A Systematic Review of Female Participation in Randomized Controlled Trials of Post-Stroke Upper Extremity Rehabilitation in Low- to Middle-Income Countries and High-Income Countries and Regions.

INTRODUCTION: Female participation is lower than males in both acute stroke and stroke rehabilitation trials. However, less is known about how female participation differs across countries and regions. This study aimed to assess the percentage of female participants in randomized controlled trials (RCTs) of post-stroke rehabilitation of upper extremity (UE) motor disorders in low-middle-income (LMICs) and high-income countries (HICs) as well as different high-income world regions. METHODS: CINAHL, Embase, PubMed, Scopus, and Web of Science were searched from 1960 to April 1, 2021. Studies were eligible for inclusion if they (1) were RCTs or crossovers published in English; (2) ≥50% of participants were diagnosed with stroke; 3) included adults ≥18 years old; and (4) applied an intervention to the hemiparetic UE as the primary objective of the study. Countries were divided into HICs and LMICs based on their growth national incomes. The HICs were further divided into the three high-income regions of North America, Europe, and Asia and Oceania. Data analysis was performed using SPSS and RStudio v.4.3.1. RESULTS: A total of 1,276 RCTs met inclusion criteria. Of them, 298 RCTs were in LMICs and 978 were in HICs. The percentage of female participants was significantly higher in HICs (39.5%) than LMICs (36.9%). Comparing high-income regions, there was a significant difference in the overall female percentages in favor of RCTs in Europe compared to LMICs but not North America or Asia and Oceania. There was no significant change in the percentage of female participants in all countries and regions over the last 2 decades, with no differences in trends between the groups. CONCLUSIONS: Sufficient female representation in clinical trials is required for the generalizability of results. Despite differences in overall percentage of female participation between countries and regions, females have been underrepresented in both HICs and LMICs with no considerable change over 2 decades.

Post Stroke Exercise Training: Intensity, Dosage, and Timing of Therapy.

More intense, earlier exercise in rehabilitation results in improved motor outcomes following stroke. Timing and intensity of therapy delivery vary from study to study. For more intensive therapies, there are practical challenges in implementation. However, there are also opportunities for high intensity treatment through innovative approaches and new technologies. Timing of rehabilitation is important. As time post stroke increases, the dosage of therapy required to improve motor recovery outcomes increases. Very early rehabilitation may improve motor outcomes but should be delayed for at least 24 hours post stroke.

Female Enrollment in Rehabilitation Trials: A Systematic Review of Reporting Sex and Female Participation in Randomized Controlled Trials of Poststroke Upper Extremity Rehabilitation Over 50 Years.

OBJECTIVE: To systematically assess the reporting of sex and the percentage of female participants in randomized controlled trials (RCTs) examining interventions for the post-stroke rehabilitation of upper extremity (UE) motor disorders. DATA SOURCES: CINAHL, Embase, PubMed, Scopus and Web of Science were searched from 1960 to April 1, 2021. Additional articles were identified using the Evidence-Based Review of Stroke Rehabilitation. STUDY SELECTION: Studies were eligible for inclusion if they (1) were RCTs or crossovers published in English, (2) ≥50% of participants were diagnosed and affected by stroke, (3) included adults ≥18 years old, and (4) applied an intervention to the hemiparetic UE as the primary objective of the study. DATA EXTRACTION: Two investigators independently screened the title and abstracts, and duplicates were removed. A full-text review was done for studies that met all inclusion criteria. Data were extracted using a custom data extraction template in Covidence and were transferred to online Excel (V16) for data management. Study characteristics and extracted variables were summarized using standard descriptive statistics. Data analyses were performed using SPSS (V29.0). DATA SYNTHESIS: A total of 1276 RCTs met inclusion criteria, and of these, 5.2% did not report results on sex, accounting for 5.6% of participants. Women have been underrepresented in stroke RCTs, accounting for 38.8% of participants. Female participation was greater in the acute poststroke phase than in the chronic and subacute phases. Over almost 5 decades, there has been a small decrease in the proportion of female participants in these trials. CONCLUSIONS: Evidence-based medicine for the treatment and prevention of stroke is guided by results from RCTs. Generalizability depends on sufficient representation in clinical trials. Stakeholders, such as funders and journal editors, play a key role in encouraging researchers to enroll enough of both sexes and to report the presence or absence of sex differences in RCTs.

