Kathleen Potter

Reducing Inappropriate Polypharmacy: The Process of Deprescribing

Inappropriate polypharmacy, especially in older people, imposes a substantial burden of adverse drug events, ill health, disability, hospitalization, and even death. The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed drugs. Deprescribing is the process of tapering or stopping drugs, aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies. A deprescribing protocol is proposed comprising 5 steps: (1) ascertain all drugs the patient is currently taking and the reasons for each one; (2) consider overall risk of drug-induced harm in individual patients in determining the required intensity of deprescribing intervention; (3) assess each drug in regard to its current or future benefit potential compared with current or future harm or burden potential; (4) prioritize drugs for discontinuation that have the lowest benefit-harm ratio and lowest likelihood of adverse withdrawal reactions or disease rebound syndromes; and (5) implement a discontinuation regimen and monitor patients closely for improvement in outcomes or onset of adverse effects. Whereas patient and prescriber barriers to deprescribing exist, resources and strategies are available that facilitate deliberate yet judicious deprescribing and deserve wider application.

Ultrasound settings significantly alter arterial lumen and wall thickness measurements

BackgroundFlow-mediated dilation (FMD) and carotid intima-medial thickness (CIMT), measured by ultrasound, are widely used to test the efficacy of cardioprotective interventions. Although assessment methods vary, automated edge-detecting image analysis software is routinely used to measure changes in FMD and CIMT. We aimed to quantify the effect that commonly adjusted ultrasound settings have on arterial lumen and wall thickness measurements made with CIMT measurement software.MethodsWe constructed phantom arteries from a tissue-mimicking agar compound and scanned them in a water bath with a 10 MHz multi-frequency linear-array probe attached to a high-resolution ultrasound machine. B-mode images of the phantoms were recorded with dynamic range (DR) and gain set at five decibel (dB) increments from 40 dB to 60 dB and -10 dB to +10 dB respectively. Lumen diameter and wall-thickness were measured off-line using CIMT measurement software.ResultsLumen measurements: there was a strong linear relationship between DR and gain and measured lumen diameter. For a given gain level, a 5 dB increase in DR reduced the measured lumen diameter by 0.02 ± 0.004 mm (p < 0.001). For a given DR level, a 5 dB increase in gain reduced measured lumen diameter by 0.04 ± 0.004 mm (p < 0.001). A 5 mm increase in distance between the ultrasound probe and the artery reduced measured lumen diameter by 0.04 ± 0.03 mm (p < 0.001)CIMT measurements: For a fixed gain level, a 5 dB increase in DR increased measured wall thickness by 0.003 ± 0.002 mm (p < 0.001). The effects of increasing gain were not consistent and appeared to vary depending on the distance between the artery and the ultrasound probe and the thickness of the artery wall.ConclusionDR, gain and probe distance significantly alter lumen diameter and CIMT measurements made using image analysis software. When CIMT and FMD are used to test the efficacy of cardioprotective interventions, the DR, gain and probe position used to record baseline scans should be documented and replicated in post-treatment scans in individual trial subjects. If more than one sonographer or imaging centre is used to collect data, the study protocol should document specific DR and gain settings to be used in all subjects.

The effect of long-term homocysteine-lowering on carotid intima-media thickness and flow-mediated vasodilation in stroke patients: a randomized controlled trial and meta-analysis

