ORIGINAL RESEARCH published: 31 August 2016 doi: 10.3389/fphar.2016.00296
Polypharmacy Cut-Off for Gait and Cognitive Impairments Antoine Langeard 1† , Kristell Pothier 1† , Remy Morello 2 , Véronique Lelong-Boulouard 3 , Pascale Lescure 4 , Marie-Laure Bocca 1 , Christian Marcelli 5 , Pablo Descatoire 4 and Chantal Chavoix 1* 1
Normandie Université, Université de Caen Normandie, Institut National de la Santé et de la Recherche Médicale, COMETE, Caen, France, 2 Centre Hospitalier Universitaire de Caen, Departments of Statistics and Clinical Research, Normandie Université, Université de Caen Normandie, Caen, France, 3 Centre Hospitalier Universitaire de Caen, Departments of Pharmacology, Normandie Université, Université de Caen Normandie Université, Institut National de la Santé et de la Recherche Médicale, COMETE, Caen, France, 4 Centre Hospitalier Universitaire de Caen, Departments of Geriatrics, Normandie Université, Université de Caen Normandie Université, Institut National de la Santé et de la Recherche Médicale, COMETE, Caen, France, 5 Centre Hospitalier Universitaire de Caen, Departments of Rheumatology, Normandie Université, Institut National de la Santé et de la Recherche Médicale, COMETE, Caen, France
Edited by: Iñaki Gutiérrez-Ibarluzea, OSTEBA – Basque Office for Health Technology Assessment, Spain Reviewed by: Domenico Criscuolo, Genovax, Italy Sandor Kerpel-Fronius, Semmelweis University, Hungary *Correspondence: Chantal Chavoix [email protected] † These
authors have contributed equally to this work.
Specialty section: This article was submitted to Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology Received: 05 July 2016 Accepted: 22 August 2016 Published: 31 August 2016 Citation: Langeard A, Pothier K, Morello R, Lelong-Boulouard V, Lescure P, Bocca M-L, Marcelli C, Descatoire P and Chavoix C (2016) Polypharmacy Cut-Off for Gait and Cognitive Impairments. Front. Pharmacol. 7:296. doi: 10.3389/fphar.2016.00296
Background: Polypharmacy is a well-established risk factor for falls, and these are one of the major health problems that affect the quality of life as people age. However, the risk of mobility and cognitive impairments consecutive to polypharmacy has been little addressed, despite the association between these adverse outcomes and falls. Moreover, the rare polypharmacy cut-offs were all but one arbitrarily determined. Objective: Studying relationships between polypharmacy and both mobility and cognitive impairments, and statistically determining a cut-off point in the number of medicinal molecule beyond which polypharmacy has deleterious consequences with respect to mobility and cognitive impairment. Methods: We enrolled 113 community-dwelling adults aged 55 years and older with a fall history, with or without injury, in the previous year. We carefully collected information about daily medicinal molecules taken. We assessed basic mobility and global cognition with the Time-Up-and-Go and the Montreal Cognitive Assessment (MoCA) test, respectively (clinicaltrials.gov NCT02292316). Results: Timed-Up and Go test and MoCA scores were both significantly correlated with the number of molecule, used. Receiver Operating Characteristic curves indicate, with high prediction (p < 0.002), that daily consumption of five or more molecules is associated with risk for both impaired mobility and global cognition. These relationships were independent of the number of comorbidities and of the pharmacological class. Conclusion: Community-dwelling adults aged 55 years and older who take five or more daily medicinal molecules are at high risk for both mobility and cognitive impairments. Physicians and patients should be aware of these new findings, especially when there are multiple prescribers involved in the care of the patient. Keywords: polypharmacy, cut-off, mobility, gait, cognition, middle age, aging
INTRODUCTION Some drugs are well-known for increasing the risk of falling, especially psychotropics (Hartikainen et al., 2007). Concomitant use of several pharmacological molecules, here called polypharmacy, is also incriminated in falls regardless of their pharmacological class (Tinetti et al., 1988; Ambrose et al., 2013; Fried et al., 2014) because of the deleterious drug–drug interactions that result from
Frontiers in Pharmacology | www.frontiersin.org
1
August 2016 | Volume 7 | Article 296
Langeard et al.
