Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2009 Sep;68(3):447–454. doi: 10.1111/j.1365-2125.2009.03474.x

Population-based studies of antithyroid drugs and sudden cardiac death

Charlotte van Noord 1,4, Miriam C J M Sturkenboom 1,3, Sabine M J M Straus 1,4, Albert Hofman 1, Jacqueline C M Witteman 1, Bruno H Ch Stricker 1,2,5
PMCID: PMC2766485  PMID: 19740403

Abstract

AIM

Thyroid free T4 is associated with QTc-interval prolongation, which is a risk factor for sudden cardiac death (SCD). Hyperthyroidism has been associated with SCD in case reports, but there are no population-based studies confirming this. The aim was to investigate whether use of antithyroid drugs (as a direct cause or as an indicator of poorly controlled hyperthyroidism) is associated with an increased risk of SCD.

METHODS

We studied the occurrence of SCD in a two-step procedure in two different Dutch populations. First, the prospective population-based Rotterdam Study including 7898 participants (≥55 years old). Second, we used the Integrated Primary Care Information (IPCI) database, which is a longitudinal general practice research database to see whether we could replicate results from the first study. Drug use at the index date was assessed with prescription information from automated pharmacies (Rotterdam Study) or drug prescriptions from general practices (IPCI). We used a Cox proportional hazards model in a cohort analysis, adjusted for age, gender and use of QTc prolonging drugs (Rotterdam Study) and conditional logistic regression analysis in a case–control analysis, matched for age, gender, practice and calendar time and adjusted for arrhythmia and cerebrovascular ischaemia (IPCI).

RESULTS

In the Rotterdam Study, 375 participants developed SCD during follow-up. Current use of antithyroid drugs was associated with SCD [adjusted hazard ratio 3.9; 95% confidence interval (CI) 1.7, 8.7]. IPCI included 1424 cases with SCD and 14 443 controls. Also in IPCI, current use of antithyroid drugs was associated with SCD (adjusted odds ratio 2.9; 95% CI 1.1, 7.4).

CONCLUSIONS

Use of antithyroid drugs was associated with a threefold increased risk of SCD. Although this might be directly caused by antithyroid drug use, it might be more readily explained by underlying poorly controlled hyperthyroidism, since treated patients who developed SCD still had low thyroid-stimulating hormone levels shortly before death.

Keywords: antithyroid drugs, hyperthyroidism, sudden cardiac death

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

  • Thyroid hormone free T4 is associated with QTc-interval prolongation, which is a risk factor for sudden cardiac death.

  • The association between hyperthyroidism and ventricular arrhythmias or sudden cardiac death has been reported in several case reports.

WHAT THIS STUDY ADDS

  • We investigated in a prospective population-based cohort study and in a case–control study whether use of antithyroid drugs (as a direct cause or as an indicator of poorly controlled hyperthyroidism) is associated with an increased risk of sudden cardiac death.

  • Use of antithyroid drugs was associated with a threefold increased risk of sudden cardiac death.

  • Although this might be due to antithyroid drug use, it could be more readily explained by underlying hyperthyroidism.

Introduction

Hyperthyroidism is a common disease in the elderly with an estimated prevalence between 0.5% and 6% [1–3]. Thyroid hormone excess in the elderly affects the cardiovascular system [4]. A strong positive correlation between free T3 and the QTc interval has been reported [5, 6]. Recently, we demonstrated that free T4 is associated with QTc prolongation in men [7]. Prolongation of ventricular repolarization may result in early after depolarizations (EAD), which in turn may induce re-entry and thereby provoke torsade de pointes and fatal ventricular arrhythmias [8–12].

Cardiovascular disease is the leading cause of death in the western world and sudden cardiac death (SCD) accounts for almost half of these cardiovascular deaths [13]. Clinical or subclinical hyperthyroidism is associated with increased overall mortality, in particular mortality due to circulatory and cardiovascular diseases. Even subclinical hypo- and hyperthyroidism have been associated with an increased risk of mortality in patients with cardiac disease [5, 14, 15]. In a previous study, no difference was demonstrated in mortality or serious vascular events in users of antithyroid drugs [16]. No effects of subclinical hyperthyroidism on cardiovascular events were demonstrated in two prospective studies [17, 18]. Two meta-analyses resulted in different conclusions [19, 20].

There have been several case reports describing an association between undiagnosed hyperthyroidism and ventricular arrhythmias [21, 22]. SCD in patients with undiagnosed hyperthyroidism has been described in a few case reports, often associated with a thyrotoxic crisis [23, 24]. The association of hyperthyroidism with SCD has not been described in large epidemiological studies.

