Garbage codes in the Norwegian Cause of Death Registry 1996-2019.

BACKGROUND: Reliable statistics on the underlying cause of death are essential for monitoring the health in a population. When there is insufficient information to identify the true underlying cause of death, the death will be classified using less informative codes, garbage codes. If many deaths are assigned a garbage code, the information value of the cause-of-death statistics is reduced. The aim of this study was to analyse the use of garbage codes in the Norwegian Cause of Death Registry (NCoDR). METHODS: Data from NCoDR on all deaths among Norwegian residents in the years 1996-2019 were used to describe the occurrence of garbage codes. We used logistic regression analyses to identify determinants for the use of garbage codes. Possible explanatory factors were year of death, sex, age of death, place of death and whether an autopsy was performed. RESULTS: A total of 29.0% (290,469/1,000,128) of the deaths were coded with a garbage code; 14.1% (140,804/1,000,128) with a major and 15.0% (149,665/1,000,128) with a minor garbage code. The five most common major garbage codes overall were ICD-10 codes I50 (heart failure), R96 (sudden death), R54 (senility), X59 (exposure to unspecified factor), and A41 (other sepsis). The most prevalent minor garbage codes were I64 (unspecified stroke), J18 (unspecified pneumonia), C80 (malignant neoplasm with unknown primary site), E14 (unspecified diabetes mellitus), and I69 (sequelae of cerebrovascular disease). The most important determinants for the use of garbage codes were the age of the deceased (OR 17.4 for age ≥ 90 vs age < 1) and death outside hospital (OR 2.08 for unknown place of death vs hospital). CONCLUSION: Over a 24-year period, garbage codes were used in 29.0% of all deaths. The most important determinants of a death to be assigned a garbage code were advanced age and place of death outside hospital. Knowledge of the national epidemiological situation, as well as the rules and guidelines for mortality coding, is essential for understanding the prevalence and distribution of garbage codes, in order to rely on vital statistics.

Completeness and correctness of acute myocardial infarction diagnoses in a medical quality register and an administrative health register.

Aims: Health registers are used for administrative purposes, disease surveillance, quality assessment, and research. The value of the registers is entirely dependent on the quality of their data. The aim of this study was to investigate and compare the completeness and correctness of the acute myocardial infarction (AMI) diagnosis in the Norwegian Myocardial Infarction Register and in the Norwegian Patient Register. Methods: All Norwegian patients admitted directly to St Olavs hospital, Trondheim University Hospital, Trondheim University Hospital from 1 July to 31 December 2012 and who had plasma levels of cardiac troponin T measured during their hospitalization (n=4835 unique individuals, n=5882 hospitalizations) were identified in the hospital biochemical database. A gold standard for AMI was established by evaluation of maximum troponin T levels and by review of the information in the medical records. Cases of AMI in the registers were classified as true positive, false positive, true negative, and false negative according to the gold standard. We calculated sensitivity, positive predictive value (PPV), specificity, and negative predictive value (NPV). Results: The Norwegian Myocardial Infarction Register had a sensitivity of 86.0% (95% confidence interval (CI) 82.8-89.3%), PPV of 97.9% (96.4-99.3%), and specificity of 99.9% and NPV of 98.9% (98.6-99.2%) (99.8-100%). The corresponding figures for the Norwegian Patient Register were 85.8% (95% CI 82.5-89.1%), 95.1% (92.9-97.2%), and 99.7% (99.5-99.8%) and 98.9% (98.6-99.2%), respectively. Both registers had a sensitivity higher than 95% when compared to hospital discharge diagnoses. The results were similar for men and women and for cases below and above 80 years of age. Conclusions: The Norwegian Myocardial Infarction Register and the Norwegian Patient Register are adequately complete and correct for administrative purposes, disease surveillance, quality assessment, and research.

Injury death certificates without specification of the circumstances leading to the fatal injury - the Norwegian Cause of Death Registry 2005-2014.

