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Archived articles here      Updated June 12, 2006

IV drugs are given by injection or directly into a blood vessel. This kind of therapy for heart failure is usually only offered when you are decompensated and in the hospital. This may be changing, though. IV therapy should always be started in the hospital. Currently, IV drugs for heart failure can be roughly separated into two categories: inotropes and non-inotropes.

Inotropic Drugs

Inotropes are drugs that make your heart beat more strongly. They come in two basic flavors. The first type is called "b-adrenergic agonists". These include dobutamine and dopamine.

Dobutamine
improves heart function and may lower blood pressure. It is used as a continuous IV infusion. It helps your body make more use of a substance called norepinephrine, which your body makes on its own. Norepinephrine stimulates your heart to work harder. You can become tolerant to dobutamine faster than to dopamine, and larger doses are necessary to get the same effect over time. Eventually it might stop helping you entirely. Potential side effects include irregular heart rhythm (although less than with dopamine), and increased demand for oxygen by the heart
Dopamine
improves heart output and may raise blood pressure. It is also a continuous IV infusion. It increases the amount of norepinephrine active in your body. You become tolerant to dopamine, so larger and larger doses are necessary to get the same effect over time. Dopamine is often used to help get rid of edema because of how it affects receptors in the kidney's blood vessels. Potential side effects include irregular heart rhythm, and increased demand for oxygen by the heart
Phosphodiesterase-III Inhibitors
The other main type of inotropes are drugs called "phosphodiesterase-III inhibitors.". These drugs make your heart beat more strongly and also relax your blood vessels. Milrinone (Primacor) is the most widely used drug of this type. Milrinone is usually given by IV at 0.375 to 0.75 micrograms per kilogram of body weight per minute.
     If the patient is in critical condition, an IV at 50 micrograms per kilogram of patient body weight may be used. This has to be done very carefully in patients with low blood pressure. Since milrinone does not increase the heart's oxygen demand, it is preferred over other inotropes in patients with ischemic cardiomyopathy. Milrinone is also better for treating severe CHF episodes in patients taking beta-blockers.
     Other drugs like amrinone (Inocor) are not used much these days because they are more likely to cause dangerous arrhythmias. Pill forms of some inotropes have been tried but taking them on a regular basis increased risk of death in CHFers. The pill forms don't seem to help CHFers nearly as much as IV inotropes do either.

Using IV inotropes is still controversial among doctors because they increase your risk of death. However, if a CHFer suffers severe symptoms that standard drugs don't help, he might want inotropes anyway. Keep in mind that using IV inotropes will probably shorten your life. On the other hand, they may greatly improve your quality of life, even if only for a short while. It's your body, your life, and your call.
     Some patients who don't respond to standard therapy use IV inotropes every so often on a regular basis. This is called "intermittent" therapy. It's controversial but if nothing else works, you might consider it. Generally speaking, patients taking intermittent IV inotropes should try weaning off the drug every 6 months. It's possible that your heart has grown stronger in that time and you may no longer need the drug.

Non-Inotropic IV/Injectable Drugs

Currently, the main non-inotrope IV drug for heart failure is Natrecor (nesiritide). The FDA approved it in August of 2001. It's not an inotrope. It's a synthetic version of a hormone called BNP that your body makes naturally in the heart's ventricle. Natrecor is a vasodilator, meaning it enlarges and relaxes your blood vessels. This reduces the load on your heart - both coming and going - making its job easier, so you feel better.

