Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study.

BACKGROUND: Inhibition of leukocyte adhesion can reduce myocardial infarct size in animals. This study was designed to define the safety and efficacy of a recombinant, humanized, monoclonal antibody to the CD18 subunit of the beta2 integrin adhesion receptors (rhuMAb CD18), in reducing infarct size in patients treated with a thrombolytic agent. METHODS AND RESULTS: The Limitation of Myocardial Infarction following Thrombolysis in Acute Myocardial Infarction Study (LIMIT AMI) was a randomized, double-blind, placebo-controlled, multicenter study conducted in 60 centers in the United States and Canada. A total of 394 subjects who presented within 12 hours of symptom onset with ECG findings (ST-segment elevation) consistent with AMI were treated with recombinant tissue plasminogen activator and were also given an intravenous bolus of 0.5 or 2.0 mg/kg rhuMAb CD18 or placebo. Coronary angiography was performed at 90 minutes, 12-lead ECGs were obtained at baseline, 90, and 180 minutes, and resting sestamibi scans were performed at >/=120 hours. Adjunctive angioplasty and use of glycoprotein IIb/IIIa antiplatelet agents at the time of angiography were discretionary. There were no treatment effects on coronary blood flow, infarct size, or the rate of ECG ST-segment elevation resolution, despite the expected induction of peripheral leukocytosis. A slight trend toward an increase in bacterial infections was observed with rhuMAb CD18 (P=0.33). CONCLUSIONS: RhuMAb CD18 was well tolerated but not effective in modifying cardiac end points.

Dynamic limitation of coronary vasodilator reserve in patients with dilated cardiomyopathy and chest pain.

Twenty-six patients with dilated cardiomyopathy and angiographically normal coronary arteries, 12 of whom gave a history of anginal chest pain, underwent noninvasive and invasive hemodynamic study. During treadmill exercise testing, patients with a history of angina demonstrated worse effort tolerance (7.4 +/- 4.9 versus 13.6 +/- 5.1 minutes, p less than 0.005) and a lower end-exercise systolic blood pressure-heart rate product (17.9 +/- 3.4 versus 23.6 +/- 4.9 mm Hg.beats/min x 10(3), p less than 0.005) compared with patients without a history of angina. During rapid atrial pacing after ergonovine, 0.15 mg intravenously, 11 of the 12 patients with a history of angina experienced their typical chest pain, in contrast to only 1 of 12 patients without a history of angina. The angina group, compared with the nonangina group, had significantly lower great cardiac vein flow (118 +/- 24 versus 160 +/- 43 ml/min, p less than 0.01), and higher coronary resistance (0.87 +/- 0.21 versus 0.66 +/- 0.25 mm Hg.min/ml, p less than 0.05), significant widening of the arterial--great cardiac vein oxygen difference and a significant fall in cardiac index during pacing. Further, ergonovine resulted in higher coronary resistance during pacing in the angina group compared with pacing alone (+0.16 +/- 0.16 mm Hg min/ml, p less than 0.01), in the absence of significant reduction in epicardial coronary artery luminal diameter. After dipyridamole, 0.5 to 0.75 mg/kg intravenously, to 21 patients, the 7 patients with a history of angina had significantly lower flow (149 +/- 37 versus 218 +/- 73 ml/min, p less than 0.05) and higher coronary resistance (0.59 +/- 0.09 versus 0.43 +/- 0.17 mm Hg.min/ml, p less than 0.05) than did the nonangina group. It is concluded that patients with dilated cardiomyopathy and chest pain unrelated to epicardial coronary artery disease exhibit impaired vasodilator responses to both metabolic and pharmacologic stimuli, and an increased sensitivity to the vasoconstrictor effects of ergonovine. Whether these findings are of etiologic or long-term prognostic significance is unknown.

Diabetes mellitus in cardiogenic shock complicating acute myocardial infarction: a report from the SHOCK Trial Registry. SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK?