Polypharmacy Effect on Mobility and Cognition
of alcohol per week (14 for women), and impaired vision (acuity < 6/10). The present study was approved by the Lower Normandy Ethics Committee (no. 2011A00556-35; clinical trial registration number: NCT02292316). Each participant provided written informed consent.
interferences between pharmacokinetic and pharmacodynamic properties of the different drugs (Chen et al., 2014). The more drugs people take, the more drug–drug interactions occur (Johnell and Klarin, 2007), and the higher the fall risk is (Kojima et al., 2011). Nevertheless, adverse effects of polypharmacy are seldom taken into consideration by the physicians, partly because of lack of awareness. Gait and cognitive disorders are two other major risk factors for falls in older adults (Tinetti et al., 1988; Ambrose et al., 2013). However, the number of medicinal molecules that can result in mobility and cognitive impairment has rarely been addressed. A negative linear relationship has previously been reported between the number of medications used and a composite score of balance measures (Agostini et al., 2004). Participants taking five or more medications showed worsened functional abilities over a 7-year follow-up (Pugh et al., 2007). One of the rare studies in the cognitive field showed that incidence of dementia increases steadily with the number of medications used (Lai et al., 2012). The only study that used the Receiver Operating Characteristic (ROC), a powerful tool for risk prediction, to search for a number of medications that could predict cognitive impairment could not find a cut-off value that led to accurate prediction (Gnjidic et al., 2012). Adverse effects of polypharmacy on dynamic balance and cognition were all observed in populations of over 65 years (Agostini et al., 2004; Pugh et al., 2007; Gnjidic et al., 2012; Lai et al., 2012). Fall risk has, however, been associated with the use of polypharmacy when the study population included younger individuals of 55–65 years (Ziere et al., 2006). This is an important finding since many younger adults are also polymedicated and that occurrence of adverse health outcomes associated with polypharmacy would be even more worrying if occurring so early in life. The objective of the present study was thus to determine whether, and to what extent, polypharmacy could lead to mobility and cognitive impairments. This was performed in two ways in community-dwelling adults aged 55 years and older: (i) by exploring the relationships between the number of pharmacological molecules taken and both basic mobility and cognitive performance; and (ii) by determining whether there is an optimal number of molecules that could discriminate risk for mobility and cognitive impairment using statistical method for risk prediction.
Outcome Measures We collected information about drugs, vitamins, and supplements taken via medical prescriptions which was confirmed by history taking during the clinical examination. We used the total number of prescribed molecules to estimate medication exposure (e.g., two molecules were counted in case of the combination of two molecules in a single tablet), and the Kaplan–Feinstein scale (Kaplan and Feinstein, 1974) to determine the number of comorbidities. We assessed basic functional mobility with the Timed-Up and Go test (TUG) that requires standing up from an arm chair, walking 3 m, turning, walking back to the chair, and sitting down. The task was performed twice at a comfortable pace, and we recorded the shortest time to complete the task. We measured global cognition with the Montreal Cognitive Assessment test (MoCA; Nasreddine et al., 2005), a 30-point test that covers six cognitive domains: visuospatial/executive functions, naming, attention, abstraction, recall, and orientation. Cut-off score for impairment was based on the normative reference values corrected for age for the TUG (Bohannon, 2006), and set at 26/30 for the MoCA (Nasreddine et al., 2005). The experimenters who performed the gait and cognitive evaluation were blind to participants’ medical treatment.
Statistical Analysis We used adjusted Pearson correlations to analyze relationships between the number of pharmacological molecules taken and mobility score, cognitive score and number of comorbidities. Adjustment variables were age and body mass index (BMI) for the correlations with TUG score, and age only with those with the MoCA score that already takes into account education level. We performed ROC analyses on TUG and MoCA scores (normal vs. impaired) to determine whether there is an optimal cut-off value for the number of molecules that could be responsible for cognitive and mobility impairments. The area under the ROC curve (AUC) provides a measure of accuracy of the prediction. We then performed several analyses using the optimal cut-off values thus obtained. First, we computed analyses of variance (ANOVAs) to compare TUG score, MoCA score, and the number of psychotropic, antihypertensive, opioid analgesic and others molecules between the participants taking fewer and “as many or more” molecules than the cut-off value. We verified the conditions of validity with Levene’s test. Second, we explored the relationships between the number of molecules prescribed (≥cut-off vs.