The association between inpatient rehabilitation intensity and outcomes after stroke in Ontario, Canada.

BACKGROUND: Several studies have demonstrated improved outcomes poststroke when higher intensity rehabilitation is provided. Canadian Stroke Best Practice Recommendations advise patients receive 180 min of therapy time per day; however, the exact amount required to reach benefit is unknown. AIMS: The primary aim of this study was to determine the association between rehabilitation intensity (RI) and total Functional Independence Measure (FIM) Instrument change. Secondary aims included determining the association between RI and discharge location, 90-day home time, rehabilitation effectiveness, and motor and cognitive FIM change. METHODS: A retrospective cohort study was conducted using available administrative databases of acute stroke patients discharged to inpatient rehabilitation facilities in Ontario, Canada, from January 2017 to December 2021. RI was defined as number of minutes per day of direct therapy by all providers divided by rehabilitation length of stay. The association between RI and the outcomes of interest were analyzed using regression models with restricted cubic splines. RESULTS: A total of 12,770 individuals were included. Mean age of the sample was 72.6 years, 46.0% of individuals were female, and 87.6% had an ischemic stroke. Mean RI was 74.7 min (range: 5-162 min) per day. Increased RI was associated with an increase in mean FIM change. However, there was diminishing incremental increase after reaching 95 min/day. Increased RI was positively associated with motor and cognitive FIM change, rehabilitation effectiveness, 90-day home time, and discharge to preadmission setting. Higher RI was associated with a lower likelihood of discharge to long-term care. CONCLUSIONS: None of the patients met the recommended RI of 180 min/day based on the Canadian Stroke Best Practice Recommendations. Despite this, higher intensity was associated with better outcomes. Given that most positive associations were observed with a RI ⩾95 min/day, this may be a more feasible target.

A systematic review examining the effect of vitamin D supplementation on functional outcomes post-stroke.

OBJECTIVE: The objective of this systematic review was to explore the effect of vitamin D supplementation on functional outcomes (motor function, mobility, activities of daily living and stroke impairment) among individuals post-stroke (PROSPERO CRD42022296462). DATA SOURCES: MEDLINE, PsycINFO, EMBASE, and CINAHL were searched for all articles published up to March 5, 2023. METHODS: Only interventional studies assessing vitamin D supplementation compared to placebo or usual care in adult stroke patients were selected. After duplicate removal, 2912 studies were screened by two independent reviewers. A total of 43 studies underwent full text review; 10 studies met inclusion criteria (8 randomized controlled trials and 2 non-randomized studies of intervention). Data were extracted by two independent reviewers using Covidence software. Motor function (Brunnstrom Recovery Stage, Berg Balance Score), mobility (Functional Ambulation Category), activities of daily living (Barthel Index, Functional Independence Measure) and stroke impairment (modified Rankin Scale, National Institutes for Health Stroke Severity, Scandinavian Stroke Severity) were the outcome measures of interest reported in the included studies. RESULTS: In total, 691 patients were studied for which 11 of 13 outcome measures showed improvement with vitamin D supplementation. CONCLUSIONS: The majority of studies showed a statistical improvement in motor function, mobility, and stroke impairment with vitamin D supplementation; however, the evidence did not support an improvement in activities of daily living with treatment. Despite this, there may not be clinical significance. Strong, methodologically sound, randomized controlled trials are required to verify these findings.

Hypocalcemia Risk of Denosumab Across the Spectrum of Kidney Disease: A Population-Based Cohort Study.