Since the association between hyperthyroidism and ventricular arrhythmias or SCD has been reported in several case reports, but not in large epidemiological studies, we investigated in a prospective population-based cohort study whether use of antithyroid drugs (as a direct cause or as an indicator of poorly controlled hyperthyroidism) is associated with an increased risk of SCD. Subsequently, we performed a case–control study in a separate population to see whether we could replicate findings from the first study.

Methods

Setting and study design

Rotterdam study

The Rotterdam Study is a prospective population-based cohort study, which started with a baseline visit between 1990 and 1993. The Medical Ethics Committee of the Erasmus Medical Centre (Rotterdam, the Netherlands) approved the study. All inhabitants of Ommoord, a suburb of Rotterdam, aged ≥55 years were invited to participate (n= 10 275). Of them, 7983 (78%) gave their written informed consent and took part in the baseline examination. Objectives and methods of the Rotterdam Study have been described in detail elsewhere [25, 26]. At baseline, all participants were visited at home for a standardized questionnaire, and 7151 were subsequently examined at the research centre. Since the start of the study, three follow-up visits took place approximately every 3 years. In addition to follow-up examinations, the cohort is continuously monitored for major morbidity and mortality through linkage with general practitioner (GP) and municipality records. Drug prescriptions dispensed to participants by automated pharmacies with computerized records and a history of several years have been routinely stored in the database since 1 January 1991. To have at least 4 months of medication history, the study period started on 1 May 1991. The study ended on one of the censoring dates (death or transferring out) or the end of the study period (1 January 2006). Overall, 7898 participants were included.

Integrated Primary Care Information

Data were retrieved from the Integrated Primary Care Information (IPCI) project, a longitudinal observational database, containing data from computer-based medical patient records of a large group of GPs in the Netherlands, for a population-based case–control study. In the Dutch healthcare system, the GP has a pivotal role by acting as a gatekeeper for all medical care. Details of the database have been described elsewhere [27, 28]. Briefly, the database contains the complete medical records of approximately 800 000 patients. The electronic records contain coded and anonymous data on patient demographics, symptoms (in free text), diagnoses (using the International Classification for Primary Care [29] and free text) from GPs and specialists, referrals, laboratory findings, hospitalizations, and drug prescriptions, including their indications and dosage regimen. To maximize completeness of the data, GPs participating in the IPCI project are not allowed to maintain a system of paper-based records besides the electronic medical records. The system complies with European Union guidelines on the use of medical data for medical research and has been proven valid for pharmacoepidemiological research in several validation studies that evaluated the quality of the available information [27]. The Scientific and Ethical Advisory Board of the IPCI project approved this study.

The source population comprised all patients of ≥18 years in the IPCI database with a valid database history (date of registration with GP) of at least 1 year. The study population comprised all cases with SCD occurring in the source population during the study period plus their matched controls (see below). The study period started on 1 January 1995 and ended on 1 May 2007. All subjects were followed until death, transferral out of the GP practice, last data draw down or end of the study period, whichever came first.

Sudden cardiac death definition

In both the Rotterdam Study and in IPCI, SCDs were defined as: (i) a witnessed natural death attributable to cardiac causes, heralded by abrupt loss of consciousness, within 1 h of onset of acute symptoms, or (ii) an unwitnessed, unexpected death of someone seen in a stable medical condition <24 h previously with no evidence of a noncardiac cause [30, 31].

Rotterdam study

The ascertainment of SCD cases in the Rotterdam Study has been described previously [12]. In short, information on vital status is obtained from municipal health authorities in Rotterdam and GPs. Two research physicians independently coded all reported events, blinded to exposure, and judged the likelihood of SCD according to the definition above. In cases of disagreement, consensus was sought and, finally, a cardiologist reviewed all events. The index date was the date of death.

IPCI: case and control definition

The computerized medical and demographic data were screened for all deaths that occurred during the study period. The medical records of all identified cases of death were reviewed manually to assess whether death could be classified as SCD. Validation was performed independently by two medically trained persons blinded to exposure and, in case of discrepancy, a specialized physician arbitrated. To each case of SCD, up to 20 controls were randomly drawn from the source population matched for age (year of birth), gender and practice (GP). The index date was defined as the date on which SCD occurred in cases. This date was also the index date for matched controls.

Use of antithyroid drugs

In this study, the exposure of interest included the available antithyroid drugs carbimazole, thiamazole and propylthiouracil. The duration of each prescription was calculated by dividing the total number of units issued per prescription by the prescribed daily number of units. Use of antithyroid drugs was defined as current if the index date fell within a period of use or within a maximum of 40 days after the end of the last prescription (to deal with carry-over effects and/or irregular use by patients). Past use was defined as discontinuation of an antithyroid drug >40 days before the index date. If patients had no prescription for an antithyroid drug prior to the index date, they were considered as non-exposed. Among current users we evaluated the effect of duration (≤365 days; >365 days) of use which was defined as the delay between first intake and the index date, and the effect of dosage [<1 defined daily dosage (DDD); ≥1 DDD). The DDD is the recommended average maintenance dose per day for a drug used for its main indication in adults [32].