AbstractBackgroundExperimental and epidemiological evidence suggests that homocysteine (tHcy) may be a causal risk factor for atherosclerosis. B-vitamin supplements reduce tHcy and improve endothelial function in short term trials, but the long-term effects of the treatment on vascular structure and function are unknown.MethodsWe conducted a sub-study of VITATOPS, a randomised, double-blind, placebo-controlled intervention trial designed to test the efficacy of long term B-vitamin supplementation (folic acid 2 mg, vitamin B6 25 mg and vitamin B12 0.5 mg) in the prevention of vascular events in patients with a history of stroke. We measured carotid intima-medial thickness (CIMT) and flow-mediated dilation (FMD) at least two years after randomisation in 162 VITATOPS participants. We also conducted a systematic review and meta-analysis of studies designed to test the effect of B-vitamin treatment on CIMT and FMD.ResultsAfter a mean treatment period of 3.9 ± 0.9 years, the vitamin-treated group had a significantly lower mean plasma homocysteine concentration than the placebo-treated group (7.9 μmol/L, 95% CI 7.5 to 8.4 versus 11.8 μmol/L, 95% CI 10.9 to 12.8, p < 0.001). Post-treatment CIMT (0.84 ± 0.17 mm vitamins versus 0.83 ± 0.18 mm placebo, p = 0.74) and FMD (median of 4.0%, IQR 0.9 to 7.2 vitamins versus 3.0%, IQR 0.6 to 6.6 placebo, p = 0.48) did not differ significantly between groups. A meta-analysis of published randomised data, including those from the current study, suggested that B-vitamin supplements should reduce CIMT (-0.10 mm, 95% CI -0.20 to -0.01 mm) and increase FMD (1.4%, 95% CI 0.7 to 2.1%). However, the improvement in endothelial function associated with homocysteine-lowering treatment was significant in short-term studies but not in longer trials.ConclusionAlthough short-term treatment with B-vitamins is associated with increased FMD, long-term homocysteine-lowering did not significantly improve FMD or CIMT in people with a history of stroke.Trial RegistrationClinical Trial Registration URL: http://www.actr.org.au/ Trial Registration number: 12605000005651

Homocysteine or Renal Impairment Which Is the Real Cardiovascular Risk Factor

Objective—The purpose of this study was to determine whether adjustment for renal function eliminates the relationship between total plasma homocysteine (tHcy) and vascular risk, assessed by carotid intima medial thickness (CIMT) and flow-mediated dilation (FMD) of the brachial artery. Methods and Results—We used cross-sectional data from 173 stroke patients treated with B-vitamins (folic acid 2 mg, vitamin B6 25 mg, and vitamin B12 0.5 mg) or placebo in a randomized double-blinded trial to test the relationships between posttreatment tHcy, cystatin C (a marker of glomerular filtration rate), estimated glomerular filtration rate (eGFR, Modification of Diet in Renal Disease equation) creatinine, CIMT, and FMD in stepwise and multivariable regression models. The strong linear relationship between tHcy and cystatin C was not altered by long-term B-vitamin treatment. tHcy lost significance as a predictor of the vascular measurements after adjustment for any single marker of renal function. Cystatin C, but not tHcy, was a significant independent predictor of FMD after adjustment for age, sex, smoking, systolic blood pressure, high-density lipoprotein cholesterol, and treatment group. Conclusions—Adjusting for renal function eliminates the relationship between tHcy and CIMT and FMD, supporting the hypothesis that elevated tHcy is a marker for renal impairment rather than an independent cardiovascular risk factor.

The feasibility and effect of deprescribing in older adults on mortality and health: a systematic review and meta‐analysis

AIMS Deprescribing is a suggested intervention to reverse the potential iatrogenic harms of inappropriate polypharmacy. The review aimed to determine whether or not deprescribing is a safe, effective and feasible intervention to modify mortality and health outcomes in older adults. METHODS Specified databases were searched from inception to February 2015. Two researchers independently screened all retrieved articles for inclusion, assessed study quality and extracted data. Data were pooled using RevMan v5.3. Eligible studies included those where older adults had at least one medication deprescribed. The primary outcome was mortality. Secondary outcomes were adverse drug withdrawal events, psychological and physical health outcomes, quality of life, and medication usage (e.g. successful deprescribing, number of medications prescribed, potentially inappropriate medication use). RESULTS A total of 132 papers met the inclusion criteria, which included 34 143 participants aged 73.8 ± 5.4 years. In nonrandomized studies, deprescribing polypharmacy was shown to significantly decrease mortality (OR 0.32, 95% CI: 0.17-0.60). However, this was not statistically significant in the randomized studies (OR 0.82, 95% CI 0.61-1.11). Subgroup analysis revealed patient-specific interventions to deprescribe demonstrated a significant reduction in mortality (OR 0.62, 95% CI 0.43-0.88). However, generalized educational programmes did not change mortality (OR 1.21, 95% CI 0.86-1.69). CONCLUSIONS Although nonrandomized data suggested that deprescribing reduces mortality, deprescribing was not shown to alter mortality in randomized studies. Mortality was significantly reduced when applying patient-specific interventions to deprescribe in randomized studies.

