Sidney O. Gottlieb

Silent Ischemia as a Marker for Early Unfavorable Outcomes in Patients with Unstable Angina

We examined the prevalence and prognostic importance of silent myocardial ischemia detected by continuous electrocardiographic monitoring in 70 patients with unstable angina. All the patients received intensive medical treatment with nitrates, beta-blockers, and calcium-channel blockers. Continuous electrocardiographic recordings were made during the first two days in the coronary care unit to quantify the frequency and duration of asymptomatic ischemic episodes, defined as a transient ST-segment shift of 1 mm or more. Thirty-seven patients (Group 1) had at least one episode of silent ischemia, and the other 33 patients had no silent ischemia (Group 2). Over the subsequent month, myocardial infarction occurred in 6 patients in Group 1 and in only 1 in Group 2 (P less than 0.01); bypass surgery or angioplasty was required for recurrent symptomatic angina in 10 patients in Group 1 and only 3 in Group 2 (P = 0.02). Survival-curve analysis demonstrated that silent ischemia was associated with these outcomes (P less than 0.002), and multivariate analysis showed that silent ischemia was the best predictor of these outcomes among the 15 variables tested (P less than 0.002). Patients in Group 1 with 60 minutes or more of silent ischemia per 24 hours had a worse prognosis than those with under 60 minutes per 24 hours (P = 0.04). Silent ischemia occurred in more than 50 percent of our patients with unstable angina, despite intensive medical therapy, and it identified a subset who were at high risk for early unfavorable outcomes.

A Dose-Dependent Increase in Mortality with Vesnarinone among Patients with Severe Heart Failure

Background Vesnarinone, an inotropic drug, was shown in a short-term placebo-controlled trial to improve survival markedly in patients with severe heart failure when given at a dose of 60 mg per day, but there was a trend toward an adverse effect on survival when the dose was 120 mg per day. In a longer-term study, we evaluated the effects of daily doses of 60 mg or 30 mg of vesnarinone, as compared with placebo, on mortality and morbidity. Methods We enrolled 3833 patients who had symptoms of New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 30 percent or less despite optimal treatment. The mean follow-up was 286 days. Results There were significantly fewer deaths in the placebo group (242 deaths, or 18.9 percent) than in the 60-mg vesnarinone group (292 deaths, or 22.9 percent) and longer survival (P=0.02). The increase in mortality with vesnarinone was attributed to an increase in sudden death, presumed to be due to arrhythmia. The quality of life had ...

Perioperative Morbidity in Patients Randomized to Epidural or General Anesthesia for Lower Extremity Vascular Surgery

Background:Perioperative morbidity may be modifiable in high risk patients by the anesthesiologists choice of either regional or general anesthesia. This clinical trial compared outcomes between epidural (EA) and general (GA) anesthesia/analgesia regimens In a group of patients at high risk for cardiac and other morbidity who were undergoing similarly stressful surgical procedures. Methods:One hundred patients scheduled for elective vascular reconstruction of the lower extremities were randomized to receive either EA for surgery followed by epidural analgesia, or GA for surgery followed by intravenous patient-controlled analgesia. Hemodynamic monitoring, blood pressure, and heart rate limits were determined prior to randomization. Management of anesthesia in the immediate postoperative period was standardized. The data collected included continuous electrocardiographic monitoring from the day before surgery through the third postoperative day, serial electrocardiograms, and cardiac enzymes. Cardiac ischemia, myocardial infarction, unstable angina, and cardiac death were identified by a cardiologist blinded to the type of anesthesia received. Other major morbidity was determined at the time of hospital discharge and at 1 and 6 months after surgery. Results:Eleven patients who received GA required regrafting or an embolectomy during their hospital stay, compared with two patients who received EA. This association of GA with reoperation remained significant after adjustment for baseline differences. Cardiac outcomes were similar in the two groups with respect to perioperative death (1 EA and 1 GA), death within 6 months (4 EA and 3 GA), nonfatal myocardial infarction within 7 days (2 EA and 2 GA), unstable angina (0 EA and 2 GA), and myocardial ischemia following randomization (17 EA and 23 GA). Rates of major infections in the two groups (1 EA and 2 GA), renal failure (3 EA and 3 GA), and pulmonary complications (3 EA and 7 GA) also were similar. Conclusions:Carefully conducted epidural and general anesthesia appear to be associated with comparable rates of cardiac and most other morbidity in patients undergoing lower extremity vascular surgery. However, compared with general anesthesia, epidural anesthesia is associated with a lower incidence of reoperatlon for inadequate tissue perfusion and, therefore, may be advantageous for this surgical population.