Covariates

Rotterdam study

Clinical measures were obtained during the visits at the Rotterdam Study research centre. Diabetes mellitus was defined as the use of blood glucose-lowering medication and/or a nonfasting serum glucose level of 11.1 mmol l−1 or higher and/or serum glucose levels ≥7 mmol l−1 (1997–2000) [33]. Hypertension was identified through the use of antihypertensive medication and/or the assessment of blood pressure measurements [34]. Prevalence and incidence of myocardial infarction, heart failure, stroke and transient ischaemic attacks were assessed as previously described [31, 35–38]. Hypercholesterolaemia was defined as a total serum cholesterol level >6.2 mmol l−1 or the use of cholesterol-lowering drugs [39]. Use of QTc prolonging drugs (list 1) of the website-based registry (http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm), use of β-blocking drugs and use of nondihydropyridine calcium channel blockers at the index date were considered as a covariate [40].

IPCI

Known risk factors and other covariates for SCD were gathered from the medical records through computerized searches and manual assessment. Cerebro- and cardiovascular ischaemia and heart failure were assessed, based on the diagnoses provided by the GP and by specialists in the medical records. Hypertension was identified through the diagnoses in the medical records, the use of antihypertensive medication and/or the assessment of blood pressure measurements [34]. Diabetes mellitus, arrhythmias and hypercholesterolaemia were identified through diagnoses in the medical records from GPs and specialists and/or the use of antidiabetic, antiarrhythmic or lipid-lowering medication. Use of QTc prolonging drugs, use of β-blocking drugs and use of nondihydropyridine calcium channel blockers at the index date were considered as a covariate [40].

Statistical analysis

The relative risk of SCD associated with use of antithyroid drugs was estimated by calculation of the hazard ratios (HRs) using Cox proportional hazards models in the Rotterdam Study, and by calculation of the odds ratios (ORs) using conditional logistic regression analyses in IPCI.

Covariates which were univariately associated with SCD (at a P < 0.1 level) were included in the regression analyses if they changed the point estimate of the association between use of antithyroid drugs and SCD by >10% [41]. We investigated potential effect modification by age, gender, duration of use and dosage with interaction terms and subsequent stratifications. We performed several sensitivity analyses: by excluding users of amiodarone, participants with atrial fibrillation and adjusted for heart rate at baseline. The analyses were performed using SPSS for Windows version 15.0 (SPSS Inc., Chicago, IL, USA).

Results

Subject characteristics

Rotterdam study

The baseline characteristics of all participants are presented in Table 1. The mean age of the study population (7898 participants) at baseline was 70.5 years (SD 9.7 years), 38.9% were male.

Table 1.

Baseline characteristics, demographics, distribution of covariates

Rotterdam Study (cohort study) IPCI (case–control study)
Characteristic Current use of antithyroid drugs at baseline (n= 61) No use of antithyroid drugs at baseline (n= 7837) Sudden cardiac death cases (n= 1424) Controls (n= 14 443)
Gender
Male 11 (18.0%)* 3064 (39.1%)* 831 (58.4%) 8739 (60.5%)
Female 50 (82.0%)* 4773 (60.9%)* 593 (41.6%) 5704 (39.5%)
Age (mean, SD) (years) 76.7 (9.0)* 70.6 (9.7)* 72.9 (13.9)* 66.7 (13.8)*
≤55 – – 170 (11.9%) 3008 (20.8%)
55–65 10 (16.4%) 3001 (38.3%) 193 (13.6%) 2853 (19.8%)
66–75 17 (27.9%) 2614 (33.3%) 366 (25.7%) 4274 (29.6%)
>75 34 (55.7%) 2222 (28.4%) 695 (48.8%) 4308 (29.8%)
Comorbidities
Myocardial infarction 5 (8.2%) 868 (11.1%) 77 (5.4%)* 271 (1.9%)*
Transient ischaemic attack 1 (1.6%)* 416 (5.3%)* 65 (4.6%)* 383 (2.7%)*
Cerebrovascular accident 10 (16.4%) 941 (12.0%) 59 (4.1%)* 259 (1.8%)*
Arrhythmia – – 141 (9.9%)* 837 (5.8%)*
Hypertension 27 (44.3%) 2549 (32.5%) 268 (18.8%)* 2284 (15.8%)*
Body mass index (mean, SD) 26.1 (3.7) 26.3 (3.7) – –
Diabetes mellitus 15 (24.6%)* 839 (10.7%)* 284 (19.9%)* 1274 (8.8%)*
Smoking – – 283 (19.9%) 2857 (19.8%)
Current smoking 7 (11.5%) 1385 (17.7%) – –
Past smoking 11 (18.0%)* 2579 (32.9%)* – –
Alcohol abuse (0%)* 176 (2.2%)* 30 (2.1%)* 107 (0.1%)*
Heart failure 3 (4.9%) 271 (3.5%) 272 (19.1%)* 615 (4.3%)*
Hypercholesterolaemia 18 (29.5%)* 2995 (38.2%)* 204 (14.3%)* 1619 (11.2%)*
Use of list 1 QTc prolonging drugs 17 (27.9%)* 491 (6.3%)* 58 (4.1%)* 283 (2.0%)*
Use of β-blocking drugs 18 (29.5%)* 1467 (18.7%)* 209 (14.7%)* 1608 (11.1%)*
Use of nondihydropyridine calcium channel blockers 4 (6.6)* 259 (3.3%)* 58 (4.1%)* 279 (1.9%)*
Open in a new tab
*