Denosumab can be used in patients with chronic kidney disease (CKD) but has been linked with cases of severe hypocalcemia. The incidence of and risk factors for hypocalcemia after denosumab use are not well established. Using linked health care databases at ICES, we conducted a population-based cohort study of adults >65 years old with a new prescription for denosumab or a bisphosphonate between 2012 and 2020. We assessed incidence of hypocalcemia within 180 days of drug dispensing and stratified results by estimated glomerular filtration rate (eGFR in mL/min/1.73 m2 ). We used Cox proportional hazards to assess risk factors for hypocalcemia. There were 59,151 and 56,847 new denosumab and oral bisphosphonate users, respectively. Of the denosumab users, 29% had serum calcium measured in the year before their prescription, and one-third had their serum calcium checked within 180 days after their prescription. Mild hypocalcemia (albumin corrected calcium <2.00 mmol/L) occurred in 0.6% (95% confidence interval [CI] 0.6, 0.7) of new denosumab users and severe hypocalcemia (<1.8 mmol/L) in 0.2% (95% CI 0.2, 0.3). In those with an eGFR <15 or receiving maintenance dialysis, the incidence of mild and severe hypocalcemia was 24.1% (95% CI 18.1, 30.7) and 14.9% (95% CI 10.1, 20.7), respectively. In this group, kidney function and baseline serum calcium were strong predictors of hypocalcemia. We did not have information on over-the-counter vitamin D or calcium supplementation. In new bisphosphonate users, the incidence of mild hypocalcemia was 0.3% (95% CI 0.3, 0.3) with an incidence of 4.7% (95% CI 1.5, 10.8) in those with an eGFR <15 or receiving maintenance dialysis. In this large population-based cohort, we found that the overall risk of hypocalcemia with new denosumab use was low but increased substantially in those with eGFR <15 mL/min/1.73 m2 . Future studies should investigate strategies to mitigate hypocalcemia. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Higher-Dose Gabapentinoids and the Risk of Adverse Events in Older Adults With CKD: A Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Gabapentinoids are opioid substitutes whose elimination by the kidneys is reduced as kidney function declines. To inform their safe prescribing in older adults with chronic kidney disease (CKD), we examined the 30-day risk of serious adverse events according to the prescribed starting dose. STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: 74,084 older adults (64% women; median age, 79 [interquartile range, 73-85] years) with CKD (defined for this study as an estimated glomerular filtration rate <60 mL/min/1.73 m2 and excluding those receiving dialysis) and a newly prescribed gabapentinoid between 2008 and 2020 in Ontario, Canada. EXPOSURE: Higher-dose gabapentinoids (gabapentin >300 mg/d or pregabalin >75 mg/d) versus lower-dose gabapentinoids (gabapentin ≤300 mg/d or pregabalin ≤75 mg/d). OUTCOMES: The primary composite outcome was the 30-day risk of a hospital visit with encephalopathy, a fall, or a fracture or a hospitalization with respiratory depression. ANALYTICAL APPROACH: Comparison groups were balanced on indicators of baseline health using inverse probability of treatment weighting using propensity score analysis that generated a pseudosample for the reference group with a distribution of measured covariates similar to the exposed group. Weighted risk ratios were estimated using modified Poisson regression, and weighted risk differences were estimated using binomial regression. Prespecified subgroup analyses were conducted by estimated glomerular filtration rate category and type of gabapentinoid. RESULTS: Among 74,084 patients identified with CKD and a new prescription for gabapentin or pregabalin, 41% started at >300 or >75 mg/d, respectively. From this set of patients, a weighted study population with a size of 61,367 was generated. Patients who started at a higher dose had a higher 30-day risk of the primary outcome than patients who started at lower dose. Within the weighted population, the numbers of events for higher versus lower dose were 585 of 30,660 (1.9%) versus 462 of 30,707 (1.5%), respectively. The weighted risk ratio was 1.27 (95% CI, 1.13-1.42), and the weighted risk difference was 0.40% (95% CI, 0.21%-0.60%). In subgroup analyses, neither multiplicative nor additive interactions were statistically significant. LIMITATIONS: Residual confounding. CONCLUSIONS: In this population-based study, starting a gabapentinoid at a higher versus a lower dose was associated with a slightly higher risk of a hospital visit with encephalopathy, a fall, or a fracture or hospitalization with respiratory depression. If verified, these risks should be balanced against the benefits of using a higher-dose gabapentinoid.

Palato-pharyngo-laryngeal myoclonus with recurrent retrograde feeding tube migration after cerebellar hemorrhagic stroke: a case report and review of hypertrophic olivary degeneration.

