Age of population is an important health factor that is of great importance for analysis of the biological structure of population and is determined by ratio of older population in the total population in a given territory. The age of 65 years and older is considered as social age limit in modern living conditions1,2. Due to the intensive aging of the population nowadays, older population is emerging as biggest drug users, primarily due to the significantly higher frequency of various diseases at that age. Often, these patients suffer from several associated illnesses, which imposes need for simultaneous usage of bigger number of drugs at same time, whether it is causal or symptomatic treatment. Older people are often treated in several different health care institutions, which belong to different levels of health care, from primary to tertiary. Every visit to another health institution creates an additional risk for irrational use of drugs, due to lack of information related to history of disease coming from different sources and/or unsatisfactory communication between health care professionals and between health professionals and patients3.
Aging leads to a decrease in neurons density of central nervous system (CNS). It is estimated that people over the age of 80 lose about 30% of brain mass, primarily gray mass, which is contributed by atherosclerosis, which leads to impaired brain function. Production of important neurotransmitters, including catecholamine, serotonin and acetylcholine, is reduced, which is associated with changes in mood, memory and motor functions4. The older population is particulary sensitive to substances that have an effect on the CNS. Therefore, they need to adjust doses of psychotropic drugs (benzodiazepines, barbiturates, antidepressants). Even drugs that do not have side effects on CNS, these effects are more noticeable at people over 65 years of age5.
The significance of IPD problem older population is reflected in its high prevalence ranging from about 15% to almost 80% depending on study site (country, region, primary, secondary or tertiary level of health care) and overall methodological approach. In the examination (especially the type of instrument by which the IPD was identified)6,7.
The aim of this research is to determine significant risk factors for potentially inappropriate prescribing of psychotropic drugs in a population of patients over 65 years of age with associated pathological conditions who are on an outpatient treatment regimen, using explicit STOPP START criteria8 from 2015.
The research was conducted on a sample of 492 consecutively selected, chronically ill patients aged ≥ 65 years, both sexes, with different sociodemographic and clinical characteristics, who receive health services at the expense of the compulsory health insurance fund.
Research was conducted in five out of nine general practice institutions that operate within the General Medicine Service of the Primary Health Care Center Kragujevac, in the period May 2020 – December 2021. It was conducted after the approval by the Ethics Committee of the Kragujevac Health Center. The research was conducted in compliance with the principles of the Declaration of Helsinki and in accordance with the principles of Good Clinical Practice. In order to collect the highest quality data, an unstructured questionnaire was prepared for patients or their caregivers and their Selected physicians (sGP). The research included nine selected general practitioners.
The design of the study is a cross-sectional study, in which they are with the help of STOPP and START criteria and sociodemographic questionnaire identified risk factors for Potentially Inappropriate Medicines (PIM) of psychotropic drugs and Potential Prescription Omissions (PPO) psychotropic drugs in patients over 65 years of age.
In order to collect as many patients as possible who have inappropriately prescribed psychotropic drugs in their therapy, following criteria for inclusion in the study will be respected when selecting study participents:
patients on outpatient treatment are in primary health care;
have at least two chronic diseases that require daily use of drugs, to use at least two prescription drugs every day;
they have been prescribed the same prescription drugs in the last three months, and that they have received dated and signed informed consent for participation and testing.
Excluding criteria:
patients under 65 years of age,
patients who have not seen a doctor in the last 6 months,
patients who died during the recruitment period,
terminally or seriously ill patients who receive health care through the home treatment service,
patients hospitalized during the research period, patients with malignant diseases who underwent chemotherapy and / or radiotherapy,
patients with incomplete documentation,
patients who are already involved in another study and patients who are treated on their own initiative in private health care institutions.
The required sample size was calculated using G* Power software9 calculation of the sample size is based on the expected difference between subjects who have IPPD, ie those who do not have risk, in the prevalence of exposure to main risk factors for PIP and PMP recorded in previous studies.10 Taking into account recently conducted studies in this field in the region of the world, 492 respondents were needed to conduct the research in terms of the minimum number of participants for this cross-sectional study.