Unintentional Hypothermia Is Associated with Postoperative Myocardial Ischemia

BackgroundHypothermia occurs commonly during surgery and can be associated with increased metabolic demands during rewarming in the postoperative period. Although cardiac complications remain the leading cause of morbidity after anesthesia and surgery, the relationship between unintentional hypothermia and myocardial ischemia during the perioperative period has not been studied. MethodsOne hundred patients undergoing lower extremity vascular reconstruction received continuous Hotter monitoring throughout the first 24 h postoperatively. Myocardial ischemia was determined by a cardiologist masked to clinical variables. The patients sublingual temperature on arrival at the intensive care unit immediately after the surgical procedure was used to divide the patients into two groups: hypothermic (temperature, < 35°C; n = 33) and normothermic (temperature, ≤ 35°C; n = 67). The relationship between unintentional hypothermia and myocardial ischemia occurring during the first postoperative day was evaluated by univariate and multivariate analyses. ResultsA greater percentage of patients had electrocardiographic changes consistent with myocardial ischemia in the hypothermic group (36%, 12 of 33) compared with those in the normothermic group (13%, 9 of 67, P = 0.008). Preoperative risk factors for perioperative cardiac morbidity were similar between the two groups, except for patient age. The mean age was 70 ± 2 yr and 62 ± 1 yr in the hypothermic and normothermic groups, respectively (P = 0.001). When subgroup and multivariate analyses were used to adjust for differences in age, temperature remained an independent predictor of ischemia (odds ratio, 1.82 per degree Celsius; 95% confidence interval, 1.09–3.02). The incidence of postoperative angina was greater in the hypothermic group (18%, 6 of 33) than in the normothermic group (1.5%, 1 of 67, P = 0.002). The incidence of PaO2 < 80 mmHg in the arterial blood was greater in the hypothermic group (52%, 17 of 33) than in the normothermic group (30%, 20 of 67, P = 0.03). ConclusionsUnintentional hypothermia is associated with myocardial ischemia, angina, and PaO2 < 80 mmHg during the early postoperative period in patients undergoing lower extremity vascular surgery.

A Randomized Trial of Intravenous Tissue Plasminogen Activator for Acute Myocardial Infarction with Subsequent Randomization to Elective Coronary Angioplasty

Patients presenting within four hours of the onset of acute myocardial infarction were randomly assigned to receive 80 to 100 mg of recombinant human-tissue plasminogen activator (t-PA) intravenously over a period of three hours (n = 72) or placebo (n = 66). Administration of the study drug was followed by coronary arteriography, and candidates for percutaneous transluminal coronary angioplasty were randomly assigned either to undergo angioplasty on the third hospital day (n = 42) or not to undergo angioplasty during the 10-day study period (n = 43). The patency rates of the infarct-related arteries were 66 percent in the t-PA group and 24 percent in the placebo group. No fatal or intracerebral hemorrhages occurred, and episodes of bleeding requiring transfusion were observed in 7.6 percent of the placebo group and 9.8 percent of the t-PA group. As compared with the use of placebo, administration of t-PA was associated with a higher mean (+/- SEM) ejection fraction on the 10th hospital day (53.2 +/- 2.0 vs. 46.4 +/- 2.0 percent, P less than 0.02), an improved ejection fraction during the study period (+3.6 +/- 1.3 vs. -4.7 +/- 1.3 percentage points, P less than 0.0001), and a reduction in the prevalence of congestive heart failure from 33 to 14 percent (P less than 0.01). Angioplasty improved the response of the ejection fraction to exercise (+8.1 +/- 1.4 vs. +1.2 +/- 2.2 percentage points, P less than 0.02) and reduced the incidence of postinfarction angina from 19 to 5 percent (P less than 0.05), but did not influence the ejection fraction at rest. These data support an approach to the treatment of acute myocardial infarction that includes early intravenous administration of t-PA and deferred cardiac catheterization and coronary angioplasty.

Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors

OBJECTIVES A subgroup analysis of the Valsartan Heart Failure Trial (Val-HeFT) was performed to evaluate the effects of the angiotensin II receptor blocker, valsartan, in the patients with chronic heart failure (HF) not receiving angiotensin-converting enzyme (ACE) inhibitors. BACKGROUND The ACE inhibitors reduce mortality and morbidity in patients with HF. Nonetheless, nearly 20% of potentially eligible patients may not be prescribed ACE inhibitors. RESULTS Val-HeFT was an international, randomized, double-blinded trial that compared valsartan with placebo when added to the prescribed treatment of patients with HF. The two primary end points of the study were all-cause mortality and the composite of all-cause mortality and morbidity (sudden death with resuscitation, hospital admission for HF, or administration of intravenous inotropic or vasodilator drugs for >or=4 h without hospital admission). Of the 5,010 patients enrolled in the trial, 366 (7.3%) were not treated with ACE inhibitors at baseline. The effects of valsartan on the primary and secondary end points of the study were assessed in this subgroup of patients. RESULTS Both all-cause mortality and combined mortality and morbidity for patients not treated with ACE inhibitors were significantly reduced in the valsartan treatment group compared with the placebo group (17.3% vs. 27.1%, p = 0.017 and 24.9% vs. 42.5%, p < 0.001, respectively). Consistent with the data on clinical events, patients randomized to valsartan showed improvements in physiologic variables, such as ejection fraction, left ventricular internal diameter in diastole, and plasma neurohormone levels. Permanent discontinuation of study treatment because of adverse experiences was comparable between the two groups. CONCLUSIONS Val-HeFT has provided the first placebo-controlled outcome data demonstrating a favorable effect of an angiotensin receptor blocker on mortality and morbidity in patients with HF not treated with ACE inhibitors. Based on these results, valsartan appears to be an effective therapy in ACE inhibitor-intolerant patients.

The effects of different anesthetic regimens on fibrinolysis and the development of postoperative arterial thrombosis

Background:The purpose of this clinical trial was to compare the effects of different anesthetic and analgesic regimens on hemostatic function and postoperative arterial thrombotic complications. Methods:Ninety-five patients scheduled for elective lower extremity vascular reconstruction were randomized to receive either epidural anesthesia followed by epidural fentanyl (RA) or general anesthesia followed by intravenous morphine (GA). Intraoperative and postoperative care were controlled by protocol using predetermined limits for heart rate, blood pressure, and other monitoring criteria. Data collection included serial physical examinations, electrocardiograms, and cardiac isoenzymes to detect arterial thrombosis (defined as unstable angina, myocardial infarction, or vascular graft occlusion requiring reoperation). Fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and D-dimer levels were measured preoperatively and at 24 and 72 h postoperatively. Results:Preoperative fibrinogen levels were similar in both groups, remained unchanged after 24 h, and increased equally (45%) in the first 72 h postoperatively. PAI-1 levels in the GA group increased from 13.6 ± 2.1 activity units (AU)/ml to 20.2 ± 2.6 AU/ml at 24 h and returned to baseline at 72 h. In contrast, PAI-1 levels in the RA group remained unchanged over time. Twenty-two of 95 patients (23%) had postoperative arterial thrombosis, 17 of whom had received GA and 5 of whom, RA. Preoperative PAI-1 levels were higher in patients who developed postoperative arterial thrombosis (20.5 ± 3.6 AU/ml vs. 11.2 ± 1.4 AU/ml). Multiple logistic regression analysis indicated that GA and preoperative PAI-1 levels were predictive of postoperative arterial thrombotic complications. Conclusions:Impaired fibrinolysis may be related causally to postoperative arterial thrombosis. Because RA combined with epidural fentanyl analgesia appears to prevent postoperative inhibition of fibrinolysis, this form of perioperative management may decrease the risk of arterial thrombotic complications in patients undergoing lower extremity revascularization.

Short-Term Effects of Carbon Monoxide Exposure on the Exercise Performance of Subjects with Coronary Artery Disease

Patients with atherosclerotic cardiovascular disease may be adversely affected by the presence of carboxyhemoglobin, even at low concentrations. We investigated the effects of carbon monoxide exposure on myocardial ischemia during exercise in 63 men with documented coronary artery disease. On each test day, subjects performed two symptom-limited incremental exercise tests on a treadmill; the tests were separated by a recovery period and 50 to 70 minutes of exposure to either room air or air containing one of two concentrations of carbon monoxide (117 +/- 4.4 ppm or 253 +/- 6.1 ppm). The order of exposure was assigned randomly. On each occasion, neither the subjects nor the study personnel knew whether the subjects had been exposed to room air or to one of the concentrations of carbon monoxide. Exposure to room air resulted in a mean carboxyhemoglobin level of 0.6 percent, exposure to the lower level of carbon monoxide resulted in a carboxyhemoglobin level of 2.0 percent, and exposure to the higher level of carbon monoxide resulted in a level of 3.9 percent. An effect of carbon monoxide on myocardial ischemia was demonstrated objectively by electrocardiographic changes during exercise. We observed a decrease of 5.1 percent (90 percent confidence interval, 1.5 to 8.7 percent; P = 0.02) and a decrease of 12.1 percent (90 percent confidence interval, 9.0 to 15.3 percent; P less than or equal to 0.0001) in the length of time to a threshold ischemic ST-segment change (ST end point) after carbon monoxide exposures that produced carboxyhemoglobin levels of 2.0 percent and 3.9 percent, respectively. The length of time to the onset of angina decreased by 4.2 percent (90 percent confidence interval, 0.7 to 7.9 percent; P = 0.054) at the 2.0 percent carboxyhemoglobin level and by 7.1 percent (90 percent confidence interval, 3.1 to 10.9 percent; P = 0.004) at the 3.9 percent carboxyhemoglobin level. Significant dose-response relations were found in both the change in the length of time to the ST end point (P less than or equal to 0.0001) and the change in the length of time to the onset of angina (P = 0.02). We conclude that low levels of carboxyhemoglobin exacerbate myocardial ischemia during graded exercise in subjects with coronary artery disease.