BACKGROUND: Palato-pharyngo-laryngeal myoclonus, a variant of palatal myoclonus, is characterized by involuntary rhythmic movements of palatal, pharyngeal, and laryngeal muscles. Symptomatic palatal myoclonus is classically associated with hypertrophic olivary degeneration on MRI imaging due to a lesion in the triangle of Guillain-Mollaret. CASE PRESENTATION: We report a case of palato-pharyngo-laryngeal myoclonus in a patient post-cerebellar hemorrhagic stroke who presented with recurrent retrograde migration of his gastrojejunostomy feeding tubes. Treatment with either divalproex sodium or gabapentin resulted in a significant decrease in his gastrointestinal symptoms and no further episodes of gastrojejunostomy tube migration. CONCLUSIONS: This case study indicates that the movement disorder associated with hypertrophic olivary degeneration may involve the gastrointestinal system. Anticonvulsants, such as gabapentin and divalproex sodium, may reduce the severity of gastrointestinal symptoms in cases associated with hypertrophic olivary degeneration. The anatomy of the Guillain-Mollaret triangle and the pathophysiology of hypertrophic olivary degeneration are reviewed.

Arm Numbness at 45 Degrees Abduction: A Case Report of Thoracic Outlet Syndrome After Brachial Neuritis.

OBJECTIVE: To describe a case of nerve kinking correlating with surgical findings in neurogenic thoracic outlet syndrome in a patient with history of brachial neuritis. Thoracic outlet syndrome and brachial neuritis are briefly reviewed. CASE REPORT: A 32-year-old woman with a history of bilateral brachial neuritis presented with paraesthesias in her hand when abducting her shoulder to 45° or higher. A kink in the superior trunk of the brachial plexus, as well as asymmetrically narrowed costoclavicular space, was found on magnetic resonance imaging with the shoulder abducted. Conservative measures failed, leading to partial anterior scalenectomy and neurolysis, which led to improvement in her symptoms. CONCLUSION: Anatomical variations in combination with biomechanical changes after brachial neuritis can be associated with neurogenic thoracic outlet syndrome.

Risk of rhabdomyolysis with donepezil compared with rivastigmine or galantamine: a population-based cohort study.

BACKGROUND: Donepezil, rivastigmine and galantamine are popular cholinesterase inhibitors used to manage the symptoms of Alzheimer disease and other dementias; regulatory agencies in several countries warn about a possible risk of rhabdomyolysis with donepezil, based on information from case reports. Our goal was to investigate the 30-day risk of admission to hospital with rhabdomyolysis associated with initiating donepezil versus other cholinesterase inhibitors. METHODS: We conducted a retrospective cohort study in Ontario, Canada, from 2002 to 2017. Participants were adults aged 66 years or older with a newly dispensed prescription for donepezil compared with rivastigmine or galantamine. The primary outcome was hospital admission with rhabdomyolysis (assessed using hospital diagnostic codes) within 30 days of a new prescription of a cholinesterase inhibitor. Odds ratios were estimated using logistic regression, with inverse probability of treatment weights calculated from propensity scores. RESULTS: The average age in our 2 groups was 81.1 years, and 61.4% of our population was female. Donepezil was associated with a higher risk of hospital admission with rhabdomyolysis compared with rivastigmine or galantamine (88 events in 152 300 patients [0.06%] v. 16 events in 68 053 patients [0.02%]; weighted odds ratio of 2.21, 95% confidence interval [CI] 1.52-3.22). Most hospital admissions with rhabdomyolysis after donepezil use were not severe, and no patient was treated with acute dialysis or mechanical ventilation. INTERPRETATION: Initiating donepezil is associated with a higher 30-day risk of admission to hospital with rhabdomyolysis compared with initiating rivastigmine or galantamine. The proportion of patients who develop severe rhabdomyolysis within 30 days of initiating donepezil is very low.

Gabapentin dose and the 30-day risk of altered mental status in older adults: A retrospective population-based study.

