Coreg & beta-blockers
ICDs & More
|More info here and here||Updated January 3, 2007|
Drug Trials are called Phase 1, Phase 2 or Phase 3
Phase 1 trials only study safety. More trials cannot take place unless Phase I trials show a drug to be reasonably safe when given to humans. People in a Phase I trial are closely watched for any sign of harm caused by the drug. Because safety is the question, Phase 1 trials are small but they also allow researchers to start understanding how the drug will work in people. At this point in testing, no one even knows if the new drug will do what it is designed to do. Phase I trials are the most dangerous for patients.
Phase 2 trials confirm that a new drug is safe enough for more people to try, and show whether a drug is effective over the short-term. Phase 2 trials also help decide what doses will be used in Phase 3 trials. Phase 2 trials are usually placebo-controlled and double-blinded. Neither the patient nor the doctors know if a patient is getting the drug or a placebo. These trials are larger than Phase I trials and take longer. There is still significant risk because only a small group of people has tested the drug for safety so far.
Phase 3 trials prove or disprove the effectiveness and safety of a drug over the "longer" term. They are usually double-blinded and placebo-controlled. They can involve hundreds or thousands of patients over months or years. Although the number of patients can be large, risks for patients are smaller because of all the earlier testing. The large scope of these trials lets researchers observe benefits and overall safety of the drug as well as identify less common side effects. Phase 3 trials are incredibly expensive and only drugs which look very profitable make it to this type testing.
January 21, 1999 - The newest recommendations for treating heart failure patients calls for 4 drug therapy. The new guidelines add beta-blockers to digoxin, diuretics and ACE inhibitors for CHF.
A complete patient history and physical exam are necessary to identify the cause of heart failure, said co-chair Dr. Milton Packer. He adds that the "single most useful diagnostic test in patients with heart failure is the echocardiogram." Managing heart failure depends partly on its cause. Aggravating factors should be changed, meaning that fat patients should lose weight, smokers should stop smoking; diabetes, high lipids and high cholesterol should be controlled.
The panel advises flu shots for CHFers and also regular exercise, except during times of decompensation. Exercise improves symptoms and exercise capacity. Restricting sodium in the diet improves the action of diuretics like furosemide, allowing lower drug doses.
The experts say that ACE inhibitors "have favorable effects on heart remodeling and survival," and that these drugs "produce long-term benefits." Adding beta-blockers to treatment "has produced favorable effects on symptoms in trials," the experts say. Dr. Packer notes that CHF treatment "is literally the situation where 4 drugs are more effective than 3 drugs, and 3 drugs are more effective than 2 drugs."
Source: Am J Cardiol 1999;83(2A):00-00
March 14, 2000 - PRAISE-2 was a follow-up trial to PRAISE-1. PRAISE-1 included 1100 cardiomyopathy patients who took either the calcium channel blocker amlodipine or placebo. All-cause mortality and heart-related complications were the same for the amlodipine and placebo groups in the first trial. However, in amlodipine patients with non-ischemic cardiomyopathy all-cause mortality was 46% lower. This benefit was not seen in patients with ischemic heart disease taking the drug.
All PRAISE-2 patients had chronic heart failure due to non-ischemic cardiomyopathy, with class 3 to class 4 symptoms despite diuretics, digoxin and ACE inhibitors. All patients had an EF less than 30%. No patients took beta-blockers.
Patients took either amlodipine or placebo. Amlodipine was started at 5mg a day and then increased to 10mg a day after 2 weeks. The trial eventually included 1652 patients with an average age of 60 years.
There were no differences in all-cause mortality between the 2 groups. No differences were seen in subgroups either, according to sex, heart class, or ejection fraction. Trial results show that long-term amlodipine neither helps nor hurts patients with severe chronic heart failure. Please note that other calcium channel blockers do raise risk of death for CHFers. If you need one, it should probably be amlodipine (Norvasc).
Source: American College of Cardiology's 49th Annual Scientific Sessions, 2000
Title: Prospective Randomized Amlodipine Survival Evaluation
Presenter: Dr. Milton Packer
1998 - Amiodarone is an effective drug for heart arrhythmia but its use is limited by its dangerous side effects. Lung toxicity caused by the drug can be fatal. Since 1980, five to 17% of amiodarone patients have suffered this side effect. It usually shows up as lung inflammation, and scarring of the lungs may occur. Symptoms are vague and are often mistaken for heart failure symptoms. This delays diagnosis, increasing risk of death.
Help making a correct diagnosis may come from lung function tests, lab tests, and occasionally from MUGA. Risk of amiodarone-induced lung toxicity is highest in the first year of treatment, regardless of dose. Heart and lung surgery combined with oxygen use can make patients prone to this side effect. Before starting amiodarone, at least one chest x-ray and lung function tests should be done. Any high-risk patients should have regular 3-month follow-ups to monitor for possible lung problems.
Once lung toxicity is diagnosed, the best option is to stop the drug if possible. However, toxic effects often persist because of amiodarone's (Cordarone's) long half-life of up to 45 days. If amiodarone is stopped, an alternative anti-arrhythmic drug can be tried, or amiodarone can be stopped for several days and then restarted at the lowest effective dose. Non-drug methods such as implanting an ICD or RFA may also be considered.
Early steroid treatment (like prednisone) seems to help reverse pulmonary toxicity in about 60% of amiodarone patients. Because of the risk of relapse, steroids should be continued for at least 6 months. However, despite steroids it is estimated that 10% to 15% of patients still die.
