Diagnostic errors in the new millennium: a follow-up autopsy study.

A systematic review of the second half of the last century suggested that diagnostic errors have decreased over time. Our previous study covering the years 1972-1992 was then the only time series showing a significant reduction of diagnostic errors from a single institution. We report here the results of a follow-up study a decade later. We analyzed discrepancies between clinical and autoptic diagnoses in 100 randomly selected medical patients who died in the wards and in the medical intensive care unit at a tertiary-care teaching hospital in Switzerland in the year 2002. Autopsy rate declined from around 90% in the years from 1972 to 1992 to 54% in the present study. Major diagnostic errors (class I and II) declined significantly from 30 to 7% (P<0.001) over the last 30 years. Class I errors decreased from 16 to 2% (P<0.001) in the year 2002. Sensitivity for cardiovascular diseases increased from 69 to 92% (P=0.006), for infectious diseases from 25 to 90% (P=0.013) and for neoplastic diseases from 89 to 100% (P=0.053). Specificity for cardiovascular diseases increased from 85 to 98% (P<0.001) but was unchanged at a high level for infectious diseases and neoplastic diseases. The number of diagnostic procedures increased from 144 to 281 (P<0.001) with an increase in the number of computer tomography investigations and of tissue sampling in the last decade. The frequency of major diagnostic errors has been further reduced at the beginning of the new millennium probably due in large part to new diagnostic tools.

Interaction of vitamin K antagonists with heparin affect monitoring by activated clotting times.

BACKGROUND: Unfractionated heparin is recommended during atrial fibrillation (AF) ablation to achieve activated clotting time (ACT) above 250-300 s to prevent clot. Many patients on therapeutic international normalised ratio (INR) undergo AF ablation procedures; however, it is unknown whether they require less heparin to achieve similar ACT levels. METHODS: During AF ablation, the ACT was measured before and 10 min after administration of i.v. unfractionated heparin in patients with and without anticoagulation. The association of INR, heparin, pre-procedure ACT and body weight with ACT after heparin administration was tested using multivariable linear regression models. RESULTS: The subjects of this study were 149 patients undergoing AF ablation, among them 40 (27%) with subtherapeutic INR < 2, 79 (53%) with an INR between 2 and 3, and 30 (20%) patients with INR > 3. Baseline ACT was associated with INR (r = 0.33, p < 0.001). After a mean of 8,685 +/- 2,015 U (range, 5,000-15,000 IU) unfractionated heparin, univariate predictors of ACT were baseline INR (p < 0.001), heparin dose (p = 0.012) and baseline ACT (p = 0.027). In the multivariable model, baseline INR (part r = 0.64, p < 0.001) and heparin dose (part r = 0.33, p < 0.001) strongly predicted post-heparin ACT. Estimated from the regression model, the heparin dose reductions by approximately one third in those with an INR of 2-3 and by at least two thirds in those with an INR above 3 may be favourable. Over the following 3 months, no thromboembolism and acute bleeding were observed. CONCLUSION: The INR was the strongest predictor of post-heparin ACT, even more important than the heparin dose itself. The reduction of heparin dose by one third if INR is between 2-3 and by two thirds if INR is above 3 may be favourable.

Diagnostic performance in a primary referral hospital assessed by autopsy: evolution over a ten-year period.