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 Inotropic Heart Failure Therapy

December 17, 1998 - (Jon's note: I was in the major vesnarinone trial and was taking the highest dose. Luckily - depending on who you ask - it didn't kill me) In 1990 heart failure was considered a condition that could be helped by using drugs that made the heart beat more forcefully. IV dopamine and dobutamine were widely used to increase cardiac output.
     Amrinone and milrinone do increase heart pumping strength but small trials of amrinone raised concerns about a higher risk of death using these drugs. Milrinone had fewer side effects but stopping it after 2 to 10 weeks caused patients to slip back into worse shape than before. A trend was seen toward higher mortality with long-term use.
     In a trial started in 1989, milrinone (Primacor) was linked to mortality of 30%, compared to 24% with placebo at 6 months. Two other inotropes also bit the dust around this time. Despite improved exercise ability and better quality of life, pimobendan increased risk of death. Flosequinan improved ability to function and was widely prescribed until increased mortality got it taken off the market. In other words, these drugs make you feel better and function better, but you'll probably die sooner.
     Reports of improved survival with vesnarinone came as a surprise in 1993. A trial was started to include placebo patients, 30mg vesnarinone per day patients and 60mg per day patients. After 232 deaths in the placebo group, the trial was stopped. There was a 21% increase in risk of death for people taking vesnarinone.
     CHF is now seen as a disease of heart remodeling. Current therapy includes ACE inhibitors to slow the disease, reduce risk of death, and improve symptoms. Loop diuretics relieve fluid buildup. Beta-blockers should be taken by all stable CHFers. Standard CHF treatment guidelines can be seen at chfpatients.com/faq/guidelines_99.htm.
     Despite ACE inhibitors and beta-blockers, heart failure is still a disease that tends to get worse over time. There are many patients for whom even the best drugs do little. Many of them don't care as much about survival as about symptom relief. Therapies that improve symptoms - even without improving survival - attract patients. Are we ready to consider therapies that offer symptom relief but worsen survival? (Jon's Note: This shows the arrogance of doctors - this is our decision, not theirs - because it's our life!).
     Some patients may want to trade greater risk of death for a chance to feel better. Even with only class 2 to class 3 symptoms, 40% of patients expressed willingness to accept a 5% risk of death in order to gain a small improvement in quality of life. Patients hospitalized while waiting for heart transplant said they were willing to take a 50% risk of death for a chance at better health. In those with class 3 to class 4 heart failure, 49% were willing to trade at least half of their remaining time alive in order to feel well.
     In clinical trials study drug is kept constant. However, in reality doctors and patients adjust therapies by trial and error. Treatments that coincide with improvement are continued; others are often stopped, especially if they carry a lot of risk. What would be the effect on patients if a drug like vesnarinone were continued only when symptoms improved? Would the risk be reduced? How long should we wait for a patient to respond?
     Inotropic therapy does not have a role in the treatment of most heart failure patients. Looking forward, however, there may be a place for drugs that give enough symptom relief to justify an increased risk of death for some patients. This group should include those in whom the best available therapies have failed.
 
Author: Lynne Warner Stevenson, MD, Harvard Medical School
Source: The New England Journal of Medicine Vol. 339, No. 25

 Short-term IV Inotropes May Benefit CHF

January 9, 2001 - Ken Priskorn needed a heart transplant; but last summer while waiting for a donor heart, Priskorn got an infection requiring antibiotics. The drugs permanently weakened his kidneys, making heart surgery impossible. However, by fall Priskorn had improved so much that he was up and walking around. His improvement comes from a small container of inotropic drug tucked into a waist pouch. It is pumped intravenously into a tube in his arm. The IV line runs up under Priskorn's shirt into an implanted port. It's a little awkward, especially when he showers, because he can't get it wet. The Priskorns say it's well worth it.
     Dr. Barry Levine says that many CHFers can live longer, with reduced symptoms this way. About 10 years ago, Levine began noticing "that a number of patients taking IV inotropes improved so much that they didn't need a transplant." He and his wife, Dr. Arlene Levine, began to prescribe the therapy to be used at home. The Levines' study of 49 patients on IV inotropes was published in the March issue of Clinical Cardiology.
     Their study showed improved health and fewer hospitalizations in 35 of the 49 patients. The other 14 patients needed to stay on the therapy for another 6 to 10 months. Compared to the larger group that responded well, the 14 patients needing repeated infusions were more likely to do poorly.
     The doctors use outpatient IV inotropic therapy with caution in carefully selected patients; mostly patients who have extremely low blood pressure. Over the years, the Levines have learned how to fine-tune different meds for CHF patients. They also preach the benefits of a low sodium diet and exercise.
     "The term 'end-stage' to describe heart failure is overused," Levine says. "The fact is, many patients benefit from therapy, including this type of inotropic support, without a transplant."
 