Although blood amiodarone levels relate to increased risk of side effects, it is not possible to predict or confirm amiodarone-induced lung toxicity by measuring body levels of the drug.
Title: Careful Monitoring Required to Minimise the Damage of Amiodarone-Induced Pulmonary Toxicity
From: Drug & Ther Perspect 12(12):14-16, 1998
July 4, 2001 - Unlike amiodarone, dofetilide does not reduce the heart's pumping strength, and seems safer for CHFers. Dr. Michel Rousseau studied 32 patients with mild to moderate heart failure. The patients were in normal heart rhythm, but agreed to be randomly given an infusion of 8 micrograms/kg dofetilide, 5mg/kg amiodarone, or placebo.
The researchers checked heart function and cath data just before drugs were given and again 30 minutes afterward. Although heart rate slowed in dofetilide patients, the heart's pumping strength did not change. However, amiodarone lowered the heart's beating strength.
Although dofetilide prolonged the QT interval it "did not slow the overall relaxation rate," Dr. Rousseau said. The researchers conclude that dofetilide has advantages for treating arrhythmias in heart failure patients. However, they point out that "caution should be exercised when using IV dofetilide."
Source: Am J Cardiol 2001;87:1250-1254
September 30, 2005 - A pair of phase 3 trials (ACT 1 and ACT 3) have now tested an IV drug called RSD1235 for converting a-fib to normal heart rhythm. Head researcher Dr. Denis Roy said the drug acts almost entirely on the heart's atriums, where a-fib actually happens, with very little effect on the ventricles - the heart's main pumping chambers.
ACT 3 studied RSD1235 in 276 patients. Many of them (170 patients) had recent-onset a-fib of more than 3 hours but less than 7 days. Sixty-nine patients had their a-fib more than 7 days but less 45 days. Twenty-three patients with atrial flutter were also in the trial - the drug was not effective for atrial flutter.
The drug converted a-fib to normal rhythm in 52% of patients with recent-onset a-fib. Average time to conversion in ACT 3 was 8 minutes. There was no reported dangerous arrhythmia from RSD1235 use, a huge plus for this drug.
Thirty days after treatment, only 2% of RSD1235 patients had any serious drug-related side effects versus one percent of placebo patients. Messed up sense of taste, tingly skin, sneezing, itching, nausea, and a drop in blood pressure were the most common side effects.
|Patients converted to normal rhythm|
|Recent-onset A-fib only||52%||52%|
|Longer-duration A-fib only||8%||9%|
RSD1235 blocks ion channels in the upper heart chambers (atriums). It has very little influence on the heart's main pumping chambers or ventricles.Astellas Pharma will manufacture RSD1235 in the USA for Cardiome Pharmaceuticals. An oral form of drug for keeping a-fib patients in normal heart rhythm is now in phase 2 trials.
Source: Cardiome Fact Sheet 050920-RSD1235.
Source: J Am Coll Cardiol. 2004 Dec 21;44(12):2355-61.
Title: A randomized, controlled trial of RSD1235, a novel anti-arrhythmic agent, in the treatment of recent onset atrial fibrillation.
Authors: Roy D, Rowe BH, Stiell IG, Coutu B, Ip JH, Phaneuf D, Lee J, Vidaillet H, Dickinson G, Grant S, Ezrin AM, Beatch GN.
January 16, 2001 - Immunoglobulins are immune system proteins. They help protect the body from tiny infection-causing organisms. When given in large doses, they may stop an immune response that is too strong. "When we supply the immunoglobulins artificially, the body doesn't produce as many anti-inflammatory substances," says Dr. Pal Aukrust.
Several studies have shown that CHFers have a highly active immune system. They have high blood levels of inflammatory substances, including tumor necrosis factor and interleukin-beta. Some bodily systems that are hyper-active in heart failure are not corrected by current treatments. Immune system over-activity (inflammation) may not stop.
Researchers studied 40 CHFers with an EF less than 40%. Half got IV immunoglobulin and half got a placebo once a day for 5 days, then once a month for 5 months. They were already taking standard CHF meds including diuretics, ACE inhibitors or ARBs, and beta-blockers. Patients kept taking their regular meds during the study.
In immunoglobulin patients, 14 showed improved EF, and 10 of these improved by more than 5%. Also, 73% of immunoglobulin patients said their quality of life improved. In the placebo group, 40% reported improved quality of life.
Immunoglobulin had a strong anti-inflammatory effect. Levels of some anti-inflammatory "factors" increased by as much as 65%. No changes were seen in those who got placebo. After 6 months, immunoglobulin patients' TNF went down, while placebo patients' TNF went up. Levels of interleukin-beta remained the same in the treatment group, but went up in the placebo group.
Source: Circulation 2001;103:220-225
October, 2003 - Dr. Chiharu Kishimoto studied 3 patients with acute dilated cardiomyopathy and 6 with active myocarditis. They were given IV immunoglobulin at one to 2 grams per kilogram of body weight for 2 days. Immunoglobulins are protein-like substances produced by the body to fight infection. They come in many different "flavors" such as IgG, IgM, IgA, IgD and IgE.
At 12 days of follow-up, EF rose from 19 to 35%. In addition, C-reactive protein fell from 9 to 4 mg/mL. Blood levels of tumor necrosis factor-alpha and interleukin-6 also went down. These are markers of internal inflammation.
At study start, patients were class 3 to class 4. When they left the hospital after treatment, they were class one to class 2. In the after-discharge follow-up of 3 months to 4-1/2 years, none were rehospitalized for heart failure.
