEfficacy in CHF established with low doses Archives of Internal Medicine. 2003;163(22):2716-24.

18. H2 blockers in Renal Impairment Avoidance of maximum dose for GFR < 50 ml/minAvoidance of maximum dose for GFR < 50 ml/min –Cimetidine (Tagamet) > 1200 mg –Nizatidine (Axid) > 150 mg –Famotidine (Pepcid) > 20 mg –Ranitidine (Zantac) > 150 mg Safety concernsSafety concerns –Potential adverse reactions include delirium, confusion and agitation –Mechanism unclear, possibly due to histamine receptors in the CNS and/or anticholinergic effects Nephrology Dialysis Transplantation. 2005;20(11):2376-84.

20. Macrolide antibiotics (excluding azithromycin) and digoxinMacrolide antibiotics (excluding azithromycin) and digoxin Tetracycline and digoxinTetracycline and digoxin Itraconazole and statinItraconazole and statin Lithium and thiazide diureticLithium and thiazide diuretic Methotrexate and trimethoprimMethotrexate and trimethoprim Sulfonylurea and sulfamethoxazole in patients > 65 yrsSulfonylurea and sulfamethoxazole in patients > 65 yrs Potential Drug – Drug Interactions © PPRNet, 2010.

21. Potential Drug-Drug Interactions Definition of eligible patients for reportsDefinition of eligible patients for reports –Patients with active prescriptions for either medication

22. Macrolides + Digoxin Safety concernSafety concern –Increased absorption of digoxin and potential toxicity –Older patients admitted to the hospital for digoxin toxicity were 12 times more likely to have received clarithromycin in the past week Indicator excludes patients on azithromycinIndicator excludes patients on azithromycin Management recommendationsManagement recommendations –Use alternative antibiotic –No clear guidance on reducing digoxin dose JAMA 2003;289:1652-1658.

23. Statins + Itraconazole Safety concernSafety concern –Increased risk of rhabdomyolysis due to inhibition of statin metabolism Management recommendationsManagement recommendations –Use alternative(s) to itraconazole –Some data suggest lower interaction risk with pravastatin or rosuvastatin

24. Lithium + Thiazide diuretics Safety concernSafety concern –Decreased lithium clearance  lithium toxicity (confusion, weakness, GI) Management recommendationsManagement recommendations –Use non-diuretic HTN treatment –Reduce lithium dose and monitor regularly

25. Methotrexate + TMP/SMX Safety concernSafety concern –Pancytopenia via displaced protein binding of MTX and additive antifolate activity Management recommendationManagement recommendation –Use alternative to TMP/SMX

26. Sulfonylurea + SMX in the Elderly Safety concernSafety concern –Hypoglycemia via displacement of sulfonylurea from protein binding sites –Older patients admitted to the hospital for hypoglycemia on glyburide were 6 times more likely to have received SMX in the past week Management recommendationsManagement recommendations –Use alternative antibiotic –Depending on glycemic control, hold sulfonylurea during SMX course JAMA. 2003;289:1652-1658.

27. Drug Interaction Alerts

28. Improving the accuracy of interaction alerts

29. Anticholinergics in dementiaAnticholinergics in dementia Bupropion in epilepsyBupropion in epilepsy Metformin in pts with SCr >1.4 (female), 1.5 (male)Metformin in pts with SCr >1.4 (female), 1.5 (male) Metoclopramide in Parkinson’s DiseaseMetoclopramide in Parkinson’s Disease NSAID or COX2 Inhibitor in CHF, HTN or GFR < 20 ml/minNSAID or COX2 Inhibitor in CHF, HTN or GFR < 20 ml/min NSAID in peptic ulcer diseaseNSAID in peptic ulcer disease Thiazolidinediones in CHFThiazolidinediones in CHF Potential Drug – Disease Interactions

30. Anticholinergics in Dementia Antihistamines, skeletal muscle relaxants, urinary incontinence, GI antispasmodicsAntihistamines, skeletal muscle relaxants, urinary incontinence, GI antispasmodics –Indicator excludes tricyclic antidepressants Safety concernSafety concern –Disorientation, confusion, delirium by further reduction of acetylcholine in CNS –Increased potential for problems in patients on acetylcholinesterase inhibitors for dementia J Am Geriatr Soc 2002;50:1165-1166. Am J Geriatr Psychiatry 2003;11:458-461..

31. Bupropion in Seizures Safety concernSafety concern –Antidepressants are associated with seizures to varying degrees –Bupropion carries higher risk than SSRIs Biological Psychiatry 2007;62(4):345-354.