The IBM SPSS Statistics 23 software package was used for statistical data processing. Frequencies and percentages are shown for category variables. Mean values and standard deviation are shown for continuous variables that follow the normal distribution, and the median and IQR are shown for continuous variables that do not follow the normal distribution Continuous variables were compared between groups by the Mann-Whitney-U test, while for the categorical ones the chi-square or Fisher's exact test was used. Univariate and multivariate logistic regression analysis was performed to identify significant predictors for the presence of START and STOPP criteria. Raw as well as adjusted odds ratio (OR) values are shown along with a 95% confidence interval.
Out of 515 respondents, 492 respondents agreed to participate in the study (96%). Socio-demographic characteristics of the respondents are shown in Table 1. The average age of the respondents was 71.77 ± 5.95, with 62.2% of women participating in the study. The number of diagnoses established in the study was 914. At least two psychotropic drugs were used in 240 patients (48.8%). The average number of prescribed drugs per patient was 4.37 ± 2.234.
Sociodemographic characteristics of the study population
| Characteristics of the study population | Total (n=492) n (%); mean+SD; median (IQR) |
|---|---|
| Age | 71.77±5.954; 70.0; (6.0) |
| Sex (female) | 306 (62.2%); 186; (37.8) |
| Total number of prescribed medications | 4.37±2.234; 4.0; (3.0) |
| Most common diagnoses | |
| arterial hypertension | 254 (51.6%); 238; (48.4) |
| cardiac insufficiency | 218 (44.3%); 274; (55.7) |
| depression | 106 (21.5%); 386; (78.5) |
| type 1 diabetes mellitus | 80 (16.3%); 412; (83.7) |
| benign prostatic hyperplasia | 70 (14.2%); 422; (85.8) |
| asthma | 26 (5.3%); 466; (94.7) |
| epilepsy | 18 (3.7%); 474; (96.3) |
According to the STOPP criteria, 164 PIM of psychotropic drugs were identified in 139 patients (28.2%). Nine out of 14 STOPP criteria were identified as inappropriate prescribing in this study. The most common use of benzodiazepines over 4 weeks (43.9%) and concurrent use of different groups of antidepressants (20.3%). 69.5% of PIM of psychotropic drugs were associated with four diagnoses: anxiety, depression, heart failure, and arterial hypertension. Using multivariate logistic regression, we identified independent risk factors for PIM of psychotropic drugs in our study (Table 2). Patients with more than 5 prescribed medications are at higher risk for PIM of psychotropic medications. A statistically significant higher risk for PIM was identified in patients diagnosed with depression [adjusted OR 18.13, 95% CI (3.36–97.70)], p=0.001. The total number of diseases shows a statistically significant risk for PIM of psychotropic drugs [adjusted OR 8.80, 95% CI (1.91–7.57)], p=0.001. Patients number of sGP may be a potential risk factor for PIM of psychotropic drugs [adjusted OR 1.03, 95% SI (1.00–1.05)], p=0.027. Patient's place of residence [adjusted OR 2.73, 95% SI (1.05–7.078)], p=0.038 and bad life habits [adjusted OR 0.098, 95% SI (0.017–0.560)], p=0.009 such as cigarettes usage more than one pack per day, may be risk factors for PIM of psychotropic drugs. Visits number of PSR may be a risk factor for PIM of psychotropic drugs, [adjusted OR 0.069, 95% CI (0.020–0.232)], p=0.001.