P < 0.05. SD, standard deviation.

The mean follow-up period for men was 9.6 years, for women 10.0 years. During the follow-up period, 3589 participants died of all causes. Overall, 297 persons were classified as definite SCD and 78 as probable SCD. Of the 375 SCD events, 173 were male. The mean age at baseline of the cases was 74.2 years (SD 8.5).

IPCI

The source population for this study comprised 478 661 subjects with at least 1 year of valid history during the study period. The total number of person-years of follow-up was 1 905 382 years, 14 259 persons died, 926 persons were classified as definite SCD, 498 as probable SCD. Overall, there were 1424 cases and 14 443 matched controls.

The mean age of the cases was 72.9 years and 58.4% were male, on average the controls were younger (66.7 years) and 60.5% were male, but this apparent imbalance did not influence the analysis due to the individual matching. The imbalance is caused by the different number of cases for older than for younger persons (Table 1).

Association between antithyroid drugs and SCD

Rotterdam study

Of all SCD cases, six participants were current users of antithyroid drugs at the index date and five participants had used antithyroid drugs in the past but were no longer using them (Table 2). Two of these currently exposed cases were classified as definite SCD and four as probable. Ages ranged from 66 to 87 years. One of the patients was diagnosed with multinodular goitre, the underlying cause of the hyperthyroidism in the other patients was unknown. One of the patients had episodes of ventricular tachycardia and ventricular fibrillation in the recent history, possibly due to underlying hyperthyroidism. One patient used amiodarone at the time of SCD. One patient had a thyroid-stimulating hormone (TSH) of 0.13 (6 days before SCD), one a TSH of <0.01 (15 days before SCD). In the third case, the treating physician required blood test (including TSH) 11 days before SCD. The conclusion some days later was ‘hyperthyroidism’, but no values were given in the medical records. Thyroid function was not known for the other three cases.

Table 2.

Risk of SCD

Rotterdam study IPCI
SCD (n= 375) No SCD (n= 7523) HR (95% CI)* HR (95% CI)† Cases (n= 1424) Controls (n= 14 443) OR (95% CI)‡ OR (95% CI)§
Use of antithyroid drugs
Never use of antithyroid drugs 364 7383 1.0 (reference) 1.0 (reference) 1415 14 386 1.0 (reference) 1.0 (reference)
Past use of antithyroid drugs 5 81 2.0 (0.8, 4.8) 2.0 (0.8, 4.8) 2 40 0.5 (0.1, 1.9) 0.5 (0.1, 1.9)
Current use of antithyroid drugs 6 59 4.3 (1.9, 9.6) 3.9 (1.7, 8.8) 7 17 3.3 (1.3, 8.5) 2.9 (1.1, 7.4)
Open in a new tab
*

Hazard ratios adjusted for gender and time-depending age.

†

Hazard ratios adjusted for gender and time-depending age and use of list 1 QTc prolonging drugs.

‡

Odds ratios matched for age, gender, practice and calendar time.

§

Odds ratios matched for age, gender, practice and calendar time and adjusted for arrhythmia and cerebrovascular ischaemia. SCD, sudden cardiac death.

Current use of antithyroid drugs was associated with a significantly increased risk of SCD, adjusted for gender and age and use of list 1 QTc prolonging drugs [HR 3.9; 95% confidence interval (CI) 1.7, 8.8]. Past use was not associated with an increased risk of SCD (HR 2.0; 95% CI 0.8, 4.8).