BACKGROUND: For injury deaths, the underlying cause of death is defined as the circumstances leading to the injury. When this information is missing, the ICD-10 code X59 (Exposure to unspecified factor) is used. Lack of knowledge of factors causing injuries reduces the value of the cause of death statistics. The aim of this study was to identify predictors of X59-coded deaths in Norway, and to assess methods to identify the true underlying cause of injury deaths. METHODS: We used data from the Norwegian Cause of Death Registry from 2005 to 2014. We used logistic regression to identify determinants of X59-coded deaths. For redistribution of the X59 deaths, we used a multinomial logistic regression model based on the cases where injury circumstances were known. The data were divided into training and test sets. The model was developed on the training set and assessed on the test set before it was applied to the X59 deaths. The models used death certificate information on the nature of injury and demographic characteristics as predictor variables. Furthermore, we mailed a query to the certifying physicians of X59 deaths reported in the year 2015, where we asked for additional information on the circumstances leading to the fatal injury. RESULTS: There were 24,963 injury deaths reported to the Cause of Death Registry of Norway 2005-2014. Of these, 6440 (25.8%) lacked information on the circumstances leading to the death. The strongest predictor for a X59 death was the nature of injury (hip fracture), followed by lack of information on the scene of injury. Applying our redistribution algorithm, we estimated that 97% of the X59-coded deaths were accidental falls. The strongest covariate was the nature of injury, followed by place of death and age at death. In 2015, there were 591 X59-coded deaths. Queries were sent to the certifying doctors in 559 cases. Among the informative replies to the query, 88% of the deaths were reclassified to accidental falls. CONCLUSIONS: A large proportion of injury deaths in Norway lack information on the circumstances leading to the fatal injury. Typically, these deaths represent accidental falls causing hip fracture in elderly individuals.

Births in Norwegian midwife-led birth units 2008-10; a population-based study. / Fødestuefødsler i Norge 2008­10 ­ en populasjonsbasert studie.

BAKGRUNN: Fødestuene utgjør en del av en differensiert og desentralisert fødselsomsorg i Norge. Hensikten med studien var å undersøke forekomst og karakteristika ved planlagte og ikke-planlagte fødestuefødsler og årsaker til overflytting samt resultater for mor og barn. MATERIALE OG METODE: I perioden 2008-10 ble et tilleggsskjema til rutinemeldingen til Medisinsk fødselsregister fortløpende utfylt av jordmor for 2 514 av i alt 2 556 (98,4 %) fødestuefødsler og for 220 fødsler som var planlagt i fødestue, men der fødselen foregikk andre steder. Data fra tilleggsskjema ble så koblet med rutinedata i Medisinsk fødselsregister og resultater fra fødestuefødsler sammenlignet med resultater fra en lavrisikofødepopulasjon i sykehus. RESULTATER: Av de 2 514 fødestuefødslene var 2 320 (92,3 %) planlagt å foregå der, mens 194 (7,7 %) ikke var det. Ved planlagt fødestuefødsel ble totalt 6,9 % overflyttet til sykehus under fødsel, hvorav 19,5 % blant førstegangsfødende. Det var 0,4 % operative vaginale fødsler ved vanlige fødestuer, 3,5 % ved forsterkede fødestuer og 12,7 % ved fødsler overflyttet fra fødestue til sykehus. Blant barn født i fødestue hadde 0,6 % apgarskår < 7 ved 5 minutter, mot 1,0 % blant barn født i lavrisikosammenligningsgruppen i sykehus (p = 0,04). FORTOLKNING: Fødestuer bør rapportere resultater for alle som var selektert for å føde der, uansett om fødselen endte med å foregå i fødestuen eller andre steder.

Validation of data in the Medical Birth Registry of Norway on delivery after a previous cesarean section.

INTRODUCTION: Trial of labor (TOL) is an option in most deliveries after a previous cesarean section (CS). The Medical Birth Registry of Norway (MBRN) has received compulsory notification of all deliveries in the country since 1967, including data that could identify TOL in epidemiologic research. The objective of this study was to validate MBRN data for identification of TOL deliveries after a previous cesarean section (CS). MATERIAL AND METHODS: The MBRN provided a random national sample of 500 birth order two deliveries during 1989-2012 in women with a registered birth order one CS delivery. The reporting maternity units were asked to complete a questionnaire on data items in both deliveries, using hospital record data as the gold standard. RESULTS: Completed questionnaires were returned for 477 women (95.5%) with data on both deliveries. An algorithm to identify TOL using MBRN data from the birth order two delivery had a positive predictive value of 93.2%, a negative predictive value of 93.5%, a sensitivity of 96.1%, and a specificity of 88.8%. Validity of MBRN data on mode and onset of delivery, CS subtype, and planned mode of delivery is also reported. CONCLUSIONS: MBRN data on planned and actual mode of delivery, CS subtype, and the algorithm to identify TOL in deliveries after a previous CS had satisfactory quality for a registry-based study of TOL.