Risk factors associated with potentially inappropriate prescribing of psychotropic drugs according to STOPP/START criteria
| STOPP criteria | Raw OR 95% (CI) | Adjusted OR 95% (CI) | ||
|---|---|---|---|---|
| Risk factors | ||||
| Arterial hypertension | 2.451 (1.705–3.522) | 0.000 | 0.419 (0.141–1.245) | 0.118 |
| Cardiac insufficiency | 0.604 (0.422–0.864) | 0.006 | 1.296 (0.470–3.575) | 0.617 |
| Asthma | 2.431 (1.036–5.701) | 0.041 | 1.329 (0.231–7.644) | 0.750 |
| Depression | 93.449 (22.711–384.515) | 0.000 | 18.138 (3.367–97.704) | 0.001 |
| Number of diseases | 2.332 (1.858–2.927) | 0.000 | 3.805 (1.911–7.578) | 0.001 |
| Total number of drugs | 1.391 (1.265–1.530) | 0.000 | 1.031 (0.812–1.310) | 0.801 |
| Problems with the use of psychotropic drugs | 24.554 (5.863–102.834) | 0.000 | 43.517 (5.453–347.267) | 0.001 |
| Number of OTC sales | 2.029 (1.536–2.680) | 0.000 | 1.625 (0.892–2.959) | 0.113 |
| Number of dietary supplements | 1.538 (1.218–1.942) | 0.002 | 1.262 (0.689–2.309) | 0.451 |
| Use of antidepressants | 84.389 (20.501–347.370) | 0.000 | 52.810 (6.217–448.561) | 0.000 |
|
|
|
|
|
| Number of patient examinations in the last 12 months | 1.388 (1.255–1.535) | 0.000 | 1.307 (1.005–1.699) | 0.046 |
| Number of hospitalizations in the last 12 months | 1.540 (1.248–1.900) | 0.000 | 1.089 (0.736–1.612) | 0.669 |
| Number of performed diagnostic procedures | 1.233 (1.111–1.369) | 0.000 | 1.196 (0.930–1.539) | 0.163 |
| Years of service of the eGP | 1.138 (1.104–1.173) | 0.000 | 1.017 (0.926–1.116) | 0.728 |
| Number of patients of the sGP | 1.004 (1.003–1.006) | 0.000 | 1.003 (1.000–1.005) | 0.027 |
| Number of adverse reactions to psychotropic drugs | 6.411 (2.222–18.500) | 0.001 | 0.572 (0.029–11.313) | 0.714 |
| Age | 1.031 (1.001–1.063) | 0.045 | 0.920 (0.861–0.982) | 0.012 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
p-statistical significance
The influence of several risk factors on the probability that PIM of psychotropic drugs occurred in the study is explained by the values of coefficient between 59.6% (Cox and Snell) and 79.5% (Negelkerke), which confirm the IPPD.
According to the START criteria, 439 psychotropic PPO were identified in 270 patients (54.8%). Four out of 6 START criteria were identified as a potential failure of prescribing psychotropic drugs. The most common omissions in prescribing psychotropic drugs were related to the use of antipsychotics [adjusted OR 4.04, 95% CI (1.73–9.47)], p=0.001 and anxiolytics [adjusted OR 0.303, 95% CI (0.140–0.657)], p=0.002. Using multivariate logistic regression, we identified independent risk factors for PPO of psychotropic drugs in our study (Table 3). The number of diagnostic procedures performed in the last year may be a risk factor for PPO of psychotropic drugs [adjusted OR 1,262, 95% CI (1,036–1,537)], p = 0.002. Place of residence [rural life adjusted OR 11.33, 95% CI (2,838–45,273], p=0.001, and single life [adjusted OR 0.27, 95% CI (0.14–0.51], p=0.001, can be potential risk factors for PPO of psychotropic drugs.
Risk factors associated with potential failure to prescribe psychotropic drugs according to STOPP / START criteria
| START criteria | Raw OR 95% (CI) | Adjusted OR 95% (CI) | ||
|---|---|---|---|---|
| Risk factors | ||||
| Arrhythmia | 0.478 (0.303–0.752) | 0.001 | 0.756 (0.331–1.724) | 0.505 |
| COPD | 0.242 (0.075–0.782) | 0.018 | 0.033 (0.005–0.207) | 0.001 |
| Depression | 3.929 (2.278–6.779) | 0.000 | 1.507 (0.499–4.552) | 0.467 |
| Number of diseases | 1.277 (1.060–1.537) | 0.010 | 1.198 (0.787–1.826) | 0.400 |
| Total number of drugs | 1.227 (1.120–1.344) | 0.000 | 1.458 (1.172–1.815) | 0.001 |
| Number of OTC sales | 1.757 (1.321–2.338) | 0.000 | 1.514 (0.943–2.433) | 0.086 |
| Number of dietary supplements | 1.445 (1.136–1.838) | 0.003 | 1.328 (0.867–2.036) | 0.192 |
| Antipsychotics | 1.866 (1.167–2.982) | 0.009 | 4.049 (1.730–9.476) | 0.001 |
| Anxiolytics | 0.578 (0.349–0.849) | 0.005 | 0.303 (0.140–0.657) | 0.002 |
|
|
|
|
|
| Number of patient examinations in the last 12 months | 1.110 (1.016–1.214) | 0.021 | 0.968 (0.766–1.225) | 0.788 |
| Number of hospitalizations in the last 12 months | 1.355 (1.090–1.685) | 0.006 | 1.104 (0.820–1.486) | 0.514 |
| Number of performed diagnostic procedures | 1.174 (1.056–1.305) | 0.003 | 1.262 (1.036–1.537) | 0.021 |
|
| 0.000 | 0.953 (0.205–4.440) | 0.952 |
| Number of patients of the sGP | 1.003 (1.002–1.004) | 0.000 | 1.002 (1.000–1.004) | 0.091 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
p-statistical significance
The influence of several risk factors on the probability that PPO psychotropic drugs occurred in the research is explained by the values of coefficient between 41.6% (Cox and Snell) and 56.5% (Negelkerke), which confirm the IPPD.