From: Free Press
By: Patricia Anstett

 Milrinone Use At Home

January, 1998 - Although inotropes can help end-stage heart failure patients, their use in outpatient settings is limited because the more you take them, the more likely you will need higher and higher doses to get the same benefit.
     We studied low-dose, intermittent home use of IV milrinone in 10 end-stage CHFers. After showing improvement on milrinone while hospitalized, central lines were placed and patients were given the drug at home with small portable infusion pumps. They started at 3 days a week, for 6 hours at a time, over a 3-month period.
     Patients tolerated the drug well, with no deaths and 400% fewer hospitalizations during the study. There were few arrhythmias and angina improved in 2 patients. Quality of life also improved.
     The improvement lasted longer after each infusion, with an average of 25 hours of improvement after an infusion during the final week. At the end of the 3-month period, heart function was better. This is the first study to show safety, effectiveness; and better heart function and exercise ability in patients taking low-dose, intermittent outpatient IV milrinone. Given properly, inotropes may have an important role in outpatient treatment of end-stage heart failure.
 
Title: Beneficial effects of intermittent home administration of the inotrope/vasodilator milrinone in patients with end-stage congestive heart failure: a preliminary study
Author: Cesario D, Clark J, Maisel A
Source: Am Heart J 1998 Jan;135(1):121-9
PMID: 9453531, UI: 98114276

 Intermittent Milrinone For Severe CHF

November, 1999 - (Jon's Note: You had to respond favorably to a test infusion before you got into this study) Milrinone is a vasodilator and inotropic drug which increases calcium flow into the heart. This leads to better heart function. Milrinone is similar to amrinone but 20 to 30 times stronger.
     We studied IV milrinone in hospitalized patients with severe CHF during their hospitalization and at 4 month follow-up. CHFers who did not respond to standard meds were screened. Each patient had a 72-hour milrinone infusion while in an ICU. Patients who responded well were selected for the study. Thirty-six patients (28 men and 8 women, average age 66 years) with class 4 heart failure were selected for the trial. Average starting EF measured by MUGA was 17%. Each patient had DCM with CHF for at least 3 years from ischemic heart disease (69%) or unknown causes (31%). Digoxin and diuretics were continued. ACE inhibitors or other vasodilators were stopped 24 hours before starting IV milrinone to avoid too-low blood pressure. Many patients were not allowed into this trial.
     Patients took four 72-hour cycles of IV milrinone, one every 20 days. Each cycle was started with a loading dose of 50 micrograms/kilogram over 10 minutes, followed by continuous IV of 0.5 micrograms/kg/minute over 72 hours.
     We measured PCWP, PAP, and RAP (right atrial pressure) via cath. Cardiac output and arterial pressure were measured. The measured values were used to calculate SVR (systemic vascular resistance), PVR (pulmonary vascular resistance), and CI.
     Before the 4-month measurements, patients had a full clinical exam, including electrolyte levels, kidney function, liver function, and more. Measurements that improved during IV milrinone use were average PAP, average PCWP, CI, SVR, and PVR. Heart rate was unchanged. From study start to day 3, areas that significantly changed were:

Starting values changing between the first and fourth cycles:
At 4 month follow-up, changes that occurred during therapy were still there:

The exam at 4-months showed that 58% of the patients were still class 4 but were somewhat improved, 36% were now class 3, and 6% were between class 2 and 3. No patients died during the study. Quality of life was not measured.
     This study shows that in patients with severe heart failure, IV milrinone improves heart function. The improvement is sustained by repeated infusions. Four months after therapy, those improvements were still present. This study suggests that milrinone infusion up to 72 hours, repeated every 20 days, does not lead to resistance to the drug.
 