Educational inequalities in mortality of patients with atrial fibrillation in Norway.

OBJECTIVES: We explored the educational gradient in mortality in atrial fibrillation (AF) patients. DESIGN: We prospectively followed patients hospitalized with AF as primary discharge diagnosis in the Cardiovascular Disease in Norway 2008-2012 project. The average length of follow-up was 2.4 years. Mortality by educational level was assessed by Cox proportional hazard models. Population attributable fractions (PAF) were calculated. Analyses stratified by age (≤75 and >75 years of age), and adjusted for age, gender, medical intervention, and Charlson Comorbidity Index. RESULTS: Of 42,138 AF patients, 16% died by end of 2012. Among younger patients, those with low education (≤10 years) had a HR of 2.3 (95% confidence interval 2.0, 2.6) for all-cause mortality relative to those with any college or university education. Similar results were observed for cardiovascular mortality. Disparities in mortality were greater among younger than older patients. A PAF of 35.9% (95% confidence interval 27.9, 43.1) was observed for an educational level of high school/vocational school or less versus higher education in younger patients. CONCLUSIONS: Increasing educational level associated with better prognosis suggesting underlying education-related behavioral and medical determinants of mortality. A considerable proportion of mortality within 5 years following hospital discharge could be prevented.

The universal 2012 definition of myocardial infarction compared to the 2007 definition.

OBJECTIVES: The third Universal 2012 definition of myocardial infarction (MI) has not been compared to the Universal 2007 definition with regard to the number of cases identified, classification and mortality. DESIGN: We examined potential MI events according to the two universal definitions in 1494 patients admitted to the University hospital during the 12 months. Patients were included either because of an MI discharge diagnosis (815 patients) or due to elevated troponin I levels without an MI discharge diagnosis (679 patients). RESULTS: Applying the Universal 2012 definition resulted in 760 of the 1494 patients suffering from MI, as compared to 769 according to the Universal 2007 definition. The lower number of MI events applying the 2012 definition was mainly explained by the stricter definition of Type 4a MI. The 760 MI events were classified as Type 1 (685), 2 (27), 3 (28), 4a (13), 4b (3) and 5 (4). CONCLUSIONS: The application of the third Universal 2012 definition of MI instead of the Universal 2007 definition resulted in a 1% reduction of the total number of MIs. For a practical clinical purpose, the reduction was confined to patients with Type 4a MI. The change of definition had no impact on all-cause mortality.

Comparison of the validity of stroke diagnoses in a medical quality register and an administrative health register.

AIMS: Health registers are essential sources of data used in a wide range of stroke research, including epidemiological, clinical and healthcare studies. Regardless of the type of register, the data must be of high quality to be useful. In this study, we investigated and compared the correctness and completeness of the Norwegian Patient Register (an administrative health register) and the Norwegian Stroke Register (a medical quality register for acute stroke). METHODS: We reviewed the medical records for 5192 admissions to hospital in 2012 and defined cases of stroke in the two registers as true positive, false positive, true negative or false negative. We calculated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value with 95% confidence intervals assuming a normal approximation of the binomial distribution. RESULTS: The Norwegian Stroke Register was highly correct and relatively complete (sensitivity 88.1%, specificity 100% and PPV 98.6%). The Norwegian Patient Register was more complete, but less correct, when we included both the main and secondary diagnoses of stroke (sensitivity 96.8%, specificity 99.6% and PPV 79.7%); restricting the analyses to the main diagnoses of stroke resulted in less complete and more correct registrations (sensitivity 86.1%, specificity 99.9% and PPV 93.5%). CONCLUSIONS: The Norwegian Stroke Register and the Norwegian Patient Register are adequately complete and correct to serve as valuable sources of data for epidemiological, clinical and healthcare studies, as well as for administrative purposes.

Comparison of data from the Cause of Death Registry and the Norwegian Patient Register.