The researchers believe this treatment reduces inflammation and oxidative stress.
Source: Int J Cardiol 2003;91:173-178
May 22, 2000 - Two new studies show that lowering cholesterol lowers mental function, but does not affect mood. Dr. Matthew Muldoon studied the psychological effects of lovastatin treatment for high cholesterol. Researchers randomized 209 healthy adults with LDL cholesterol at least 160 mg/dL, to 6-month therapy with 20mg lovastatin per day or placebo. Mental function and psychological well-being were measured at the beginning and end of treatment.
Placebo patients improved in all 5 neuropsychological tests, which is normal due to the practice that comes from taking a test over and over. In contrast, lovastatin-treated patients only showed improvements in one - the memory recall test. So when compared to placebo, there was small but significant lowering of psychomotor speed and mental attention by lovastatin. Muldoon's group speculates that "lovastatin could affect performance on tasks like driving a car."
In the second report, Dr. Jane Wardle randomly assigned 176 patients to a low-fat diet, a Mediterranean diet, or to a waiting-list. They tested cholesterol levels, psychological well-being, and mental function at study start and at 6 and 12 weeks. Both diets successfully reduced cholesterol levels. All 3 groups showed similar improvements in psychological well-being, which may be due to increased attention and support during the study.
The groups did the same on 3 measures of mental function. However, on the fourth and hardest measure, the 2 intervention groups did a lot worse. Researchers point out that the mental impairment in the 2 intervention groups was worst in patients with the biggest reduction in blood cholesterol levels.
Dr. Wardle's group concludes that the adverse effect of lowering cholesterol on mental function needs further study. "If the effect proves to be strong, we need to explain it."
Source: Am J Med 2000;108:538-553
July 3, 2000 - The FDA has approved a new blood thinner to prevent and treat abnormal blood clotting related to heparin use. The drug is argatroban (Novastan), developed by Texas Biotech. It blocks thrombin, a key factor in blood clotting.
Heparin is given to more than 12 million people a year to prevent blood clots. As many as 360,000 of these patients develop abnormal blood clotting, known as HIT (heparin-induced thrombocytopenia). About 120,000 of these patients develop a serious complication from HIT, such as stroke or limb amputation. Up to 36,000 patients a year die from complications.
HIT usually happens 5 to 10 days after heparin treatment. Diagnosis can be difficult and is made tougher because doctors expect bleeding - not clotting - with this kind of condition. So doctors sometimes worsen the condition by continuing blood thinner therapy. Argatroban is the first direct thrombin inhibitor approved to prevent and treat abnormal clotting in HIT patients.
Argatroban's safety and effectiveness were shown in 2 clinical trials of 568 patients getting the drug versus 193 untreated "controls." All were diagnosed with HIT. Argatroban improved outcomes for the HIT patients. In trials with patients monitored for over a month, 34% of argatroban patients suffered death, amputation or new clot compared to 43% of controls.
Source: Reuters Health
January 23, 2001 - This study found that medical journals devote only about 1/3 of one page to safety information such as dangerous side effects when reporting on drug trials.
Researchers often gloss over or ignore key information about the safety of drugs in their trials. Of 7 major drug categories studied - including AIDS, high blood pressure, and stroke - the authors could not find even one example in which safety reporting was "satisfactory." "Adequate reporting of drug safety problems is critical because clinical trials have always been the foundation of high-quality medical practice," said Dr. John Eisenberg.
Drs. John Ioannidis and Joseph Lau studied 192 randomized drug trials, each with at least 100 patients and at least 50 patients per study group. Only 39% of the trials properly reported side effects of the drugs being studied. Only 29% did a good job reporting drug toxicity through abnormal test results.
Although 75% of trial reports mentioned the number of patients who had to withdraw from a study because of drug side effects, specific reasons for those withdrawals were only mentioned 46% of the time. Most high-quality trials collect enormous amounts of safety and side effects data, the team noted. "Yet, the selective filtering of all this info into 1/4 of one page can hardly be adequate," they said.
Source: JAMA 2001;285:437-443
November 13, 2001 - A drug often prescribed for gout - allopurinol - may help CHFers by blocking an enzyme called XO (xanthine oxidase). Dr. Joshua Hare studied XO activity, which creates free radicals.
The researchers gave allopurinol infusions to 9 CHFers with an average EF of 29% who were already taking standard CHF meds. The infusions were 0.5, 1.0, and 1.5mg per minute, each for 15 minutes. Testing before and after treatment showed that the drug boosted their hearts' pumping efficiency.
When researchers studied samples of heart tissue from CHF patients who had heart transplants, they found higher levels of XO in the old diseased heart tissue than in normal heart muscle.
The authors think that oxidative stress may cause some of the dysfunction seen in heart failure. Perhaps reducing XO activity helps. They also note that other experiments suggest that another XO inhibitor - oxypurinol - could have similar effects.
Title: Allopurinol Improves Myocardial Efficiency in Patients With Idiopathic Dilated Cardiomyopathy
Authors: Dr. Thomas Cappola, Dr. David Kass, Dr. Gregory Nelson, Dr. Ronald Berger, Dr. Gisele Rosas, Dr. Zoulficar Kobeissi, Dr. Eduardo Marban, Dr. Joshua Hare
March 4, 2002 - Regular high-dose allopurinol may improve survival in heart failure patients. Dr. Allan Struthers identified 1760 CHF patients. He compared heart-related events in patients taking allopurinol (in several different ways) to heart-related events in patients not taking the gout drug.
