The authors have declared that no competing interests exist.
¶ Membership of the SPPiRE Study team is listed in the Acknowledgements.
There is a rising prevalence of multimorbidity, particularly in older patients, and a need for evidence-based medicines management interventions for this population. The Supporting Prescribing in Older Adults with Multimorbidity in Irish Primary Care (SPPiRE) trial aimed to investigate the effect of a general practitioner (GP)-delivered, individualised medication review in reducing polypharmacy and potentially inappropriate prescriptions (PIPs) in community-dwelling older patients with multimorbidity in primary care.
We conducted a cluster randomised controlled trial (RCT) set in 51 GP practices throughout the Republic of Ireland. A total of 404 patients, aged ≥65 years with complex multimorbidity, defined as being prescribed ≥15 regular medicines, were recruited from April 2017 and followed up until October 2020. Furthermore, 26 intervention GP practices received access to the SPPiRE website where they completed an educational module and used a template for an individualised patient medication review that identified PIP, opportunities for deprescribing, and patient priorities for care. A total of 25 control GP practices delivered usual care. An independent blinded pharmacist assessed primary outcome measures that were the number of medicines and the proportion of patients with any PIP (from a predefined list of 34 indicators based predominantly on the STOPP/START version 2 criteria). We performed an intention-to-treat analysis using multilevel modelling. Recruited participants had substantial disease and treatment burden at baseline with a mean of 17.37 (standard deviation [SD] 3.50) medicines. At 6-month follow-up, both intervention and control groups had reductions in the numbers of medicines with a small but significantly greater reduction in the intervention group (incidence rate ratio [IRR] 0.95, 95% confidence interval [CI]: 0.899 to 0.999,
The SPPiRE intervention resulted in a small but significant reduction in the number of medicines but no evidence of a clear effect on PIP. This reduction in significant polypharmacy may have more of an impact at a population rather than individual patient level.
ISRCTN Registry
Caroline McCarthy and colleagues investigate the effect of a general practitioner-delivered, individualized medication review on polypharmacy and potentially inappropriate prescribing in community dwelling older patients with multimorbidity in Irish primary care.
Polypharmacy is frequently cited as a major concern by patients with multimorbidity.
More evidence-based medicines management interventions are needed to improve care for this growing and vulnerable population.
We conducted a pragmatic, 2-arm cluster randomised controlled trial (RCT) in Irish primary care to investigate whether a general practitioner (GP)-delivered individualised medication review with a deprescribing approach could reduce polypharmacy and improve prescribing in older people with multimorbidity and significant polypharmacy.
There was a small but significant reduction in the number of medicines in the intervention compared to control group at follow-up but no significant effect on potentially inappropriate prescribing (PIP).
Out of 826 medicines stopped in the intervention group, just 15 adverse drug withdrawal events (ADWEs) were reported.
A primary care–based medication review intervention that aims to reduce significant polypharmacy is safe and could lead to the deprescription of unnecessary medicines. However, this may have a greater impact at a population rather than individual patient level.
Improvements in the control group suggest that identification of patients with significant polypharmacy may in itself lead to reduction in the number of medicines.
Recruitment and retention of patients with a high degree of disease and treatment burden into RCTs are possible but require significant resource and planning, and targeting those with less severe disease burden may be more appropriate and may lead to greater gains for individual patients.
Advances in healthcare and therapeutics have led to increases in life expectancy and a rising population of older people living with multiple long-term conditions or multimorbidity. Multimorbidity, commonly defined as 2 or more chronic conditions, is associated with adverse outcomes for patients including increased mortality and reduced quality of life [
Prescribing for patients with multimorbidity is particularly complex, and, although explicit measures are useful in identifying potential drug–drug and drug–disease interactions, consideration must be given to the individual context and patient priorities [
The development of the Supporting Prescribing in Older Adults with Multimorbidity in Irish Primary Care (SPPiRE) intervention has been extensively described elsewhere [
The methods for the SPPiRE cluster RCT have been described in the trial protocol [
Eligible patients were aged ≥65 years and prescribed ≥15 repeat medicines. A repeat medicine was defined as any unique item with a World Health Organization Anatomical Therapeutic Chemical code on the patient’s current repeat prescription, i.e., indicated by their GP as being an ongoing treatment, for ease of issuing further prescriptions within the patient record. Patients were excluded if they had been recruited into a practice that was unable to recruit at least 4 other participants, they were judged by their GP as unable to give informed consent, or they were unable to attend the practice for a face-to-face medication review (e.g., nursing home residents and housebound patients). Recruited GPs ran the SPPiRE patient finder tool and screened the generated list to ensure that only eligible patients were invited. Practices who identified more than 40 eligible patients were supported in selecting a random sample of 30 patients to invite. All recruited practices and patients gave fully informed consent, and baseline data were collected prior to practice allocation, to reduce the likelihood of selection bias.
