Evaluation of prescription pattern of psycholeptic medications at hospital discharge for patients with cardiovascular diseases in national cardiovascular disease hospital of Bangladesh

1 Department of Pharmacy, University of Chittagong, Chittagong 4331, Bangladesh. 2 Department of Pharmacy, International Islamic University Chittagong, Chittagong-4203, Bangladesh. 3 Department of Pharmaceutical Sciences, North South University, Bashundhara, Dhaka 1229, Bangladesh. 4 Queensland Brain Institute, University of Queensland, Australia. 5 Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kakuma-machi, Kanazawa 920-1192, Japan. 6 Department of Pharmaceutical Technology, University of Dhaka, Dhaka, Bangladesh.


INTRODUCTION
Cardiovascular disease (CVD) costs nearly 17.3 million people around the world every year (WHO, 2011).Among them, 80% are from low and middle-income nations.The death toll might be increased up to 23.3 million by 2030 (Mathers and Loncar, 2006).Major risk factors that may aggravate cardiovascular disease are obesity, hypertension, high cholesterol and high glucose.Additional factors including mental illness also contribute to the cardiovascular disease.Accumulating evidence suggests that depression and anxiety level are closely linked to heart disease (Chen et al., 2013;Elderon and Whooley, 2013;Nakamura et al., 2013;Thurston et al., 2013).Extremely stressful events radically raise cardiac morbidity as well as cardiac mortality.Study surveyed on adults who are residing in 17 countries in the world including Europe, Asia, and Americas.
The authors reported an association between anxiety and mood disorders among the patient with cardiovascular disease (Ormel et al., 2007).Chronic stress including the mental stress from workplace enhances the risk of coronary heart disease (CHD).Hypertension is the commonest phenomenon observed due to the extreme stress and anxiety in daily life (Hildrum et al., 2008;Player and Peterson, 2011).There exists a huge published reports to the correlation of stress with coronary artery disease (CAD) (Bunevicius et al., 2013;Roest et al., 2010), implanted cardioverter-defibrillators (ICD) (Hegel et al., 1997;Luyster et al., 2006;Sola and Bostwick, 2005) and congestive heart failure (CHF) (Kulcu et al., 2007;Serafini et al., 2010).
Sleep disorder and CVD both affect each other bidirectionally.Sleep deprivation is strongly associated with CVD since it causes hypertension.On the contrary, CVD disrupts normal sleep; e.g., patients with CHF suffers paroxysmal nocturnal dyspnea (PND), a state where shortens of breath usually occurs at night.Thus patients become awake and cannot sleep.Sleep apnea is associated with hypertension and diabetes, putting these patients at high risk of developing CVD (Herrscher et al., 2013).Moreover, sufficient sleep duration is independently connected with a lower risk of composite and fatal CVD (Hoevenaar-Blom et al., 2013).Additionally, short sleep duration increases many major cardiac risk factors such as overweight, obesity, hypertension, total cholesterol and triglycerides (Ikehara et al., 2009).

Study design
The cross-sectional study was conducted at the National Institute of Cardiovascular Diseases (NICVD) in Bangladesh.NICVD is a specialized hospital for cardiovascular disease management.It is the most renowned health care institution containing 431-beds located at Sher-e-Bangla Nagar in the capital of Bangladesh (Banglapedia, 2012).Patients choose to get admission at this hospital due to the high-quality health care at low cost.
A report demonstrated that around 900 indoor patients are admitted at NICVD while nearly 800 -900 outdoor patients received treatment every day from the emergency and outside service.Moreover, approximately 150 patients are being admitted and released per day (Uzzal, 2014).

Sampling technique
Data were collected from the patients (n=1076) who were admitted during the period from 1 st July 2012 to 30 th June 2013 at the National Institute of Cardiovascular Diseases (NICVD) in Bangladesh.NICVD hospital has 431 beds where each patient requires on an average a length of five (05) days for getting the treatment (Majumder, 2014).So, this hospital provides health service to the 31463 in-bed patients per year.Hence, this study aims to describe a population of cardiovascular prescription (n=1076) within the population (n= 31463) by surveyed prescription.
The prescription has covered the total of around 3.42% population.This sample was taken by 95% confidence level and 1.06 confidence intervals.

Variables
Demographic information of every patient: age, gender, hospital admission, discharge dates, drugs prescribed, disease identified were recorded.Disease types were assessed in fulfillment with the 10 th Revision of the International Classification of Diseases (ICD-10) (WHO, 2012b).The patient who have four or more diseases considered as polymorbid (Wawruch et al., 2008) and who were advised five or more drugs found as polypharmacy.We have followed the Anatomical Therapeutic Chemical classification (ATC) for determining drug classes (WHO, 2012a).