BACKGROUND: Despite remarkable progress in modern laboratory testing and imaging technology in recent years, diagnostic errors still occur. To assess whether diagnostic performance in a primary referral hospital improves with new diagnostic tools and algorithms, autopsy reports were analyzed over a ten-year period to monitor diagnostic errors. METHODS: Medical reports from 1997 to 2006 were compared retrospectively with autopsy reports. A diagnostic error was assumed when the main clinical diagnosis was missed, independently of whether this influenced the patient's survival or whether this error led to incorrect treatment without effect on survival. Two cardiovascular markers with high sensitivity, namely cardiac troponin T and D-dimer testing and two algorithms for thoracic pain and thromboembolic disease were introduced during the study period. RESULTS: 970 cases were included; the autopsy rate was 50.1%. Cardiovascular diseases were misdiagnosed in 18.7%, followed by infectious diseases in 12.9%, oncological 3.6% and neurological diseases in 1.8%. The most commonly missed diagnoses were myocardial infarction, pulmonary embolism and aortic dissection; however, the rate of errors for cardiovascular diseases decreased over the 10 years (p<0.002). Overall diagnostic sensitivity and specificity rose from 67% to 87% and from 94% to 99%, respectively. CONCLUSION: Autopsy remains a valuable tool to measure diagnostic performance. Errors occur most frequently in cardiovascular events, whereas in malignant and neurological diseases they are rare. The significant improvement of diagnostic accuracy for cardiovascular diseases is associated with the introduction of new sensitive laboratory tests and algorithms for thoracic pain and thromboembolic diseases.

The c.-292C>T promoter polymorphism increases reticulocyte-type 15-lipoxygenase-1 activity and could be atheroprotective.

BACKGROUND: Reticulocyte-type 15-lipoxygenase-1 (ALOX15) has anti-inflammatory and inflammatory effects and is implicated in the development of asthma, arthritis and atherosclerosis. Previously, we screened the human ALOX15 gene for variations because genetic variability in ALOX15 might influence these diseases. We found a C>T substitution at position c.-292 in the ALOX15 promoter that created a novel binding site for the transcription factor SPI1 and increased ALOX15 mRNA levels in monocytes from c.-292CT heterozygous volunteers. METHODS: To test whether the higher mRNA levels led to higher ALOX15 activity, we performed an activity assay and measured the arachidonic acid metabolite 15(S)-hydroxy-eicosatetraenoic acid [15(S)-HETE] by HPLC analysis. To test whether this polymorphism was associated with coronary artery disease (CAD), we investigated its association in a case-control study involving 498 Caucasians. RESULTS: The c.-292C>T polymorphism was associated with higher enzyme activity in heterozygous carriers. Intriguingly, this polymorphism also showed a tendency to be protective against atherosclerosis. CONCLUSIONS: These results suggest that increased ALOX15 activity may attenuate inflammation, which could be caused by an increase in 15(S)-HETE and eventually by its metabolites, the lipoxins.

Ethnicity-dependent genetic association of ABCA2 with sporadic Alzheimer's disease.

A recent study demonstrated a significant genetic association between the ATP-binding cassette transporter A2 (ABCA2) and the risk for Alzheimer's disease (AD) in a large Caucasian sample. The rare T allele of the synonymous exonic single nucleotide polymorphism (SNP) rs908832 was overrepresented in early-onset AD patients as compared to cognitively healthy controls. Here we confirm the association of rs908832 with AD in a Western European population (n = 291, P = 0.008). In a second sample from Southern Europe, rs908832 was not associated with AD. Interestingly, rs908832 was not polymorphic in a Japanese sample. Furthermore, rs908832 was not associated with either serum cholesterol levels or with the risk for coronary artery disease, but seemed to be related to cholesterol levels in the cerebrospinal fluid. These data suggest that ABCA2 may exert population-dependent effects on the genetic risk for sporadic AD and support a role of ABC lipid transporters in the pathogenesis of this disease.

Admission glucose concentrations independently predict early and late mortality in patients with acute myocardial infarction treated by primary or rescue percutaneous coronary intervention.