After exclusion of users of amiodarone, the point estimates did not change substantially [risk of SCD (HR 3.7; 95% CI 1.5, 8.9)]. There was effect modification by gender (P= 0.005): men had a higher risk of SCD (HR 10.4; 95% CI 2.6, 42.5) than women (HR 2.9; 95% CI 1.1, 7.7). There was no effect modification by age (P= 0.74). The risk of SCD in current users of antithyroid drugs remained unchanged, after adjusting for age, gender, list 1 QTc prolonging drugs and heart rate at baseline (HR 3.1; 95% CI 1.0, 9.7). After exclusion of participants with prevalent atrial fibrillation, the HR for current use slightly increased (4.3; 95% CI 1.9, 9.6). There was effect modification by dosage (P= 0.017), participants using ≥1 DDD having a higher risk of SCD (HR 4.1; 95% CI 1.3, 12.7) than participants using <1 DDD (HR 1.5; 95% CI 0.2, 10.8). There was also effect modification by duration of treatment (P= 0.005), participants using antithyroid drugs for < 1 year having a higher risk of SCD (HR 4.5; 95% CI 1.1, 18.3) than participants using antithyroid drugs >1 year (HR 2.3; 95% CI 1.2, 4.6).

IPCI

Of all cases, seven patients were current users of antithyroid drugs at the index date and two were past users. Three of these cases were classified as definite SCD and four as probable. Ages ranged from 60 to 90 years. Two patients were diagnosed with toxic multinodular goitre, one with diffuse toxic goitre and one with multinodular goitre with degenerate changes; the cause of hyperthyroidism in the other three patients was unknown. None of the patients used amiodarone at the time of SCD. Six patients died within a few weeks after start of antithyroid drugs, when they probably still had low TSH levels and increased free T4 levels.

There was a significant association between SCD and use of antithyroid drugs, adjusted for arrhythmia and cerebrovascular ischaemia (OR 2.9; 95% CI 1.1, 7.4). Past use was not associated with an increased risk of SCD.

Sensitivity analysis showed that after exclusion of users of amiodarone, point estimates did not change substantially (OR 3.3; 95% CI 1.3, 8.5). Stratified analyses showed that the association between SCD and use of antithyroid drugs tended to be higher in patients <70 years old (OR 16.1; 95% CI 1.0, 262.0) than in patients older than 70 years (OR 1.8; 95% CI 0.5, 7.3), but this difference was not statistically significant. Effect modification for gender could not be demonstrated.

Discussion

In this study, we have demonstrated in two independent populations that use of antithyroid drugs was associated with an increased risk of SCD. There are two potential explanations for our findings. First, SCD might be an adverse reaction to the antithyroid drugs. However, this seems unlikely since different antithyroid drugs were involved and it lacks a biologically plausible mechanism. Second, patients may still have had inadequately treated hyperthyroidism with increased levels of free T4. Since TSH and free T4 levels were available in only a minority of patients, we could not verify this. Validation of the exposed SCD cases demonstrated that the exposed cases with known TSH measurements had low TSH levels a few days before the index date. This could indicate that these patients were still hyperthyroid at that time. Our findings could suggest that these deaths were caused by undertreatment of hyperthyroidism.

Sudden deaths have been described after therapy with radioactive iodine. However, in the Rotterdam Study none of the exposed patients had received radioactive iodine. In IPCI, one of the exposed controls received radioactive iodine before the index date and none of the exposed cases. Amiodarone may cause iodine-induced thyrotoxicosis, which might worsen arrhythmias and increase mortality [42]. However, excluding all users of amiodarone did not change the point estimates substantially. The association between antithyroid drugs and SCD in our study tended to be higher in younger persons in the case–control study. We did not find effect modification for age in the Rotterdam Study, possibly since in a study of an elderly population there is less age variability. Participants who were treated with a higher dosage had a higher risk of SCD, probably because these participants had more severe hyperthyroidism. Furthermore, participants who were treated for <1 year had an increased risk, possibly due to depletion of susceptibles.

Subclinical hyperthyroidism is associated with increased cardiovascular mortality among persons aged ≥60 years [14]. Hyperthyroidism has been associated with ventricular arrhythmias and SCD in several case reports [16, 21–24, 43]. Recently, we found an association of free T4 with a higher risk of QTc prolongation in men [7]. A potential explanation for this association is increased activity of cardiac Na+/ K+ ATPase in thyroid hormone excess, leading to increased intracellular K+ with subsequent membrane hyperpolarization and an increase in QTc duration [5, 6]. In the Rotterdam Study, the association of antithyroid drugs and SCD tended to be higher in men, which supports the association of free T4 and QTc prolongation in men we found earlier. As far as we know, this is the first time that use of antithyroid drugs has been associated with SCD in two large epidemiological studies.