Mortality was similar between groups except that patients taking long-term, low-dose allopurinol had worse mortality than the other groups. Patients taking long-term, high-dose allopurinol had the same mortality risk as the no-allopurinol group. This suggests that CHFers with gout should take at least 300mg allopurinol per day even if a lower dose keeps the gout under control.
Jon's note - Be wary of studies that examine old data as opposed to trials that test a theory in real patients with specific endpoints.
Source: Heart 2002;87:229-234
June 17, 2002 - "These results are the first to show that allopurinol can improve vessel dilation in heart failure patients," author Dr. Allan Struthers said. He said this is important because, "allopurinol is safe and relatively cheap." This was a double-blind, crossover study of 11 class 2 to 3 CHFers. They took either 300mg allopurinol or placebo daily for one month.
Allopurinol improved endothelial function 3% more than placebo as shown by increased blood flow in the forearm. Allopurinol also reduced stress caused by free radicals. Uric acid levels went down nearly 60% in patients even when beginning levels were normal.
Dr. Struthers says, "Much work on reducing free radicals focused on using antioxidant vitamins. This is another way to prevent formation of oxygen-free radicals."
Source: Circulation. Rapid Access Publication, June 17, 2002
December 4, 2001 - Because the bioavailability of oral Lasix (furosemide) is erratic and often incomplete, we studied whether torsemide (Demadex) - a more completely absorbed diuretic - would give CHFers better outcomes.
Dr. Michael Murray randomized 234 CHFers with an average age of 64 years to furosemide (121 patients) or torsemide (113 patients). During the one-year trial, patients taking torsemide were less likely to be readmitted to the hospital for CHF (17%) compared to patients taking furosemide (32%).
Admissions for all heart-related causes were lower in torsemide patients (44%) than in furosemide patients (59%). However, there was no difference in all-cause hospital admission between torsemide patients (71%) and furosemide patients (76%). Patients in the torsemide group had improved shortness of breath and fatigue. Torsemide patients also spent a lot fewer days in the hospital than furosemide patients.
Title: Open-label randomized trial of torsemide compared with furosemide therapy for patients with chronic heart failure
Authors: Michael Murray, Melissa Deer, Jeffrey Ferguson, Paul Dexter, Susan Bennett, Susan Perkins, Faye Smith, Kathleen Lane, Laurie Adams, William Tierney, Craig Brater
Source: Am J Med 2001;111:513-520,577
March 4, 2002 - Heart patients who stopped cholesterol-lowering drugs while hospitalized for chest pain had triple the risk of death or heart attack as people who kept taking the statin drugs. Three drugs accounted for 95% of the statins in this study: simvastatin (Zocor), lovastatin (Mevacor), and pravastatin (Pravachol).
Researchers studied the medical records of 1616 patients from the PRISM trial. That study compared two blood-thinning drugs in heart disease patients hospitalized with worsening chest pain. Four hundred sixty-five of those patients had been taking a statin drug for 6 months. The cholesterol-lowering drugs were continued in 379 patients and stopped in 86.
After 30 days, patients still taking statins were only half as likely to have died or had a heart attack as patients who never took a statin drug. Patients who stopped the drugs after hospitalization were 3 times as likely to die or have a heart attack as those still on the drugs.
Statins increase the release of nitric oxide from the cells lining artery walls. Animal studies show that suddenly stopping statins causes a rebound effect: instead of returning to normal, nitric oxide released by cells drops below normal.
Source: American Heart Association
Authors: Christian Hamm, Christopher Heeschen, Ulrich Laufs, Steven Snapinn, Michael Bohm, Harvey White
February 18, 2003 - Your digoxin blood level may be too high. The best blood level may be lower than current medical practice. A level of 0.5 to 0.8 ng/mL may be best for men with heart failure.
Researchers analyzed the already completed DIG trial, which included 3782 men. The men all had an EF of 45% or less. These men were analyzed by grouping them into digoxin blood level groups of:
|Different Digoxin Blood Levels|
|0.5 to 0.8 ng/mL
|0.9 to 1.1 ng/mL
|1.2 ng/mL or greater
|All cause mortality at 37 months||30%||39%||48%|
|Mortality rate compared to placebo||6% lower||3% higher||12% higher|
The authors say that since no study has shown benefit for higher dig blood levels, it might be smart to aim for a level of 0.5 to 0.8 ng/mL. This applies to men with stable heart failure. Be sure your dig levels are being regularly tested.
Source: JAMA 2003;289:871-878
August 22, 2005 - Doctors from the University of North Carolina studied whether digoxin doses are also too high in female CHFers (see above article about doses in male CHFers). The researchers studied 4944 patients from the DIG study. Women with digoxin levels from 1.2 to 2 ng/ml were 33% more likely to die during follow-up but women with levels between 0.5 and 0.9 ng/ml were 20% less likely to die and 27% less likely to die or be hospitalized for heart failure.
The researchers say that digoxin dose should be tailored to the individual patient's needs, and given at no more than 0.125 mg per day until blood level reaches 0.5 to 0.9 ng/ml. They also say that once proper blood level is reached and steady for 4 weeks, further blood testing is only needed if meds are changed, kidney function lessens, or toxicity is suspected.
Source: J Am Coll Cardiol 2005;46:497-507.
Source: Reuters News
August 5, 2002 - A trial suggests that Viagra is safe and effective for erectile dysfunction (ED) in heart failure patients. If heart failure meds aggravate their problems getting an erection, men may not take those meds all the time - not good.