Gabapentin is an effective treatment for chronic neuropathic pain but may cause dizziness, drowsiness, and confusion in some older adults. The goal of this study was to assess the association between gabapentin dosing and adverse outcomes by obtaining estimates of the 30-day risk of hospitalization with altered mental status and mortality in older adults (mean age 76 years) in Ontario, Canada initiated on high dose (>600 mg/day; n = 34,159) compared to low dose (≤600 mg/day; n = 76,025) oral gabapentin in routine outpatient care. A population-based, retrospective cohort study assessing new gabapentin use between 2002 to 2014 was conducted. The primary outcome was 30-day hospitalization with an urgent head computed tomography (CT) scan in the absence of evidence of stroke (a proxy for altered mental status). The secondary outcome was 30-day all-cause mortality. The baseline characteristics measured in the two dose groups were similar. Initiation of a high versus low dose of gabapentin was associated with a higher risk of hospitalization with head CT scan (1.27% vs. 1.06%, absolute risk difference 0.21%, adjusted relative risk 1.29 [95% CI 1.14 to 1.46], number needed to treat 477) but not a statistically significant higher risk of mortality (1.25% vs. 1.16%, absolute risk difference of 0.09%, adjusted relative risk of 1.01 [95% CI 0.89 to 1.14]). Overall, the risk of being hospitalized with altered mental status after initiating gabapentin remains low, but may be reduced through the judicious use of gabapentin, use of the lowest dose to control pain, and vigilance for early signs of altered mental status.

Validity of administrative database code algorithms to identify vascular access placement, surgical revisions, and secondary patency.

BACKGROUND:: We assessed the validity of physician billing codes and hospital admission using International Classification of Diseases 10th revision codes to identify vascular access placement, secondary patency, and surgical revisions in administrative data. METHODS:: We included adults (≥18 years) with a vascular access placed between 1 April 2004 and 31 March 2013 at the University Health Network, Toronto. Our reference standard was a prospective vascular access database (VASPRO) that contains information on vascular access type and dates of placement, dates for failure, and any revisions. We used VASPRO to assess the validity of different administrative coding algorithms by calculating the sensitivity, specificity, and positive predictive values of vascular access events. RESULTS:: The sensitivity (95% confidence interval) of the best performing algorithm to identify arteriovenous access placement was 86% (83%, 89%) and specificity was 92% (89%, 93%). The corresponding numbers to identify catheter insertion were 84% (82%, 86%) and 84% (80%, 87%), respectively. The sensitivity of the best performing coding algorithm to identify arteriovenous access surgical revisions was 81% (67%, 90%) and specificity was 89% (87%, 90%). The algorithm capturing arteriovenous access placement and catheter insertion had a positive predictive value greater than 90% and arteriovenous access surgical revisions had a positive predictive value of 20%. The duration of arteriovenous access secondary patency was on average 578 (553, 603) days in VASPRO and 555 (530, 580) days in administrative databases. CONCLUSION:: Administrative data algorithms have fair to good operating characteristics to identify vascular access placement and arteriovenous access secondary patency. Low positive predictive values for surgical revisions algorithm suggest that administrative data should only be used to rule out the occurrence of an event.

Statin Safety in Chinese: A Population-Based Study of Older Adults.

BACKGROUND: Compared to Caucasians, Chinese achieve a higher blood concentration of statin for a given dose. It remains unknown whether this translates to increased risk of serious statin-associated adverse events amongst Chinese patients. METHODS: We conducted a population-based retrospective cohort study of older adults (mean age, 74 years) newly prescribed a statin in Ontario, Canada between 2002 and 2013, where 19,033 Chinese (assessed through a validated surname algorithm) were matched (1:3) by propensity score to 57,099 non-Chinese. This study used linked healthcare databases. FINDINGS: The follow-up observation period (mean 1.1, maximum 10.8 years) was similar between groups, as were the reasons for censoring the observation period (end of follow-up, death, or statin discontinuation). Forty-seven percent (47%) of Chinese were initiated on a higher than recommended statin dose. Compared to non-Chinese, Chinese ethnicity did not associate with any of the four serious statin-associated adverse events assessed in this study [rhabdomyolysis hazard ratio (HR) 0.61 (95% CI 0.28 to 1.34), incident diabetes HR 1.02 (95% CI 0.80 to 1.30), acute kidney injury HR 0.90 (95% CI 0.72 to 1.13), or all-cause mortality HR 0.88 (95% CI 0.74 to 1.05)]. Similar results were observed in subgroups defined by statin type and dose. CONCLUSIONS: We observed no higher risk of serious statin toxicity in Chinese than matched non-Chinese older adults with similar indicators of baseline health. Regulatory agencies should review available data, including findings from our study, to decide if a change in their statin dosing recommendations for people of Chinese ethnicity is warranted.