Our study has several strengths. First, the availability of data on a large group of participants in two independent study populations. We were able to take advantage of the fact that in most cases of SCD, extensive information on the facts surrounding the event was available, which allowed rigorous adjudication of SCD events. Second, the complete coverage of drug-dispensing records in the Rotterdam Study and of prescription data in IPCI allowed us to study the association between antithyroid drugs and SCD. Since the Rotterdam Study is a prospective cohort study within a circumscribed population with little loss to follow-up, selection bias is unlikely. Selection bias is also unlikely in IPCI, which covers the complete population in a circumscribed area, and both cases and controls were selected from the same source population. There is no information bias, since we used pharmacy data and GP data, which are automatically registered, prospectively and irrespective of disease status. Confounding was minimized by adjusting for all known cardiovascular risk factors of SCD. However, our study has also some potential limitations. Not all acute deaths may have been of cardiac origin. We determined SCD, however, on the basis of the full medical records, and all circumstances surrounding the death were available. Recently, an evaluation comparing different methods of determining the incidence of SCD suggested that this method provides a very reliable way of determining SCD cases [44]. Because of the small number of users of antithyroid drugs in our analysis in the Rotterdam Study, we tested the validity of our findings by replication in the IPCI database. The fact that the association was not only demonstrated and subsequently replicated in two independent study populations but also that the point estimates were quite similar confirms the validity of the association between current use of antithyroid drugs and SCD. Second, we could not investigate the mechanism of the association between hyperthyroidism and SCD. The patients using antithyroid drugs could have hyper-, hypo- or normothyroid values. However, since the exposed SCD cases with a thyroid measurement,had a decreased TSH measurement shortly before the index date, it is more likely to be due to the underlying hyperthyroidism than to the antithyroid drugs. Earlier, we demonstrated that free T4 is associated with QTc prolongation in men [7] and also that QTc prolongation is associated with an increased risk of SCD [12].

In conclusion, we have demonstrated that use of antithyroid drugs seems to be associated with a threefold increased risk of SCD. Although this might be due to antithyroid drug use, it could be more readily explained by underlying hyperthyroidism, since increased free T4 levels are associated with QTc prolongation and treated patients who developed SCD still had low TSH levels shortly before death. This suggests that hyperthyroidism may be a risk factor for SCD.

Competing interests

C.V.N. and S.M.J.M.S. work at the Dutch Medicines Evaluation Board. M.C.J.M.S. has acted as a consultant to Pfizer, Servier, Celgene, Novartis and Lundbeck on issues not related to this paper. As an employee of Erasmus MC, M.C.J.M.S. has been involved as project leader and in analyses contracted by various pharmaceutical companies and has received unconditional research grants, none of which are related to the subject of this study, from Pfizer, Merck, Johnson & Johnson, Amgen, Roche, GSK, Boehringer, Yamanouchi and Altana. B.H.Ch.S. works at the Dutch Inspectorate for Health Care.