The first phase of this study was a double-blind, randomized, crossover trial of 23 men with moderate or severe heart failure, averaging 50 years old, with ED. On each of 2 separate days, the men did a 6-minute walk test and a maximum exercise treadmill test. About an hour before testing, the men got either 50mg Viagra or placebo. On the second day of treatment, the men got the other treatment before exercise. The second phase of the study was a trial of Viagra for their ED.
During Viagra treatment, patients reported no harmful effects. Compared to placebo, Viagra improved exercise performance, exercise time, blood pressure and heart rate, and oxygen consumption and carbon dioxide production. Erection problems also improved.
Viagra blocks phosphodiesterase-5 (PDE5). This increases production of nitric oxide, which improves blood vessel function and lowers heart rate. Maybe Viagra's ability to lower heart rate during exercise lowers the heart's oxygen use during sex - which is a form of exercise.
CHFers and especially their wives often fear that their spouses will have heart failure symptoms or even death during sex. This study suggests that the benefits may outweigh harmful side effects with Viagra if used properly with a doctor's supervision.
Source: Circulation. 2002;106:1097-1103
March 8, 2004 - The authors of this study say that about half of men between 40 and 70 years old with heart failure have difficulty getting an erection. Sildenafil (Viagra) can dangerously lower blood pressure in men taking nitrates (like isosorbide or nitroglycerine) so these men should not take it. Men with ischemia are also at risk, so they should not take the drug either.
Researchers studied sildenafil use in 35 carefully selected men with CHF who were not taking nitrates. All had a history of chronic difficulty getting and maintaining erections. None had ischemia - they had negative results from exercise stress tests or nuclear scans.
These men took either sildenafil for 6 weeks then switched to a placebo for another 6 weeks; or took placebo for 6 weeks then switched to sildenafil for 6 weeks. Follow-up was done at 2, 4, 6, 8, 10, and 12 weeks.
Blood pressure was measured for 4 hours while patients moved around freely after a single dose of 50mg sildenafil. Surveys (questionnaires) measured improvement in erection and depression.
Using sildenafil only reduced blood pressure about 6 mmHg. There were no dangerous blood pressure drops while on the drug. There were no other side effects. Sildenafil improved ability to get erections and also seemed to reduce depression. The researchers concluded that men with class 2 or class 3 CHF who don't take nitrates and who don't have ischemia can use Viagra safely.
Source: Arch Intern Med. 2004;164:514-520.
Title: Use of Sildenafil for Safe Improvement of Erectile Function and Quality of Life in Men With New York Heart Association Classes II and III Congestive Heart Failure; A Prospective, Placebo-Controlled, Double-blind Crossover Trial.
Authors: Linda Webster, Evangelos Michelakis, Terry Davis, Stephen Archer.
March 31, 2003 - Epleronone is a selective aldosterone blocker. It does roughly what Aldactone (spironolactone) does but without the nasty side effects. Dr. Jon Kobasigawa commented on the much fewer side effects with epleronone: There was no excess gynecomastia (breast growth and pain in men) or impotence from the drug. "Those side effects occur about 10% of the time (with Aldactone)," said Dr. Inder Anand.
One drawback to the new drug is that it may cost $3 a pill versus 2¢ a pill for Aldactone. While eplerenone is more expensive, Dr. Bert Pitt told a reporter it is still, "pennies compared to the cost of an ICD."
The EPHESUS trial enrolled 6632 patients who had suffered a heart attack 3 to 14 days before entering the study. All patients had an EF under 41% and had been diagnosed with heart failure. Patients got either best standard drug therapy plus eplerenone, or best drug therapy plus placebo. The starting eplerenone dose was 25mg, later raised to 50mg.
Eplerenone patients had 15% less overall deaths, 17% less heart-related deaths, and 21% fewer sudden cardiac deaths. Total hospitalizations were 8% lower in the epleronone group and hospitalizations for heart failure decreased by 15%. There were cases of too-high potassium: 6% in the eplerenone group versus 4% in the placebo group. During 16 months of follow-up, there were 478 deaths in the eplerenone group and 554 deaths in the placebo group.
Source: N Engl J Med. 2003;348:1309-1321, 1380-1383; 52nd annual ACC scientific session; Medscape
October 8, 2003 - The US FDA today approved Pfizer's Inspra (eplerenone) pills to improve CHFers' survival after a heart attack. Inspra is the first aldosterone blocker approved for heart failure. In a trial, it reduced risk of death 15% in these patients. Since the patients were also taking other standard therapy so this improvement was "on top" of current treatment. Inspra was FDA approved in 2002 for treating high blood pressure.
Source: Reuters Health.
June 9, 2003 - The RAS controls a great deal of action in the cardiovascular system. Doctors have focused on controlling one part of the RAS (angiotensin 2) with ACE inhibitors and ARBs. Now blocking aldosterone also looks good for heart failure.
Aldosterone acts in the kidney, colon, sweat glands, and salivary glands to retain sodium and to get rid of potassium. Recent research has found new aldosterone receptors called "mineral-corticoid receptors" in the brain, heart, and blood vessels. Aldosterone at these sites encourages fibrosis and remodeling, both bad news for CHFers.
Aldosterone's actions also include increasing cytokine production. Cardiovascular tissues may also produce aldosterone. Aldosterone levels go up in CHFers and it is important to block at least some of it to reduce harmful effects.