Recruited practices were allocated to intervention (26) or control groups (25) by minimisation using MinimPy software [
Intervention GPs received unique log-in details to the SPPiRE website where they had access to 5 training videos and a template for performing the SPPiRE medication review. The training videos provided background information on multimorbidity and polypharmacy, PIP, eliciting patient treatment priorities, and conducting a brown bag medication review. GPs were instructed to book a double appointment and to ask their patients to bring all their medicines in to the medication review visit with them. The SPPiRE medication review process had 2 main components: gather and record information and then to discuss and agree upon any changes with their patient based on the recorded information, with a focus on deprescribing medicines that were potentially inappropriate (
ADR, adverse drug reaction; GP, general practitioner; PIP, potentially inappropriate prescribing; SPPiRE, Supporting Prescribing in Older Adults with Multimorbidity in Irish Primary Care.
Control GPs delivered usual care during the 6- to 12-month study period. At the time of intervention delivery, there was no structured chronic disease management programme in Irish primary care, and many patients with multimorbidity attended multiple hospital specialists. In Ireland, the majority of people aged 70 years of age have access to free GP visits and medicines with some prescription charge co-payments. In the 65- to 69-year-old age category, a lower proportion have access to both free GP visits and prescription medicines. Access to specialists and diagnostics in secondary care is free for the entire population.
The 2 primary outcomes were the number of repeat medicines and the proportion of patients with any PIP, from a list of 34 prespecified indicators (see
the number of medicines stopped and started;
the proportion of patients with a reduction in significant polypharmacy (defined as ≥15 repeat medicines);
the number of PIP;
the proportion of patients with a high-risk PIP (see
the proportion of patients with any reduction in PIP.
Secondary patient-reported outcomes measures were included to capture the effectiveness of the intervention from the patients’ perspective. These were the following:
Health-related Quality of life (EuroQoL 5-dimension 5-level, EQ-5D-5L) [
revised Patients’ Attitudes Towards Deprescribing (rPATD) [
Multimorbidity Treatment Burden Questionnaire (MTBQ) [
Healthcare utilisation data were collected to assess the effect of the intervention on healthcare usage and for the trial’s economic evaluation.
Outcomes were collected at baseline and at 6 months after intervention delivery. Patient-reported measures were collected by postal questionnaires. Data for all other measures including prescribed medicines, medical and investigations history, and healthcare utilisation were collected by participating GPs and submitted to the study manager (CMC). This was a deviation from the original protocol, which indicated that these data would be collected by the research team. This deviation related to changes in data protection and national health research regulations during the study period, which precluded the research team access to the patients’ full clinical record.
Information on adverse events such as mortality, emergency department (ED) presentations, and hospital admissions was collected at follow-up. Given the deprescribing approach of the intervention, a safety protocol for identifying and reporting any suspected adverse drug withdrawal events (ADWEs) was developed. An ADWE is defined as either recurrence of the condition for which the drug was prescribed (e.g., recurrence of angina after stopping a beta blocker) or a physiologic reaction to drug withdrawal (e.g., selective serotonin reuptake inhibitor [SSRI] withdrawal syndrome) [
There was no formal patient and public involvement (PPI) during the intervention development process. However, there was PPI representation on the independent trial steering committee that oversaw the completion of the trial, reviewed all trial documentation, and was involved in the development of the safety protocol and methods for monitoring adverse events.
As outlined in the trial protocol [
Descriptive statistics were used to describe baseline characteristics of recruited practices and participants. All analyses were conducted under the intention-to-treat principle, and those lost to follow-up had their baseline data carried forward. The primary analysis was carried out using multilevel modelling. The first primary outcome measure, number of repeat medications, was assessed using mixed effects Poisson regression with the individual as the unit of analysis and the practice included as the random effect to control for the effects of clustering and results presented using incidence rate ratios (IRRs) and 95% confidence intervals (CIs). The baseline number of medicines, GP size (number of GP sessions per week), and GP location (urban/rural) were included in the analysis as fixed effects. The second outcome measure, proportion of patients with a PIP, was analysed in a similar manner using mixed effects logistic regression, including PIP at baseline, GP size and location, and results presented using odds ratios (ORs) and 95% CIs. A number of prespecified sensitivity analyses were conducted: complete case analysis, per-protocol analysis, and including “presence of a repeat prescribing policy” as a covariate. All secondary outcomes were analysed in a similar manner to the primary outcomes, using appropriate mixed effects regression methods (i.e., linear, logistic, and Poisson).
Between April 2017 and December 2019, 139 practices and 1,626 patients were invited to take part. A total of 51 practices were recruited giving an overall practice enrollment rate of 36.7% (see
GP, general practitioner; PROM, patient-reported outcome measure; SPPiRE, Supporting Prescribing in Older Adults with Multimorbidity in Irish Primary Care.
