Statistical evaluation of biomedical studies.

The aim of this chapter is to familiarize the reader with the basic information and common statistical analyses used in medical research. The chapter will aid in deciding what type of analyses best fit the study data and how each analysis differs. The chapter was written to be user-friendly from a medical research and statistical consultant perspective.

A randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of dual ACE/NEP inhibitor GW660511X in mild-to-moderate hypertensive patients.

This multicentre, double-blind, placebo-controlled, parallel-group study determined the efficacy and safety of GW660511 200 mg, a dual inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), in mild-to-moderate hypertensive patients (diastolic blood pressure (DBP), > or =90 and < or =109 mm Hg; systolic blood pressure (SBP), > or =150 and < or =180 mm Hg). After a single-blind 2- to 4-week placebo run-in period, 123 patients (aged 18-65 years) were randomized to either placebo (n=62) or to active treatment (n=61) consisting of two consecutive 3-day dose titration periods of GW660511X 50 mg once daily and 100 mg once daily followed by GW660511X 200 mg once daily for 14 days. GW660511X 200 mg significantly lowered (baseline and placebo-corrected) both trough mean cuff SBP (-8.00 mm Hg, P=0.002) and DBP (-5.38 mm Hg, P=0.003). GW660511X 200 mg significantly reduced placebo-corrected mean 24-h and daytime but not night-time ambulatory SBP and DBP. Over the 0-24 h time period following GW660511X 200 mg, there were significant (P<0.001) reductions in serum ACE activity and significant (P<0.001) increases in plasma ANP concentration compared with placebo in terms of both peak and trough effects. In addition, treatment with GW660511X 200 mg significantly (P=0.003) increased (placebo-corrected, 1.52-fold) urinary excretion of cGMP over the 0-24 h interval. Treatment-related adverse events were experienced by 43% of the patients administered GW660511X 200 mg and 44% of those dosed with placebo with headache the most commonly reported. In conclusion, GW660511X 200 mg is an effective antihypertensive in mild-to-moderate hypertensive patients with potent effects on biological markers of ACE and NEP inhibition.

HDL cholesterol level predicts survival in men after coronary artery bypass graft surgery: 20-year experience from The Cleveland Clinic Foundation.

BACKGROUND: HDL cholesterol (HDL-C) is an important independent predictor of atherosclerosis, yet the role that HDL-C may play in the prediction of long-term survival after CABG remains unclear. The risk associated with a low HDL-C level in post-CABG men has not been delineated in relation to traditional surgical variables such as the use of arterial conduits, left ventricular function, and extent of disease. METHODS AND RESULTS: We performed a prospective, observational study of 432 men who underwent CABG between 1978 and 1979 in whom preoperative HDL-C values were available. Baseline lipid and lipoprotein values, history of diabetes mellitus and hypertension, left ventricular ejection fraction, extent of disease, and use of internal thoracic arteries were recorded. Hazard ratios (HRs) were determined in the patients with and without a low HDL-C level, which was defined as the lowest HDL-C quartile (HDL-C 35 mg/dL) were 50% more likely to survive at 15 years than were patients with low HDL-C level (35 mg/dL were 50% more likely to survive without a subsequent myocardial infarction or revascularization (HR 1.42, P:=0.02). CONCLUSIONS: HDL-C is an important predictor of survival in post-CABG patients. In this study of >8500 patient-years of follow-up, HDL-C was the most important metabolic predictor of post-CABG survival. One third fewer patients survive at 15 years if their HDL-C levels are

Effect of hydroxymethylglutaryl coenzyme a reductase inhibitors on the progression of calcific aortic stenosis.