BACKGROUND: In patients with acute myocardial infarction (MI), increased plasma glucose levels at hospital admission are associated with worse outcome. We aimed to assess the predictive value of admission glucose concentrations on short- and long-term mortality in patients with acute MI undergoing primary or rescue percutaneous coronary intervention (PCI). METHODS: We analyzed the 30-day and long-term (mean follow-up 3.7 years) outcome of 978 patients prospectively included in a single-center registry of patients with acute MI treated with PCI within 24 hours after onset of symptoms. Patients were classified according to plasma glucose levels at admission: < 7.8 mmol/L (group I, n = 322), 7.8 to 11 mmol/L (group II, n = 348), and > 11.0 mmol/L (group III, n = 308). RESULTS: Mortality at 30 days was 1.2% in group I, 6.3% in group II, and 16.6% in group III (P < .001). After multivariate adjustment for age, the presence of cardiogenic shock, and TIMI 3 flow after PCI, the association of mortality with glucose classification remained significant (P value for trend = .003). The relative risk of death at 30 days for group III versus group I was 3.9 (95% CI 1.2-13.2). During long-term follow-up, mortality was similar in groups I and II. However, in group III adjusted mortality remained significantly increased compared with group I (relative risk 1.76, CI 1.01-3.08). CONCLUSIONS: In patients undergoing emergency PCI for acute MI, glucose levels at hospital admission are predictive for short- and long-term survival. Knowledge of admission glucose levels may improve initial bedside risk stratification.

Effects of aggressive versus conventional lipid-lowering therapy by simvastatin on human atherosclerotic lesions: a prospective, randomized, double-blind trial with high-resolution magnetic resonance imaging.

OBJECTIVES: This study sought to compare the effects of aggressive and conventional lipid lowering by two different dosages of the same statin on early human atherosclerotic lesions using serial noninvasive magnetic resonance imaging (MRI). BACKGROUND: Regression of atherosclerotic lesions by lipid-lowering therapy has been reported. METHODS: Using a double-blind design, newly diagnosed hypercholesterolemic patients (n = 51) with asymptomatic aortic and/or carotid atherosclerotic plaques were randomized to 20 mg/day (n = 29) or 80 mg/day (n = 22) simvastatin. Mean follow-up was 18.1 months. A total of 93 aortic and 57 carotid plaques were detected and sequentially followed up by MRI every six months after lipid-lowering initiation. The primary MRI end point was change in vessel wall area (VWA) as a surrogate for atherosclerotic burden. RESULTS: Both statin doses reduced significantly total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) versus baseline (p < 0.001). Total cholesterol decreased by 26% versus 33% and LDL-C by 36% versus 46% in the conventional (20 mg) versus aggressive (80 mg) simvastatin groups, respectively. Although the simvastatin 80-mg group had significantly higher baseline TC and LDL-C levels, both groups reached similar absolute values after treatment. A significant reduction in VWA was already observed by 12 months. No difference on vascular effects was detected between the randomized doses. Post-hoc analysis showed that patients reaching mean on-treatment LDL-C < or = 100 mg/dl had larger decreases in plaque size. CONCLUSIONS: Effective and protracted lipid-lowering therapy with simvastatin is associated with a significant regression of atherosclerotic lesions. No difference in vessel wall changes was seen between high and conventional doses of simvastatin. Changes in vessel wall parameters are more related to LDL-C reduction rather than to the dose of statin.

The CAG repeat polymorphism in the androgen receptor gene is associated with HDL-cholesterol but not with coronary atherosclerosis or myocardial infarction.

BACKGROUND: Age-adjusted morbidity and mortality rates from coronary heart disease (CHD) are higher in men than in women. Androgens are suspected to be responsible for the male disadvantage. The genomic effect of androgens is mediated by the androgen receptor (AR), which has a polymorphic CAG repeat in exon 1. The number of repeats is inversely related to the transcriptional activity of the AR on target genes. METHODS: We investigated the association of this CAG repeat polymorphism with CHD and myocardial infarction (MI) in 2 independent case-control studies involving 544 Caucasian men. RESULTS: The number of CAG repeats in the AR gene correlated significantly with HDL-cholesterol (HDL-C) in controls (r = 0.21; P = 0.015). This effect was independent of triglycerides, body mass index, alcohol intake, smoking, and age in a multiple regression model (R(2) = 50%). Despite decreased HDL-C, lower CAG repeat numbers were not associated with increased risk for CHD (odds ratio = 0.82; 95% confidence interval, 0.50-1.36; P = 0.44) or MI in carriers of AR genes with lower CAG repeat numbers (odds ratio = 0.72; 95% confidence interval, 0.37-1.39; P = 0.33). CONCLUSIONS: Shorter, more androgenic AR alleles with fewer CAG repeats are associated with lower HDL-C, but not with an increased risk for CHD or MI, which argues against a detrimental androgen effect on cardiovascular risk under physiologic conditions.