Title: Intermittent Milrinone Effect on Long-Term Hemodynamic Profile in Patients With Severe Congestive Heart Failure
Authors: Anthony Hatzizacharias, Thomas Makris, Panagiota Krespi, Filippos Triposkiadis, Paraskevi Voyatzi, Nicholas Dalianis, Michael Kyriakidis
Source: Am Heart J 138(2):241-247, 1999

 Milrinone As An Extra Therapy

March 15, 2000 - (OPTIME-CHF trial) We studied whether IV milrinone added to standard meds reduces hospital days in a 60-day period for CHFers not requiring inotropes.
     Within 48 hours of hospital admission, 951 patients were randomized to take either IV milrinone (477 patients) or placebo. Patients were followed for 60 days. Primary endpoint was re-hospitalization for heart-related events. Secondary endpoints included quality of life, length of first hospitalization, mortality, and adverse events of any kind.
     Average patient age was 65 years, and 65% were white males. Average time from admission to treatment was 15 hours. Heart class was 3 to 4 and average EF was 23%. More than 70% were taking ACE inhibitors and digoxin, 90% were taking diuretics, and 20% were taking beta-blockers.
     There was no difference in days of hospitalization for heart-related events. There were no differences in quality of life or length of hospital stay. The milrinone group had more complications (13% vs 2%). This was partly due to more a-fib and low blood pressure in the milrinone group. Total mortality rates were the same for both groups.
     Patients admitted for an episode of chronic CHF but who are not believed to require inotropes do not get any benefit from milrinone..
 
Source: ACC Scientific Session 2000 - Day 4 - March 15, 2000
Title: Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure: OPTIME-CHF
Presenter: Dr. Mihai Gheorghiade

 Milrinone Reduces Ischemia After Bypass

October 23, 2000 - Milrinone may reduce risk of ischemia if given at the end of bypass surgery. Dr. Mark Blas said that he has data on 50 patients so far. Twenty-five took milrinone at the end of bypass surgery and the others were given epinephrine.
     There have been significantly fewer episodes of ischemia in the milrinone group. There were 9 ischemic episodes in 3 milrinone patients versus 22 episodes in 6 epinephrine patients. Only 4 milrinone patients have had a heart attack after bypass, compared to 7 in the epinephrine group, said Dr. Blas. Cardiac output was similar in both groups.
 
Source: The American Society of Anesthesiologists annual meeting, 2000

 What Is Natrecor, Exactly?

Natrecor is the brand name of nesiritide BNP, an IV-only drug for relieving acute, decompensated heart failure. Called BNP for B-type natriuretic peptide), it's a hormone naturally produced in the human heart. BNP production is part of the body's natural response to a failing heart so levels of this hormone in CHFers are higher than normal.
     Natrecor is also a vasodilator and diuretic. BNP should not be confused with ANP (atrial natriuretic peptide). ANP is produced in the heart's upper chambers while BNP is produced in the heart's lower chambers or ventricles. Both these hormones make the body get rid of sodium, thus acting as diuretics. Both are also vasodilators, but BNP is stronger and lasts longer than ANP.

 Natrecor Approved For CHF

August, 2001 - The US FDA has approved Natrecor for treating decompensated heart failure patients who have shortness of breath at rest or with minimal activity. Natrecor is IV-only and is given while in the hospital.