BACKGROUND: Recent studies have supported the hypothesis that calcific aortic stenosis is the product of an active inflammatory process, with similarities to atherosclerosis. We sought to determine whether therapy with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) might slow the progression of aortic stenosis. METHODS AND RESULTS: A retrospective study of 174 patients (mean age 68+/-12 years) with mild to moderate calcific aortic stenosis was conducted. Patients required normal left ventricular function, /=2 echocardiograms performed at least 12 months apart. Fifty-seven patients (33%) received treatment with a statin; the remaining 117 (67%) did not. The statin group was older and had a higher prevalence of hypertension, diabetes mellitus, and coronary disease. During a mean follow-up of 21 months, patients treated with statin had a smaller increase in peak and mean gradient and a smaller decrease in aortic valve area. When annualized, the decrease in aortic valve area for the nonstatin group was 0.11+/-0.18 cm(2) compared with 0.06+/-0.16 cm(2) for those treated with a statin (P=0.03). In multivariate analysis, statin usage was a significant independent predictor of a smaller decrease in valve area (P=0.01) and a lesser increase in peak gradient (P=0.02). CONCLUSIONS: Statin-treated patients, despite a higher risk profile for progression, had reduced aortic stenosis progression compared with those not treated with a statin. These data provide justification for a prospective randomized trial to substantiate whether statin therapy slows the progression of aortic stenosis.

How deadly is the "deadly quartet"? A post-CABG evaluation.

OBJECTIVES: The aim of the study was to determine the value of a cluster of metabolic risk factors in predicting mortality after coronary artery bypass surgery (CABG). BACKGROUND: The "deadly quartet" of metabolic risk factors (i.e., obesity, diabetes, hypertension, and hypertriglyceridemia) has been associated with coronary heart disease in healthy population studies. The expected influence of the cluster on survival in secondary prevention remains untested overall as well as by gender. METHODS: Patients with lipid profiles undergoing primary isolated CABG (n = 6,428) between 1987 and 1992 were followed a median of eight years. Cox models were used to evaluate all-cause mortality. Metabolic risk factors were incorporated as the sum of deadly quartet risk factors present in each patient (0 to 4). The role of gender as it relates to survival and metabolic risk clusters was also examined. RESULTS: The sum of deadly quartet risk factors showed a significant relationship to mortality as the hazard ratio increased from 1.64 (confidence interval [CI] = 1.34-2.01) for one risk factor to 3.95 (2.73-5.69) for four risk factors. Annualized mortality ranged from 1% per year in patients with no risk factors to 3.3% per year in patients with all four risk factors. Within gender, the hazard ratio associated with four risk factors was 2.58 for men and 13.39 for women. The expected clustering of risk factors was 8% compared to the observed clustering of 10% in men and 21% in women. CONCLUSIONS: This cohort showed risk factor clustering beyond that expected due to chance, particularly in women. Even after revascularization, survival is diminished for patients with members of a family of metabolic risk factors at the time of surgery.

Impact of electrical cardioversion for atrial fibrillation on left atrial appendage function and spontaneous echo contrast: characterization by simultaneous transesophageal echocardiography.

