Eric J. Eichhorn

A comparative analysis of the results from 4 trials of β-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS

BACKGROUND Recent large randomized, controlled trials (BEST [Beta-blocker Evaluation of Survival Trial], CIBIS-II [Cardiac Insufficiency Bisoprolol Trial II], COPERNICUS [Carvedilol Prospective Randomized Cumulative Survival Study], and MERIT-HF [Metoprolol Randomized Intervention Trial in Congestive Heart Failure]) have addressed the usefulness of beta-blockade in the treatment of advanced heart failure. CIBIS-II, COPERNICUS, and MERIT-HF have shown that beta-blocker treatment with bisoprolol, carvedilol, and metoprolol XL, respectively, reduce mortality in advanced heart failure patients, whereas BEST found a statistically nonsignificant trend toward reduced mortality with bucindolol. We conducted a post hoc analysis to determine whether the response to beta-blockade in BEST could be related to differences in the clinical and demographic characteristics of the study populations. We generated a sample from BEST to resemble the patient cohorts studied in CIBIS-II and MERIT-HF to find out whether the response to beta-blocker therapy was similar to that reported in the other trials. These findings are further compared with COPERNICUS, which entered patients with more severe heart failure. METHODS To achieve conformity with the entry criteria for CIBIS-II and MERIT-HF, the BEST study population was adjusted to exclude patients with systolic blood pressure <100 mm Hg, heart rate <60 bpm, and age >80 years (exclusion criteria employed in those trials). The BEST comparison subgroup (BCG) was further modified to more closely reflect the racial demographics reported for patients enrolled in CIBIS-II and MERIT-HF. The association of beta-blocker therapy with overall survival and survival free of cardiac death, sudden cardiac death, and progressive pump failure in the BCG was assessed. RESULTS In the BCG subgroup, bucindolol treatment was associated with significantly lower risk of death from all causes (hazard ratio (HR)=0.77 [95% CI=0.65, 0.92]), cardiovascular death (HR=0.71 [0.58, 0.86]), sudden death (HR=0.77 [0.59, 0.999]), and pump failure death (HR=0.64 [0.45, 0.91]). CONCLUSIONS Although not excluding the possibility of differences resulting from chance alone or to different properties among beta-blockers, this study suggests the possibility that different heart failure population subgroups may have different responses to beta-blocker therapy.

Treatment of calcific aortic stenosis by balloon valvuloplasty

Recent reports have established the feasibility of using balloon valvuloplasty to reduce left ventricular outflow tract obstruction due to a calcified aortic valve. The present study summarizes experiences with this technique in 9 patients (7 women, 2 men, mean age 78 years) in whom balloon valvuloplasty was used to treat calcific aortic stenosis. Peak aortic valve gradient (mm Hg) decreased from 68 +/- 8 (mean +/- standard error of the mean) before valvuloplasty to 35 +/- 5 after valvuloplasty (p = 0.003). Mean aortic valve gradient decreased from 57 +/- 7 before valvuloplasty to 30 +/- 5 after valvuloplasty (p = 0.006). Calculated aortic valve area increased from 0.42 +/- 0.04 to 0.81 +/- 0.06 cm2 (p = 0.005). Balloon valvuloplasty failed to diminish aortic valve obstruction in only 1 patient who, at subsequent surgery, had a congenitally bicuspid aortic valve. Significant aortic regurgitation was not observed in any of the 9 patients after valvuloplasty. One patient did have a highly focal, presumably embolic, brain stem infarct during the procedure. Femoral arterial blood loss, related to wire-guided exchange of balloon catheters too large for a 12Fr introducer sheath, was minimized by direct arterial exposure in 8 of the 9 patients. Thus, these findings confirm the efficacy of balloon valvuloplasty for the treatment of calcific aortic stenosis. The procedure, however, is not without hazard.

