New potential for milrinone therapy?
Some experts take issue with a study’s findings
A group of researchers from Texas is taking a fresh look at milrinone therapy to see how it can be used to stabilize patients with severe CHF so they can proceed with beta-blocker therapy. Reynolds M. Delgado III, MD, Cathy A. Eastwood, RN, MN, and Mohamad Nawar, MD, MPH, who work at the heart failure center of St. Luke’s Episcopal Hospital in Houston, followed a group of 19 patients with NYHA class IV CHF who were on continuous milrinone infusion.
"We wanted to see if we could possibly improve on their oral meds and get them off milrinone," says Eastwood, who is clinical coordinator of the heart failure program. "We wanted to see if there’s a possibility that this is not a terminal treatment, but rather a treatment that allows us to support patients to get oral drugs on board and show heart improvement — better ejection fraction and some decrease in heart size — once they are on the maximum oral drugs."
The team presented a poster at the Sept. 23-24 National Heart Failure Society meeting in San Francisco. Their stated conclusions:
¤ Continuous home infusion of low-dose milrinone followed by initiation and titration of beta-blocker therapy is an effective strategy.
¤ Beta-blockers may facilitate milrinone weaning.
All patients in the study were no longer able to take standard medications necessary to keep their disease on track and had low cardiac output prior to the study. When they were stabilized in-hospital on IV milrinone, cardiac output improved significantly.
All 19 were discharged home with a PICC line (peripherally inserted central catheter) and continuous milrinone. All but four of the 19 were started on a low dose beta-blocker prior to discharge, either metoprolol 25-50 mg po bid or carvedilol 25-50 mg bid.
Milrinone (New York City-based Sanofi’s Primacor) was infused at a rate of 0.3-0.375 mcg/kg/min. Outpatient beta-blocker uptitration was done gradually, every three or four weeks. "We added a beta-blocker slowly, then weaned them off the infusion," says Eastwood.
The patients’ functional status improved to an average NYHA class of 2.82 at the end of follow-up. Hospitalizations decreased from 37, six months prior to home therapy, to 14.
The study patients got a continuous infusion of the drug through a "fanny pack" that contained a portable pump. (See photo of a patient wearing the pump-carrying accessory, above.)
"The fanny pack is customized for infusion," says Eastwood. "It has space for the tubing, a flap for the medicine bag, and a slot for the pump." Patients have freedom to move about and resume most, if not all, of their daily activities. "They can even take a shower by covering the site with Saran wrap," she says. "It allows them to lead a fairly normal life."
Two patients died while on the IV therapy, neither of them on a maximal dose of a beta-blocker. One suffered sudden cardiac death three months after initiation of therapy, and the other died after milrinone was inadvertently stopped for six hours due to a mechanical failure. Six patients were weaned off milrinone while on maximal beta-blockers after an average of 21 months and are currently NYHA class I or II.
Typically, when beta-blockers are taken by CHF patients, during a six-week period of uptitration, hypotension and weakness may occur. The researchers’ goal was to see if beta-blockers can be used concurrently with milrinone in those patients, says Eastwood.
Patients were maintained on the combination of milrinone and beta-blockers for an average of one year. Weaning was considered for six patients who achieved and maintained NYHA I-II symptoms. Weaning involved first discontinuing milrinone for 12 hours every other day and infusing 12 hours at night for one week, then infusing only 12 hours every day for one week, then off completely.
"When a patient was weaned," says Eastwood, "the infusion was turned off during the day and on at night. The IV was left in. When the infusion ran at night, we used the same pump as that in the fanny pack."
The PICC line was removed after one week if the patient remained stable off milrinone and tolerated therapeutic doses of beta-blockers and ACE inhibitors or an adrenergic receptor blocker (ARB) agent. The ability to be weaned was independent of ischemic vs. non-ischemic etiology, but NYHA class improvement on milrinone predicted weaning success. Patients not weaned improved their NYHA class by 20.5%, achieving between class III and IV. Those weaned improved from IV to nearly II by 54%, and their left ventricular end-diastolic dimensions (LVDd) improved slightly. Both weaned and unweaned patients showed dramatically decreased hospitalizations and hospital days once on home therapy, but the weaned group had nearly 90% fewer days six months after follow-up compared to six months before.