The feasibility and the effect of deprescribing in older adults on mortality and health: A systematic review

AIMS Deprescribing is a suggested intervention to reverse the potential iatrogenic harms of inappropriate polypharmacy. The review aimed to determine whether or not deprescribing is a safe, effective and feasible intervention to modify mortality and health outcomes in older adults. METHODS Specified databases were searched from inception to February 2015. Two researchers independently screened all retrieved articles for inclusion, assessed study quality and extracted data. Data were pooled using RevMan v5.3. Eligible studies included those where older adults had at least one medication deprescribed. The primary outcome was mortality. Secondary outcomes were adverse drug withdrawal events, psychological and physical health outcomes, quality of life, and medication usage (e.g. successful deprescribing, number of medications prescribed, potentially inappropriate medication use). RESULTS A total of 132 papers met the inclusion criteria, which included 34 143 participants aged 73.8 ± 5.4 years. In nonrandomized studies, deprescribing polypharmacy was shown to significantly decrease mortality (OR 0.32, 95% CI: 0.17-0.60). However, this was not statistically significant in the randomized studies (OR 0.82, 95% CI 0.61-1.11). Subgroup analysis revealed patient-specific interventions to deprescribe demonstrated a significant reduction in mortality (OR 0.62, 95% CI 0.43-0.88). However, generalized educational programmes did not change mortality (OR 1.21, 95% CI 0.86-1.69). CONCLUSIONS Although nonrandomized data suggested that deprescribing reduces mortality, deprescribing was not shown to alter mortality in randomized studies. Mortality was significantly reduced when applying patient-specific interventions to deprescribe in randomized studies.

A pilot randomized controlled trial of deprescribing

Objective: Polypharmacy and adverse drug reactions are frequent and important among older people. Few clinical trials have evaluated systematic withdrawal of medications among older people. This small, open, study was conducted to determine the feasibility of a randomized controlled deprescribing trial. Methods: Ten volunteers living in the community (recruited by media advertising) and 25 volunteers living in residential aged-care facilities (RCFs) were randomized to intervention or control groups. The intervention was gradual withdrawal of one target medication. The primary outcome was the number of intervention participants in whom medication withdrawal could be achieved. Other outcomes measures were quality of life, medication adherence, sleep quality, and cognitive impairment. Results: Participants were aged 80 ± 11 years and were taking 9 ± 2 medications. Fifteen participants commenced medication withdrawal and all ceased or reduced the dose of their target medication. Two subjects withdrew; one was referred for clinical review, and one participant declined further dose reductions. Conclusions: A randomized controlled trial of deprescribing was acceptable to participants. Recruitment in RCFs is feasible. Definitive trials of deprescribing are required.

Carotid intima-medial thickness measured on multiple ultrasound frames : evaluation of a DICOM-based software system

BackgroundCarotid intima-media thickness (CIMT) measured by B-mode ultrasonography is a marker of atherosclerosis and is commonly used as an outcome in intervention trials. We have developed DICOM-based software that measures CIMT rapidly on multiple end-diastolic image frames. The aims of this study were to compare the performance of our new software with older bitmap-based CIMT measurement software and to determine whether a ten-fold increase in the number of measurements used to calculate mean CIMT would improve reproducibility.MethodsTwo independent sonographers recorded replicate carotid scans in thirty volunteers and two blinded observers measured CIMT off-line using the new DICOM-based software and older bitmap-based software. A Bland-Altman plot was used to compare CIMT results from the two software programs and t-tests were used to compare analysis times. F-tests were used to compare the co-efficients of variation (CVs) from a standard six-frame measurement protocol with CVs from a sixty-frame measurement protocol. Ordinary least products (OLP) regression was used to test for sonographer and observer biases.ResultsThe new DICOM-based software was much faster than older bitmap-based software (average measurement time for one scan 3.4 ± 0.6 minutes versus 8.4 ± 1.8 minutes, p < 0.0001) but CIMT measurements were larger than those made using the alternative software (+0.02 mm, 95%CI 0.01–0.03 mm). The sixty-frame measurement protocol had worse reproducibility than the six-frame protocol (inter-observer CV 5.1% vs 3.5%, p = 0.004) and inter and intra-observer biases were more pronounced in the sixty-frame than the six-frame results.ConclusionWhile the use of DICOM-based software significantly reduced analysis time, a ten-fold increase in the number of measurements used to calculate CIMT did not improve reproducibility. In addition, we found that observer biases caused differences in mean CIMT of a magnitude commonly reported as significant in intervention trials. Our results highlight the importance of good study design with concurrent controls and the need to ensure that no observer drift occurs between baseline and follow-up measurements when CIMT is used to monitor the effect of an intervention.

