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To STOPP or to START? Potentially inappropriate prescribing in older patients with falls and syncope
Maturitas 131 (2020) 65–71
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To STOPP or to START? Potentially inappropriate prescribing in older patients with falls and syncope
T
Susanne C. de Ruitera,d,*, Sophie S. Biesheuvela,b, Ingrid M.M. van Haelstb, Rob J. van Marumc, René W.M.M. Jansena a
Department of Geriatric Medicine, Northwest Clinics Alkmaar, the Netherlands Department of Pharmacy, Northwest Clinics Alkmaar, the Netherlands c Department of General Medicine and Geriatric Medicine, Free University, Amsterdam, the Netherlands d Currently employed at: Section of Geriatric Medicine, Department of Internal Medicine, St. Antonius Hospital Nieuwegein, Utrecht and Woerden, the Netherlands b
A R T I C LE I N FO
A B S T R A C T
Keywords: Potentially inappropriate prescribing Syncope Falls Older patients
Objectives: To investigate the prevalence of potentially inappropriate prescribing (PIP) according to the revised STOPP/START criteria in older patients with falls and syncope. Study design: We included consecutive patients with falls and syncope aged ≥65 years at the day clinic of the Northwest Clinics, the Netherlands, from 2011 to 2016. All medication use before and after the visit was retrospectively investigated using the revised STOPP/START criteria. Main outcome measures: The prevalence/occurrence of PIP before the visit, persistent PIP after the visit, and unaddressed persistent PIP not explained in the patient’s chart. Results: PIP was present in 98 % of 374 patients (mean age 80 (SD ± 7) years; 69 % females). 1564 PIP occurrences were identified. 1015 occurrences persisted (in 91 % of patients). 690 occurrences (in 80 % of patients) were not explained in the patient’s chart. The most frequent unaddressed persistent forms of PIP were prescriptions of vasodilator drugs for patients with orthostatic hypotension (16 %), and benzodiazepines for > 4 weeks (10 %) or in fall patients (8 %), and omission of vitamin D (28 %), antihypertensive drugs (24 %), and antidepressants (17 %). 54 % of all medication changes were initiated for reasons beyond the scope of the STOPP/START criteria. Conclusions: Almost every patient in our study population suffered from PIP. In 80 %, PIP continued after the clinical visit, without an explanation in the patient’s chart. The most frequent PIP concerned medication that increased the risk of falls or syncope, specifically vasodilator drugs and benzodiazepines. Physicians should be aware of PIP in older patients with falls and syncope. Further studies should investigate whether a structured medication review may improve clinical outcomes.
1. Introduction Syncope and falls are common problems in older patients [1,2]. In the Netherlands, in 2017, 102,000 persons aged ≥65 years visited the emergency department (ED), and 3849 persons died due to falls. The total financial burden of fall-related injuries in those aged ≥65 years was almost 900 million euros2]. Medication use is an important risk factor for both syncope and falls [3,4]. Older people are vulnerable to adverse drug reactions, due to physiologic changes and polypharmacy [5,6]. With the number of drugs used, the likelihood of potentially inappropriate prescribing (PIP) increases [7,8]. PIP includes ‘prescription of medication with potential
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risks that outweigh potential benefit in a specific patient’ (potentially inappropriate medicines (PIMs)), and ‘omission of medication where there is an indication for treatment or prevention’ (potential prescribing omissions (PPOs)) [9]. The Screening Tool of Older Person’s Prescriptions (STOPP) and Screening Tool to Alert doctors to Right Treatment (START) were developed to detect PIP in older patients [10,11]. With these tools, PIMs are identified in about one third, and PPOs in 85 % of primary care patients aged ≥65 years [7,12]. In patients with polypharmacy, PIMs were significantly associated with falls in one study12]. Another study found PIP in over 50 % of fall patients aged ≥70 years at the ED [8]. To our knowledge, PIP has not been investigated in syncope patients.
Corresponding author at: Department of Internal Medicine (Geriatrics), St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, the Netherlands. E-mail address: [email protected] (S.C. de Ruiter).
https://doi.org/10.1016/j.maturitas.2019.10.013 Received 1 June 2019; Received in revised form 18 October 2019; Accepted 28 October 2019 0378-5122/ © 2019 Elsevier B.V. All rights reserved.
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second (as will be further explained later on) may rather overestimate. Nevertheless, since these modifications were based on the real-life limitations FSC physicians have to deal with, we felt that our findings would still realistically reflect on the burden of PIP in our population. Primary outcome was the prevalence of PIP (defined as percentage of patients exposed to any given PIP) before and after the visit. If PIP was not adjusted or medication changes caused a new occasion of PIP, this was classified as ‘persistent PIP’. An investigator checked the physician’s notes to see whether this was deliberate (see Appendix B in Supplementary material); if not, this was classified as ‘unaddressed persistent PIP’. We also identified the number and type of medication changes outside the scope of the STOPP/START-criteria.
Investigating PIMs in patients with falls/syncope is important, since these may relate to fall/syncope-risk-inducing drugs, and therefore iatrogenic falls/syncope. PPOs are just as relevant a problem. For instance, underprescription of cardiovascular drugs may result in rhythm disorders, increased risk of orthostatic hypotension, and even balance and gait disturbances through cerebrovascular disease. We therefore performed a retrospective study to investigate PIP in older patients presenting to the Fall and Syncope Clinic (FSC) of the Northwest Clinics, Alkmaar, the Netherlands [13]. The STOPP/STARTcriteria are not routinely used for medication review at our FSC. To examine whether treating physicians recognized PIP without consciously applying the STOPP/START-criteria, or would benefit from implementation of these criteria, we also investigated persistent PIP after the patient’s visit.
2.4. Statistical analysis 2. Methods Statistical analyses were performed using SPSS for Windows, version 20 (SPSS, Inc., Chicago, IL, USA). Continuous variables were compared using the Student’s T-Test, or the Mann-Whitney U test where appropriate. Nominal variables were compared using Pearson’s ChiSquare Test or Fisher’s Exact Test when indicated. Two-tailed P-values < 0.01 were considered statistically significant to correct for the problem of multiple comparisons.
2.1. Study design and population We performed a retrospective study, including consecutive patients aged ≥65 years at the FSC of the Northwest Clinics, Alkmaar, the Netherlands, from November 2011 to June 2016. In case of multiple visits, only the first visit was included. Syncope was defined as ‘transient loss of consciousness due to cerebral hypoperfusion, characterized by a rapid onset, short duration, and spontaneous complete recovery’ [1]. Patients who experienced a fall without syncope, were defined as fall patients. Patients who did not experience a fall and/or syncope were excluded. Since this study was conducted outside the criteria for the Medical Research Involving Human Subjects Act (WMO), it was judged as exempt from review by the medical ethics committee. It was registered and overseen as institutional QI. This study complied with the revised version of the European Data protection regulation.
3. Results 3.1. Patient characteristics We included 374 out of 432 consecutive patients (mean age 80 SD ± 7 years; 69 % female); 12 patients were excluded because they were < 65 years, and 42 patients because they did not experience a fall/syncope. Of 4 patients who visited the FSC multiple times, only their first visit was included. Table 1 shows baseline characteristics, medication use, and general FSC outcomes. There were no significant differences between syncope patients (N = 190) and fall patients (N = 184), except for the presence of osteoporosis (12 % in syncope patients vs. 21 % in fall patients, P = 0.01), and OH (72 % in syncope patients vs. 57 % in fall patients, P = 0.001).