The emergence of inappropriate prescribing of drugs is present today at all levels of health care in countries with different levels of socio-economic development, and the factors that affect it are monitored and examined over the years. According to results of literature search so far, this is one of the first researches that deals with the inappropriate prescribing of psychotropic drugs.
The results of the research indicate a high rate of IPPD. Excessive use of benzodiazepines for more than four weeks in patients over 65 years of age is present in Switzerland11, United Kingdom12 and Australia13. The reason for frequent use may be the problem that benzodiazepines do not have a restrictive diagnosis when prescribing, but also availability in pharmacies. In our study, the place of getting the therapy in terms of private or public pharmacies, did not show statistical significance (p>0.005). Concurrent use of antidepressants and benzodiazepines coincident with use in Asian countries14. Simultaneous application is most often due to overlapping reports at the primary and tertiary levels health care. According to STOPP criteria, antidepressants are contraindicated in patients with heart disease and dementia15,16. The use of antidepressants of different groups (SSRI/SNRI) can lead to worsening of the symptoms of the underlying diseases (dementia, heart failure). A statistically significant higher risk for PIM in patients diagnosed with depression [adjusted OR 18,13, 95% SI (3.36 – 97.70)], p = 0.001, indicates that sGP should pay more attention to this phenomenon. The number of patients of sGP, place of residence of patients proved to be risk factors for PIM outcomes of psychotropic drugs. The obtained results coincide with the results from Serbia17, which indicate that the avoidance of large poly-pharmaceuticals and the application of non - pharmacological measures can reduce the risk of PIM. Reducing the exposure of sGP to promotion material of PSR can also reduce the risk of PIM18,19.
With this research, the potential prescribing failure of psychotropic drugs is reflected in the omission of antipsychotic and anxiolytic therapy. This phenomenon can be partly explained by the abuse of benzodiazepines20 so the symptoms of these psychotic disorders are often masked by the use of benzodiazepines. A study in Serbia from 2018 showed that benzodiazepines from the group of anxiolytics are used in a high percentage in our population, which coincides with the results of our research. On the other hand, benzodiazepines, as effective and almost irreplaceable drugs in some indication areas, are exposed to a negative campaign by the pharmaceutical industry for pharmacoeconomic reasons21, which is also confirmed by this study.
The shortcomings of this research relate to the limitations of “face to face” survey due to the current COVID-19 pandemic in our country, which has affected population of patients over 65 years old the most. Prescribing therapy with sGP was done in person, but also by phone. Often, the data from the socio-demographic questionnaire regarding patient were obtained from family members/guardians who came to the outpatient clinics of the Kragujevac Medical Center mainly to extend the therapy or to receive instructions for emergency specialist-consultative services.
28.2% of patients with PIM and 54.8% of patients with PPO indicate a high rate of IPPD, which suggests that STOPP/START criteria may be useful in identifying inappropriate prescribing, improving current prescribing and dispensing of psychotropic drugs. The implementation of STOPP/START criteria in everyday practice would greatly improve the current regulatory policy. Pharmacists should also focus more on patients with over four drugs that suffer from anxiety, depression, heart failure and arterial hypertension, as these patients may be at higher risk for PIM. In addition, more frequent diagnostic procedures, adequate therapy for depression and anxiety disorders can reduce the risk of PPO psychotropic drugs. All of the above, requires greater synchronization of health care in the relationship medical specialist – sGP - pharmacist.