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Updated May 22, 2005

Ace Inhibitors benazepril - Lotensin by Novartis captopril - Capoten by Bristol-Myers Squibb enalapril - Vasotec by Merck fosinopril - Monopril by Bristol-Myers Squibb imidapril - Not approved for human use in the USA - approved in Japan lisinopril - Prinivil by Merck or Zestril by Astra-Zeneca moexipril - Univasc by Schwarz Pharma quinapril - Accupril by Pfizer perindopril erbumine - Aceon by Rhone-Polenc Rorer ramipril - Altace by Hoechst Marion Roussel, King Pharmaceuticals trandolapril - Mavik by Knoll Pharmaceutical (BASF) ARBS - Angiotension II Receptor Blockers candesartan cilexetil - Atacand by Astra Merck eprosartan - Teveten irbesartan - Avapro by Sanofi losartan - Cozaar by Merck olmesartan medoxomil - Benicar by Sankyo Pharma telmisartan - Micardis valsartan - Diovan by Novartis

Angiotensin II - The Problem

We are talking about the chemical messengers in the body called neurohormones. For those of us with heart failure, the neurohormone called angiotensin II is not a good thing. Angiotensin II helps controls the cardiovascular system. It causes blood vessels to shrink (vasoconstriction), which raises blood pressure. Angiotensin II also causes the body to release aldosterone - a substance that causes our kidneys to retain sodium and fluid, causing edema. Angiotensin II also causes the body to release a substance called vasopressin or ADH, which causes us to retain fluid even more. Angiotensin II is a real bug-a-boo for us CHFers.

ACE Inhibitors - Why They Work

We all have angiotensin one in our systems. Angiotensin one is converted into angiotensin II by an enzyme in your body called ACE (Angiotensin Converting Enzyme). ACE is what we block with ACE inhibitors - blocking it prevents angiotensin I from converting into angiotensin II. Reducing angiotensin II lets our blood vessels relax and expand. This lowers blood pressure, which makes the heart's job a lot easier. Think of it this way: If you pump the same amount of water at the same speed through a little pipe as through a big pipe, there's higher pressure in the small one. The fluid shoots out of the small pipe, but calmly flows out of the big one, even though they are both moving the same amount of water. The pump pushing the water through that skinny pipe has to work a lot harder than the pump glushing it through the big pipe. The same principle applies to our blood vessels. If our arteries relax, they get bigger (vasodilation) and the pump has an easier job - less pressure. That's called reducing "afterload." ACE inhibitors do this for us. "Super" ACE inhibitors called vasopeptidase inhibitors were also tested for CHF but carry higher risk for side effects. ACE also helps control the amount of blood in your body - your blood "volume." Blocking ACE reduces the overall amount of blood in your body. This means your tired old heart has less blood to pump, which makes its job easier. ACE inhibitors increase the level of potassium in your blood, so they partly offset potassium loss caused by diuretics like Lasix and Demadex. Finally, ACE inhibitors help us live longer and feel better. The articles below show that ACE inhibitors reduce our risk of death by 20% to 40%. The other two types of drugs that do this are beta-blockers and Aldactone (spironolactone). ACE inhibitors slow heart remodeling, preventing our hearts from getting even weaker over time. It can take several months for the full effect of ACE inhibitors to show up, and improve our quality of life. Hang in there, because ACE inhibitors do work and all CHFers should be on them if possible. It's even in the official heart failure treatment guidelines. Unfortunately, many doctors don't offer us ACE inhibitors if we have any kidney problems or if our blood pressure is low. This is unwise - see this article. Monopril (fosinopril) is processed by the liver as well as the kidneys, so CHFers with kidney problems can usually take it okay. People with low blood pressure, surprisingly enough, often tolerate ACE inhibitors quite well (although not always).