Differential effects of milrinone and dobutamine on right ventricular preload, afterload and systolic performance in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

To compare the effects of intravenous dobutamine and milrinone on right ventricular (RV) systolic function, 14 patients with severe congestive heart failure underwent simultaneous radionuclide-hemodynamic study. Patients were randomized to receive intravenous milrinone (50 micrograms/kg bolus then 0.5 microgram/kg/min) or dobutamine (2.5 to 15 micrograms/kg/min) to achieve equal increases in cardiac output. Both drugs significantly improved cardiac performance, with identical 24% increases in mean cardiac index (p less than 0.05 vs baseline; difference not significant for milrinone vs dobutamine) and no change in heart rate. Neither drug substantially altered RV preload, as reflected by mean right atrial pressure and RV end-diastolic volume. Both drugs caused similar increases in RV ejection fraction (mean +/- standard deviation; dobutamine: 0.32 +/- 0.09 to 0.40 +/- 0.11; p less than 0.05; milrinone: 0.35 +/- 0.19 to 0.43 +/- 0.21; p less than 0.05) resulting from reductions in RV end-systolic volume. RV afterload reduction contributed substantially to drug effect on RV systolic performance in patients treated with milrinone but not those treated with dobutamine. With doses effecting equal increases in cardiac index and RV systolic performance, pulmonary artery end-systolic pressure was significantly reduced by milrinone (40 +/- 12 to 33 +/- 12 mm Hg; p less than 0.05), but not by dobutamine. Thus, in patients with congestive heart failure milrinones effect on RV systolic function is explainable, at least in part, by RV afterload reduction, whereas RV inotropic augmentation contributed more strongly to dobutamines effect.

Myocardial Contractile Reserve by Dobutamine Stress Echocardiography Predicts Improvement in Ejection Fraction With β-Blockade in Patients With Heart Failure. The β-Blocker Evaluation of Survival Trial (BEST)

Background—&bgr;-Blockers improve survival and reduce hospitalization in chronic heart failure (CHF) by biologically improving left ventricular ejection fraction (LVEF). However, a good predictor of improvement with this therapy has not been identified. This substudy of BEST examined whether myocardial contractile reserve, as determined by dobutamine stress echocardiography, predicts improvement in LVEF. Methods and Results—Seventy-nine patients with class III/IV CHF underwent dobutamine stress echocardiography before treatment with bucindolol (n=41) or placebo (n=38). Regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. WMSI was compared with change in LVEF after 3 months of therapy as determined by gated radionuclide scan. Change in WMSI correlated inversely with change in LVEF after 3 months of bucindolol (r =−0.72, P <0.0001) and was the most significant multivariate predictor of change in LVEF (P =0.0002). Patients with contractile reserve had demographics similar to those of patients without contractile reserve, including RVEF, LVEF, systolic blood pressure, and CHF duration. However, patients without contractile reserve had higher baseline plasma norepinephrine levels (687±333 versus 420±246 pg/mL, P <0.05) and greater decrease in plasma norepinephrine in response to bucindolol (−249±171 versus −35±277 pg/mL, P <0.05). Conclusions—This study suggests a direct relationship between contractile reserve and improvement in LVEF with &bgr;-blocker therapy in patients with advanced CHF. Patients without contractile reserve have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may experience greater sympatholytic effects from bucindolol.

Efficacy of Retrograde Coronary Sinus Cardioplegia in Patients Undergoing Myocardial Revascularization: A Prospective Randomized Trial

