Investigation of Effectiveness of Clozapine

Investigation of Effectiveness of clozapineCatarina Scott-BeaulieuAbstract (250) Background clozapine is an atypical antipsychotic used for discussion-resistant dementia praecox. It is military issueive in treating the positivistic and interdict symptoms of schizophrenia with a curbd meet of extrapyramidal billet personal effects comp argond with opposite typical antipsychotics. clozapine is known to give birth cardiac case effects including, but non limited to, myocardial inflammation and cardiomyopathy. Approximately 75% of instances, of clozapine-induced myocarditis, descend within the runner month of titration, highlighting the need for observe.Objectives To treasure the tip to which the observe guidelines for myocarditis, at a capital of the United Kingdom mental health send, argon creation fol embarrasseded. system Patients who were registered with ZTAS from June 2014 to October 2016, at the trust, were identified. Data was viewed ground on the e xamine legal document created from the guidelines. Using the persevering n angiotensin-converting enzymes and laboratory selective information, found utilize the trusts operating systems, data was collected and stored in the inspect tool.Key findings The supervise standards were met for full pipeline view in the week antecedent to de bulls eye and in week 3. No an separate(prenominal) standards were met.ConclusionIntroduction (500- one hundred0)Clozapine is the starting time exercise atypical antipsychotic created and is used in give-and-take-resistant schizophrenia, which is defined as a lack of or an inadequate response to at least two antipsychotics.1 It is a dibenzodiazepine derivative antipsychotic and interferes with dopamine binding with a strong affinity for D4-dopaminergic receptors and 5-HT2a serotonergic receptor affinity 2, in addition it has an anticholinergic drug effect and antagonizes histaminergic receptors. 3, 4Clozapine is useful in treating both th e positive and shun symptoms of schizophrenia 4 and is slight likely to cause extrapyramidal side effects when comp ard to set-backly generation typical antipsychotics much(prenominal) as haloperidol5, 6. It has as well been shown to soft touchifi butttly shrivel up the suicidal behaviors in schizophrenic patients 1, 7.However, it is not used as a first line sermon due to its extensive side effect profile, closely recognized macrocosm agranulocytosis which occurs in approximately 1% of patients in the first year of treatment 8, 9, explaining the need for fixedness, mandatory hematologic tests for the duration of clozapine treatment. Other side effects include pyrexia 4, metabolic effects and seizures.4, 6, 10Agranulocytosis, however, is not the besides potentially fatal side effect of clozapine use. at that place is an increasing number of clozapine-related cardiac complaints account in the literature, momenting in cardiac effects from clozapine treatment having cat ch to a greater extent recognized over the past few days. 5, 7 Whilst tachycardia is a car park side effect it can be indicative of other, potentially more serious, cardiac effects such(prenominal) as cardiomyopathy and myocarditis. 9Myocarditis is an instigative process of the myocardium, which is often of viral aetiology but may also include bacterial, fungal and drug-induced.11, 12 The condition presents with a wide range of symptoms such as chest discomfort, flu-like symptoms and abnormal vital signs 9 and most are non-specific.2 inform cases of clozapine-induced myocarditis range from 0.15% to 1.2%,5, 8, 13-15 with the highest incidence being reported in Australia, 1%. 16 snip to onset varies, but over 75% of cases occur within the first month of treatment. 12, 16-18Endomyocardial biopsy was the gold standard for diagnosing myocarditis, but the procedure has only limited sensibility and specificity. It was by proposed Ronaldson et al.18 in 2011 that combining C-reactive p rotein (CRP) and troponin T/I would give a sensitivity for clozapine-induced myocarditis of 100%. This is a less invasive method of diagnosis, with a higher specificity and sensitivity for myocarditis and has light-emitting diode to the current guidelines that are in place for the observe of clozapine treatment.Whilst clozapine-induced myocarditis is still rare, the need for consistent supervise within the first month of treatment is needed to ensure any possible cases are spy early, allowing for prompt treatment, increasing the chances of a better outcome for the patient.1This size up aims to assess the extent to which the supervise guidelines for myocarditis, at a London mental health trust, are being followed. Assessments will explore the extent to which the recommended additional inception tests, CRP and troponin, are being realized and the extent to which the cognizant echocardiogram (cardiogram) are being followed. Additionally, it will aim to go bad to see if a clin ician is checking the above objectives and assess the extent to which the