ARBs Angiotensin II Receptor Blockers

Angiotensin II is also made at other places in the body. So ACE inhibitors can't completely stop angiotensin II from affecting you. After starting an ACE inhibitor, there is a period where angiotensin II is almost completely stopped. Over time, your angiotensin II level rises again, from these other places in the body. Since ACE inhibitors can't do it all, it seems like a good idea to block the stuff at other places too. ARBs block angiotensin II receptors on cell walls. If angiotensin II can't connect to cell receptors, it can't affect us. The most important receptor is called the AT-1 receptor (there is also an AT-2 receptor). ARBs do help CHF. The question is: Do ARBs help CHFers already taking an ACE inhibitor? This has not been completely decided yet. The RESOLVD study compared an ARB alone to using an ACE inhibitor alone to using both an ACE inhibitor and an ARB. Using both worked better to improve heart enlargement and EF. The ValHeft trial added an ARB to standard CHF therapy. Complications and mortality improved most in CHFers taking the ARB with either an ACE inhibitor or a beta-blocker, but not in those taking all 3 drugs. Why taking all 3 drugs gave worse results is unknown. ARBs do have some excellent uses we are sure about. In patients who develop a bad cough from using an ACE inhibitor, an ARB can often be used without the cough. In patients who don't tolerate an ACE inhibitor for some other reason, an ARB will often do the job. Note - Telmisartan can significantly raise blood digoxin levels.

In Conclusion,...
High doses are better than low doses but doctors don't usually prescribe them - due to simple ignorance. Double-check your doc on this to be sure you are getting a high enough dose! Even if you improve to normal heart function and consider yourself "cured," a good CHF specialist will keep you on an ACE inhibitor for life, and that's smart. It may stop you from getting CHF again down the road - which can happen. ACE inhibitor use may reduce your zinc level so you might want to take a zinc supplement. Your sense of taste could possibly go goofy on you after starting an starting ACE inhibitor too - especially on captopril.

ACE Inhibitor & ARB Links

Med Line Plus On ACE Inhibitors Post Grad Med On ARBs Ace Inhibitors For Chronic CHF

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More CHFers Need To Take - And Keep Taking - ACE Inhibitors ACE Inhibitors Should Be Standard Treatment For CHF Aspirin, ACE Inhibitors, and Mortality ACE Inhibitors Slow Heart Damage Caused By CHF High Dose Better For CHF High Doses Better Once Again Higher Doses Well Tolerated In CHF Patients Losartan Eases ACE Inhibitor Cough ELITE 2 - Losartan Versus Captopril In Elderly Losartan Improves Heart Size Blood Levels Of Angiotensin II Point To Prognosis HOPE Trial Results HOPE Trial - Diabetic Results ARBs Slow Worsening Of Diabetic Nephropathy ACE Inhibitors & ARBs Reduce Death And Complications In CHFers ACE Inhibitors For CHFers With Low Blood Pressure Works Fine ACE Inhibitors Improve Artery "Stretchability" in CHF Patients Stomach Pain Side Effect Must Be Considered In ACE Inhibitor Patients NSAIDs (Indomethacin) & ACE Inhibitors Don't Mix NSAIDs Interfere With ACE Inhibitors Valsartan Better than Coreg Regarding Sexual Ability In Men ACE Inhibitors Help Patients With Extra Problems Even More ACE Inhibitors Help Prevent CHF In High-Risk Patients The CHARM trials for ARBs In Heart Failure ARB Plus ACE Inhibitor FDA-Approved For Heart Failure NEW

CHFers Need To Keep Taking ACE Inhibitors

June 2, 2004 - Many CHFers either do not start taking ACE inhibitors or stop taking them just one month after they go home from the hospital. More CHFers need to leave the hospital already on ACE inhibitors and also need more help refilling their prescriptions once they get home. Data was studied on 219 CHFers with reduced EF and 960 heart failure patients in general. All were enrolled in both the Medicare and the Tennessee Medicaid program when they entered the hospital. Federal and state records allowed researchers to collect clinical information and track prescription drug purchases. Only 67% of patients with reduced EF were sent home with ACE inhibitors. Eighty-one percent of these patients filled an ACE inhibitor prescription within 30 days. After a year, only 66% of these patients were still filling their prescriptions. Among all CHFers (including those with normal EF), only 55% left the hospital with ACE inhibitors. Of this group, 77% filled a prescription within 30 days and only 63% were still filling prescriptions a year later. In patients who did not receive ACE inhibitors when leaving the hospital, only about one in eight filled a prescription within 30

days. Title: Outpatient utilization of angiotensin-converting enzyme inhibitors among heart failure patients after hospital discharge. Authors: Javed Butler, Patrick Arbogast, James Daugherty, Manoj Jain, Wayne Ray, Marie Griffin. Source: June 2, 2004, Volume 43, Issue 11 Pages 2036-2043.