We now know that neither ACE inhibitors nor ARBs fully suppress aldosterone. This is called "aldosterone escape." ACE inhibitor therapy may actually encourage aldosterone escape because ACE inhibitors increase potassium, which is a powerful spur to aldosterone.
Two aldosterone blockers - Aldactone (spironolactone) and Inspra (eplerenone) - are now approved for treating heart failure. The RALES trial showed that 25mg spironolactone daily reduced all-cause death by 30% in patients with severe heart failure. Spironolactone is now part of the official CHF treatment guidelines. Spironolactone has some side effects that really impact CHFers, like enlarged and painful breasts in men as well as impotence; and menstrual irregularity in women. This is because the drug affects sex hormone receptors as well as those "mineralcorticoid receptors."
Inspra is a "selective" aldosterone blocker. It blocks mostly just mineral-corticoid receptors. This means far fewer side effects. In CHFers, adding eplerenone to ACE inhibitor therapy gives greater improvement. It also reduces the body's protein loss through the urine, something not easy to conrol. The EPHESUS trial showed clear benefit for CHFers from adding this drug to their therapy. Patients with a history of high blood pressure benefited even more than other CHFers.
The things to watch for are angioedema - just as in ACE inhibitor use - and hyperkalemia (high potassium level).
Title: Aldosterone Receptor Blockade: A Therapy Resurrected.
Author: Domenic A. Sica, MD.
Source: Heart Dis 5(2):85-88, 2003.
January 31, 2003 - RALES showed that low-dose spironolactone reduces risk of death in severe heart failure. However, doctors are using this drug more broadly than recommended, causing more complications for patients.
Dr. Biykem Bozkurt says that spironolactone is being widely used for heart failure without considering heart class or ejection fraction, and without properly using other heart failure meds first. He also says that follow-up is poorly done, causing complications. The authors of this report followed 104 men who started spironolactone after pre-release of RALES trial results.
Only 26% were class 3 or 4, which was the patient group proven to benefit, and 65% had no record of their heart class at all. Only 55% of the men had a recorded EF less than 35%, as was recommended before starting the drug. The average daily dose was 40mg, much higher than the 25mg used in the RALES trial.
Although 31% had weak kidneys and 46% had diabetes, only 38% had proper blood test follow-up and only 34% had proper office follow-up. Even though they did not have low potassium levels, 42 patients (40%) were kept on potassium supplements. Twenty-five patients (24%) developed high potassium levels, reaching dangerous levels in 12 patients (12%).
Low blood sodium levels developed in 32 patients (31%), kidney failure in 26 patients (25%), and low blood pressure in 7 patients (7%). For what it's worth, the authors say that: "Cardiologists provided more appropriate care than primary care providers."
Jon - Obviously we CHFers need to carefully study trials and always double-check our own treatment - no matter how much we trust our doctors.
Source: J Am Coll Cardiol. 2003;41(2):211-214, 215-216
March 19, 2004 - Adenosine may reduce kidney function through its effect on blood vessels in the kidneys. We studied the effects of blocking adenosine in patients taking Lasix (furosemide) and ACE inhibitors.
This was a randomized, double-blind, crossover trial of drug Adentri (BG9719 or CVT-124) in 63 CHFers. Patients took placebo or one of 3 doses of Adentri on one day and the same med plus Lasix on a separate day. Kidney function, and electrolyte and water elimination were measured.
Adentri alone improved kidney function (GFR) at the 2 lower doses. Lasix alone worsened kidney function. When Adentri was added to Lasix, creatinine clearance remained at starting levels at the 2 lower drug doses, meaning kidney function stayed the same.
This study shows that in CHFers on standard meds, Adentri increased both urine output and kidney function. Lasix increased urine output but reduced kidney function. When Adentri was given in addition to Lasix, urine output increased and there was no lessening of kidney function. Using an A1 adenosine blocker may be one way to really help heart failure patients cope with constant diuretic use.
Source: Circulation. 2002 Mar 19;105(11):1348-53.
Erratum: Circulation 2002 Sep 24;106(13):1743.
Title: BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy.
Authors: Gottlieb SS, Brater DC, Thomas I, Havranek E, Bourge R, Goldman S, Dyer F, Gomez M, Bennett D, Ticho B, Beckman E, Abraham WT.
November 10, 2003 - Levels of the hormone vasopressin are high in CHFers. This hormone may cause edema and low blood sodium levels (low blood sodium in severe CHF means higher risk for death). Tolvaptan is a new drug that "blocks" vasopressin2 receptors. Using this drug may mean lower diuretic doses and fewer side effects for CHFers. This drug does not hurt kidney function or screw up electrolyte balance.
This was a phase 2 trial called ACTIV in CHF. It was double-blind and placebo-controlled. Patients were followed for 60 days.A total of 319 patients were enrolled. End points were body weight reduction at 24 hours; worsening CHF at 60 days; body weight at hospital discharge; urine output; and electrolyte levels.