OBJECTIVES: We sought to examine the role of diabetes mellitus in cardiogenic shock (CS) complicating acute myocardial infarction (AMI) in the SHOCK Trial Registry. BACKGROUND: The characteristics, outcomes and optimal treatment of diabetic patients with CS complicating AMI have not been well described. METHODS: Baseline characteristics, clinical and hemodynamic measures, treatment variables, shock etiologies and comorbid conditions were compared for 379 diabetic and 784 nondiabetic patients. Logistic regression was used to examine the association between diabetes and in-hospital mortality, after adjustment for baseline differences. RESULTS: Diabetics were less likely than nondiabetics to undergo thrombolysis (28% vs. 37%; p = 0.002) or attempted revascularization (40% vs. 49%; p = 0.008). The survival benefit for diabetics selected for percutaneous or surgical revascularization (55% vs. 19% without revascularization) was similar to that for nondiabetics (59% vs. 25%). Overall unadjusted in-hospital mortality was significantly higher for diabetics (67% vs. 58%; p = 0.007), but diabetes was only a borderline predictor of mortality after adjustment for baseline and treatment differences (odds ratio for death, 1.36; 95% confidence interval, 1.00 to 1.84; p = 0.051). CONCLUSIONS: Diabetics with CS complicating AMI have a higher-risk profile at baseline, but after adjustment, diabetics have an in-hospital survival rate that is only marginally lower than that of nondiabetics. Diabetics who undergo revascularization derive a survival benefit similar to that of nondiabetics.

Impact of thrombolysis, intra-aortic balloon pump counterpulsation, and their combination in cardiogenic shock complicating acute myocardial infarction: a report from the SHOCK Trial Registry. SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK?

OBJECTIVES: We sought to investigate the potential benefit of thrombolytic therapy (TT) and intra-aortic balloon pump counterpulsation (IABP) on in-hospital mortality rates of patients enrolled in a prospective, multi-center Registry of acute myocardial infarction (MI) complicated by cardiogenic shock (CS). BACKGROUND: Retrospective studies suggest that patients suffering from CS due to MI have lower in-hospital mortality rates when IABP support is added to TT. This hypothesis has not heretofore been examined prospectively in a study devoted to CS. METHODS: Of 1,190 patients enrolled at 36 participating centers, 884 patients had CS due to predominant left ventricular (LV) failure. Excluding 26 patients with IABP placed prior to shock onset and 2 patients with incomplete data, 856 patients were evaluated regarding TT and IABP utilization. Treatments, selected by local physicians, fell into four categories: no TT, no IABP (33%; n = 285); IABP only (33%; n = 279); TT only (15%; n = 132); and TT and IABP (19%; n = 160). RESULTS: Patients in CS treated with TT had a lower in-hospital mortality than those who did not receive TT (54% vs. 64%, p = 0.005), and those selected for IABP had a lower in-hospital mortality than those who did not receive IABP (50% vs. 72%, p < 0.0001). Furthermore, there was a significant difference in in-hospital mortality among the four treatment groups: TT + IABP (47%), IABP only (52%), TT only (63%), no TT, no IABP (77%) (p < 0.0001). Patients receiving early IABP (< or = 6 h after thrombolytic therapy, n = 72) had in-hospital mortality similar to those with late IABP (53% vs. 41%, n = 64, respectively, p = 0.172). Revascularization rates differed among the four groups: no TT, no IABP (18%); IABP only (70%); TT only (20%); TT and IABP (68%, p < 0.0001); this influenced in-hospital mortality significantly (39% with revascularization vs. 78% without revascularization, p < 0.0001). CONCLUSIONS: Treatment of patients in cardiogenic shock due to predominant LV failure with TT, IABP and revascularization by PTCA/CABG was associated with lower in-hospital mortality rates than standard medical therapy in this Registry. For hospitals without revascularization capability, a strategy of early TT and IABP followed by immediate transfer for PTCA or CABG may be appropriate. However, selection bias is evident and further investigation is required.

Mechanisms contributing to precipitation of unstable angina and acute myocardial infarction: implications regarding therapy.