2.2. Data collection The FSC is a diagnostic program for older fall and syncope patients, involving geriatricians, cardiologists, neurologists, nurses, and physiotherapists [13]. A pharmacologist is not part of the team. Patients underwent a comprehensive geriatric assessment, including medical history, eyewitness account, and physical examination with standardized blood pressure (BP) measurements for orthostatic hypotension (OH) and postprandial hypotension (PPH). Laboratory tests, 12-lead electrocardiogram, and an MRI-scan of the brain were performed, unless contraindicated. Appropriate patients underwent an additional cardiac, neurological and/or psychiatric evaluation. Patients brought an up-to-date medication list from their pharmacy, and were asked about inconsistencies, compliance, side effects, and use of non-prescription drugs by the geriatrician. At the end of the visit, a final diagnosis and treatment plan was devised by the multidisciplinary team. Changes in medication were accomplished – in accordance with local agreements – through a written advice to the patient’s general practitioner (GP), who then wrote the prescriptions. If an immediate change was required, the geriatrician provided the prescription.
3.2. Prevalence of PIP 98 % of patients had ≥1 PIP (PIMs 75 %, PPOs 93 %). After the visit, 91 % of patients had ≥1 persistent PIP (PIMs 62 %, PPOs 78 %), and 80 % of patients had ≥1 unaddressed persistent PIP (PIMs 41 %, PPOs 69 %) (Fig. 1A). In total, 1564 PIP occurrences were identified (670 PIMs, 894 PPOs). 1015 PIP occurrences persisted (418 PIMs, 597 PPOs), of which 690 were unaddressed (244 PIMs, 446 PPOs) (Fig. 1B). Fig. 1C shows the number of PIP per patient. 3.3. Specific PIMs and PPOs Table 2 shows all PIMs/PPOs with a prevalence of ≥10 %. Most frequent PIMs at the start of the visit were vasodilator drugs in OH patients (STOPP-K3; 41 %), antithrombotic drugs in patients with a concurrent significant bleeding risk (STOPP-C2; 30 %), and benzodiazepines for > 4 weeks (STOPP-D5; 19 %) or in fall patients (STOPP-K1; 18 %). After the visit, most frequent unaddressed persistent PIMs were vasodilator drugs in OH patients (16 %), and benzodiazepines for > 4 weeks (10 %) or in fall patients (8 %). In 92 % of patients on antithrombotic drugs with concurrent significant bleeding risk (STOPP-C2), antithrombotic drugs were continued (i.e. persistent PIM). However, this was deliberate in all but one patient (i.e. unaddressed persistent PIM in only 0,3 % of the population). Most frequent PPOs were vitamin D in fall patients (START-E5; 64 %), antihypertensive drugs in increased BP (START-A4; 42 %), antidepressants for depressive symptoms (START-C2; 21 %), statin therapy
2.3. Data evaluation Medication use at the start and all changes at the end of the visit, including any written advice to the GP, were retrospectively analysed, using the Dutch revised STOPP/START-criteria [11]. Because information to assess certain criteria was not available, and some drugs fell beyond the scope of expertise of the FSC staff, we used a modified version (see Appendix A in Supplementary material), excluding some criteria and using surrogate measures to assess a few others. While the first may result in an underestimation of the total burden of PIP, the 66
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patients had a change in medication (1029 changes) (see Table 3); this includes medication within an outside of the scope of the STOPP/ START-criteria. 629 medications were started (in 69 % of patients), primarily antihypertensive drugs (74 occurrences in 18 % of patients), and vitamin supplements (440 occurrences in 57 % of patients), including vitamin D (138 occurrences in 37 % of patients). 299 medications were stopped (in 47 % of patients), mainly antihypertensive drugs (109 occurrences in 24 % of patients), including diuretics (55 occurrences in 13 % of patients), and psychoactive medication (55 occurrences in 12 % of patients), primarily benzodiazepines (37 occurrences in 9 % of patients). 101 doses were altered (in 22 % of patients), mostly for antihypertensive drugs (45 occurrences in 11 % of patients) and vitamin supplements (25 occurrences in 6 % of patients). 54 % of all changes were initiated for reasons that fell beyond the scope of the STOPP/START-criteria, including 489 medications started (in 62 % of patients), 137 medications stopped (in 28 % of patients), and 68 dose alterations (in 15 % of patients).
Table 1 Baseline characteristics and general outcomes of the FSC evaluation. Baseline characteristics
N = 374
Female gender, N (%) Age in years, mean (SD) Dependent in activities of daily living (ADL), N (%) Dependent in instrumental ADL, N (%) History of hypertension, N (%) History of ischemic heart disease, N (%) History of rhythm disorder, N (%) History of congestive heart failure, N (%) History of cerebrovascular accident, N (%) History of peripheral vascular disease, N (%) Parkinson’s disease, N (%) Type 2 diabetes mellitus, N (%) History of fractures, N (%) History of osteoporosis, N (%) History of psychiatric disorder, N (%) History of cognitive impairment, N (%) Alcohol use, N (%) Medication use No. of medications used, median (Q1,Q3) Antihypertensive drugs, N (%) Diuretics, N (%) ACE inhibitors/ARBs, N (%) Beta blockers, N (%) Calcium channel blockers, N (%) Nitrates, N (%) Antiarrhythmic drugs (digoxin/amiodarone), N (%) Lipid lowering drugs, N (%) Antithrombotic drugs, N (%) Antiplatelet drugs, N (%) (N)OAC or LMWH, N (%) Proton pump inhibitors, N (%) Antidiabetic drugs, N (%) Psychoactive medication, N (%) Benzodiazepines, zolpidem, zopiclone, N (%) Antidepressants, N (%) Antipsychotics, N (%) Acetylcholinesterase inhibitors, N (%) Bisphosphonates/denosumab, N (%) Vitamin supplements, N (%) Anti-inflammatory drugs, N (%) Analgesics, N (%) Alpha antagonists, N (%) Antimuscarin/anticholinergic agents, N (%) General outcomes of the FSC evaluation Syncope, N (%) Fall without syncope, N (%) Orthostatic hypotension, N (%) Symptomatic, N (%) Postprandial hypotension, N (%) Symptomatic, N (%) Cognitive impairment†, N (%) MoCA score, median (Q1,Q3) MMSE score, median (Q1,Q3)
255 (68) 80 (7) 88 (24) 155 (41) 247 (66) 97 (26) 103 (28) 33 (9) 90 (24) 44 (12) 16 (4) 80 (21) 159 (43) 60 (16) 88 (24) 45 (12) 184 (49)
• • • • • • • • •
• • • •
†
4. Discussion
7 (5,9) 265 (71) 124 (33) 175 (47) 161 (43) 68 (18) 35 (9) 28 (8) 172 (46) 218 (58) 135 (36) 88 (24) 168 (45) 66 (18) 119 (32) 76 (20) 63 (17) 10 (3) 8 (2) 42 (11) 150 (41) 87 (23) 108 (29) 23 (6) 33 (9)
4.1. Main findings PIP was present in nearly all of our older fall and syncope patients. In most cases, PIP persisted after the evaluation. Of 1564 PIP occurrences, 1015 persisted after the FSC visit, of which 690 occurrences were unaddressed in the patient’s chart. Approximately two thirds of all medication changes were initiated for reasons that fell outside the scope of the STOPP/START-criteria. Although medication review is part of the FSC, the STOPP/STARTcriteria are not regularly applied. Treating physicians may therefore not have been aware that PIP was present in their patients. It is also important to note that the STOPP/START-criteria have been designed as a guide to improve prescribing, rather than commandments which should be adhered to at all times. Even so, one would expect physicians working at an FSC to at least be mindful of fall/syncope-risk-increasing drugs. However, most frequent unaddressed persistent PIMs in our population concerned medication that increases fall/syncope risk, i.e. vasodilator drugs in OH patients, and benzodiazepines for > 4 weeks or in fall patients. PIMs concerning benzodiazepines are frequently reported in older patients [7,14]. Motivating long-term users to reduce the dosage may be time-consuming and requires regular follow-up, which might explain physicians’ reluctance to raise this issue. Some physicians may also feel that fear of falling requires continued benzodiazepine treatment, despite the fact that these drugs increase fall risk. Indeed, Walgers et al. showed that benzodiazepine use is more frequent among older fall patients with fear of falling compared with patients without fear of falling [15]. Overall, the prevalence of unaddressed persistent PPOs was considerably higher in this population than the prevalence of unaddressed persistent PIMs (69 % vs. 41 %). This is similar to the findings of others [4,7]. Underprescribing is a widespread problem in older patients, especially in those with polypharmacy [16]. Since the FSC focuses on identifying causes of falls/syncope, fall/syncope-risk-inducing medication (i.e. PIMs) would be expected to get more attention than PPOs (even though these might be just as harmful). While PIMs were less frequent than PPOs (75 % vs. 93 %), far less PIMs persisted without explanation than PPOs (55 % of all PIMs vs. 74 % of all PPOs). It may be that in cases where many PPOs are found at the same time, treating physicians decide not to start medication for every omission, so as not to burden the patient with too many changes at once. It has also been reported that in case of PPOs, more often than not, treating physicians have good reasons for not prescribing appropriate drugs [17]. It may therefore be that rather than omitting to prescribe, physicians omitted to report their reasons for not prescribing. A further question is whether all PIP identified by the STOPP/
190 (51) 184 (49) 241 (64) 138 (37) 208 (56) 79 (21) 188 (61) 25 (21,27) 28 (26,29)
Montreal Cognitive Assessment score ≤26 (N = 309).
