BACKGROUND/RATIONALE:
Prevention and recognition of drug-related problems in the elderly as principal health care safety issues for this decade. Successful interventions cannot be developed without valid definitions of potentially inappropriate prescribing in the elderly (PIPE). The National Committee on Quality Assurance (NCQA) defined PIPE using two measures incorporated into future Health Plan Employer Data and Information Sets (HEDIS): specific drugs to avoid (High Risk Medications in the Elderly; HRME), and clinically relevant drug-disease interactions (Rx-DIS).

OBJECTIVE(S):
Objective 1: Assess the association between HRME and Rx-DIS exposure and general outcomes measures.

Objective 2: Assess the association between HRME and Rx-DIS exposure and patient outcomes more specific to PIPE such as fall-related injuries.

Objective 3: Develop PIPE-specific utilization measures and assess their association with HRME and Rx-DIS exposure.

Objective 4: Identify the extent to which VA hospitalizations are caused by adverse drug events associated with HRME or Rx-DIS exposure.

For these objectives, we hypothesized that exposure to HRME and Rx-DIS would be associated with increased risk of adverse outcomes.

METHODS:
This retrospective database study examined exposure to drugs included in the HRME and Rx-DIS measures in FY06, and outcomes for 12 months following that exposure. Using national VA inpatient and outpatient data, we first identified Veterans who were 65 years of age in FY06, and who received VA care between FY04-06 to assess HRME. A sub-sample of individuals with conditions relevant to Rx-DIS (dementia, falls/hip fracture and chronic renal failure) was identified using NCQA criteria.

VA Pharmacy (PBM) data were used to define HRME and Rx-DIS exposure based on NCQA criteria. We examined outcomes only among individuals having new exposure compared to no exposure; those with chronic exposure were excluded from analyses.

Outcomes included general adverse outcomes (mortality, emergency [ER]/hospital care), outcomes more specific to PIPE, and PIPE-specific outcomes, developed using an expert consensus process. We conducted hierarchical multivariable logistic regression analyses to assess the relationship of HRME and Rx-DIS measures with adverse outcomes. To minimize confounding, analyses controlled for disease burden. For more specific and PIPE-specific outcomes we also controlled for similar events prior to exposure. We also stratified analyses focusing on patients with similar disease conditions/medication patterns to gain a better understanding of the impact of PIPE in similar types of patients.

Finally, we conducted a fine grained analysis using medical chart abstraction of 1000 randomly selected VA hospitalizations to determine the extent to which unplanned hospitalizations were precipitated by an adverse drug event (ADE; identified by two clinical pharmacists using the Naranjo method). For those ADE-related hospitalizations, we further examined the extent to which the ADE was caused by HRME/Rx-DIS exposure. Odds ratios (OR) below are adjusted for potential confounders.

FINDINGS/RESULTS:
Among the 1,780,787 veterans who met inclusion criteria, 276,825 (15.5%) had prevalent HRME exposure in FY06; exposure was incident for 80,475 (4.5% of cohort). Of the 305,041 older veterans with dementia, falls, and acute renal failure, the one-year prevalence of HEDIS Rx-DIS exposure was 15.2%; prevalence was 20.2% for dementia, 16.2% for falls, and 8.5% for chronic renal failure; the overall incidence of Rx-DIS was 3.2%.

Analyses examining mortality and general ER/hospital care found that HRME was significantly associated with subsequent mortality (OR 1.60, [1.54-1.67]) and ER/hospital care (2.54, [2.48-2.60]). Similar results were found for mortality with regard to Rx-DIS (1.61, [1.52-1.71]) and while statistically significant, the effect size for ER/hospital care was small (1.08, [1.01-1.16]).

Analyses of of more specific outcomes indicated that incident HRME exposure was associated with an increased risk of emergency or hospital care for falls and fall related injuries (2.69 [2.64-2.74]).