OBJECTIVES: This study assessed the function of the left atrial appendage in the pericardioversion period to gain insights into mechanisms involved in thromboembolism after cardioversion of atrial fibrillation. BACKGROUND: Systemic embolization associated with electrical cardioversion of atrial fibrillation is thought to originate from the left atrium or left atrial appendage, or both. However, the mechanism involved is poorly understood. METHODS: We studied left atrial appendage function with transesophageal echocardiography in 20 patients with atrial fibrillation before and after successful electrical cardioversion. We measured left atrial appendage emptying and filling velocities by pulsed wave Doppler echocardiography, characterized Doppler emptying patterns, measured atrial appendage areas and assessed the presence or absence of spontaneous echo contrast or thrombus. RESULTS: Organized left atrial appendage function returned in 16 (80%) of 20 patients immediately after cardioversion. Atrial appendage emptying velocities before cardioversion were greater in patients without (0.39 +/- 0.02 m/s) than in those with (0.25 +/- 0.12 m/s) spontaneous echo contrast (p = 0.045). Furthermore, emptying velocities before cardioversion were significantly greater than late diastolic emptying velocities after cardioversion (0.31 +/- 0.15 vs. 0.14 +/- 0.12 m/s, p = 0.0001), as well as in both the group with (0.25 +/- 0.12 vs. 0.13 +/- 0.13 m/s, p = 0.001) and the group without (0.39 +/- 0.02 vs. 0.15 +/- 0.12 m/s, p = 0.01) spontaneous echo contrast. In addition, left atrial and atrial appendage spontaneous echo contrast developed in 4 of 20 patients and increased in intensity in 3 of 20 patients in the immediate postcardioversion period. CONCLUSIONS: Organized left atrial appendage function returns in most patients immediately after cardioversion of atrial fibrillation. However, its function is impaired compared with that before cardioversion. Furthermore, spontaneous echo contrast increased in 7 (35%) of 20 patients after cardioversion. These observations suggest that stunned left atrial appendage function after cardioversion may predispose the chamber to thrombus formation, which may play a role in the mechanism involved in the occurrence of embolization after cardioversion.

Differentiation of constrictive pericarditis from restrictive cardiomyopathy by Doppler transesophageal echocardiographic measurements of respiratory variations in pulmonary venous flow.

OBJECTIVES: The purpose of this study was to test the utility of measuring respiratory variation in pulmonary venous flow by transesophageal echocardiography. BACKGROUND: Respiratory variation of atrioventricular and central venous flow velocities by Doppler echocardiography has been used to differentiate constrictive pericarditis from restrictive cardiomyopathy. METHODS: We performed pulsed wave Doppler transesophageal echocardiography of the left or right pulmonary veins in 31 patients with diastolic dysfunction. Fourteen patients had constrictive pericarditis, and 17 had restrictive cardiomyopathy. We measured the pulmonary venous peak systolic and diastolic flow velocities and the systolic/diastolic flow ratio with transesophageal echocardiography during expiration and inspiration. The percent change in Doppler flow velocity from expiration to inspiration (%E) was calculated. RESULTS: Pulmonary venous peak systolic flow in both inspiration and expiration was greater in constrictive pericarditis than in restrictive cardiomyopathy. The %E for peak systolic flow tended to be higher in constrictive pericarditis (19% vs. 10%, p = 0.09). In contrast, pulmonary venous peak diastolic flow during inspiration was lower in constrictive pericarditis than in restrictive cardiomyopathy. The %E for peak diastolic flow was larger in constrictive pericarditis (29% vs. 16%, p = 0.008). The pulmonary venous systolic/diastolic flow ratio was greater in constrictive pericarditis in both inspiration and expiration. The combination of pulmonary venous systolic/diastolic flow ratio > or = 0.65 in inspiration and a %E for peak diastolic flow > or = 40% correctly classified 86% of patients with constrictive pericarditis. CONCLUSIONS: The relatively larger pulmonary venous systolic/diastolic flow ratio and greater respiratory variation in pulmonary venous systolic, and especially diastolic, flow velocities by transesophageal echocardiography can be useful signs in distinguishing constrictive pericarditis from restrictive cardiomyopathy.

Transesophageal Doppler echocardiography of pulmonary venous flow: a new marker of mitral regurgitation severity.

