Clinical endpoint adjudication in a contemporary all-comers coronary stent investigation: methodology and external validation.

BACKGROUND: Globalisation in coronary stent research calls for harmonization of clinical endpoint definitions and event adjudication. Little has been published about the various processes used for event adjudication or their impact on outcome reporting. METHODS AND RESULTS: We performed a validation of the clinical event committee (CEC) adjudication process on 100 suspected events in the RESOLUTE All-comers trial (Resolute-AC). Two experienced Clinical Research Organisations (CRO) that had already extensive internal validation processes in place, participated in the study. After initial adjudication by the primary-CEC, events were cross-adjudicated by an external-CEC using the same definitions. Major discrepancies affecting the primary end point of target-lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction (TV-MI), or clinically-indicated target-lesion revascularization (CI-TLR), were analysed by an independent oversight committee who provided recommendations for harmonization. Discordant adjudications were reconsidered by the primary CEC. Subsequently, the RAC database was interrogated for cases that based on these recommendations merited re-adjudication and these cases were also re-adjudicated by the primary CEC. Final discrepancies in adjudication of individual components of TLF occurred in 7 out of 100 events in 5 patients. Discrepancies for the (hierarchical) primary endpoint occurred in 5 events (2 cardiac deaths and 3 TV-MI). After application of harmonization recommendations to the overall RAC population (n=2292), the primary CEC adjudicated 3 additional clinical-TLRs and considered 1 TV-MI as no event. CONCLUSIONS: A harmonization process provided a high level of concordance for event adjudication and improved accuracy for final event reporting. These findings suggest it is feasible to pool clinical event outcome data across clinical trials even when different CECs are responsible for event adjudication.

Recurrent ischaemia during continuous multilead ST-segment monitoring identifies patients with acute coronary syndromes at high risk of adverse cardiac events; meta-analysis of three studies involving 995 patients.

AIMS: Recurrent ischaemia, detected by continuous ECG monitoring, in patients with unstable angina increases the risk of unfavourable outcome. Studies that evaluated this relationship have been limited by the small series of patients. By combining data from three studies, the present analysis aims to provide an accurate assessment of the impact of recurrent ischaemia detected by multilead ECG-ischaemia monitoring on the occurrence of death and myocardial infarction in patients with acute coronary syndromes. METHODS AND RESULTS: Data were obtained from CAPTURE, PURSUIT and FROST, three trials evaluating glycoprotein IIb/IIIa blockers in patients with non-ST-elevation acute coronary syndromes. Patients were monitored for 24 h after enrollment with a computer-assisted 12-lead or a vectorcardiographic ECG-ischaemia monitoring device. In a retrospective blinded analysis, recurrent ischaemic episodes were identified by a computer algorithm. The number of ischaemic episodes was normalized to 24 h. Ischaemic episodes were detected in 271 (27%) of 995 patients. There was a direct proportional relationship between the number of ischaemic episodes per 24 h and the probability of cardiac events at 5 and 30 days. The 30-day composite of death and myocardial infarction occurred in 5.7% of patients without episodes and increased to 19.7% in patients with >/=5 episodes. After adjustment for baseline predictors of adverse outcome, the relative risk of death or myocardial infarction at 5 and 30 days increased by 25% for each additional ischaemic episode per 24 h. CONCLUSIONS: This analysis emphasizes the need for integration of multilead ECG-ischaemia monitoring systems in coronary care units and emergency wards to improve early risk stratification in patients with acute coronary syndromes.

Accurate assessment of mitral valve area in patients with mitral stenosis by three-dimensional echocardiography.

The accuracy of measurements of mitral valve orifice area (MVA) from three-dimensional echocardiographic (3DE) image data sets obtained by a transthoracic or transesophageal rotational imaging probe was studied in 15 patients with native mitral stenosis. The smallest MVA was identified from a set of eight parallel short-axis cut planes of the mitral valve between the anulus and the tips of leaflets (paraplane echocardiography) and measured by planimetry. In addition, MVA was measured from the two-dimensional short-axis view (2DE). Values of MVA measured by 3DE and 2DE were compared with those calculated from Doppler pressure half-time (PHT) as a gold standard. Observer variabilities were studied for 3DE. MVA measured from PHT ranged between 0.55 and 3.19 cm2 (mean +/- SD 1.57 +/- 0.73 cm2), from 3DE between 0.83 and 3.23 cm2 (mean +/- SD 1.55 +/- 0.67 cm2), and from 2DE between 1.27 and 4.08 cm2 (mean +/- SD 1.9 +/- 0.7 cm2). The variability of intraobserver and interobserver measurements for 3DE measurements was not significantly different (p = 0.79 and p = 0.68, respectively); for interobserver variability, standard error of the estimate = 0.25. There was excellent correlation, close limits of agreement (mean difference +/- 2 SD), and nonsignificant differences between 3DE and PHT for MVA measurements (r = 0.98 [0.02 +/- 0.3] and p = 0.6), respectively. There was moderate correlation, wider limits of agreement, and significant difference between 2DE and PHT for MVA measurements (r = 0.89 [0.32 +/- 0.66] and p = 0.002), respectively. This may be related to the difficulties in visualization of the smallest orifice in precordial short-axis views. This study suggests that three-dimensional image data sets, by providing the possibility of "computer slicing" to generate equidistant parallel cross sections of the mitral valve independently from physically dictated ultrasonic windows, allow accurate and reproducible measurement of the MVA.