The hypoglycemic risk of glyburide (glibenclamide) compared with modified-release gliclazide.

OBJECTIVES: The risk for hypoglycemia when taking glyburide compared with modified-release gliclazide remains to be established in older adults in routine care. We investigated the risk of a hospital encounter with hypoglycemia following a new prescription for glyburide compared with modified-release gliclazide. METHODS: In 2 population-based matched retrospective cohort studies in Ontario, Canada, between 2002 and 2011, we examined older adults who were newly prescribed glyburide or gliclazide as monotherapy or in the presence of metformin. Our primary outcome was a hospital encounter with hypoglycemia assessed within 90 days. RESULTS: The baseline characteristics between matched groups were similar. Initiating glyburide vs. gliclazide as monotherapy was associated with a higher risk for a hospital encounter with hypoglycemia (69 patients of 4374 taking glyburide [1.58%] vs. 8 patients of 4374 taking gliclazide [0.18%], absolute risk increase 1.40% [95% CI 1.01% to 1.79%], number needed to harm 71 [55 to 99], odds ratio 8.63 [95% CI 4.15 to 17.93], p<0.0001). Similar findings were noted when glyburide vs. gliclazide was initiated in the presence of metformin (110 patients of 8038 taking glyburide [1.37%] vs. 19 patients of 8038 taking gliclazide [0.24%], absolute risk increase 1.13% [95% CI 0.86% to 1.40%], number needed to harm 77 [71 to 116], odds ratio 6.06 [95% CI 3.68 to 9.97], p<0.0001). CONCLUSIONS: Glyburide was associated with a higher risk for hypoglycemia than modified-release gliclazide. The results of our studies may help to convince healthcare professionals who use glyburide to consider modified-release gliclazide as a safer alternative.

Angiotensin Converting Enzyme Inhibitor Dialyzability and Outcomes in Older Patients Receiving Hemodialysis.

BACKGROUND/AIMS: Some angiotensin converting enzyme (ACE) inhibitors are efficiently removed from circulation by hemodialysis ('high dialyzability'), whereas others are not ('low dialyzability'). In patients receiving hemodialysis, this may influence the effectiveness of ACE inhibitors. METHODS: Using linked healthcare databases we identified older patients receiving chronic hemodialysis who filled new ACE inhibitor prescriptions. The low dialyzability group (n = 3,369) included fosinopril and ramipril. The high dialyzability group (n = 5,974) included enalapril, lisinopril, and perindopril. The primary outcome was all-cause mortality within 180 days of first ACE inhibitor prescription. RESULTS: There were 361 deaths among 5,974 patients (6.0%) prescribed with low dialyzability ACE inhibitors and 179 deaths among 3,369 patients (5.3%) prescribed with high dialyzability ACE inhibitors (relative risk 1.1, 95% CI 0.9-1.3, p = 0.6). CONCLUSION: In this study of older patients receiving hemodialysis, the dialyzability of ACE inhibitors was not associated with mortality or cardiovascular outcomes.

The risk of pancreatitis with sitagliptin therapy in older adults: a population-based cohort study.