The efficacy of retrograde coronary sinus cardioplegia (RCSC) administered through the right atrium compared with aortic root cardioplegia (ARC) has not been examined critically in patients undergoing coronary artery bypass grafting (CABG). Twenty patients having elective CABG were randomized prospectively to receive cold blood ARC (Group I, 10 patients) or cold blood RCSC (Group II, 10 patients). Patient demographics were similar in both groups. Ventricular function was assessed preoperatively by radionuclide ventriculography and postoperatively by simultaneous hemodynamic and radionuclide ventriculographic studies with volume loading. There was no change in ejection fraction (EF) (preoperative versus postoperative value) in Group I (50 +/- 6% versus 53 +/- 6%) but in group II, at similar peak systolic pressure and similar left ventricular end-diastolic volume index (LVEDVI), LVEF improved significantly (49 +/- 6% versus 60 +/- 12%, p less than 0.05). Postoperative ventricular function (stroke work index versus EDVI) for the left ventricle and right ventricle were similar in both groups. Evaluation of postoperative LV systolic function (end-systolic blood pressure versus end-systolic volume index) and diastolic function (pulmonary capillary wedge pressure versus EDVI) were also similar in both groups. Retrograde coronary sinus cardioplegia is as effective as ARC for intraoperative myocardial protection, and provides excellent postoperative function in patients undergoing elective CABG.

Current Clinical Outcomes of Percutaneous Coronary Intervention and Coronary Artery Bypass Grafting

BACKGROUND Randomized trials have compared coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). However, results of these trials in select patients may not accurately reflect current clinical practice using drug-eluting stents (DES) and off-pump CABG. We undertook a prospective registry of coronary revascularization by CABG on-pump and off-pump, and PCI with or without DES, to determine clinical outcomes. METHODS All patients undergoing isolated coronary revascularization in 8 community-based hospitals were enrolled. Preprocedural, intraprocedural, and postprocedural data were captured, with outcomes obtained at 18 months by patient and physician contact, and the Social Security Death Index. RESULTS The study enrolled 4336 patients, 71.2% PCI and 28.8% CABG. DESs were used in 2249 PCIs (73.1%), and 596 CABG procedures (47.8%) were off-pump. Incidence of major adverse cardiac events at 18 months was 14.7% for CABG vs 23.3% for PCI (p < 0.001). Cardiac death and myocardial infarction had similar rates. The need for repeat revascularization was significantly less with CABG (6.2% vs 13.6%, p < 0.001). Hazard ratio of CABG to PCI was 0.76 (95% confidence interval, 0.571 to 0.872). CABG outcome was similar on-pump and off-pump, as was repeat revascularization with DES (12.1%) vs BMS (14.9%; p = 0.096). Overall event-free survival was 85.3% in CABG and 76.8% in PCI (p < 0.001). CONCLUSIONS Rates of repeat revascularization were significantly higher for PCI than for CABG, but mortality and myocardial infarction were the same. There were no significant differences in outcomes between DES and BMS or between on-pump and off-pump CABG.

Dual balloon technique for valvuloplasty of aortic stenosis in adults

A dual balloon technique was studied in 16 patients with aortic stenosis in whom results with a single balloon (up to 20 mm, 5.5 cm or 25 mm, 3.0 cm in diameter and length, respectively) were judged to be suboptimal. Dual balloon valvuloplasty was performed using 2 balloons advanced and inflated simultaneously across the stenotic aortic valve orifice. For the group as a whole, the average peak transvalvular gradient was reduced from 79 +/- 8 to 57 +/- 7 mm Hg (mean +/- standard error) using a single balloon (p less than 0.0005), and reduced further to 36 +/- 4 mm Hg using dual balloons (p less than 0.0005 compared with single balloon results). Similarly, calculated aortic valve orifice area was increased from 0.45 +/- 0.04 to 0.57 +/- 0.05 cm2 using a single balloon (p less than 0.0005), and further increased to 0.77 +/- 0.06 cm2 using dual balloons (p less than 0.0005). Dual balloon dilation caused no complications directly attributable to the use of 2 balloons, including no exacerbation of aortic regurgitation. These results suggest that dual balloon valvuloplasty is safe and efficacious in selected patients with aortic stenosis.

Protective effects of retrograde compared with antegrade cardioplegia on right ventricular systolic and diastolic function during coronary bypass surgery.