32. Metformin in Renal Impairment Avoidance in men with SCr > 1.5 mg/dl and women > 1.4 mg/dlAvoidance in men with SCr > 1.5 mg/dl and women > 1.4 mg/dl Safety concern: lactic acidosisSafety concern: lactic acidosis –Conclusion from analysis of ~200 studies: “No evidence to date…an increased risk of lactic acidosis compared to other antihyperglycemic treatments if the drug is prescribed under study conditions” Consistent with contraindications from product labelingConsistent with contraindications from product labeling Arch Int Med 2003;163:2594-2602.

33. Metoclopramide in Parkinson’s Disease Safety concernSafety concern –Tardive dyskinesia through metoclopramide’s antagonism of dopamine receptors Clinical Therapeutics 2006;28(8):1133-43.

34. NSAIDs, COX2 Inhibitors in CHF Safety concernsSafety concerns –Fluid retention and risk of exacerbation –Association established across classes for increased cardiovascular morbidity and mortality Published warnings through FDA “black box” and public health advisoriesPublished warnings through FDA “black box” and public health advisories American Heart Association and American Geriatrics Society panels include CHF as contraindication to NSAID, COX2 therapyAmerican Heart Association and American Geriatrics Society panels include CHF as contraindication to NSAID, COX2 therapy Circulation 2007; 115:1634-1642; Journal of the American Geriatrics Society 2009;57:1331–1346; Arch Intern Med. 2009;169(2):141-9.

35. NSAIDs, COX2 Inhibitors in HTN Safety concernsSafety concerns –Increased BP (+5 mmHg) by inhibiting vasodilation from prostaglandins –May interfere w/antihypertensive efficacy Longer rx duration = greater likelihood of adverse drug reactionLonger rx duration = greater likelihood of adverse drug reaction Unknown if effect is agent or class-specificUnknown if effect is agent or class-specific JAMA 1994;272:781-786; Annals of Pharmacotherapy 2003;37(3):442-446.

36. NSAIDs, COX2 Inhibitors in GFR < 20 ml/min Safety concernsSafety concerns –Decreased renal blood flow via prostaglandin inhibition 12% of Medicare beneficiaries with renal failure received an NSAID or COX2 in 200912% of Medicare beneficiaries with renal failure received an NSAID or COX2 in 2009 American Geriatrics Society panel includes CKD as contraindication to NSAID, COX2 therapyAmerican Geriatrics Society panel includes CKD as contraindication to NSAID, COX2 therapy Journal of the American Geriatrics Society 2009;57:1331–1346; 2009 NCQA State of Health Care Quality Report.

37. NSAIDs, COX2 Inhibitors in Peptic ulcer disease Safety concernsSafety concerns –Decreased renal blood flow via prostaglandin inhibition American Geriatrics Society panel includes CKD as contraindication to NSAID, COX2 therapyAmerican Geriatrics Society panel includes CKD as contraindication to NSAID, COX2 therapy Journal of the American Geriatrics Society 2009;57:1331–1346; 2009 NCQA State of Health Care Quality Report.

38. TZDs in CHF Safety concernsSafety concerns – –Cautions published by American Heart Association and American Diabetes Association in 2004 – –Potential fluid retention and weight gain (+ 2-5 kg) – –Increased risk of developing CHF established vs placebo in >20,000 pts (RR 1.72) Diabetes Care 2004; 27:256-263. Lancet 2007;9593:1129-1136.

39. Disease Interaction Alerts

40. Serum creatinine monitoringSerum creatinine monitoring –Annual ACEI or ARBACEI or ARB DigoxinDigoxin DiureticDiuretic MetforminMetformin NSAID or COX-2 InhibitorNSAID or COX-2 Inhibitor –Every 6 months Pts > 65 yrs or GFR 65 yrs or GFR < 50 ml/min on ACEI/ARB and K- sparing diuretic Monitoring of Potential Adverse Drug Events © PPRNet, 2010.

41. Potassium monitoringPotassium monitoring –Annual ACEI or ARBACEI or ARB DigoxinDigoxin DiureticDiuretic –Every 6 months Pts > 65 yrs or GFR 65 yrs or GFR < 50 ml/min on ACEI/ARB and K- sparing diuretic –Most recent value > 3.5 meq/L in pts on thiazide diuretics Monitoring of Potential Adverse Drug Events © PPRNet, 2010.