 Natrecor Outperforms Nitroglycerin

November 16, 2000 - A head-to-head comparison between IV nitroglycerin and Natrecor shows that Natrecor gives better results. Investigators with the VMAC study, led by Dr. James Young, randomized 498 patients to one of 4 treatment groups: fixed-dose IV Natrecor, adjustable-dose IV Natrecor, IV nitroglycerin, or placebo. Patients kept taking their usual heart meds.
     Natrecor significantly reduced PCWP in as little as 15 minutes. By the 3-hour mark, it was significantly outperforming both placebo and nitroglycerin. The effect remained at 24 and 48 hours.
     Natrecor did not require ever-increasing doses nor did patients build up a tolerance to it. Both these effects can occur with nitroglycerin. Only 8% of patients on Natrecor had headaches compared to 20% of nitroglycerin patients. Too-low blood pressure occurred in 4% of Natrecor patients and in 5% of nitroglycerin patients.
 
Source: AHA 2000 Scientific Sessions

 Natrecor Versus Dobutamine

March 20, 2002 - Natrecor may be a cheaper alternative than dobutamine for treating decompensated heart failure. Dobutamine works well to improve heart pumping power but it has a lot of risky side effects, including too-fast heart rate, irregular heart rhythms, and reducing blood flow to the heart (ischemia).
     Natrecor improves heart function and symptoms through multiple effects, including vasodilation, suppressing neurohormones, and causing your body to get rid of sodium and fluid. This study included 305 CHFers requiring hospitalization. Fifty-eight patients got dobutamine, 103 patients got Natrecor at 0.015 micrograms/kg/minute, and 100 patients got Natrecor at 0.03 micrograms/kg/minute.
     Compared to dobutamine, both doses of Natrecor were given in a shorter amount of time. There was no difference in length of hospital stay between the 3 groups. Readmissions were less in the Natrecor groups (8% and 11%) than in the dobutamine group (20%). Six-month mortality was lower in the low-dose Natrecor group (18%) than in the dobutamine group (31%), with the high-dose Natrecor group in between at 24%.
     The study authors say, Treating decompensated heart failure with Natrecor may be cheaper and reduce mortality more than dobutamine. However, the study has limitations, including a nonrandomized design and small group sizes. Natrecor's manufacturer paid for this study.
 
Source: J Am Coll Cardiol. 2002;39(5):798-803
From: WebMD, by Dr. Laurie Barclay

 Natrecor May Worsen Kidney Function

March 21, 2005 - We wanted to know how Natrecor affects kidney function so we analyzed five previous Natrecor trials that included 1,269 patients with severe decompensated heart failure. Worsening kidney function was defined as an increase in creatinine level greater than 0.5 mg/dL. We also looked at how often medical treatment for worsening kidney function was needed.
     FDA-approved doses of Natrecor significantly raised risk for worsening kidney function compared to other treatments used. Even low-doses significantly increased risk. There was no difference in need for dialysis between therapies.
 
Title: Risk of Worsening Renal Function With Nesiritide in Patients With Acutely Decompensated Heart Failure.
Authors: Jonathan Sackner-Bernstein, Hal Skopicki, Keith Aaronson.
Source: Circulation 2005, doi:10.1161/01.CIR.0000159340.93220.E4; Published online before print March 21, 2005

 Continuous Dobutamine And Mortality

July 29, 1999 - In patients with advanced heart failure, continuous IV dobutamine may increase risk of death and adverse events. This comes form the FIRST trial. Dr. Christopher O'Connor studied outcomes of 487 patients with class 3 to class 4 heart failure, with an average patient age of 65. Eighty patients took continuous dobutamine infusion, with an average dose of 9 micrograms/kg/minute for 14 days.
     Within 6 months, a first adverse event occurred in 85% of dobutamine patients versus 65% of those not taking the drug. "Adverse events" were defined as worsening heart failure; need for IV vasodilators or mechanical assist device; resuscitated sudden cardiac death, heart attack, or death. Six-month mortality was nearly twice as high in dobutamine patients (71%), as in the non-dobutamine patients (37%).
     "Dobutamine was one of the most important independent risk factors for death in the study." The authors conclude that intravenous continuous dobutamine may increase risk of death in patients with advanced heart failure. Dr. Wendy Gattis of Duke University noted that this study did not address short-term therapy. She said, "Dobutamine may be very helpful on a short-term basis."
 