Participant selection procedure, inclusion criteria
We went to visit National Institute of Cardiovascular Diseases (NICVD) in Bangladesh.Our selection principles were (i) should be a patient with the cardiovascular disorder, (ii) should have minimum one cardiovascular disease, (iii) discharged from the NICVD hospital, (iv) participants who was admitted to this hospital in the bed.

Consent form and Ethical Issues
The aim, objectives, and procedures of the present study were described to the participants before collection of data.The participants were approved verbally to copy their prescription from the nearest Xerox shop.The institutional review board of North South University approved this cross-sectional study (Approval Number: 2013/NSU/HR/00123/MN334).

Statistical analysis
All the data presented as mean ± standard deviation (SD) value.Categorical variables were expressed by frequencies and percentages.All statistical tests were performed at a significance level lower than 0.05 in SPSS (version 22, IBM Software Inc, USA) and GRAPHPAD PRISM® (version 6.02; GraphPad Software Inc., San Diego, CA, USA).Moreover, we performed linear regression analysis between age and polypharmacy; age and polymorbidity; age and length of hospital stay, etc.

RESULTS
The analysis of our data showed that male (78%)and female (22%) of mean age 53.87 ± 13.12 (mean± SD)were discharged from the hospital.A minimum of 3 years and maximum 96 years old patient was discharged.Moreover, seven patients were below 20years old while 11 patients were greater than 80 years old.The average age of male (54.05±12.84)and female (53.21±14.09)CVD patients was almost equal.
Patients suffer a minimum number of one to maximum six diseases; mean disease was 2.49±1.1 (mean± SD).The average number of drugs advised by the physicians was 8.56±1.93(mean± SD).We found a minimum number of 3 drugs that were prescribed in 1 prescription while a maximum of 14 medications was prescribed in 5 prescriptions.No gender difference was found in some drugs advised between the male (8.52) and female (8.49) patients.The patient had spent a minimum of 1 to a maximum of 50 days in the hospital; average duration in the hospital 5.35±5.1 (mean± SD).
Blood pressure data showed no difference between psycholeptic and non-psycholeptic groups.In psycholeptic group, mean systolic blood pressure was 120.5±10.5 while mean diastolic pressure was 82±5.6 (mm/Hg).In the case of a non-psycholeptic group, mean systolic blood pressure was 120.5±10.7 while diastolic pressure was 83±5.9 (mm/Hg).Mean arterial pressure (MAP) did not significantly differ in between psycholeptic (94.66±7.23)and non-psycholeptic groups (96.16±11.63).Pulse rate was higher than healthy people (72) in both psycholeptic (83±11.2) and non-psycholeptic (84±12.1)groups.There were no significant differences observed for HDL, LDL, Total Cholesterol and Triglyceride level in the plasma between psycholeptic and non-psycholeptic groups.
Psycholeptics was given to the 887 patients (81.91%)out of 1083 patients.Most of the prescribed psycholeptics (98.09%) are under benzodiazepines groups (Table 2).The other suggested drugs (1.91%) belong to antidepressants, anti-vertigo, antiparkinson, nootropic and anti-epileptics.We have analyzed the ratio between the number of prescription and number of psycholeptics prescribed.The ratio between total drugs and psycholeptic drugs on an average in each prescription was 8.56:0.82.Bromazepam was the most (87.49%)advised generic for the CVD patient followed by Clonazepam (6.88%), midazolam (2.59%), alprazolam (1.13%) and flupenthixol plus melitracen combination (0.68%).Flunarizine and procyclidine were prescribed for 3 CVD patients.Cinnarizine was suggested for two patients.Escitalopram, piracetam, and carbamazepine were found only one occasion.Most of the physicians recommended benzodiazepines for 15 days (38.77%) followed by 10 (19.91%), 30 (15.72%), 7 (13.39%)days (figure 1) and 60 days (4.31%) (Table 3).Interestingly, "NM" (Nothing Mentioned) (3.38%) and "continue" (1.98%) were also found.Benzodiazepines were .suggested as solid dosage forms (tablet) and should be taken before sleep at night.We analyzed the position of psycholeptics in the prescription.Except few cases (3.5%), most benzodiazepines (96.5%) were written as the last medication on the prescription.Analysis of benzodiazepines in various age brackets showed that they were mostly advised in 41-50 and 51-60 age groups (fig.2).There were very limited instances where these medications were prescribed for below 20 years and over 80 years age bracket.Benzodiazepines were advised to the 31-40, 61-70 and 71-80 age groups in similar fashions.
From linear regression analysis we have found that the prescription data showed the great length of hospital stay in response to age (R 2 =0.004, p<0.05) (Fig 3).As age is increased patient, need more nursing time from the hospital.Also, there was a significant relation between the age and disease (R 2 =0.006, p<0.05).As age is increased patient suffer more disease (polymorbid condition).Also, some diseases are related to the number of drugs (R 2 =0.007, p<0.05).Polymorbidity is associated with polypharmacy.There was no correlation between age vs a number of drug intake; age vs duration of psycholeptics intake; the number of disease vs length of psycholeptics intake; the number of disease vs length of hospital stay; the number of drug intake vs length of hospital stay; length of psycholeptics intakes length of hospital stay., 7, 10, 14, 15, 20, 21, 30, 60, 90 days, not mentioned (111) and to continue (365).