BACKGROUND: The quality of the data in the Cause of Death Registry is crucial to produce reliable statistics on causes of death. The Cancer Registry of Norway uses data from the Norwegian Patient Register to request information from hospitals regarding patients registered with cancer in the patient registry, but not in the cancer registry. We wanted to investigate whether data from the Norwegian Patient Register can also be used to advantage in the Cause of Death Registry. MATERIAL AND METHOD: Data from the Cause of Death Registry on deaths that occurred during the period 2009 ­ 2011 (N = 124,098) were collated with data on contact with somatic hospitals and psychiatric institutions during the last year of life, retrieved from the Norwegian Patient Register. Causes of death were grouped in the same way as in standard statistics on causes of death. RESULTS: Out of 124,098 deaths, altogether 34.9% occurred in somatic hospitals. A total of 80.9% of all deceased had been admitted to a somatic hospital and/or had attended an outpatient consultation during their last year of life. The proportion with hospital contact was highest for those whose cause of death was cancer. In cases of unknown/unspecified cause of death, more than half also had contact with hospitals, but the majority of these were registered with only outpatient consultations. Altogether 5.4% of all deceased had been admitted to and/or had an outpatient consultation in a psychiatric institution during their last year of life. For those whose cause of death was suicide, this proportion amounted to 41.8%. INTERPRETATION: In case of incomplete information on the cause of death, data from the Norwegian Patient Register can supply valuable information on where the patient has been treated, thus enabling the Cause of Death Registry to contact the hospitals in question. However, any potential benefit is restricted by the fact that deceased persons with unknown/unspecified causes of death had less frequently been admitted to hospital during their last year of life.

Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50,000 individuals.

BACKGROUND: Some countries fortify flour with folic acid to prevent neural tube defects but others do not, partly because of concerns about possible cancer risks. We aimed to assess any effects on site-specific cancer rates in the randomised trials of folic acid supplementation, at doses higher than those from fortification. METHODS: In these meta-analyses, we sought all trials completed before 2011 that compared folic acid versus placebo, had scheduled treatment duration at least 1 year, included at least 500 participants, and recorded data on cancer incidence. We obtained individual participant datasets that included 49,621 participants in all 13 such trials (ten trials of folic acid for prevention of cardiovascular disease [n=46,969] and three trials in patients with colorectal adenoma [n=2652]). All these trials were evenly randomised. The main outcome was incident cancer (ignoring non-melanoma skin cancer) during the scheduled treatment period (among participants who were still free of cancer). We compared those allocated folic acid with those allocated placebo, and used log-rank analyses to calculate the cancer incidence rate ratio (RR). FINDINGS: During a weighted average scheduled treatment duration of 5·2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57·3 nmol/L for the folic acid groups vs 13·5 nmol/L for the placebo groups), but had no significant effect on overall cancer incidence (1904 cancers in the folic acid groups vs 1809 cancers in the placebo groups, RR 1·06, 95% CI 0·99­1·13, p=0·10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p=0·23), or between the two overall results in the cadiovascular prevention trials and the adenoma trials (p=0·13). Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site. INTERPRETATION: Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials. FUNDING: British Heart Foundation, Medical Research Council, Cancer Research UK, Food Standards Agency.

Plasma dimethylglycine and risk of incident acute myocardial infarction in patients with stable angina pectoris.

OBJECTIVE: Dimethylglycine is linked to lipid metabolism, and increased plasma levels may be associated with adverse prognosis in patients with coronary artery disease. We evaluated the relationship between plasma dimethylglycine and risk of incident acute myocardial infarction in a large prospective cohort of patients with stable angina pectoris, of whom approximately two thirds were participants in a B-vitamin intervention trial. Model discrimination and reclassification when adding plasma dimethylglycine to established risk factors were obtained. We also explored temporal changes and the test-retest reliability of plasma dimethylglycine. APPROACH AND RESULTS: Four thousand one hundred fifty patients (72% men; median age 62 years) were included. Plasma dimethylglycine was associated with several traditional coronary artery disease risk factors. During a median follow-up of 4.6 years, 343 (8.3%) patients experienced an acute myocardial infarction. The hazard ratio (95% confidence interval) for acute myocardial infarction was 1.95 (1.42-2.68; P<0.001) when comparing plasma dimethylglycine quartile 4 to 1 in a Cox regression model adjusted for age, sex, and fasting status. Adjusting for traditional coronary artery disease risk factors only slightly modified the estimates, which were particularly strong among nonsmokers and among patients with serum triglyceride or apolipoprotein B100 levels ≤ median (P for interaction=0.004, 0.004, and 0.03, respectively). Plasma dimethylglycine improved discrimination and reclassification and had high test-retest reliability. CONCLUSIONS: Plasma dimethylglycine is independently related to incident acute myocardial infarction and enhances risk prediction in patients with stable angina pectoris. Our results motivate further studies on the relationship between 1-carbon metabolism and atherothrombosis. A potential interplay with lipid and energy metabolism merits particular attention.