Practices were excluded either because they were unable to identify (n = 23) or recruit (n = 23) a sufficient number of eligible patients. In some practices, the finder tool did not function as anticipated due to problems with how prescription data were coded in that practice. Of the practices who declined to take part, most cited time constraints as the primary reason. Practices recruited into the trial were larger compared to the national average, for example, 39% of SPPiRE practices had 4 GPs, compared to 19% nationally.
Of the 1,626 patients invited, 404 were ultimately recruited into the trial giving an enrollment rate of 24.8% (see
Recruited patients had a mean age of 76.5 years (SD 6.83), a mean number of medicines of 17.37 (SD 3.50), and a mean number of PIP per person of 2.52 (SD 1.48). Between one quarter and one-third of participants scored in the severe or extreme domains of the EQ-5D-5L for impairments to mobility, activities of daily living, and pain at baseline. Practices and patients in each group had similar characteristics at baseline; see
Characteristic | Intervention, |
Control, |
---|---|---|
Mean (SD) | 30.42 (17.35) | 27.54 (13.78) |
Median (IQR) | 29.50 (18 to 37) | 26 (16 to 35.5) |
Mean (SD) | 12.40 (7.09) | 10.79 (5.68) |
Median (IQR) | 10 (9 to 15) | 10 (7.5 to 12.5) |
None (%) | 3 (11.5) | 6 (24.0) |
Part time (%) | 9 (34.6) | 9 (36.0) |
Full time (%) | 14 (53.8) | 10 (40.0) |
Mean (SD) | 6,877.72 (3,354.24) | 6,512.56 (3,942.18) |
Median (IQR) | 6,850 (5,484 to 7,994) | 5,948 (3,265 to 8,519) |
Mean (SD) | 1,192.78 (916.78) | 1,192.78 (650.66) |
Median (IQR) | 974.5 (625 to 1,248) | 714 (591 to 1,422) |
Urban (%) | 14 (53.8) | 16 (64) |
Rural (%) | 4 (15.4) | 2 (8) |
Mixed (%) | 8 (30.8) | 7 (28) |
Written repeat prescribing policy (%) | 14 (53.8) | 11 (44) |
IQR, interquartile range; SD, standard deviation.
Patient demographic detail | Intervention ( |
Control ( |
|||
---|---|---|---|---|---|
Mean (SD) | 76.67 (6.80) | 76.33 (3.89) | |||
Median (IQR) | 76 (71 to 82) | 76 (70 to 82) | |||
Male | 89 | 42.79 | 84 | 42.86 | |
Female | 119 | 57.21 | 112 | 57.14 | |
GMS card | 164 | 78.85 | 167 | 85.20 | |
No GMS card | 36 | 17.31 | 19 | 9.69 | |
Unknown | 8 | 3.85 | 10 | 5.10 | |
Language other than English | 3 | 1.44 | 2 | 1.02 | |
English | 195 | 93.75 | 180 | 91.84 | |
Unknown | 11 | 5.29 | 14 | 7.14 | |
Professional worker | 13 | 6.25 | 11 | 5.61 | |
Managerial and technical | 38 | 18.27 | 25 | 12.76 | |
Nonmanual | 30 | 14.42 | 26 | 13.27 | |
Skilled manual | 26 | 12.50 | 26 | 13.27 | |
Semiskilled | 11 | 5.29 | 18 | 9.18 | |
Unskilled | 9 | 4.33 | 7 | 3.57 | |
Farmer, size of farm unspecified | 5 | 2.40 | 10 | 5.10 | |
Unknown | 52 | 25.00 | 51 | 26.02 | |
Homemaker | 24 | 11.54 | 22 | 11.22 | |
No schooling | 0 | 0.00 | 3 | 1.53 | |
Primary school education only | 69 | 33.17 | 86 | 43.88 | |
Some secondary education | 53 | 25.48 | 44 | 22.45 | |
Complete secondary education | 40 | 19.23 | 20 | 10.20 | |
Some third level education | 20 | 9.62 | 19 | 9.69 | |
Complete third level education | 16 | 7.69 | 13 | 6.63 | |
Unknown | 10 | 4.81 | 11 | 5.61 | |
Employed | 1 | 0.48 | 0 | 0.00 | |
Self employed | 7 | 3.37 | 4 | 2.04 | |
Retired | 156 | 75.00 | 146 | 74.49 | |
Homemaker | 32 | 15.38 | 31 | 15.82 | |
Other/unknown | 12 | 5.77 | 15 | 7.65 |
GMS, general medical services; IQR, interquartile range; SD, standard deviation.
