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More articles here and here    Updated June 7, 2004

 ACE Inhibitors Lower Death Rate

June, 1987 - We studied the effect of Vasotec (enalapril) at 2.5 to 40mg per day on people with severe (class 4) CHF. Two hundred and fifty-three patients took either placebo or enalapril. Regular CHF treatment was continued in both groups. Follow-up averaged 188 days.
     Mortality in the enalapril group after 6 months was 26%, and 44% in the placebo group - a 40% reduction in risk of death for enalpapril patients. Mortality was reduced by 31% at one year.
     No difference was seen in sudden cardiac death between the 2 groups. Enalapril patients died less often because their heart failure did not get worse as often. The reduction in mortality came in CHFers whose heart failure got worse. In the enalapril group, heart class improved, heart size went down, and fewer other heart failure meds were needed.
     Seven patients dropped out of the enalapril group because of too-low blood pressure versus none in the placebo group but lowering the dose corrected this problem in most patients.
     The researchers conclude, "Adding enalapril to regular therapy in patients with severe CHF can reduce mortality and improve symptoms."
 
Title: Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).
Authors: The CONSENSUS Trial Study Group
Source: N Engl J Med 1987 Jun 4;316(23):1429-1435
PMID: 2883575, UI: 87201805

 Deaths and Hospitalizations Down

August, 1991 - CHF patients have a high mortality rate and are hospitalized a lot. We studied the effect of enalapril (Vasotec) on mortality and hospitalization in CHF patients with ejection fractions less than 35%.
     Patients were given either placebo (1284 patients) or enalapril (1285 patients) at doses of 2.5 to 20mg per day. About 90% of patients were class 2 and class 3. Follow-up averaged 3 1/2 years.
     There were 510 deaths in the placebo group (40%) versus 452 in the enalapril group (35%). The largest reduction was in deaths caused by progressive heart failure: 251 in the placebo group versus 209 in the enalapril group - a risk reduction of 22%. There was little effect on deaths from arrhythmia.
     Fewer enalapril patients died or were hospitalized for worsening heart failure - 736 in the placebo group versus 613 in the enalapril group. Adding enalapril to therapy significantly reduced mortality and hospitalizations for heart failure in low EF patients.
 
Title: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators
Source: N Engl J Med 1991 Aug 1;325(5):293-302
PMID: 2057034, UI: 91278933

 Vasotec Brings Major Improvement

August, 1993 - (Jon's note: Diastole is when the ventricles relax and fill with blood. Systole is when the heart squeezes to pump out blood) We studied changes in left ventricular diastole in patients with severe CHF taking ACE inhibitors. Left and right-sided heart measurements were taken by MUGA at study start, and after an average of 12 1/2 months in patients with an EF of 35% or less.
     Ten patients were then given placebo and 26 were given enalapril at 10mg twice a day. In the placebo group, the left ventricle got bigger at both diastole and systole. This heart enlargement was not seen in enalapril patients. Heart wall stress increased in placebo patients but decreased in enalapril patients. Heart wall stiffness decreased in placebo patients but remained steady in enalapril patients. The shape, or roundness, of the left ventricule improved in enalapril patients but worsened in placebo patients.
     This shows that in most CHF patients, progressive heart enlargement is accompanied by reduced left ventricular stiffness; enalapril prevents or partially reverses these changes and also reduces heart size and improves heart shape.
 
Title: Effects of long-term enalapril therapy on left ventricular diastolic properties in patients with depressed ejection fraction. SOLVD Investigators.
Pouleur H, Rousseau MF, van Eyll C, Stoleru L, Hayashida W, Udelson JA, Dolan N, Kinan D, Gallagher P, Ahn S, et al
Source: Circulation 1993 Aug;88(2):481-491
PMID: 8101772, UI: 93338869

 9000 Cases Can't Be Wrong

March, 1996 - Ace inhibitors should now be considered first-line therapy in CHF. In the SOLVD trial, taking Vasotec significantly improved prognosis in patients with mild to moderate heart failure. This confirms the findings of the CONSENSUS trial and shows that ACE inhibiters benefit patients in all classes of CHF.
     In the Prevention Trial of SOLVD, and the SAVE study, taking enalapril or captopril improved prognosis in patients with poor left heart function even if they showed no CHF symptoms. Their risk of developing heart failure symptoms was reduced.
     Importantly, a definite anti-ischemic effect of ACE inhibitor use was seen in both the SOLVD and SAVE trials. Clinical data from nearly 9,000 patients prove a substantial role for ACE inhibitors in patients with all classes of heart failure, as well as for those with left ventricular dysfunction but no CHF.
 