REFERENCES

  • 1.Campbell AJ, Reinken J, Allan BC. Thyroid disease in the elderly in the community. Age Ageing. 1981;10:47–52. doi: 10.1093/ageing/10.1.47. [DOI] [PubMed] [Google Scholar]
  • 2.Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf) 1991;34:77–83. doi: 10.1111/j.1365-2265.1991.tb01739.x. [DOI] [PubMed] [Google Scholar]
  • 3.Diez JJ. Hyperthyroidism in patients older than 55 years: an analysis of the etiology and management. Gerontology. 2003;49:316–23. doi: 10.1159/000071713. [DOI] [PubMed] [Google Scholar]
  • 4.Gambert SR. Hyperthyroidism in the elderly. Clin Geriatr Med. 1995;11:181–8. [PubMed] [Google Scholar]
  • 5.Colzani RM, Emdin M, Conforti F, Passino C, Scarlattini M, Iervasi G. Hyperthyroidism is associated with lengthening of ventricular repolarization. Clin Endocrinol (Oxf) 2001;55:27–32. doi: 10.1046/j.1365-2265.2001.01295.x. [DOI] [PubMed] [Google Scholar]
  • 6.Polikar R, Burger AG, Scherrer U, Nicod P. The thyroid and the heart. Circulation. 1993;87:1435–41. doi: 10.1161/01.cir.87.5.1435. [DOI] [PubMed] [Google Scholar]
  • 7.van Noord C, van der Deure W, Sturkenboom M, Straus S, Hofman A, Visser T, Kors J, Witteman J, Stricker B. High free T4 levels are associated with QTc prolongation in males. J Endocrinol. 2008;198:253–60. doi: 10.1677/JOE-08-0140. [DOI] [PubMed] [Google Scholar]
  • 8.Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002;287:2215–20. doi: 10.1001/jama.287.17.2215. [DOI] [PubMed] [Google Scholar]
  • 9.Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350:1013–22. doi: 10.1056/NEJMra032426. [DOI] [PubMed] [Google Scholar]
  • 10.Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should know about the QT interval. JAMA. 2003;289:2120–7. doi: 10.1001/jama.289.16.2120. [DOI] [PubMed] [Google Scholar]
  • 11.Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89:1363–72. doi: 10.1136/heart.89.11.1363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Straus SM, Kors JA, De Bruin ML, van der Hooft CS, Hofman A, Heeringa J, Deckers JW, Kingma JH, Sturkenboom MC, Stricker BH, Witteman JC. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol. 2006;47:362–7. doi: 10.1016/j.jacc.2005.08.067. [DOI] [PubMed] [Google Scholar]
  • 13.Fox CS, Evans JC, Larson MG, Kannel WB, Levy D. Temporal trends in coronary heart disease mortality and sudden cardiac death from 1950 to 1999: the Framingham Heart Study. Circulation. 2004;110:522–7. doi: 10.1161/01.CIR.0000136993.34344.41. [DOI] [PubMed] [Google Scholar]
  • 14.Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet. 2001;358:861–5. doi: 10.1016/S0140-6736(01)06067-6. [DOI] [PubMed] [Google Scholar]
  • 15.Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med. 2002;137:904–14. doi: 10.7326/0003-4819-137-11-200212030-00011. [DOI] [PubMed] [Google Scholar]
  • 16.Flynn RW, Macdonald TM, Jung RT, Morris AD, Leese GP. Mortality and vascular outcomes in patients treated for thyroid dysfunction. J Clin Endocrinol Metab. 2006;91:2159–64. doi: 10.1210/jc.2005-1833. [DOI] [PubMed] [Google Scholar]
  • 17.Walsh JP, Bremner AP, Bulsara MK, O'Leary P, Leedman PJ, Feddema P, Michelangeli V. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med. 2005;165:2467–72. doi: 10.1001/archinte.165.21.2467. [DOI] [PubMed] [Google Scholar]
  • 18.Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL, Tracy RP, Ladenson PW. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006;295:1033–41. doi: 10.1001/jama.295.9.1033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Sarma JS, Venkataraman K, Nicod P, Polikar R, Smith J, Schoenbaum MP, Singh BN. Circadian rhythmicity of rate-normalized QT interval in hypothyroidism and its significance for development of class III antiarrhythmic agents. Am J Cardiol. 1990;66:959–63. doi: 10.1016/0002-9149(90)90933-r. [DOI] [PubMed] [Google Scholar]
  • 20.Ochs N, Auer R, Bauer DC, Nanchen D, Gussekloo J, Cornuz J, Rodondi N. Meta-analysis subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Ann Intern Med. 2008;148:832–45. doi: 10.7326/0003-4819-148-11-200806030-00225. [DOI] [PubMed] [Google Scholar]
  • 21.Fisher J. Thyrotoxic periodic paralysis with ventricular fibrillation. Arch Intern Med. 1982;142:1362–4. [PubMed] [Google Scholar]
  • 22.Carey D, Hurst JW, Jr, Silverman ME. Coronary spasm and cardiac arrest after coronary arteriography in unsuspected thyrotoxicosis. Am J Cardiol. 1992;70:833–4. doi: 10.1016/0002-9149(92)90576-k. [DOI] [PubMed] [Google Scholar]
  • 23.Ohshima T, Maeda H, Takayasu T, Fujioka Y, Nakaya T, Saito K, Nagano T. An autopsy case of sudden death due to hyperthyroidism. Nihon Hoigaku Zasshi. 1990;44:365–70. [PubMed] [Google Scholar]
  • 24.Terndrup TE, Heisig DG, Garceau JP. Sudden death associated with undiagnosed Graves' disease. J Emerg Med. 1990;8:553–5. doi: 10.1016/0736-4679(90)90448-5. [DOI] [PubMed] [Google Scholar]