Analyses of PIPE-specific outcomes by drug group found that HRME exposure was associated with PIPE-specific adverse outcomes for cardiac medications (5.12 [1.75-15.07]), skeletal muscle relaxants (2.6 [2.23-3.25]), opioids (2.47 [1.92-3.17]), antihistamines (1.49 [1.42-1.55]), and gastrointestinal antispasmodics (1.47 [1.11-1.95]). The only commonly used drug group that did not have a significant association with condition-specific adverse outcomes was non-steroidal anti-inflammatory drugs (tramadol). There was a significant association between Rx-DIS and PIPE-specific outcomes for those with dementia (1.29 [1.11-1.51]) but not for those with chronic renal failure (0.97 [0.75-1.25]). The direction of the significant effect for falls (0.47 [0.41-0.53]) was opposite of what was expected.

Of 1000 randomly selected hospitalizations, 678 were unplanned admissions. Seventy ADEs involving 113 drugs occurred in 68 (10%) veterans; of these, 38.6% were preventable. The most common ADEs that occurred were bradycardia (n=6; beta blockers, digoxin), hypoglycemia (n=6; sulfonylureas not included in HRME, insulin), falls (n=6; antidepressants, ACE-inhibitors), and mental status changes (n=6; anticonvulsants, benzodiazepines not included in HRME). Only one ADE-related hospitalization was associated with HRME exposure (GI antispasmodic associated constipation), and two ADE-related hospitalizations for ibuprofen associated acute renal failure (Rx-DIS). Using multivariable logistic regression and controlling for potential confounders, polypharmacy (9+ and 5-8 medications/year) was associated with an increased risk of ADEs (3.90 [1.43-10.61] and 2.85 [1.03-7.85] respectively).


IMPACT:
Data indicate that exposure to HRME/Rx-DIS is lower than NCQA's assessment using Medicare data, and that exposure diminished over the time of this study, which is an indicator of improved quality of care. While large database analyses largely supported the link between exposure and adverse outcomes, analyses based on medical chart abstraction found no relationship between ADE-related hospitalizations and HRME/Rx-DIS. It is, however, possible that the small sample size limited the power to detect significant differences.

Findings from the chart abstraction are consistent with previous research indicating specific drugs (e.g., warfarin, short half-life benzodiazepines) and drug disease interactions (NSAIDs in peptic ulcer disease) NOT included in the HRME/ Rx-DIS measures are more tightly linked with adverse outcomes than many medications currently included in these measures.

These findings are being used to re-assess the HRME and Rx-DIS measures. For instance, the NCQA is considering the addition of short-half-life benzodiazepines to the HRME measure, and adding peptic ulcer disease/ NSAIDs to the Rx-DIS measure based in part on these findings. It is possible that these data will provide impetus to further re-evaluate medications included in the HRME and Rx-DIS measures.

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External Links for this Project

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PUBLICATIONS:

Journal Articles

1. Pugh MJ, Copeland LA, Zeber JE, Wang CP, Amuan ME, Mortensen EM, Tabares JV, Van Cott AC, Cooper TL, Cramer JA. Antiepileptic drug monotherapy exposure and suicide-related behavior in older veterans. Journal of the American Geriatrics Society. 2012 Nov 1; 60(11):2042-7. [view]
2. Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ, Simes RJ, Durrington P, Hitman GA, Welch KM, DeMicco DA, Zwinderman AH, Clearfield MB, Downs JR, Tonkin AM, Colhoun HM, Gotto AM, Ridker PM, Kastelein JJ, Pederson T. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA. 2012 Mar 28; 307(12):1302-9. [view]
3. Alvarez CA, Mortensen EM, Makris UE, Berlowitz DR, Copeland LA, Good CB, Amuan ME, Pugh MJ. Association of skeletal muscle relaxers and antihistamines on mortality, hospitalizations, and emergency department visits in elderly patients: a nationwide retrospective cohort study. BMC geriatrics. 2015 Jan 27; 15:2. [view]
4. Hanlon JT, Aspinall SL, Semla TP, Weisbord SD, Fried LF, Good CB, Fine MJ, Stone RA, Pugh MJ, Rossi MI, Handler SM. Consensus guidelines for oral dosing of primarily renally cleared medications in older adults. Journal of the American Geriatrics Society. 2009 Feb 1; 57(2):335-40. [view]
5. Pugh MJ, Starner CI, Amuan ME, Berlowitz DR, Horton M, Marcum ZA, Hanlon JT. Exposure to potentially harmful drug-disease interactions in older community-dwelling veterans based on the Healthcare Effectiveness Data and Information Set quality measure: who is at risk? Journal of the American Geriatrics Society. 2011 Sep 1. [view]
6. Gellad WF, Good CB, Amuan ME, Marcum ZA, Hanlon JT, Pugh MJ. Facility-level variation in potentially inappropriate prescribing for older veterans. Journal of the American Geriatrics Society. 2012 Jul 1; 60(7):1222-9. [view]
7. Mortensen EM, Copeland LA, Pugh MJ, Restrepo MI, de Molina RM, Nakashima B, Anzueto A. Impact of statins and ACE inhibitors on mortality after COPD exacerbations. Respiratory Research. 2009 Jun 3; 10:45. [view]
8. Pugh JA, Wang CP, Espinoza SE, Noël PH, Bollinger M, Amuan M, Finley E, Pugh MJ. Influence of frailty-related diagnoses, high-risk prescribing in elderly adults, and primary care use on readmissions in fewer than 30 days for veterans aged 65 and older. Journal of the American Geriatrics Society. 2014 Feb 1; 62(2):291-8. [view]
9. Diaz K, Faverio P, Hospenthal A, Restrepo MI, Amuan ME, Pugh MJ. Obstructive sleep apnea is associated with higher healthcare utilization in elderly patients. Annals of thoracic medicine. 2014 Apr 1; 9(2):92-8. [view]
10. Marcum ZA, Pugh MJ, Amuan ME, Aspinall SL, Handler SM, Ruby CM, Hanlon JT. Prevalence of potentially preventable unplanned hospitalizations caused by therapeutic failures and adverse drug withdrawal events among older veterans. The journals of gerontology. Series A, Biological sciences and medical sciences. 2012 Aug 1; 67(8):867-74. [view]
11. Marcum ZA, Amuan ME, Hanlon JT, Aspinall SL, Handler SM, Ruby CM, Pugh MJ. Prevalence of unplanned hospitalizations caused by adverse drug reactions in older veterans. Journal of the American Geriatrics Society. 2012 Jan 1; 60(1):34-41. [view]
12. VanCott AC, Cramer JA, Copeland LA, Zeber JE, Steinman MA, Dersh JJ, Glickman ME, Mortensen EM, Amuan ME, Pugh MJ. Suicide-related behaviors in older patients with new anti-epileptic drug use: data from the VA hospital system. BMC medicine. 2010 Jan 11; 8:4. [view]
13. Pugh MJ, Hesdorffer D, Wang CP, Amuan ME, Tabares JV, Finley EP, Cramer JA, Kanner AM, Bryan CJ. Temporal trends in new exposure to antiepileptic drug monotherapy and suicide-related behavior. Neurology. 2013 Nov 26; 81(22):1900-6. [view]
14. Pugh MJ, Marcum ZA, Copeland LA, Mortensen EM, Zeber JE, Noël PH, Berlowitz DR, Downs JR, Good CB, Alvarez C, Amuan ME, Hanlon JT. The quality of quality measures: HEDIS® quality measures for medication management in the elderly and outcomes associated with new exposure. Drugs & aging. 2013 Aug 1; 30(8):645-54. [view]
15. Pugh MJ, Hanlon JT, Wang CP, Semla T, Burk M, Amuan ME, Lowery A, Good CB, Berlowitz DR. Trends in use of high-risk medications for older veterans: 2004 to 2006. Journal of the American Geriatrics Society. 2011 Oct 1; 59(10):1891-8. [view]
16. Zeber JE, Copeland LA, Pugh MJ. Variation in antiepileptic drug adherence among older patients with new-onset epilepsy. The Annals of pharmacotherapy. 2010 Dec 1; 44(12):1896-904. [view]