Clinical and autopsy studies indicate that most patients who present with unstable angina or an acute myocardial infarction (AMI) have significant underlying coronary atherosclerosis. This review discusses 4 mechanisms that may contribute to the precipitation of these acute ischemic clinical syndromes: progression of atherosclerosis, acute coronary thrombosis, coronary artery spasm, and platelet aggregation. Numerous clinical trials using thrombolytic agents early during AMI have shown the incidence of thrombosis to be at least 60%. Other studies suggest that platelet aggregation frequently contributes to the evolution of AMI from unstable angina and that spasm may occasionally play a similar role. The therapeutic implications of these mechanisms are also considered in light of their potential to restore coronary artery blood flow (vs conventional methods thought mainly to reduce myocardial oxygen demand) and thereby limit the infarct process. The role of vasodilators, thrombolytic agents, antiplatelet drugs and beta-adrenergic blocking drugs are discussed. Finally, therapeutic guidelines for the treatment of acutely ill patients are constructed that emphasize the need for a comprehensive yet time-efficient treatment strategy that uses nitrates, calcium channel-blocking drugs, streptokinase, heparin, aspirin and, in selected patients in an unstable condition, emergency percutaneous transluminal coronary angioplasty and coronary artery bypass grafting.

Diagnostic and prognostic significance of minimally elevated creatine kinase-MB in suspected acute myocardial infarction.

CK-MB changes were studied using agarose gel electrophoresis in 244 patients admitted to a coronary care unit for suspected acute myocardial infarction (AMI). A range of minimally elevated CK-MB levels, from 1 to 24 IU/liter, was identified as representing uncertain AMI events. Positive AMI events were defined by elevations of 25 IU/liter or more documented in patients with new Q waves or abnormalities in all enzyme and isoenzyme levels. Negative AMI events were defined by elevation of 0 IU/liter, observed in all control subjects. The 1-year cardiac mortality rates in the "positive"-AMI (n = 91) and "uncertain"-AMI (n = 22) groups were identical (22%), and significantly higher than that in the "negative"-AMI group (n = 93) (6%) (p less than 0.05). However, when a larger uncertain-AMI group of 115 patients was compiled by 2 collaborating centers, the 1-year cardiac mortality rate in the 39 patients with chest pain alone was 0%, vs 33% in the 76 patients with accompanying severe medical problems such as cardiac or respiratory failure. Whether minimal CK-MB elevations represent AMI of limited extent is not clear. These elevations occur most often in association with severe medical problems, and in patients without such problems, they may not indicate a poor prognosis.

Prospective evaluation of doxorubicin cardiotoxicity by rest and exercise radionuclide angiography.

The role of rest and exercise radionuclide angiography (RNA) in predicting the cardiotoxic effects of doxorubicin was assessed prospectively in 48 patients who received a mean total doxorubicin dose of 522 mg/m2 (range 480 to 600). Thirty-three of these patients also received cyclophosphamide (mean 5,220 mg/m2). Left ventricular (LV) ejection fraction (EF) at rest progressively decreased from the baseline value of 55 +/- 9% to 52 +/- 8% after 338 mg/m2 to 47 +/- 8% after completion of doxorubicin therapy (p less than 0.001). In 42 patients (88%) EF at rest decreased after doxorubicin administration. Although no patient had known prior heart disease, the EF response to exercise was abnormal in 11 patients before doxorubicin. EF at rest after doxorubicin was significantly lower (41 +/- 6% vs 49 +/- 8%, p less than 0.02) in these 11 patients than in the 29 patients in whom the pretreatment EF response to exercise was normal, and in 4 of the 11 patients congestive heart failure developed. While age was an independent risk factor, cyclophosphamide did not appear to enhance the cardiotoxicity of doxorubicin. By multivariate analysis, age (p = 0.01) and EF at the midcourse of doxorubicin therapy (p less than 0.001) were the most significant predictors of final EF after completion of doxorubicin therapy; neither rest nor exercise EF before doxorubicin appreciably improved the predictive value of age and EF at midcourse of therapy. Thus, some depression of LV function occurs in most patients receiving doxorubicin, and patients with abnormal baseline function appear to be at greater risk of clinical congestive heart failure after doxorubicin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of serial QRS changes during acute inferior myocardial infarction using a QRS scoring system.