The effect of retrograde cardioplegia delivered through the right atrium on right ventricular performance has not been critically examined in humans. We randomized 20 patients with right coronary artery lesions to receive cold blood cardioplegia solution either retrograde through the right atrium (group 1, n = 10) or antegradely (group 2, n = 10). The patients were similar in age, sex, severity of coronary artery disease, cross-clamp time, and completeness of revascularization. Before operation, right ventricular function was assessed by radionuclide ventriculography, and 18-24 hours after operation, right ventricular volumes and performance were assessed at a constant-paced heart rate by simultaneous hemodynamic-radionuclide measurements, before and after a fluid challenge. Intraoperative right ventricular temperatures were not different between the groups. Right ventricular volumes and ejection fractions were not different at baseline. After operation, at similar heart rates and loading conditions, there was a trend for the antegrade group to increase right ventricular end-systolic volume (p less than 0.1) whereas the retrograde group had no change in this parameter from the preoperative state. Postoperative ventricular function curves (p = NS, retrograde versus antegrade) suggest equivalent systolic performance in both groups. Right ventricular diastolic performance showed no significant differences between the two groups, suggesting no detriment to compliance due to right ventricular distension during operation. This suggests that retrograde cardioplegia adequately protects the right ventricular myocardium during bypass surgery and may be used as an alternative procedure in situations where ventricular cooling is inadequate with antegrade delivery due to severe coronary artery disease or aortic valvular disease.

Evaluation of a personal computer-based quantitative coronary analysis system for rapid assessment of coronary stenoses

Quantitative coronary analysis (QCA) is a technique that is rarely used because of the complexity and expense of existing systems. We studied a new personal computer-based QCA system that is capable of both geometric and densitometric analysis and compared it to a previously validated QCA system. Both systems performed extremely well in phantom analysis with 11 phantoms filmed in both 5-inch and 7-inch magnifications (R greater than 0.97 and SEE less than 0.33 mm for all modes). In 28 abnormal coronary angiograms analyzed at end diastole, stenosis and reference diameter correlations between the two systems were excellent (R = 0.90 and 0.96 and SEE = 0.43 and 0.33 mm for densitometric and geometric modes, respectively). Intraobserver and interobserver correlation was also excellent for both analysis modes. The new QCA system was able to perform analysis in approximately one third the time required by previously validated system and was much less expensive. We conclude that personal computer-based coronary analysis is an accurate, quick, and relatively inexpensive means for performing QCA that may help to make this technique feasible for nonresearch settings.

Left ventricular inotropic effect of atrial pacing after coronary artery bypass grafting

The effect of atrial pacing on left ventricular (LV) performance was studied in 19 patients, 24 hours after coronary artery bypass grafting (CABG). LV volumes were calculated from simultaneous radionuclide-thermodilution measurements at rest (heart rate 82 +/- 12 beats/min), 10 minutes after the start of atrial pacing (100 beats/min), and with atrial pacing plus volume loading to return preload toward baseline. Atrial pacing reduced preload as reflected by LV end-diastolic volume index (69 +/- 14 vs 60 +/- 14 ml/m2, mean +/- standard deviation) (p less than 0.0001), but returned to baseline with volume loading. Afterload, as reflected by arterial end-systolic pressure, did not change with atrial pacing (63 +/- 9 at baseline vs 64 +/- 8 mm Hg with pacing, difference not significant). Afterload increased with volume loading (68 +/- 10 mm Hg, p less than 0.025 vs baseline and pacing). LV stroke volume decreased with atrial pacing due to reduced preload, but returned to baseline with volume loading. Cardiac index increased with atrial pacing and increased further with volume loading. Compared with baseline, LV end-systolic volume index was reduced during atrial pacing both before and after volume loading, despite unchanged or augmented afterload. The combination of atrial pacing and volume loading resulted in augmentation of LV stroke work, despite no increase in preload compared with baseline. Thus, after CABG, increased (paced) heart rate augments inotropic state, as indicated by reduced LV end-systolic volume under conditions of unchanged or increased afterload, and elevated LV stroke work without an increase in preload or a decrease in afterload.