Abstract
Background:
Antipsychotic drugs have the potential to cause QT-interval prolongation (QTIP), which may lead to Torsades de Pointes and sudden cardiac death. Thus, it is important to know about the incidence and risk factors for QTIP.
Aim:
The primary objective of the study was to find out the incidence of QTIP due to the use of antipsychotic drugs in patients with schizophrenia and acute psychosis after two weeks of drug use. The secondary objective was to find the risk factors for QTIP.
Materials and Methods:
The study included 160 consenting patients, aged ≥18 years, either sex, diagnosed with schizophrenia or acute psychosis, who had not taken oral/water-based injectable antipsychotics during the last 15 days or any long-acting antipsychotic injectable during the previous 6 months. Patients with other psychiatric disorders, substance use other than nicotine/caffeine, low serum levels of potassium/calcium/magnesium, congenital long QT syndrome, history of cardiac conditions, or those taking drugs with high risk to cause QTIP were excluded. ECG was recorded before starting treatment and after at least 2 weeks of treatment with antipsychotic drugs. Corrected QT interval (QTc) was calculated using Fridericia’s and Bazett’s formulae. QTc >450 ms in males and >460 ms in females was considered prolonged.
Results:
The mean age of study participants was 35.88 years (SD: 13.32), and 88 (55%) were males; 138 (86.3%) suffered from schizophrenia. Seventy-one (44.4%) and 74 (46.3%) received risperidone and olanzapine, respectively. Twelve (7.5%) developed QTIP (QTc calculated using Fridericia’s formula). Twenty-five (15.6%) were seen to develop QTIP (QTc calculated using Bazett’s formula). Additional risk factors for QTIP could not be identified in the study sample.
Conclusion:
QTIP is present in a reasonable number of participants. Careful screening and assessment for risk factors that could increase the chances of QTIP must be done regularly in patients getting antipsychotic drugs.
Keywords: Acute psychosis, antipsychotic drugs, patient safety, QT interval prolongation, schizophrenia
Schizophrenia and acute and transient psychotic disorders (ATPD, commonly known as “acute psychosis”) are two frequently encountered conditions in psychiatry clinics. Both conditions generally start in early adulthood and are characterized by hallucinations and delusions and lead to a significant impairment in the daily functioning of the affected patients. While schizophrenia is often a chronic condition with frequent relapses and needs long-term treatment, ATPD has an acute onset followed by short duration and quick resolution of symptoms, leading to rapid recovery.[1] However, patients with ATPD also require drug treatment for many months and, sometimes, for a longer duration if they experience a recurrence of the condition.[2]
The mainstay of treatment for both conditions is antipsychotic drugs. Antipsychotic drugs cause several adverse reactions. Among them, QT interval prolongation (QTIP) in the electrocardiogram (ECG) of a patient is an important concern.[3,4] In an ECG record, QT interval is measured from the beginning of the QRS complex to the end of the T wave. QT interval varies with heart rate and hence needs to be corrected for the same (QTc). The correction could be done using the popular Bazett’s formula (QTcB = QT/(RR)1/2) or a more accurate Fridericia’s formula (QTcF = QT/(RR)1/3).[3,4] QTIP is defined as QTc more than 460 ms among women and 450 ms among men.[5] QTIP could lead to Torsades de Pointes (TdP) and result in sudden cardiac death among patients who do not have any pre-existing structural cardiac problems.[3,4] The risk of dying from cardiovascular disease is particularly elevated among individuals with schizophrenia.[6] Individuals with chronic schizophrenia are more likely to have weight gain, obesity, dyslipidemia, comorbid medical conditions, concurrent medication use, poor dietary habits, and sedentary lifestyles than first-episode schizophrenia patients. These circumstances raise the possibility of the presence of additional risk factors for QTIP.[7] Additionally, the presence of multiple psychiatric and medical conditions and tolerance to approved therapeutic doses make polypharmacy and the use of high doses of drugs unavoidable in this group.[8] Patients with schizophrenia frequently overlook cardiovascular signs such as palpitations, chest discomfort, or pre-syncope. In this light, improving therapeutic outcomes for this population may involve the early identification of cardiovascular disease by objective screening methods.[9] ECG is a readily available, non-invasive, and affordable tool to determine the risk of cardiac events, especially those related to heart rhythm problems. Thus, knowledge about the incidence and prevalence of antipsychotic drug-induced QTIP and putting appropriate measures in place to ensure the safety of the patients is a must.