Deprescribing in Frail Older People: A Randomised Controlled Trial

Objectives Deprescribing has been proposed as a way to reduce polypharmacy in frail older people. We aimed to reduce the number of medicines consumed by people living in residential aged care facilities (RACF). Secondary objectives were to explore the effect of deprescribing on survival, falls, fractures, hospital admissions, cognitive, physical, and bowel function, quality of life, and sleep. Methods Ninety-five people aged over 65 years living in four RACF in rural mid-west Western Australia were randomised in an open study. The intervention group (n = 47) received a deprescribing intervention, the planned cessation of non-beneficial medicines. The control group (n = 48) received usual care. Participants were monitored for twelve months from randomisation. Primary outcome was change in the mean number of unique regular medicines. All outcomes were assessed at baseline, six, and twelve months. Results Study participants had a mean age of 84.3±6.9 years and 52% were female. Intervention group participants consumed 9.6±5.0 and control group participants consumed 9.5±3.6 unique regular medicines at baseline. Of the 348 medicines targeted for deprescribing (7.4±3.8 per person, 78% of regular medicines), 207 medicines (4.4±3.4 per person, 59% of targeted medicines) were successfully discontinued. The mean change in number of regular medicines at 12 months was -1.9±4.1 in intervention group participants and +0.1±3.5 in control group participants (estimated difference 2.0±0.9, 95%CI 0.08, 3.8, p = 0.04). Twelve intervention participants and 19 control participants died within 12 months of randomisation (26% versus 40% mortality, p = 0.16, HR 0.60, 95%CI 0.30 to 1.22) There were no significant differences between groups in other secondary outcomes. The main limitations of this study were the open design and small participant numbers. Conclusions Deprescribing reduced the number of regular medicines consumed by frail older people living in residential care with no significant adverse effects on survival or other clinical outcomes. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12611000370909

Effect of long-term homocysteine reduction with B vitamins on arterial wall inflammation assessed by fluorodeoxyglucose positron emission tomography: a randomised double-blind, placebo-controlled trial.

Background: Homocysteine may promote atherosclerosis by exacerbating inflammatory processes within the arterial wall. B-vitamin supplements reduce total plasma homocysteine concentrations (tHcy), but it is not known whether the treatment also reduces arterial wall inflammation. We used 18F-fluorodeoxygluose positron emission tomography (18F-FDG PET) to investigate whether long-term homocysteine-lowering treatment alters arterial wall inflammation in patients with a history of ischemic stroke. Methods: 30 stroke patients were randomly assigned to B-vitamin therapy (folic acid 2 mg, vitamin B6 25 mg and vitamin B12 0.5 mg) or placebo in a double-blind clinical trial. After a mean treatment period of 4.0 ± 0.7 years, all subjects had tHcy, carotid intima-medial thickness (CIMT) and flow-mediated dilation (FMD) of the brachial artery measured and underwent an 18F-FDG PET scan. Standardised uptake values (SUV) were measured at six sites in the carotid, femoral and aortic arteries. Areas of locally increased tracer uptake in the arterial wall (‘hot spots’) were also identified and counted. Results: Long-term B-vitamin treatment significantly reduced tHcy compared with placebo (8.4 μmol/l, 95% confidence interval, CI, 7.2–9.6 vs. 11.6 μmol/l, 95% CI 10.0–13.4, p = 0.002). The treatment did not affect mean arterial SUV (2.0 ± 0.3 vitamins vs. 2.1 ± 0.3 placebo, p = 0.65) or the number of hot spots (n = 1.1 ± 1.0 vitamins vs. n = 1.2 ± 1.0 placebo, p = 0.65). There was no significant correlation between mean arterial SUV and CIMT or FMD. Conclusions: These results suggest that a long-term Hcy reduction with B vitamins does not affect arterial wall inflammation assessed by 18F-FDG PET.