in patients with a history of coronary, cerebral, or peripheral vascular disease (START-A5; 15 %), angiotensin-converting-enzyme inhibitors or angiotensin-II-receptor blockers (ACEi/ARB) in patients with systolic heart failure or coronary artery disease (START-A6; 13 %), beta blockers after a myocardial infarction or angina (START-A7; 12 %), and vitamin D, calcium supplements, and anti-osteoporosis drugs in osteoporosis patients (START-E3 and -E4; 10 %). The most frequent unaddressed persistent PPOs were vitamin D in fall patients (28 %), antihypertensive drugs in increased BP (24 %), and antidepressants for depressive symptoms (17 %).
3.4. Secondary outcomes After the visit, the mean number of drugs per patient increased from 7 (SD 4, range 0–27) to 8 (SD 4, range 0–26) (P = 0.000. 84 % of 67
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Fig. 1. A: Potentially inappropriate prescribing in 374 older fall and syncope patients. B: Occurrences of potential inappropriate prescribing in 374 older fall and syncope patients. C: Number of occurrences of potentially inappropriate prescribing per patient.
Another frequent unaddressed persistent PPO concerned antidepressants. In our practice, patients suffering from depressive symptoms are referred to an old age psychiatrist for evaluation before starting treatment. Furthermore, the presence of depressive symptoms may not always warrant medication; oftentimes, non-medical treatment may suffice [21]. According to STOPP-C2 – a frequent persistent PIM – bleeding risk should be assessed using the HASBLED score [22], and antithrombotic
START-criteria is clinically relevant. For instance, the most frequent unaddressed persistent PPO was vitamin D in fall patients. At the FSC, however, vitamin D was only prescribed in case of a proven deficiency, since supplementation in persons with normal vitamin D levels has not been shown to reduce falls [18,19]. After adjusting for PPOs concerning patients with normal vitamin D levels, 342 unaddressed persistent PPOs occurrences in 57 % of patients remain. This is much more in agreement with the findings of others [14,20]. 68
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No. of patients with unaddressed persistent PIM/PPO (% of total population; % of patients with PIM/PPO)
60 (16; 39) 1 (0.3; 1) 36 (10; 51) 30 (8; 45) 10 (3; 18)
104 (28; 43) 91 (24; 58) 64 (17; 81) 36 (10; 63)
36 (10; 73)
24 (6; 55) 10 (3; 26) 6 (2; 16)
No. of patients with persistent PIM/PPO (% of total population; % of patients with PIM/PPO)
116 (31; 76) 102 (27; 92) 40 (11; 56) 33 (9; 49) 10 (3; 18)
105 (28; 44) 98 (26; 62) 74 (20; 94) 53 (14; 93)
42 (11; 86)
40 (11; 91) 11 (3; 29) 13 (3; 34)
4.2. Implications It is understandable that physicians focusing on falls and syncope, would overlook PIP that does not concern these problems. Nevertheless, the fact that most frequent unaddressed persistent PIMs actually concerned fall/syncope-risk-increasing medication, implies that current clinical practice needs improvement. It remains unclear, however, whether a standardized medication review would be the answer. In two relatively small studies, discontinuation of fall-risk-increasing drugs (especially cardiovascular and psychotropic medication) significantly lowered fall incidents in older patients [25,26], and an RCT providing an educational program on medication review to GPs found a lower adjusted odds ratio for falls after 12 months follow-up in the intervention group [27]. However, withdrawal of fall-risk-increasing-drugs in the IMPROveFALL trial did not reduce falls during 12-months followup, nor was it cost-effective, although patients in the intervention group had less decline in health-related quality of life compared to controls [28,29]. These discrepancies underline the idea that, although PIP certainly plays a role in falls and syncope, the best way to deal with this problem has yet to be determined.
Our study has several limitations. As explained before, certain STOPP/START-criteria could not be included in the analysis since information to assess them was not available (leading to an underestimation of the total burden of PIP), or surrogate measures needed to be used. For instance, we used BP measurements at the FSC as a surrogate for the diagnosis of hypertension, although repeated measurements should be taken [30]. White-coat hypertension may therefore have resulted in an overestimation of untreated hypertension, and the number of PPOs. It is likely that doctors are cautious to prescribe antihypertensive drugs in fall and syncope patients when they are not entirely certain of their diagnosis. To assess START-C2, depressive symptoms were used as a surrogate for depressive disorder. Because diagnosing and treating psychiatric disorders are not the primary purposes of the FSC, it is possible that depressive symptoms were not always recognized. On the other hand, the presence of depressive symptoms is not the same as having a major depressive disorder. Consequently, the number of omissions of antidepressants is possibly overestimated. Changes in the medical staff during the study period may have affected choices made. Although we were unable to investigate whether GPs implemented recommendations, they should have done so according to local agreements. To improve implementation by GPs, the number of recommendations was kept to a minimum, in accordance with FSC guidelines. This might explain why certain PIP was not addressed. FSC physicians may have wanted to emphasize the most relevant PIP, leaving out the rest. This does not explain the high prevalence of unaddressed persistent PIP concerning fall/syncope-risk-
44 (12) 38 (10) 38 (10)
49 (13)
241 (64) 157 (42) 79 (21) 57 (15)
152 (41) 111 (30) 71 (19) 67 (18) 56 (15)
4.3. Limitations
STOPP K3 Vasodilator drugs in patients with orthostatic hypotension C2 Antithrombotic drugs with concurrent significant bleeding risk D5 Use of benzodiazepines for longer than 4 weeks K1 Benzodiazepines in patients with a tendency to fall A1 Any drug prescribed without an evidence-based clinical indication START E5 Vitamin D supplement in older people experiencing falls A4 Antihypertensive in case of an increased blood pressure C2 Antidepressant for depressive symptoms A5 Statin therapy in patients with a history of coronary, cerebral or peripheral vascular disease A6 ACE inhibitor or AT-II antagonist in patients with systolic heart failure and/or coronary heart disease A7 Beta blocker after a myocardial infarction or angina E3 Vitamin D and calcium supplement in patients with osteoporosis E4 Bisphosphonates or other anti-osteoporosis medication in patients with osteoporosis
No. of patients with PIM/ PPO (%) Criteria
Table 2 Most frequent PIMs and PPOs in patients at the FSC.
drugs discontinued when this score is ≥3 [11]. However, this tool was not designed to assess risks of antiplatelet therapy, while bleeding risk in the case of oral anticoagulants should be compared to risk of thrombosis using, for instance, the CHA2DS2-VASc tool [23]. In our opinion, use of the HASBLED-score alone is not suitable to decide whether antithrombotic drugs should be discontinued, especially since this score has not been validated for patients aged > 80 years, and bleeding risk models in general have a low performance in the very old [22,24]. The continuation of vasodilators in case of OH (STOPP-K3) was also deliberate in most cases, as physicians chose to discontinue diuretics instead of vasodilators. We considered this a good clinical alternative, although it is not mentioned in the STOPP-criteria, especially when stopping an ACEi/ARB would have resulted in a new PPO, for instance according to START-A6.