nursing staff are asking the patients about signs and symptoms of myocarditis. order (500-1000)This audit was designed to investigate the extent to which the monitoring requirements, in regards to clozapine first appearance and titration within the first quadruplet weeks of treatment, at a London mental health trust had been blameless. The monitoring requirements audited were specific to the detection and diagnosis of myocarditis. Data collection occurred between October 2016 and February 2017. It is a baseline, retrospective audit of case notes and laboratory data. As per the Health Research Authority regulations, this audit did not require ethical approval.Audit standards and audit tool The standards used in this audit were taken from the trusts clozapine guideline, which can be found in defer 3. The monitoring requirements for the detection of myocarditis involve an electrocardiogram, vital sign monit oring (pulse, furrow pressure, temperature) and CRP and troponin T blood tests. These had to be completed former to initiation and weekly for the first cardinal weeks later initiation. It is also essential for clinicians to verify the results of the CRP and troponin T tests, and for the nurses or clinicians to check if the patient has had any signs or symptoms of myocarditis. For the purpose of this audit, banner 1 and 3 (table 3) will be met if the results of the investigations were documented. measure 2 (table 3) will be met if the clinician has do specific reference to CRP and troponin T tests in the patient notes, criterion 4 (table 3) will be met if in that respect is specific reference to questions being asked about myocarditis symptoms. An audit tool was created using the specified monitoring requirements mentioned in the clozapine guideline, a templet of the audit tool can be found in table x.Identifying patients to be involved in the auditClozapine patients require r egular and frequent prophylactic blood tests in order to initiate and extend treatment. As such, there is a mandatory need for patients to be registered to a clozapine monitoring service database, which collects and stores the results from the weekly blood tests. Zaponex Treatment rise to power System (ZTAS) is the monitoring company that was used by the trust. ZTAS provided a mention of patients who were registered with them whilst under the cathexis of the trust, from June 2014 to October 2016. This resulted in a total of n=57 patients. The patients were selected to be used in the audit after they adhered to the inclusion criteria, which are shown below.Data CollectionData was collected using various tuition sources at the hospital. Data on haematological tests were collected systematically from ZTAS, bloodresults.co.uk, and the trust clinical portal. ZTAS and bloodresults.co.uk offered culture on the standard full blood count (FBC) monitoring that takes place weekly. The tr usts clinical portal was used to collect information on other heamatological tests, CRP and troponin T this source was also used to check any other available FBC test results. RiO, the trusts operating system, was used to collect information on the other standards being carry onful in this audit (criterion 2, 3 and 4)(table 3). The data collected was stored in the audit tool. ( table x) inclusion body and exclusion criteriaThe inclusion of the patients in the audit needed them to hit been registered with ZTAS at the trust between June 2014 and October 2016. It was also necessary for the patient to have started most (at least two) of the required monitoring standards prior to initiation. antecedent monitoring requirements include an electrocardiogram within a maximum of 3 months prior to initiation and FBC, CRP and troponin T within 10 days of the initiation date. Vital sign monitoring such as pulse, blood pressure and temperature were include if they had been completed a maxi mum of 7 days before initiation.Patients were excluded from the audit if they had been transferred from some other trust and were already on a controlled clozapine treatment regime.Method of data analysisData analysis and statistical analysis was completed using Microsoft Excel 2013.Overview As stated previously, clozapine is associated with an increased essay of myocarditis, which has been fatal in some cases. Preventative monitoring measures for myocarditis are advised at this trust. Baseline troponin T, CRP and ECG should be done prior to beginning treatment and then weekly for the pursuit first quaternion weeks after initiation. These measures are specific in identifying myocarditis, but should also be done in concordance with standard monitoring during treatment. The standard monitoring procedures include pulse, blood pressure and temperature to be completed any other day and FBC weekly. These monitoring procedures are necessary in helping to call myocarditis symptoms of myocarditis are non-specific, but tend to indicate the figurehead of an infection (fever) or simulate myocardial infarction (chest pain). Nurses and