Rate-dependent AV delay optimization in cardiac resynchronization therapy.

BACKGROUND: During cardiac resynchronization therapy (CRT), cardiac performance is dependent on an optimized atrioventricular delay (AVD). However, the optimal AVD at different heart rates has not been defined yet during CRT. METHOD: The effects of an increase in heart rate by pacing or physical exercise on optimal AVD were studied in 36 patients with biventricular pacemakers/defibrillators. The velocity time integral (VTI) in the left ventricular outflow tract (LVOT) was measured with pulsed Doppler either at three different paced heart rates in the supine position or in seated position before and after physical exercise. RESULTS: The baseline AVD was optimized to 99 +/- 19 ms in the supine and 84 +/- 22 ms in the seated position. When the heart rate was increased by DDD pacing, there was a positive linear relationship between an increase in heart rate, in AVD and in VTI (LVOT-VTI + 0.047 cm/s per 10 beats per minute (bpm) heart rate increase per 20 ms increase in AVD, P = 0.007). A similar but more pronounced relationship was found after physical exercise in the seated position (LVOT-VTI + 0.146 cm/s per 10 bpm heart rate increase per 20 ms increase of AVD, P = 0.013). This effect was observed in patients with and without AV block and mitral regurgitation. CONCLUSIONS: In conclusion, the systolic performance of the dilated ventricle, which depends on an elevated preload, is critically affected by the appropriate timing of the AVD during exercise. In contrast to normal pacemaker patients, in CRT the relatively short baseline AVD should be prolonged at increased heart rates. Further studies with other means of measuring exercise cardiac performance are needed to confirm these unexpected findings.

Texture analysis in digitally-acquired echocardiographic images: the effect of JPEG compression and video storage.

The analysis of texture in video-stored echocardiographic images is an established method to characterize myocardial pathologies. We investigated whether or not texture parameters calculated from video-stored images and those derived from the joint photographic expert group (JPEG) format compressed data are equivalent to those calculated from uncompressed digital images. Texture parameters were calculated using uncompressed digital data, images stored on videotape, and three forms of compressed digital data (baseline JPEG, JPEG 2000 and lossless JPEG 2000). Video storage heavily affected most texture parameters. Although first-order texture parameters derived from JPEG-compressed images were generally equivalent to those derived from the uncompressed data, several second-order parameters differed significantly. We conclude that texture of video-stored images is not comparable to that of digitally-stored images and that JPEG compression changes important second-order texture parameters. This observation should be taken into account when analyzing texture of modern image data (uncompressed or compressed) and comparing the results with earlier studies utilizing video-stored data.

Folic Acid improves baroreceptor sensitivity in hypertension.

In hypertension baroreceptor-mediated modulation of heart rate is impaired, resulting in a decreased vagal control. Reactive oxygen species produced locally in the vasculature decrease baroreceptor sensitivity. Folic acid has antioxidant properties. Therefore, the aim of this study was to test whether folic acid improves baroreceptor function in hypertension. Twenty-one male patients with hypertension not taking any drugs for 2 weeks participated in the study and were randomized to folic acid 5 mg or matching placebo. Cardiac and vascular sympathetic baroreceptor functions were tested before and after a single dose of folic acid or placebo with two different methods: the alpha-coefficient method and the phenylephrine (PE) and sodium nitroprusside (SNP) bolus method. In the folic acid group both methods showed significantly improved cardiac and vascular sympathetic baroreceptor sensitivity compared with placebo. This study provides evidence that folic acid improves cardiac and vascular sympathetic baroreceptor sensitivity in hypertensive patients, which suggests an improved vagal control and an enhanced baroreceptor modulation of sympathetic vasomotor tone. Thus, folic acid may represent a novel treatment for prevention of orthostatic dysregulation and/or arrhythmic complications resulting from baroreceptor dysfunction.