Pulmonary venous flow varies with different cardiac conditions. Flow patterns in response to mitral regurgitation have not been well studied, but flows may vary enough to differentiate among different grades of regurgitation. Accordingly, pulmonary venous flow velocities were recorded in 50 consecutive patients referred for outpatient (n = 26) or intraoperative (mitral valve repair; n = 24) echocardiographic examination for mitral regurgitation. Recordings were made of right and left upper pulmonary veins with pulsed wave Doppler transesophageal echocardiography. Mitral regurgitation was graded from 1+ to 4+ by an independent observer using transesophageal color flow mapping. The results of cardiac catheterization performed 5 weeks earlier in 43 of the patients were also graded for mitral regurgitation by an independent observer. Pulmonary venous flow patterns, the presence of reversed systolic flow and peak systolic and diastolic flow velocities were compared with the severity of mitral regurgitation indicated by each technique. Of the 28 patients with 4+ regurgitation by transesophageal color flow mapping, 26 (93%) had reversed systolic flow. The sensitivity of reversed systolic flow in detecting 4+ mitral regurgitation by transesophageal color flow mapping was 93% and the specificity was 100%. The sensitivity and specificity of reversed systolic flow in detecting 4+ mitral regurgitation by cardiac catheterization were 86% and 81%, respectively. Discordant flows were observed in 9 (24%) of 38 patients; the left vein usually showed blunted systolic flow and the right showed reversed systolic flow. In 22 intraoperative patients, there was "normalization" of pulmonary venous systolic flow after mitral valve repair in the postcardiopulmonary bypass study compared with the prebypass study after the mitral regurgitant leak was corrected.(ABSTRACT TRUNCATED AT 250 WORDS)

Preoperative triglycerides predict post-coronary artery bypass graft survival in diabetic patients: a sex analysis.

OBJECTIVE: Hypertriglyceridemia is commonly observed in association with diabetes. Despite cross-sectional studies and isolated longitudinal analyses in patients without coronary artery disease, the suggestion that triglyceride levels are relevant to subsequent cardiovascular events in the setting of diabetes remains controversial. This study evaluates the predictive value of serum triglyceride levels on mortality in post-coronary artery bypass graft (CABG) diabetic patients with subsequent analysis by sex. RESEARCH DESIGN AND METHODS: This longitudinal observational study involving a large metropolitan hospital consists of 1,172 diabetic post-CABG patients (792 men and 380 women) with lipid data collected between the years 1982 and 1992. Cox proportional hazards regression models were used to estimate the risk of mortality and cardiac events associated with triglyceride levels in the highest quartile (> 2.90 mmol/l for men and > 3.12 mmol/l for women). RESULTS: Elevated preoperative serum triglyceride values in post-CABG subjects with diabetes were correlated with increased overall mortality (hazard ratio [HR] 1.26, 95% CI 1.00-1.59). The greatest influence of triglyceride levels was observed on overall (1.89, 1.30-2.73) and event-free survival (1.49, 1.06-2.08) in women. High triglyceride values were also modestly related to risk of cardiac events in diabetic men (1.28, 0.99-1.66). CONCLUSIONS: These data suggest that increased preoperative triglyceride levels predict increased late mortality and cardiac event risk in diabetic post-CABG patients, more strongly in women than in men.

Lipoprotein(a) associated with coronary artery disease in older women: age and gender analysis.

BACKGROUND: Lipoprotein (a) has been associated with increased coronary artery disease (CAD) risk in men, but relatively little data exists in women. While age influences the cardiovascular risk associated with Lp(a) in men, little is known about this phenomenon in women. The impact of gender on Lp(a) has not been fully studied in an ongoing clinical practice. METHODS AND RESULTS: Baseline Lp(a) values were measured in 918 CAD and 829 non-CAD patients (603 females, 1144 males) entering an outpatient prevention clinic. The age-specific association of elevated Lp(a) (> 30 mg/dl) with CAD was examined after adjustment for traditional risk factors. Lp(a) was a significant risk factor (OR = 1.9, CI, 1.4-2.6) in men and women (OR = 1.9, CI 1.3-2.9). In men age < or = 55 years the odds ratio for increased cardiovascular risk in high vs low Lp(a) was 2.5 (CI 1.6-3.9). In men < or = 55, CAD increased from 32 to 61% as Lp(a) progressively rose from < or = 5 to > or = 45 mg/dl (P value for trend < 0.001). No significant increase was observed in men > 55 years (OR = 1.3, CI 0.9-2.1). In women < or = 55 years, the risk of CAD increased from 22 to 35% (OR 1.6, CI 0.8-3.2), and increased from 38 to 63% in women > 55 (OR 2.1, CI 1.3-3.5). Further, of high-risk patients (men < or = 55 and women > 55 years) with an Lp(a) in the range of 20-44 mg/dl (third quartile), younger men showed a greater incidence of CAD (51%) than older women (43%). Both genders revealed substantial risk when the Lp(a) values were above 45 mg/dl. (OR = 3.7, CI = 2.0-6.8 in younger men; OR = 3.3, CI = 1.6-6.6 in older women). CONCLUSIONS: In this cross sectional study of both men and women, elevated Lp(a) was associated with a significantly increased risk of CAD in men and women. While we corroborate previous reports on the lack of association in older men, the determination of an enhanced Lp(a)-related risk in older women was new and unanticipated. Further, in this population of high risk patients, substantial cardiovascular risk appeared to be represented by higher concentrations of Lp(a) in women than observed in men.