With respect to primary outcome measures, the intervention group had lower number of medicines at baseline (16.96 compared to 17.82), although this was adjusted for in the analysis. The prevalence of PIP was similar in both groups. See
All 404 patients were included in the intention-to-treat analysis of primary outcome measures. There were significantly more medicines and PIP in each group at follow-up (
Outcome measure | Intervention ( |
Control ( |
Adjusted difference (95% CI); |
---|---|---|---|
Number of medicines |
16.02 (3.93) | 17.55 (4.10) | 0.95 |
Patients with at least 1 PIP |
181 (87.44) | 179 (91.79) | 0.39 |
Number of medicines stopped, Mean (SD) | 3.97 (3.15) | 2.92 (3.17) | 1.48 |
Number of medicines started, Mean (SD) | 3.02 (3.03) | 2.67 (2.91) | 1.12 |
Proportion prescribed ≥15 medicines, |
132 (63.46) | 161 (82.14) | 0.37 |
Number of PIP, Mean (SD) | 2.16 (1.44) | 2.35 (1.43) | 0.92 |
Proportion with any reduction in PIP, |
73 (35.10) | 58 (29.51) | 1.42 |
Proportion with at least 1 high-risk PIP, |
117 (57.07) | 119 (62.30) | 0.93 |
EQ-5D-5L index score, Mean (SD) | 0.517 (0.382) | 0.456 (0.357) | 0.011 |
Global MTBQ score, Mean (SD) [ |
12.33 (13.50) | 17.05 (16.42) | −2.80 |
Satisfied with medicines (rPATD [ |
4.21 (0.76) | 3.94 (0.76) | 1.06 |
Willing to stop a medicine (rPATD [ |
4.38 (0.71) | 4.11 (0.82) | 1.05 |
Number of GP visits, Mean (SD) | 4.42 (3.51) | 3.83 (3.26) | 1.06 |
Telephone consultations, Mean (SD) | 1.55 (2.12) | 1.41 (2.21) | 1.75 |
Repeat prescription requests, Mean (SD) | 2.51 (2.55) | 2.38 (2.57) | 1.08 |
ED presentations, Mean (SD) | 0.46 (1.01) | 0.33 (0.85) | 1.31 |
Number of inpatient days, Mean (SD) | 2.43 (6.19) | 3.07 (9.79) | 1.50 |
Number of outpatient visits, Mean (SD) | 2.62 (5.54) | 2.39 (2.28) | 0.97 |
§ Intracluster correlation coefficient at baseline was 0.053 (95% CI: 0.000 to 0.122).
¥ Intracluster correlation coefficient at baseline was 0.171 (95% CI: 0.074 to 0.269).
ǂ IRR from multilevel Poisson regression.
¶ OR from multilevel logistic regression.
₱ Beta coefficient from multilevel linear regression.
* Five-point Likert score where 1 represents strongly disagree and 5 strongly agree.
CI, confidence interval; ED, emergency department; EQ-5D-5L, EuroQoL 5-dimension 5-level; GP, general practitioner; IRR, incidence rate ratio; MTBQ, Multimorbidity Treatment Burden Questionnaire; OR, odds ratio; PIP, potentially inappropriate prescribing; PROM, patient-reported outcome measure; rPATD, revised Patients’ Attitudes Towards Deprescribing; SD, standard deviation.
With respect to secondary prescribing-related measures, there was a significant reduction in the number of medicines stopped and a significant reduction in the odds of being prescribed ≥15 medicines in the intervention compared to the control group at follow-up. There was no evidence of an effect demonstrated on any of the PIP-related or patient-reported outcome measures or on healthcare utilisation. There was a reduction in the number of GP visits and an increase in the number of telephone consultations in both groups at follow-up. Over a quarter of SPPiRE participants had follow-up dates after the outbreak of the Coronavirus Disease 2019 (COVID-19) pandemic in March 2020, and, unsurprisingly, this group had significantly less face-to-face GP visits and significantly more telephone consultations.
There were 21 deaths during the study period: 9 in the control and 12 in the intervention group. None of the intervention deaths were reported as being related to the intervention. A total of 15 ADWEs out of 826 stopped drugs in intervention patients (1.81%) were reported by intervention group GPs and 10 of these events were assessed as being probably related to drug withdrawal (control group GPs did not collect these data as they continued to provide care as usual). One of the ADWEs was categorised as serious by the intervention GP, a severe depressive episode requiring inpatient admission 8 weeks after discontinuing a serotonin–norepinephrine reuptake inhibitor (SNRI). The remaining reactions were categorised as mild and all resolved with reinstitution of the drug (examples included an itch after discontinuing an antihistamine and dyspepsia after discontinuing a proton pump inhibitor).
