Drug-induced orthostatic hypotension: Cluster analysis of co-prescription patterns in older people in UK primary care.

PURPOSE: Over 250 medications are reported to cause orthostatic hypotension, associated with serious adverse outcomes in older adults. Studies suggest a harmful cumulative risk of orthostatic hypotension with multiple medication use. However, there is limited evidence on the potential for harm in practice, particularly which drugs is co-prescribed and may increase risk of orthostatic hypotension. METHODS: Retrospective cohort study and cluster analysis using general practice data from IQVIA Medical Research Data (IMRD) in patients aged ≥50 contributing data between 1 January 2018 and 31 December 2018. Thirteen drug groups known to be associated with orthostatic hypotension by mechanism, were analyzed and clusters generated by sex and age-band. RESULTS: A total of 602 713 individuals aged ≥50 with 283 912 (47%) men and 318 801 (53%) women were included. The most prevalent prescriptions that might contribute to orthostatic hypotension were ACE inhibitors, calcium-channel blockers, beta-blockers, selective serotonin reuptake inhibitors and uroselective alpha-blockers. We identified distinct clusters of cardiovascular system (cardiovascular system) drugs in men and women at all ages. cardiovascular system plus psychoactive drug clusters were common in women at all ages, and in men aged ≤70. cardiovascular system plus uroselective alpha-blockers were identified in men aged ≥70. CONCLUSIONS: Distinct clusters of drugs associated with orthostatic hypotension exist in practice, which change over the life course. Our findings highlight potentially harmful drug combinations that may cause cumulative risk of orthostatic hypotension in older people. This may guide clinicians about the potential of synergistic harm and to monitor for orthostatic hypotension if using combinations of cardiovascular system drugs, cardiovascular system plus psychoactive drugs and/or alpha-blockers-particularly in patients aged ≥70 or at high-risk due to comorbidity. Future research should consider quantifying the risk of drug-induced orthostatic hypotension with such drug combinations.

Orthostatic Hypotension and Antiparkinsonian Drugs: A Systematic Review and Meta-analysis.

BACKGROUND: Orthostatic hypotension (OH) is multifactorial in Parkinson's disease (PD). Antiparkinsonian medication can contribute to OH, leading to increased risk of falls, weakness and fatigue. METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) of antiparkinsonian drugs associated with OH as an adverse effect, compared to placebo. We searched EMBASE, MEDLINE and Web of Science databases until November 2020. Analysis used fixed-effects models and the GRADE tool to rate quality of evidence. Meta-analysis was performed if 3 or more studies of a drug group were available. RESULTS: Twenty-one RCTs including 3783 patients were included comparing 6 PD drug groups to placebo (MAO-B inhibitors, dopamine agonists, levodopa, COMT inhibitors, levodopa and adenosine receptor antagonists). OH was recorded as an adverse event or measurement of vital signs, without further specification on how this was defined or operationalised. Meta-analysis was performed for MAO-B inhibitors and dopamine agonists, as there were 3 or more studies for these drug groups. In this analysis, compared with placebo, neither MAO-B inhibitors or dopamine agonists were associated with increased risk of OH, (OR 2.28 [95% CI:0.81-6.46]), (OR 1.39 [95% CI:0.97-1.98]). CONCLUSIONS: Most studies did not specifically report OH, or reporting of OH was limited, including how and when it was measured. Furthermore, studies specifically reporting OH included participants that were younger than typical PD populations without multimorbidity. Future trials should address this, for example,, by including individuals over the age of 75, to improve estimations of how antiparkinsonian medications affect risk of OH.

Simple and high sample throughput LC/ESI-MS/MS method for bioequivalence study of prazosin, a drug with risk of orthostatic hypotension.