Polypharmacy Cut-Off for Gait and Cognitive Impairments Antoine Langeard 1† , Kristell Pothier 1† , Remy Morello 2 , Véronique Lelong-Boulouard 3 , Pascale Lescure 4 , Marie-Laure Bocca 1 , Christian Marcelli 5 , Pablo Descatoire 4 and Chantal Chavoix 1* 1
Normandie Université, Université de Caen Normandie, Institut National de la Santé et de la Recherche Médicale, COMETE, Caen, France, 2 Centre Hospitalier Universitaire de Caen, Departments of Statistics and Clinical Research, Normandie Université, Université de Caen Normandie, Caen, France, 3 Centre Hospitalier Universitaire de Caen, Departments of Pharmacology, Normandie Université, Université de Caen Normandie Université, Institut National de la Santé et de la Recherche Médicale, COMETE, Caen, France, 4 Centre Hospitalier Universitaire de Caen, Departments of Geriatrics, Normandie Université, Université de Caen Normandie Université, Institut National de la Santé et de la Recherche Médicale, COMETE, Caen, France, 5 Centre Hospitalier Universitaire de Caen, Departments of Rheumatology, Normandie Université, Institut National de la Santé et de la Recherche Médicale, COMETE, Caen, France
Edited by: Iñaki Gutiérrez-Ibarluzea, OSTEBA – Basque Office for Health Technology Assessment, Spain Reviewed by: Domenico Criscuolo, Genovax, Italy Sandor Kerpel-Fronius, Semmelweis University, Hungary *Correspondence: Chantal Chavoix [email protected] † These
authors have contributed equally to this work.
Specialty section: This article was submitted to Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology Received: 05 July 2016 Accepted: 22 August 2016 Published: 31 August 2016 Citation: Langeard A, Pothier K, Morello R, Lelong-Boulouard V, Lescure P, Bocca M-L, Marcelli C, Descatoire P and Chavoix C (2016) Polypharmacy Cut-Off for Gait and Cognitive Impairments. Front. Pharmacol. 7:296. doi: 10.3389/fphar.2016.00296
Background: Polypharmacy is a well-established risk factor for falls, and these are one of the major health problems that affect the quality of life as people age. However, the risk of mobility and cognitive impairments consecutive to polypharmacy has been little addressed, despite the association between these adverse outcomes and falls. Moreover, the rare polypharmacy cut-offs were all but one arbitrarily determined. Objective: Studying relationships between polypharmacy and both mobility and cognitive impairments, and statistically determining a cut-off point in the number of medicinal molecule beyond which polypharmacy has deleterious consequences with respect to mobility and cognitive impairment. Methods: We enrolled 113 community-dwelling adults aged 55 years and older with a fall history, with or without injury, in the previous year. We carefully collected information about daily medicinal molecules taken. We assessed basic mobility and global cognition with the Time-Up-and-Go and the Montreal Cognitive Assessment (MoCA) test, respectively (clinicaltrials.gov NCT02292316). Results: Timed-Up and Go test and MoCA scores were both significantly correlated with the number of molecule, used. Receiver Operating Characteristic curves indicate, with high prediction (p < 0.002), that daily consumption of five or more molecules is associated with risk for both impaired mobility and global cognition. These relationships were independent of the number of comorbidities and of the pharmacological class. Conclusion: Community-dwelling adults aged 55 years and older who take five or more daily medicinal molecules are at high risk for both mobility and cognitive impairments. Physicians and patients should be aware of these new findings, especially when there are multiple prescribers involved in the care of the patient. Keywords: polypharmacy, cut-off, mobility, gait, cognition, middle age, aging
INTRODUCTION Some drugs are well-known for increasing the risk of falling, especially psychotropics (Hartikainen et al., 2007). Concomitant use of several pharmacological molecules, here called polypharmacy, is also incriminated in falls regardless of their pharmacological class (Tinetti et al., 1988; Ambrose et al., 2013; Fried et al., 2014) because of the deleterious drug–drug interactions that result from
Frontiers in Pharmacology | www.frontiersin.org
1
August 2016 | Volume 7 | Article 296
Langeard et al.
