Marco Bobbio

Colchicine in Addition to Conventional Therapy for Acute Pericarditis Results of the COlchicine for acute PEricarditis (COPE) Trial

Background—Colchicine is effective and safe for the treatment and prevention of recurrent pericarditis and might ultimately serve as the initial mode of treatment, especially in idiopathic cases. The aim of this work was to verify the safety and efficacy of colchicine as an adjunct to conventional therapy for the treatment of the first episode of acute pericarditis. Methods and Results—A prospective, randomized, open-label design was used. A total of 120 patients (mean age 56.9±18.8 years, 54 males) with a first episode of acute pericarditis (idiopathic, viral, postpericardiotomy syndromes, and connective tissue diseases) were randomly assigned to conventional treatment with aspirin (group I) or conventional treatment plus colchicine 1.0 to 2.0 mg for the first day and then 0.5 to 1.0 mg/d for 3 months (group II). Corticosteroid therapy was restricted to patients with aspirin contraindications or intolerance. The primary end point was recurrence rate. During the 2873 patient-month follow-up, colchicine significantly reduced the recurrence rate (recurrence rates at 18 months were, respectively, 10.7% versus 32.3%; P=0.004; number needed to treat=5) and symptom persistence at 72 hours (respectively, 11.7% versus 36.7%; P=0.003). After multivariate analysis, corticosteroid use (OR 4.30, 95% CI 1.21 to 15.25; P=0.024) was an independent risk factor for recurrences. Colchicine was discontinued in 5 cases (8.3%) because of diarrhea. No serious adverse effects were observed. Conclusions—Colchicine plus conventional therapy led to a clinically important and statistically significant benefit over conventional treatment, decreasing the recurrence rate in patients with a first episode of acute pericarditis. Corticosteroid therapy given in the index attack can favor the occurrence of recurrences.

Development and validation of a logistic regression-derived algorithm for estimating the incremental probability of coronary artery disease before and after exercise testing

OBJECTIVES Our goals were to develop and validate a multivariate algorithm for estimating the incremental probability of the presence of coronary artery disease. BACKGROUND Multivariate methods, including logistic regression analysis, have been extensively applied to diagnostic exercise testing. However, few previous studies have included both an incremental design and external validation. METHODS A retrospective collection of clinical, exercise test and catheterization data was performed involving four U.S. referral medical centers. All patients had no prior history of coronary disease and had undergone coronary angiography < or = 3 months after exercise stress testing. An algorithm was developed in one center (590 patients with a 41% prevalence of coronary artery disease) with the use of logistic regression analysis and was validated in the other three centers (1,234 patients, 70% prevalence). The algorithm incorporated pretest variables (age, gender, symptoms, diabetes, cholesterol), exercise electrocardiographic (ECG) variables (mm of ST segment depression, ST slope, peak heart rate, metabolic equivalents [METs], exercise angina) and one thallium variable. Discrimination was measured with receiver operating characteristic curve analysis. Calibration (that is, reliability) was assessed from a comparison of probability estimates and the actual prevalence of disease. RESULTS The overall incremental receiver operating characteristic curve areas for the validation group were pretest, -0.738 +/- 0.016; postexercise ECG, 0.78 (SE 0.017); and postthallium, 0.82 (SE 0.016); p < 0.01 for both increments. Within the three validation institutions, the institution with a disease prevalence closest to that of the derivation institution had the best incremental receiver operating characteristic curve areas. There was a stepwise incremental improvement in calibration especially from exercise ECG to thallium testing. CONCLUSIONS An incremental multivariate algorithm derived in one center reliably estimated disease probability in patients from three other centers. The incremental value of testing was best demonstrated when the derivation and validation groups had a similar disease prevalence. This algorithm may be useful in decision making that relates to the diagnosis of coronary disease.

Inaccuracy of four coronary surgery risk-adjusted models to predict mortality in individual patients

OBJECTIVES This study was undertaken to evaluate the accuracy of four different risk-adjusted models in predicting mortality in individual patients who are undergoing coronary artery by-pass graft surgery. In the last decade several models to stratify patients before open heart surgery, according to factors affecting mortality, were developed with the aim of retrospectively comparing outcomes of open heart surgery, based on reliable stratification of case-mix, and of prospectively identifying high risk patients as a basis for a meaningful informed consent for patients counseling. METHODS The pre-operative risk of death was calculated with four different models in 418 consecutive patients who underwent coronary artery by-pass surgery and then compared with the actual outcome. To discriminate patients with favorable and unfavorable outcome, the logistic regression analysis and the areas under the receiver-operating-characteristic curves were applied. The accuracy score was used to evaluate the reliability of each score to predict the individual outcome. RESULTS Seven deaths (1.7%) were observed within 30 days from the operation, and the overall incidence was similar to that predicted by all models. Only the NBI score was not able to discriminate survivors from patients who will die, and the areas under the curves were 0.596 for the Parsonnet score, 0.861 for the Cleveland Clinic Foundation score, 0.823 for the French score, and 0.806 for the EuroSCORE. The four models were highly accurate (between 0.97 and 0.98) to predict the overall mortality. In seven patients who died the mean predictive scores were very low and ranged between 2.1 and 4.6, but were significantly higher than those of patients who survived (between 1.1 and 2.2). CONCLUSIONS The four pre-surgical predictive models were similarly able to discriminate favorable vs. unfavorable outcomes and highly accurate to predict overall mortality, but very inaccurate to predict mortality in individual patients.

Incremental value of exercise electrocardiography and thallium-201 testing in men and women for the presence and extent of coronary artery disease

Our goal was to assess the incremental value of exercise testing in men and women for the diagnosis and extent of coronary artery disease. With data from one center, incremental logistic algorithms were developed and evaluated in a separate set of 865 patients from four centers. Variables included were pretest (age, sex, symptoms, diabetes, smoking, and cholesterol concentration); exercise electrocardiogram (ECG) (ST-segment depression [millimeters], ST-segment slope, peak heart rate, and change in systolic blood pressure); and thallium-201 scintigram (defect presence, reversibility, and intensity of hypoperfusion). End points were coronary disease presence (50% diameter stenosis) and extent (multivessel disease). Accuracy and incremental value were assessed by receiver operating characteristic (ROC) curve analysis. Incremental ROC curve areas for disease presence were pretest 0.75 +/- 0.02, post-exercise ECG 0.82 +/- 0.01, and post-thallium scintigram 0.85 +/- 0.01 and for disease extent were pretest 0.71 +/- 0.02, post-exercise ECG 0.76 +/- 0.02, and post-thallium scintigram 0.78 +/- 0.02 (p < 0.005 for all increments). Incremental increases in accuracy were similar for men and women. We conclude that when multivariable algorithms derived from one center were applied to a separate group, there was a significant incremental increase in accuracy associated with exercise testing for the presence and extent of coronary disease. This increase in accuracy was similar for men and women.

Exercise-induced ST depression and ST/heart rate index to predict triple-vessel or left main coronary disease: A multicenter analysis

The aim of this investigation was to determine the difference in accuracy between two frequently published noninvasive indicators of severity of coronary artery disease (exercise-induced ST segment depression and heart rate-adjusted ST depression [ST/HR index]). The study was designed as a survey of consecutive patients undergoing exercise electrocardiography and coronary angiography. There were a total of 2,270 patients without prior myocardial infarction or cardiac valvular disease referred for angiography from eight institutions in three countries; 401 of these patients had triple-vessel or left main coronary artery disease. The sensitivities of ST depression and ST/HR index in detecting triple-vessel or left main coronary artery disease were, respectively, 75% and 78% (p = 0.08) at cut point values where their specificities were equal (64%). This small increase in the accuracy of the ST/HR index was evident only at peak exercise heart rates below the median value of 132 beats/min, where the sensitivities of ST depression and ST/HR index were 73% and 76% (p = 0.03), respectively, at cut point values corresponding to a specificity of 60%. These results were consistent at all eight participating institutions. The increase in accuracy achieved by dividing exercise-induced ST depression by heart rate is small and confined exclusively to a low exercise heart rate. This lack of superiority cannot be generalized to all methods of heart rate adjustment.

Growth hormone-independent cardiotropic activities of growth hormone-releasing peptides in normal subjects, in patients with growth hormone deficiency, and in patients with idiopathic or ischemic dilated cardiomyopathy

Growth hormone releasing peptides (GHRPs) are synthetic molecules endowed with potent neuroendocrine activities mediated by specific receptors in the pituitary and in the central nervous system. GHRPs receptors have been reported even in perpheral tissues, particularly in the myocardium, where they probably mediate growth hormone (GH)-independent activities. We studied in humans the cardiac effects of hexarelin administration in 7 normal adults, in 7 severe GH-deficient patients, and in 12 patients with severe dilated cardiomyopathy. Left ventricular ejection fraction (LVEF), mean blood pressure (MBP), heart rate (HR), and GH levels were evaluated at baseline and every 15 min up to 60 min after acute 2.0 μg/kg iv hexarelin administration. Basal LVEF in dilated cardiomyopathy was impaired and lower (p<0.001) than in GH deficiency, in turn lower (p<0.001) than in normal subjects. Hexarelin significantly (p<0.05) increased LVEF in normal and in GH-deficient subjects, but not in dilated cardiomyopathy, without significant variations in MBP and HR. Hexeralin significantly (p<0.05) increased GH levels in normal subjects and in dilated cardiomyopathy but not in GH deficiency. These findings suggest that, in humans, the acute administration of hexarelin exerts a GH-independent positive inotropic effect likely mediated by specific GHRPs myocardial receptors.

Incremental evaluation of exercise capacity as an independent predictor of coronary artery disease presence and extent

To determine the independent incremental value of exercise capacity (METS) concerning the presence and extent of coronary artery disease, we analyzed data from 800 patients with suspected coronary disease who underwent both exercise testing and coronary angiography. We performed logistic regression analysis of clinical and exercise test data with an incremental design to mimic the usual flow of data acquisition. Separate analyses were performed concerning coronary disease presence (> or = 1 vessel with a > or = 50% lesion) and extent (three-vessel/left main disease). Diagnostic accuracy was determined by calculating receiver operating characteristic (ROC) curve areas. When considered alone, METS was a significant predictor of both presence and extent of disease. Multivariate analysis revealed that METS was an independent predictor of disease extent but not presence. However, comparison of ROC curve areas failed to show any loss of accuracy when METS was removed from the coronary disease extent analysis. Despite the strong univariate relationship between exercise capacity and coronary disease presence and extent and the independence of exercise capacity as a predictor of coronary disease extent, the lack of an additional incremental accuracy attributed to its consideration virtually cancels its value as a diagnostic variable for assessing both coronary disease presence and extent.

Risk stratification for open heart operations: comparison of centers regardless of the influence of the surgical team.

BACKGROUND Risk-adjusted mortality was previously used to compare institutions as a whole or surgeons. Because the same surgical team is working in two different hospitals, the aim of our study was to assess whether the institution can make a difference in surgical mortality. METHODS Preoperative data of 554 patients in institution A and 500 in institution B were prospectively collected during the same period of time. All patients were operated on by the same surgeon with the same first assistant and anesthesiology staff in both institutions. Patient population was stratified according to Parsonnets predictive model, in five risk groups, and mortality was adjusted by the direct standardization method. RESULTS At institution A it was observed that in-hospital mortality was 2.3% (95% confidence interval, 1.3% to 4.0%), and in institution B 4.0% (95% confidence interval, 2.5% to 6.1%). The difference between the two mortality rates (1.7%; 95% confidence interval, -0.5% to 3.8%) is not statistically significant (p = 0.16), nor is the difference within each class. The standardized mortality ratio was 3.6% (95% confidence interval, 2.7% to 4.8%) and 5.8% (95% confidence interval, 4.6% to 7.2%), respectively. The difference of 2.2% (95% confidence interval, 0.5% to 3.8%) is statistically significant (p = 0.01). CONCLUSIONS The institution can affect mortality of patients undergoing open heart operations, regardless of the influence of the surgical team.

Normal IGF-I and enhanced IGFBP-3 response to very low rhGH dose in patients with dilated cardiomyopathy

Well-nourished patients with dilated cardiomyopathy (DCM) show slight reduction of mean basal IGF-I levels which, however, display a response to a rhGH dose as low as 5.0 μg/kg/day similar to that of age-matched control subjects (CS). To further investigate peripheral GH sensitivity, we studied the IGF-I and IGFBP-3 responses to 4-day sc 2.5 μg/kg/day rhGH administration, the lowest effective dose able to increase IGF-I levels in normal subjects, in 10 DCM patients [age (mean±SE): 57.6±1.0 yr, body mass index (BMI): 24.0±1.2 kg/m2, left ventricular ejection fraction: 26.2±3.2%, NYHA (New York Heart Association): I/0, II/4, III/4, IV/2] and in 9 age-matched healthy CS (age: 55.3±1.2 yr, BMI: 23.7±1.8 kg/m2). Basal IGF-I levels in DCM were lower though not significantly than those in CS (147.7±9.8 vs 174.7±17.0 μg/l). Basal IGFBP-3 levels in DCM were similar to those in CS (3.1±0.3 vs 2.7±0.2 mg/l). In CS 4-day rhGH increased IGF-I levels (222.4±14.9 μg/l; p<0.01 vs baseline) but did not modify IGFBP-3 levels (3.0±0.2 mg/l). In DCM IGF-I levels were increased by 4-day rhGH administration (175.7±11.0 μg/l; p<0.05 vs baseline) with a similar percent extent than in CS. On the other hand, in DCM, but not in CS, 4-day rhGH significantly increased IGFBP-3 levels (3.5±0.3 mg/l; p<0.05 vs baseline). Therefore, in conclusion, testing with the lowest effective rhGH dose further suggest that peripheral GH sensitivity in well-nourished DCM is preserved. On the other hand, DCM patients show enhanced IGFBP-3 sensitivity to stimulation by rhGH.

Value of exercise stress test, radionuclide angiography and coronary angiography in predicting new coronary events in asymptomatic patients after a first episode of myocardial infarction

One-hundred-and-fifty-five consecutive symptom-free patients underwent maximal treadmill exercise testing, rest and stress radionuclide angiography at least two months after an uncomplicated acute myocardial infarction; of these, 90 underwent coronary angiography. All patients were followed-up for a mean of 32 +/- 13 months regarding the prediction of hard (death and reinfarction) and soft (angina and coronary surgery) coronary events. The specificity, sensitivity, positive and negative predictive value of exercise stress test were 47%, 76% and 41% for any coronary events; none of the patients who incurred a hard coronary event showed ischemia during electrocardiographic exercise tests. Sensitivity, specificity and positive predictive value for failure to increase the ejection fraction of at least 5% were 60%, 45% and 30% for any coronary event and 25%, 49% and 2% for any hard coronary event. The presence of multivessel disease at coronary angiography showed a sensitivity of 62% for any coronary event and of 67% for hard coronary events; specificities were 66% and 57%, and predictive values were 52% and 10%, respectively. It is concluded that electrocardiographic exercise testing, radionuclide angiography and coronary angiography are not helpful two months after an episode of uncomplicated myocardial infarction in order to identify patients who will suffer a new coronary event.