Title: Angiotensin-converting enzyme inhibitors in heart failure: new strategies justified by recent clinical trials
Author: Young JB
Source: J Card Fail 1996 Mar;2(1):47-54
PMID: 8181869, UI: 94237623

 Doctors Under-Prescribe ACE Inhibitors

March, 1996 - Primary care physicians are often confused about which patients would benefit the most from ACE inhibitors. As a result, these drugs are under-prescribed. Proper trials testing ACE inhibitors' effectiveness in CHFers have clearly shown that ACE inhibitors improve survival in patients with symptomatic CHF. In patients with non-symptomatic systolic dysfunction, these drugs also decrease hospitalizations for heart failure.
     ACE inhibitors improve survival in all patients who experienced an acute heart attack. With the huge amount of evidence showing the positive effects these drugs have on the quality of life and survival of such patients, it is unclear why doctors do not use them more often. Primary care physicians need to be educated on when to use ACE inhibitor.
 
Title: Angiotensin-converting enzyme inhibitors in left ventricular dysfunction
Author: Linn WD
Source: Pharmacotherapy 1996 Mar;16(2 Pt 2):50S-58S
PMID: 8668606, UI: 96249998

 ACE Inhibitors Are Cardioprotective

June, 1996 - ACE inhibitor use lowers blood pressure, improves insulin response, prevents potassium loss, lowers heart oxygen demand, and reduces catecholamine levels. These benefits cause improved blood flow to vital organs, an easier workload for the heart and protection of blood vessels. Left ventricular function improves, there is less angina, and a lower death rate in CHF patients. The cardioprotective effects of ACE inhibition have been shown in many multi-center long-term trials.
 
Title: Cardioprotective potential of angiotensin converting enzyme inhibitors
Authors: Gavras I, Gavras H
Source: Braz J Med Biol Res 1996 Jun;29(6):701-705
PMID: 9070382, UI: 97223691

 Monopril Versus Vasotec

1998 - ACE inhibitors are now the primary treatment for chronic heart failure but we don't know if it makes any difference which one is used. This study followed patients for one year.
     All patients had mild to moderate CHF, with EF less than 40%. All patients were class 2 or 3, and all took diuretics. None took ACE inhibitors, beta-blockers or calcium channel blockers. Patients were from 18 to 85 years old, with at least 33% over age 65. The study was done in medical centers in Britain, France, Italy and Russia. Bristol-Myers sponsored this study.
     One hundred and twenty-two patients took 5 to 20mg fosinopril (Monopril) every day and 132 patients took 5 to 20mg enalapril (Vasotec) every day for one year. Primary endpoints were total deaths and hospitalizations for worsening CHF, and time to first critical event. "Critical events" were death, hospitalization for worsening CHF, need for extra Lasix, and emergency room visits for CHF.
     Side effects were about the same in both groups. The 2 groups in general were about the same at each follow-up, except at week 12, when Monopril patients improved more in heart class. The Monopril group had longer event-free time (1.6 months versus one month for Vasotec patients) and fewer hospitalizations (20% versus 25% on placebo) with Monopril than with Vasotec. Dizziness when standing up was less with Monopril. However, all the differences were pretty small.
     There were no differences between groups in neck vein swelling, third heart sound, heart murmur, wheezing, liver enlargement, or edema. 5 to 20mg Monopril every day was slightly more effective in improving symptoms than the same amount of enalapril every day.
     Jon's note  60% of Monopril patients in this trial improved in heart class - ACE inhibitors work. I also should point out that enalapril (Vasotec) was given once a day in this trial but is usually given twice a day in "real life." Does that matter? I don't know. The authors of this trial say, "Twice daily 2.5 to 10mg enalapril might have been more effective and better tolerated than 5 to 20mg every day." One upside to Monopril is that it is eliminated equally through kidneys and liver, so patients with kidney failure may be able to take it even if they cannot take other ACE inhibitors.
 