Intravenous amiodarone for the prevention of atrial fibrillation after open heart surgery: the amiodarone reduction in coronary heart (ARCH) trial

OBJECTIVES This study was designed to test whether intravenous (i.v.) amiodarone would prevent atrial fibrillation and decrease hospital stay after open heart surgery. BACKGROUND Atrial fibrillation commonly occurs after open heart procedures and is thought to be a significant determinant for prolongation of hospitalization. Oral amiodarone given preoperatively appears to reduce the incidence of atrial fibrillation. This study was designed to test whether the more rapid-acting i.v. formulation of amiodarone given postoperatively would reduce the incidence of atrial fibrillation. METHODS Three hundred patients undergoing standard open heart surgery were randomized in a double-blind fashion to i.v. amiodarone (1 g/day for 2 days) versus placebo immediately after open heart surgery. The primary end points of the trial were incidence of atrial fibrillation and length of hospital stay. Baseline clinical variables and mortality and morbidity data were collected. RESULTS Atrial fibrillation occurred in 67/142 (47%) patients on placebo versus 56/158 (35%) on amiodarone (p = 0.01). Length of hospital stay for the placebo group was 8.2 +/- 6.2 days, and 7.6 +/- 5.9 days for the amiodarone group (p = 0.34). No differences were noted in baseline variables, morbidity or mortality. CONCLUSIONS Low-dose i.v. amiodarone was safe and effective in reducing the incidence of atrial fibrillation after heart surgery, but did not significantly alter length of hospital stay.

The Effects of Antihypertensive Therapy on Left Ventricular Mass in Elderly Patients

Left ventricular mass sometimes decreases during treatment of hypertension, but this response is inconsistent and its effects on left ventricular function are unknown. In a six-month randomized trial, we studied the ability of verapamil and atenolol to reduce left ventricular mass in 42 elderly patients with hypertension and the effects of this reduction in mass on cardiac function. The mean blood pressure (+/- SE) decreased in both the group that received verapamil (from 171.4 +/- 3.2/93.0 +/- 2.5 mm Hg to 142.9 +/- 2.8/79.0 +/- 2.0 mm Hg) and the group that received atenolol (from 179.6 +/- 4.6/98.5 +/- 2.4 mm Hg to 148.1 +/- 3.3/83.4 +/- 1.2 mm Hg), but the atenolol-treated patients more frequently required the addition of chlorthalidone to achieve blood-pressure reduction (P less than 0.01). Verapamil resulted in a reduction in the left-ventricular-mass index from 104 +/- 5 g per square meter of body-surface area to 85 +/- 5 g per square meter (P less than 0.01). Atenolol did not produce a reduction in the left-ventricular-mass index (109 +/- 9 g per square meter before treatment vs. 112 +/- 10 g per square meter after treatment). Two weeks after the withdrawal of antihypertensive therapy, blood pressure returned to pretreatment values. Nevertheless, in patients whose left ventricular mass had decreased, two measures of diastolic filling, the peak diastolic filling rate to the peak ejection rate, were significantly higher than before treatment (2.42 +/- 0.2 vs. 3.31 +/- 0.4 [P less than 0.05] and 0.61 +/- 0.03 to 0.85 +/- 0.05 [P less than 0.05], respectively). Diastolic filling was unchanged in the group that had no reduction in left ventricular mass. Cardiac output and the ejection fraction at rest and during mild exercise were unchanged in both groups as compared with baseline values. We conclude that left ventricular mass can be reduced in elderly patients with hypertension and mild ventricular hypertrophy who receive antihypertensive therapy. Reduction occurs more frequently with verapamil than with atenolol therapy, increases diastolic filling, and does not impair systolic function.