Urinary excretion of kynurenine and tryptophan, cardiovascular events, and mortality after elective coronary angiography.

AIMS: Kynurenine is a potent endothelium-derived vasodilator. Its synthesis from tryptophan is stimulated by interferon γ and may represent an important compensatory pathway for the regulation of vascular function in inflammatory conditions. We assessed associations of urine kynurenine to tryptophan ratio (KTR) levels to incident major coronary events (MCEs), acute myocardial infarction (AMI), and ischaemic stroke and mortality in patients with suspected stable coronary artery disease (CAD). METHODS AND RESULTS: A total of 3224 patients (mean age 62 years, 69% men) underwent urine and blood sampling prior to elective coronary angiography and were subsequently followed up for median 55 months. A total of 8.4% experienced an MCE, 7.8% suffered an AMI, and 7.6% died. In age- and gender-adjusted analyses, the hazard ratios [HRs; 95% confidence intervals (CI)] of MCE, AMI, and all-cause mortality were 1.43 (1.29-1.59), 1.44 (1.29-1.59), and 1.38 (1.23-1.54) per standard deviation increment of the (log-transformed) urinary KTR, respectively. These estimates were only minimally attenuated after adjustment for potential confounders. The addition of the urine KTR to a model of conventional risk factors significantly improved goodness of fit, discrimination, and risk classification for these clinical endpoints. No association was seen between the urine KTR and the risk of incident ischaemic stroke. CONCLUSION: A novel urinary inflammation marker, KTR, is strongly associated with adverse prognosis in patients with suspected stable CAD. Underlying pathomechanisms should be further elucidated.

Systemic markers of interferon-γ-mediated immune activation and long-term prognosis in patients with stable coronary artery disease.

OBJECTIVE: Interferon γ (IFN-γ) is centrally involved in atherosclerosis-related inflammation, but its activity cannot be reliably assessed by systemic measurements. In activated macrophages, IFN-γ stimulates production of neopterin and conversion of tryptophan to kynurenine. We evaluated the relationships of plasma neopterin and plasma kynurenine:tryptophan ratio (KTR) to long-term prognosis in patients with stable angina pectoris and angiographically verified significant coronary artery disease. METHODS AND RESULTS: Samples were obtained from 2380 patients with a mean age of 63.7 years; 77.3% were men. During a median follow-up of 56 months, 10.8% of patients experienced a major coronary event (MCE), and 9.5% died. For MCE, each SD increment of neopterin and KTR (logarithmically transformed) was associated with multivariable adjusted hazard ratios and 95% CIs of 1.28 (1.10 to 1.48) and 1.28 (1.12 to 1.48), respectively. The corresponding hazard ratios (95% CIs) for all-cause mortality were 1.40 (1.21 to 1.62) (neopterin) and 1.23 (1.06 to 1.43) (KTR). CONCLUSIONS: In patients with stable angina pectoris, systemic markers of IFN-γ activity, plasma neopterin, and plasma KTR provide similar risk estimates for MCE and mortality. Our results support experimental data linking IFN-γ to acute atherosclerotic complications.

Low plasma vitamin B-6 status affects metabolism through the kynurenine pathway in cardiovascular patients with systemic inflammation.

