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October, 1996 - Patients with with class 3 or class 4 heart failure, who were already on standard drug treatment, were enrolled in an outpatient program. This program included IV inotropic drugs, patient education, and close follow-up. Researchers tracked number of hospital admissions, length of stay, and number of emergency room visits during the following year.
This information was compared to similar data from the year before, for each patient. Thirty-six patients with stable class 3 to class 4 heart failure received milrinone or dobutamine as outpatients. The cause of heart failure was ischemic heart disease in 12, idiopathic in 11, high blood pressure in 8 and pulmonary hypertension in 5. Four patients took dobutamine and 32 patients took milrinone.
|Inotropes versus Standard Drug Therapy|
|Before program & inotropes||After program & inotropes|
|21 emergency room visits||10 emergency room visits|
|75 admissions||34 admissions|
|528 days spent in the hospital||150 days spent in the hospital|
This outpatient program reduced the number of hospital admissions, days spent in the hospital, and emergency room visits. Our study shows that using some inotropic therapy in the outpatient setting helps manage severely ill CHF patients.
Title: Intermittent inotropic therapy in an outpatient setting: a cost-effective therapeutic modality in patients with refractory heart failure.
Author: Marius-Nunez AL; Heaney L; Fernandez RN; Clark WA; Ranganini A; Silber E; Denes P
Source: Am Heart J, 1996 Oct, 132:4, 805-8
Unique Identifier: 96428267
January 7, 1997 - Scios Inc, today confirmed that its Phase 3 safety study of Natrecor BNP for treatment of acute CHF was completed in the third quarter of 1997. Early results confirm that Natrecor rapidly improved patients' symptoms. This new data will be included in the New Drug Application for Natrecor, which Scios plans to file with the FDA in the first half of 1998.
In an earlier study, Natrecor lowered PCWP by up to 31%, depending on the dose. That lowers the resistance against which the heart must pump, making the heart's job easier. Patients' symptoms and cardiac index also improved. More than 500 patients have now been treated with Natrecor and no unexpected adverse events have been seen.
May, 1999 - Scios has done now 10 trials since 1993 on Natrecor. Nine of the 10 trials were with CHF patients. Scios filed their first new drug application (NDA) to the FDA for Natrecor in April of 1998. In January of 1999, an FDA committee recommended approving Natrecor for treating severe CHF short-term. In April of 1999, Scios was refused FDA anyway.
Scios began a new Phase 3 clinical trial called VMAC (Vasodilation in the Management of Acute Congestive Heart Failure) in October of 1999. About 500 patients will be included in the VMAC trial, and Scios hopes to complete the trial and finally get FDA approval by October of 2001. The primary effectiveness endpoint is improvement in PCWP. VMAC is a randomized, double-blind trial to compare Natrecor to nitroglycerin therapy for decompensated (severe) CHF. The trial will also compare the effects of Natrecor to placebo.
Source: Scios Inc.
May, 1999 - Two separate studies show that Natrecor significantly improves heart function and well-being in patients hospitalized with severe heart failure. "Natrecor would be a valuable new first treatment for patients admitted for acute severe CHF," said Dr. Colucci, one study's lead author. "The drug's good benefits on heart function and lack of harmful side effects make it a good choice."
Study 1 In a double-blind, placebo-controlled trial of 127 CHFers at 23 USA medical centers, researchers tested the short-term effectiveness of 2 different Natrecor doses on heart function and heart failure symptoms. Both doses of Natrecor improved "numbers" and symptoms like severe shortness of and fatigue compared to placebo.
Study 2 In a separate randomized study of 305 patients done at 46 USA medical centers, researchers compared 2 different Natrecor doses to standard IV drugs. Again, both doses of Natrecor improved "numbers" and CHF symptoms. Natrecor patients needed fewer diuretics. There was no difference between groups in length of therapy, length of hospitalization, readmissions, procedures, or mortality.
In both trials, the most common side effect in Natrecor patients was low blood pressure, which usually did not cause symptoms.
Source: July 28, 2000 New England Journal of Medicine and MedscapeWire
1996 - CHFers' hearts don't increase pumping speed very well in response to activity. This may be due to changes in their beta-adrenergic receptors - what beta-blockers block. Some researchers think intermittent heart stimulation might improve heart function in patients who can't exercise. In case the usual intervals being tested are too long, we used intermittent inotropes to mimic short periods of exercise.
Ten heart failure patients were matched by age and heart class to 10 control patients. Patients in the treatment group got 30-minute IV dobutamine 4 days a week for 3 weeks. The dose was changed as needed to keep heart rate at 70 to 80% of the maximum seen during exercise at study start.
After 3 weeks, patients in the treatment group increased 25% in exercise tolerance and 10% in Vo2max. They also had lower heart rate and more change between resting and peak heart rate. Heart output increased. Patients in the treatment group rated their symptoms as substantially better. Six weeks after treatment, exercise tolerance in these patients was lower but still higher than at study start. Controls showed no changes in exercise tolerance.