The prevalence of QTIP due to antipsychotic drugs varies from 1.1% to 36.5% among published studies.[7,10,11,12,13,14,15,16,17,18] Most of the published studies have taken data for inpatients with varied diagnoses and treatments. A good number of participants in these studies were getting more than one psychotropic concurrently, including antidepressants and mood stabilizers.[7,10,11,12,17] Thus, the results of these studies do not give a clear picture regarding QTIP due to antipsychotics. Hence, there is a need for a prospective study where patients are assessed before and after exposure to antipsychotic drugs. In addition, the study participants need to be screened for common risk factors that could lead to QTIP and to exclude such participants. This would help to attribute the observed adverse reaction only to the drug. The primary objective of this study was to find out the incidence of QTIP due to the use of antipsychotic drugs in patients with schizophrenia and acute psychosis. The secondary objective was to find out the risk factors associated with QTIP.
MATERIAL AND METHODS
Setting and ethical considerations
This prospective study was carried out at the Department of Psychiatry, All India Institute of Medical Sciences, Raipur, from November 2022 to June 2023. It is being reported using STROBE guidelines.[19] The study was approved by the institutional ethics committee (IEC proposal no. AIIMSRPR/IEC/2022/1215, letter dated Nov 2, 2022). Adult participants (aged 18 years and above) were included in this study after taking written informed consent.
Participants
The study included consenting patients aged ≥18 years, either sex, diagnosed with schizophrenia or ATPD according to the International Classification of Diseases and Related Health Problems, 10th revision, Classification of Mental and Behavioral Disorders- Diagnostic Criteria for Research (ICD-10-DCR), who had not taken oral/water-based injectable antipsychotics during the last 15 days or any long-acting antipsychotic injectable during previous 6 months. They were excluded if they had psychiatric comorbidities (organic mental disorder or mental retardation), substance dependence (other than caffeine or nicotine), presence of hypokalemia, hypocalcemia, hypomagnesemia, hypothermia, Congenital Long QT Syndrome, diagnosis of or history of myocardial infarction or cardiomyopathy, or if they were taking any drugs during last 15 days that have known or possible risk to cause QTIP, according to the list available at CredibleMeds.org.[20]
Procedure
Prospective participants who fulfilled the inclusion and exclusion criteria were included if they were willing to participate and provided written informed consent. Their details were noted, and rating scales were applied (discussed below). ECG (Schiller AT-II, Florida, US) was recorded at the baseline and after at least 2 weeks of the treatment. The patients received treatment as per their clinical needs and the advice of the treating psychiatrist. Their clinical status, drug-treatment details, and adherence were noted at the follow-up visit. QTc was calculated primarily using Fridericia’s formula. Additionally, Bazett’s formula was also used to calculate QTc. All the participants were assessed by a trainee pursuing residency in Psychiatry, qualified psychiatrists, and a cardiologist.
Assessment/Questionnaire
Using a specially designed proforma, the investigators recorded participants’ sociodemographic and clinical details. Socioeconomic status was assessed using the Modified Kuppuswamy Scale.[21] The patients were diagnosed using ICD-10-DCR. The severity of illness was assessed using the 18-item Brief Psychiatric Rating Scale (BPRS).[22] It is a popular and quick scale that assesses both significant psychotic and nonpsychotic symptoms in people with severe psychiatric disorders, including schizophrenia. During their follow-up visit (after at least 2 weeks of drug use), the patients were assessed for adherence to treatment using the Brief Adherence Rating Scale (BARS).[23] The BARS is a valuable tool for assessing treatment adherence due to its brevity, objectivity, sensitivity, predictive validity, and ease of integration into clinical practice.
Statistical analysis
Continuous variables were described using mean and standard deviation (SD), and nominal variables were described using frequencies and percentages. An independent samples t-test was used to compare the means of variables among patients with and without QTIP. The nominal variables were compared between the two groups using the Chi-square test, Fisher’s exact test, or Fisher-Freeman-Halton test (as applicable). All analyses were conducted using Statistical Package for Social Sciences, version 29.0.0.0 (IBM Corp. Armonk, USA).
Sample size calculation
In an earlier study, 11.6% of the participants had QTIP.[17] Based on this prevalence figure, with a 5% probability of type 1 error and 5% absolute error, the sample size was calculated to be 157.