Title: Differential Effects of Fosinopril and Enalapril in Patients with Mild to Moderate Chronic Heart Failure
Authors: Faiez Zannad, Zukai Chati, Maryline Guest, Francis Plat, and the Fosinopril in Heart Failure Study Investigators
Source: Am Heart J 136(4):672-680, 1998

 High Vs Low-Dose ACE Inhibitors

1998 - We tested different doses of ACE inhibitors in heart failure patients. Primary endpoint was change in maximum exercise time after 12 weeks. Secondary endpoints were changes in heart failure symptoms, whether heart failure got worse, and hormone levels.
     We studied 3 doses: 2.5mg, 5mg, and 10mg of the long acting ACE inhibitor Imidapril (used in Japan but not in the USA). We studied 244 patients in heart class 2 to 3 who were stable on digoxin and diuretics. They were 21 to 75 years old, had EF less than 45%, and a maximum exercise time of 10 minutes for patients up to age 45, 8 minutes for patients ages 46 to 60, and 6 minutes for patients over 60 years old.
     At study start, ANP and BNP blood levels were high. Patients were treated for 12 weeks. This study was done in The Netherlands, Germany, and Belgium.
     Imidapril is a long-acting ACE inhibitor. Blood pressure was still lower 24 hours after taking the drug, and blood ACE levels were also still 60% suppressed. Maximum reduction in blood pressure and blood ACE level was seen with 10mg imidapril once daily, with no added effect from higher doses.
     After 8 weeks, no improvement in exercise time was seen; but after 12 weeks exercise time increased in the 10mg group, not changing in the 5mg and 2.5mg group, compared to placebo. Imidapril did not affect heart rate or blood pressure enough to matter. There was quite a decrease in ANP and BNP.
     Within 3 months after treatment began, high-dose ACE inhibitor use was shown to be better than low-dose. This is shown by longer exercise times and lower neurohormone levels. The current practice of prescribing lower doses may be due to the belief that low doses are equally effective. The present study shows that a higher dose is more effective than a low dose.
 
Title: High Versus Low-Dose ACE Inhibition in Chronic Heart Failure A Double-Blind, Placebo-Controlled Study of Imidapril
Author: Dirk J. van Veldhuisen, MD, PhD, FACC, et al
Source: J Am Coll Cardiol 1998;32:1811-1818

 How To Find Right Dose For CHF

December 29, 1999 - BNP level can be used to adjust ACE inhibitor dose in patients with mild to moderate heart failure.
     Most CHF patients are treated with the same ACE inhibitor dose because there is no way to know what the best dose really is for any given person, says Dr. David Murdoch. He tested raising ACE inhibitor dose according to measurements of blood BNP levels versus basing the dose on symptoms, in 20 CHF patients. Patients were studied for 8 weeks.
     Blood BNP levels went down compared to study start in BNP-based-dose patients, and were lower than in the other group after 4 weeks. While both treatments were well tolerated and had good results, the BNP-based-dose group had greater drops in heart rate.
     But elsewhere in the journal, Dr. P. Poole-Wilson says that blood BNP level cannot be recommended for adjusting ACE inhibitor dose. Large studies with hard endpoints such as mortality rate, hospitalization or complications are needed first, he says.
 
Source: Am Heart J 1999;138:1005-1006,1126-1132

 ACE Inhibitors Often Not Properly Used

April 26, 2000 - ACE inhibitors are under-prescribed and are often prescribed in below-recommended doses. Dr. Faiez Zannad and EPICAL study researchers examined ACE inhibitor use in 417 patients with severe CHF.
     Only 75% of the patients received ACE inhibitors, and 38% were prescribed lower-than-recommended doses. Patients most likely to be denied ACE inhibitors were those over 65 years of age with reduced kidney function, patients with abnormal heart rhythm, and patients taking potassium-sparing diuretics.
     The researchers say the findings show the real state of ACE inhibitor use in severe heart failure patients. The data were collected from a large geographic area and in 35 hospitals, so they believe these patients better represent the severe CHF population than patients in clinical trials.
     Dr. Zannad's group concludes that ACE inhibitors "are under-used in daily practice, even in patients with severe CHF."
 