DISCUSSION
The result of the present study showed that a significant number of generics were advised to the patient with cardiovascular disease.In most of the cases, more than eight drugs were suggested.Highest prescribed psycholeptic class and molecules were Benzodiazepine and Bromazepam.Psycholeptics were advised for the duration of 15, 10, 30 and seven days.Patient without psycholeptic medication had an extended length of hospital stay than the psycholeptic medication.Age was associated with the duration of hospital stay and polymorbidity.Also, polymorbidity is associated with the polypharmacy.There was no association between age and polypharmacy.Duration of psycholeptics intake was not related to neither age nor polymorbidity nor length of hospital stay.
The treatment of cardiovascular disease may depend on multiple factors.Prescribing one molecule is not enough for the management and treatment of this kind of chronic illness.Various factors should consider while writing the prescriptions; for example, high blood pressure, high cholesterol level, water volume, coagulating factors, nutrition, mental health, and rest.
Our present study demonstrated that most of the patients are advised to take one psycholeptic, and that is a benzodiazepine (e.g., bromazepam).The age range of prescribing benzodiazepine was 31 to 80 years.There were several instances where benzodiazepines were prescribed to below 30 and over 80 years.Probably benzodiazepine offers very limited therapeutic effect and more prone to show side effects in this stage of life (Windle et al., 2007).Additionally, these people take other cardiac medications.So, advising a large number of drugs will create a perilous situation where patients would be more susceptible to drug interaction, polypharmacy and side effects.The analysis of prescription data showed that blood pressure, lipid profile, blood glucose levels (RBS) and serum creatinine was not varied in between psycholeptic medication presence or absence in the prescription.Lipid profiles of both psycholeptic and nonpsycholeptic medication containing prescriptions were in the same level.The present finding is consistent with the previous report (Khan and Majumder, 2011).We observed a high pulse rate in both groups of cardiovascular patients than healthy people.The result of the current study demonstrated that CVD patients with psycholeptics had spent shorter length in the hospital.This finding can be interpreted as; patients spending long duration in the hospital get received more nursing care and more time to restore their normal body function.We found an association of age with polymorbidity, age, and length of hospital stay, polymorbidity and polypharmacy.Interestingly, the length of suggested psychiatric medication treatment was not associated with either age nor polymorbidity or length in the hospital stay.Our result showed that middle-aged people are mostly suffering cardiovascular disease.It may happen since CVD risk factors such as smoking, sedentary lifestyle, cholesterol, obesity, uncontrolled food habits gradually facilitates to develop cardiac disease.These people are not being noticed until they have the first incident like first heart attack, hypertension, stroke, angina pain, etc.We found that males are more prone to cardiac disease than female.This may be explained by the association of cardiac risk factors including smoking and male hormones.In developed and developing countries male was reported to smoke more than their female counterpart (Mackay and Amos, 2003).The most important point to emerge from our present study is the common prescribing habit of benzodiazepines.Bromazepam was the mostly advised generic for the patient followed by clonazepam, midazolam, and alprazolam.The appearance of benzodiazepines in almost every prescription was observed in the age range between 31 to 70 years indicating the requirement of sleep and rest for discharged patients with cardiovascular diseases.A review study assesses the relationship between duration of sleep and morbidity and mortality from coronary heart disease (CHD), stroke, and total cardiovascular disease.The study revealed that the duration of sleep is predictors, or markers, of cardiovascular outcomes (Cappuccio et al., 2011b).In another study, the role of benzodiazepines in CHD and other CVD were investigated (Williams Jr, 1990).The authors suggest that benzodiazepines might control angina and silent ischemia and another cardiac disease by blunting the responses arise from stress hormones.Benzodiazepine (alprazolam) reduces the duration of silent ischemia by 70% in coronary patients (Shell and Swan, 1986).The therapeutic benefit of alprazolam was explained as they help to reduce stress induced by adrenaline, noradrenalin, and corticosteroids.Benzodiazepine has been prescribed for the postmyocardial infarction for a long time (Strik et al., 2001).Most