Between January 2, 2018 and May 11, 2020, 163 of 208 (78.37%) intervention patients had a SPPiRE medication review. Due to individual practice circumstances, there were delays in some intervention practices in completing SPPiRE reviews. The trial management committee took a flexible approach and allowed some additional time when requested by intervention practices. This led to a chance imbalance in the median number of days to follow-up between groups: 431 days (interquartile range [IQR] 366 to 494) in the control group and 557 days (IQR 418 to 627.5) in the intervention group. Due to this identified discrepancy, a sensitivity analysis was performed including number of days to follow-up as a covariate (see
Of the 45 intervention patients (21.63%) that did not have a SPPiRE medication review, 36 patients did not have a review because of GP factors, primarily insufficient time. A total of 9 patients did not have a review as they had either died, moved to another GP practice, or were too unwell at the time of the review to attend the practice. There were 3 control practices who had a large reduction in the mean number of medicines per participant during the study period of 8.6, 5.4, and 3.5 medicines per person, respectively. See
The SPPiRE intervention resulted in a significant reduction in the number of medicines in the intervention compared to the control group at follow-up. The impact of this reduction (equating to 0.85 medicines per person on average) on an individual patient is unclear. However, the intention with widespread implementation of this type of intervention would be ongoing medication reviews every 6 to 12 months, as opposed to a once off review, and that may lead to incremental improvements and deprescribing of unnecessary or inappropriate medicines over time. There is also a possibility that normalisation of deprescribing as a concept would in itself lead to a change in attitudes and behaviours among prescribers. Although the effect size was small, if implemented at scale, it would have a significant impact at a population level. One of the explanations for the small effect size was that there was also a reduction in the number of medicines in the control group during the study period. This is unexpected in the context of the trends observed in cross-sectional and prospective cohort studies that suggest polypharmacy increases in individuals as they age [
This pragmatic trial recruited to target a vulnerable group of patients with substantial disease and treatment burden and a high baseline prevalence of PIP, and the intervention was delivered in routine primary care with no other resource or material necessary aside from the SPPiRE website. In line with findings from international deprescribing trials, the SPPiRE intervention was both safe and feasible [
This study has some limitations. First, only a quarter of invited patients agreed to participate, and this is lower than other similar studies [
Although returning broadly similar results, the per-protocol analysis showed an unexpected slight reduction in treatment effect. A total of 3 intervention practices that did not perform any reviews using the SPPiRE website showed a higher reduction in the number of medicines and PIP compared to the intervention group average. As these GPs had access to all intervention material, it is possible that they incorporated aspects of the intervention into their practice during the intervention period.
Finally, a chance imbalance in the number of days from baseline to follow-up between groups was identified. With respect to the impact on the primary outcomes, there is evidence that polypharmacy in this age cohort increases over time [
Compared to other recently published studies of medicines management multimorbidity interventions, the SPPiRE intervention was not as intensive, involving a once off 30- to 40-minute review per patient with online educational material available for intervention GPs. In addition, patients recruited to the SPPiRE trial were on average older and with a notably higher mean number of medicines. While SPPiRE did have some effect, it may be that a more intensive approach is needed for patients with this degree of multimorbidity. However, 3 recently published multimorbidity intervention studies incorporated a GP-delivered medication review as part of a wider multidisciplinary delivered intervention [
With respect to polypharmacy studies, similar to SPPiRE, a systemic review looking at interventions to improve the appropriate use of polypharmacy in older people concluded that there was no consistent effect on PIP across the 32 included studies [
Patient-reported outcome measures are used in multimorbidity studies to capture the patient’s perspective of intervention effectiveness [
Due to our ageing population, the provision of safe, effective, and equitable healthcare for those with complex multimorbidity will become an ever pressing challenge. The SPPiRE trial demonstrated that a once off GP-delivered medication review had a small effect in reducing the number of medicines in older adults with significant polypharmacy, but no clear effect on the quality of prescribing. Patients with this degree of multimorbidity may be less amenable to the benefits of a once off medication review type intervention. The aims of the intervention to address PIP, unnecessary polypharmacy, and patient treatment priorities may have been overambitious given the degree of treatment burden in this population, which has not been extensively studied previously. Future medicines management multimorbidity studies should consider identifying patients who have some but not severe treatment burden using longitudinal assessments of medication-related outcome measures and carefully prioritising the use of patient-reported outcome measures. Although the effect size of the SPPiRE intervention was small and there was no clear effect demonstrated on the quality of prescribing, there is potential cost saving implications at a population level with system-wide implementation and deprescription of unnecessary medicines.
SPPiRE, Supporting Prescribing in Older Adults with Multimorbidity in Irish Primary Care.
(DOCX)
CONSORT, Consolidated Standards of Reporting Trials.
(DOCX)
SPPiRE, Supporting Prescribing in Older Adults with Multimorbidity in Irish Primary Care.
