Kenneth Egstrup

Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.

BACKGROUND Hyperlipidemia has been suggested as a risk factor for stenosis of the aortic valve, but lipid-lowering studies have had conflicting results. METHODS We conducted a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events. RESULTS During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients (35.3%) in the simvastatin-ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin-ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59). Aortic-valve replacement was performed in 267 patients (28.3%) in the simvastatin-ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97). Fewer patients had ischemic cardiovascular events in the simvastatin-ezetimibe group (148 patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), mainly because of the smaller number of patients who underwent coronary-artery bypass grafting. Cancer occurred more frequently in the simvastatin-ezetimibe group (105 vs. 70, P=0.01). CONCLUSIONS Simvastatin and ezetimibe did not reduce the composite outcome of combined aortic-valve events and ischemic events in patients with aortic stenosis. Such therapy reduced the incidence of ischemic cardiovascular events but not events related to aortic-valve stenosis. (ClinicalTrials.gov number, NCT00092677.)

Dofetilide in patients with congestive heart failure and left ventricular dysfunction

BACKGROUND Atrial fibrillation occurs frequently in patients with congestive heart failure and commonly results in clinical deterioration and hospitalization. Sinus rhythm may be maintained with antiarrhythmic drugs, but some of these drugs increase the risk of death. METHODS We studied 1518 patients with symptomatic congestive heart failure and severe left ventricular dysfunction at 34 Danish hospitals. We randomly assigned 762 patients to receive dofetilide, a novel class III antiarrhythmic agent, and 756 to receive placebo in a double-blind study. Treatment was initiated in the hospital and included three days of cardiac monitoring and dose adjustment. The primary end point was death from any cause. RESULTS During a median follow-up of 18 months, 311 patients in the dofetilide group (41 percent) and 317 patients in the placebo group (42 percent) died (hazard ratio, 0.95; 95 percent confidence interval, 0.81 to 1.11). Treatment with dofetilide significantly reduced the risk of hospitalization for worsening congestive heart failure (risk ratio, 0.75; 95 percent confidence interval, 0.63 to 0.89). Dofetilide was effective in converting atrial fibrillation to sinus rhythm. After one month, 22 of 190 patients with atrial fibrillation at base line (12 percent) had sinus rhythm restored with dofetilide, as compared with only 3 of 201 patients (1 percent) given placebo. Once sinus rhythm was restored, dofetilide was significantly more effective than placebo in maintaining sinus rhythm (hazard ratio for the recurrence of atrial fibrillation, 0.35; 95 percent confidence interval, 0.22 to 0.57; P<0.001). There were 25 cases of torsade de pointes in the dofetilide group (3.3 percent) as compared with none in the placebo group. CONCLUSIONS In patients with congestive heart failure and reduced left ventricular function, dofetilide was effective in converting atrial fibrillation, preventing its recurrence, and reducing the risk of hospitalization for worsening heart failure. Dofetilide had no effect on mortality.

Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure

BACKGROUND The benefit of an implantable cardioverter-defibrillator (ICD) in patients with symptomatic systolic heart failure caused by coronary artery disease has been well documented. However, the evidence for a benefit of prophylactic ICDs in patients with systolic heart failure that is not due to coronary artery disease has been based primarily on subgroup analyses. The management of heart failure has improved since the landmark ICD trials, and many patients now receive cardiac resynchronization therapy (CRT). METHODS In a randomized, controlled trial, 556 patients with symptomatic systolic heart failure (left ventricular ejection fraction, ≤35%) not caused by coronary artery disease were assigned to receive an ICD, and 560 patients were assigned to receive usual clinical care (control group). In both groups, 58% of the patients received CRT. The primary outcome of the trial was death from any cause. The secondary outcomes were sudden cardiac death and cardiovascular death. RESULTS After a median follow-up period of 67.6 months, the primary outcome had occurred in 120 patients (21.6%) in the ICD group and in 131 patients (23.4%) in the control group (hazard ratio, 0.87; 95% confidence interval [CI], 0.68 to 1.12; P=0.28). Sudden cardiac death occurred in 24 patients (4.3%) in the ICD group and in 46 patients (8.2%) in the control group (hazard ratio, 0.50; 95% CI, 0.31 to 0.82; P=0.005). Device infection occurred in 27 patients (4.9%) in the ICD group and in 20 patients (3.6%) in the control group (P=0.29). CONCLUSIONS In this trial, prophylactic ICD implantation in patients with symptomatic systolic heart failure not caused by coronary artery disease was not associated with a significantly lower long-term rate of death from any cause than was usual clinical care. (Funded by Medtronic and others; DANISH ClinicalTrials.gov number, NCT00542945 .).

Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction : a randomised trial

BACKGROUND Arrhythmias cause much morbidity and mortality after myocardial infarction, but in previous trials, antiarrhythmic drug therapy has not been convincingly effective. Dofetilide, a new class III agent, was investigated for effects on all-cause mortality and morbidity in patients with left-ventricular dysfunction after myocardial infarction. METHODS In 37 Danish coronary-care units, 1510 patients with severe left-ventricular dysfunction (wall motion index < or = 1.2, corresponding to ejection fraction < or = 0.35) were enrolled in a randomised, double-blind study comparing dofetilide (n=749) with placebo (n=761). The primary endpoint was all-cause mortality. Secondary endpoints included cardiac and arrhythmic mortality and total arrhythmic deaths. Analyses were by intention to treat. FINDINGS No significant differences were found between the dofetilide and placebo groups in all-cause mortality (230 [31%] vs 243 [32%]), cardiac mortality (191 [26%] vs 212 [28%]), or total arrhythmic deaths (129 [17%] vs 140 [18%]). Atrial fibrillation or flutter was present in 8% of the patients at study entry. In these patients, dofetilide was significantly better than placebo at restoring sinus rhythm (25 of 59 vs seven of 56; p=0.002). There were seven cases of torsade de pointes ventricular tachycardia, all in the dofetilide group. INTERPRETATION In patients with severe left-ventricular dysfunction and recent myocardial infarction, treatment with dofetilide did not affect all-cause mortality, cardiac mortality, or total arrhythmic deaths. Dofetilide was effective in treating atrial fibrillation or flutter in this population.

Outcome of Patients With Low-Gradient “Severe” Aortic Stenosis and Preserved Ejection Fraction

Background— Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area <1.0 cm2 and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient “severe” stenosis (defined as aortic valve area <1.0 cm2 and mean gradient ⩽40 mm Hg) in the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Methods and Results— Outcome in patients with low-gradient “severe” aortic stenosis was compared with outcome in patients with moderate stenosis (aortic valve area 1.0 to 1.5 cm2; mean gradient 25 to 40 mm Hg). The primary end point of aortic valve events included death from cardiovascular causes, aortic valve replacement, and heart failure due to aortic stenosis. Secondary end points were major cardiovascular events and cardiovascular death. In 1525 asymptomatic patients (mean age, 67±10 years; ejection fraction, ≥55%), baseline echocardiography revealed low-gradient severe stenosis in 435 patients (29%) and moderate stenosis in 184 (12%). Left ventricular mass was lower in patients with low-gradient severe stenosis than in those with moderate stenosis (182±64 versus 212±68 g; P<0.01). During 46 months of follow-up, aortic valve events occurred in 48.5% versus 44.6%, respectively (P=0.37; major cardiovascular events, 50.9% versus 48.5%, P=0.58; cardiovascular death, 7.8% versus 4.9%, P=0.19). Low-gradient severe stenosis patients with reduced stroke volume index (⩽35 mL/m2; n=223) had aortic valve events comparable to those in patients with normal stroke volume index (46.2% versus 50.9%; P=0.53). Conclusions— Patients with low-gradient “severe” aortic stenosis and normal ejection fraction have an outcome similar to that in patients with moderate stenosis.

Outcome of Patients With Low-Gradient “Severe” Aortic Stenosis and Preserved Ejection Fraction The Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) Study