practitioners are advised to question patients on the appearance of any side effects uniform to myocardial infarction to help ascertain if they could have myocarditis.Patient demographics and meditate dataIn total, n=57 patients were reviewed. Of those, n=3 patients were excluded based upon the inclusion and exclusion criteria described in the method. Of the remaining n=54 patients, n= 6 (11.11%) patients did not initiate clozapine treatment, but n=5 were included in the audit as they had started the monitoring required prior to initiating treatment. Reasons for not initiating treatment are outlined in table 1. A total of n= 3 patients ceased clozapine treatment in week one (n=2) and during week three (n=1) one patient was persistently tachycardic, one patient refused to continue treatment and one patient was seriously hypotensive.T he patient group (n=53) was predominantly male 66% (n=35), 34% (n=18) were female. The squiffy age of patients who initiated treatment (n=48) was 34.42 years old, with the youngest patient age being 16.92 years old and the oldest being 65.21 years old.Length of treatment was mensurable as the time between a patient commencing clozapine treatment and any ceasing clozapine or the end of the audit period. A total of n=10 patients were excluded from the calculation, as they either did not start treatment or the end of treatment time was not able to be calculated reasons for exclusion are explained in table 2. The mean length of treatment was 387 days 268, with the shortest length of treatment being 1 day and the long being 873 days. Of the 53 patients involved at the start of the audit, 65% (n=35) were initiated on an inpatient basis this means the patients were initiated at the hospital, on a ward.ECG monitoring A baseline ECG had been completed in 96% (n=51)(Figure 1) of patients wi thin 3 months prior to the commencement of clozapine. matchless patient refused to have an ECG prior to initiation. The percentage of patients who standard ECGs decreased to 20% (n=9), 24% (n=11), 17%(n=8) and 9% (n=4) of patients for the following 4 weeks after commencement respectively. A total of 41 out of 45 (Table 4) patients did not receive an ECG in week quatern of clozapine titration. During week one, a patient complained of flu like symptoms and was given an ECG to rule out myocarditis likewise, one patient during week three was given an ECG after complaining of centralized chest pain.Temperature monitoringThe quantity of patients who had recorded temperatures fluctuated through-out the weeks, being highest in week two of monitoring (n=. calendar week four had the terminal recorded amount of temperature monitoring of all 5 weeks at patients 69% (n=31) (table 4). In week one, n=2 patients refused to have measurements taken.Pulse and blood pressure monitoringThe amount o f patients who did not receive BP monitoring was highest in the week prior to initiating clozapine (n=13) and in week four (n=13). The highest semblance of patients who had their blood pressures taken occurred during week one at 96% (n=44 ), with 63% (n=29) of them having their blood pressure taken once and 34% (n=15) having their blood pressure taken twice (one reading measured whilst lying or sitting and one reading measured whilst standing). Week four had the highest resemblance of patients who did not have their pulse measured at 29% (n=13) (table 4). One patient was discontinued from clozapine after one day of treatment when the BP check revealed them to be extremely hypotensive, in conjunction with a rapid pulse. panoptic blood count monitoringFBC monitoring occurred in the highest analogy of patients throughout the monitoring period 100%, 98%, 93%, 100% and 96% respectively.CRP and Troponin monitoringThe majority (50%) of patients did not receive CRP or troponin T blood t ests throughout the duration of the monitoring period. Figure 2 shows a substantial decrease in the number of patients who had CRP tests prior to initiation (n=25) and the following weeks (n=10, n=11,n=11, n=7 respectively). A large propotion of patients (84%, n= 38) did not receive CRP blood tests during their fourth week of clozapine treatement. The number of patients who received troponin T tests were less than those who received CRP tests. Only 36%(n=19) of patients received troponin T tests prior to initiation, reducing to 26%(n=12), 20%(n=9), 15%(n=7) and 9%(n=4) in the following four weeks after initiation respectively. There were n=14 patients who had no CRP or troponin T tests throughout the entirety of the monitoring period. There were no patients who had weekly CRP and troponin T tests throughout the duration of the mointoring period.Other monitoring parametersIn total, the number of patients who had their CRP and troponin checked by clinicians was less than 100% in all c ases (69% (n=9), 75% (n=9), 56% (n=6) and 63% (n=5) for weeks one through four respectively). Due to the lack of data regarding criterion 4 (table 3), there are no results available to be discussed.Summary