RESULTS
Among the 183 prospective participants approached, 174 were enrolled. Fourteen patients did not come for follow-up. Finally, 160 patients were included in the study. The process of recruitment is depicted in Figure 1.
Figure 1.
Recruitment of participants for the study
The mean age of the patients in the study was 35.88 years (SD: 13.32), ranging between 18 and 75 years; 88 participants (55%) were males, and 92 participants (57.5%) were from rural areas. More sociodemographic details of the participants are presented in Table 1.
Table 1.
Sociodemographic characteristics of the participants (n=160)
| Variables | Mean/n (SD/%) | |
|---|---|---|
| Age (years) | 35.88 (13.32) | |
| Sex | Male | 88 (55.0) |
| Female | 72 (45.0) | |
| Residential area | Rural | 92 (57.5) |
| Urban | 68 (42.5) | |
| Occupation | Unemployed | 123 (76.9) |
| Elementary Occupation | 6 (3.8) | |
| Plant & Machine Operators and Assemblers | 1 (0.6) | |
| Craft & Related Trade Workers | 3 (1.9) | |
| Skilled Agricultural & Fishery Workers | 12 (7.5) | |
| Skilled Workers and Shop & Market Sales Workers | 10 (6.3) | |
| Professionals | 5 (3.1) | |
| Education | Illiterate | 14 (8.8) |
| Primary school certificate | 24 (15.0) | |
| Middle school certificate | 46 (28.8) | |
| High school certificate | 40 (25.0) | |
| Intermediate or diploma | 9 (5.6) | |
| Graduate | 25 (15.6) | |
| Profession or Honors | 2 (1.3) | |
| Monthly income of the participants (₹) | 2359.38 (6793.49) | |
| Monthly income of family (₹) | 21315.63 (39605.63) | |
| Socioeconomic class* | Lower | 1 (0.6) |
| Upper lower | 106 (66.3) | |
| Lower middle | 24 (15.0) | |
| Upper middle | 27 (16.9) | |
| Upper | 2 (1.3) | |
| Marital status | Married | 92 (57.5) |
| Never married | 56 (35.0) | |
| Divorced/Separated | 8 (5.0) | |
| Widow/Widower | 4 (2.5) | |
| Type of family | Nuclear | 146 (91.3) |
| Joint | 14 (8.8) | |
| Religion | Hinduism | 152 (95.0) |
| Islam | 4 (2.5) | |
| Christianity | 2 (1.3) | |
| Sikhism | 2 (1.3) | |
SD: Standard deviation. *According to Modified Kuppuswamy’s scale for socioeconomic status for the year 2022
After the recruitment of the participants, their anthropometric and vital parameters were measured [Table 2]. The findings were within normal limits.
Table 2.
Anthropometric measurement and vital parameters of the participants (n=160)
| Variables | Mean (SD) |
|---|---|
| Height (cm) | 158.49 (10.70) |
| Weight (kg) | 53.91 (10.26) |
| BMI (kg/m2) | 21.42 (4.48) |
| Waist circumference (cm) | 80.84 (9.49) |
| Hip circumference (cm) | 88.11 (9.97) |
| Waist-hip ratio | 0.92 (0.04) |
| Pulse rate (beats/min) | 80.99 (13.65) |
| Systolic BP (mmHg) | 113.94 (4.85) |
| Diastolic BP (mmHg) | 74.28 (3.70) |
SD: Standard deviation
Among the 160 patients, the majority suffered from schizophrenia (138, 86.3%), and the rest (22, 13.8%) had acute psychosis. Only three patients (1.9%) had hypertension. Eighty-two (51.3%) used to consume tobacco. The mean total duration of the disorder was 108.59 weeks (SD: 123.36), ranging from 2 weeks to 720 weeks. The mean total duration of schizophrenia and acute psychosis was 125.55 weeks (SD: 124.82) and 2.82 weeks (SD: 0.39), respectively. The mean duration of the current episode was 46.56 weeks (SD: 57.01), ranging from 2 weeks to 288 weeks.
The mean score of patients on BPRS was 46.58 (SD: 3.84) at baseline and 35.07 (SD: 3.57) at follow-up. Regarding treatment profile, the majority received olanzapine (74, 46.3%) and risperidone (71, 44.4%). A few received aripiprazole (10, 6.3%), quetiapine (3, 1.9%), clozapine (1, 0.6%), and cariprazine (1, 0.6%). The dose of antipsychotic drugs at the time of follow-up visit is shown in Table 3. Fifty-two patients (32.5%) received trihexyphenidyl. Benzodiazepines were given to 144 (90%) patients. Only nine patients (5.6%) received proton pump inhibitors, and only three (1.9%) received antihypertensives. The findings of BARS suggest that the patients adhered to the prescribed treatment.
Table 3.
Dose of antipsychotic drugs at the follow-up visit
| Variables | Mean (SD) (mg) |
|---|---|
| Risperidone | 3.08 (1.08) |
| Olanzapine | 10.88 (2.50) |
| Aripiprazole | 11.50 (2.42) |
| Quetiapine | 200 (173.21) |
| Clozapine | 112.5 |
| Cariprazine | 3 |
SD: Standard deviation
When QTc was calculated using Fridericia’s formula, the mean QTc at baseline and follow-up was 382.84 ms (SD: 23.61) and 409.04 ms (SD: 27.85), respectively. The increase in the mean value of QTc following treatment was statistically significant (P value < 0.001). QTIP was seen in 12 (7.5%) patients. Among those receiving risperidone, six (8.45%) developed QTIP. Six (8.11%) of those getting olanzapine developed QTIP. None of the patients who received aripiprazole, quetiapine, clozapine, or cariprazine had QTIP.
On using Bazett’s formula to calculate QTc, the mean value at baseline and follow-up was 399.08 (SD: 27.81) and 430.73 (SD: 31.59), respectively. The increase in the mean value of QTc after the use of antipsychotic drugs was statistically significant (P value < 0.001). Twenty-five (15.6%) study participants were found to have QTIP. Among 71 patients who received risperidone, 10 (14.08%) had developed QTIP. Thirteen (17.57%) out of 74 patients who were on olanzapine developed QTIP. Only one (10%) among the 10 who received aripiprazole had QTIP. One patient was on clozapine and developed QTIP. None of the patients receiving quetiapine and cariprazine had QTIP.
Means of age, anthropometric and vital parameters, total duration of the disorder, duration of the current episode, number of episodes in the past, and total number of medicines received did not differ significantly among the participants with and without QTIP. There was no difference in the distribution of sex, primary psychiatric diagnosis, hypertension, use of tobacco, or use of trihexyphenidyl, benzodiazepines, proton pump inhibitors, and antihypertensive drugs among participants with and without QTIP.
DISCUSSION
Existing literature points towards a possible relationship between antipsychotic use and QTIP. In this study, 7.5% of participants developed QTIP (QTc calculated using Fridericia’s formula). The mean value of QTc also showed a statistically significant increase after treatment. Table 4 provides a quick summary of some of the studies on QTIP due to psychotropic drugs, published in the last 10 years. As mentioned earlier, many of the studies have included patients who had diagnoses other than schizophrenia or ATPD and were getting multiple psychotropics. All the studies discussed in Table 4 are cross-sectional.
Table 4.
Summary of studies on QTIP due to psychotropic drugs
| Authors (country) | Type of study Setting for recruitment of patients | Inclusion criteria/patient characteristics | Formula used for QTc calculation | Sample size Prevalence of QTIP | Risk factors identified |
|---|---|---|---|---|---|
| Ali et al., 2020 (Pakistan)[10] | Cross-sectional | Patients receiving psychotropic medications for≥7 days, aged ≥18 years, and of either gender | Fridericia’s | 405 | Male sex |
| Indoor | 5.7% | ||||
| Berling et al., 2018 (Australia)[12] | Retrospective review of records | Mental health inpatient with availability of ECG record | QT nomogram | 50 | Getting one or more drugs known to cause QTIP |
| Mental health inpatient records | 8% | ||||
| Cao et al., 2021 (China)[7] | Case-control study | Hospitalized patients with chronic schizophrenia | Bazett’s | 436 patients and 291 controls | Older age, antipsychotic polypharmacy, higher PANSS total score, and lower LDL |
| Indoor | 8.26% | ||||
| Ansermot et al., 2019 (Switzerland)[11] | Retrospective, cross-sectional | Patients aged 18–65 years with at least one valid ECG, performed at admission or during the stay | Automatic QT interval measurement by software integrated with the ECG machine | 600 | Female sex, age, triglyceride level, and use of drugs that cause QTIP |
| Inpatient records | 7.6% | ||||
| Elliott et al., 2018 (Denmark)[13] | Cross-sectional | Outpatients with chronic schizophrenia | Fridericia’s | 65 | Female sex, polypharmacy |
| Outpatient | 6% | ||||
| Nosè et al., 2016 (Italy)[14] | Cross-sectional | Patients receiving psychotropic drugs on the day of ECG | Bazett’s | 2411 | Female sex, age, heart rate, alcohol and/or substance abuse, cardiovascular diseases and cardiovascular drug treatment, and drug overdose |
| Indoor and outdoor | 7.75% for men and 9.63% for women | ||||
| Park et al., 2020 (15 Asian countries)[15] | Cross-sectional | Patients with schizophrenia getting antipsychotic drugs | Bazett’s | 2553 | Use of amisulpride or clozapine, and presence of rigidity or hypercholesterolemia |
| Indoor and outdoor | 1.1% | ||||
| Salvati et al., 2022 (Italy)[17] | Cross-sectional | Inpatient psychiatry unit patients who received antipsychotics | Bazett’s | 597 | Female sex, age>65 years, decreased heart rate, high blood pressure, low potassium, hemoglobin, clozapine, clotiapine |
| Indoor | 11.6% | ||||
| Polcwiartek et al., 2020 (Denmark)[16] | Register-based case-control | Patients with schizophrenia | Friedricia’s | 4486 patients and 22430 controls | Prescription of antipsychotics, antipsychotic polypharmacy, and use of benzodiazepines |
| Indoor and outdoor | 3.4% | ||||
| Sankaranarayanan et al., 2024 (Australia)[18] | Cross-sectional | Patients with treatment-resistant schizophrenia getting clozapine | Not mentioned | 104 | Tachycardia and higher clozapine level |
| Outpatient | 36.5% |
QTIP: QT interval prolongation, QTc: QT interval corrected for heart rate, PANSS: Positive and negative syndrome scale for schizophrenia, LDL: Low-density lipoprotein cholesterol
It seems that a multi-national study where participants from 15 Asian countries were included has reported the lowest prevalence of QTIP (1.1%).[15] The highest prevalence (36.5%) of QTIP has been reported in a study from Australia.[18] It is notable that all the participants in this study were suffering from treatment-resistant schizophrenia and were getting clozapine. Other studies have reported the prevalence of QTIP in the range of around 5%–11%. Findings of the current study fall in the same bracket.
It must be noted that the diagnostic and treatment profiles of patients included in this study differ from those assessed in many of the previous studies. In the current study, patients with schizophrenia and ATPD were included, who were getting antipsychotic drugs only, and none of them were receiving more than one antipsychotic drug. This was expected as we recruited patients who were coming for treatment for the first time or those who were off drugs for a defined period. In the long term, many patients may require more than one psychotropic drug, if they have inadequate response or develop other psychiatric comorbidities. Polypharmacy is believed to increase the risk for QTIP.[3,4]
There are at least two recently published studies from India, which are prospective in nature.[24,25] In one study, 78 patients were seen before, and after 4 weeks of treatment with antipsychotic drugs (olanzapine, risperidone, and aripiprazole). QTc was calculated using the Framingham heart formula. None of the participants experienced QTIP.[24] In another prospective study, 135 drug-free patients coming to psychiatry outpatient were included, irrespective of diagnosis.[25] They were assessed at baseline, and after 2 and 4 weeks of treatment, respectively. Here too, none of the participants developed QTIP. It is notable that more than half of the patients were suffering from depression and anxiety disorders and were getting selective serotonin reuptake inhibitors, which are less likely to cause QTIP.