It is unclear whether reduced plasma pyridoxal 5'-phosphate (PLP) during inflammation reflects an altered distribution or increased requirement of vitamin B-6 that may impair overall vitamin B-6 status in tissues. In plasma from 3035 patients undergoing coronary angiography for suspected coronary heart disease, we investigated if plasma concentrations of any metabolites in the kynurenine pathway, which depend on PLP as cofactor, may serve as metabolic marker(s) of vitamin B-6 status. We also examined the association of vitamin B-6 status with serum or plasma concentrations of several inflammatory markers. Among the kynurenines, only 3-hydroxykynurenine (HK) was inversely related to PLP and showed a positive relation to 4 investigated inflammatory markers. A segmented relationship was observed between PLP and HK, with a steep slope at PLP concentrations < 18.4 nmol/L, corresponding to the 5th percentile, and an almost zero slope at higher PLP concentrations. Low PLP and the steep PLP-HK slope were essentially confined to participants with 1 or more inflammatory markers in the upper tertile. Oral supplementation with pyridoxine hydrochloride (40 mg/d) for 1 mo increased plasma PLP 8-fold, reduced the geometric mean (95% CI) of HK from 29.5 to 20.2 nmol/L (P < 0.001), and abolished the steep segment of the PLP-HK curve. The steep inverse relationship of plasma PLP with HK at low plasma PLP and the lowering of HK by pyridoxine suggest plasma HK as a metabolic marker of vitamin B-6 status. Thus, low plasma PLP during inflammation may reflect impaired cellular vitamin B-6 status, as indicated by the concurrent increase in plasma HK.

Long- and short-term effects of tobacco smoking on circulating concentrations of B vitamins.

BACKGROUND: Smoking is associated with decreased concentrations of several antioxidant vitamins. We sought to determine the relation between circulating concentrations of selected B vitamins and smoking status, with particular attention to longitudinal associations. METHODS: We used baseline data from 2 B-vitamin intervention trials that included 6837 patients with ischemic heart disease. Smoking habits were ascertained by interview. Vitamins and metabolites, including the nicotine metabolite cotinine, were measured in plasma and serum by microbiological assays or gas/liquid chromatography-tandem mass spectrometry. RESULTS: The highest circulating concentrations of folate and pyridoxal 5'phosphate (PLP) and lowest concentrations of total plasma homocysteine, a functional marker of folate status, were observed for self-reported never smokers, followed by self-reported ex-smokers and current smokers (P(trend) < 0.001). Cobalamin and its functional marker methylmalonic acid were not associated with smoking status. Based on their low cotinine concentrations, we were able to identify a group of smokers that had abstained from smoking for 3 days or more. Compared with smokers with high plasma cotinine, smokers with low cotinine had significantly higher circulating concentrations of folate, PLP, and riboflavin (all P < 0.005), and this trend continued for ex-smokers, with increasing time since smoking cessation. CONCLUSIONS: Smoking lowered circulating concentrations of folate, PLP, and riboflavin, but concentrations increased significantly after a few days of smoking cessation. We propose that short-term effects may be related to acute smoking-induced oxidative stress, whereas the longer-lasting effects among ex-smokers may reflect changes in diet and/or restoration of vitamin concentrations in tissue during the first few months to years after smoking cessation.

Cancer incidence and mortality after treatment with folic acid and vitamin B12.

CONTEXT: Recently, concern has been raised about the safety of folic acid, particularly in relation to cancer risk. OBJECTIVE: To evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality in 2 randomized controlled trials. DESIGN, SETTING, AND PARTICIPANTS: Combined analysis and extended follow-up of participants from 2 randomized, double-blind, placebo-controlled clinical trials (Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial). A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007. INTERVENTIONS: Oral treatment with folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) and vitamin B(6) (40 mg/d) (n = 1708); folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) (n = 1703); vitamin B(6) alone (40 mg/d) (n = 1705); or placebo (n = 1721). MAIN OUTCOME MEASURES: Cancer incidence, cancer mortality, and all-cause mortality. RESULTS: During study treatment, median serum folate concentration increased more than 6-fold among participants given folic acid. After a median 39 months of treatment and an additional 38 months of posttrial observational follow-up, 341 participants (10.0%) who received folic acid plus vitamin B(12) vs 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03-1.41; P = .02). A total of 136 (4.0%) who received folic acid plus vitamin B(12) vs 100 (2.9%) who did not receive such treatment died from cancer (HR, 1.38; 95% CI, 1.07-1.79; P = .01). A total of 548 patients (16.1%) who received folic acid plus vitamin B(12) vs 473 (13.8%) who did not receive such treatment died from any cause (HR, 1.18; 95% CI, 1.04-1.33; P = .01). Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B(12). Vitamin B(6) treatment was not associated with any significant effects. CONCLUSION: Treatment with folic acid plus vitamin B(12) was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00671346.