  • 25.Hofman A, Grobbee DE, de Jong PT, van den Ouweland FA. Determinants of disease and disability in the elderly: the Rotterdam Elderly Study. Eur J Epidemiol. 1991;7:403–22. doi: 10.1007/BF00145007. [DOI] [PubMed] [Google Scholar]
  • 26.Hofman A, Breteler MM, van Duijn CM, Krestin GP, Pols HA, Stricker BH, Tiemeier H, Uitterlinden AG, Vingerling JR, Witteman JC. The Rotterdam Study: objectives and design update. Eur J Epidemiol. 2007;22:819–29. doi: 10.1007/s10654-007-9199-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Vlug AE, van der Lei J, Mosseveld BM, van Wijk MA, van der Linden PD, Sturkenboom MC, van Bemmel JH. Postmarketing surveillance based on electronic patient records: the IPCI project. Methods Inf Med. 1999;38:339–44. [PubMed] [Google Scholar]
  • 28.van der Lei J, Duisterhout JS, Westerhof HP, van der Does E, Cromme PV, Boon WM, van Bemmel JH. The introduction of computer-based patient records in The Netherlands. Ann Intern Med. 1993;119:1036–41. doi: 10.7326/0003-4819-119-10-199311150-00011. [DOI] [PubMed] [Google Scholar]
  • 29.Lamberts H, Wood M, Hofmans-Okkes IM. International primary care classifications: the effect of fifteen years of evolution. Fam Pract. 1992;9:330–9. doi: 10.1093/fampra/9.3.330. [DOI] [PubMed] [Google Scholar]
  • 30.Myerburg RJ, Castellanos A. Language and interpretation of clinical trial outcomes: alternates, surrogates, and composites. Heart Rhythm. 2004;1:538–9. doi: 10.1016/j.hrthm.2004.08.005. [DOI] [PubMed] [Google Scholar]
  • 31.Priori SG, Aliot E, Blomstrom-Lundqvist C, Bossaert L, Breithardt G, Brugada P, Camm AJ, Cappato R, Cobbe SM, Di Mario C, Maron BJ, McKenna WJ, Pedersen AK, Ravens U, Schwartz PJ, Trusz-Gluza M, Vardas P, Wellens HJ, Zipes DP. Task Force on Sudden Cardiac Death of the European Society of Cardiology. Eur Heart J. 2001;22:1374–450. doi: 10.1053/euhj.2001.2824. [DOI] [PubMed] [Google Scholar]
  • 32.WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2009. Available at http://www.whocc.no/atcddd/ (last accessed 1 July 2009.
  • 33.Diabetes Mellitus. Technical Reports Series 894. Geneva: World Health Organisation; 1985. [Google Scholar]
  • 34.WHO. World Health Organization–International Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Subcommittee. J Hypertens. 1999;17:151–83. [PubMed] [Google Scholar]
  • 35.Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation. 1997;96:1432–7. doi: 10.1161/01.cir.96.5.1432. [DOI] [PubMed] [Google Scholar]
  • 36.Vliegenthart R, Oudkerk M, Song B, van der Kuip DA, Hofman A, Witteman JC. Coronary calcification detected by electron-beam computed tomography and myocardial infarction. The Rotterdam Coronary Calcification Study. Eur Heart J. 2002;23:1596–603. doi: 10.1053/euhj.2002.3240. [DOI] [PubMed] [Google Scholar]
  • 37.Bleumink GS, Knetsch AM, Sturkenboom MC, Straus SM, Hofman A, Deckers JW, Witteman JC, Stricker BH. Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure. The Rotterdam Study. Eur Heart J. 2004;25:1614–9. doi: 10.1016/j.ehj.2004.06.038. [DOI] [PubMed] [Google Scholar]
  • 38.Mosterd A, Hoes AW, de Bruyne MC, Deckers JW, Linker DT, Hofman A, Grobbee DE. Prevalence of heart failure and left ventricular dysfunction in the general population; The Rotterdam Study. Eur Heart J. 1999;20:447–55. [PubMed] [Google Scholar]
  • 39.Expert Panel on Detection EaToHBCiA. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III) JAMA. 2001;285:2486–97. doi: 10.1001/jama.285.19.2486. [DOI] [PubMed] [Google Scholar]
  • 40.Woosley RL. Drugs that prolong the QTc interval and/ or induce Torsade de Pointes. Available at http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm (last accessed 1 July 2009.
  • 41.Greenland S. Modeling and variable selection in epidemiologic analysis. Am J Public Health. 1989;79:340–9. doi: 10.2105/ajph.79.3.340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.O'Sullivan AJ, Lewis M, Diamond T. Amiodarone-induced thyrotoxicosis: left ventricular dysfunction is associated with increased mortality. Eur J Endocrinol. 2006;154:533–6. doi: 10.1530/eje.1.02122. [DOI] [PubMed] [Google Scholar]
  • 43.Shirani J, Barron MM, Pierre-Louis ML, Roberts WC. Congestive heart failure, dilated cardiac ventricles, and sudden death in hyperthyroidism. Am J Cardiol. 1993;72:365–8. doi: 10.1016/0002-9149(93)90691-5. [DOI] [PubMed] [Google Scholar]
  • 44.Chugh SS, Jui J, Gunson K, Stecker EC, John BT, Thompson B, Ilias N, Vickers C, Dogra V, Daya M, Kron J, Zheng ZJ, Mensah G, McAnulty J. Current burden of sudden cardiac death: multiple source surveillance versus retrospective death certificate-based review in a large U.S. community. J Am Coll Cardiol. 2004;44:1268–75. doi: 10.1016/j.jacc.2004.06.029. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES