Hartzell V. Schaff

Valvular heart disease associated with fenfluramine phentermine

BACKGROUND Fenfluramine and phentermine have been individually approved as anorectic agents by the Food and Drug Administration (FDA). When used in combination the drugs may be just as effective as either drug alone, with the added advantages of the need for lower doses of each agent and perhaps fewer side effects. Although the combination has not been approved by the FDA, in 1996 the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million. METHODS We identified valvular heart disease in 24 women treated with fenfluramine-phentermine who had no history of cardiac disease. The women presented with cardiovascular symptoms or a heart murmur. As increasing numbers of these patients with similar clinical features were identified, there appeared to be an association between these features and fenfluramine-phentermine therapy. RESULTS Twenty-four women (mean [+/-SD] age, 44+/-8 years) were evaluated 12.3+/-7.1 months after the initiation of fenfluramine-phentermine therapy. Echocardiography demonstrated unusual valvular morphology and regurgitation in all patients. Both right-sided and left-sided heart valves were involved. Eight women also had newly documented pulmonary hypertension. To date, cardiac surgical intervention has been required in five patients. The heart valves had a glistening white appearance. Histopathological findings included plaque-like encasement of the leaflets and chordal structures with intact valve architecture. The histopathological features were identical to those seen in carcinoid or ergotamine-induced valve disease. CONCLUSIONS These cases arouse concern that fenfluramine-phentermine therapy may be associated with valvular heart disease. Candidates for fenfluramine-phentermine therapy should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease.

Coronary Bypass Surgery with Internal-Thoracic-Artery Grafts — Effects on Survival over a 15-Year Period

BACKGROUND Aortocoronary bypass surgery has been performed most often with the patients saphenous vein as the conduit. The internal-thoracic-artery graft, which has superior patency rates, has been shown to have clinical advantages, but it is not known how long these advantages persist. METHODS We identified all the patients in the registry of the Coronary Artery Surgery Study who had undergone first-time coronary-artery bypass grafting. Those with internal-thoracic-artery bypass grafts (749 patients) were compared with those with saphenous-vein bypass grafts only (4888 patients) with respect to survival over a 15-year follow-up period. RESULTS In a multivariate analysis to account for differences between the two groups, the presence of an internal-thoracic-artery graft was an independent predictor of improved survival and was associated with a relative risk of dying of 0.73 (95 percent confidence interval, 0.64 to 0.83). This improved survival was also observed in subgroups including patients 65 years of age or older, both men and women, and patients with impaired ventricular function. The survival curves of the two groups showed further separation over the years of follow-up, with a more marked downsloping after eight years in the curve for the group with saphenous-vein grafts only than in that for the group with internal-thoracic-artery grafts. CONCLUSIONS As compared with saphenous-vein coronary bypass grafts, internal-thoracic-artery grafts conferred a survival advantage throughout a 15-year follow-up period. The survival advantage increased with time, suggesting that the initial selection of the conduit was a more important factor in survival than problems appearing long after surgery, such as the progression of coronary disease.

2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention

Sidney C. Smith, JR, MD, FACC, FAHA, Chair Ted E. Feldman, MD, FACC, FSCAI[‡][1] John W. Hirshfeld, JR, MD, FACC, FAHA,FSCAI[‡][1] Alice K. Jacobs, MD, FACC, FAHA, FSCAI Morton J. Kern, MD, FACC, FAHA, FSCAI[‡][1] Spencer B. King III, MD, MACC, FSCAI Douglass A. Morrison, MD, PhD, FACC

Clinical Outcome of Mitral Regurgitation Due to Flail Leaflet

BACKGROUND Mitral regurgitation due to flail leaflet is difficult to manage, because it is frequently asymptomatic yet carries a high risk of left ventricular dysfunction and because the natural history of the condition is poorly defined. METHODS We obtained clinical follow-up data through 1994-1995 in 229 patients with isolated mitral regurgitation due to flail leaflet; this condition was first diagnosed by echocardiography between 1980 and 1989. RESULTS The 86 patients who were treated medically had a mortality rate significantly higher than expected (6.3 percent yearly, P=0.016 for the comparison with the expected rate in the U.S. population according to the 1990 census). Independent determinants of mortality were an older age, the presence of symptoms, and a lower ejection fraction. Patients who were even transiently in New York Heart Association functional class III or IV had a high mortality rate (34 percent yearly), but the rate was also notable (4.1 percent yearly) among those in class I or II. At 10 years, the mean (+/- SE) rates of heart failure, atrial fibrillation, and death or surgery were 63 +/- 8, 30 +/- 12, and 90 +/- 3 percent, respectively. In a multivariate analysis, surgical correction of mitral regurgitation (performed in 143 patients) was associated with a reduced mortality rate (hazard ratio, 0.29; 95 percent confidence interval, 0.15 to 0.56; P<0.001). CONCLUSIONS When treated medically, mitral regurgitation due to flail leaflet is associated with excess mortality and high morbidity. Surgery is almost unavoidable within 10 years after the diagnosis and appears to be associated with an improved prognosis; this finding suggests that surgery should be considered early in the course of the disease.

Echocardiographic prediction of survival after surgical correction of organic mitral regurgitation.

BackgroundLeft ventricular dysfunction is a frequent cause of death after successful surgical repair of mitral regurgitation. The role of preoperative echocardiographic left ventricular variables in the prediction of postoperative survival and thus their clinical implications remain uncertain. Methods and ResultsThe survival of 409 patients operated on between 1980 and 1989 for pure, isolated, organic mitral regurgitation and with a preoperative echocardiogram (within 6 months of operation) was analyzed. The overall survival was 75% at 5 years (90% of expected), 58% at 10 years (88% of expected), and 44% at 12 years (73% of expected). Operative mortality was 6.6% and markedly improved from 1980 to 1984 (10.7%) to 1985 to 1989 (3.7%). Multivariate analysis showed that age (P=.0003), date of operation (P=.003), and functional class (P=.016) but not left ventricular function were predictors of operative mortality. In the most recent period (1985 to 1989), operative mortality was 12.3% in patients age 75 years or older and 1.1% in patients younger than 75 years. Late survival was analyzed in the operative survivors. Multivariate analysis showed that the most powerful predictor was echocardiographic ejection fraction (EF) (P=.0004), followed by age (P=.0031), creatinine level (P=.0062), systolic blood pressure (P=.0164), and presence of coronary artery disease (P=.0237). The late survival at 10 years was 32±12% for patients with EF <50%, 53±9% for EF 50% to 60%, and 72±4% for EF ≤60%. The hazard ratio compared with EF.60% was 2.79 (95% confidence interval, 1.65 to 4.72) for EF ≤50% and 1.81 (95% confidence interval, 1.11 to 2.95) for EF 50% to 60%. Echocardiographic EF remained the best predictor of late survival, even when combined with left ventricular angiographic variables. The survival of patients with EF >60% was 100% of expected at 10 years but was better in patients in class I or II than in those in class III or IV (82±6% versus 59±6%, respectively, at 10 years; P=.0021). The preoperative predictors of operative and late mortality remained significant independent of the type of surgical correction performed in combined multivariate analyses. ConclusionsIn organic mitral regurgitation, (1) operative mortality has markedly decreased recently, being at a low 1.1% in patients younger than 75 years, and is predicted by age and symptoms and not by left ventricular function, and (2) left ventricular EF measured by echocardiography is the most powerful predictor of late survival. These results suggest that surgical treatment should be considered early, even in the absence of severe symptoms, in patients with severe mitral regurgitation, before left ventricular dysfunction occurs.

Five- to fifteen-year follow-up after Fontan operation.

BackgroundThe purpose of this study was to estimate survival and quality of outcome and assess factors associated with outcome for patients out 5 to 15 years from their Fontan operation. Methods and ResultsWe studied 352 patients who had the Fontan operation prior to 1985. The overall 1-, 5-, and 10-year survival was 77%, 70%, and 60%, respectively. The following factors were significantly associated with lower survival: univentricular heart or complex congenital anomalies other than tricuspid atresia, early calendar year of operation, heterotaxia syndromes, early age at operation, increased pulmonary artery pressure, atrioventricular valve dysfunction, and higher (worse) New York Heart Association class. Reoperations were necessary for 103 of the 352 patients. At least 20%, of the survivors have or have had cardiac arrhythmias requiring antiarrhythmic medication or mechanical pacemaker insertion. Between 7% and 10% of the patients have had or had protein-losing enteropathy/hypoproteinemia. At 5 years postoperatively, 122 patients (34.7%) were alive with a better New York Heart Association functional classification than preoperatively. Fifty-eight patients (16.5%) were alive and in the same functional classification, but 126 (35.8%) died within the first 5 years or were in a worse functional classification. Thirty-nine patients were doing excellently and 29 patients poorly 5 years after the operation. Of the surviving patients, 43% can do as much exercise as their peers, whereas 3% are incapable of exercise. ConclusionsTo assure good functional long-term outcome in addition to survival, clinicians must exclude from selection for Fontan operation patients known to be at high risk for death or poor outcome.

Intensive Intraoperative Insulin Therapy versus Conventional Glucose Management during Cardiac Surgery: A Randomized Trial

Context Intensive insulin therapy used to maintain normoglycemia during intensive care after cardiac surgery improves perioperative outcomes. Its effect during cardiac surgery is unknown. Contributions The authors randomly assigned 400 cardiac surgical patients to tight glycemic control (blood glucose level, 4.4 to 5.6 mmol/L [80 to 100 mg/dL]) during surgery or usual intraoperative care. All patients received tight glycemic control in the cardiac intensive care unit. The groups had the same risk for perioperative adverse events (risk ratio, 1.0 [95% CI, 0.8 to 1.2]). The intensive treatment group had more strokes (8 vs. 1) and more deaths (4 vs. 0) than the conventional treatment group. Caution The authors performed the study at a single center. Implications Maintaining normoglycemia during cardiac surgery does not improve outcomes and might worsen them. The Editors Hyperglycemia occurs frequently in patients with and without diabetes during cardiac surgery, especially during cardiopulmonary bypass surgery (1, 2). In a study by Van den Berghe and colleagues (3), intensive insulin therapy after surgery reduced morbidity and death in critically ill patients, most of whom underwent cardiac surgery. As a result, professional organizations have recommended rigorous glycemic control in hospitalized patients (4) and strict glycemic control is now routine practice during the postoperative period in cardiac surgical patients. However, no consensus exists on the optimal management of intraoperative hyperglycemia in cardiac surgical patients because of the lack of evidence from randomized trials. Researchers are increasingly extrapolating evidence from studies that assess the role of strict postoperative glycemic control in critically ill patients to advocate for intravenous insulin therapy for patients in the operating room (3, 57). Evidence, strictly from observational studies, suggests that tight intraoperative glycemic control may reduce postoperative complications (810). We recently reported, in a retrospective, observational study of 409 cardiac surgical patients, that intraoperative hyperglycemia was an independent risk factor for perioperative complications, including death, after adjustment for postoperative glucose concentrations. Each 1.1-mmol/L (20 mg/dL) increase in glucose concentration greater than 5.6 mmol/L (>100 mg/dL) during surgery was associated with a 34% increase in the likelihood of postoperative complications (8). An association between intraoperative hyperglycemia and adverse outcomes based on observational studies does not prove causality. Because hyperglycemia can adversely affect immunity, wound healing, and vascular function, the concept that normoglycemia be maintained during the relatively brief duration of cardiac surgery seems plausible (1116). On the other hand, the degree of intraoperative hyperglycemia may merely reflect the severity of underlying stress. If so, prevention of hyperglycemia might not reduce perioperative complications, and the risks and costs of intensive intraoperative glycemic management may outweigh the benefits. Simple, safe, and effective insulin infusion algorithms that achieve rigorous intraoperative glycemic control are lacking. To address these questions, we conducted a randomized, controlled trial at 1 center to determine whether maintenance of near normoglycemia during cardiac surgery by using intraoperative intravenous insulin infusion reduced perioperative death and morbidity when added to rigorous postoperative glycemic control. Methods Design Overview This was a randomized, open-label, controlled trial with blinded assessment. We randomly assigned patients to receive intensive insulin therapy to maintain intraoperative glucose levels between 4.4 (80 mg/dL) and 5.6 mmol/L (100 mg/dL) or conventional treatment. By design, both groups were postoperatively treated with strict glycemic control to ensure that the observed difference in outcome could be attributed to the effects of intraoperative glycemic control. Setting We performed the study at St. Marys Hospital, Rochester, Minnesota, which is a tertiary care teaching hospital with 1157 beds and an average of more than 41000 admissions per year. Participants Adults undergoing elective cardiac surgery between July 2004 and April 2005 were eligible for enrollment in our study. We excluded patients who had off-pump cardiopulmonary bypass procedures. The Mayo Foundation Institutional Review Board, Rochester, Minnesota, approved the protocol. Randomization and Interventions Before we enrolled patients in our randomized trial, we enrolled 20 patients in a 2-week pilot trial to ensure that the anesthesiologists in the operating room and the nursing staff in the intensive care units (ICUs) had adequate experience with the study insulin infusion algorithm. The 20 patients received intensive insulin therapy during surgery and for 24 hours after surgery. The pilot period data allowed us to modify the graded insulin infusion to achieve desired glucose concentration goals. We built safety features into our infusion protocol to minimize hypoglycemia. We discontinued the infusion when glucose levels were less than 4.4 mmol/L (<80 mg/dL) and initiated dextrose infusion. When glucose levels decreased to less than 3.3 mmol/L (<60 mg/dL), we treated hypoglycemia according to a standardized hypoglycemia protocol. Per protocol, patients treated in the pilot phase were not included in the analyzed cohort. Study coordinators obtained written informed consent from all patients who met eligibility criteria. We randomly assigned patients to receive intensive or conventional intraoperative insulin therapy. Randomization was computer-generated with permuted blocks of 4, with stratification according to surgeon, surgical procedure (coronary artery bypass grafting [CABG] with or without other procedures and no CABG), and diabetes. The randomization assignments were concealed in opaque, sealed, tamper-proof envelopes that were opened sequentially by study personnel after participants signed the patient consent form. We could not possibly know, before obtaining consent, the few patients who would not have intraoperative hyperglycemia (glucose concentration of 5.6 mmol/L or more [100 mg/dL]). Therefore, per protocol, patients who gave consent were randomly assigned, and those whose glucose levels were less than 5.6 mmol/L (<100 mg/dL) during surgery were not included in the final analyses. Intraoperative Period Intensive Treatment Patients in the intensive treatment group received a continuous intravenous insulin infusion, 250 units of NovoLin R (Novo Nordisk, Princeton, New Jersey) in 250 mL of 0.45% sodium chloride, when their blood glucose levels exceeded 5.6 mmol/L (>100 mg/dL). We adjusted the infusions to maintain blood glucose levels between 4.4 (80 mg/dL) and 5.6 mmol/L (100 mg/dL). We adjusted the dose according to a standardized algorithm used by anesthesiologists (Appendix Table 1). Appendix Table 1. Insulin Infusion Protocol* Conventional Treatment Patients in the conventional treatment group did not receive insulin during surgery unless their glucose levels exceeded 11.1 mmol/L (200 mg/dL). If glucose concentration was between 11.1 (200 mg/dL) and 13.9 mmol/L (250 mg/dL), patients received an intravenous bolus of 4 units insulin every hour until the glucose concentration was less than 11.1 mmol/L (<200 mg/dL). If the intraoperative glucose concentration was greater than 13.9 mmol/L (>250 mg/dL), patients received an intravenous infusion of insulin that was continued until the glucose level was less than 8.3 mmol/L (<150 mg/dL). In both study groups, we measured arterial plasma glucose concentration every 30 minutes, starting just before anesthetic induction by using hexokinase method on a Double P Modular System (Roche Diagnostics, Indianapolis, Indiana). Intraoperative procedures, including cardiopulmonary bypass, monitoring, laboratory testing, and treatment, were left to the discretion of anesthesiologists and cardiac surgeons. There was no standard protocol for monitoring and managing intraoperative potassium levels. Postoperative Period Intravenous insulin infusion was started in patients in the conventional treatment group on their arrival in the ICU. Thereafter, both study groups were treated identically, with the intravenous insulin infusion rates adjusted by a nursing staff that was not involved with the study according to a standard protocol. The target blood glucose range was 4.4 (80 mg/dL) to 5.6 mmol/L (100 mg/dL) (Appendix Table 1). Arterial blood glucose levels were measured every 1 to 2 hours by using the Accu-Check Inform blood glucose monitoring system (glucometer) (Roche Diagnostics). During the first 24 hours after surgery, patients were given only clear liquids by mouth; we did not administer subcutaneous insulin or oral diabetic medications during this time. Thereafter, the hospital diabetes consulting service saw all patients and provided individualized recommendations for ongoing care. Outcomes and Measurements The primary outcome variable was a composite of death, sternal wound infections, prolonged pulmonary ventilation, cardiac arrhythmias (new-onset atrial fibrillation, heart block requiring permanent pacemaker, or cardiac arrest), stroke, and acute renal failure within 30 days after surgery. Secondary outcome measures were length of stay in the ICU and hospital. Trained study personnel identified the occurrence of a complication through chart abstraction by using confirmable, objective criteria in accordance with standardized definitions from the Society of Thoracic Surgeons (STS) database committee (17). Personnel who assessed outcomes were not aware of patient treatment assignment or of the study hypothesis. Follow-up Procedures We contacted patients by telephone and used a standardized telephone survey at 30 days after surgery to assess outcomes that occurred after discharge. We considered pat

A Platelet-Inhibitor-Drug Trial in Coronary-Artery Bypass Operations: Benefit of Perioperative Dipyridamole and Aspirin Therapy on Early Postoperative Vein-Graft Patency

To prevent occlusion of aortocoronary-artery-bypass grafts, we conducted a prospective, randomized-double-blind trial comparing dipyridamole (instituted two days before operation) plus aspirin (added seven hours after operation) with placebo in 407 patients. Vein-graft angiography was performed in 360 patients (88 per cent) within six months of operation (median, eight days). Within one month of operation, 3 per cent of vein-graft distal anastomoses (10 of 351) were occluded in the treated patients, and 10 per cent (38 of 362) in the placebo group; the proportion of patients with one or more distal anastomoses occluded was 8 per cent (10 of 130) in the treated group and 21 per cent (27 of 130) in th placebo group. This benefit in graft patency persisted in each of over 50 subgroups. Early postoperative bleeding was similar in the two groups. In this trial dipyridamole and aspirin were effective in preventing graft occlusion early after operation.

Constrictive Pericarditis in the Modern Era Evolving Clinical Spectrum and Impact on Outcome After Pericardiectomy

BACKGROUND The clinical spectrum of constrictive pericarditis (CP) has been affected by a change in incidence of etiological factors. We sought to determine the impact of these changes on the outcome of pericardiectomy. METHODS AND RESULTS The contemporary spectrum of CP in 135 patients (76% male) evaluated at the Mayo Clinic from 1985 to 1995 was compared with that of a historic cohort. Notable trends were an increasing frequency of CP due to cardiac surgery and mediastinal radiation and presentation in older patients (median age, 61 versus 45 years). Perioperative mortality decreased (6% versus 14%, P = 0.011), but late survival was inferior to that of an age- and sex-matched US population (57+/-8% at 10 years). The long-term outcome was predicted independently by 3 variables in stepwise logistic regression analyses: (1) age, (2) NYHA class, and most powerfully, (3) a postradiation cause. Of 90 late survivors in whom functional class could be determined, functional status had improved markedly (2.6+/-0.7 at baseline versus 1.5+/-0.8 at latest follow-up [P<0.0001]), with 83% being free of clinical symptoms. CONCLUSIONS The evolving profile of CP, with increasingly older patients and those with radiation-induced disease in the past decade, significantly affects postoperative prognosis. Long-term results of pericardiectomy are disappointing for some patient groups, especially those with radiation-induced CP. By contrast, surgery alleviates or improves symptoms in the majority of late survivors.

Effect of Dipyridamole and Aspirin on Late Vein-Graft Patency after Coronary Bypass Operations

To study the prevention of occlusion of aortocoronary-artery bypass grafts, we concluded a prospective, randomized, double-blind trial comparing long-term administration of dipyridamole (begun two days before operation) plus aspirin (begun seven hours after operation) with placebo in 407 patients. Results at one month showed a reduction in the rate of graft occlusion in patients receiving dipyridamole and aspirin. At vein-graft angiography performed in 343 patients (84 per cent) 11 to 18 months (median, 12 months) after operation, 11 per cent of 478 vein-graft distal anastomoses were occluded in the treated group, and 25 per cent of 486 were occluded in the placebo group. The proportion of patients with one or more distal anastomoses occluded was 22 per cent of 171 patients in the treated group and 47 per cent of 172 in the placebo group. All grafts were patent within a month of operation in 94 patients in the placebo group and 116 patients in the treated group; late development of occlusions was reduced from 27 per cent in the placebo group to 16 per cent in the treatment group. The results show that dipyridamole and aspirin continue to be effective in preventing vein-graft occlusion late after operation, and we believe that such treatment should be continued for at least one year.