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Table 3 Medication changes at the FSC.
Antihypertensive drugs Diuretics ACE inhibitor/ARB Beta blocker Calcium channel blockers Others Nitrates Antiarrhythmic drugs (digoxin/ amiodarone) Lipid lowering drugs Antithrombotic drugs Psychoactive medication Benzodiazepines Antidepressants Antipsychotics Acetylcholinesterase inhibitor Proton pump inhibitors Anti-inflammatory drugs Bisphosphonates/denosumab Alpha antagonists Analgesics Laxatives Vitamin supplements Other medication Total
No. of drugs started (% of patients; no. of drugs started for other reason than STARTcriteria)
No. of drugs stopped (% of patients; no. of drugs stopped for other reason than STOPP-criteria)
No. of drugs altered (% of patients; no. of drugs altered for other reason than STOPP/ START-criteria)
74 (18; 23) 4 (1; 1) 25 (7; 9) 14 (4; 9) 15 (4; 1) 16 (4; 3) 1 (0.3; 1) 1 (0.3; 1)
109 (24; 54) 55 (13; 33) 17 (5; 5) 17 (5; 10) 20 (5; 6) 0 (0; 0) 8 (2; 1) 3 (0.8; 2)
45 (11 ; 23) 6 (2; 6) 12 (3; 3) 23 (6; 13) 4 (1; 1) 0 (0; 0) 1 (0.3; 1) 3 (0.8; 3)
4 (1; 0) 11 (3; 4) 9 (2; 3) 1 (0.3; 1) 6 (2; 2) 0 (0; 0) 2 (0.5; 0) 9 (2; 1) 1 (0.3; 1) 27 (7; 4) 0 (0; 0) 4 (1; 2) 18 (5; 17) 440 (57; 405) 30 (8; 27) 629 (69; 489)
2 (0.5; 2) 20 (4; 11) 55 (12; 13) 37 (9; 0) 12 (3; 11) 6 (2; 2) 0 (0; 0) 0 (0; 0) 7 (2; 5) 5 (1; 4) 13 (3; 5) 13 (3; 7) 2 (0.5; 2) 15 (3; 3) 47 (9; 28) 299 (47; 137)
14 (4; 12) 0 (0; 0) 6 (1; 2) 3 (0.8; 0) 2 (0.5; 1) 0 (0; 0) 1 (0.3; 1) 0 (0; 0) 0 (0; 0) 0 (0; 0) 0 (0; 0) 0 (0; 0) 2 (0.5; 2) 25 (6; 20) 5 (1; 5) 101 (22; 68)
methodology, validation, formal analysis and investigation, data curation, visualization, writing the original draft, review and editing, and project administration. Sophie S. Biesheuvel contributed to methodology, validation, formal analysis and investigation, data curation, visualization, and writing the original draft. Ingrid M. M. van Haelst contributed to conceptualization, methodology, writing the original draft, review and editing, and supervision. Rob J. van Marum contributed to conceptualization, methodology, writing the original draft, review and editing, and supervision. René W. M. M. Jansen contributed to conceptualization, methodology, writing the original draft, review and editing, and supervision.
increasing medication, though. Since the Dutch STOPP/START-criteria do not differ much from the international version (see Appendix A in Supplementary material), we do not think our findings are limited to the Netherlands. Due to our study setting, our findings are limited to older fall and syncope out patients, though. It was not possible to link our findings to clinically relevant events, such as recurrence of falling or syncope, due to lack of follow-up. We therefore cannot make a statement about the changes in well-being of the patient as a result of the medication changes at the FSC. In spite of these limitations, this study in a respectable number of patients gives a complete overview of medication use and changes in older patients at a FSC. Furthermore, the prevalence of PIP in older syncope patients has not been reported before, while this group of patients especially might be sensitive to adverse drug reactions and therefore would benefit from medication reconciliation and evaluation.
Conflict of interest The authors declare that they have no conflict of interest.
4.4. Conclusion
Funding
Almost all older fall and syncope patients at this multidisciplinary FSC suffered from PIP. The prevalence of unaddressed persistent PIP was 80 %. Most frequent PIMs concerned fall/syncope-risk-increasing medication. It is doubtful whether implementation of the STOPP/ START-criteria would improve prescribing, since many occurrences of PIP identified by the STOPP/START-criteria were not considered clinically relevant, and two thirds of all medication changes were initiated for reasons that fell outside the scope of the STOPP/START-criteria. Rather than being subjected to the whole set of STOPP/START-criteria, FSC patients might benefit more from an approach focusing on those drugs that increase risk of falling and/or syncope. Overall, this study shows that physicians should be aware of inappropriate medication use in older fall and syncope patients. Further studies should be conducted to investigate whether a structured medication review may improve clinical outcomes in these patients.
No external funding was received for this study. Ethics Since this study was conducted outside the criteria for the Medical Research Involving Human Subjects Act (WMO), it was judged as exempt from review by the medical ethics committee. This study complied with the revised version of the European data protection regulation. Provenance and peer review This article has undergone peer review. Research data (data sharing and collaboration)
Contributors Susanne
C.
de
Ruiter
contributed
to
There are no linked research data sets for this paper. Data will be made available on request.
conceptualization, 70
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Acknowledgements
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The authors wish to thank E.J. Roosendaal, MD, and J.J. Walgers, MD, for their help in collection of the data. We also like to thank the nursing staff of the Northwest Clinics Alkmaar for their help in the clinical patient care. Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.maturitas.2019.10. 013. References [1] M. Brignole, A. Moya, F.J. de Lange, et al., ESC Guidelines for the diagnosis and management of syncope, Eur. Heart J. 39 (21) (2018) 1883–1948, https://doi.org/ 10.1093/eurheartj/ehy037. [2] Veiligheid.nl, Privé-valongevallen bij ouderen, Ongevalscijfers 2017, (2017), pp. 1–25. [3] S. Musich, S.S. Wang, J. Ruiz, K. Hawkins, E. Wicker, Falls-related drug use and risk of falls among older adults: a study in a US medicare population, Drugs Aging 34 (7) (2017) 555–565, https://doi.org/10.1007/s40266-017-0470-x. [4] O. Dalleur, A. Spinewine, S. Henrard, C. Losseau, N. Speybroeck, B. Boland, Inappropriate prescribing and related hospital admissions in frail older persons according to the stopp and start criteria, Drugs Aging 29 (10) (2012) 829–837, https://doi.org/10.1007/s40266-012-0016-1. [5] L.C. Sera, M.L. McPherson, Pharmacokinetics and pharmacodynamic changes associated with aging and implications for drug therapy, Clin. Geriatr. Med. 28 (2) (2012) 273–286, https://doi.org/10.1016/j.cger.2012.01.007. [6] G. Ziere, J.P. Dieleman, A. Hofman, H.A.P. Pols, T.J.M. Van Der Cammen, B.H.C. Stricker, Polypharmacy and falls in the middle age and elderly population, Br. J. Clin. Pharmacol. 61 (2) (2006) 218–223, https://doi.org/10.1111/j.13652125.2005.02543.x. [7] L. Bruin-Huisman, A. Abu-Hanna, H.C.P.M. van Weert, E. Beers, Potentially inappropriate prescribing to older patients in primary care in the Netherlands: a retrospective longitudinal study, Age Ageing 46 (4) (2017) 614–619, https://doi. org/10.1093/ageing/afw243. [8] C.G. McMahon, C.A. Cahir, R.A. Kenny, K. Bennett, Inappropriate prescribing in older fallers presenting to an Irish emergency department, Age Ageing 43 (1) (2014) 44–50, https://doi.org/10.1093/ageing/aft114. [9] M.N. OʼConnor, P. Gallagher, D. OʼMahony, Inappropriate prescribing, Drugs Aging 29 (6) (2012) 437–452, https://doi.org/10.2165/11632610-000000000-00000. [10] D. O’Mahony, D. O’Sullivan, S. Byrne, M.N. O’Connor, C. Ryan, P. Gallagher, STOPP/START criteria for potentially inappropriate prescribing in older people: version 2, Age Ageing 44 (2) (2015) 213–218, https://doi.org/10.1093/ageing/ afu145. [11] W. Knol, M.M. Verduijn, A. (Rian) Lelie-van der Zande, et al., Onjuist medicatie gebruik bij ouderen, Ned Tijdschr Geneeskd 159 (2015) A8904. [12] S. Masumoto, M. Sato, T. Maeno, Y. Ichinohe, T. Maeno, Potentially inappropriate medications with polypharmacy increase the risk of falls in older Japanese patients: 1-year prospective cohort study, Geriatr. Gerontol. Int. 18 (7) (2018) 1064–1070, https://doi.org/10.1111/ggi.13307. [13] J.F.H. Wold, J.H. Ruiter, J.H. Cornel, R.L.C. Vogels, R.W.M.M. Jansen, A multidisciplinary care pathway for the evaluation of falls and syncope in geriatric patients, Eur. Geriatr. Med. 6 (5) (2015) 487–494, https://doi.org/10.1016/j.eurger. 2015.05.007. [14] K. Mulvogue, J.A. Roberts, I. Coombes, N. Cottrell, S. Kanagarajah, A. Smith, The effect of pharmacists on ward rounds measured by the STOPP/START tool in a specialized geriatric unit, J. Clin. Pharm. Ther. 42 (2) (2017) 178–184, https://doi.
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To STOPP or to START? Potentially inappropriate prescribing in older patients with falls and syncope
T
Susanne C. de Ruitera,d,*, Sophie S. Biesheuvela,b, Ingrid M.M. van Haelstb, Rob J. van Marumc, René W.M.M. Jansena a
Department of Geriatric Medicine, Northwest Clinics Alkmaar, the Netherlands Department of Pharmacy, Northwest Clinics Alkmaar, the Netherlands c Department of General Medicine and Geriatric Medicine, Free University, Amsterdam, the Netherlands d Currently employed at: Section of Geriatric Medicine, Department of Internal Medicine, St. Antonius Hospital Nieuwegein, Utrecht and Woerden, the Netherlands b
A R T I C LE I N FO
A B S T R A C T
Keywords: Potentially inappropriate prescribing Syncope Falls Older patients
Objectives: To investigate the prevalence of potentially inappropriate prescribing (PIP) according to the revised STOPP/START criteria in older patients with falls and syncope. Study design: We included consecutive patients with falls and syncope aged ≥65 years at the day clinic of the Northwest Clinics, the Netherlands, from 2011 to 2016. All medication use before and after the visit was retrospectively investigated using the revised STOPP/START criteria. Main outcome measures: The prevalence/occurrence of PIP before the visit, persistent PIP after the visit, and unaddressed persistent PIP not explained in the patient’s chart. Results: PIP was present in 98 % of 374 patients (mean age 80 (SD ± 7) years; 69 % females). 1564 PIP occurrences were identified. 1015 occurrences persisted (in 91 % of patients). 690 occurrences (in 80 % of patients) were not explained in the patient’s chart. The most frequent unaddressed persistent forms of PIP were prescriptions of vasodilator drugs for patients with orthostatic hypotension (16 %), and benzodiazepines for > 4 weeks (10 %) or in fall patients (8 %), and omission of vitamin D (28 %), antihypertensive drugs (24 %), and antidepressants (17 %). 54 % of all medication changes were initiated for reasons beyond the scope of the STOPP/START criteria. Conclusions: Almost every patient in our study population suffered from PIP. In 80 %, PIP continued after the clinical visit, without an explanation in the patient’s chart. The most frequent PIP concerned medication that increased the risk of falls or syncope, specifically vasodilator drugs and benzodiazepines. Physicians should be aware of PIP in older patients with falls and syncope. Further studies should investigate whether a structured medication review may improve clinical outcomes.
1. Introduction Syncope and falls are common problems in older patients [1,2]. In the Netherlands, in 2017, 102,000 persons aged ≥65 years visited the emergency department (ED), and 3849 persons died due to falls. The total financial burden of fall-related injuries in those aged ≥65 years was almost 900 million euros2]. Medication use is an important risk factor for both syncope and falls [3,4]. Older people are vulnerable to adverse drug reactions, due to physiologic changes and polypharmacy [5,6]. With the number of drugs used, the likelihood of potentially inappropriate prescribing (PIP) increases [7,8]. PIP includes ‘prescription of medication with potential
⁎
risks that outweigh potential benefit in a specific patient’ (potentially inappropriate medicines (PIMs)), and ‘omission of medication where there is an indication for treatment or prevention’ (potential prescribing omissions (PPOs)) [9]. The Screening Tool of Older Person’s Prescriptions (STOPP) and Screening Tool to Alert doctors to Right Treatment (START) were developed to detect PIP in older patients [10,11]. With these tools, PIMs are identified in about one third, and PPOs in 85 % of primary care patients aged ≥65 years [7,12]. In patients with polypharmacy, PIMs were significantly associated with falls in one study12]. Another study found PIP in over 50 % of fall patients aged ≥70 years at the ED [8]. To our knowledge, PIP has not been investigated in syncope patients.
Corresponding author at: Department of Internal Medicine (Geriatrics), St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, the Netherlands. E-mail address: [email protected] (S.C. de Ruiter).
https://doi.org/10.1016/j.maturitas.2019.10.013 Received 1 June 2019; Received in revised form 18 October 2019; Accepted 28 October 2019 0378-5122/ © 2019 Elsevier B.V. All rights reserved.
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second (as will be further explained later on) may rather overestimate. Nevertheless, since these modifications were based on the real-life limitations FSC physicians have to deal with, we felt that our findings would still realistically reflect on the burden of PIP in our population. Primary outcome was the prevalence of PIP (defined as percentage of patients exposed to any given PIP) before and after the visit. If PIP was not adjusted or medication changes caused a new occasion of PIP, this was classified as ‘persistent PIP’. An investigator checked the physician’s notes to see whether this was deliberate (see Appendix B in Supplementary material); if not, this was classified as ‘unaddressed persistent PIP’. We also identified the number and type of medication changes outside the scope of the STOPP/START-criteria.
Investigating PIMs in patients with falls/syncope is important, since these may relate to fall/syncope-risk-inducing drugs, and therefore iatrogenic falls/syncope. PPOs are just as relevant a problem. For instance, underprescription of cardiovascular drugs may result in rhythm disorders, increased risk of orthostatic hypotension, and even balance and gait disturbances through cerebrovascular disease. We therefore performed a retrospective study to investigate PIP in older patients presenting to the Fall and Syncope Clinic (FSC) of the Northwest Clinics, Alkmaar, the Netherlands [13]. The STOPP/STARTcriteria are not routinely used for medication review at our FSC. To examine whether treating physicians recognized PIP without consciously applying the STOPP/START-criteria, or would benefit from implementation of these criteria, we also investigated persistent PIP after the patient’s visit.
2.4. Statistical analysis 2. Methods Statistical analyses were performed using SPSS for Windows, version 20 (SPSS, Inc., Chicago, IL, USA). Continuous variables were compared using the Student’s T-Test, or the Mann-Whitney U test where appropriate. Nominal variables were compared using Pearson’s ChiSquare Test or Fisher’s Exact Test when indicated. Two-tailed P-values < 0.01 were considered statistically significant to correct for the problem of multiple comparisons.
2.1. Study design and population We performed a retrospective study, including consecutive patients aged ≥65 years at the FSC of the Northwest Clinics, Alkmaar, the Netherlands, from November 2011 to June 2016. In case of multiple visits, only the first visit was included. Syncope was defined as ‘transient loss of consciousness due to cerebral hypoperfusion, characterized by a rapid onset, short duration, and spontaneous complete recovery’ [1]. Patients who experienced a fall without syncope, were defined as fall patients. Patients who did not experience a fall and/or syncope were excluded. Since this study was conducted outside the criteria for the Medical Research Involving Human Subjects Act (WMO), it was judged as exempt from review by the medical ethics committee. It was registered and overseen as institutional QI. This study complied with the revised version of the European Data protection regulation.
3. Results 3.1. Patient characteristics We included 374 out of 432 consecutive patients (mean age 80 SD ± 7 years; 69 % female); 12 patients were excluded because they were < 65 years, and 42 patients because they did not experience a fall/syncope. Of 4 patients who visited the FSC multiple times, only their first visit was included. Table 1 shows baseline characteristics, medication use, and general FSC outcomes. There were no significant differences between syncope patients (N = 190) and fall patients (N = 184), except for the presence of osteoporosis (12 % in syncope patients vs. 21 % in fall patients, P = 0.01), and OH (72 % in syncope patients vs. 57 % in fall patients, P = 0.001).
2.2. Data collection The FSC is a diagnostic program for older fall and syncope patients, involving geriatricians, cardiologists, neurologists, nurses, and physiotherapists [13]. A pharmacologist is not part of the team. Patients underwent a comprehensive geriatric assessment, including medical history, eyewitness account, and physical examination with standardized blood pressure (BP) measurements for orthostatic hypotension (OH) and postprandial hypotension (PPH). Laboratory tests, 12-lead electrocardiogram, and an MRI-scan of the brain were performed, unless contraindicated. Appropriate patients underwent an additional cardiac, neurological and/or psychiatric evaluation. Patients brought an up-to-date medication list from their pharmacy, and were asked about inconsistencies, compliance, side effects, and use of non-prescription drugs by the geriatrician. At the end of the visit, a final diagnosis and treatment plan was devised by the multidisciplinary team. Changes in medication were accomplished – in accordance with local agreements – through a written advice to the patient’s general practitioner (GP), who then wrote the prescriptions. If an immediate change was required, the geriatrician provided the prescription.
3.2. Prevalence of PIP 98 % of patients had ≥1 PIP (PIMs 75 %, PPOs 93 %). After the visit, 91 % of patients had ≥1 persistent PIP (PIMs 62 %, PPOs 78 %), and 80 % of patients had ≥1 unaddressed persistent PIP (PIMs 41 %, PPOs 69 %) (Fig. 1A). In total, 1564 PIP occurrences were identified (670 PIMs, 894 PPOs). 1015 PIP occurrences persisted (418 PIMs, 597 PPOs), of which 690 were unaddressed (244 PIMs, 446 PPOs) (Fig. 1B). Fig. 1C shows the number of PIP per patient. 3.3. Specific PIMs and PPOs Table 2 shows all PIMs/PPOs with a prevalence of ≥10 %. Most frequent PIMs at the start of the visit were vasodilator drugs in OH patients (STOPP-K3; 41 %), antithrombotic drugs in patients with a concurrent significant bleeding risk (STOPP-C2; 30 %), and benzodiazepines for > 4 weeks (STOPP-D5; 19 %) or in fall patients (STOPP-K1; 18 %). After the visit, most frequent unaddressed persistent PIMs were vasodilator drugs in OH patients (16 %), and benzodiazepines for > 4 weeks (10 %) or in fall patients (8 %). In 92 % of patients on antithrombotic drugs with concurrent significant bleeding risk (STOPP-C2), antithrombotic drugs were continued (i.e. persistent PIM). However, this was deliberate in all but one patient (i.e. unaddressed persistent PIM in only 0,3 % of the population). Most frequent PPOs were vitamin D in fall patients (START-E5; 64 %), antihypertensive drugs in increased BP (START-A4; 42 %), antidepressants for depressive symptoms (START-C2; 21 %), statin therapy
2.3. Data evaluation Medication use at the start and all changes at the end of the visit, including any written advice to the GP, were retrospectively analysed, using the Dutch revised STOPP/START-criteria [11]. Because information to assess certain criteria was not available, and some drugs fell beyond the scope of expertise of the FSC staff, we used a modified version (see Appendix A in Supplementary material), excluding some criteria and using surrogate measures to assess a few others. While the first may result in an underestimation of the total burden of PIP, the 66
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patients had a change in medication (1029 changes) (see Table 3); this includes medication within an outside of the scope of the STOPP/ START-criteria. 629 medications were started (in 69 % of patients), primarily antihypertensive drugs (74 occurrences in 18 % of patients), and vitamin supplements (440 occurrences in 57 % of patients), including vitamin D (138 occurrences in 37 % of patients). 299 medications were stopped (in 47 % of patients), mainly antihypertensive drugs (109 occurrences in 24 % of patients), including diuretics (55 occurrences in 13 % of patients), and psychoactive medication (55 occurrences in 12 % of patients), primarily benzodiazepines (37 occurrences in 9 % of patients). 101 doses were altered (in 22 % of patients), mostly for antihypertensive drugs (45 occurrences in 11 % of patients) and vitamin supplements (25 occurrences in 6 % of patients). 54 % of all changes were initiated for reasons that fell beyond the scope of the STOPP/START-criteria, including 489 medications started (in 62 % of patients), 137 medications stopped (in 28 % of patients), and 68 dose alterations (in 15 % of patients).
Table 1 Baseline characteristics and general outcomes of the FSC evaluation. Baseline characteristics
N = 374
Female gender, N (%) Age in years, mean (SD) Dependent in activities of daily living (ADL), N (%) Dependent in instrumental ADL, N (%) History of hypertension, N (%) History of ischemic heart disease, N (%) History of rhythm disorder, N (%) History of congestive heart failure, N (%) History of cerebrovascular accident, N (%) History of peripheral vascular disease, N (%) Parkinson’s disease, N (%) Type 2 diabetes mellitus, N (%) History of fractures, N (%) History of osteoporosis, N (%) History of psychiatric disorder, N (%) History of cognitive impairment, N (%) Alcohol use, N (%) Medication use No. of medications used, median (Q1,Q3) Antihypertensive drugs, N (%) Diuretics, N (%) ACE inhibitors/ARBs, N (%) Beta blockers, N (%) Calcium channel blockers, N (%) Nitrates, N (%) Antiarrhythmic drugs (digoxin/amiodarone), N (%) Lipid lowering drugs, N (%) Antithrombotic drugs, N (%) Antiplatelet drugs, N (%) (N)OAC or LMWH, N (%) Proton pump inhibitors, N (%) Antidiabetic drugs, N (%) Psychoactive medication, N (%) Benzodiazepines, zolpidem, zopiclone, N (%) Antidepressants, N (%) Antipsychotics, N (%) Acetylcholinesterase inhibitors, N (%) Bisphosphonates/denosumab, N (%) Vitamin supplements, N (%) Anti-inflammatory drugs, N (%) Analgesics, N (%) Alpha antagonists, N (%) Antimuscarin/anticholinergic agents, N (%) General outcomes of the FSC evaluation Syncope, N (%) Fall without syncope, N (%) Orthostatic hypotension, N (%) Symptomatic, N (%) Postprandial hypotension, N (%) Symptomatic, N (%) Cognitive impairment†, N (%) MoCA score, median (Q1,Q3) MMSE score, median (Q1,Q3)
255 (68) 80 (7) 88 (24) 155 (41) 247 (66) 97 (26) 103 (28) 33 (9) 90 (24) 44 (12) 16 (4) 80 (21) 159 (43) 60 (16) 88 (24) 45 (12) 184 (49)
• • • • • • • • •
• • • •
†
4. Discussion
7 (5,9) 265 (71) 124 (33) 175 (47) 161 (43) 68 (18) 35 (9) 28 (8) 172 (46) 218 (58) 135 (36) 88 (24) 168 (45) 66 (18) 119 (32) 76 (20) 63 (17) 10 (3) 8 (2) 42 (11) 150 (41) 87 (23) 108 (29) 23 (6) 33 (9)
4.1. Main findings PIP was present in nearly all of our older fall and syncope patients. In most cases, PIP persisted after the evaluation. Of 1564 PIP occurrences, 1015 persisted after the FSC visit, of which 690 occurrences were unaddressed in the patient’s chart. Approximately two thirds of all medication changes were initiated for reasons that fell outside the scope of the STOPP/START-criteria. Although medication review is part of the FSC, the STOPP/STARTcriteria are not regularly applied. Treating physicians may therefore not have been aware that PIP was present in their patients. It is also important to note that the STOPP/START-criteria have been designed as a guide to improve prescribing, rather than commandments which should be adhered to at all times. Even so, one would expect physicians working at an FSC to at least be mindful of fall/syncope-risk-increasing drugs. However, most frequent unaddressed persistent PIMs in our population concerned medication that increases fall/syncope risk, i.e. vasodilator drugs in OH patients, and benzodiazepines for > 4 weeks or in fall patients. PIMs concerning benzodiazepines are frequently reported in older patients [7,14]. Motivating long-term users to reduce the dosage may be time-consuming and requires regular follow-up, which might explain physicians’ reluctance to raise this issue. Some physicians may also feel that fear of falling requires continued benzodiazepine treatment, despite the fact that these drugs increase fall risk. Indeed, Walgers et al. showed that benzodiazepine use is more frequent among older fall patients with fear of falling compared with patients without fear of falling [15]. Overall, the prevalence of unaddressed persistent PPOs was considerably higher in this population than the prevalence of unaddressed persistent PIMs (69 % vs. 41 %). This is similar to the findings of others [4,7]. Underprescribing is a widespread problem in older patients, especially in those with polypharmacy [16]. Since the FSC focuses on identifying causes of falls/syncope, fall/syncope-risk-inducing medication (i.e. PIMs) would be expected to get more attention than PPOs (even though these might be just as harmful). While PIMs were less frequent than PPOs (75 % vs. 93 %), far less PIMs persisted without explanation than PPOs (55 % of all PIMs vs. 74 % of all PPOs). It may be that in cases where many PPOs are found at the same time, treating physicians decide not to start medication for every omission, so as not to burden the patient with too many changes at once. It has also been reported that in case of PPOs, more often than not, treating physicians have good reasons for not prescribing appropriate drugs [17]. It may therefore be that rather than omitting to prescribe, physicians omitted to report their reasons for not prescribing. A further question is whether all PIP identified by the STOPP/
190 (51) 184 (49) 241 (64) 138 (37) 208 (56) 79 (21) 188 (61) 25 (21,27) 28 (26,29)
Montreal Cognitive Assessment score ≤26 (N = 309).
in patients with a history of coronary, cerebral, or peripheral vascular disease (START-A5; 15 %), angiotensin-converting-enzyme inhibitors or angiotensin-II-receptor blockers (ACEi/ARB) in patients with systolic heart failure or coronary artery disease (START-A6; 13 %), beta blockers after a myocardial infarction or angina (START-A7; 12 %), and vitamin D, calcium supplements, and anti-osteoporosis drugs in osteoporosis patients (START-E3 and -E4; 10 %). The most frequent unaddressed persistent PPOs were vitamin D in fall patients (28 %), antihypertensive drugs in increased BP (24 %), and antidepressants for depressive symptoms (17 %).
3.4. Secondary outcomes After the visit, the mean number of drugs per patient increased from 7 (SD 4, range 0–27) to 8 (SD 4, range 0–26) (P = 0.000. 84 % of 67
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Fig. 1. A: Potentially inappropriate prescribing in 374 older fall and syncope patients. B: Occurrences of potential inappropriate prescribing in 374 older fall and syncope patients. C: Number of occurrences of potentially inappropriate prescribing per patient.
Another frequent unaddressed persistent PPO concerned antidepressants. In our practice, patients suffering from depressive symptoms are referred to an old age psychiatrist for evaluation before starting treatment. Furthermore, the presence of depressive symptoms may not always warrant medication; oftentimes, non-medical treatment may suffice [21]. According to STOPP-C2 – a frequent persistent PIM – bleeding risk should be assessed using the HASBLED score [22], and antithrombotic
START-criteria is clinically relevant. For instance, the most frequent unaddressed persistent PPO was vitamin D in fall patients. At the FSC, however, vitamin D was only prescribed in case of a proven deficiency, since supplementation in persons with normal vitamin D levels has not been shown to reduce falls [18,19]. After adjusting for PPOs concerning patients with normal vitamin D levels, 342 unaddressed persistent PPOs occurrences in 57 % of patients remain. This is much more in agreement with the findings of others [14,20]. 68
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No. of patients with unaddressed persistent PIM/PPO (% of total population; % of patients with PIM/PPO)
60 (16; 39) 1 (0.3; 1) 36 (10; 51) 30 (8; 45) 10 (3; 18)
104 (28; 43) 91 (24; 58) 64 (17; 81) 36 (10; 63)
36 (10; 73)
24 (6; 55) 10 (3; 26) 6 (2; 16)
No. of patients with persistent PIM/PPO (% of total population; % of patients with PIM/PPO)
116 (31; 76) 102 (27; 92) 40 (11; 56) 33 (9; 49) 10 (3; 18)
105 (28; 44) 98 (26; 62) 74 (20; 94) 53 (14; 93)
42 (11; 86)
40 (11; 91) 11 (3; 29) 13 (3; 34)
4.2. Implications It is understandable that physicians focusing on falls and syncope, would overlook PIP that does not concern these problems. Nevertheless, the fact that most frequent unaddressed persistent PIMs actually concerned fall/syncope-risk-increasing medication, implies that current clinical practice needs improvement. It remains unclear, however, whether a standardized medication review would be the answer. In two relatively small studies, discontinuation of fall-risk-increasing drugs (especially cardiovascular and psychotropic medication) significantly lowered fall incidents in older patients [25,26], and an RCT providing an educational program on medication review to GPs found a lower adjusted odds ratio for falls after 12 months follow-up in the intervention group [27]. However, withdrawal of fall-risk-increasing-drugs in the IMPROveFALL trial did not reduce falls during 12-months followup, nor was it cost-effective, although patients in the intervention group had less decline in health-related quality of life compared to controls [28,29]. These discrepancies underline the idea that, although PIP certainly plays a role in falls and syncope, the best way to deal with this problem has yet to be determined.
Our study has several limitations. As explained before, certain STOPP/START-criteria could not be included in the analysis since information to assess them was not available (leading to an underestimation of the total burden of PIP), or surrogate measures needed to be used. For instance, we used BP measurements at the FSC as a surrogate for the diagnosis of hypertension, although repeated measurements should be taken [30]. White-coat hypertension may therefore have resulted in an overestimation of untreated hypertension, and the number of PPOs. It is likely that doctors are cautious to prescribe antihypertensive drugs in fall and syncope patients when they are not entirely certain of their diagnosis. To assess START-C2, depressive symptoms were used as a surrogate for depressive disorder. Because diagnosing and treating psychiatric disorders are not the primary purposes of the FSC, it is possible that depressive symptoms were not always recognized. On the other hand, the presence of depressive symptoms is not the same as having a major depressive disorder. Consequently, the number of omissions of antidepressants is possibly overestimated. Changes in the medical staff during the study period may have affected choices made. Although we were unable to investigate whether GPs implemented recommendations, they should have done so according to local agreements. To improve implementation by GPs, the number of recommendations was kept to a minimum, in accordance with FSC guidelines. This might explain why certain PIP was not addressed. FSC physicians may have wanted to emphasize the most relevant PIP, leaving out the rest. This does not explain the high prevalence of unaddressed persistent PIP concerning fall/syncope-risk-
44 (12) 38 (10) 38 (10)
49 (13)
241 (64) 157 (42) 79 (21) 57 (15)
152 (41) 111 (30) 71 (19) 67 (18) 56 (15)
4.3. Limitations
STOPP K3 Vasodilator drugs in patients with orthostatic hypotension C2 Antithrombotic drugs with concurrent significant bleeding risk D5 Use of benzodiazepines for longer than 4 weeks K1 Benzodiazepines in patients with a tendency to fall A1 Any drug prescribed without an evidence-based clinical indication START E5 Vitamin D supplement in older people experiencing falls A4 Antihypertensive in case of an increased blood pressure C2 Antidepressant for depressive symptoms A5 Statin therapy in patients with a history of coronary, cerebral or peripheral vascular disease A6 ACE inhibitor or AT-II antagonist in patients with systolic heart failure and/or coronary heart disease A7 Beta blocker after a myocardial infarction or angina E3 Vitamin D and calcium supplement in patients with osteoporosis E4 Bisphosphonates or other anti-osteoporosis medication in patients with osteoporosis
No. of patients with PIM/ PPO (%) Criteria
Table 2 Most frequent PIMs and PPOs in patients at the FSC.
drugs discontinued when this score is ≥3 [11]. However, this tool was not designed to assess risks of antiplatelet therapy, while bleeding risk in the case of oral anticoagulants should be compared to risk of thrombosis using, for instance, the CHA2DS2-VASc tool [23]. In our opinion, use of the HASBLED-score alone is not suitable to decide whether antithrombotic drugs should be discontinued, especially since this score has not been validated for patients aged > 80 years, and bleeding risk models in general have a low performance in the very old [22,24]. The continuation of vasodilators in case of OH (STOPP-K3) was also deliberate in most cases, as physicians chose to discontinue diuretics instead of vasodilators. We considered this a good clinical alternative, although it is not mentioned in the STOPP-criteria, especially when stopping an ACEi/ARB would have resulted in a new PPO, for instance according to START-A6.
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Table 3 Medication changes at the FSC.
Antihypertensive drugs Diuretics ACE inhibitor/ARB Beta blocker Calcium channel blockers Others Nitrates Antiarrhythmic drugs (digoxin/ amiodarone) Lipid lowering drugs Antithrombotic drugs Psychoactive medication Benzodiazepines Antidepressants Antipsychotics Acetylcholinesterase inhibitor Proton pump inhibitors Anti-inflammatory drugs Bisphosphonates/denosumab Alpha antagonists Analgesics Laxatives Vitamin supplements Other medication Total
No. of drugs started (% of patients; no. of drugs started for other reason than STARTcriteria)
No. of drugs stopped (% of patients; no. of drugs stopped for other reason than STOPP-criteria)
No. of drugs altered (% of patients; no. of drugs altered for other reason than STOPP/ START-criteria)
74 (18; 23) 4 (1; 1) 25 (7; 9) 14 (4; 9) 15 (4; 1) 16 (4; 3) 1 (0.3; 1) 1 (0.3; 1)
109 (24; 54) 55 (13; 33) 17 (5; 5) 17 (5; 10) 20 (5; 6) 0 (0; 0) 8 (2; 1) 3 (0.8; 2)
45 (11 ; 23) 6 (2; 6) 12 (3; 3) 23 (6; 13) 4 (1; 1) 0 (0; 0) 1 (0.3; 1) 3 (0.8; 3)
4 (1; 0) 11 (3; 4) 9 (2; 3) 1 (0.3; 1) 6 (2; 2) 0 (0; 0) 2 (0.5; 0) 9 (2; 1) 1 (0.3; 1) 27 (7; 4) 0 (0; 0) 4 (1; 2) 18 (5; 17) 440 (57; 405) 30 (8; 27) 629 (69; 489)
2 (0.5; 2) 20 (4; 11) 55 (12; 13) 37 (9; 0) 12 (3; 11) 6 (2; 2) 0 (0; 0) 0 (0; 0) 7 (2; 5) 5 (1; 4) 13 (3; 5) 13 (3; 7) 2 (0.5; 2) 15 (3; 3) 47 (9; 28) 299 (47; 137)
14 (4; 12) 0 (0; 0) 6 (1; 2) 3 (0.8; 0) 2 (0.5; 1) 0 (0; 0) 1 (0.3; 1) 0 (0; 0) 0 (0; 0) 0 (0; 0) 0 (0; 0) 0 (0; 0) 2 (0.5; 2) 25 (6; 20) 5 (1; 5) 101 (22; 68)
methodology, validation, formal analysis and investigation, data curation, visualization, writing the original draft, review and editing, and project administration. Sophie S. Biesheuvel contributed to methodology, validation, formal analysis and investigation, data curation, visualization, and writing the original draft. Ingrid M. M. van Haelst contributed to conceptualization, methodology, writing the original draft, review and editing, and supervision. Rob J. van Marum contributed to conceptualization, methodology, writing the original draft, review and editing, and supervision. René W. M. M. Jansen contributed to conceptualization, methodology, writing the original draft, review and editing, and supervision.
increasing medication, though. Since the Dutch STOPP/START-criteria do not differ much from the international version (see Appendix A in Supplementary material), we do not think our findings are limited to the Netherlands. Due to our study setting, our findings are limited to older fall and syncope out patients, though. It was not possible to link our findings to clinically relevant events, such as recurrence of falling or syncope, due to lack of follow-up. We therefore cannot make a statement about the changes in well-being of the patient as a result of the medication changes at the FSC. In spite of these limitations, this study in a respectable number of patients gives a complete overview of medication use and changes in older patients at a FSC. Furthermore, the prevalence of PIP in older syncope patients has not been reported before, while this group of patients especially might be sensitive to adverse drug reactions and therefore would benefit from medication reconciliation and evaluation.
Conflict of interest The authors declare that they have no conflict of interest.
4.4. Conclusion
Funding
Almost all older fall and syncope patients at this multidisciplinary FSC suffered from PIP. The prevalence of unaddressed persistent PIP was 80 %. Most frequent PIMs concerned fall/syncope-risk-increasing medication. It is doubtful whether implementation of the STOPP/ START-criteria would improve prescribing, since many occurrences of PIP identified by the STOPP/START-criteria were not considered clinically relevant, and two thirds of all medication changes were initiated for reasons that fell outside the scope of the STOPP/START-criteria. Rather than being subjected to the whole set of STOPP/START-criteria, FSC patients might benefit more from an approach focusing on those drugs that increase risk of falling and/or syncope. Overall, this study shows that physicians should be aware of inappropriate medication use in older fall and syncope patients. Further studies should be conducted to investigate whether a structured medication review may improve clinical outcomes in these patients.
No external funding was received for this study. Ethics Since this study was conducted outside the criteria for the Medical Research Involving Human Subjects Act (WMO), it was judged as exempt from review by the medical ethics committee. This study complied with the revised version of the European data protection regulation. Provenance and peer review This article has undergone peer review. Research data (data sharing and collaboration)
Contributors Susanne
C.
de
Ruiter
contributed
to
There are no linked research data sets for this paper. Data will be made available on request.
conceptualization, 70
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Acknowledgements
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