The evolution of changes in the QRS complex during the initial 3 days after the onset of an initial inferior myocardial infarction (MI) was studied in 82 consecutive patients. Each patient's standard 12-lead electrocardiogram was assigned points (a QRS score) according to the absolute duration of the Q and R waves and the amplitude ratios of R-to-Q and R-to-S waves. This QRS score has been demonstrated to correlate (r = 0.74) with the anatomic extent of single inferior MI. By this system, 43 patients (53% of the study group) had an initial electrocardiogram that registered a score of 0 and developed QRS points only after admission. The QRS scores of 18 additional patients (22% of the study group) changed after admission. Forty-nine score changes were noted on Day 2 and 18 on Day 3. All of these changes resulted in an increased QRS score. Alteration of the QRS complex during initial inferior MI evolves over 2 to 3 days in many patients. There is a distinct pattern to this evolution, which results in sequential increases in a QRS score based upon electrocardiographic indicators of the extent of myocardial necrosis. This QRS scoring system might be applied to evaluate clinically interventions aimed at limiting the extent of necrosis in patients with initial acute inferior MI.

Value of radionuclide angiography for predicting specific cardiac events after acute myocardial infarction.

The value of rest and exercise radionuclide angiography (RNA) for predicting specific events including death, recurrent acute myocardial infarction (AMI), coronary care unit readmission for unstable chest pain, and medically refractory angina after AMI was studied in 106 consecutive survivors of AMI. Analysis of the RNA variables using the Cox proportional hazards regression model yielded significant associations of the time to death with ejection fraction at rest and during exercise (X2 = 11.1 and 14.0, respectively). Both variables added significant prognostic information to the clinical assessment (X2 = 4.3 and 5.7, respectively). The change in ejection fraction from rest to exercise predicted the time to coronary artery bypass grafting for medically refractory angina before (X2 = 21.0) and after (X2 = 13.2) adjustment for the clinical descriptors, but did not predict death or other non-fatal events. Significant correlations were found between RNA variables and a variety of clinical descriptors previously reported to have prognostic significance. Clinical and RNA variables that are measures of left ventricular function were predictive of subsequent mortality, whereas those that reflect residual potentially ischemic myocardium were predictive of subsequent nonfatal ischemic events. Rest and exercise RNA after AMI provides significant prognostic information regarding specific events during follow-up independent of that provided by clinical assessment.

Effects of prior aspirin and anti-ischemic therapy on outcome of patients with unstable angina. TIMI 7 Investigators. Thrombin Inhibition in Myocardial Ischemia.

Both aspirin and beta-adrenergic blocking drugs have been shown to reduce the risk of death or acute myocardial infarction (AMI) in patients with unstable angina, but their effect during chronic use on the presentation of acute coronary syndromes is less well defined. Calcium antagonists and oral nitrates are also widely prescribed for patients with coronary disease, but their effect on presentation of acute myocardial ischemia is unknown. We retrospectively examined the effects of prior aspirin and anti-ischemic medical therapy on clinical events in 410 patients hospitalized for unstable angina. Ischemic pain occurred at rest for a duration of 5 to 60 minutes. During hospitalization, 97% of patients received aspirin and all received the direct thrombin inhibitor bivalirudin for at least 72 hours. Despite being older and more likely to have risk factors for coronary disease and poor outcome, patients receiving aspirin before admission were less likely to present with non-Q-wave AMI (5% vs 14% in patients not on aspirin, p = 0.004). Prior beta blocker, calcium antagonist, or nitrate administration did not appear to modify presentation as unstable angina or non-Q-wave AMI. In a multivariate model, the combined incidence of death, AMI not present at enrollment, or recurrent angina was best predicted by age (adjusted odds ratio [95% confidence interval] 2.38 [1.14 to 3.98]) and presence of electrocardiographic changes with pain on presentation (adjusted odds ratio 2.83 [1.50 to 5.35]) but was not related to prior or in-hospital medical therapy. Thus, aspirin but not anti-ischemic therapy before hospitalization of patients with unstable angina was associated with a decreased incidence of non-Q-wave AMI on admission.

Prospective study of cardiomyopathy induced by adjuvant doxorubicin therapy in patients with soft-tissue sarcomas.