Source: Am Heart J 2000;139:624-631, Reuters Health

 Trandolapril Increases Life Span

July 3, 1999 - Long-term treatment with trandolapril (Mavik) may lengthen life expectancy in patients with poor heart function after a heart attack. This is based on 6 years of follow-up from the TRACE study.
     The survival benefit seen after taking trandolapril for 2 years continued throughout the 6 year follow-up. Trandolapril-treated patients had a life expectancy of 6.2 years compared to a life expectancy of 4.6 years for placebo-treated patients. This is a 27% increase in life expectancy. Patients were advised to stay on trandolapril at the end of the study.
     It was also discovered that diabetic and high blood pressure patients "may have their life expectancy more than doubled with trandolapril treatment," says study author Dr. Kober. It is important to note that critically ill patients should not be started on trandolapril.
 
Source: Lancet 1999;354:9-12

 Avapro (irbesartan) Lasts Longer

October 27, 1999 - The effects of irbesartan (Avapro) seem to last longer than some other ARBs like valsartan (Diovan) and losartan (Cozaar), according to a study comparing the 3 drugs.
     The findings were reported by Dr. Gustav Belz. He studied the effect of standard doses of irbesartan, valsartan and losartan in a crossover trial of 18 healthy men. The men got 150mg irbesartan, 80mg valsartan or 50mg losartan.
     The rightward shift of the angiotensin 2 curve - a measure of how well the drug blocks angiotensin II - was greater for irbesartan than for the other two drugs. This difference remained significant up to 36 hours compared to valsartan and up to 47 hours compared to losartan. "The rate of decay for irbesartan was half that of the other drugs," Dr. Belz writes. "So when starting from the same level, the effects of irbesartan stay in the body about twice as long as valsartan and losartan."
     The findings suggest that irbesartan may be better than the other 2 drugs in actual practice. For instance, if patients don't take their meds exactly on schedule, they still have some protection after 24 hours with irbesartan. Data from 2 separate trials comparing irbesartan with losartan have shown this difference.
 
Clin Pharmacol Ther 1999;66:367-373

 Valsartan Both Good and Bad?

December 6, 2001 - Dr. Jay Cohn and Dr. Gianni Tognoni randomly assigned 5,010 class 2 to class 4 heart failure patients to 160mg valsartan twice daily or placebo. The patients were already taking ACE inhibitors, diuretics, digoxin and/or beta-blockers.
     Overall mortality was similar in both groups. In valsaratan patients, risk of nonfatal heart attack or hospital admission for heart failure was slightly lower than in placebo patients. Valsartan patients were hospitalized for CHF 14% versus 18% in the placebo group. Compared to placebo, valsartan improved heart class, ejection fraction, and quality of life.
     However, in patients already taking both beta-blockers and ACE inhibitors when they started the study, valsartan worsened mortality, and was linked to an increase in combined mortality plus complications.
     Valsaratan added to CHF meds in patients taking either an ACE inhibitor or a beta-blocker helps patients, but adding valsartan to CHF meds in patients taking an ACE inhibitor and a beta-blocker may be a bad idea.
 
Title: A Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic Heart Failure
Authors: Jay Cohn, Gianni Tognoni
Source: N Engl J Med 2001;345:1667-1675

 Captopril May Stunt Kids' Growth

December 5, 2000 - Captopril has been shown to slow growth in young rats. Since captopril is often used in children with high blood pressure, research is needed to see if this is also true in human children, according to Dr. Maria da Penha de Nascimento.
     Dr. Nascimento randomised rats with high blood pressure into 3 groups that took either placebo, captopril, or hydralazine during their 15-week growth phase. High blood pressure was well controlled with both drugs compared to placebo. However, captopril-treated rats showed a 20% reduction in weight gain compared to the other study rats.
     Dr. Nascimento explained, "This is an experimental study, so further work is needed to determine the effect of the drug on growth patterns of human children."

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.

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