Patients had EF less than 40% and edema requiring hospitalization. Within 72 hours of admission, patients started one of 4 therapies: 30mg tolvaptan plus standard treatment, 60mg tolvaptan plus standard treatment, 90mg tolvaptan plus standard treatment, or placebo plus standard treatment.
| Tolvaptan 30mg|
| Tolvaptan 60mg|
| Tolvaptan 90mg|
|With High Blood Pressure||75%||76%||69%||68%|
|Had Previous Heart Attack||43%||35%||35%||36%|
|Had Previous Bypass Surgery||35%||24%||26%||39%|
|Average Systolic Blood Pressure||116 mmHg||123 mmHg||119 mmHg||119 mmHg|
|On Placebo|| Tolvaptan|
|Died in the hospital||2.5%||0||1.1%||0|
|Had worsening CHF||30%||29%||43%||27%|
At 24 hours and throughout the hospital stay, all tolvaptan patients lost significant body weight (from fluid loss) compared to placebo patients. Tolvaptan patients had greater urine output and their CHF signs and symptoms improved more. Tolvaptan patient with low blood sodium saw those levels come back to normal. There was no difference in mortality or worsening of heart failure during the hospital stay.
At 60 days, in placebo patients risk of death was highest for those with low blood sodium level, kidney failure, and congestion on admission. Tolvaptan patients with these problems were the very patients who were helped the most. The most common side effect was thirst; low blood pressure was not reported in any tolvaptan patients.
Title: ACTIV in CHF: Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist (Tolvaptan) in Congestive Heart Failure.
Author: Luis Gruberg, MD
Source: AHA Scientific Sessions, 2003.
March, 2006 - Lead researcher Dr. William Abraham is planning a phase 3 trial of lixivaptan after a phase 2 trial gave good results. Okay, let's start at the beginning. Vasopressin is a hormone called an anti-diuretic. It makes your kidneys hang onto water. So with heart failure, too much vasopressin increases edema - a bad thing. Lixivaptan is a "V2 receptor arginine vasopressin antagonist." I'm gonna call it a "vasopressin blocker" even though doctors are calling them AVPs.
You know how Coreg blocks both beta-1 and beta-2 receptors, while Toprol-XL blocks just beta-1 receptors. Lixivaptan is a V2 blocker because it blocks vasopressin 2 receptors.
Right now, we CHFers take diuretics like furosemide and torsemide (Lasix and Demadex) to make the kidneys let go of sodium - all that water we pee out with the sodium is really just along for the ride. Actually, we're peeing out much more than water, including potassium, magnesium, sodium and other substances our bodies need. In fact, low blood sodium levels mean our risk of death is quite a bit higher than with normal blood sodium levels.
Lixivaptan gets your kidneys to remove all that extra fluid without removing the potassium, magnesium, sodium, etc. That's a huge benefit. This phase 2 trial included 42 class two to class 3 CHFers who all needed diuretics.In the phase 2 trial, CHFers drank no fluid overnight, then took a placebo (12 patients), or lixivaptan at doses of 10mg, 30mg, 75mg, 150mg, 250mg, or 400mg (5 patients per dose) on day one, followed by 4 hours of continued fluid restriction. Then patients could drink when they wanted.
At every dose but the lowest (10 mg), lixivaptan significantly increased urine output over 4 hours compared to placebo. Over 24 hours, output was about 2 liters for placebo patients versus 4 liters in patients taking 400 mg of lixivaptan. The amount of sodium removed along with the liquid in lixivaptan patients was much less (called solute-free water excretion). Now, this is obviously good news to us CHFers. It also shows that vasopressin plays an important role in CHF edema.
These kind of drugs are called "aquaretics." They include conivaptan, lixivaptan, tolvaptan, and one just called SR-121463 as far as I know. Added to diuretics, they may really help us get rid of extra fluid without increasing risk from losing electrolytes too. They may also help CHFers who don't respond well to regular diuretics.
Source: Ohio State University Medical Center. Editor: Emily Caldwell. Source: J Am Coll Cardiol, 2006; 47:1615-1621, doi:10.1016/j.jacc.2005.11.071 (Published online 24 March 2006).
Title: Aquaretic Effect of Lixivaptan, an Oral, Non-Peptide, Selective V2 Receptor Vasopressin Antagonist, in New York Heart Association Functional Class II and III Chronic Heart Failure Patients.
Authors: William Abraham, Alireza Shamshirsaz, Kim McFann, Ron Oren, Robert Schrier.
PMID: 16630999. Source: Congest Heart Fail. 2006 Jan-Feb;12(1):55-60. 12;1:55.
Title: Hyponatremia and heart failure--treatment considerations.
Author: Sica DA.
Source: Am J Med. 2006 Jul;119(7 Suppl 1):S87-92.
Title: Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.
Author: Palm C, Pistrosch F, Herbrig K, Gross P.
September 16, 2004 - The phase 3 A-heFT trial (African American Heart Failure Trial) was stopped early because the study drug helped black CHFers so much. The trial was a randomized, double blind, placebo controlled study of over 1000 black Americans with class 3 to class 4 heart failure. All patients had reduced EF and enlarged hearts. The drug used is a combination of 2 old generic heart failure drugs that were commonly used in all CHFers before ACE inhibitors were found to work better in general - it is called BiDil and is made by NitroMed. BiDil combines isosorbide dinitrate and hydralazine.
A-HeFT added isosorbide dinitrate and hydralazine to standard heart failure meds including beta-blockers, ACE inhibitors/ARBs, aldosterone inhibitors like Inspra and spironolactone (Aldactone) - as well as digoxin (Lanoxin) and diuretics. Over 1,000 patients in 170 sites across the USA participated. The reported benefit of BiDil was strong enough to stop the trial early so placebo patients in it could take the drug, acccording to Dr. Anne Taylor, Chairman of the A-HeFT Steering Committee. Actual trial data should be available before the end of this year. The drug may be widely available sometime in 2005.