Background— Retrospective studies have suggested that patients with a low transvalvular gradient in the presence of an aortic valve area <1.0 cm2 and normal ejection fraction may represent a subgroup with an advanced stage of aortic valve disease, reduced stroke volume, and poor prognosis requiring early surgery. We therefore evaluated the outcome of patients with low-gradient “severe” stenosis (defined as aortic valve area <1.0 cm2 and mean gradient ⩽40 mm Hg) in the prospective Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Methods and Results— Outcome in patients with low-gradient “severe” aortic stenosis was compared with outcome in patients with moderate stenosis (aortic valve area 1.0 to 1.5 cm2; mean gradient 25 to 40 mm Hg). The primary end point of aortic valve events included death from cardiovascular causes, aortic valve replacement, and heart failure due to aortic stenosis. Secondary end points were major cardiovascular events and cardiovascular death. In 1525 asymptomatic patients (mean age, 67±10 years; ejection fraction, ≥55%), baseline echocardiography revealed low-gradient severe stenosis in 435 patients (29%) and moderate stenosis in 184 (12%). Left ventricular mass was lower in patients with low-gradient severe stenosis than in those with moderate stenosis (182±64 versus 212±68 g; P<0.01). During 46 months of follow-up, aortic valve events occurred in 48.5% versus 44.6%, respectively (P=0.37; major cardiovascular events, 50.9% versus 48.5%, P=0.58; cardiovascular death, 7.8% versus 4.9%, P=0.19). Low-gradient severe stenosis patients with reduced stroke volume index (⩽35 mL/m2; n=223) had aortic valve events comparable to those in patients with normal stroke volume index (46.2% versus 50.9%; P=0.53). Conclusions— Patients with low-gradient “severe” aortic stenosis and normal ejection fraction have an outcome similar to that in patients with moderate stenosis.

Pseudonormal and restrictive filling patterns predict left ventricular dilation and cardiac death after a first myocardial infarction: a serial color M-mode Doppler echocardiographic study.

OBJECTIVES We sought to assess the prognostic value of left ventricular (LV) filling patterns, as determined by mitral E-wave deceleration time (DT) and color M-mode flow propagation velocity (Vp), on cardiac death and serial changes in LV volumes after a first myocardial infarction (MI). BACKGROUND Combined assessment of DT and Vp allows separation of the effects of compliance and relaxation on LV filling, thereby allowing identification of pseudonormal filling. This may be valuable after MI, where abnormal LV filling is frequently present. METHODS Echocardiography was performed within 24 h, five days and one and three months after MI in 125 unselected consecutive patients. Normal filling was defined as DT 140 to 240 ms and Vp > or =45 cm/s; impaired relaxation as DT > or =240 ms; pseudonormal filling as DT 140 to 240 ms and Vp <45 cm/s; and restrictive filling as DT <140 ms. RESULTS Left ventricular filling was normal in 38 patients; impaired relaxation in 38; pseudonormal in 23; and restrictive in 26. End-systolic and end-diastolic volume indexes were significantly increased during the first three months after MI in patients with pseudonormal or restrictive filling (37+/-15 vs. 47+/-19 ml/m2, p<0.0005 and 71+/-20 vs. 88+/-24 ml/m2, p<0.0005, respectively). During a follow-up period of 12+/-7 months, 33 patients died. Mortality was significantly higher in patients with impaired relaxation (p = 0.02), pseudonormal filling (p<0.00005) and restrictive filling (p<0.00005), compared with patients with normal filling. On Cox analysis, restrictive filling (p = 0.003), pseudonormal filling (p = 0.006) and Killip class > or =II (p = 0.008) independently predicted cardiac death, compared with clinical and echocardiographic variables. CONCLUSIONS Pseudonormal or restrictive filling patterns are related to progressive LV dilation and predict cardiac death after a first MI.

Effect of preload alternations on a new Doppler echocardiographic index of combined systolic and diastolic performance.

The objective of the study was to assess the effect of preload alternations on a nongeometric Doppler index of combined systolic and diastolic myocardial performance (MPI). Doppler echocardiography was performed during Valsalva maneuver, passive leg lifting, and after sublingual administration of nitroglycerin in 50 healthy volunteers (group 1) and 25 patients (group 2) with previous myocardial infarction. MPI was significantly lower in group 1 (0.34 +/- 0.04) compared with group 2 (0.52 +/- 0.14), P <.0005. In group 1 MPI was significantly increased during preload manipulations (P =. 001). The largest change in MPI was induced by nitroglycerin (0.034 +/- 0.05). In group 2 no significant changes in MPI were found. In both groups peak E-wave velocity (P <.0005), E/A-ratio (P <.0005), and E-wave deceleration time (P <.0005) were found to change during preload alternations. In conclusion, we found in normal subjects and to a lesser extent in patients with previous myocardial infarction that MPI is influenced by preload.

Longitudinal changes and prognostic implications of left ventricular diastolic function in first acute myocardial infarction.