Comparison of Doppler and two-dimensional echocardiography for assessment of pericardial effusion.

Respiratory changes in left ventricular inflow velocities by Doppler echocardiography have been used to assess cardiac tamponade; however, Doppler echocardiography has not been compared to right atrial or right ventricular collapse. Pulsed Doppler echocardiography of left ventricular inflow velocities was performed with respiratory monitoring in 28 patients with small to large pericardial effusions. Ten of the 17 patients (59%) with large effusions had equalization of right-sided diastolic pressures before pericardial drainage. The measurements performed included percent change in left ventricular inflow peak early velocity, isovolumic relaxation time, change in inferior vena cava diameter from apnea to inspiration, and the presence of right atrial and right ventricular collapse. Percent change in early left ventricular inflow velocities significantly correlated with pericardial effusion size (p = 0.001) and right ventricular collapse (p = 0.007), and showed a trend with right atrial collapse (p = 0.10). Pericardial effusions with a left ventricular inflow velocity change > 22% were found to have right-sided equalization at a 95% confidence interval. Our data indicate that the respiratory changes in Doppler echocardiographic parameters are useful in the assessment of pericardial effusion and tamponade. This study concurs with the hypothesis that there is a continuum of hemodynamic compromise in pericardial effusion that is easily detected by Doppler echocardiography.

Effects of mitral stenosis on pulmonary venous flow as measured by Doppler transesophageal echocardiography.

Pulmonary venous flow as assessed by transesophageal echocardiography (TEE) is influenced by changes in left atrial pressure and function. In mitral stenosis (MS), normal left atrial hemodynamics are altered because there is a prolonged decay in diastolic pressure from the left atrium to the left ventricle and atrial function may be altered because of atrial fibrillation. To assess the effect of the prolonged atrial diastolic pressure decay caused by MS on pulmonary venous flow, we studied 27 patients with MS (mitral valve range 0.7 to 2.4 cm2) by pulsed-wave Doppler TEE of the left or right upper pulmonary vein, and compared results with those of 13 normal subjects. Of the 27 subjects with MS, 61% showed a blunted systolic flow pattern and 39% showed a normal flow pattern with greater systolic to diastolic flow ratio. Patients with atrial fibrillation had a predominantly blunted pattern, whereas patients with normal sinus rhythm exhibited both blunted and normal flow patterns. Patients with MS had a lower pulmonary venous peak systolic flow velocity and a longer diastolic pressure halftime than control subjects. Pulmonary venous peak systolic flow velocity was significantly decreased in the presence of atrial fibrillation (p = 0.004). The mitral valve pressure halftime significantly correlated with pulmonary venous diastolic pressure halftime (r = 0.54; p = 0.004) mitral valve area (r = -0.46; p = 0.02). In conclusion, it was found that MS alters pulmonary venous flow patterns, showing a decreased pulmonary venous systolic flow and a prolonged diastolic flow, which may be useful in assessing the hemodynamics of MS.