Since a combination of surgery and adjuvant high-dose doxorubicin therapy can prolong survival in patients with extremity sarcomas, but at the expense of significant cardiomyopathic changes, we prospectively studied the differences in cardiotoxicity in 118 patients with sarcomas treated with high- vs low-dose doxorubicin therapy following surgery. Cardiac function, as assessed by left ventricular ejection fraction (EF), was determined by standard radionuclide angiography during rest and exercise. No patients in this study developed congestive heart failure. While both regimens produced net decreases in EF during rest and exercise, the high-dose doxorubicin regimen resulted in significantly greater declines in EF than the low-dose protocol. Of patients with normal baseline values, a greater percentage of patients receiving the high-dose regimen developed an abnormal EF than did those receiving the low-dose regimen, even after separating younger from older individuals. Thus, treatment-induced cardiomyopathy appears to be a significant clinical problem after both high- and low-dose doxorubicin therapy. The use of the low-dose regimen decreases the magnitude of the cardiomyopathic changes.

Coronary angioplasty in unstable angina: contemporary experience.

OBJECTIVE: To evaluate the role of percutaneous transluminal coronary angioplasty (PTCA) in the treatment of patients with unstable angina. DESIGN: Retrospective analysis of administrative records of all acute care hospital discharges at Robert Wood Johnson University Hospital from 1987 to 1993 with International Classification of Diseases, 9th revision, codes for coronary angioplasty and corresponding catheterization laboratory reports. SETTING: Tertiary care teaching hospital. RESULTS: Of 4826 PTCA cases, unstable angina was identified in 780 as the main indication for the procedure. Baseline clinical features of patients with unstable angina were not different from those in patients with stable angina. The overall success rate for PTCA in patients with unstable angina was significantly higher (707 of 780, 91%) than the success rate in patients with stable angina (3466 of 4046, 86%). The major complication rate in unstable angina patients was low (29 of 780, 3.7%) and did not differ from that in stable angina patients (136 of 4046, 3.4%). The success and complication rates in patients with unstable angina were analyzed in terms of time of PTCA, ie, early (less than 48 h from admission) versus late (48 h or more from admission). The procedure was successful in 343 of 380 (90%) patients treated early and 364 of 400 (91%) patients treated late (not significant), and the complication rates were low (12 of 380, 3.2% versus 17 of 400, 4.3%; not significant in both groups). However, length of hospital stay was considerably shorter for patients treated early than for patients treated late (4.5 +/- 3.3 days versus 10.4 +/- 6.6 days, respectively, P < 0.0001). CONCLUSION: Contemporary results of PTCA in patients with unstable angina parallel those reported for stable angina. Thus, PTCA appears to be an effective and safe treatment for unstable angina patients, and treating these patients soon after admission does not appear to affect the success or complication rates.

Bacterial endocarditis complicating systemic lupus erythematosus.

Culture proven bacterial endocarditis occurred in 6 of 571 patients with systemic lupus erythematosus (SLE) admitted to the National Institutes of Health (NIH). Although 4 of the patients had a murmur noted on examination prior to developing endocarditis, only one of the 6 had a recognized valvular abnormality. Bacterial endocarditis followed dental procedures in 2 of the 6 patients; no precipitating events were recorded in the remaining 4. M-mode and 2-D echocardiography of 20 unselected SLE patients did not reveal previously unrecognized cardiac disease. There was an unexpectedly high frequency of bacterial endocarditis among SLE patients relative to all other connective tissue disease patients seen at the NIH.

Assessment of left ventricular function by resting and exercise radionuclide angiocardiography following acute myocardial infarction.

Left ventricular function was evaluated by first-pass radionuclide angiocardiography in 42 patients at 3 and 8 weeks following acute myocardial infarction. Left ventricular ejection fraction, diastolic volume, and wall motion were measured at rest and submaximal exercise at 3 weeks and at rest, submaximal and maximal exercise at 8 weeks. The mean ejection fraction, end-diastolic volume, and wall motion index did not change between 3 and 8 weeks in any group either at rest or during submaximal exercise. Ventricular function was decreased at rest in patients with previous and anterior myocardial infarctions, but not in patients with inferior and subendocardial myocardial infarctions. During maximal exercise at 8 weeks, nine patients (21%) had ST segment depression, whereas 25 patients (60%) had a decrease in ejection fraction or a deterioration in wall motion. These abnormalities of ventricular function during exercise occurred equally among the infarct groups. Radionuclide angiography in patients with recent myocardial infarction demonstrated highly variable ventricular function at rest and/or during exercise in each infarct subgroup.

Prospective evaluation of doxorubicin-induced cardiomyopathy resulting from postsurgical adjuvant treatment of patients with soft tissue sarcomas.