Polypharmacy Effect on Mobility and Cognition
of alcohol per week (14 for women), and impaired vision (acuity < 6/10). The present study was approved by the Lower Normandy Ethics Committee (no. 2011A00556-35; clinical trial registration number: NCT02292316). Each participant provided written informed consent.
interferences between pharmacokinetic and pharmacodynamic properties of the different drugs (Chen et al., 2014). The more drugs people take, the more drug–drug interactions occur (Johnell and Klarin, 2007), and the higher the fall risk is (Kojima et al., 2011). Nevertheless, adverse effects of polypharmacy are seldom taken into consideration by the physicians, partly because of lack of awareness. Gait and cognitive disorders are two other major risk factors for falls in older adults (Tinetti et al., 1988; Ambrose et al., 2013). However, the number of medicinal molecules that can result in mobility and cognitive impairment has rarely been addressed. A negative linear relationship has previously been reported between the number of medications used and a composite score of balance measures (Agostini et al., 2004). Participants taking five or more medications showed worsened functional abilities over a 7-year follow-up (Pugh et al., 2007). One of the rare studies in the cognitive field showed that incidence of dementia increases steadily with the number of medications used (Lai et al., 2012). The only study that used the Receiver Operating Characteristic (ROC), a powerful tool for risk prediction, to search for a number of medications that could predict cognitive impairment could not find a cut-off value that led to accurate prediction (Gnjidic et al., 2012). Adverse effects of polypharmacy on dynamic balance and cognition were all observed in populations of over 65 years (Agostini et al., 2004; Pugh et al., 2007; Gnjidic et al., 2012; Lai et al., 2012). Fall risk has, however, been associated with the use of polypharmacy when the study population included younger individuals of 55–65 years (Ziere et al., 2006). This is an important finding since many younger adults are also polymedicated and that occurrence of adverse health outcomes associated with polypharmacy would be even more worrying if occurring so early in life. The objective of the present study was thus to determine whether, and to what extent, polypharmacy could lead to mobility and cognitive impairments. This was performed in two ways in community-dwelling adults aged 55 years and older: (i) by exploring the relationships between the number of pharmacological molecules taken and both basic mobility and cognitive performance; and (ii) by determining whether there is an optimal number of molecules that could discriminate risk for mobility and cognitive impairment using statistical method for risk prediction.
Outcome Measures We collected information about drugs, vitamins, and supplements taken via medical prescriptions which was confirmed by history taking during the clinical examination. We used the total number of prescribed molecules to estimate medication exposure (e.g., two molecules were counted in case of the combination of two molecules in a single tablet), and the Kaplan–Feinstein scale (Kaplan and Feinstein, 1974) to determine the number of comorbidities. We assessed basic functional mobility with the Timed-Up and Go test (TUG) that requires standing up from an arm chair, walking 3 m, turning, walking back to the chair, and sitting down. The task was performed twice at a comfortable pace, and we recorded the shortest time to complete the task. We measured global cognition with the Montreal Cognitive Assessment test (MoCA; Nasreddine et al., 2005), a 30-point test that covers six cognitive domains: visuospatial/executive functions, naming, attention, abstraction, recall, and orientation. Cut-off score for impairment was based on the normative reference values corrected for age for the TUG (Bohannon, 2006), and set at 26/30 for the MoCA (Nasreddine et al., 2005). The experimenters who performed the gait and cognitive evaluation were blind to participants’ medical treatment.
Statistical Analysis We used adjusted Pearson correlations to analyze relationships between the number of pharmacological molecules taken and mobility score, cognitive score and number of comorbidities. Adjustment variables were age and body mass index (BMI) for the correlations with TUG score, and age only with those with the MoCA score that already takes into account education level. We performed ROC analyses on TUG and MoCA scores (normal vs. impaired) to determine whether there is an optimal cut-off value for the number of molecules that could be responsible for cognitive and mobility impairments. The area under the ROC curve (AUC) provides a measure of accuracy of the prediction. We then performed several analyses using the optimal cut-off values thus obtained. First, we computed analyses of variance (ANOVAs) to compare TUG score, MoCA score, and the number of psychotropic, antihypertensive, opioid analgesic and others molecules between the participants taking fewer and “as many or more” molecules than the cut-off value. We verified the conditions of validity with Levene’s test. Second, we explored the relationships between the number of molecules prescribed (≥cut-off vs.