BACKGROUND: The risk of pancreatitis with sitagliptin use in routine care remains to be established in older patients. We aimed to determine this risk in older adults who were newly prescribed sitagliptin versus an alternative hypoglycemic agent in the outpatient setting. METHODS: In a population-based retrospective cohort study in Ontario from 2010 until 2012 involving adults aged 66 years and older, we studied those who were newly prescribed sitagliptin or an alternative hypoglycemic agent. Our primary outcome of interest was a hospital encounter (emergency department visit or hospital admission) with acute pancreatitis within 90 days. We used inverse probability of treatment weighting to balance the 2 groups and logistic regression with a robust variance estimate to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 57 689 patients (mean age 74 yr) were newly prescribed sitagliptin, and 83 405 patients (mean age 75 yr) were given an alternative hypoglycemic agent (metformin, glyburide, gliclazide or insulin) during the study period. After weighting, there were no significant differences in measured baseline characteristics between groups. In the weighted sample, sitagliptin was not associated with an increased risk of a hospital encounter with pancreatitis compared with alternative hypoglycemic agents (weighted total 46 of 57 689 patients taking sitagliptin [0.08%] v. 48 of 55 705 patients taking alternative hypoglycemic agents [0.09%], absolute risk difference -0.01% [95% CI -0.05% to 0.02%], OR 0.92 [95% CI 0.55 to 1.55]). INTERPRETATION: Older adults newly prescribed sitagliptin in routine care were not at a substantially higher risk of pancreatitis than those prescribed alternative hypoglycemic agents. These findings are reassuring for those who use or prescribe sitagliptin in the management of type 2 diabetes.

The Hypoglycemic Risk of Glyburide (Glibenclamide) Compared with Modified-Release Gliclazide.

OBJECTIVES: The risk for hypoglycemia when taking glyburide compared with modified-release gliclazide remains to be established in older adults in routine care. We investigated the risk of a hospital encounter with hypoglycemia following a new prescription for glyburide compared with modified-release gliclazide. METHODS: In 2 population-based matched retrospective cohort studies in Ontario, Canada, between 2002 and 2011, we examined older adults who were newly prescribed glyburide or gliclazide as monotherapy or in the presence of metformin. Our primary outcome was a hospital encounter with hypoglycemia assessed within 90 days. RESULTS: The baseline characteristics between matched groups were similar. Initiating glyburide vs. gliclazide as monotherapy was associated with a higher risk for a hospital encounter with hypoglycemia (69 patients of 4374 taking glyburide [1.58%] vs. 8 patients of 4374 taking gliclazide [0.18%], absolute risk increase 1.40% [95% CI 1.01% to 1.79%], number needed to harm 71 [55 to 99], odds ratio 8.63 [95% CI 4.15 to 17.93], p<0.0001). Similar findings were noted when glyburide vs. gliclazide was initiated in the presence of metformin (110 patients of 8038 taking glyburide [1.37%] vs. 19 patients of 8038 taking gliclazide [0.24%], absolute risk increase 1.13% [95% CI 0.86% to 1.40%], number needed to harm 77 [71 to 116], odds ratio 6.06 [95% CI 3.68 to 9.97], p<0.0001). CONCLUSIONS: Glyburide was associated with a higher risk for hypoglycemia than modified-release gliclazide. The results of our studies may help to convince healthcare professionals who use glyburide to consider modified-release gliclazide as a safer alternative.

ß-Blocker dialyzability and mortality in older patients receiving hemodialysis.

Some ß-blockers are efficiently removed from the circulation by hemodialysis ("high dialyzability") whereas others are not ("low dialyzability"). This characteristic may influence the effectiveness of the ß-blockers among patients receiving long-term hemodialysis. To determine whether new use of a high-dialyzability ß-blocker compared with a low-dialyzability ß-blocker associates with a higher rate of mortality in patients older than age 66 years receiving long-term hemodialysis, we conducted a propensity-matched population-based retrospective cohort study using the linked healthcare databases of Ontario, Canada. The high-dialyzability group (n=3294) included patients initiating atenolol, acebutolol, or metoprolol. The low-dialyzability group (n=3294) included patients initiating bisoprolol or propranolol. Initiation of a high- versus low-dialyzability ß-blocker was associated with a higher risk of death in the following 180 days (relative risk, 1.4; 95% confidence interval, 1.1 to 1.8; P<0.01). Supporting this finding, we repeated the primary analysis in a cohort of patients not receiving hemodialysis and found no significant association between dialyzability and the risk of death (relative risk, 1.0; 95% confidence interval, 0.9 to 1.3; P=0.71). ß-Blocker exposure was not randomly allocated in this study, so a causal relationship between dialyzability and mortality cannot be determined. However, our findings should raise awareness of this potentially important drug characteristic and prompt further study.