Black Americans with heart failure are usually diagnosed at a younger age, have less a-fib, and are much more likely to have high blood pressure. Discovering that this drug combination works better for black CHFers in reducing risk of death and hospitalizations should improve their risk factors for CHF episodes after being diagnosed.
Isosorbide dinitrate increases nitric oxide. Hydralazine is a vasodilator. Hydralazine may protect the nitric oxide formed by isosorbide dinitrate from deactivating.
June 23, 2005 - The US FDA has approved BiDil for use specifically in black patients. ACE inhibitors work better in white patients. BiDil is a combination of isosorbide dinitrate and hydralazine. It will take the place of ACE inhibitors to better treat heart failure in black patients. The approval is based on results of the A-HeFT trial.
January 27, 2006 - CHF screws up the way your skeletal muscles work, causes inflammation, and reduces your blood vessels ability to widen. In men, these may all improve using testosterone therapy. Dr. Kevin Channer led this study and said that testosterone in men helps fight inflammation and improves blood vessels ability to dilate - very important in CHFers. (Jon's Note: I use testosterone therapy due to low blood levels of it with my own heart failure. I use a gel rubbed on the skin instead of the patch used in this trial.)
Researchers did a randomized, double-blind, placebo-controlled, parallel trial of 76 men for one year. Five mg testosterone was used every day. Patients were an average age of 64 years with an average EF of 33%. At study start, blood testosterone levels were below normal in 24% of the men. Men with lower testosterone did worse on the walking test and the hand grip strength test, the endpoints in this trial.
After testosterone therapy, walk distance improved an average of 15% versus placebo patients, while 35% of treated men improved at least one heart class versus 8% in placebo patients. There were no significant changes in body mass, muscle bulk, or inflammatory warning markers.
The bottom line is that if you are male and have heart failure, you should have your blood testosterone level checked to see if you need testosterone gel to keep it in the normal range - it may really help.
Source: Reuters Health
Title: Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial.
Authors: Malkin CJ, Pugh PJ, West JN, van Beek EJ, Jones TH, Channer KS.
Source: Eur Heart J. 2006 Jan;27(1):57-64.
September, 2006 - Trimetazidine is actually a free fatty acid (FFA) oxidation inhibitor, which I will call an FFA-blocker. Trials in Europe and Asia suggest it improves left heart function and heart class. Trimetazidine is approved in those areas for angina treatment.
Trimetazidine has anti-ischemic properties - that means it helps the heart sustain high-enough blood/oxygen levels. However, this drug does not affect oxygen consumption. The drug reduces cell acidosis, calcium overload and free-radical injury that leads to ischemia. It changes the heart's energy production from FFA use to glucose use, so left heart function is preserved.
Researchers gave 28 CHFers 20mg trimetazidine 3 times a day plus standard CHF drugs and gave 27 CHFers standard treatment only. Average follow-up was 13 months. At study start all CHFers had exercise and echo tests. EF and heart class were measured.
In trimetazidine patients, heart class improved versus standard therapy patients. Trimetazidine improved left heart volume (a good thing) from an average of 98ml to 81ml, and increased EF from 36 to 43%. In standard therapy patients, left heart end-diastolic volume increased from an average 142ml to 156ml and systolic volume from 86ml to 104ml. EF in standard therapy patients went down from an average of 38 to 34%.
Trimetazidine appears to protect the heart from the bad effects of ischemia, and it improves the heart's pumping strength in CHFers with hibernating cells - hibernating means heart muscle cells that aren't currently working but aren't dead and might work again over time).
CHF worsens quality and length of life more in those with diabetes. Trimetazidine, reduces fatty acid beta-oxidation (a type of energy source for the heart), so the heart uses the sugar pathway for its energy instead. This change helps the heart function better in diabetics
Researchers studied heart function after one month of trimetazidine (Vastarel) added on to standard therapies for type 2 diabetics with CHF. Twenty diabetic patients with ischemic heart failure were involved. Their average age was 66 years and their average heart class was 2 to 3. They took trimetazidine (60mg daily) or placebo in a double-blind crossover design, meaning they first added the drug, then the placebo or the other way around, with no one involved knowing which order was used in each CHFer. Exercise tolerance, echo, and tissue doppler imaging were done both at rest and exercise before and during treatment.
Exercise tolerance did not change in either group. EF at rest and moderate exercise only improved with trimetazidine during the first treatment period. TDI measures did not change much during treatment. In this early trial, there were only weak signs of improved heart output at rest and during exercise. More research is needed in diabetic CHFers.
Source: Reuters Health Source: J Am Coll Cardiol. 2006 Sep 5;48(5):992-8. Epub 2006 Aug 17.
Comment in: J Am Coll Cardiol. 2006 Sep 5;48(5):999-1000.
Title: A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure.
Authors: Fragasso G, Palloshi A, Puccetti P, Silipigni C, Rossodivita A, Pala M, Calori G, Alfieri O, Margonato A.
Source: Am J Cardiol. 2006 Sep 4;98(5A):19J-24J. Epub 2006 Jul 24.
Title: Role of trimetazidine in management of ischemic cardiomyopathy.
Authors: Bertomeu-Gonzalez V, Bouzas-Mosquera A, Kaski JC
Source: J Cardiovasc Pharmacol. 2004 Jul;44(1):101-8.
Title: Effects of trimetazidine on left ventricular function in patients with type 2 diabetes and heart failure.
Authors: Thrainsdottir IS, von Bibra H, Malmberg K, Ryden L.
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, 2005, 2006, 2007 Jon C.