pharmacoepidemiology and drug safety 2014; 23: 999–1001 Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.3664
LETTER TO THE EDITOR
Validity of non-fatal idiopathic serious ventricular arrhythmia in UK-based Clinical Practice Research Datalink To the Editor The UK Clinical Practice Research Datalink (CPRD, formerly General Practice Research Database) is a large primary care database that has been extensively used in pharmacoepidemiological research.1 One of the main benefits of using the CPRD is the ability to access data from large populations exposed to particular drugs. While the CPRD is well-known for its high levels of accuracy and data completeness,2–4 it is recognized that researchers using the CPRD should verify the coded diagnoses of study diseases, particularly for conditions not reliably diagnosed.5 In 2008 Hennessy et al reported that the positive predictive value (PPV) for sudden cardiac death and ventricular arrhythmia among patients receiving cisapride, domperidone, or metoclopramide in an oupatient setting was only 23% in the CPRD, and concluded that studies of sudden cardiac death and ventricular arrhythmia in the CPRD should verify events on a case-by-case basis.6 Because some types of opioids including methadone, propoxyphene, and oxycodone were reported to cause QT prolongation,7–9 we proposed a study to examine the association between opioids and risk of idiopathic serious ventricular arrhythmia (SVA) using the CPRD. In this letter we briefly described the process used to identify and verify idiopathic SVA cases in the study population, and the results of the investigation. Among 1.7 million people who had received at least 1 prescription for an opioid between January 1, 1990 and December 31, 2008 in the CPRD, and who did not have a diagnosis of cancer any time before the first-recorded opioid prescription, we identified all potential SVA cases by screening the relevant Read codes (available on request). We required that all potential SVA cases were aged 18 – 80 years at their first diagnosis of SVA, and had at least one year of recorded medical history in the CPRD before the index date, i.e., date of the first SVA diagnosis. Since we intended to identify SVA cases where no alternative causes for SVA were documented in their electronic record (idiopathic cases), we excluded potential cases Copyright © 2014 John Wiley & Sons, Ltd.
with cancer, a history of implantable cardioverterdefibrillator placement, heart transplantation, congenital heart disease, serious renal or liver disease, alcohol or drug abuse any time before the index date, or congestive heart failure, acute myocardial infarction, cardiomyopathy, ischemic heart disease, stroke, aortic aneurysm dissection, valvular heart disease, pulmonary hypertension or pulmonary embolism, recorded within one year before the index date, and those with terminal illness or hospice care within 30 days before the index date. We also excluded any SVA cases who died on the index date or within 30 days after the index date, because original clinical records are unavailable in the CPRD for patients who have died. We categorized each qualifying suspected SVA case into one of 3 levels of likelihood (probable, possible, or unlikely) according to the pre-determined algorithm for non-fatal SVA cases using the information in the electronic record (Table 1). This algorithm was developed by two of the authors (LL and SS) based on ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death.10 The clinical judgment formulated from this process was based on a clinical impression from available information, such as recorded symptoms, treatments and referrals, rather than on clinical criteria. We then randomly selected a sample of probable SVA cases and sent for copies of their original clinical records. Two of the authors (LL and SS) separately reviewed all returned paper records and judged the validity of the SVA diagnosis. All disagreements were resolved after discussion. The study was reviewed and approved by the Independent Scientific Advisory Committee for UK Medicines and Healthcare products Regulatory Agency database research. Among the study population we identified 1720 eligible non-fatal SVA cases including 1097 (64%) men and 623 (36%) women. Among them there were 103 (6%) probable SVAs, 615 (36%) possible SVAs, and 1002 (58%) unlikely cases. Among the 103 probable SVA cases we requested original clinical records for a random sample of 25 (24%). We ultimately obtained
1000
letter to the editor
Table 1. Classification algorithm for non-fatal serious ventricular arrhythmia cases Category Probable (meet at least one of criteria)