Relation of sex, age and concomitant diseases to drug prescription for heart failure in primary care in Europe.

AIM: To study the role of sex, age and concomitant diseases for prescription of cardiovascular drugs among patients with heart failure cared for in the community. METHODS AND RESULTS: In 15 European countries, a survey was conducted during 1999 and 2000 among 1363 primary care physicians who included 8256 patients with symptoms of heart failure. Predictors of drug prescription were assessed with multivariate logistic regression. Overall prescription rates for ACE-inhibitors/angiotensin receptor blockers (ACE-I/ARB), beta-blockers, digitalis, diuretics and oral anticoagulants were 69%, 30%, 41%, 75% and 18%. Women had no reduced likelihood to receive ACE-I/ARB and beta-blockers (odds ratio [OR]=0.96 [95% CI 0.87-1.06] and 1.02 [0.92-1.13], respectively), but prescription of oral anticoagulants was decreased (OR=0.74, 95% CI 0.65-0.84). Compared to patients <65 years of age, ACE-I/ARB prescription did not materially decline up to 75-85 years (R=0.91, 95% CI 0.81-1.04), whereas beta-blocker prescription was already significantly decreased in this age category (OR=0.49, 95% CI 0.43-0.56). There was no general under-prescription of evidence-based cardiovascular drugs in patients with concomitant diseases. CONCLUSIONS: Among heart failure patients cared for in the community advanced age strongly predicts decreased prescription of beta-blockers. Female sex and comorbidity is not associated with a consistent underutilization of evidence-based cardiovascular drugs.

Gender and noninvasive diagnosis of coronary artery disease in women and men.

OBJECTIVES: The purpose of this prospective study was to investigate the impact of the gender of physicians and patients on the accuracy of diagnosing coronary artery disease (CAD) based on the patient history only. METHODS: Screening involved 1082 consecutive patients undergoing coronary angiography for suspected CAD. Known CAD was an exclusion criterion. The inclusion criteria were met by 144 patients (47 females). All patients were inverviewed by both an experienced male cardiologist (n=6) and an experienced female cardiologist (n=5), who had to state before coronary angiography if CAD was present relying solely on the patient interview. Eligible subjects also answered a questionnaire. Diagnostic performance to assess the presence or absence of CAD by history taking by male and female cardiologists, exercise testing, patient self-assessment, and the questionnaire were compared. RESULTS: Coronary angiography showed significant CAD in 20 females (43%) and 70 males (72%). Diagnostic accuracy was not different between male (79%) and female (79%) cardiologists and comparable to the results of exercise testing (74%) but better than self-assessment by the patients (65%, p=0.01) or a questionnaire (68%, p=0.01). The accuracy of female physicians was better in men than in women (85% vs. 66%, p=0.01). The specificity of male physicians tended to be better in women than in men (74% vs. 59%, p=0.25). Female cardiologists overestimated the presence of CAD in women (specificity 48% vs. 74%, p=0.04). CONCLUSIONS: The female cardiologists did not assess women more accurately than did their male colleagues. The diagnostic accuracy of these male and female cardiologists was quite good. However, both tend to assess patients of the opposite gender more specifically. There may be an impact of the gender of the physician on the accuracy of diagnosis of CAD by history taking.

National survey on prescription of cardiovascular drugs among outpatients with coronary artery disease in Switzerland.