of main findingsFBC monitoring requirements were met in the week prior to monitoring and in week three. All other standards were not met in any of the quintette weeks. Over all, there was a better outcome seen in the week prior to initiation for most of the standards. CRP and troponin T tests were completed in less than 50% of patients throughout the five weeks measured. Likewise, excluding the week prior to initiation, less than 50% of patients received an ECG for weeks one to four.LimitationsStudy data was collected using patient notes and the trusts clinical portal, data was therefore reliant on the pertinent health care master copy entering the information onto the systems. Consequently, the lack of data could be attributed to the lack of accompaniment of the monitoring, a s opposed to the lack of monitoring all together, especially in regards to criterion 4 (table 3). No useful results could be drawn for criterion 4 and criterion 2 may have also been significantly bear upon by a lack of documentation.The sample size of this audit was small (n=53), any conclusions drawn from this data may not be relevant to a larger sample size. However, in future studies, a larger sample size could be used, if this is not possible the audit could be expanded to include other trusts.Results could also be affected if the patient refused to have the relevant monitoring required, as advised in the trusts clozapine guidelines. This audit is the first one to be completed at this trust, therefore it cannot be compared to any previous data. However, the results are being measured against set standards (table x) and can be used to compare to future audits.Results in context Clozapine is highly effective in the management of treatment-resistant schizophrenia it reduces the risk of suicidal behaviours5, 6and it is effective in the treatment of both the positive and negative symptoms of schizophrenia.1 It is not widely used due to its extensive side effect profile 8, most recognised being haematological disorders, such as agranulocytosis and neutropenia which have strict monitoring protocols in place.However, cardiac side effects of clozapine treatment have become more widely recognised over the past few years.5 Myocarditis is an instigative condition of the myocardium, which is normally attributed to viral aetiology. Clozapine-induced myocarditis is a rare, but potentially fatal result of treatment. Over 75% of cases occur within the first month of treatment, making it important to monitor for myocarditis during the first four weeks of treatment.2, 14-16A study by Ronaldson et al.18 developed an evidence-based monitoring tool, based on 75 cases and 94 controls for routine monitoring up to 28 days. It suggested that an ECG, CRP and troponin I/T should be completed at baseline, with routine vitals every other day. CRP and troponin I/T tests should also be repeated on days 7, 14, 21 and 28. This study proposes that combining CRP and troponin tests provides a 100% sensitivity for myocarditis. The trusts clozapine guidelines also suggest the same monitoring protocol, with the addition of an ECG every week, for the first four weeks.Individuals with schizophrenia have a 20% shorter life expectancy than that of the general population and a greater photograph to several illnesses (diabetes, coronary heart disease).19 Due to the nature of the illness and the heightened health risks associated with schizophrenia and the antipsychotic medications used in its treatment, it is important to adhere to the relevant monitoring protocols.It is evident, from the results, that the proposed guidelines for the monitoring of clozapine-induced myocarditis are not being met. Likewise, a number of studies have shown a poor adherence to standards in the m onitoring of antipsychotic medications.20Physicians may have doubts about the relevance of monitoring, or face that it is not necessary as the incidence of myocarditis is very low rate of incidence occur in approximately 0.15-1.2%1, 13, 21 of patients. If we consider other medications with stringent monitoring protocols, such as insulin, due to health care professionals awareness of this medication and the imports if the standards are not met, there is often a higher standard of monitoring.There may also be an implication of cost extensive monitoring is often expensive, making it appear to be an unnecessary expense, particularly when the chances of myocarditis occurring are very low.Health care professionals may have a lack of awareness of the need for the monitoring of myocarditis, and the implications if these are not met. The incidence of fatality due to clozapine-induced myocarditis can be as high as 50%1, making it important to abide by the set guidelines. The monitoring guide lines are made to reduce the harm caused to patients and reduce the possibility of fatalities. However, a delayed diagnosis could result in poorer outcomes for the patients.1 The standards allow for earlier detection and diagnosis of myocarditis, reducing