Relation of serum triglyceride levels to survival after coronary artery bypass grafting.

We performed a prospective observational study on 6,602 subjects (94% for 5 years and 34% for 10 to 15 years) who underwent coronary artery bypass graft surgery (CABG) between 1982 and 1992. We examined whether triglyceride concentrations adjusted for other factors (total cholesterol, history of diabetes mellitus, systemic hypertension, left ventricular function, number of coronary arteries significantly narrowed, and use of the internal thoracic arteries) explained total and event-free survival. These analyses were duplicated within gender (1,354 women and 5,248 men). This approach allowed a determination of any gender-related disparities in lipid predictors. Triglycerides in the highest quartile were associated with an increased risk of mortality of 20% (confidence interval [CI] 1.0 to 1.4). Similar risk was seen for event-free survival. Although there was no evidence of gender differences in adjusted survival (p = 0.33), a gender by triglyceride interaction (p = 0.004) indicated that the response to high triglycerides as related to survival did differ by gender. Specifically, women had a dramatically higher risk (hazard ratio [HR] 1.5, CI 1.1 to 2.1) than men (HR 1.1, CI 0.9 to 1. 3). Both men and women did have triglyceride-associated risk with regard to event-free survival (HR in men 1.2, CI 1.1 to 1.4; HR in women 1.4, CI 1.1 to 1.8). Examination of high-density lipoprotein cholesterol in a subcohort did not eliminate the observed triglyceride effects. Thus, triglyceride baseline values are primary determinants (similar to baseline left ventricular function or extent of coronary disease) for long-term total and event-free mortality after CABG in women but not in men.

Prescription-event monitoring: methodology and recent progress.

Event monitoring was first suggested 25 years ago as a way of detecting adverse reactions to drugs. Prescription-event monitoring (PEM), which has been developed by the Drug Safety Research Unit, is the first large-scale systematic post-marketing surveillance method to use event monitoring in the U.K. PEM identifies patients, who have been prescribed a particular drug, and their doctors from photocopies of National Health Service prescriptions which are processed centrally in England. A personalized follow-up questionnaire ("green form") is mailed to each patient's general practitioner, usually on the first anniversary of the initial prescription, asking for information about the patient, especially any "events" that he or she may have experienced since beginning treatment with the drug. The methodology of PEM is presented, together with examples of analyses that can be performed using results from recent studies. The problems and benefits of PEM are discussed.

Safety profile of tolterodine as used in general practice in England: results of prescription-event monitoring.

BACKGROUND: Unstable bladder symptoms are a common problem in general practice. Drug therapy with anticholinergic drugs is frequently used in the management of this condition. However such drugs are associated with a high incidence of anticholinergic adverse effects. Tolterodine is a competitive anticholinergic agent, selective for the bladder as opposed to the salivary glands. OBJECTIVE: To monitor the safety of tolterodine as used in general practice patients in England for the treatment of urinary frequency, urgency and incontinence. DESIGN: Prospective observational cohort study. PATIENTS AND PARTICIPANTS: 14,526 patients [mean age 62.7 (SD 16.4) years; 68.6% female]. METHODS: Patients prescribed tolterodine in general practice, soon after the release of the drug in the UK, were followed up for a minimum of 6 months using the technique of prescription-event monitoring (PEM). RESULTS: The most common adverse events reported were dry mouth, headache, malaise, constipation, dyspepsia, nausea and vomiting and pain in abdomen. We identified some uncommon events as possible adverse drug reactions--notably hallucinations, tachycardia and palpitations. The prevalence of these events was compared with that in patient cohorts for other drugs on the PEM database. The age- and sex-adjusted relative risk of hallucinations on tolterodine compared with 10 drugs of other therapeutic classes, and with terodiline, another drug indicated for bladder instability, was 4.85 [95% confidence interval (CI) 2.72 to 8.66] and 1.25 (95% CI 0.62 to 2.53), respectively. There was no significant difference for tachycardia/palpitation in this comparison. CONCLUSIONS: Tolterodine is well tolerated in general practice at the recommended daily dose. Hallucinations, tachycardia and palpitations are infrequently associated with the drug.