One hundred and one soft tissue sarcoma patients from an adjuvant chemotherapy study of the Surgery Branch, National Cancer Institute who had received greater than or equal to 430 mg/m2 (range, 430-600 mg/m2) of doxorubicin were followed for evidence of cardiomyopathy. Fourteen patients developed clinical congestive heart failure attributable to doxorubicin. Nine of these fourteen were evaluated by radionuclide angiography (RNA), and all were abnormal with mean ejection fraction both at rest and exercise less than 30%. Sixty-one asymptomatic patients were studied at least once with RNA. In this asymptomatic group, 13 of 61 patients (21%) had abnormal resting left ventricular function. Exercise studies identified an additional 19 abnormal individuals (31%). Overall incidence of cardiomyopathy, as evidenced by RNA, in the asymptomatic group was 52%. By including the fourteen symptomatic patients, the incidence of cardiomyopathy detected either clinically or by RNA in the 75 evaluated patients was 46%. Comparison of patients by age (less than 40 versus greater than 40) revealed a highly significant difference in the incidence of cardiomyopathy (P less than .001). Fourteen of 36 patients (38%) less than or equal to 40 had either clinical or RNA evidence of cardiotoxicity while 32 of 39 (82%) individuals greater than 40 demonstrated cardiomyopathy. No significant difference was seen in those asymptomatic patients in whom RNA was performed less than or equal to 12 months as compared with greater than 12 months after the end of doxorubicin treatment. In the entire group there was no apparent improvement in cardiomyopathy with time, but results suggest that left ventricular function in the group older than 40 years does deteriorate. The cardiac function of patients younger than age 40 appeared to remain stable or possibly improve with time after the completion of treatment. Sex, tumor location, and radiation treatment were not associated with an increased risk of cardiomyopathy. These results emphasize the dangers of full-dose doxorubicin therapy. This high incidence of cardiomyopathy became apparent because of our ability to prospectively evaluate a large group of patients with prolonged life expectancy that received adjuvant doxorubicin chemotherapy after surgery.

Evaluation of a QRS scoring system for estimating myocardial infarct size. I. Specificity and observer agreement.

We evaluated a simplified version of a previously developed QRS scoring system for estimating infarct size using observations of Q- and R-wave durations and R/Q and R/S amplitude ratios in the standard 12-lead ECG. Groups of subjects with a minimal likelihood of having myocardial infarcts and minimal likelihood of having common noninfarction sources of QRS modification were studied to establish the specificity of each of the 37 criteria. Only two criteria required modification to achieve 95% specificity. These 37 criteria form the basis of a 29-point QRS scoring system. A 98% specificity was achieved when a score of more than 2 points was required to identify a myocardial infarct. Fifty patients were studied to determine the intra- and interobserver agreement with this scoring system. Each criterion achieved at least 91% intra- and interobserver agreement. These impressive levels of specificity and observer agreement must be matched by high sensitivity of the scoring system and a good correlation between the point score and infarct size in patients with proven infarcts if the point score is to be useful for detecting and sizing infarcts. Sensitivity and correlation between point score and infarct size are evaluated in later studies in this series. The standard ECG is inexpensive and can be obtained repetitively and noninvasively; its QRS complex may be an important means of estimating the size, presence and location of myocardial infarcts.

A QRS scoring system for assessing left ventricular function after myocardial infarction.

A QRS scoring system for estimating the size of a myocardial infarct was evaluated in 55 patients who did not have left ventricular hypertrophy or conduction abnormalities. Serial 12-lead surface electrocardiograms were scored according to a 29-point system based on the duration of Q and R waves and on the ratios of R-to-Q amplitude and R-to-S amplitude. The scores were proportional to the severity of wall-motion abnormalities, which was determined by radionuclide blood-pool scanning and which correlated inversely with the radionuclide-determined left ventricular ejection fraction (LVEF). A score less than 3 was 93 per cent sensitive and 88 per cent specific for both severe regional dyssynergy and major depression of the global LVEF. The following equation was used to estimate the LVEF from the QRS score: LVEF (%) = 60 - (3 x QRS score). After acute myocardial infarction, an electrocardiogram can provide important indirect quantitative information about left ventricular function.