The figure for incidence/prevalence of QTIP reported in published literature also depends upon the method/formula used to estimate QTc. The studies that have used the popular Bazett’s formula for measuring QTc have reported higher incidence/prevalence of QTIP.[14,17] Ali et al. (2020) reported the prevalence of QTIP as 5.7% and 27.2% when using Fridericia’s and Bazett’s formula, respectively.[10] In the current study, the incidence of QTIP gets nearly doubled if QTc is calculated using Bazett’s formula. Notably, Bazett’s formula is not considered accurate as it tends to overestimate QTc for a heart rate above 60 per minute and underestimate QTc for a heart rate less than 60 per minute. Fridericia’s formula is preferred as the outcome is not affected by extremes of heart rate.[3]
In the current study, no risk factors for development of QTIP could be identified. It was planned to compare the sociodemographic, clinical, and treatment-related variables among those with and without QTIP, to identify the risk factors for the same. Previous studies have found various risk factors for QTIP due to psychotropic drugs [Table 4]. Common findings include old age, polypharmacy, use of drugs such as clozapine and clotiapine, and concomitant use of other drugs that are known to cause QTIP, raised heart rate, dyselectrolytemia, and dyslipidemia.[7,11,12,13,14,15,16,17,18] There are conflicting findings regarding sex being a risk factor for QTIP. An authoritative review lists female sex as a risk factor for TdP.[3] It seems that the sample size of this study was adequately powered for the primary objective only, that is, the assessment of the incidence of QTIP due to antipsychotic drugs. It was probably not large enough to achieve the secondary objective, that is, the evaluation of risk factors for QTIP due to antipsychotic drugs.
The findings of this study indicate that there is a risk for development of QTIP in patients getting antipsychotic drugs. Though none of the participants in this study had QTc >500 ms, (threshold for significantly increased chances to develop TdP), there is a need for treating psychiatrists to be aware of issues around this adverse effect. British Heart Rhythm Society recommends conducting ECG for all patients getting antipsychotic drugs at admission, discharge, and once every year.[26] Those with additional risk factors shall need more attention, frequent assessments, and maybe examination by a specialist (physician/cardiologist).
Limitations
A single-site study may limit the generalizability of the findings to other settings or populations. The side effects of any drug vary among populations with different ethnic origins. Representation from more sites is desirable. No patient received thioridazine, haloperidol, chlorpromazine, pimozide, or ziprasidone, which have a higher risk of QTc prolongation. However, the use of these drugs is limited in current clinical practice, and their under-representation might not impact the utility of the findings of this study. The majority of the patients in this study received olanzapine or risperidone, which is attributable to the pattern of prescription at our center. Number of patients receiving other antipsychotic drugs was very small. To overcome this problem in future studies, it is suggested to have a larger sample size recruited through systematic sampling so that a balanced representation of all the antipsychotic drugs being used could be achieved. The study observed patients for a short time only (2 weeks). While this is believed to be sufficient to look for the manifestation of QTIP, there is a possibility that the picture may change over time. Thus, predicting QTIP in the long term is not possible.
The design of this study excluded people with high risk of QTIP, that is, those with congenital long QT syndrome, pre-existing cardiac conditions, hypothermia, low levels of potassium/calcium/magnesium, or those getting other drugs with high risk for QTIP. Only a few elderly participants were included. There were only three patients with hypertension. Thus, the contribution of multiple risk factors and concomitant medications to QTIP in those who are also getting antipsychotic drugs could not be assessed.
CONCLUSION
A reasonable number of young and physically healthy patients who did not have other risk factors were seen to develop QTIP due to antipsychotic drugs. The findings vary across studies done within our country and outside. The explanation for this finding is not known. There could be a variation in the genetic, pharmacokinetic, or pharmacodynamic profiles of the participants recruited in different studies, which may explain differences in sensitivity toward certain adverse effects of drugs. QTIP and TdP may not be common among the general and psychiatric population, but there is a risk. Even if the risk is modest in absolute terms, it could be successfully minimized by appropriate risk stratification. Future studies with large sample sizes, pan-India representation, and long-term follow-up are recommended.
Authors’ contributions
Anirban Saha: Conceptualization, data collection, methodology, writing (original draft). Ajay Kumar: Conceptualization, interpretation and analysis, writing (review and editing). Satyajit Singh: Conceptualization, interpretation and analysis, writing (review and editing). Aditya Somani: Conceptualization, methodology, interpretation and analysis, writing (review and editing).
Ethics approval
Institutional Ethics Committee, All India Institute of Medical Sciences, Raipur (email: iec@aiimsraipur.edu.in), IEC proposal no. AIIMSRPR/IEC/2022/1215, vide letter dated 02nd Nov., 2022.
Data availability statement
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Patients’ consent
The participants were included in this study after taking written informed consent.
Conflicts of interest
There are no conflicts of interest.
Acknowledgments
The authors acknowledge that their Institute waived off charges of the investigations carried out for the purpose of this research project.
Funding Statement
Nil.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author, upon reasonable request.