Thrombolysis-induced coronary reperfusion causes acute and massive interstitial release of cardiac muscle cell proteins.

OBJECTIVE: Reperfusion of the infarct-related artery in patients with acute myocardial infarction limits infarct size, but also causes accelerated release into plasma of cardiac tissue proteins. The latter effect could reflect either enhanced protein washout from the heart or abrupt disruption of myocyte membranes. The present study indicates that the latter mechanism prevails. METHODS: In 26 patients, patency of the infarct-related artery was determined by coronary angiography 90 min and 5-7 days after thrombolytic treatment. Continuous electrocardiography was performed during the first 24 h after admission. Cumulative release of myoglobin (Mb) and creatine kinase (CK) into plasma was calculated from frequently sampled plasma concentrations. RESULTS: In patients with a patent infarct-related artery after 90 min, onset of a rapid (> 50%) decrease in ST-vector magnitude coincided with an equally rapid increase in QRS-vector magnitude, and with a sudden onset of release into plasma of Mb as well as CK. In these patients, a maximal initial release rate was observed and cumulative release conformed closely to a simple model for sudden interstitial liberation of proteins. In contrast, protein release started more gradually and could not be fitted to this model, in patients with persistent occlusion of the infarct-related artery at 90 min and absence of ST-vector normalisation. CONCLUSIONS: Previous studies have demonstrated significant myocardial salvage by timely reperfusion therapy. Nevertheless, this study indicates that the moment of recanalisation of the infarct-related artery coincides with sudden and massive disruption of myocyte membranes. Attenuation of this effect, if possible, could further improve the benefits of reperfusion therapy.

Intracoronary heparin delivery in humans. Acute feasibility and long-term results.

BACKGROUND: Inefficacy of systemic drug administration for restenosis prevention may partially relate to insufficient local drug concentration. This study aimed to evaluate the acute feasibility and long-term outcome of using an infusion-perfusion coil balloon, Dispatch. METHODS AND RESULTS: In 22 patients after balloon angioplasty, the coil balloon was studied for (1) feasibility of local heparin delivery, (2) symptoms and signs of ischemia during prolonged deployment compared with angioplasty balloon occlusion, (3) coronary pressure and flow distal to the inflated device, and (4) long-term clinical and angiographic results. During prolonged intracoronary deployment of the coil balloon (29 +/- 8 minutes), 5 of 22 patients developed mild chest pain versus 20 of 22 during angioplasty (275 +/- 283 seconds). Neither hemodynamic nor vectorcardiographic signs of ischemia were detected, in contrast to angioplasty balloon occlusion. Baseline flow across the coil balloon was 44 +/- 31 mL/min, increasing by a factor of 1.8 +/- 0.7 during pharmacologically induced hyperemia. A mean volume of 14.2 +/- 6.1 mL containing 1416 +/- 608 IU of heparin was infused locally at a pressure of 122 +/- 54 mm Hg. At 7 +/- 1-month follow-up, 1 asymptomatic patient had died, and of the remaining 21, 17 (81%) were asymptomatic. Angiographic follow-up was obtained in 15 of 21 patients (71%), including all 4 symptomatic patients. Mean minimal luminal diameter after the procedure was 2.16 +/- 0.49 mm and at follow-up, 1.89 +/- 0.45 mm, which corresponds to a restenosis rate (diameter stenosis > or = 50%) of 7% (1/15). CONCLUSIONS: Intracoronary use of the coil balloon after balloon angioplasty proved to be feasible and subjectively as well as objectively well tolerated during prolonged deployment by virtue of its perfusion properties. High volumes of heparin solution can be infused locally at very low pressure. No unfavorable clinical or angiographic long-term effects were observed.

Noninvasive assessment of reperfusion and reocclusion after thrombolysis in acute myocardial infarction.

The clinical significance of ST-segment changes and of the time course of appearance in serum of different cardiac proteins has been reviewed for the diagnosis of coronary reperfusion and reocclusion after thrombolysis. In particular, the value of serial 12-lead electrocardiographic (ECG) studies, of Holter monitoring, and of continuous multilead computer-assisted ECG monitoring is compared. Regarding the serum proteins, the clinical significance of reperfusion indices described so far for serum creatine kinase (CK), its isoenzyme serum creatinine kinase MB, the CK isoforms, and myoglobin is reviewed. Emphasis is placed on (1) the calculation method used for deriving the reperfusion indices; (2) the sensitivity and the specificity of the reperfusion indices; (3) the minimum turn-around time needed to produce the reperfusion indices (depending on the practicability of the analytical and calculation methods and their applicability in an emergency laboratory); (4) the ability of the indices to produce reliable estimates of reperfusion efficacy of the thrombolytic agents under study; and (5) the ability of the marker proteins to detect reinfarction as well as the suitability of the markers to detect real-time necrosis.