Source: Am Heart J 1999;138:78-86

 Intermittent Dobutamine For CHF

April 21, 1999 - People with end-stage heart failure have poor quality of life and wind up in the hospital a lot. Intermittent dobutamine therapy may help these CHFers. Intermittent treatment helps prevent drug tolerance. Many previous studies used very high drug doses and few used a proper control group so we designed a randomized, controlled, multicenter trial called DICE to study intermittent low-dose dobutamine in patients with severe heart failure.
     Thirty-eight patients were included. All were stable for at least 48 hours and had an average age of 65 years. These patients were heart class 3 to 4, with an average cardiac index of 1.9 liters/minute/meter·2, and had an average EF of 22%. They were randomly assigned to take either intermittent dobutamine or standard CHF meds.
     A long-term catheter was implanted in a vein for IV drug infusion. Patients used an external battery-powered infusion pump. This included a disposable container holding a concentrated solution of dobutamine. The drug was infused at 2.5 micrograms/kg/minute, 48 hours per week for 6 months.
     Primary endpoint was reduced hospitalizations for worsening heart failure. Changes in heart class, 6-minute walk test, and risk of death were secondary endpoints.
     During the 6-month follow-up, all patients had weekly clinic visits with blood tests for sodium and potassium levels. Heart rhythm was recorded by Holter monitor at 2 weeks, and a 6-minute walk test and right heart cath were done after 8 weeks. The 6-minute walk test was repeated at 6 months.
     Hospitalizations for all causes over the 6-month period were 17 in the control group (11 for CHF) and 11 in the dobutamine group (7 for CHF). Four control patients but zero dobutamine patients had more than one hospitalization for worsening heart failure. At study start, average heart class was class 4 in both groups. At the 8-week follow-up it was class 3 in the control group and class 2 in the dobutamine group. At 6 months, average heart class was class 2 in the control group and class 2.5 in the dobutamine group.
     Three patients in the control group died and 5 in the dobutamine group. Two patients in the dobutamine group had a heart transplant. In 3 dobutamine patients, drug dose was increased to 5 micrograms/kg/minute because of heart class. Dobutamine did not increase how many patients had arrhythmias.
     Six-month intermittent low-dose dobutamine was well tolerated by patients with severe heart failure. It improved their functional class and did not increase their risk of death. Hospitalizations for all causes and for worsening heart failure were fewer in the dobutamine group. Intermittent dobutamine could be an alternative for carefully selected patients with severe heart failure, when conventional therapies have failed.
 
Title: Intermittent 6-Month Low-Dose Dobutamine Infusion in Severe Heart Failure: DICE Multicenter Trial
Authors: Fabrizio Oliva, MD, Roberto Latini, MD, Alessandro Politi, MD, Lidia Staszewsky, MD, Aldo P. Maggioni, MD, Enrico Nicolis, BS, Francesco Mauri, MD, for the DICE (Dobutamina nell'Insufficienza Cardiaca Estrema) Investigators
Source: Am Heart J 138(2):247-253, 1999

 Dobutamine and Beta-blockers

June, 2003 - Coreg is a non-selective beta-blocker: It blocks both beta-1 and beta-2 heart receptors. Toprol-XL is a selective beta-blocker: It blocks mostly beta-1 heart receptors.
     In a crossover study, Dr. Bert Andersson studied blood flow in 10 CHFers while they took IV dobutamine. All were on either Coreg or Toprol-XL. Patients were treated for 8 weeks, then had a stress echo using 5micrograms/kg/minute of dobutamine for the first phase and 15micrograms/kg/minute dobutamine for the second phase.
     No significant differences were seen at rest between the two treatments. No difference in EF was seen between groups during dobutamine.
     In Toprol-XL patients, heart rate and cardiac output increased more during dobutamine infusion than in Coreg patients. In Coreg paients during low-dose dobutamine, cardiac output increased - but with higher-dose dobutamine, blood pressure went up.
     The researchers conclude that the right inotropic drug for a CHFer may partly depend on what beta-blocker he takes.
 