ACE Inhibitors Should Be Standard Therapy

November 3, 2000 - Dr. James Mason collected data on 7,487 patients taking enalapril (Vasotec) at the start of a medical trial. Of these patients, 2,569 had CHF. Researchers studied how many patients stopped treatment (seeing if they tolerated the drug) within a year of starting it for the first time. They also measured the cost of treatment. During the test dose part of the trial, only 8% of patients reported side effects; 2% of those patients stopped taking the drug because of their side effects. "Overall, there was no difference in the rate of side effects leading to dose reduction or withdrawal between the ACE inhibitor and placebo groups," said researchers. Dr. Mason's group notes that the costs of identifying and treating these patients is small "and do not affect the costeffectiveness of ACE inhibitors for CHF." Based on these findings, Dr. Mason's group concludes that "doctors' perceptions of the risks of ACE inhibitors for CHF patients are exaggerated." In an editorial, Dr. John Cleland says that fear of side effects is not what prevents doctors from effectively treating CHF patients, but rather "lack of resources and expertise." Source: BMJ 2000;321:1113-1116,1095-1096

Aspirin, ACE Inhibitors, and Mortality

1999 - Taking aspirin may improve survival in patients with CAD (coronary artery disease) who are also taking ACE inhibitors especially in CHF patients. These findings contradict a theory that aspirin might reduce ACE inhibitor benefit in heart failure patients. Researchers studied mortality data on 11,575 CAD patients who were screened for a heart attack prevention trial. They compared 579 patients taking ACE inhibitors only (the control group) to 618 patients taking both ACE inhibitors and aspirin. After a 5 year follow-up, the authors found that mortality was higher in patients taking only ACE inhibitors (27%) than in patients taking both ACE inhibitors and aspirin (19%). Risk of death remained lower in aspirin users after adjusting for factors such as age, sex, diabetes, high blood pressure, heart class , and other drugs being taken such as beta-blockers, digoxin and diuretics. The protective effect of aspirin when used with ACE inhibitors was even more pronounced in patients with congestive heart failure. In the CHF patients, mortality was lower in the 221 taking both aspirin and ACE inhibitor (24%) than among 243 taking only an ACE inhibitor (35%). A relatively low aspirin dose of 250mg was used in the study, compared with doses of 325 to 350mg in other trials - aspirin safety and effectiveness may depend on taking a lower dose. The data suggest that use of low-dose aspirin (250mg or less) with ACE inhibitors is safe and may benefit CAD patients, with or without CHF. Title: Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors: a cohort study of 11,575 patients with coronary artery disease Authors: Leor J, Reicher-Reiss H, Goldbourt U, et al Source: J Am Coll Cardiol. 1999;33:1920-1925

Ace Inhibitors Slow Heart Remodeling

May, 1995 - The SOLVD trial showed that enalapril (Vasotec) greatly improves quality of life for patients with left ventricular dysfunction. In this sub-study we examined changes in heart structure and heart function in SOLVD patients to see if enalapril slowed remodeling. The 301 patients in our study had echos and were then given either enalapril or placebo. They had echos again after 4 and 12 months of therapy. The enalapril group had a lot less progressive damage to their hearts than the placebo group. Heart size increased in placebo patients and decreased in enalapril-treated patients. This study shows that enalapril slows progressive heart enlargement in CHF patients. Title: Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiography substudy. Greenberg B, Quinones MA, Koilpillai C, Limacher M, Shindler D, Benedict C, Shelton B Source: Circulation 1995 May 15;91(10):2573-2581 Comment in: Circulation 1995 May 15;91(10):2504-7 PMID: 7743619, UI: 95262234