Possible (meet at least one of criteria)
Unlikely (meet at least one of criteria)
Criteria a. Experienced CPR, or defibrillation on index date b. With a discharge letter of SVA diagnosis c. Had complications probably suffered from SVA such as brain damage a. initiated a new antiarrhythmic drug within 30 days before, on, or 30 days after index date b. Experienced ICD within three months after index date c. meet at least one of the following conditions: • relevant symptoms (including palpitations, dyspnea, chest pain or syncope/presyncope) • electrocardiogram (including ECG/EKG or Holter monitor) evidence • referred to a hospital • referred to a cardiologist a. Meet none of the following conditions: • relevant symptoms (including palpitations, dyspnea, chest pain or syncope/presyncope) • electrocardiogram evidence • referred to a hospital • referred to a cardiologist b. Experienced cardiac surgery (such as angioplasty, stent, and CABG) within 3 months before or on index date c. With an alternative cardiac problem (such as AMI, heart failure, cardiomyopathy and IHD, triple vessel disease of the heart, and complete atrioventricular block) recorded on index date d. Experienced serious non-cardiac surgery (such as thyroidectomy) or other serious accidents (such as hip fracture, and motorvehicle accidents) on index date e. Others such as medical history does not support SVA diagnosis based on their symptoms, hospitalization, treatment history or medical diagnosis codes recoded in the CPRD
Abbreviations: AMI, acute myocardial infarction; CABG, coronary artery bypass graft; CPR, cardiopulmonary resuscitation; ECG/EKG, electrocardiogram; CPRD, Clinical Practice Research Datalink; ICD, implantable cardioverter-defibrillator; IHD, ischemic heart disease; SVA, serious ventricular arrhythmias
with an earlier study in the CPRD where only 18 of 86 (21%) potential ventricular arrhythmia patients were confirmed non-fatal idiopathic cases.11 The estimated PPV was based on 20 idiopathic non-fatal SVA cases who should have been representative of all probable SVA cases since they were randomly selected. If we had taken into account all valid non-fatal SVA cases irrespective of either potential causes or severity of disease, the PPV could have reached as high as 65% (13 out of 20 cases). It should be noted that we were not able to validate fatal SVA cases as their medical records were no longer held in the practice. Nor were we able to validate possible or unlikely non-fatal SVA cases because the cost to verify such SVA cases was considerable and the yield likely to be low. In addition, since we restricted the SVA cases to adults aged 18 – 80 years in a cohort of opioid users in the CPRD, there may be variations in SVA validity in different study populations. This validation exercise illustrated the challenges in accurately identifying cases of idiopathic SVA in the CPRD. Because of the low PPV observed in our study, it was not possible to examine the association between opioid use and risk of SVA without validating all potential SVA cases. Furthermore, we did not assess the accuracy of non-cases, and therefore were not able to estimate either the false negative rate or the sensitivity. While this approach is common and useful in validating the accuracy of outcomes in etiologic studies, especially when the PPV is high, we were not able to assess whether our algorithm missed some true cases and if so how many. Given the increasing use of the CPRD in clinical research it is important to consider sending for original clinical records to validate cases particularly for outcomes that are difficult to diagnose and where the Read codes are not specific and reliable. CONFLICT OF INTEREST
responses for 20 of these, resulting in a response rate of 80%. Of these 20 patients, 5 (25%) had a confirmed idiopathic SVA diagnosis, 7 (35%) had a confirmed but non-idiopathic SVA diagnosis (had at least one of the clinical conditions listed in the pre-defined exclusion criteria), 1 (5%) was a non-sustained SVA (mild and transient) who was diagnosed via occasional electrocardiogram examination, 4 (20%) were false positive SVA cases, and in 3 (15%) validity could not be determined because the notes were returned with insufficient detail to verify the diagnosis. The PPV for idiopathic non-fatal SVA was 25% (95% confidence interval 10% - 47%). In this study we found that the PPV for idiopathic non-fatal SVA was very low (25%) in a small but randomly selected sample of cases, which was consistent Copyright © 2014 John Wiley & Sons, Ltd.
This study was not funded. All authors declare no competing interests. REFERENCES 1. Khan NF, Harrison SE, Rose PW. Validity of diagnostic coding within the General Practice Research Database: a systemateic review. Br J Gen Pract 2010; 60: e128–e136. 2. Jick H, Jick SS, Derby LE. Validation of information recorded on general practitioner based computerised data resource in the United Kingdom. BMJ 1991; 302: 766–768. 3. Jick H, Terris BZ, Derby LE, Jick SS. Further validation of information recorded on a general practitioner based computerized data resource in the United Kingdom. Pharmacoepidemiol Drug Saf 1992; 1: 347–349. 4. Jick SS, Kaye JA, Vasilakis-Scaramozza C, et al. Validity of the general practice research database. Pharmacotherapy 2003; 23: 686–689. 5. Herrett E, Thomas SL, Schoonen WM, Smeeth L, Hall AJ. Validation and validity of diagnoses in the General Practice Research Database: a systematic review. Br J Clin Pharmacol 2010; 69: 4–14. 6. Hennessy S, Leonard CE, Palumbo CM, Bilker WB, Newcomb C, Kimmel SE. Diagnostic codes for sudden cardiac death and ventricular arrhythmia functioned poorly to identify outpatient events in EPIC’s General Practice Research Database. Pharmacoepidemiol Drug Saf 2008; 17: 1131–1136.
Pharmacoepidemiology and Drug Safety, 2014; 23: 999–1001 DOI: 10.1002/pds
1001
letter to the editor 7. Andrews CM, Krantz MJ, Wedam EF, Marcuson MJ, Capacchione JF, Haigney MC. Methadone-induced mortality in the treatment of chronic pain: role of QT prolongation. Cardiol J 2009; 16: 210–217. 8. U.S. Food and Drug Administration, MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Propoxyphene: withdrawal risk of cardiac toxicity. Available at: http://www.fda.gov/Safety/MedWatch/ SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm234389.htm; accessed 05/10/2011. 9. Fanoe S, Jensen GB, Sjøgren P, Korsgaard MP, Grunnet M. Oxycodone is associated with dose-dependent QTc prolongation in patients and low-affinity inhibiting of hERG activity in vitro. Br J Clin Pharmacol 2009; 67: 172–179. 10. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006; 114: e385–e484. 11. de Abajo FJ, Rodríguez LA. Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs. Br J Clin Pharmacol 1999; 47: 307–313.
Copyright © 2014 John Wiley & Sons, Ltd.
LIN LI1* SOKO SETOGUCHI2 SUSAN JICK1 1
Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, Lexington, MA, USA 2
Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
*Lin Li, Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, 11 Muzzey Street, Lexington, MA 02421, USA. E-mail: [email protected]
Pharmacoepidemiology and Drug Safety, 2014; 23: 999–1001 DOI: 10.1002/pds
LETTER TO THE EDITOR
Validity of non-fatal idiopathic serious ventricular arrhythmia in UK-based Clinical Practice Research Datalink To the Editor The UK Clinical Practice Research Datalink (CPRD, formerly General Practice Research Database) is a large primary care database that has been extensively used in pharmacoepidemiological research.1 One of the main benefits of using the CPRD is the ability to access data from large populations exposed to particular drugs. While the CPRD is well-known for its high levels of accuracy and data completeness,2–4 it is recognized that researchers using the CPRD should verify the coded diagnoses of study diseases, particularly for conditions not reliably diagnosed.5 In 2008 Hennessy et al reported that the positive predictive value (PPV) for sudden cardiac death and ventricular arrhythmia among patients receiving cisapride, domperidone, or metoclopramide in an oupatient setting was only 23% in the CPRD, and concluded that studies of sudden cardiac death and ventricular arrhythmia in the CPRD should verify events on a case-by-case basis.6 Because some types of opioids including methadone, propoxyphene, and oxycodone were reported to cause QT prolongation,7–9 we proposed a study to examine the association between opioids and risk of idiopathic serious ventricular arrhythmia (SVA) using the CPRD. In this letter we briefly described the process used to identify and verify idiopathic SVA cases in the study population, and the results of the investigation. Among 1.7 million people who had received at least 1 prescription for an opioid between January 1, 1990 and December 31, 2008 in the CPRD, and who did not have a diagnosis of cancer any time before the first-recorded opioid prescription, we identified all potential SVA cases by screening the relevant Read codes (available on request). We required that all potential SVA cases were aged 18 – 80 years at their first diagnosis of SVA, and had at least one year of recorded medical history in the CPRD before the index date, i.e., date of the first SVA diagnosis. Since we intended to identify SVA cases where no alternative causes for SVA were documented in their electronic record (idiopathic cases), we excluded potential cases Copyright © 2014 John Wiley & Sons, Ltd.
with cancer, a history of implantable cardioverterdefibrillator placement, heart transplantation, congenital heart disease, serious renal or liver disease, alcohol or drug abuse any time before the index date, or congestive heart failure, acute myocardial infarction, cardiomyopathy, ischemic heart disease, stroke, aortic aneurysm dissection, valvular heart disease, pulmonary hypertension or pulmonary embolism, recorded within one year before the index date, and those with terminal illness or hospice care within 30 days before the index date. We also excluded any SVA cases who died on the index date or within 30 days after the index date, because original clinical records are unavailable in the CPRD for patients who have died. We categorized each qualifying suspected SVA case into one of 3 levels of likelihood (probable, possible, or unlikely) according to the pre-determined algorithm for non-fatal SVA cases using the information in the electronic record (Table 1). This algorithm was developed by two of the authors (LL and SS) based on ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death.10 The clinical judgment formulated from this process was based on a clinical impression from available information, such as recorded symptoms, treatments and referrals, rather than on clinical criteria. We then randomly selected a sample of probable SVA cases and sent for copies of their original clinical records. Two of the authors (LL and SS) separately reviewed all returned paper records and judged the validity of the SVA diagnosis. All disagreements were resolved after discussion. The study was reviewed and approved by the Independent Scientific Advisory Committee for UK Medicines and Healthcare products Regulatory Agency database research. Among the study population we identified 1720 eligible non-fatal SVA cases including 1097 (64%) men and 623 (36%) women. Among them there were 103 (6%) probable SVAs, 615 (36%) possible SVAs, and 1002 (58%) unlikely cases. Among the 103 probable SVA cases we requested original clinical records for a random sample of 25 (24%). We ultimately obtained
1000
letter to the editor
Table 1. Classification algorithm for non-fatal serious ventricular arrhythmia cases Category Probable (meet at least one of criteria)
Possible (meet at least one of criteria)
Unlikely (meet at least one of criteria)
Criteria a. Experienced CPR, or defibrillation on index date b. With a discharge letter of SVA diagnosis c. Had complications probably suffered from SVA such as brain damage a. initiated a new antiarrhythmic drug within 30 days before, on, or 30 days after index date b. Experienced ICD within three months after index date c. meet at least one of the following conditions: • relevant symptoms (including palpitations, dyspnea, chest pain or syncope/presyncope) • electrocardiogram (including ECG/EKG or Holter monitor) evidence • referred to a hospital • referred to a cardiologist a. Meet none of the following conditions: • relevant symptoms (including palpitations, dyspnea, chest pain or syncope/presyncope) • electrocardiogram evidence • referred to a hospital • referred to a cardiologist b. Experienced cardiac surgery (such as angioplasty, stent, and CABG) within 3 months before or on index date c. With an alternative cardiac problem (such as AMI, heart failure, cardiomyopathy and IHD, triple vessel disease of the heart, and complete atrioventricular block) recorded on index date d. Experienced serious non-cardiac surgery (such as thyroidectomy) or other serious accidents (such as hip fracture, and motorvehicle accidents) on index date e. Others such as medical history does not support SVA diagnosis based on their symptoms, hospitalization, treatment history or medical diagnosis codes recoded in the CPRD
Abbreviations: AMI, acute myocardial infarction; CABG, coronary artery bypass graft; CPR, cardiopulmonary resuscitation; ECG/EKG, electrocardiogram; CPRD, Clinical Practice Research Datalink; ICD, implantable cardioverter-defibrillator; IHD, ischemic heart disease; SVA, serious ventricular arrhythmias
with an earlier study in the CPRD where only 18 of 86 (21%) potential ventricular arrhythmia patients were confirmed non-fatal idiopathic cases.11 The estimated PPV was based on 20 idiopathic non-fatal SVA cases who should have been representative of all probable SVA cases since they were randomly selected. If we had taken into account all valid non-fatal SVA cases irrespective of either potential causes or severity of disease, the PPV could have reached as high as 65% (13 out of 20 cases). It should be noted that we were not able to validate fatal SVA cases as their medical records were no longer held in the practice. Nor were we able to validate possible or unlikely non-fatal SVA cases because the cost to verify such SVA cases was considerable and the yield likely to be low. In addition, since we restricted the SVA cases to adults aged 18 – 80 years in a cohort of opioid users in the CPRD, there may be variations in SVA validity in different study populations. This validation exercise illustrated the challenges in accurately identifying cases of idiopathic SVA in the CPRD. Because of the low PPV observed in our study, it was not possible to examine the association between opioid use and risk of SVA without validating all potential SVA cases. Furthermore, we did not assess the accuracy of non-cases, and therefore were not able to estimate either the false negative rate or the sensitivity. While this approach is common and useful in validating the accuracy of outcomes in etiologic studies, especially when the PPV is high, we were not able to assess whether our algorithm missed some true cases and if so how many. Given the increasing use of the CPRD in clinical research it is important to consider sending for original clinical records to validate cases particularly for outcomes that are difficult to diagnose and where the Read codes are not specific and reliable. CONFLICT OF INTEREST
responses for 20 of these, resulting in a response rate of 80%. Of these 20 patients, 5 (25%) had a confirmed idiopathic SVA diagnosis, 7 (35%) had a confirmed but non-idiopathic SVA diagnosis (had at least one of the clinical conditions listed in the pre-defined exclusion criteria), 1 (5%) was a non-sustained SVA (mild and transient) who was diagnosed via occasional electrocardiogram examination, 4 (20%) were false positive SVA cases, and in 3 (15%) validity could not be determined because the notes were returned with insufficient detail to verify the diagnosis. The PPV for idiopathic non-fatal SVA was 25% (95% confidence interval 10% - 47%). In this study we found that the PPV for idiopathic non-fatal SVA was very low (25%) in a small but randomly selected sample of cases, which was consistent Copyright © 2014 John Wiley & Sons, Ltd.
This study was not funded. All authors declare no competing interests. REFERENCES 1. Khan NF, Harrison SE, Rose PW. Validity of diagnostic coding within the General Practice Research Database: a systemateic review. Br J Gen Pract 2010; 60: e128–e136. 2. Jick H, Jick SS, Derby LE. Validation of information recorded on general practitioner based computerised data resource in the United Kingdom. BMJ 1991; 302: 766–768. 3. Jick H, Terris BZ, Derby LE, Jick SS. Further validation of information recorded on a general practitioner based computerized data resource in the United Kingdom. Pharmacoepidemiol Drug Saf 1992; 1: 347–349. 4. Jick SS, Kaye JA, Vasilakis-Scaramozza C, et al. Validity of the general practice research database. Pharmacotherapy 2003; 23: 686–689. 5. Herrett E, Thomas SL, Schoonen WM, Smeeth L, Hall AJ. Validation and validity of diagnoses in the General Practice Research Database: a systematic review. Br J Clin Pharmacol 2010; 69: 4–14. 6. Hennessy S, Leonard CE, Palumbo CM, Bilker WB, Newcomb C, Kimmel SE. Diagnostic codes for sudden cardiac death and ventricular arrhythmia functioned poorly to identify outpatient events in EPIC’s General Practice Research Database. Pharmacoepidemiol Drug Saf 2008; 17: 1131–1136.
Pharmacoepidemiology and Drug Safety, 2014; 23: 999–1001 DOI: 10.1002/pds
1001
letter to the editor 7. Andrews CM, Krantz MJ, Wedam EF, Marcuson MJ, Capacchione JF, Haigney MC. Methadone-induced mortality in the treatment of chronic pain: role of QT prolongation. Cardiol J 2009; 16: 210–217. 8. U.S. Food and Drug Administration, MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Propoxyphene: withdrawal risk of cardiac toxicity. Available at: http://www.fda.gov/Safety/MedWatch/ SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm234389.htm; accessed 05/10/2011. 9. Fanoe S, Jensen GB, Sjøgren P, Korsgaard MP, Grunnet M. Oxycodone is associated with dose-dependent QTc prolongation in patients and low-affinity inhibiting of hERG activity in vitro. Br J Clin Pharmacol 2009; 67: 172–179. 10. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (writing committee to develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006; 114: e385–e484. 11. de Abajo FJ, Rodríguez LA. Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs. Br J Clin Pharmacol 1999; 47: 307–313.
Copyright © 2014 John Wiley & Sons, Ltd.
LIN LI1* SOKO SETOGUCHI2 SUSAN JICK1 1
Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, Lexington, MA, USA 2
Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
*Lin Li, Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, 11 Muzzey Street, Lexington, MA 02421, USA. E-mail: [email protected]
Pharmacoepidemiology and Drug Safety, 2014; 23: 999–1001 DOI: 10.1002/pds
