Biventricular pacing (BiV) has documented benefit in New York Heart Association functional class III patients. Whether BiV offers benefit to class IV patients on inotropic therapy is unclear.

Retrospective review was performed on 38 consecutive heart failure patients who received BiV while on inotropic support or within 30 days of inotropic administration; the mean age was 63 [plus minus] 13 yrs; 9 were women. Fourteen who received inotropic agents did so in conjunction with coronary artery bypass grafting, or valve or infarct exclusion surgery.

Twenty-three patients received inotropic therapy only before BiV. Nine other patients received inotropic therapy before BiV and at another point (5 at implant and 4 after BiV); 6 were on inotropic support only at implant. Mean follow-up was 1.2 [plus minus] 0.9 years. There were 14 deaths. Survival estimates at 6 months, 1 year, and 2 years were 74%, 71%, and 61%, respectively. When patients on inotropic therapy before BiV (n=32) were compared with patients never on such therapy before BiV (n=6), there was a survival difference (P < 0.0001); all 6 patients not on inotropic therapy before BiV died within the first 2 years. Estimated 6-month and 1-year survival for those on inotropic support before BiV was 84% and 81%, compared with 23% and 23% for the other group.

Patients who required inotropic agents only before BiV fared better than those requiring inotropic support at other times. Although the patients in this survey were a very high-risk group, a small subset was weaned and had stable short-term survival.

Key words: Dobutamine, heart failure, congestive, inotropic support, milrinone, pacing, biventricular, ventricular resynchronization

Despite advances in the treatment of congestive heart failure (CHF), the mortality rate remains high at 50% after 5 years.¹ The lifetime risk of developing CHF for persons 40 years and older is 20% for both men and women, exceeding the lifetime risk of many conditions screened for in the community.² Given the aging population of the United States, the clinical and economic burden of CHF is expected to increase over time. Therefore, it is crucial that research continues in both pharmacologic and nonpharmacologic therapies for heart failure.

A promising nonpharmacologic treatment for heart failure is resynchronization therapy with biventricular (BiV) pacing. For cardiomyopathy patients with an intraventricular conduction delay, numerous studies have shown that restoring synchrony of right and left ventricular contractions can result in improved ejection fraction and clinical status in heart failure patients.^{3 --10} However, the clinical trials have focused primarily on New York Heart Association (NYHA) functional class III patients, not on class IV patients on inotropic agents such as dobutamine or milrinone.

At our institution, a small subset of CHF patients on inotropic agents was known to have received BiV pacing. The goal of this study was to perform a retrospective review of those CHF patients who were on inotropic support at the time of, or 30 days before or after, BiV pacemaker implantation, in order to determine whether these sickest patients, who were excluded from trials, derived any clinical benefit from resynchronization therapy.

Subsequently, the Social Security database was queried for deaths that had occurred in the interim. A heart failure research nurse contacted the surviving patients for follow-up data. The study was explained and telephone informed consent was obtained. The patients were then queried regarding their need to resume inotropic agents or their inability to be weaned, and regarding their NYHA functional class.

There was no significant difference in length of survival between patients who were on inotropic support only before BiV pacing (n=23) and the others (n=15), P =0.09. This is shown in the 1st stratified Kaplan-Meier plot (Fig. 2).

However, if patients who were on inotropic support before BiV pacing (n=32) were compared with patients who were never on inotropic support before BiV pacing (n=6), there appeared to be a survival difference (P <0.0001), because all 6 patients who were never on inotropic support before BiV pacing died within the first 2 years (Fig. 3). The estimated 6-month and 1-year survival for those on inotropic support before BiV pacing was 84% and 81%, compared with 23% and 23% in the other group.