BACKGROUND Left ventricular (LV) diastolic dysfunction contributes to signs and symptoms of clinical heart failure and may be related to prognosis in heart diseases. LV diastolic dysfunction is reported to be present in acute myocardial infarction (MI); however, little is known about the time course of changes in LV diastolic function and its relation to prognosis after acute MI. METHODS AND RESULTS Two-dimensional and Doppler echocardiographic examinations were performed in 58 consecutive patients with first acute MI. The patients were studied serially within 1 hour and at days 5, 90, and 360 after arrival to the coronary care unit. LV diastolic function was assessed by Doppler measurements of transmitral and pulmonary venous flow. On the basis of mitral inflow, patients with MI were stratified at baseline to 3 LV diastolic filling patterns: normal, impaired relaxation, or pseudonormal/restrictive. Patients with MI were observed for development of congestive heart failure (Killip class >I) during hospitalization and for death during 1-year follow-up, and these complications were related to LV diastolic function. LV diastolic dysfunction was present in the very early phase of acute MI, with signs of impaired relaxation or restrictive LV filling dynamics in 38% and 24% of the patients, respectively, whereas 38% had normal LV filling characteristics. Impaired relaxation of the LV was most pronounced and found in 60% after 1-year follow-up. In-hospital congestive heart failure (Killip class >I) was found in 50% of the patients with initial impaired LV relaxation and in 71% of the patients with initially pseudonormal or restrictive LV filling dynamics, whereas patients with normal LV filling were free of heart failure. Patients with initial impaired relaxation and restrictive LV filling dynamics demonstrated a significant LV dilation during 1-year follow-up. Patients with initial pseudonormal/restrictive LV filling pattern were more frequently readmitted to the hospital for heart failure and had significant higher New York Heart Association class score compared with patients with normal or impaired relaxation during follow-up. Cardiac death was (n = 6) only observed in patients with pseudonormal or restrictive LV filling pattern. In a multivariate stepwise regression analysis, mitral E deceleration time </=140 ms and age were identified as independent variables related to development of in-hospital congestive heart failure and cardiac death during 12 months of follow-up. CONCLUSIONS LV diastolic dysfunction is present in the very early phase of MI. LV remodeling and development of in-hospital congestive heart failure appear in patients with very early signs of LV diastolic dysfunction. Furthermore, mitral E deceleration time </=140 ms best identified patients at risk of development of in-hospital congestive heart failure and cardiac death after MI.

Ratio of left ventricular peak E-wave velocity to flow propagation velocity assessed by color M-mode Doppler Echocardiography in first myocardial infarction prognostic and clinical implications

OBJECTIVES To determine the ability of the ratio of peak E-wave velocity to flow propagation velocity (E/Vp) measured with color M-mode Doppler echocardiography to predict in-hospital heart failure and cardiac mortality in an unselected consecutive population with first myocardial infarction (MI). BACKGROUND Several experimental studies indicate color M-mode echocardiography to be a valuable tool in the evaluation of diastolic function, but data regarding the clinical value are lacking. METHODS Echocardiography was performed within 24 h of arrival at the coronary care unit in 110 consecutive patients with first MI. Highest Killip class was determined during hospitalization. Patients were divided into groups according to E/Vp <1.5 and > or =1.5. RESULTS During hospitalization 53 patients were in Killip class > or =II. In patients with E/Vp > or =1.5, Killip class was significantly higher compared with patients with E/Vp <1.5 (p < 0.0001). Multivariate logistic regression analysis identified E/Vp > or =1.5 to be the single best predictor of in-hospital clinical heart failure when compared with age, heart rate, E-wave deceleration time (Dt), left ventricular (LV) ejection fraction, wall motion index, enzymatic infarct size and Q-wave MI. At day 35 survival in patients with E/Vp <1.5 was 98%, while for patients with E/Vp > or =1.5, it was 58% (p < 0.0001). Cox proportional hazards model identified Dt <140 ms, E/Vp > or =1.5 and age to be independent predictors of cardiac death, with Dt < 140 ms being superior to age and E/Vp. CONCLUSIONS In the acute phase of MI, E/Vp > or =1.5 measured with color M-mode echocardiography is a strong predictor of in-hospital heart failure. Furthermore, E/Vp is superior to systolic measurements in predicting 35 day survival although Dt <140 ms is the most powerful predictor of cardiac death.