Profiles of hepatic and dysrhythmic cardiovascular events following use of fluoroquinolone antibacterials: experience from large cohorts from the Drug Safety Research Unit Prescription-Event Monitoring database.

OBJECTIVE: To investigate how frequently serious dysrhythmic cardiovascular, and hepatotoxic events are reported during routine clinical use of fluoroquinolones (quinolones) in general practice. DESIGN: Cohorts prescribed quinolones (cohort sizes: ciprofloxacin 11 477; enoxacin 2790; ofloxacin 11 033 and norfloxacin 11 110; mean age in each cohort of 48.6 to 57.0 years) were selected from the Drug Safety Research Unit's Prescription-Event Monitoring (PEM) database. The monitoring periods were November 1988 to January 1989 for ciprofloxacin; April 1989 to January 1991 for enoxacin; May 1991 to December 1991 for ofloxacin and October 1990 to October 1991 for norfloxacin. Data collected over the total PEM surveillance period on selected gastrointestinal events were extracted and reviewed to identify possible hepatic events, together with selected cardiovascular events associated with dysrhythmias. For each quinolone, times to onset of the event and patient-months of observation (denominator values) were calculated. The analysis was based on two observation periods: rate of event during the first 7 days following dispensing of a prescription for each drug (W(1)), and rate of event during the second to sixth week inclusive (W(2)). RESULTS: Scrutiny of original green forms revealed no evidence of drug-induced hepatic dysfunction within 42 days of drug administration for any of the quinolones monitored. No evidence was found of drug-induced dysrhythmic events associated with enoxacin within 42 days of drug administration. Of the other quinolones, 'atrial fibrillation' was reported most often within 42 days following ciprofloxacin administration, with no change in event rate over that time, crude relative risk (CRR)[W(1)/W(2)] 1.0 [95% confidence interval (CI) 0.02 to 8.92]. Other less serious events associated with dysrhythmia were reported with varying incidence within 42 days of quinolone administration. The crude rate of palpitation did not change significantly over that time for ciprofloxacin, ofloxacin and norfloxacin: CRR 0.83 (95% CI 0.02 to 6.86), 2.00 (95% CI 0.19 to 12.20) and 4.99 (95% CI 0.06 to 391.94), respectively. Syncope and tachycardia were also reported for ofloxacin [CRR 9.99 (95% CI 0.52 to 589.49 for both events)] and ciprofloxacin [1.0 (95% CI 0.02, 8.92)] and 2.50 (95% CI 0.04, 47.96) for syncope and tachycardia, respectively]. CONCLUSION: It cannot be ruled out that some rare hepatic and dysrhythmic events associated with quinolones may be drug related. The primary purpose of PEM is signal generation. Compared with the other quinolones, ciprofloxacin was associated with the highest number of reports of dysrhythmic cardiovascular events occurring within 42 days of administration. This requires further investigation by other types of epidemiological study.

Importance of sampling both pulmonary veins in grading mitral regurgitation by transesophageal echocardiography.

Pulmonary venous flow patterns have been used to assess severity of mitral regurgitation; however, the issue of which pulmonary veins to sample has not been determined. We performed pulsed wave Doppler transesophageal echocardiography of both the left and right upper pulmonary veins in 80 patients who had mitral regurgitation determined by independent transesophageal echocardiography color flow mapping. Pulmonary venous flow patterns, peak systolic and diastolic flow, and the presence of reversed systolic flow were compared between the left and right pulmonary veins for each grade of mitral regurgitation. Flow patterns were discordant in 20 (25%) of the 80 patients. Of the 43 patients with 4+ mitral regurgitation, there was discordant flow in 16 (37%) of the patients with mainly reversed systolic flow in the right upper vein, while there was blunted or normal systolic flow in the left upper vein. Of the 16 patients with discordant flows, 14 had eccentric jets, mainly anteromedial jets. We conclude that if discordant flow can occur in 25% of patients with mitral regurgitation and in 37% of patients with 4+ mitral regurgitation, then both pulmonary veins must be evaluated when assessing the severity of mitral regurgitation with pulsed wave Doppler transesophageal echocardiography.