(DOCX)
(DOCX)
(DOCX)
(DOCX)
We thank all the patients and GP practice staff who took part in this research. Membership of the wider SPPiRE Study group who contributed to this research (administration, pilot study, practice recruitment, data collection, data entry, and website development) were Tom Fahey, Derek Corrigan, Bridget Kiely, Aisling Croke, James Larkin, Oscar James, Clare Lambert, and Brenda Quigley. The independent members of the trial steering committee were Patricia Kearney (Chair), Andrew Murphy, Cathal Cadogan, Carmel Hughes, Paddy Gillespie, and Brid Nolan (PPI).
adverse drug withdrawal event
confidence interval
Consolidated Standards of Reporting Trials
Coronavirus Disease 2019
emergency department
EuroQoL 5-dimension 5-level
general practitioner
intraclass correlation
interquartile range
incidence rate ratio
Multimorbidity Treatment Burden Questionnaire
Optimizing Prescribing for Older People in Primary Care, a cluster-randomized controlled trial
odds ratio
Pharmacist-Led Information Technology Intervention for Medication Errors
potentially inappropriate prescription
practice management system
patient and public involvement
Prioritising Multimedication in Multimorbidity
randomised controlled trial
revised Patients’ Attitudes Towards Deprescribing
standard deviation
serotonin–norepinephrine reuptake inhibitor
Supporting Prescribing in Older Adults with Multimorbidity in Irish Primary Care
selective serotonin reuptake inhibitor
Dear Dr McCarthy,
Thank you for submitting your manuscript entitled "Effectiveness of a GP delivered medication review in reducing polypharmacy and potentially inappropriate prescribing in older patients with multimorbidity in Irish primary care: a cluster randomised controlled trial (SPPiRE study)" for consideration by PLOS Medicine.
Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external peer review.
However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.
Please re-submit your manuscript within two working days, i.e. by May 26 2021 11:59PM.
Login to Editorial Manager here:
Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.
Feel free to email us at
Kind regards,
Beryne Odeny
Associate Editor
PLOS Medicine
Dear Dr. McCarthy,
Thank you very much for submitting your manuscript "Effectiveness of a GP delivered medication review in reducing polypharmacy and potentially inappropriate prescribing in older patients with multimorbidity in Irish primary care: a cluster randomised controlled trial (SPPiRE study)" (PMEDICINE-D-21-02234R1) for consideration at PLOS Medicine.
Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:
[LINK]
In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.
In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at
In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements:
We expect to receive your revised manuscript by Aug 23 2021 11:59PM. Please email us (
***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***
We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here:
Please use the following link to submit the revised manuscript:
Your article can be found in the "Submissions Needing Revision" folder.
To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at
Please ensure that the paper adheres to the PLOS Data Availability Policy (see
We look forward to receiving your revised manuscript.
Sincerely,
Beryne Odeny,
PLOS Medicine
-----------------------------------------------------------
Requests from the editors:
1. Abstract:
a) Please ensure that all numbers presented in the abstract are present and identical to numbers presented in the main manuscript text.
b) Please provide the number of GP practices in each group (i.e., control and intervention groups)
c) Please indicates the dates during which study enrollment and follow up occurred.
d) Please include a summary of adverse events in the study.
e) In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.
2. Please include the study protocol document and analysis plan, with any amendments, as Supporting Information to be published with the manuscript if accepted.
3. Please merge the Aims section (line #111-115) with the Introduction section. Please conclude the Introduction with a clear description of the study question or hypothesis.
4. In the Methods section’s text, please indicate the number of GP practices in each arm.
5. When completing the CONSORT checklist, please use section and paragraph numbers.
6. The terms gender and sex are not interchangeable (as discussed in
7. Please replace "Social class" with "occupation" or similar throughout the paper.
8. Please use the PLOS Medicine style reference call outs throughout the text, noting the absence of spaces within the square brackets, e.g., "... quality of life [1-3]."
Comments from the reviewers:
Reviewer #1: The authors are to be congratulated on completing this cluster RCT in primary care - such trials are hard to do logistically and take a lot of effort. As others have found, including myself, the number of recruitable GP practices (only about a third) and the numbers of recruited patients (about a quarter of those screened) are always less than one hopes at the outset and clearly introduces the potential for selection bias and loss of generalisability, and attenuates the intervention effect as it is likely that GPs more interested in deprescribing specifically and research more generally may express interest in participating but whose practices are already at a more optimal level than those who do not. Similarly control patients who consented to participation, may be more open to medication review and deprescribing, coupled with the inevitable Hawthorne effect in control practices, as was seen in this study (and ours). The fact that about 20% of intervention effects did not receive the medication review, because of limited GP time or patient frailty/illness/death did not help either. The one-off nature of the intervention is a further limitation - could the authors make further comment about whether any subsequent GP consultations involved any further discussions around deprescribing. I note further process and qualitative studies are in progress but it would be interesting to see how easy GPs regarded the interaction with the SPPiRE website. While the STOPP criteria are validated they may be difficult to apply in individual cases because no set of rules will cover all possible scenarios, but also they are a limited set of rules and may not cover all potential deprescribing scenarios. I find it intriguing that intervention GPs who chose not to refer to the template but still undertook a deprescribing consultation achieved greater reduction in medications than those who did use the template and this may be explained by the former GPs internalising deprescribing concepts and applying these more generically to more drugs. This may in the end be a more effective approach than GPs referring to, and perhaps being constrained by, a pre-specified drug-class specific template and deserves further study. The loss of 45% of patients reporting PROMs is a further limitation and again introduces selection bias unless the authors can include as an appendix a comparison of characteristics of patients who did or did not report PROMs. But these limitations do not detract from the basic message that other similar studies have shown (including our own, which the authors may want to reference: Anderson K et al J Am Geriatr Soc 2020: 68:403-410), that deprescribing is not easy to do in time-pressured general practice, that the reductions in number of medication at the individual patient level are marginal but still worthwhile and do not cause harm, that follow-up consultations and longer follow-up may realise greater effects, and that remuneration policies for GPs specific to deprescribing or medication reviews are necessary if these tasks are to be performed adequately.