In cardiomyopathy, there are structural abnormalities of the myocardium that affect ventricular activation and contraction.¹² Electrical activation of the ventricles can be delayed due to disease of the conduction system or due to homogeneous spread of excitation across scar tissue, which results in bundle branch block.¹³ Subsequently, it has been hypothesized that BiV pacing can improve synchrony of contractions of both ventricles, leading to improved hemodynamics and ejection fraction.^3,14 Pacing the left ventricle is accomplished via the coronary sinus. From 2000 to the present, multiple reports of clinical trials have attested to objective functional and clinical improvements in CHF patients who received BiV pacing.^{3 --10} However, these trials excluded the sickest CHF patients ---those in advanced NYHA functional class IV who were receiving intravenous inotropic medications such as dobutamine or milrinone.

Kerwin and colleagues³ were among the early investigators who evaluated the effect of BiV pacing on ejection fraction. In 13 of their patients with improved synchrony, ejection fraction rose from 17.2% [plus minus] 7.9% to 22.5% [plus minus] 8.3% (P <0.0001).³ In the same year, Nelson and associates⁴ found that resynchronization with either left ventricular or BiV pacing improved systolic function at diminished energy cost in cardiomyopathy patients with left bundle branch block; they noted a 43% [plus minus] 6% increase in dP/dt_max in paced settings.

The MUSTIC (Multiple BiVentricular Pacing in Patients with Heart Failure and Intraventricular Conduction Delay) Study reported clinical benefits of BiV pacing.⁵ The authors reported improved exercise tolerance as determined by the 6-minute walk and peak oxygen uptake. They also described 32% improvements in quality-of-life scores among their patients, and hospitalizations decreased by two thirds.⁵ The MUSTIC Study group later reported follow-up data at 12 months, which indicated sustained 1-year improvement in exercise tolerance, quality of life, functional class, and ejection fraction, and decreased mitral insufficiency.⁶ Biventricular pacing has also been shown to benefit heart-failure patients who are in atrial fibrillation, which suggests that BiV pacing acts through ventricular resynchronization rather than through optimization of atrioventricular delay.⁷

The MIRACLE Study, a larger (n=453) double-blind study on resynchronization in heart failure, confirmed clinical improvement in CHF patients who had an intraventricular conduction delay, in terms of 6-minute walk, functional class, quality of life, treadmill time, and ejection fraction.⁸ In addition, there were fewer hospitalizations and less need for intravenous medications (diuretics, vasodilators, or inotropic agents) in the BiV pacing group.

Recent data show, over time, decreased levels of neurohormones in BiV pacing patients. Boerrigter and coworkers⁹ described significant reductions in cyclic guanosine monophosphate (cGMP) in BiV-paced patients at 6 months, which suggests reduction in natriuretic peptide activation. Bradley and colleagues¹⁰ performed a meta-analysis of randomized, controlled BiV pacing trials and found that resynchronization reduces the death rate from progressive heart failure; it also reduces CHF admissions and shows a trend toward reduction in all-cause mortality.

As mentioned earlier, the resynchronization clinical trials excluded class IV patients who were currently receiving inotropic therapy, because these patients were deemed too sick to benefit. Inotropic therapy in these heart failure patients was generally used as a "last resort" in patients who no longer responded to oral therapy alone. The agents were dobutamine and milrinone. These medications can be used short-term in hemodynamically-guided optimization of medications; as a bridge to transplant; or as a chronic, palliative therapy in patients with severe heart failure.

Our series describes 38 patients who received off-label BiV pacing while taking inotropic agents, or in temporal proximity to the use of these agents. Of 23 patients who were on inotropic agents within 30 days before BiV pacing, but not during or after, 6 died. The mean functional class of the survivors was 1.8. Of the 6 patients on inotropic therapy at BiV pacing but not after, half survived and remained off such therapy. Of the 9 who required inotropic therapy even after BiV pacing, 7 (78%) received heart transplants, died, or both.

This case series is limited by small numbers. No control group was used, because ours is a descriptive, retrospective series. However, the series does provide outcome data on these ill patients who received devices ---which have not, to the best of our knowledge, previously been described. The clinical question of whether to offer BiV pacing to advanced CHF patients on inotropic therapy continues to arise. Although our patients were a very high risk group, a small subset was able to remain off inotropic support and to survive during the study period. Larger randomized, prospective studies are needed in order to identify the point at which resynchronization no longer provides benefit.