Adverse effects associated with the use of donepezil in general practice in England.

Donepezil is an acetylcholinesterase inhibitor indicated for the symptomatic treatment of mild to moderate Alzheimer's disease. It is reported to have a relatively favourable side-effect profile. We report here on a pharmacovigilance study carried out post-marketing in England. An observational cohort study using the technique of Prescription-Event Monitoring was carried out. Some 1762 patients (mean age 72.9 years; 42% male) were followed up for 6 months minimum. The commonest adverse events were nausea, diarrhoea, malaise, dizziness and insomnia. Aggression, agitation and abnormal dreams were uncommonly associated with the drug. There were no cardiac rhythm disturbances or liver disorders causally associated. The commonest adverse drug reactions are already reported in the product information. Given the relatively small size of this cohort, the signals of abnormal dreams and psychiatric disturbance as possible adverse drug reactions need further investigation in carefully planned studies.

Comparison of cardiovascular risk and lipid profiles in patients undergoing aortic valve surgery versus those undergoing coronary artery bypass grafting.

BACKGROUND AND AIM OF THE STUDY: Hyperlipidemia is a risk factor for the progression of coronary artery disease, and possibly also valvular aortic stenosis. Thus, patients with aortic stenosis, coronary disease (or both) might be expected to have more abnormal lipid profiles than those without these two conditions. METHODS: The lipid profiles of patient subsets undergoing aortic valve replacement (AVR) with or without concomitant coronary artery bypass grafting (CABG), as well as those undergoing isolated CABG, between 1987 and 1997 were analyzed retrospectively. Four surgical groups were identified: AVR for aortic regurgitation (n = 370); AVR for predominant aortic stenosis (n = 1,072); AVR for aortic stenosis (AS) with CABG (n = 914); and isolated CABG (n = 11,156). The complete fasting lipid profiles of patients were collected, analyzed by group, and compared. RESULTS: Analysis by Spearman's correlation showed that total cholesterol levels, triglycerides and low-density lipoproteins (LDL-C) were modestly, yet significantly, increased in each successive group, while high-density lipoproteins were decreased. AS patients undergoing isolated AVR had significantly higher total cholesterol (215 versus 201 mg/dl; p <0.0001), triglycerides (125 versus 104 mg/dl; p <0.0001) and LDL-C (139 versus 132 mg/dl; p = 0.003) than those undergoing AVR for aortic regurgitation. Total cholesterol >200 mg/dl was significantly associated with AS, even after adjusting for differences in age, sex, diabetes mellitus and hypertension, with an odds ratio of 1.5 (95% confidence interval, 1.2-2.0; p = 0.001). CONCLUSION: Progressively abnormal lipid profiles are associated with AS and coronary disease in patients undergoing AVR. This evidence helps to extend the link between dyslipidemia and AS in a large consecutive series of patients.

United Kingdom experience with alendronate and oesophageal reactions.

Alendronate is indicated for the treatment of osteoporosis in post-menopausal women. Although the drug has been associated with reports of severe oesophagitis, there have been no studies establishing the incidence of such reactions. Information was collected on 1523 patients included in a study conducted by means of prescription-event monitoring. Dyspepsia, nausea/vomiting, and abdominal pain were the most frequently reported events in the first month of treatment. After follow-up, 20 patients (1.3%) experienced oesophageal events that were considered to be possibly related to alendronate.