the chance of poorer outcomes.The results of this audit indicate a need for an increased awareness of clozapine-induced myocarditis among health care professionals. This would improve the clinicians awareness of the need for the monitoring of myocarditis and highlight the implications if the standards are not met. A standardised questionnaire could be created to monitor the signs and symptoms of myocarditis and be used by nurses to document the results, this could be integrated into the clinical notes.This baseline audit emphasises the need for future re-audits, to evaluate whether the standards have improved.Table 1 Reasons for not initiating treatmentNumber of patients (n)Consistent amber results1Patient changed mind/ refused2Pr evious health conditions made the patient unsuitable to start clozapine2Unknown1Total6Table 2Reasons for not being included it length of treatment calculation Number of patients (n)Never initaited clozapine6Patient transferred to another trust2Patient returned to country of telephone circuit (unknown if they continued treatment)2Total 10Table 3insuranceTitleClozapine Guide Trust-Wide Medication Policy DateJuly 2016 local anaesthetic/NationalLocalStandard Setting amount 1Criterion 2Criterion 3Criterion 4Criterion Full blood count, including troponin T, CRP, neutrophil and white blood cell count should be done prior to initiating clozapine and then weekly for the first four weeks.A clinician verifies the blood test results every week before treatment can be approved.An ECG is to be performed prior to clozapine commencement and every week for the first four weeks after initiation of clozapine.A nurse or physician enquires about the signs and symptoms of myocarditis weekly for the fir st 4 weeks of titration.Target100%100%100%100%Exceptions no(prenominal)NoneNoneNoneTable 4 MonitoringPrior to initiating(Total number of patients n=53)Week 1(Total number of patients n=46)Week 2(Total number of patients n=46)Week 3(Total number of patients n=46)Week 4(Total number of patients n=45)ECGYes51 (96%)9 (20%)11 (24%)8 (17%)4 (9%)No2 (4%)37 (80%)35 (76%)38 (83%)41 (91%)Blood pressureTaken once36 (68%)29 (63%)26 (56%)25 (54%)21 (47%)Taken twice4 (7.5%)15 (33%)15 (33%)12 (26%)11 (24%)Not taken13 (24.5%)2 (4%)5 (11%)9 (20%)13 (29%)TemperatureYes39 (74%)38 (83%)40 (87%)37 (80%)31 (69%)No14 (26%)8 (17%)6 (13%)9 (20%)13 (31%)PulseYes42 (79%)43 (93%)41 (89%)37 (80%)32 (71%)No11 (21%)3 (7%)5 (11%)9 (20%)13 (29%)FBCYes53 (100%)45 (98%)43 (93%)46 (100%)43 (96%)No0 (0%)1 (2%)3 (7%)0 (0%)2 (4%)CRPYes25 (47%)10 (22%)11 (24%)11 (24%)7 (16%)No28 (53%)36 (78%)35 (76%)35 (76%)38 (84%)TroponinYes19 (36%)12 (26%)9 (20%)7 (15%)4 (9%)No34 (64%)34 (74%)37 (80%)39 (85%)41 (81%)References 1.Munshi , T.A., et al., Clozapine-induced myocarditis is mandatory monitoring warranted for its early recognition? character Rep Psychiatry, 2014. 2014 p. 513108.2.Aboueid, L. and N. Toteja, Clozapine-Induced Myocarditis A Case Report of an Adolescent Boy with Intellectual Disability. Case Rep Psychiatry, 2015. 2015 p. 482375.3.Fineschi, V., et al., jerky cardiac death due to hypersensitivity myocarditis during clozapine treatment. Int J healthy Med, 2004. 118(5) p. 307-9.4.Bruno, V., A. Valiente-Gmez, and O. Alcoverro, Clozapine and Fever A Case of Continued Therapy With Clozapine. Clin Neuropharmacol, 2015. 38(4) p. 151-3.5.Swart, L.E., et al., Clozapine-induced myocarditis. Schizophr Res, 2016. 174(1-3) p. 161-4.6.Castle, D., et al., A clinical monitoring system for clozapine. Australas Psychiatry, 2006. 14(2) p. 156-68.7.Annamraju, S., et al., Early recognition of clozapine-induced myocarditis. J Clin Psychopharmacol, 2007. 27(5) p. 479-83.8.Murch, S., et al., Echocardiographic monit oring for clozapine cardiac toxicity lessons from real-world experience. Australas Psychiatry, 2013. 21(3) p. 258-61.9.Wooltorton, E., Antipsychotic clozapine (Clozaril) myocarditis and cardiovascular toxicity. CMAJ, 2002. 166(9) p. 1185-6.10.Kar, N., S. Barreto, and R. Chandavarkar, Clozapine Monitoring in clinical Practice Beyond the Mandatory Requirement. Clin Psychopharmacol Neurosci, 2016. 14(4) p. 323-329.11.Cohen, R., et al., A Case of Clozapine-Induced Myocarditis in a Young Patient with bipolar Disorder. Case Rep Cardiol, 2015. 2015 p. 283156.12.Merrill, D.B., G.W. Dec, and D.C. Goff, Adverse cardiac effects associated with clozapine. J Clin Psychopharmacol, 2005. 25(1) p. 32-41.13.Ronaldson, K.J., et al., Clinical course and analysis of ten fatal cases of clozapine-induced myocarditis and comparison with 66 surviving cases. Schizophrenia Research, 2011. 128(1-3) p. 161-165.14.Haas, S.J., et al., Clozapine-Associated Myocarditis. Drug Safety, 2007. 30(1) p. 47-57.15.Barry, A.R., J.D. Windram, and M.M. Graham, Clozapine-Associated Myocarditis Case Report and lit Review. Can J Hosp Pharm, 2015. 68(5) p. 427-9.16.Ronaldson, K.J., P.B. Fitzgerald, and J.J. McNeil, Clozapine-induced myocarditis, a widely overlooked adverse reaction. Acta Psychiatr Scand, 2015. 132(4) p. 231-40.