Minor point - I would put table 2 as the first table because baseline characteristics of both groups ideally come first and place current table 1 as an appendix as I found it distracting and does not add much to what current table 2 shows. Also in appendix 4, it was unclear to me what the two sets of sensitivity analyses related to as they have identical headings and the same column variables although the data in the cells are slightly different and the IRRs are very different so the headings need further elaboration or at least a footnote.
Reviewer #2: This cluster randomised controlled trial (SPPiRE) conducted in the Republic of Ireland aims to investigate the effect of a GP-delivered, individualised medication review in reducing polypharmacy and potentially inappropriate prescribing in older patients with multimorbidity in primary care.
Comments:
Can the authors please provide a copy of the study protocol in the supplementary material?
The authors have appropriately acknowledged where the original protocol was not adhered to, and transparently discussed the reasons for deviation within the manuscript.
This includes a change in data collection methods and an updated sample size calculation.
Furthermore, the authors clearly and commendably provide a Protocol Adherence section, with appropriate sensitivity analyses and associated acknowledgement in the study limitations.
The CONSORT checklist has been suitably provided in the supplementary material.
The authors demonstrate rigor in the randomisation approach conducted and their attempts to minimise bias throughout the study design.
Appropriate sensitivity analyses have been completed, including a complete case analysis and a per protocol analysis, which help to demonstrate the robustness of the study findings.
A valid modelling methodology has been applied for the study design, data structure, and research question in hand.
Overall, this is a well written and clearly presented study, with accurately and fairly communicated study outcomes, and adequately explored study limitations in the discussion section.
A small note: "All 404 patients were included in the intention to treat analysis of primary outcome measures, see 277 Error! Reference source not found.." to be rectified under the Primary and Secondary Outcomes section.
Reviewer #3: Thank you for the opportunity to review this manuscript. The SPPiRE study presents the results of a cluster randomised controlled trial of a GP delivered medication review where the intervention GPs received a web-based education module and template for medication review. The target population was patients aged 65 years or older and with what the authors define as "complex multimorbidity, defined as being prescribed ≥15 regular medicines".
The manuscript is well written, of interest to a wide readership, and the study itself is well conducted and reported.
I do have some comments and thoughts for the authors to consider and address:
1. The definition of polypharmacy in this study is not one that is widely accepted. Can you please reference why polypharmacy was defined as 15 or more medications? Polypharmacy is most commonly defined as 5 or more medications, and the other common term is hyperpolypharmacy referring to 10 or more medications. Need to please reference your polypharmacy definition of 15 or more meds. Has implications for whether this was an appropriate target outcome.
2. Polypharmacy and multimorbidity are not the same. Why was multimorbidity defined using the criteria of polypharmacy (15 or more meds)?
Further, patients may have one medical disease e.g. heart failure and be on 5 medications for it's treatment so has implications for your study treatment effect. Please comment.
3. Would also suggest avoiding arbitrary or emotive adjectives such as "extreme level of polypharmacy" (line 84) or "significant" polypharmacy (line 175) when talking about an outcome measure or inclusion criteria. Ok to use such words in narrative writing such as in the intro etc. Unless of course this is a formal measure that you can reference. But no citations have been provided as per comment 1 above.
4. Could you please provide a definition of repeat medication (line 227)?
5. The elephant in the room is COVID-19 - worth some discussion about how you think COVID-19 affected your study.
6. Do you have data to talk about which PIPs you impacted on? The evidence for deprescribing is stronger for specific classes of medications.
7. I felt the Conclusion was introducing new concepts that were not presented in the Discussion. The discussion talks about reasons for the study intervention not being effective included its less intensive nature, but the Conclusion talks about the complexity of patients as being the potential reason for no effect. Can you tie these together?
8. Given your definition of multimorbidity was actually polypharmacy of 15 or meds. Can you compare your study to other trials that have targeted hyperpolypharmacy?