Source: Heart 2003;89:621-624

 Prostaglandin E1 For Bridge To Transplant

October, 1999 - Heart failure patients with severe symptoms not relieved by meds are usually hospitalized. Continuous IV drugs from a portable pump may allow such patients to live a fairly active life until heart transplant. Currently dobutamine is used.
     PGE1 (Prostaglandin E1) is a naturally occurring substance that is a potent vasodilator. Only lasting 10 to 20 minutes inside the body, it is only given by IV. It was shown in a double-blind trial that PGE1 lowers both preload and afterload in CHFers. A pilot study of 54 patients also suggested that chronic infusions with PGE1 at reduced doses is safe. Meanwhile, we have shown in a recent randomized trial that PGE1 is better than dobutamine as a single bridging drug - it improved event-free survival rates in these high-risk patients.
     For more, go to www.kup.at/journals/summary/1142.html and download the pdf file named Volltext.pdf.
 
Title: Prostaglandin E(1) bridge to heart transplantation - methods, technique, results
Authors: Pacher R, Stanek B
Source: Z Kardiol 1999 Oct;88 Suppl 3:S33-S35
PMID: 10552198

 Endothelin Blocker Trials

February 19, 2001 - IV endothelin blockers improve heart function in heart failure patients, according to 2 trials in the journal Circulation. Dr. Guillermo Torre-Amione did a randomized placebo-controlled trial to test tezosentan in class 3 to class 4 heart failure patients.
     Tezosentan raised heart function up to 50%, while placebo only raised it 3%. Tezosentan also reduced PCWP without affecting heart rate. The drug seems safe and well tolerated. Treatment was not stopped even once due to fast heart rate or low blood pressure.
     "This adds to the evidence that the endothelin system is heavily involved in heart failure," say researchers. "This shows the need for larger studies to define the full benefits of tezosentan in patients with acute heart failure."
     In another trial, Dr. Thomas Neunteufl tested the endothelin-A receptor blocker LU 135252 on heart function. He did a randomized placebo-controlled trial of 21 chronic heart failure patients. Eleven healthy people were controls. After 3 weeks of treatment, vasodilation improved in LU 135252 patients, but was unchanged in placebo patients.
     This improvement was only seen in low-dose patients (30mg per day). The high dose group took 300mg per day and did not improve.
     Jon's Note: The endothelin blocker tezosentan (brand-name Veletri) is now in phase 3 trials by Actelion, Ltd. Their VERITAS trial of the IV-only drug for acute heart failure will give results in 2005. Oral endothelin blockers increased risk of death in CHFers - why is unknown.
 
Source: Circulation 2001;103:973-986

 Calcium Sensitizers Look Good

February 19, 2001 - Levosimendan is a calcium sensitizer. It increases the heart's pumping strength without increasing the heart's oxygen need. It is also a vasodilator. In trials, levosimendan reduced risk of worsening CHF or death compared to dobutamine and placebo. It is well tolerated, does not cause arrhythmia, does not interact strongly with other drugs, and does not shorten life span.

In trials so far

Levosimendan has few side effects - mainly headache and low blood pressure. Levosimendan does not interact with ACE inhibitors, beta-blockers, Coreg, digoxin, warfarin, isosorbide mononitrate, felodipine, alcohol, or itraconazole. An oral pill form is being developed.
     The usual IV dose used in heart failure trials is a 6 to 12 micrograms/kg loading dose over 10 minutes followed by 0.05 to 0.2 micrograms/kg/minute as continuous IV infusion. Heart function usually responds within 5 minutes of starting the loading dose. Peak effects are seen in 10 to 30 minutes and the drug continues to act for about one to 2 hours.