David S. Roffman, PharmD, BCPS, associate professor at University of Maryland’s School of Pharmacy in Baltimore and a therapeutic consultant for the cardiac care unit in the University of Maryland’s Medical System, takes issue with the basic premise of the St. Luke’s investigators’ study. Roffman disagrees that better ejection fraction and some decrease in heart size can affect survival.
"These are surrogate endpoints," he says. "You can make someone’s ejection fraction better, but they may not live longer. In fact, they may live shorter. You can make arrhythmias go away, but the patient may die from the antiarrhythmia agent. Also, this is a small trial — 19 patients."
Eastwood says that milrinone, an inotropic agent, is used only when patients are maximized on their oral medications and refractory to them. "They are in class IV heart failure, and their oral meds are no longer effective. Milrinone does have implications for increasing risk of death, but we found a very low incidence of arrhythmias, the cause of death, and we’re comfortable using the drug."
Roffman disagrees. "No inotrope — milrinone, digoxin, dobutamine — has ever been shown to improve survival in heart failure patients. Some have been shown to increase mortality."
Closely monitor patients during infusions
Milrinone is generally well tolerated, but it may potentiate ventricular arrhythmias in some patients, and they should be closely monitored during infusions. (See article on the inotropic agent, p. 143.) Since renal function may improve during milrinone therapy, serum electrolytes must be closely monitored as well. Other common adverse effects include hypotension and angina.
"The point is," Roffman says, "you can’t predict sudden death from these drugs based on the presence of preexisting arrhythmias. Some patients die; some deaths are probably from the arrhythmias. But some die from bradycardia or from other reasons. We don’t know why the deaths occur. The misleading part of these findings is the investigators saw the risk of arrhythmia was low because they looked for arrhythmia. They are jumping over a very large chasm when they say, We saw few arrhythmias as the cause of death, therefore we’re comfortable using the drug.’ In my opinion, it doesn’t fly. Lots of patients respond to inotropes but most shouldn’t go home on the drugs. Inotropes are used mostly to tune up patients in the hospital when they come in decompensated."
Some other experts also note that IV inotropes such as dobutamine and phosphodiesterase inhibitors decrease survival. However, investigators recently conducted a study to determine whether patients with end-stage CHF could tolerate intermittent outpatient inotropic therapy. They demonstrated both symptomatic and functional improvement with the agents.1
The study looked at the effects of low-dose, intermittent home infusions of the inotrope/ vasodilator milrinone and concluded that patients’ improvement partly relates to a "training" effect on the heart or peripheral muscles and circulation. Investigators stated that the promising results suggest that, given appropriately, inotropes have an important therapeutic role in the outpatient treatment of end-stage CHF to treat symptoms.
But Roffman says that study does not talk about improvement in survival. "Inotropic agents have a potential to create tachycardia, and no inotropic has been shown to improve survival of CHF patients."
Patients with advanced CHF can receive intermittent infusions in-hospital also. "Six- to eight-hour infusions can be administered once a week or even daily if a patient chooses. It represents a heavy commitment on their part to come in every day," says Eastwood. "Intermittent infusion is controversial, though. It’s not certain how well it works. Milrinone has a long enough half-life to boost the heart for a time."
Some insurance companies won’t pay for home continuous infusion, Eastwood explains, but will pay for hospital continuous infusion. But some patients don’t want a PICC line in their arm. Some try intermittent infusion first (weekly or Monday, Wednesday, Friday) to avoid continuous infusion.
Reference
1. Cesario D, Clark J, Maisel A. Beneficial effects of intermittent home administration of the inotrope/vasodilator milrinone in patients with end-stage congestive heart failure. Am Heart J 1998; 135(1):121-129.
Suggested reading
• Bohm M, Deutsch HJ, Hartmann D, et al. Improvement of postreceptor events by metoprolol treatment in patients with chronic heart failure. J Am Coll Cardiol 1997; 30(4):992-996.
• Cusick DA, Pfeifer PB, Quigg RJ. Effects of intravenous milrinone followed by titration of high-dose oral vasodilator therapy on clinical outcome and hospitalization rates in patients with severe heart failure. Am J Cardiol 1998; 82(9):1,060-1,065.
• Packer M, et al. Consensus recommendations for the management of chronic heart failure. Am J Cardiol 1999; 83:1A-38A.
• Packer M, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991; 325:1,468.
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