9. Line 155 "discuss and agree changes" - is there a word missing before changes?
10. To reduce word count and repetitiveness the first few paragraphs of the Discussion as well the Strengths and limitations is all focussed on trying to explain your results - this could be truncated to then include comparisons with other relevant studies as per Comment 8.
Reviewer #4: Thank you for this article on a very important topic for older adults facing multimorbidity and polypharmacy. My comments are relatively minor but hope to address the international audience and also the multifaceted nature of the polypharmacy problem.
Line 24: What does SPPiRE stand for? I know that this isn't the initial work coming from this intervention but if you could define the acronym perhaps in the abstract this would help frame the idea of the activity more clearly.
Line 25: If this is an international audience then at some point also spelling out GP (which I am assuming is a general practitioner, or a primary care provider) would make sense.
Line 80-86: I appreciate your description of necessary polypharmacy and your discussion of quality of prescriptions since I feel that polypharmacy is not a "black and white" issue and that several studies treat it as such and focus on numbers rather than individualized treatment plans.
Line 135: given that these are community dwelling older adults based on your exclusion criteria you might mention that earlier in the manuscript, as homebound or nursing home patients might be more prone to polypharmacy and this study does not focus on them.
Line 144: thank you for discussing the issues in blinding in this particular study and your attempts to blind the outcome measures.
Line 149: Was there a way to assess whether intervention GPs actually played or watched the videos? Were logins tracked or some way to measure that the intervention was being deployed?
Line 188: Given the deviation in data collection with the medical history do you think that the lack of standardization of the medical history might have impacted the discussion of necessary polypharmacy? Was there a process that the study manager tried to standardize these data that they received from the practices?
Line 346: Interesting discussion of the possible Hawthorne effect having some bearing on the study.
Line 350-356: I think that this would be a very good study to undertake, as I had some concerns about the "independent study" nature of the intervention and whether the GPs were able to view and incorporate the material fully. This might also help refine the curriculum to the most high yield points (especially since it was noted that a limiting factor in participation was time constraints)
In general I would like to see more discussion about the medical issues between groups and if the polypharmacy being addressed was deemed unnecessary or necessary (and if this was not able to be measured to have it be discussed in limitations, perhaps, since it is discussed in the introduction and quality of prescribing is also addressed in the conclusion)
Any attachments provided with reviews can be seen via the following link:
[LINK]
Submitted filename:
Dear Dr. McCarthy,
Thank you very much for re-submitting your manuscript "Effectiveness of a GP delivered medication review in reducing polypharmacy and potentially inappropriate prescribing in older patients with multimorbidity in Irish primary care: a cluster randomised controlled trial (SPPiRE study)" (PMEDICINE-D-21-02234R2) for review by PLOS Medicine.
I have discussed the paper with my colleagues and the academic editor and it was also seen again by three reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.
The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:
[LINK]
***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***
In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.
Please also check the guidelines for revised papers at
We expect to receive your revised manuscript within 1 week. Please email us (
We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.
Please ensure that the paper adheres to the PLOS Data Availability Policy (see
To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at
Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.
Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at
If you have any questions in the meantime, please contact me or the journal staff on
We look forward to receiving the revised manuscript by Nov 09 2021 11:59PM.
Sincerely,
Beryne Odeny,
PLOS Medicine
------------------------------------------------------------
Requests from Editors:
1) Please revise your title. Your title must be non-declarative and not a question. You may consider the following, or similar. Ideally only the study design should be in the sidetitle (i.e., after a colon). For example, “GP delivered medication review, polypharmacy and potentially inappropriate prescribing in older patients with multimorbidity in Irish primary care (SPPiRE study): a cluster randomised controlled trial”
Comments from Reviewers:
Reviewer #1: I am satisfied with the responses from the authors to my previous comments and welcome publication of the revised manuscript.
Reviewer #3: Thank you for considering and addressing all comments.
Reviewer #4: Thank you for this manuscript and for your attention to reviewer comments. I think that you have answered all of my questions regarding the study
Any attachments provided with reviews can be seen via the following link:
[LINK]
Submitted filename:
Dear Dr McCarthy,
On behalf of my colleagues and the Academic Editor, Dr. Ian Scott, I am pleased to inform you that we have agreed to publish your manuscript "GP-delivered medication review of polypharmacy, deprescribing and patient priorities in older people with multimorbidity in Irish primary care (SPPiRE study): a cluster randomised controlled trial" (PMEDICINE-D-21-02234R3) in PLOS Medicine.
Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.
In the meantime, please log into Editorial Manager at
PUBLICATION SCHEDULE
Given our busy publication schedule for the remainder of 2021, we are planning to publish your paper in early January 2022 (the exact date will be communicated to you once confirmed).
PRESS
We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with
We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit
To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at
Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper.
Sincerely,
Beryne Odeny
PLOS Medicine