LVAD Platform for Long-Term Drug Therapy in Severe CHF

Abstract & Commentary

By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.

Source: Birks EJ, et al. Left Ventricular Assist Device and Drug Therapy for the Reversal of Heart Failure. N Eng J Med. 2006;355:1873-1884.

Stage D or class IV congestive heart failure (CHF) is an ominous clinical state associated with high mortality. Recent advances in pharmacotherapy and resynchronization therapy have been widely publicized, but destination therapy with left ventricular assist devices are unfamiliar to many cardiologists. This is a report from Harefield Hospital in the United Kingdom describing a group of 15 patients with severe CHF and marked depression of left ventricular systolic function, who were treated with a 2-stage therapeutic intervention consisting of a left ventricular assist device (LVAD) and standard CHF medical therapy, followed by treatment with clenbuterol (clen), a highly selective b2 blocker. After a mean of 10 months, 11 of the 15 patients were able to undergo explantation of the LVAD. One cardiac and one non-cardiac death occurred after explantation. Freedom from recurrent heart failure in the survivors was 100% at one year and 89% at 4 years. Multiple parameters, including echocardiography, cardiac catheterization, exercise, and the use of the Minnesota Living with Heart Failure questionnaire, confirmed marked improvement in the survivors, with a significant reduction in left ventricular size and improvement in left ventricular ejection fraction (EF) into the normal range. All hemodynamic parameters, including mean maximal oxygen uptake, were markedly better after explantation than at the implantation of LVAD treatment. This remarkable report supports the concept that prolonged, near complete unloading of left ventricle with the use of an LVAD…may be associated with structural reverse remodeling…and functional improvement." Of note, other research in this field has produced disappointing results, with only 5–24% of individuals able to undergo explantation and a high incidence of early recurrence of CHF.

The protocol consisted of the use of a Thoratec HeartMate LVAD in combination with drugs known to produce reverse LV remodeling, followed by a β2 agonist clenbuterol, which is not available in the United States. All patients had non-ischemic cardiomyopathy and no evidence of acute myocarditis on biopsy. All had class 4 or stage D heart failure, unresponsive to intensive medical therapy. Efforts to enhance reverse remodeling included an ACE inhibitor, an ARB, carvedilol, and spironolactone. After maximal regression of LV systolic and diastolic diameters with the LVAD in place (constant LV size for at least 2 weeks), clen was added to the medical regimen. Carvedilol was replaced by bisoprolol, a selective β1 blocker.

A variety of monitoring approaches were utilized, including repeated echocardiography with quantitative cardiac measurements, a 6-minute walking test in individuals who were able to go off the LVAD for 20 minutes, and subsequently a 450 meter 6-minute walk. Cardiac catheterization was performed before LVAD implantation, before clen, and before explantation. To be eligible for explantation, patients had to have an LVEDD of < 60 mm, an LVSD of < 50 mm, and LVEF of > 45%. In addition, LVEDP or pulmonary wedge pressure needed to be normal and relatively normal oxygen consumption with exercise was required. After explantation, patients underwent an echo, cardiopulmonary exercise, and repeat cardiac catheterization at 3 months and one year.

Quality of life was assessed 3 years after explantation. The initiation of the LVAD therapy occurred over a 7-month period, beginning in December of 1999. After excluding ischemic cardiomyopathy and other significant co-morbidities, a total of 15 patients were enrolled to receive the combination therapy. Myocardial histology at the time of LVAD implantation demonstrated interstitial and replacement fibrosis and myocyte hypertrophy, compatible with a dilated cardiomyopathy. Eleven of the 15 patients who completed the phase one combination therapy met LVAD explantation criteria. Mean duration of LVAD support was 320 ± 186 days. Two patients underwent cardiac transplantation after completing the full course of combination therapy. Actuarial survival rate at one and 4 years after explantation was 91% and 82%, respectively.

Minimal follow-up after explantation was 4 years on average; all survivors were in NYHA class-1, except for one person who deteriorated after excessive alcohol intake. Thus, among the survivors, the cumulative rate of freedom from recurrent CHF at 1 and 4 years was 100% and 89% respectively. Follow-up at a mean of 5 years demonstrated a mean LVEF of 64% ± 12%, an LVEDD of 59mm, an LVSD of 42.5 mm ± 13 mm, VO2 of 26 ml/kg/min. Hemodynamics by cardiac catheterization at 3 months and one year after LVAD explantation were essentially within the normal range, except for mildly depressed cardiac index.

The authors conclude that severe CHF can be reversed in selected patients without acute myocarditis with the use of a specific sequence of mechanical and pharmacologic therapy." Hemodynamic and clinical improvement to relatively normal levels occurred in all patients who were able to complete the dual therapy, and were maintained for more than 4 years in most. Thus, 75% of the 15 individuals who received the full course of combination therapy recovered, and 46% of all patients in the study had a complete recovery. The rate and duration of recovery … were significantly higher than previously reported after LVAD implantation." The authors comment that the initial phase of therapy was to reverse LV remodeling, and the second phase, not as well established, was to utilize selective β2 stimulation, for which there is positive experimental work in animals and patients. It is suggested that clen treatment may prevent some of the adverse myocyte atrophy seen in long-term mechanical unloading of the heart. Few side effects were noted, other than mild tremor and muscle cramps in phase-2. The authors asserted that sustained reversal of severe heart failure secondary to non-ischemic cardiomyopathy could be achieved in selected patients." They call for further studies to assess the reproducibility and durability of these findings.

An accompanying commentary (Renlunde DG, Kfoury AG. N Engl J Med. 2006;355:1922–1924) was supportive of this approach, while raising some questions about the study protocol. Specifically, they ask whether both a first and second phase choice of pharmacotherapy was necessary; they also question whether the patients all had severe or stage D heart failure. They stress the careful selection of the patients and point out that not all patients had a good response. Nevertheless, they conclude that there is a preponderance of evidence supporting these results." They conclude that stage D heart failure treatment now includes not only transplantation or permanent LVAD implantation, but the possibility of prolonged LVAD use, with robust pharmacologic support, followed by careful explantation in patients who improve.

Commentary

The increasing sophistication and number of heart failure programs around the United States have changed the nature of treatment for severe heart failure, with more aggressive LVAD utilization as well as enhanced standard pharmacologic support. This report of a study initiated 5–6 years ago, is an exciting preliminary description of the use of an LVAD as a platform" for pharmacologic therapy, followed by removal of the device if clinical and hemodynamic parameters are concordant with considerable reversal of remodeling, ie, diminution of LV cavity size, improvement in systolic function to within the normal range, and increases in clinical and exercise status. Clearly, the sophistication of the heart failure center needs to be great. This study was headed by a surgeon, Dr. Magdi Yacoub. It should be noted that the RAAS system was attacked both by an ACEI and an ARB, and, in addition, an aldosterone blocker. Thus, the regimen included the greatest degree of interference with the RAAS system available. Whether ACEI and ARB together were useful in improving the outcomes is difficult to assess. This report, while representing only a small number of individuals who received up-to-date approaches to the failing heart, should stimulate workers in the field to continue innovative basic and clinical research for class D patients.