A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy.

Although prednisone has been used to treat patients with idiopathic dilated cardiomyopathy, its efficacy has not been rigorously studied. We therefore randomly assigned 102 patients to either treatment with prednisone (60 mg per day) or a control group. At three months, improvement, defined prospectively as an increase in the ejection fraction of greater than or equal to 5 percentage points, was observed in 53 percent of the patients receiving prednisone and 27 percent of the controls (P = 0.005). The mean (+/- SE) ejection fraction increased 4.3 +/- 1.5 percentage points (from 17.9 +/- 1.0 to 22.2 +/- 1.6 percent) in the prednisone group, as compared with 2.1 +/- 0.8 percentage points (from 17.1 +/- 1.1 to 19.3 +/- 1.4 percent) in the control group (P = 0.054). All patients were categorized prospectively in two separately randomized subgroups. "Reactive" patients (n = 60) were those who had fibroblastic (n = 36) or lymphocytic (n = 2) infiltration or immunoglobulin deposition (n = 16) on endomyocardial biopsy, a positive gallium scan (n = 7), or an elevated erythrocyte sedimentation rate (n = 18). "Nonreactive" patients (n = 42) had none of these features. At three months, 67 percent of the reactive patients who received prednisone had improvement, as compared with 28 percent of the reactive controls (P = 0.004). Nonreactive patients did not improve significantly with prednisone (P = 0.51). After three months, reactive patients who received prednisone daily were switched to alternate-day therapy (60 mg every other day), and after six months the improvement seen earlier was no longer present. These data suggest that patients with idiopathic dilated cardiomyopathy may have some improvement when given a high dose of prednisone daily. However, the increases in the ejection fraction that we observed during prednisone treatment were small, their duration was limited, and the side effects were important. Overall, prednisone was judged to have only marginal clinical benefit, and should not be administered as standard therapy for dilated cardiomyopathy.

Randomized trial of an oral platelet glycoprotein IIb/IIIa antagonist, sibrafiban, in patients after an acute coronary syndrome: results of the TIMI 12 trial. Thrombolysis in Myocardial Infarction.

BACKGROUND: Inhibitors of the platelet glycoprotein IIb/IIIa receptor given intravenously have been shown to be effective in reducing ischemic complications after coronary angioplasty and in unstable angina, making this a promising new class of agents for the treatment and prevention of ischemic events in patients with acute coronary syndromes. Sibrafiban (Ro 48-3657) is an oral, peptidomimetic, selective antagonist of the glycoprotein IIb/IIIa receptor. METHODS AND RESULTS: The Thrombolysis in Myocardial Infarction (TIMI) 12 trial was a phase II, double-blind, dose-ranging trial designed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of sibrafiban in 329 patients after acute coronary syndromes. In the PK/PD cohort of TIMI 12, 106 patients were randomized to receive one of seven dosing regimens of sibrafiban, ranging from 5 mg daily to 10 mg twice daily for 28 days. In the safety cohort, 223 patients were randomized to one of four dose regimens of sibrafiban (ranging from 5 mg twice daily to 15 mg once daily) or aspirin for 28 days. High levels of platelet inhibition were achieved: mean peak values ranged from 47% to 97% inhibition of 20 micromol/L ADP-induced platelet aggregation on day 28 across the seven doses. Twice-daily dosing provided more sustained platelet inhibition (mean inhibition, 36% to 86% on day 28), whereas platelet inhibition returned to baseline levels by 24 hours with once-daily dosing. Major hemorrhage occurred in 1.5% of patients treated with sibrafiban and in 1.9% of patients treated with aspirin. Protocol-defined "minor" bleeding, usually mucocutaneous, occurred in 0% to 32% of patients in the various sibrafiban groups and in none of the patients treated with aspirin. Minor bleeding was related to total daily dose (P=.002), once- versus twice-daily dosing (P<.0001), renal function (P<.0001), and presentation with unstable angina (P<.01). CONCLUSIONS: The oral glycoprotein IIb/IIIa antagonist sibrafiban achieved effective, long-term platelet inhibition with a clear dose-response but at the expense of a relatively high incidence of minor bleeding. Oral IIb/IIIa inhibition deserves further study as a new treatment strategy in patients after acute coronary syndromes.