of the studies conclude that benzodiazepines are beneficial since they reduce the level of anxiety, stress hormone response and help people sleep for a long duration (Vogel et al., 1984;Williams, 1990).Insufficient sleep is an independent risk factor for CVD (Cappuccio et al., 2011a;Hoevenaar-Blom et al., 2011).Reduced sleep duration is associated with composite and fatal CVD since they cause higher risk of obesity, overweight, high total cholesterol, high HbA1c (glycosylated hemoglobin), triglycerides and high blood pressure.Also, inadequate sleep duration causes sustained low-grade inflammation and increased leptin level in the blood which accelerates appetite and little energy expenditure.These two factors (higher appetite and less energy expenditure) facilitate to develop obesity and higher cholesterol and glycemic level.Importantly, sufficient sleep reduces cardiovascular morbidity and mortality (Hoevenaar-Blom et al., 2013;Ikehara et al., 2009).
Recently a "Morgen study" was conducted in the Netherlands by Hoevenaar-Blom and co-workers.The authors reported that insufficient sleep is associated with the low level of inflammation in turn appetite enhance and energy expenditure reduces leads to higher glycemic level and obesity.Interestingly, another study report that both short and long duration of sleep is associated with the cardiac mortality (Ikehara et al., 2009).The advising of at least one psycholeptic drugs is observed as a common habit of a cardiologist.In this circumstance, cardiologist should consider several limitations of psycholeptics in CVD patients.Psychotropic drug has lethal cardiac side effects (Longo and Johnson, 2000).Benzodiazepines showed a variety of side effects including slowed psychomotor performance, ataxia, hip fracture and daytime sedation (Gleason et al., 1998).A cardiologist should remember some of the important cardiac factors in the safer selection of psychotropic drugs for the vulnerable patient in their daily clinical practice (O'Brien and Oyebode, 2003).Finally, a cardiologist should remember both positive and negative therapeutic benefits of psychotropic medicines in the cardiovascular system and follow the standard guidance for the practical management of psychotropic symptom in CVD patients (Mackin, 2008).To our knowledge, the findings of our present study are novel in many respects.Firstly; we report the prescribing pattern of psycholeptics to the discharged CVD patients in the hospital.The adherence and the necessity of benzodiazepines are discussed.Secondly; we have analyzed the duration of psycholeptics for the management of cardiovascular disease.Thirdly; middle age group is the primary target patient where cardiologist suggests benzodiazepine.There were several limitations of the present study.We analyzed around 1000 patients and included only one hospital.However, this hospital is the most modern cardiovascular hospital in Bangladesh.But we thought that, surveying only NICVD hospital is enough to investigate our current hypothesis.Around 800-900 CVD outdoor patients come in every day to this hospital from the outside of the Dhaka and rural areas.
There are limited resources and facilities to manage cardiovascular disease at the hospital that is located outside of the Dhaka.Physicians recommend their CVD patients to the NICVD.Moreover, managing CVD disease is costly except treating at NICVD.Due to the limited statistical knowledge, we conducted several tests on our data.Since we have collected data from the prescription of discharged patient, therefore we failed to measure sleep duration of the patient.Monitoring of sleep duration could be investigated in the future study.Also, prospective study will include big sample size with more variables from a large number of hospitals.Finally, we were not able to follow up the patient's biochemical parameters such as lipid profile, blood pressure.This was important to measure the outcome of psycholeptics in the patient with a cardiovascular disorder.

CONCLUSION
The aim of the present study was to investigate the prescribing pattern of the psycholeptics by the cardiologist in the hospital discharged patients with cardiovascular disease.Among the psycholeptics bromazepam was the most frequent prescribing drug molecule.The literature review showed that the addition of benzodiazepine with the cardiovascular medications could bring beneficial effect by providing sufficient sleep which in turn reduces anxiety, stress hormone response, and stress induced lowgrade inflammation.
Financial support and sponsorship: Nil.

Fig. 2 :
Fig. 2: Psycholeptics in various age brackets.The horizontal axis represents age groups in 10 years age brackets.

Fig. 3 :
Fig. 3: Psycholeptics in various age brackets.The horizontal axis represents age groups in 10 years age brackets.

Table 1 :
Characteristics of CVD patients with and without psycholeptics (n=1083).