Coronary angioplasty immediately after thrombolysis in 115 consecutive patients with acute myocardial infarction.

Between September 1981 and May 1986, coronary angioplasty immediately after intracoronary thrombolysis was attempted in 115 patients with acute myocardial infarction. The present study describes our experience with this combined procedure. Primary success was achieved in 102 patients (89%). Before discharge, 79 of these patients agreed to be restudied angiographically. The infarct-related vessel was still patent in 71 patients (patency rate of 90%). Sequential left ventricular angiograms of quality sufficient to allow automated analysis were obtained in 58 patients. Global ejection fraction improved significantly from 52 +/- 10% to 55 +/- 9% (p = 0.01) from the acute to the chronic stage. In patients with anterior infarction, the increase in global ejection fraction was primarily the result of significant improvement of the regional myocardial function of the infarct zone. No significant changes in global and regional myocardial function could be seen in patients with inferior infarction. However, when patients in whom the infarct-related vessel was reoccluded at follow-up angiography are excluded from analysis, the global and regional myocardial function did improve significantly irrespective of the location of the infarct. Median clinical follow-up of 20 months (range 4 to 50) resulted in an overall mortality rate of 4%. Preservation of global and regional left ventricular function with a low mortality rate suggests that immediate coronary angioplasty after thrombolysis can be safely used to provide reperfusion in the setting of acute myocardial infarction and that this combined procedure may be the optimal mode of therapy. Further randomized studies are warranted to precisely define the role of coronary angioplasty in acute myocardial infarction.

Recording the right atrial electrogram through the fluid column of a pulmonary artery catheter.

Analysis of the cardiac rhythm in patients with ventricular and supraventricular tachycardia can be difficult because P-waves tend to be obscured by other components of the ECG. Recording of the intracavitary electrogram by means of pacing wires and the use of esophageal leads can be very helpful under these circumstances. Because a number of these patients are monitored with pulmonary artery catheters, we developed a method to obtain the atrial electrogram using the fluid column of the pulmonary artery catheter as an electrical conductor. Only slight modifications of the ECG equipment were necessary.

Use of the fluid column in a cardiac catheter for emergency pacing.

Given the not infrequent need for intracardiac pacemaking during intensive cardiac care, a new type of cardiac pacemaker has been designed and tested [1]. With this pacemaker the heart can be stimulated through the fluid column of any conventional catheter, provided it is filled with a 0.9% NaCl solution. This fluid column pacemaker (FCP) is of the "constant current" type. The FCP was tested in 37 animals, in 30 patients in sinus rhythm, and also in two critical patients. In addition to the pacemaker circuit, a special connector was designed, enabling a fast, effective, and safe contact between patient and pacemaker. The FCP is considered to be ideally suited for use in emergency cardiac pacing in intensive care units and other areas where sudden bradycardias may occur and where intrathoracic catheters are inserted for a variety of reasons.

Intra-aortic balloon pumping in coronary artery disease.

Cardiogenic shock and severe left ventricular failure after acute myocardial infarction, refractory angina pectoris at rest either of new onset or superimposed on stable angina pectoris, or occurring in the post infarct (less than 2 weeks) period, and the suspicion of a slowly evolving infarction are the main indications for intra-aortic balloon pumping at the Thoraxcenter. 76 patients were treated with intra-aortic balloon pumping for cardiogenic shock after acute myocardial infarction and left ventricular failure, 42/76 (55%) could be weaned, 9 (12%) died within 3 months, 33 (43%) survived over 3 months, to date 29 are alive. 42 patients with refractory angina at rest were treated with intra-aortic balloon pumping. Pain relief was prompt in 41 (98%), who subsequently underwent coronary artery bypass grafting. Total myocardial infarction rate was 11% (5/42), total mortality rate was 7%. Perioperative myocardial infarction rate was 8% (4/42) and perioperative mortality was 7% (3/42). Pain relief was prompt in 14/17 patients (82%) with post infarct refractory angina. In 3 patients pain persisted despite intra-aortic balloon pumping, all sustained a myocardial infarction, 1 died, 2 other patients were excluded for surgery. 12 patients underwent coronary artery bypass grafting, none died, none developed acute myocardial infarction, 3 have mild stable angina. In 8 patients a slowly evolving myocardial infarction was suspected. Pain relief was prompt in 7/8 (88%) after institution of intra-aortic balloon pumping. Intra-aortic balloon pumping improves prognosis in cardiogenic shock after myocardial infarction, and abolishes refractory ischemic pain.