Risk of adverse events among older adults following co-prescription of clarithromycin and statins not metabolized by cytochrome P450 3A4.

BACKGROUND: The cytochrome P450 3A4 (CYP3A4) inhibitor clarithromycin may also inhibit liver-specific organic anion-transporting polypeptides (OATP1B1 and OATP1B3). We studied whether concurrent use of clarithromycin and a statin not metabolized by CYP3A4 was associated with an increased frequency of serious adverse events. METHODS: Using large health care databases, we studied a population-based cohort of older adults (mean age 74 years) who were taking a statin not metabolized by CYP3A4 (rosuvastatin [76% of prescriptions], pravastatin [21%] or fluvastatin [3%]) between 2002 and 2013 and were newly prescribed clarithromycin (n=51,523) or azithromycin (n=52,518), the latter an antibiotic that inhibits neither CYP3A4 nor OATP1B1 and OATP1B3. Outcomes were hospital admission with a diagnostic code for rhabdomyolysis, acute kidney injury or hyperkalemia, and all-cause mortality. All outcomes were assessed within 30 days after co-prescription. RESULTS: Compared with the control group, patients co-prescribed clarithromycin and a statin not metabolized by CYP3A4 were at increased risk of hospital admission with acute kidney injury (adjusted relative risk [RR] 1.65, 95% confidence interval [CI] 1.31 to 2.09), admission with hyperkalemia (adjusted RR 2.17, 95% CI 1.22 to 3.86) and all-cause mortality (adjusted RR 1.43, 95% CI 1.15 to 1.76). The adjusted RR for admission with rhabdomyolysis was 2.27 (95% CI 0.86 to 5.96). The absolute increase in risk for each outcome was small and likely below 1%, even after we considered the insensitivity of some hospital database codes. INTERPRETATION: Among older adults taking a statin not metabolized by CYP3A4, co-prescription of clarithromycin versus azithromycin was associated with a modest but statistically significant increase in the 30-day absolute risk of adverse outcomes.

Risk of hospitalization for community acquired pneumonia with renin-angiotensin blockade in elderly patients: a population-based study.

OBJECTIVE: To characterize the 90-day risk of hospitalization with pneumonia among patients treated with different anti-hypertensive drug classes. DESIGN: Population based cohort study using five linked databases. PARTICIPANTS: Individuals over the age of 65 who filled a new outpatient prescription for one of four anti-hypertensive medications: ACE inhibitors (n = 86 775), ARBs (n = 33,953), calcium channel blockers (CCB, n = 34,240), beta blockers (BB, n = 35,331) and thiazide diuretics (n = 64 186). PRIMARY OUTCOME: Hospitalization with pneumonia within 90 days of a qualifying prescription. We adjusted for ten a priori selected covariates, including age, sex, diabetes and number of visits to a family doctor. RESULTS: Baseline characteristics of the groups were relatively well matched, except for age, sex, diabetes and frequency of family doctor visits. 128 of the 86 775 patients (0.15%) initiated on an ACE inhibitor and 43 of the 33953 patients (0.13%) of patients initiated on an ARB were hospitalized with pneumonia in the subsequent 90 days. 135 of 64 186 patients (0.21%) initiated on a thiazide, 112 of 35 331 patients (.32%) initiated on a BB, and 89 of 34 240 (0.26%) patients initiated on a CCB achieved the primary outcome. Compared to calcium channel blockers, ACE inhibitors (adjusted OR 0.61, 95% CI 0.46 to 0.81) and ARBs (adjusted OR 0.52, 95% CI 0.36 to 0.76) were associated with a lower risk of pneumonia. No benefit was seen with thiazides (adjusted OR 0.87, 95% CI 0.66 to 1.14) or beta blockers (adjusted OR 1.21, 95% CI 0.91 to 1.60). CONCLUSION: Initiating medications that block the renin angiotensin system, compared to other anti-hypertensive medications, is associated with a small absolute reduction in the 90 day risk of hospitalization with pneumonia.