BACKGROUND: Secondary prevention of coronary artery disease markedly reduces cardiovascular mortality and non-fatal endpoints. Outpatient care of subjects with coronary artery disease has been assessed in several European countries, but no current data is available for Switzerland. METHODS: A random sample of office-based physicians across Switzerland recorded current drug prescription of outpatients with coronary artery disease in the years 2000/2001 by means of a mail questionnaire. We assessed treatment frequencies according to different patient characteristics. RESULTS: 565 patients were included (mean age 68 +/- 11 years, 75% male). There was no evidence for differences in drug utilisation among the regions. Drug prescription rates for antithrombotic agents, beta-blockers, ACE-inhibitors/angiotensin receptor blockers and lipid lowering drugs were 91%, 58%, 50% and 63% respectively. Lower treatment rates were observed among patients >70 years and in those without a history of myocardial infarction or coronary revascularisation. Forty-nine percent of the patients had a blood pressure >140/>90, and 60% had lipid readings above the intervention cut-off according to the Swiss recommendations. Among those without a history of myocardial infarction or coronary revascularisation, the respective figures were 60% and 80%. CONCLUSIONS: Compared to former surveys evidence based drug prescription has improved in Switzerland. Despite this, therapeutic goals for cholesterol levels and blood pressure are not being reached in a large proportion of patients. A high risk group for under use of evidence based drugs are patients without a history of myocardial infarction or coronary revascularisation.

Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality.

BACKGROUND: Although basic research suggests that vitamins may have an important role in the prevention of cardiovascular diseases (CVD), the data from cohort studies and clinical trials are inconclusive. METHODS: This prospective cohort study was conducted among 83 639 male physicians residing in the United States who had no history of CVD or cancer. At baseline, data on use of vitamin E, ascorbic acid (vitamin C), and multivitamin supplements were provided by a self-administered questionnaire. Mortality from CVD and coronary heart disease (CHD) was assessed by death certificate review. RESULTS: Use of supplements was reported by 29% of the participants. During a mean follow-up of 5.5 years, 1037 CVD deaths occurred, including 608 CHD deaths. After adjustment for several cardiovascular risk factors, supplement use was not significantly associated with total CVD or CHD mortality. For vitamin E use, the relative risks (RRs) were 0.92 (95% confidence interval [CI], 0.70-1.21) for total CVD mortality and 0.88 (95% CI, 0.61-1.27) for CHD mortality; for use of vitamin C, the RRs were 0.88 (95% CI, 0.70-1.12) for total CVD mortality and 0.86 (95% CI, 0.63-1.18) for CHD mortality; and for use of multivitamin supplements, the RRs were 1.07 (95% CI, 0.91-1.25) for total CVD mortality and 1.02 (95% CI, 0.83-1.25) for CHD mortality. CONCLUSIONS: In this large cohort of apparently healthy US male physicians, self-selected supplementation with vitamin E, vitamin C, or multivitamins was not associated with a significant decrease in total CVD or CHD mortality. Data from ongoing large randomized trials will be necessary to definitely establish small potential benefits of vitamin supplements on subsequent cardiovascular risk.

Validity of self-reported exercise-induced sweating as a measure of physical activity among patients with coronary artery disease.

BACKGROUND: In several epidemiological studies, self-reported exercise-induced sweating has been used as a measure of physical activity (PA). Among healthy subjects it is moderately well associated with other measures of PA and physical fitness, but its validity among patients with coronary artery disease (CAD) has not yet been established. METHODS: In a self-administered questionnaire, 233 patients undergoing coronary angiography replied to the question 'In the past 4 weeks, how often have you exercised vigorously enough to work up a sweat?" Patients also gave the frequency and duration of different PA. We examined the association of the sweat frequency question with light (<4 metabolic equivalents [METs]), moderate (4.0-5.9 METs) and intense (>6 METs) PA, and tested the association with maximum exercise capacity. RESULTS: The frequency of self-reported exercise-induced sweating was significantly (p <0.001) associated with both moderate and intense PA. The correlation coefficient of moderate and intense PA with sweat frequency was r = 0.34 (p<0.001), and r = 0.44 (p <0.001) for the respective PA of >30 minutes' duration. The strength of the association between sweat frequency and caloric expenditure per time was similar (moderate and intense PA, r = 0.43, p <0.001). There was a significant correlation between maximum exercise capacity measured in METs and sweat frequency (r = 0.37, p <0.001). CONCLUSIONS: These results suggest that for studies among patients with CAD, assessment of the frequency of self-reported exercise-induced sweating provides useful information regarding moderate and intense PA as well as physical exercise capacity.