OBJECTIVE: The study aimed to develop a rapid, simple and sensitive LC/ESI-MS/MS method to measure prazosin concentration in human plasma and apply bedside sampling in bioequivalence study of two prazosin tablets to resolve the adverse effect of orthostatic hypotension. SIGNIFICANCE: The LC/ESI-MS/MS prazosin method was highly sensitive and selective. Bedside sampling reduced the orthostatic hypotension incidence and subject dropout rate. METHODS: After sample preparation, prazosin and terazosin (IS) were detected on mass spectrometer operating in multiple reaction monitoring mode using positive ionization. Mobile phase flow rate was set at 0.40 mL/min with sample run time of 1.75 min. The bioanalytical method was validated as per EMEA and FDA guidelines. Bedside sampling was performed in bioequivalence study for the first 4 h after dosing. The three primary pharmacokinetic parameters, Cmax, AUC0-t and AUC0-∞ and 90% confidence interval were determined. RESULTS: The small injection volume of 1 µL minimized instrumentation contamination and prolonged the analytical column lifespan. Linearity was obtained between 0.5 and 30.0 ng/mL, with coefficient of determination, r2 ≥ 0.99. The mean extraction recovery of prazosin and IS was >92%, with precision value (CV, %) ≤ 10.3%. Only two orthostatic hypotension adverse events were reported. The two prazosin formulations were found to be bioequivalent. CONCLUSION: The LC/ESI-MS/MS method has shown robustness and reliability exemplified by the incurred sample re-analysis result. Bedside sampling should be proposed for bioequivalence or pharmacokinetic studies of drugs demonstrating adverse event of orthostatic hypotension.

Drug-induced orthostatic hypotension: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Drug-induced orthostatic hypotension (OH) is common, and its resulting cerebral hypoperfusion is linked to adverse outcomes including falls, strokes, cognitive impairment, and increased mortality. The extent to which specific medications are associated with OH remains unclear. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis to evaluate the extent to which specific drug groups are associated with OH. EMBASE, MEDLINE, and Web of Science databases were searched from inception through 23 November 2020. Placebo-controlled randomised controlled trials (RCTs) on any drug reporting on OH as an adverse effect in adults (≥18 years) were eligible. Three authors extracted data on the drug, OH, dose, participant characteristics, and study setting. The revised Cochrane risk-of-bias tool for randomised trials (RoB 2) was used to appraise evidence. Summary odds ratios (ORs) were estimated for OH using fixed effects Mantel-Haenszel statistics. We conducted subgroup analysis on validity of OH measurement, drug dose, risk of bias, age, and comorbidity. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool was used to summarise the certainty of evidence. Of 36,940 citations, 69 eligible RCTs were included in the meta-analysis comprising 27,079 participants. Compared with placebo, beta-blockers and tricyclic antidepressants were associated with increased odds of OH (OR 7.76 [95% CI 2.51, 24.03]; OR 6.30 [95% CI 2.86, 13.91]). Alpha-blockers, antipsychotics, and SGLT-2 inhibitors were associated with up to 2-fold increased odds of OH, compared to placebo. There was no statistically significant difference in odds of OH with vasodilators (CCBs, ACE inhibitors/ARBs, SSRIs), compared to placebo. Limitations of this study are as follows: data limited to placebo-controlled studies, (excluding head-to-head trials), many RCTs excluded older participants; therefore results may be amplified in older patients in the clinical setting. The study protocol is publicly available on PROSPERO (CRD42020168697). CONCLUSIONS: Medications prescribed for common conditions (including depression, diabetes, and lower urinary tract symptoms) were associated with significantly increased odds of OH. Drugs causing sympathetic inhibition were associated with significantly increased odds of OH, while most vasodilators were associated with small nonsignificant differences in odds of OH, compared to placebo. Drugs targeting multiple parts of the orthostatic blood pressure (BP) reflex pathway (e.g. sympathetic inhibition, vasodilation, cardio-inhibitory effects) may carry cumulative risk, suggesting that individuals with polypharmacy could benefit from postural BP monitoring.

Risks associated with continuation of potentially inappropriate antihypertensive medications in older adults receiving hemodialysis.

BACKGROUND AND OBJECTIVES: After dialysis initiation, older adults may experience orthostatic or post-dialysis hypotension. Some orthostasis-causing antihypertensives (i.e., central alpha agonists and alpha blockers), are considered potentially inappropriate medications (PIMs) for older adults because they carry more risk than benefit. We sought to (1) describe antihypertensive PIM prescribing patterns before and after dialysis initiation and (2) ascertain the potential risk of adverse outcomes when these medications are continued after dialysis initiation. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Using United States Renal Data System data, we evaluated monthly prevalence of antihypertensive PIM claims in the period before and after dialysis initiation among older adults aged ≥66 years initiating in-center hemodialysis in the US between 2013 and 2014. Patients with an antihypertensive PIM prescription at hemodialysis initiation and who survived for 120 days were classified as 'continuers' or 'discontinuers' based on presence or absence of a refill within the 120 days after initiation. We compared rates of hospitalization and risk of death across these groups from day 121 through 24 months after dialysis initiation. RESULTS: Our study included 30,760 total patients, of whom 5981 (19%) patients had an antihypertensive PIM claim at dialysis initiation and survived ≥120 days. Most [65% (n = 3920)] were continuers. Those who continued (versus discontinued) were more likely to be black race (26% versus 21%), have dual Medicare-Medicaid coverage (31% versus 27%), have more medications on average (12 versus 9) and have no functional limitations (84% versus 80%). Continuers experienced fewer all-cause hospitalizations and deaths, but neither were statistically significant after adjustment (Hospitalization: RR 0.93, 95% CI 0.86, 1.00; Death: HR 0.89, 95% CI: 0.78-1.02). CONCLUSIONS: Nearly one in five older adults had an antihypertensive PIM at dialysis initiation. Among those who survived ≥120 days, continuation of an antihypertensive PIM was not associated with increased risk of all-cause hospitalization or mortality.

Evaluation of Patients with Syncope in the Emergency Department: How to Adjust Pharmacological Therapy.

The rate of syncope in the Emergency Department ranges between 0.9 and 1.7%. Syncope is mostly related to a underlying reflex or orthostatic mechanism. A bradycardic or a hypotensive phenotype, may be identified. The latter is the most common and could be constitutional or drug induced. Consequently, obtaining an accurate drug history is an important step of the initial assessment of syncope. As anti-hypertensive medication might be responsible for orthostatic hypotension, managing hypertension in patients with syncope requires finding an ideal balance between hypotensive and cardiovascular risks. The choice of anti-hypertensive molecule as well as the therapeutic regimen and dosage, influences the risk of syncope. Not only could anti-hypertensive drugs have a hypotensive effect but opioids and psychoactive medications may also be involved in the mechanism of syncope. Proper drug management could reduce syncope recurrences and their consequences.

Antidepressant use and orthostatic hypotension in older adults living with mild-to-moderate Alzheimer disease.

OBJECTIVES: Antidepressant use is often reported as a risk factor for Orthostatic Hypotension (OH), however this relationship has never been explored in those with mild/moderate Alzheimer Disease (AD), who may represent a particularly vulnerable cohort. METHODS: We performed a cross-sectional analysis of baseline data from the NILVAD study. Participants with mild-moderate AD were recruited from 23 centres in nine countries. Systolic and Diastolic Blood Pressure (SBP/DBP) was recorded in the seated position and after both 1 and 5 minutes of standing. OH was defined as a drop of ≥20 mmHg SBP/≥10 mmHg DBP. We examined the relationship between antidepressant use, orthostatic BP drop and the presence of OH, controlling for important covariates. RESULTS: Of 509 participants (72.9 ± 8.3 years, 61.9% female), two-fifths (39.1%; 199/509) were prescribed a regular antidepressant. Antidepressant use was associated with a significantly greater SBP and DBP drop at 5 minutes (ß: 1.83, 0.16-3.50, P = .03 for SBP; ß: 1.13, 0.02-2.25, P < .05 for DBP). Selective Serotonin Reuptake Inhibitor (SSRI) use was associated with a significantly greater likelihood of OH (OR 2.0, 1.1-3.6, P = .02). Both findings persisted following robust covariate adjustment. CONCLUSIONS: In older adults with AD, antidepressants were associated with a significantly greater SBP/DBP drop at 5 minutes. SSRI use in particular may be a risk factor for OH. This emphasises the need to screen older antidepressant users, and particularly those with AD, for ongoing orthostatic symptoms in order to reduce the risk of falls in this vulnerable cohort.

Orthostatic hypotension in older adults: the role of medications.

Orthostatic hypotension (OH) is defined as an abnormal blood pressure reduction when standing and is frequently diagnosed in older adults. Pharmacological therapy is one of the main causes of orthostatic blood pressure impairment, leading to iatrogenic OH. Indeed, several medications may induce hypotensive effects and influence the blood pressure response to orthostatism. Hypotensive medications may also overlap with other determinants of OH, thus increasing the burden of symptoms and the risk of complications. Potentially hypotensive medications include both cardiovascular and psychoactive drugs, which are frequently prescribed in older patients. According to the available evidence, the antihypertensive treatment "per se" does not seem to predispose to OH, even if a higher risk is associated with polypharmacy and drug classes such as with diuretics and vasodilators. As concerns psychoactive medications, OH is a well-known adverse effect of tricyclic antidepressants, trazodone and antipsychotics. The knowledge of hemodynamic consequences of drug therapy may be helpful to improve OH treatment. A medication review is advisable in all patients presenting with OH, particularly at advanced age, aiming at optimizing medical treatment with a view to minimize the risk of iatrogenic OH.

The Efficacy and Safety of Prochlorperazine in Patients With Acute Migraine: A Systematic Review and Meta-Analysis.

OBJECTIVE: The aim of this review was to evaluate the efficacy and safety of prochlorperazine (PCP) in patients with acute migraine headache in the emergency department (ED). METHODS: Electronic databases (Medline, Scopus, Web of Science, and Cochrane) were searched for randomized clinical trials that investigated the effect of PCP on headache relief. The outcomes were the number of patients without headache or with reduced headache severity, the number of adverse events, and the need for rescue analgesia. RESULTS: From 450 citations, 11 studies (n = 771) with 15 comparison arms met the inclusion criteria. Overall, PCP was more effective than placebo (OR = 7.23; 95% CI = 3.82-3.68), metoclopramide (OR = 2.89; 95% CI = 1.42-5.86), and other active comparators (OR = 3.70; 95% CI = 2.41-5.67) for headache relief. The odds ratio of experiencing adverse events with PCP compared with placebo was 5.79 (95% CI = 2.43-13.79). When PCP compared with other active comparators, no statistical difference was found regarding the overall number of adverse events (OR = 1.88; 95% CI = 0.99-3.59). However, PCP significantly increased the odds of akathisia/dystonia (OR = 2.55; 95% CI = 1.03-6.31). The request for rescue analgesia was significantly lower in the PCP group compared with other groups (16% vs 84%; OR = 0.16; 95% CI = 0.09-27). CONCLUSIONS: For adult patients with acute migraine, PCP could effectively abort the acute attack and reduce the request for rescue analgesia in the ED. However, compared with placebo, PCP could increase the risk of adverse events.

The Treatment of Primary Orthostatic Hypotension.

OBJECTIVE: To review the efficacy and safety of pharmacological and nonpharmacological strategies used to treat primary orthostatic hypotension (OH). DATA SOURCES: A literature review using PubMed and MEDLINE databases searching hypotension, non-pharmacological therapy, midodrine, droxidopa, pyridostigmine, fludrocortisone, atomoxetine, pseudoephedrine, and octreotide was performed. STUDY SELECTION AND DATA EXTRACTION: Randomized or observational studies, cohorts, case series, or case reports written in English between January 1970 and November 2016 that assessed primary OH treatment in adult patients were evaluated. DATA SYNTHESIS: Based on the chosen criteria, it was found that OH patients make up approximately 15% of all syncope patients, predominantly as a result of cardiovascular or neurological insults, or offending medication. Nonpharmacological strategies are the primary treatment, such as discontinuing offending medications, switching medication administration to bedtime, avoiding large carbohydrate-rich meals, limiting alcohol, maintaining adequate hydration, adding salt to diet, and so on. If these fail, pharmacotherapy can help ameliorate symptoms, including midodrine, droxidopa, fludrocortisone, pyridostigmine, atomoxetine, sympathomimetic agents, and octreotide. CONCLUSIONS: Midodrine and droxidopa possess the most evidence with respect to increasing blood pressure and alleviating symptoms. Pyridostigmine and fludrocortisone can be used in patients who fail to respond to these agents. Emerging evidence with low-dose atomoxetine is promising, especially in those with central autonomic failure, and may prove to be a viable alternative treatment option. Data surrounding other therapies such as sympathomimetic agents or octreotide are minimal. Medication management of primary OH should be guided by patient-specific factors, such as tolerability, adverse effects, and drug-drug and drug-disease interactions.

[Hypertension en orthostatic hypotension during use of monoamine oxidase (MAO) inhibitors]. / Hypertensie en orthostatische hypotensie bij gebruik van monoamine-oxidase(MAO)-remmers1.

Monoamine oxidase (mao) inhibitors are antidepressants with potentially severe side-effects. For this reason, the registration of this drug was suspended for some time when safer alternatives became available. However, mao inhibitors can be very effective in cases where depression has proved to be treatment resistant. Consequently, last year tranylcypromine was re-registered for use in the Netherlands. Since mao inhibitors have been used only sporadically in the Netherlands over the last few years, health professionals have only limited knowledge about the side-effects. On the basis of a recent case, we discuss the two most important side-effects of using mao inhibitors, namely hypertension and orthostatic hypotension. We discuss the possible causes and suggest ways on which these two side-effects can be prevented, or treated, should they arise.

Effect of discontinuation of antihypertensive medication on orthostatic hypotension in older persons with mild cognitive impairment: the DANTE Study Leiden.

BACKGROUND: the relationship between antihypertensive medication and orthostatic hypotension in older persons remains ambiguous, due to conflicting observational evidence and lack of data of clinical trials. OBJECTIVE: to assess the effect of discontinuation of antihypertensive medication on orthostatic hypotension in older persons with mild cognitive impairment. METHODS: a total of 162 participants with orthostatic hypotension were selected from the Discontinuation of Antihypertensive Treatment in Elderly people (DANTE) Study. This randomised clinical trial included community-dwelling participants aged ≥75 years, with mild cognitive impairment, using antihypertensive medication and without serious cardiovascular disease. Participants were randomised to discontinuation or continuation of antihypertensive treatment (ratio 1:1). Orthostatic hypotension was defined as a drop of at least 20 mmHg in systolic blood pressure and/or 10 mmHg in diastolic blood pressure on standing from a seated position. Outcome was the absence of orthostatic hypotension at 4-month follow-up. Relative risks (RR) were calculated by intention-to-treat and per-protocol analyses. RESULTS: at follow-up, according to intention-to-treat analyses, of the 86 persons assigned to discontinuation of antihypertensive medication, 43 (50%) were free from orthostatic hypotension, compared with 29 (38%) of the 76 persons assigned to continuation of medication [RR 1.31 (95% confidence interval (CI) 0.92-1.87); P = 0.13]. Per-protocol analysis showed that recovery from orthostatic hypotension was significantly higher in persons who completely discontinued all antihypertensive medication (61%) compared with the continuation group (38%) [RR 1.60 (95% CI 1.10-2.31); P = 0.01]. CONCLUSION: in older persons with mild cognitive impairment and orthostatic hypotension receiving antihypertensive medication, discontinuation of antihypertensive medication may increase the probability of recovery from orthostatic hypotension.

Behavioral Disorders in Dementia: Appropriate Nondrug Interventions and Antipsychotic Use.

Behavioral and psychological symptoms of dementia pose management challenges for caregivers and clinicians. Firstline nonpharmacologic treatments include eliminating physical and emotional stressors, modifying the patient's environment, and establishing daily routines. Family members and caregivers benefit from education about dementia symptoms and reminders that the behaviors are normal and unintentional. Cognitive and emotion-oriented interventions, sensory stimulation interventions, behavior management techniques, and other psychosocial interventions are modestly effective. In refractory cases, physicians may choose to prescribe off-label antipsychotics. Aripiprazole has the most consistent evidence of symptom improvement; however, this improvement is small. Olanzapine, quetiapine, and risperidone have inconsistent evidence of benefit. Physicians should use the smallest effective dose for the shortest possible duration to minimize adverse effects, most notably an increased mortality risk. Other adverse effects include anticholinergic and antidopaminergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, postural hypotension, metabolic syndrome, cardiac arrhythmia, and sedation. Patients should be monitored for these effects while receiving treatment; however, laboratory monitoring may be limited to patients receiving long-term therapy.

The association of antihypertensives with postural blood pressure and falls among seniors residing in the community: a case-control study.

BACKGROUND: A drop in postural blood pressure (BP) may contribute to falls, while antihypertensives have been considered to induce postural drop or orthostatic hypotension (OH) and falls among older people. However, this relationship between antihypertensives, postural BP and the risk of falls has never been evaluated in a single study. OBJECTIVE: To examine the association of postural BP changes and BP therapy with the risk of falls among community-dwelling older people in a case-control manner. METHOD: Cases (n = 202) included participants aged ≥ 65 years with two falls or one injurious fall while controls (n = 156) included participants ≥ 65 years with no falls in the preceding 12 months. Antihypertensives usage and medical history were recorded. Supine BP measurements were obtained at 10 min rest and at 1, 2 and 3 min after standing. Orthostatic hypotension was defined as a reduction in BP of 20/10 mmHg within 3 min of standing. RESULTS: Individual antihypertensive classes were not associated with falls. Minimal standing systolic BP (SBP) was significantly lower among fallers [128 (± 27·3) vs. 135·7 (± 24·7) mmHg; P = 0·01], but fallers were not more likely to fulfil the diagnostic criteria for OH. Diuretics were associated with OH and α-blockers were associated with minimal standing SBP. Univariate analysis revealed that the use of ≥ 2 antihypertensives was associated with recurrent and injurious falls [OR,1.97;CI,1.2-3.1], which was no longer significant aftermultivariateadjustment for age and number of comorbidities [OR, 1.6; CI, 0.95-2.6]. DISCUSSION: Minimal standing SBP or a lower SBP at 2 or 3minutes standing was associated with falls rather than OH using consensus definition. Association between ≥ 2 antihypertensives and falls was attenuated by increasing age and comorbidities. Our findings challenge previous assumptions that OH or the use of antihypertensives is associated with falls. Future studies should now seek to link these findings prospectively with falls in order to guide decision-making for BP lowering therapy among older patients.

Phase I study assessing the safety, tolerability, and pharmacokinetics of avibactam and ceftazidime-avibactam in healthy Japanese volunteers.

Avibactam is a novel non-ß-lactam ß-lactamase inhibitor that has been shown to restore the in vitro activity of ceftazidime against pathogens producing Ambler class A, C, and some class D ß-lactamases. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of avibactam alone or with ceftazidime in healthy Japanese subjects. In this Phase I, double-blind study (NCT01291602), 16 healthy Japanese males, mean age 28.8 years, were randomized in a 2:2:1 ratio to receive avibactam 500 mg (n = 6), ceftazidime 2000 mg plus avibactam 500 mg (n = 7), or placebo (n = 3), each administered as a 100 ml intravenous infusion over 2 h, once on Day 1, every 8 h on Days 3-6, and once on Day 7. There were no deaths or serious adverse events. Nine treatment-emergent adverse events were reported in three subjects in the avibactam group - including one elevation in transaminase levels, and three vital signs events (tachycardia, palpitations, and orthostatic hypotension) - and one in the ceftazidime-avibactam group. All events were considered mild. After single or multiple dosing, plasma concentrations of avibactam and ceftazidime declined in a multi-exponential manner. No plasma concentration accumulation was observed, and the majority of avibactam was excreted unchanged in urine within 24 h. No clinically relevant changes in intestinal bacterial flora were observed. In conclusion, avibactam alone and ceftazidime-avibactam were generally well tolerated in healthy male Japanese subjects, and avibactam pharmacokinetics were comparable whether administered alone or in combination with ceftazidime.

Chlorthalidone for poorly controlled hypertension in chronic kidney disease: an interventional pilot study.

To test the hypothesis that thiazide-type diuretics effectively lower blood pressure (BP) in moderate to advanced chronic kidney disease (CKD; estimated GFR 20-45 ml/min/ 1.73 m(2)), after confirming poorly controlled hypertension with 24-hour ambulatory BP monitoring, chlorthalidone was added to existing medications in a dose of 25 mg/day, and the dose doubled every 4 weeks if the BP remained elevated. The average age of the 14 subjects was 67.5 years, a median of 4 antihypertensive drugs were used and estimated GFR was 26.8 ± 8.8 ml/min/1.73 m(2). Twelve subjects completed the 12-week treatment phase, and the 24-hour BP, which was 143.1/75.1 mm Hg at baseline, was reduced by 10.5/ 3.1 mm Hg (p = 0.01/p = 0.17). Home BP prior to initiating chlorthalidone was 152.4/82.6 mm Hg and fell at 4, 8, and 12 weeks by 10.2/4.8, 13.4/6.0, and 9.4/3.7 mm Hg (all p < 0.05). Maximal reduction in body weight and total body volume (measured by air displacement plethysmography) was seen at 8 weeks, concurrent with the maximal elevation in serum creatinine concentration and plasma renin activity. Albuminuria was significantly reduced by 40-45%. Adverse events were seen following chlorthalidone therapy in 7 subjects who experienced 18 events as follows: hypokalemia (n = 4), hyperuricemia (4), hyponatremia (3), transient creatinine changes (3), dizziness (2), hyperglycemia (1), and constipation (1). One subject had ischemic stroke during the study. In conclusion, among people with moderate to advanced CKD with poorly controlled hypertension, chlorthalidone may significantly reduce BP via volume contraction; a randomized trial is needed to define the risks and benefits. Adverse effects may occur within a few weeks and should be carefully monitored.