UPDATE Update in Geriatric Medicine: Evidence Published in 2014 Randall J. Morse, MD, and Catherine E. DuBeau, MD
The physician must . . . have two special objects in view with regard to disease, namely, to do good or to do no harm. —Hippocrates, Epidemics
“F
irst, do no harm” is especially germane in geriatric medicine. Patient-centered care of the older person requires a deliberate balance of treatment benefit versus risk in the setting of complex multiple comorbid conditions, polypharmacy, heterogeneous life expectancy, and diverse goals of care ranging from curative to comfort care. In 2014, the American Geriatrics Society published its second “Five Things Physicians and Patients Should Question” for the American Board of Internal Medicine's Choosing Wisely initiative (Table). This update continues a similar theme of avoiding overtreatment in cardiovascular disease and dementia care and reducing polypharmacy and adverse drug effects overall. We identified studies by hand-searching the American College of Physicians' JournalWise list of top articles in 2014, as well as hand-searching all studies published in 2014 in the Journal of the American Geriatrics Society and Age and Aging.
Cardiovascular Disease Guidelines Overestimate the Number of Older Persons Who Should Be Treated With Statins for Primary Prevention of Cardiovascular Disease Kavousi M, Leening MJG, Nanchen D, et al. Comparison of application of the ACC/AHA guidelines, Adult Treatment Panel III guidelines, and European Society of Cardiology guidelines for cardiovascular disease prevention in a European cohort. JAMA. 2014;311:1416-23. [PMID: 24681960] doi:10.1001/jama.2014.2632
Background: The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for primary prevention of cardiovascular disease (CVD) engendered substantial controversy because the new risk prediction model and lower risk thresholds for treatment resulted in very large numbers of patients being recommended for statin therapy. Prior work in a U.S. population that was well adjudicated for CVD outcomes suggested that the ACC/AHA guideline performed well overall but overestimated risk in patients aged 65 years or older. However, nearly 30% of patients who met criteria for prevention in this study were already receiving a statin.
Findings: This study evaluated the performance of the ACC/AHA guideline against 2 other primary prevention guidelines—the Adult Treatment Panel III (ATP III) and European Society of Cardiology (ESC) guidelines—in a well-defined Dutch population older than 55 years who were followed for 10 years (n = 4854; mean age, 66 years; 55% women). Eligibility for treatment was assessed in the 87% of persons who were not receiving a statin at baseline. On the basis of the threshold for treatment, statins would be recommended for 96% of men and 66% of women according to the ACC/AHA guideline, 52% and 36% according to ATP III, and 66% and 39% according to ESC. Each guideline had moderate to good ability to correctly designate patients who later experienced CVD events and mortality as being at high risk (ESC had the best performance). However, all 3 guidelines overestimated the actual risk. In men, the predicted versus actual risk for fatal and nonfatal coronary disease and stroke with the ACA/ AHA guideline was 21.5% versus 12.7%; for myocardial infarction and cardiac death with ATP III, 16% versus 6.8%; and for cumulative CVD mortality with ESC, 6.8% versus 3.7%. The difference between predicted and actual risk was greatest in patients with lower predicted risk. Cautions: The study population consisted of white persons who resided in a single European city. Prescription of statins to 17% of participants during the observation period and the cohorts' relatively “young” old age could have contributed to the overestimation of risk. The CVD outcome rates were low. Implications: All 3 guidelines, and particularly the ACC/ AHA guideline, probably lead to overtreatment with statins in older patients, especially those who are at low risk for CVD outcomes and mortality. Whether to initiate statin therapy to prevent CVD events in older patients, especially those older than 80 years and those with life expectancy less than 10 years, remains unclear.
Dementia Care Use of Medications With Questionable Benefit in Patients With Advanced Dementia Is Common and Costly Tjia J, Briesacher BA, Peterson D, et al. Use of medications of questionable benefit in advanced dementia. JAMA Intern Med. 2014;174:1763-71. [PMID: 25201279] doi:10.1001 /jamainternmed.2014.4103
Background: Advanced dementia is characterized by severe cognitive deficits (for example, the person no
Ann Intern Med. 2015;162:W102-W105. doi:10.7326/M15-0298 For author affiliations, see end of text. This article was published online first at www.annals.org on 30 April 2015. W102 Annals of Internal Medicine • Vol. 162 No. 9 • 5 May 2015
Downloaded From: http://annals.org/ by a Penn State University Hershey User on 05/22/2015
Annals of Internal Medicine www.annals.org
UPDATE
Update in Geriatric Medicine
Table. American Geriatrics Society: Another 5 Things That Health Care Providers and Patients Should Question* Recommendation
Rationale
Don't prescribe cholinesterase inhibitors for dementia without periodic assessment for perceived cognitive benefits and adverse gastrointestinal effects.
Although there is RCT evidence of modest efficacy of cholinesterase inhibitors in delaying cognitive and functional decline and neuropsychiatric symptoms, benefits of therapy beyond 1 y and risks and benefits of long-term therapy are not wellestablished. If goals of treatment are not attained after a reasonable trial, consider discontinuing. Dementia care should include advance care planning and nonpharmacologic interventions. For patients with a life expectancy 85 years; 78% female; 73% white; 12.5% receiving hospice care). Medications of questionable benefit in advanced dementia were defined by using a previously published list. At least 1 questionable medication was prescribed for 53.9% of nursing home residents; the most common were cholinesterase inhibitors (36.4%), memantine (25.2%), and lipid-lowering agents (22.4%). Residents less likely to be prescribed questionable medications had oral problems (adjusted odds ratio [aOR], 0.68 [95% CI, 0.59 to 0.78]), had do-not-resuscitate orders (aOR, 0.65 [CI, 0.57 to 0.95]), and were enrolled in hospice (aOR, 0.69 [CI, 0.58 to 0.82]). Facilities with a higher prevalence of feeding tubes had higher rates of questionable medication use. Drugs of questionable benefit accounted for 35% of 90-day mean total drug expenditure ($816 of $2317). Cautions: The study used a list of questionable medications that was developed on the basis of a Delphi consensus process involving faculty at a single academic center; this list has not been used in other studies. Drug administration and duration of use were not evaluated. Cost estimates were based on average wholesale price and assumed that the drugs were used for 90 days.
Implications: Nursing home residents with advanced dementia carry a high burden of medications with questionable benefit given their terminal condition, limited life expectancy, and family wishes for comfort as the goal of care. Future studies using additional criteria for potentially inappropriate medications and more direct cost estimates may help facilitate the translation of these findings into policy.
High-Dose Citalopram Decreases Agitation in Persons With Dementia but Carries Risk for Adverse Effects Porsteinsson AP, Drye LT, Pollock BG, et al; CitAD Research Group. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014;311:682-91. [PMID: 24549548] doi:10.1001/jama.2014.93
Background: Agitation affects over 40% of persons with dementia, resulting in decreased quality of life, increased caregiver distress, and earlier institutionalization. Antipsychotics are frequently used to treat agitation in this setting, yet they carry significant risks, including increased mortality. Nonpharmacologic approaches may be limited by lack of expertise and resources. Little evidence exists to guide use of alternative pharmacologic treatments. Findings: In this multicenter trial, 186 patients with probable Alzheimer dementia and clinically significant agitation were randomly assigned to receive citalopram (20 to 30 mg/d; 78% received 30 mg) or placebo for 9 weeks. All patients and caregivers received psychosocial support, including educational materials, a 24-hour crisis hotline, and individualized supportive care plans. Citalopram improved the primary outcomes: Neurobehavioral Rating Scale agitation subscale score (range, 1 to 18; estimated treatment effect, ⫺0.93 [CI, ⫺1.8 to ⫺0.06]) and the modified Alzheimer's Disease
www.annals.org
Downloaded From: http://annals.org/ by a Penn State University Hershey User on 05/22/2015
Annals of Internal Medicine • Vol. 162 No. 9 • 5 May 2015 W103
UPDATE Cooperative Study Clinical Global Impression of Change (estimated treatment effect, OR 2.13 [CI, 1.23 to 3.69]; moderate to marked improvement in 40% vs. 26% of patients; number needed to treat, 8). Citalopram also improved caregiver distress and some secondary measures of agitation, but did not improve function. Citalopram had greater adverse effects: impaired cognition (decrease in Mini-Mental State Examination score, ⫺1.05 [CI, ⫺1.97 to ⫺0.130]), prolongation of the corrected QT interval (QTc) (13% vs. 4%; number needed to harm [NNH], 12), fever, diarrhea, and anorexia. Cautions: The maximum daily dose of citalopram that is approved by the U.S. Food and Drug Administration for older adults is 20 mg; this study did not report outcomes by dose. It is unknown how soon citalopram started to take effect within the 9-week treatment period, and how long its effect continued after 9 weeks. The statistically significant increase in QTc prolongation was evident even within the small subgroup of patients who had electrocardiography (n = 48). Implications: There is no “free lunch” in the treatment of agitation in persons with dementia. The positive outcomes seen with citalopram required a dose no longer approved for clinical use, and that—like antipsychotics— caused QTc prolongation. The improvement in agitation in the placebo group reinforces the usefulness of interventions aimed at caregivers, including just-in-time support. Additional research is needed on the efficacy, cost, and dissemination of both individualized and general nonpharmacologic approaches.
Polypharmacy and Adverse Drug Effects A Patient Empowerment Booklet Decreased Inappropriate Benzodiazepine Use Tannenbaum C, Martin P, Tamblyn R, et al. Reduction of inappropriate benzodiazepine prescriptions among older adults through direct patient education: the EMPOWER cluster randomized trial. JAMA Intern Med. 2014;174:890-8. [PMID: 24733354] doi:10.1001/jamainternmed.2014.949
Background: Benzodiazepines are widely prescribed for the treatment of insomnia and anxiety in older persons, despite their inclusion in the Beers Criteria for potentially inappropriate medications in older adults and the American Geriatrics Society 2013 Choosing Wisely recommendation against their use as first-line treatment of insomnia. Because physicians often cite patient dependence and perceived benefit as reasons for not stopping benzodiazepines, patient-directed interventions may help decrease their use. Findings: 303 community-dwelling adults aged 65 years or older with polypharmacy (use of ≥5 medications), including use of a benzodiazepine for at least 3 months, were randomly assigned to receive the intervention either immediately or after a 6-month delay (control group). Patients were given an 8-page booklet
Update in Geriatric Medicine
with information on benzodiazepine risks and safety, alternative therapies for insomnia or anxiety, and a 21week tapering protocol. At 6 months, 27% of participants who received the intervention immediately had stopped taking benzodiazepines and 11% had reduced the dose, compared with 5% and 7% of the control group, respectively (aOR for discontinuation, 8.3 [CI, 3.5 to 18.5]; number needed to treat, 4). Discontinuation was not related to patient characteristics, benzodiazepine type or treatment duration, or previous attempted cessation, but tended to be more likely if patients discussed discontinuing use of benzodiazepines with their physician. However, a physician or pharmacist recommendation against tapering was the most common reason for patients not attempting discontinuation. Cautions: Withdrawal symptoms occurred in 42% of patients who attempted to taper benzodiazepine therapy, although none required hospitalization. The participants were residents of a single Canadian city, race/ ethnicity was not reported, and the recruitment rate was low (11%), all of which limit the generalizability of the findings. Implications: A “deprescribing” educational booklet focused on drug safety and self-efficacy is effective in reducing older patients' use of benzodiazepines for insomnia and anxiety. Such direct-to-consumer education may help with other aspects of polypharmacy. The study highlights the importance of shared decision making, including the negative effect that it may have if physicians are uncomfortable or unfamiliar with evidence-based guidance that is provided to patients from other sources.
Thiazide Diuretics Increase the Risk for Metabolic Adverse Events in Older Adults Makam AN, Boscardin WJ, Miao Y, et al. Risk of thiazideinduced metabolic adverse events in older adults. J Am Geriatr Soc. 2014;62:1039-45. [PMID: 24823661] doi:10.1111 /jgs.12839
Background: The Eighth Report of the Joint National Committee again established thiazide diuretics as firstline treatment of hypertension. At the same time, thiazide diuretics are associated with many adverse drug events (ADEs), to which older adults may be particularly susceptible, but the incidence and predictors of the risk are unclear. Findings: This prospective observational cohort study evaluated the risk for metabolic ADEs (electrolyte disturbance and decreased renal function) with thiazide treatment of hypertension in 2052 veterans aged 65 years or older (96% male). Patients were divided into 2 propensity-matched cohorts—those in whom thiazide treatment was started and those not treated with any first-line antihypertensive agent—and followed for 9 months. The composite primary metabolic ADE outcome was a sodium level less than 135 mmol/L (
The physician must . . . have two special objects in view with regard to disease, namely, to do good or to do no harm. —Hippocrates, Epidemics
“F
irst, do no harm” is especially germane in geriatric medicine. Patient-centered care of the older person requires a deliberate balance of treatment benefit versus risk in the setting of complex multiple comorbid conditions, polypharmacy, heterogeneous life expectancy, and diverse goals of care ranging from curative to comfort care. In 2014, the American Geriatrics Society published its second “Five Things Physicians and Patients Should Question” for the American Board of Internal Medicine's Choosing Wisely initiative (Table). This update continues a similar theme of avoiding overtreatment in cardiovascular disease and dementia care and reducing polypharmacy and adverse drug effects overall. We identified studies by hand-searching the American College of Physicians' JournalWise list of top articles in 2014, as well as hand-searching all studies published in 2014 in the Journal of the American Geriatrics Society and Age and Aging.
Cardiovascular Disease Guidelines Overestimate the Number of Older Persons Who Should Be Treated With Statins for Primary Prevention of Cardiovascular Disease Kavousi M, Leening MJG, Nanchen D, et al. Comparison of application of the ACC/AHA guidelines, Adult Treatment Panel III guidelines, and European Society of Cardiology guidelines for cardiovascular disease prevention in a European cohort. JAMA. 2014;311:1416-23. [PMID: 24681960] doi:10.1001/jama.2014.2632
Background: The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for primary prevention of cardiovascular disease (CVD) engendered substantial controversy because the new risk prediction model and lower risk thresholds for treatment resulted in very large numbers of patients being recommended for statin therapy. Prior work in a U.S. population that was well adjudicated for CVD outcomes suggested that the ACC/AHA guideline performed well overall but overestimated risk in patients aged 65 years or older. However, nearly 30% of patients who met criteria for prevention in this study were already receiving a statin.
Findings: This study evaluated the performance of the ACC/AHA guideline against 2 other primary prevention guidelines—the Adult Treatment Panel III (ATP III) and European Society of Cardiology (ESC) guidelines—in a well-defined Dutch population older than 55 years who were followed for 10 years (n = 4854; mean age, 66 years; 55% women). Eligibility for treatment was assessed in the 87% of persons who were not receiving a statin at baseline. On the basis of the threshold for treatment, statins would be recommended for 96% of men and 66% of women according to the ACC/AHA guideline, 52% and 36% according to ATP III, and 66% and 39% according to ESC. Each guideline had moderate to good ability to correctly designate patients who later experienced CVD events and mortality as being at high risk (ESC had the best performance). However, all 3 guidelines overestimated the actual risk. In men, the predicted versus actual risk for fatal and nonfatal coronary disease and stroke with the ACA/ AHA guideline was 21.5% versus 12.7%; for myocardial infarction and cardiac death with ATP III, 16% versus 6.8%; and for cumulative CVD mortality with ESC, 6.8% versus 3.7%. The difference between predicted and actual risk was greatest in patients with lower predicted risk. Cautions: The study population consisted of white persons who resided in a single European city. Prescription of statins to 17% of participants during the observation period and the cohorts' relatively “young” old age could have contributed to the overestimation of risk. The CVD outcome rates were low. Implications: All 3 guidelines, and particularly the ACC/ AHA guideline, probably lead to overtreatment with statins in older patients, especially those who are at low risk for CVD outcomes and mortality. Whether to initiate statin therapy to prevent CVD events in older patients, especially those older than 80 years and those with life expectancy less than 10 years, remains unclear.
Dementia Care Use of Medications With Questionable Benefit in Patients With Advanced Dementia Is Common and Costly Tjia J, Briesacher BA, Peterson D, et al. Use of medications of questionable benefit in advanced dementia. JAMA Intern Med. 2014;174:1763-71. [PMID: 25201279] doi:10.1001 /jamainternmed.2014.4103
Background: Advanced dementia is characterized by severe cognitive deficits (for example, the person no
Ann Intern Med. 2015;162:W102-W105. doi:10.7326/M15-0298 For author affiliations, see end of text. This article was published online first at www.annals.org on 30 April 2015. W102 Annals of Internal Medicine • Vol. 162 No. 9 • 5 May 2015
Downloaded From: http://annals.org/ by a Penn State University Hershey User on 05/22/2015
Annals of Internal Medicine www.annals.org
UPDATE
Update in Geriatric Medicine
Table. American Geriatrics Society: Another 5 Things That Health Care Providers and Patients Should Question* Recommendation
Rationale
Don't prescribe cholinesterase inhibitors for dementia without periodic assessment for perceived cognitive benefits and adverse gastrointestinal effects.
Although there is RCT evidence of modest efficacy of cholinesterase inhibitors in delaying cognitive and functional decline and neuropsychiatric symptoms, benefits of therapy beyond 1 y and risks and benefits of long-term therapy are not wellestablished. If goals of treatment are not attained after a reasonable trial, consider discontinuing. Dementia care should include advance care planning and nonpharmacologic interventions. For patients with a life expectancy 85 years; 78% female; 73% white; 12.5% receiving hospice care). Medications of questionable benefit in advanced dementia were defined by using a previously published list. At least 1 questionable medication was prescribed for 53.9% of nursing home residents; the most common were cholinesterase inhibitors (36.4%), memantine (25.2%), and lipid-lowering agents (22.4%). Residents less likely to be prescribed questionable medications had oral problems (adjusted odds ratio [aOR], 0.68 [95% CI, 0.59 to 0.78]), had do-not-resuscitate orders (aOR, 0.65 [CI, 0.57 to 0.95]), and were enrolled in hospice (aOR, 0.69 [CI, 0.58 to 0.82]). Facilities with a higher prevalence of feeding tubes had higher rates of questionable medication use. Drugs of questionable benefit accounted for 35% of 90-day mean total drug expenditure ($816 of $2317). Cautions: The study used a list of questionable medications that was developed on the basis of a Delphi consensus process involving faculty at a single academic center; this list has not been used in other studies. Drug administration and duration of use were not evaluated. Cost estimates were based on average wholesale price and assumed that the drugs were used for 90 days.
Implications: Nursing home residents with advanced dementia carry a high burden of medications with questionable benefit given their terminal condition, limited life expectancy, and family wishes for comfort as the goal of care. Future studies using additional criteria for potentially inappropriate medications and more direct cost estimates may help facilitate the translation of these findings into policy.
High-Dose Citalopram Decreases Agitation in Persons With Dementia but Carries Risk for Adverse Effects Porsteinsson AP, Drye LT, Pollock BG, et al; CitAD Research Group. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014;311:682-91. [PMID: 24549548] doi:10.1001/jama.2014.93
Background: Agitation affects over 40% of persons with dementia, resulting in decreased quality of life, increased caregiver distress, and earlier institutionalization. Antipsychotics are frequently used to treat agitation in this setting, yet they carry significant risks, including increased mortality. Nonpharmacologic approaches may be limited by lack of expertise and resources. Little evidence exists to guide use of alternative pharmacologic treatments. Findings: In this multicenter trial, 186 patients with probable Alzheimer dementia and clinically significant agitation were randomly assigned to receive citalopram (20 to 30 mg/d; 78% received 30 mg) or placebo for 9 weeks. All patients and caregivers received psychosocial support, including educational materials, a 24-hour crisis hotline, and individualized supportive care plans. Citalopram improved the primary outcomes: Neurobehavioral Rating Scale agitation subscale score (range, 1 to 18; estimated treatment effect, ⫺0.93 [CI, ⫺1.8 to ⫺0.06]) and the modified Alzheimer's Disease
www.annals.org
Downloaded From: http://annals.org/ by a Penn State University Hershey User on 05/22/2015
Annals of Internal Medicine • Vol. 162 No. 9 • 5 May 2015 W103
UPDATE Cooperative Study Clinical Global Impression of Change (estimated treatment effect, OR 2.13 [CI, 1.23 to 3.69]; moderate to marked improvement in 40% vs. 26% of patients; number needed to treat, 8). Citalopram also improved caregiver distress and some secondary measures of agitation, but did not improve function. Citalopram had greater adverse effects: impaired cognition (decrease in Mini-Mental State Examination score, ⫺1.05 [CI, ⫺1.97 to ⫺0.130]), prolongation of the corrected QT interval (QTc) (13% vs. 4%; number needed to harm [NNH], 12), fever, diarrhea, and anorexia. Cautions: The maximum daily dose of citalopram that is approved by the U.S. Food and Drug Administration for older adults is 20 mg; this study did not report outcomes by dose. It is unknown how soon citalopram started to take effect within the 9-week treatment period, and how long its effect continued after 9 weeks. The statistically significant increase in QTc prolongation was evident even within the small subgroup of patients who had electrocardiography (n = 48). Implications: There is no “free lunch” in the treatment of agitation in persons with dementia. The positive outcomes seen with citalopram required a dose no longer approved for clinical use, and that—like antipsychotics— caused QTc prolongation. The improvement in agitation in the placebo group reinforces the usefulness of interventions aimed at caregivers, including just-in-time support. Additional research is needed on the efficacy, cost, and dissemination of both individualized and general nonpharmacologic approaches.
Polypharmacy and Adverse Drug Effects A Patient Empowerment Booklet Decreased Inappropriate Benzodiazepine Use Tannenbaum C, Martin P, Tamblyn R, et al. Reduction of inappropriate benzodiazepine prescriptions among older adults through direct patient education: the EMPOWER cluster randomized trial. JAMA Intern Med. 2014;174:890-8. [PMID: 24733354] doi:10.1001/jamainternmed.2014.949
Background: Benzodiazepines are widely prescribed for the treatment of insomnia and anxiety in older persons, despite their inclusion in the Beers Criteria for potentially inappropriate medications in older adults and the American Geriatrics Society 2013 Choosing Wisely recommendation against their use as first-line treatment of insomnia. Because physicians often cite patient dependence and perceived benefit as reasons for not stopping benzodiazepines, patient-directed interventions may help decrease their use. Findings: 303 community-dwelling adults aged 65 years or older with polypharmacy (use of ≥5 medications), including use of a benzodiazepine for at least 3 months, were randomly assigned to receive the intervention either immediately or after a 6-month delay (control group). Patients were given an 8-page booklet
Update in Geriatric Medicine
with information on benzodiazepine risks and safety, alternative therapies for insomnia or anxiety, and a 21week tapering protocol. At 6 months, 27% of participants who received the intervention immediately had stopped taking benzodiazepines and 11% had reduced the dose, compared with 5% and 7% of the control group, respectively (aOR for discontinuation, 8.3 [CI, 3.5 to 18.5]; number needed to treat, 4). Discontinuation was not related to patient characteristics, benzodiazepine type or treatment duration, or previous attempted cessation, but tended to be more likely if patients discussed discontinuing use of benzodiazepines with their physician. However, a physician or pharmacist recommendation against tapering was the most common reason for patients not attempting discontinuation. Cautions: Withdrawal symptoms occurred in 42% of patients who attempted to taper benzodiazepine therapy, although none required hospitalization. The participants were residents of a single Canadian city, race/ ethnicity was not reported, and the recruitment rate was low (11%), all of which limit the generalizability of the findings. Implications: A “deprescribing” educational booklet focused on drug safety and self-efficacy is effective in reducing older patients' use of benzodiazepines for insomnia and anxiety. Such direct-to-consumer education may help with other aspects of polypharmacy. The study highlights the importance of shared decision making, including the negative effect that it may have if physicians are uncomfortable or unfamiliar with evidence-based guidance that is provided to patients from other sources.
Thiazide Diuretics Increase the Risk for Metabolic Adverse Events in Older Adults Makam AN, Boscardin WJ, Miao Y, et al. Risk of thiazideinduced metabolic adverse events in older adults. J Am Geriatr Soc. 2014;62:1039-45. [PMID: 24823661] doi:10.1111 /jgs.12839
Background: The Eighth Report of the Joint National Committee again established thiazide diuretics as firstline treatment of hypertension. At the same time, thiazide diuretics are associated with many adverse drug events (ADEs), to which older adults may be particularly susceptible, but the incidence and predictors of the risk are unclear. Findings: This prospective observational cohort study evaluated the risk for metabolic ADEs (electrolyte disturbance and decreased renal function) with thiazide treatment of hypertension in 2052 veterans aged 65 years or older (96% male). Patients were divided into 2 propensity-matched cohorts—those in whom thiazide treatment was started and those not treated with any first-line antihypertensive agent—and followed for 9 months. The composite primary metabolic ADE outcome was a sodium level less than 135 mmol/L (