Journal Other

1. Pugh MJ, Tabares J, Finley E, Bollinger M, Tortorice K, Vancott AC. Changes in antiepileptic drug choice for older veterans with new-onset epilepsy: 2002 to 2006. [Letter to the Editor]. Journal of the American Geriatrics Society. 2011 May 1; 59(5):955-6. [view]

Conference Presentations

1. Pugh MJ, Downs JR, Noel PH, Berlowitz DR, Marcum ZA, Hanlon JT. Association Between High Risk Medication in the Elderly and Drug Disease Interactions with use of Emergency/Hospital Care and Mortality. Presented at: VA HSR&D National Meeting; 2012 Jul 1; National Harbor, MD. [view]
2. Leykum L. Capacity for Learning and Relationships in VA Primary Care clinics associated with Patient Hassles Receiving Care. Poster session presented at: AcademyHealth Annual Research Meeting; 2011 Jan 1; Seattle, WA. [view]
3. Finley EP, Bollinger MJ, Van Cott AC, Pugh MJ. Changing Prescribing Patterns for Anti-epileptic Drugs among Older Veterans: Reporting on Quality Improvement, 2002-2006. Presented at: AcademyHealth Annual Research Meeting; 2011 Jun 1; Seattle, WA. [view]
4. Pugh MJ, Starner C, Berlowitz D, Hanlon JT. Drug-disease interactions: assessment by disease state. Poster session presented at: American Geriatrics Society Annual Meeting; 2010 May 16; Orlando, FL. [view]
5. Pugh MJ, Berlowitz DR, Starner CI, Amuan ME, Marcum ZA, Hanlon JT. Exposure to potentially harmful drug-disease interactions in a national cohort of older Veterans: who is at risk? Paper presented at: VA HSR&D National Meeting; 2011 Feb 17; National Harbor, MD. [view]
6. Gellad WF, Good CB, Amuan ME, Marcum ZA, Hanlon JT, Pugh MJ. Facility-level variation in the quality of prescribing for older Veterans. Paper presented at: VA HSR&D / QUERI National Meeting; 2012 Jul 17; National Harbor, MD. [view]
7. Pugh JA, Pugh MJ, Finley EP, Amuan ME, Noel PH. High Facility-variation in 30-Day Readmissions in Veterans = 65 Years of Age. Poster session presented at: VA HSR&D National Meeting; 2012 Jul 1; National Harbor, MD. [view]
8. Pugh MJ, Berlowitz DR, Starner CI, Amuan ME, Marcum ZA, Hanlon JT. Outcomes Associated with Potentially Harmful Drug-Disease Interactions in Older Veterans with Dementia. Presented at: AcademyHealth Annual Research Meeting; 2011 Jun 1; Seattle, WA. [view]
9. Van Cott AC, Pugh MJ. Potential Antiepileptic Drug Interactions with Psychotropic Medications. Presented at: American Epilepsy Society Annual Meeting; 2011 Dec 1; Baltimore, MD. [view]
10. Leykum L, Lanham HJ, Arar NH, Finley EP, Parchman ML. Relationships and learning among staff in VA primary care clinics. Poster session presented at: AcademyHealth Annual Research Meeting; 2011 Jun 13; Seattle, WA. [view]
11. Pugh MJ, Van Cott AC, Copeland LA, Zeber JE, Cramer JA. Suicidality and New AED Exposure in Older Patients: Is the FDA Warning Appropriate for all Drugs in all Populations? Paper presented at: American Epilepsy Society Annual Meeting; 2009 Dec 6; Boston, MA. [view]
12. Pugh MJ, Amuan ME. The Nexus of TBI and Epilepsy in Veterans From Afghanistan and Iraq Wars. Paper presented at: American Academy of Neurology Annual Meeting; 2012 Apr 22; New Orleans, LA. [view]
13. Pugh MJ, Van Cott AC. Trends in Antiepileptic Drug Prescribing for Older Patients with New-Onset Epilepsy: 2004-2006. Paper presented at: American Epilepsy Society Annual Meeting; 2009 Dec 6; Boston, MA. [view]

DRA: Aging, Older Veterans' Health and Care, Health Systems
DRE: Epidemiology
Keywords: none
MeSH Terms: none