Benefits include
  1. increases heart pumping strength without increasing heart oxygen needs
  2. relaxes blood vessels - vasodilates
  3. significantly reduces worsening CHF or death in patients with decompensated heart failure
  4. does not cause arrhythmia
Limitations include
  1. vasodilation can cause side effects such as headache and low blood pressure
  2. must be given by IV
  3. not yet FDA-approved for heart failure
 Comparing some IV heart failure treatments 
   Levosimendan   Milrinone   Dobutamine 
ClassCalcium sensitizerPhosphodiesterase inhibitorCatecholamine
Increases intracellular calcium levels?NoYesYes
Increases heart's pumping strength?Yes YesYes
Vasodilator?Coronary and systemicPeripheralMild peripheral
Increase heart's oxygen demand?NoNoYes
Causes arrhythmia?No evidence to dateVentricular (12%) and supraventricular (4%) arrhythmias and PVCs (5%)less than milrinone
Available formsIVIV, oralIV
Drug interactions?None clinically importantSome clinically importantNone clinically important
Can be given with beta-blockers?YesYesYes
Adverse eventsHeadache, low blood pressureVentricular irregularities, headache, low blood pressureTachycardia and increased systolic BP on overdose

Title: Levosimendan: A New Dual-Acting, Non-Arrhythmogenic Drug in Decompensated Congestive Heart Failure
Source: Drug & Ther Perspect 17(20)1-5, 2001
More info here

 Levosimendan Versus Dobutamine

July 19, 2002 - Dr. Ferenc Follath compared IV levosimendan to IV dobutamine in 203 patients with severe heart failure.
     The patients took one drug or the other for 24 hours. Improvement was defined as an increase in cardiac output of at least 30% and a decrease in PCWP of at least 25%.
     28% of levosimendan patients improved versus 15% of dobutamine patients. Mortality at 6 months in the levosimendan group was 26% versus 38% in the dobutamine group. More levosimendan patients improved in SOB and fatigue.
     Side effects were roughly the same from each drug but headaches happened more often with levosimendan, while chest pain and irregular heart rhythm happened more often with dobutamine.
 
Source: Lancet 2002;360:196-202

 Levosamendin Fails Phase 2 Trial

June 8, 2006 - In a phase 2 trial named PERSIST, oral levosimendan did not improve outcomes versus placebo in CHFers. Endpoints included symptom improvement, hospitalization, and risk of death.
     Patients with serious chronic heart failure already on standard meds were split into 3 groups. One group took placebo, while the other groups took oral levosimendan at different doses. Neither group on the active drug did better than placebo patients. The manufacturer will not do phase 3 trials.
 
Source: Orion Corporation, the drug manufacturer
Homepage: www.orion.fi

 Saterinone May Be Useful Inotrope In Acute CHF

October, 2003 - Saterinone is a phosphodiesterase (PDE) III inhibitor. This drug increases the heart's pumping strength and also relaxes blood vessels (vasodilates). In early studies, saterinone worked better than dobutamine. Dr. Arne Kieback gave constant IV saterinone for 24 hours to 12 class 3 male CHFers. Dose was 1.5 micrograms/kg of body weight per minute. Saterinone treatment:

The higher the blood level of saterinone, the higher the increase in cardiac index and the lower the PCWP. Kidney function went down slowly during the IV drug treatment, but not significantly. There were no adverse events from saterinone treatment. Larger trials are now needed.
 
Title: Pharmacokinetics and hemodynamic effects of the phosphodiesterase III inhibitor saterinone in patients with chronic heart failure.
Authors: Kieback AG, Iven H, Stolzenburg K, Eichner E, Ruckdeschel W, Baumann G.
Source: Int J Cardiol. 2003 Oct;91(2-3):201-8
PMID: 14559131.

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