Conclusions Brief, intermittent IV dobutamine can improve symptoms in heart failure patients without altering beta-receptors. This kind of therapy may be especially useful in CHF patients who can't exercise.
Title: Pulsed inotropic therapy in chronic heart failure Source: Adamopoulos S, Piepoli M, Qiang F et al: Effects of pulsed Beta-stimulant therapy on Beta-adrenoceptors and chronotropic responsiveness in chronic heart failure. Lancet 1995; 345: 344-349
Summary: Canadian Medical Association Journal 1996; 154: 208
April 21, 1999 - The FDA today announced a lable change for Dobutamine HCl in 5% Dextrose Injection in Plastic Containers. The existing text was deleted and replaced with:
"Dobutamine in 5% Dextrose Injection is indicated when parenteral therapy is necessary for inotropic support in the short-term treatment of patients with cardiac decompensation due to depressed contractility resulting either from organic heart disease or from cardiac surgical procedures. Experience with intravenous dobutamine in controlled trials does not extend beyond 48 hours of repeated boluses and/or continuous infusions.
Whether given orally, continuously intravenously, or intermittently intravenously, neither dobutamine nor any other cyclic-AMP-dependent inotrope has been shown in controlled trials to be safe or effective in the long-term treatment of congestive heart failure. In controlled trials of chronic oral therapy with various such agents, symptoms were not consistently relieved, and the cyclic-AMP-dependent inotropes were consistently associated with increased risk of hospitalization and death. Patients with Class 4 symptoms appeared to be at particular risk."
March, 1986 - To compare their effects on blood flow and the heart, we gave nitroprusside, dobutamine, and milrinone - in that order, to 10 patients with severe heart failure. Each drug significantly increased cardiac index:
Dobutamine did not produce a significant change in PCWP, which went from 27 to 24 mmHg, nor in average arterial pressure, which went from 83 to 86mm Hg. Dobutamine did raise heart rate from 85 to 99 beats per minute and myocardial oxygen need from 8.7 to 11.1ml O2/min.
In contrast, nitroprusside and milrinone each significantly lowered PCWP - nitroprusside: 27 to 19mm Hg and milrinone: 26 to 19mm Hg without significantly raising either heart rate or myocardial oxygen consumption.
Title: Milrinone, dobutamine, and nitroprusside: comparative effects on hemodynamics and myocardial energetics in patients with severe congestive heart failure
Authors: Monrad ES, Baim DS, Smith HS, Lanoue AS
Source: Circulation 1986 Mar;73(3 Pt 2):III168-74
ID: PMID: 3510773, UI: 86106689
November 12, 1991 - We randomly assigned 1088 class 3 to 4 heart failure patients to either 40mg of oral milrinone daily (561 patients) or placebo (527 patients). All patients also took digoxin, diuretics, and an ACE inhibitor. Average follow-up was 6 months.
Compared to placebo, milrinone patients had 28% higher all-cause mortality and 34% higher heart-related mortality. The sicker the milrinone patient, the more likely to have increased risk of death - class 4 patients had a 53% increase in mortality. Patients treated with milrinone had more hospitalizations, stopped treatment more often, and had more serious heart-related side effects, including low blood pressure and fainting.
Despite its benefit on heart function, long-term therapy with oral milrinone at 40mg daily increases complications and mortality of patients with severe chronic heart failure. Why is unknown.
Title: Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.
Authors: Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, et al
Source: N Engl J Med 1991 Nov 21;325(21):1468-75
Comment in: N Engl J Med 1991 Nov 21;325(21):1509-10 Comment in: N Engl J Med 1992 Jun 4;326(23):1565; discusssion 1567 Comment in: N Engl J Med 1992 Jun 4;326(23):1565-6; discusssion 1567
PMID: 1944425, UI: 92049563
March, 1986 - We studied the safety and effectiveness of oral milrinone therapy over a 2 1/2 year period in 100 patients with severe CHF. Long-term oral milrinone therapy of 27mg per day to start was well tolerated. Drug side effects occurred in only 11% of patients and led to drug withdrawal in only 4% of patients. Of 94 patients evaluated after one month, 51% had improved by at least one heart class. Despite hemodynamic improvements, there was a 39% mortality rate at 6 months and a 63% mortality rate at one year of therapy.
Some patients were more likely to die within 6 months, including those with worse heart class, impaired kidney function, lower right ventricular EF, nonsustained ventricular tachycardia, and no improvement after one month of milrinone therapy. So while milrinone is well tolerated and relieves symptoms early on in about half of CHF patients, it does not improve the high mortality rate for these patients.
Title: Survival of patients with severe congestive heart failure treated with oral milrinone
Authors: Baim DS, Colucci WS, Monrad ES, Smith HS, Wright RF, Lanoue A, Gauthier DF, Ransil BJ, Grossman W, Braunwald E
Source: J Am Coll Cardiol 1986 Mar;7(3):661-70
PMID: 3950244, UI: 86141310
1995 - We studied changes in symptoms with a single oral dose of 2.5mg, 5mg or 10mg of milrinone in 31 patients with severe heart failure. We found a significant increase in cardiac index and a significant decrease in PCWP (both good things) along with improvement in how the patient felt. These effects lasted 4 to 8 hours after each milrinone dose. The higher the dose, the better the benefit. This finding, together with results of the PROMISE trial, suggest that low-dose milrinone taken orally may be useful for short-term support in patients with severe heart failure.