42. Diuretics Adverse reactions: hypokalemia, decreased renal functionAdverse reactions: hypokalemia, decreased renal function Monitoring may prevent potential adverse events from drug-drug interactionsMonitoring may prevent potential adverse events from drug-drug interactions Lack of monitoring is commonly cited as cause of preventable ADRsLack of monitoring is commonly cited as cause of preventable ADRs Potassium target > 3.5 meq/LPotassium target > 3.5 meq/L –Pts with hypokalemia after 1 year of chlorthalidone for HTN had a similar risk of CV and CHD events as pts on placebo Hypertension 2000;35:1025-1030.

43. ACEI/ARB + K-sparing diuretic Elevations in serum creatinine and potassium are two most common adverse reactionsElevations in serum creatinine and potassium are two most common adverse reactions Admissions for and mortality from hyperkalemia significantly increased when spironolactone was added to ACEI in heart failure ptsAdmissions for and mortality from hyperkalemia significantly increased when spironolactone was added to ACEI in heart failure pts Older pts admitted to the hospital for hyperkalemia on an ACEI were 20 times more likely to have received a K-sparing diuretic in the past weekOlder pts admitted to the hospital for hyperkalemia on an ACEI were 20 times more likely to have received a K-sparing diuretic in the past week Arch Intern Med 2000;685–693. JAMA 2003;289:1652-1658. NEJM 2004;351:543-551.

44. NSAIDs, COX2 Inhibitors Renal toxicity occurs in up to 20% of high risk patientsRenal toxicity occurs in up to 20% of high risk patients Evidence-based guidelines for monitoring are lackingEvidence-based guidelines for monitoring are lacking –American Heart Association panel recommends SCr for patients on chronic rx Class is commonly identified as a cause of preventable ADEsClass is commonly identified as a cause of preventable ADEs West J Med 1991;155:39-42; Circulation 2007; 115:1634-1642

45. Annual Glucose and Weight for Antipsychotics Includes typical and atypical antipsychoticsIncludes typical and atypical antipsychotics Safety concern: weight gain and related complications of diabetes mellitus and dyslipidemia are on the rise in this populationSafety concern: weight gain and related complications of diabetes mellitus and dyslipidemia are on the rise in this population Both mechanism and understanding agent- specific versus class effect are unclearBoth mechanism and understanding agent- specific versus class effect are unclear Diabetes Care 2004;27(2):596-601.

46. Annual Hemoglobin and Platelet Count for Antiplatelets and Anticoagulants Includes new agents and excludes aspirinIncludes new agents and excludes aspirin Safety concern: Major and minor bleeding complications, thrombocytopeniaSafety concern: Major and minor bleeding complications, thrombocytopenia Evidence for monitoring benefit on outcomes is lackingEvidence for monitoring benefit on outcomes is lacking Availability of trends may improve ability to detect minor bleeding episodesAvailability of trends may improve ability to detect minor bleeding episodes CHEST 2008;133(6) suppl:199S-233S.

47. Annual Glucose and Weight for Antipsychotics Includes typical and atypical antipsychoticsIncludes typical and atypical antipsychotics Safety concern: weight gain and related complications of diabetes mellitus and dyslipidemia are on the rise in this populationSafety concern: weight gain and related complications of diabetes mellitus and dyslipidemia are on the rise in this population Both mechanism and understanding agent- specific versus class effect are unclearBoth mechanism and understanding agent- specific versus class effect are unclear Diabetes Care 2004;27(2):596-601.

48. Warfarin Two indicators: INR within 45 days and most recent INR < 5Two indicators: INR within 45 days and most recent INR < 5 2008 American College of Chest Physician guidelines recommend INR every 4 weeks in stable patients2008 American College of Chest Physician guidelines recommend INR every 4 weeks in stable patients Correlation between major bleeding events and INRs > 5 in ambulatory clinicsCorrelation between major bleeding events and INRs > 5 in ambulatory clinics CHEST 2008;133(6) suppl:160S-198S.

49. Folic Acid and Methotrexate Adverse reactions of MTX: GI intolerance, hepatotoxicity, pancytopeniaAdverse reactions of MTX: GI intolerance, hepatotoxicity, pancytopenia Cochrane reviewCochrane review –Folic acid 5 mg/week (or less) d ecreased mucosal and GI adverse events by 80% in patients on low- dose MTX for rheumatoid arthritis Use of folic acid improves MTX continuation rates by reducing LFT changes and GI intoleranceUse of folic acid improves MTX continuation rates by reducing LFT changes and GI intolerance Cochrane Database of Systematic Reviews 1999, Issue 4. Art. No.: CD000951; Rheumatology 2004;43(3):267-71.

50. HM Monitoring Prompts