Title: Hemodynamic effects and pharmacokinetics of oral milrinone for short-term support in acute heart failure.
Author: Seino Y; Takano T; Hayakawa H; Kanmatsuse K; Saitoh S; Saitoh T; Kamishima G; Watanabe K; Motomiya T; Murata M; et al
Source: Cardiology, 1995, 86:1, 34-40
April, 1997 - We studied the effects - good and bad - of short-term IV milrinone to treat severe heart failure. Measurements were taken in 24 patients with an average age of 65 years. They were all class 4 and had an ejection fraction averaging 24%. Measurements were taken at study start, after IV milrinone, and after maintenance doses of milrinone at 1/2 hour and at 3, 24, and 48 hours. Heart function improved and PCWP went down in 24 patients only 30 minutes after beginning therapy.
These favorable responses and more continued throughout the 48-hour study in 19 patients (79%). Severe low blood pressure occurred in 3 patients. One patient had repeated tachycardia and another became tolerant to milrinone, so that it no longer worked for him. In this study, IV milrinone gave significant short-term benefits in most patients with severe heart failure.
Title: Short-term intravenous milrinone for severe congestive heart failure: the good, bad, and not so good.
Authors: Varriale P, Ramaprasad S
PMID: 9085331, MUID: 97239670
July, 1997 - We did a nonrandomized trial in 71 patients dependent on inotropic therapy. Group one (22 patients) required treatment with both milrinone and dobutamine to be stable. Group 2 (49 patients) needed just milrinone (subgroup 2A) or dobutamine (subgroup 2B), but later required both IV drugs.
Of the 71 patients, 38% required a device (intra-aortic balloon pump) to achieve stability, and 68% were successfully bridged to heart transplant. Patients were maintained on milrinone for up to 8 weeks and had few bad heart-related side effects (7%) or non-heart-related (4%) events. Subgroup 2A (28%) had a lot less need than subgroup 2B (52%) for a device. Mortality was similar in subgroups 2A (28%) and 2B (35%).
Improved heart function proves long-term effects. Long-term IV milrinone is safe and well tolerated. Milrinone use may reduce need for mechanical support.
Title: Safety and clinical utility of long-term intravenous milrinone in advanced heart failure
Authors: Mehra MR, Ventura HO, Kapoor C, Stapleton DD, Zimmerman D, Smart FW
Source: Am J Cardiol 1997 Jul 1;80(1):61-4
PMID: 9205021, UI: 97349017
March, 1995 - Fourteen class 4 heart failure patients 75 years old or older were in this trial. Average cardiac index was 1.8 liters/minute/meter·2, average PCWP was 26 mmHg, and average ejection fraction was 26%. Patients were randomly assigned to receive either 2-hour infusions of amrinone (7 patients) or dobutamine (7 patients) at fixed doses of 5 and 10 micrograms/kg/minute.
Echocardiogram was done at study start and after the 10microgram infusion. We compared the effects of both drugs on cardiac index and stroke volume at each dose.
Both amrinone and dobutamine had positive effects on heart function: Cardiac index, stroke volume, and PCWP all improved. Stroke volume was higher with dobutamine at the 10 microgram dose. Two dobutamine patients withdrew from the study after the lower dose, due to fast heart rate.
Both amrinone and dobutamine are effective for improving heart function in older patients with severe heart failure. Dobutamine is as effective as amrinone but may be cause more irregular heart rhythms.
Title: A randomized comparison of intravenous amrinone versus dobutamine in older patients with decompensated congestive heart failure
Authors: Rich MW, Woods WL, Davila-Roman VG, Morello PJ, Kurz H, Barbarash R, Spinner L, Sperry J, Beckham V, Coulter L, et al
Source: J Am Geriatr Soc 1995 Mar;43(3):271-4
PMID: 7884117, UI: 95190181
February 12, 2001 - Actelion and Genentech have announced that tezosentan - an IV endothelin blocker - improved heart function in 292 patients suffering from acute heart failure.
Detailed results of RITZ II are being presented at this year's meeting of the American College of Cardiology. RITZ II is the first of two trials making up the tezosentan study program. The other is RITZ I, a 670 patient study of the drug for acute heart failure.
Source: Genentech press release
All information on this site is opinion only. All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor. Use the reference information at the end of each article to search MedLine for more complete and accurate information. All original copyrights apply. No information on this page should be used by any person to affect their medical, legal, educational, social, or psychological treatment in any way. I am not a doctor. This web site and all its pages, graphics, and content copyright © 1997, 1998, 1999, 2000, 2001, 2002, 2003, 2004 Jon C.