High Dose Better For CHF

November 15, 1999 - Chronic heart failure patients should be kept on high doses of ACE inhibitors instead of low doses.. Dr. Milton Packer studied more than 3,100 patients with class 2 to class 4 CHF and an EF of 30% or less. Patients took either low or high doses of lisinopril for up to 5 years. The study used low lisinopril doses of 2.5 to 5mg per day and high lisinopril doses of 32.5 to 35mg per day during the trial. Patients with moderate to severe CHF had 12% lower risk of death or hospitalization for any reason, if placed on a high dose of ACE inhibitor compared to a low dose. "It is noteworthy," the authors write, "that patients taking high doses did not see any more improvement in heart class than those who took low doses. This lack of difference suggests that changes in symptoms cannot be used as a guide in selecting ACE inhibitor dose, because a higher dose may reduce risk of death and hospitalization even if there is no improvement in symptoms." High dose patients did have more side effects such as dizziness, low blood pressure, high potassium levels and kidney problems. However, coughing occurred less often in the high-dose group.

Source: Circulation 1999;100:rt1-rt7

Higher Doses Better

1999 - We studied 45 patients (43 men and 2 women) aged 33 to 74 years with an average EF of 28%. At study start, exercise capacity was poor and neurohormone levels were high. The dose of enalapril (Vasotec) at study start was either 5mg BID (16 patients), 10mg BID (18 patients), or 20mg BID (11 patients). All patients were treated for 4 weeks with each different dose. There were no changes in heart class, shortness of breath when lying down, or edema. However, patients had more CHF symptoms on low doses (10mg) than when taking higher doses. Neurohormone levels were 25% higher when patients were on the low dose. Vo2max increased when patients were on the highest dose - a good thing. Higher ACE inhibitor dose improves daily functioning and lowers blood levels of harmful hormones in CHF patients. Patients had less CHF symptoms on the highest dose. Serious adverse events happened more often on lower doses. Angiotensin II causes great harm in CHF patients over time. During long-term therapy, angiotensin II receptors in the body may become more sensitive, so lowering blood levels of it is important. High dose ACE inhibitor improves not only CHF symptoms and exercise ability, but also reduces chemicals that worsen CHF. Heart failure patients benefit from higher doses of ACE inhibitors. Title: Within-Patient Comparison of Effects of Different Dosages of Enalapril on Functional Capacity and Neurohormone Levels in Patients With Chronic Heart Failure Authors: H. Brunner-La Rocca, D. Weilenmann, W. Kiowski, E. Maly, R. Candinas, F. Follath Source: Am Heart J 138(4):654-662, 1999

Higher Doses Well Tolerated

January 22, 2001 - The ATLAS study showed that higher doses of Prinivil/Zestril are better than lower doses for reducing death and hospitalizations in CHFers. This is also the first large trial studying whether low blood pressure and kidney problems happen more often on high doses. ATLAS included 3,164 class 2 to class 4 CHFers with ejection fractions of 30% or less. All patients were stabilized at 12.5 to 15mg daily for 2 to 4 weeks, then they were split into 2 groups. One group took a low dose of 2.5 to 5mg daily while the other group took a high dose of 32.5 to 35mg daily. About the same number of patients withdrew from each group (high-dose and lowdose) due to side effects. Some groups are thought to be at higher risk for side effects from high-dose ACE inhibitor use. These groups were closely watched, including people with low blood pressure, poor kidney function, age of 70 years or older, or diabetes. Episodes of low blood pressure happened only 5% more often in the high-dose group. Cases of worsening kidney function or high potassium level were few. These results "provide a clear message that higher ACE inhibitor doses can and should be used in most patients," says Dr. Massie's group. Source: Arch Intern Med 2001:161:165-171

Losartan Eases Ace Cough

March 15, 1997 - About 10% of heart failure patients develop a chronic, irritating cough from ACE inhibitor use. ARBs block receptors for angiotensin II rather than ACE formation, so they not cause as much coughing. In ELITE, 722 patients over age 65 with class 2 to class 4 CHF, who had never taken ACE inhibitors, took either the ARB Cozaar (losartan) or the ACE inhibitor Capoten (captopril). Captopril was started at 6.25mg and increased to 50mg TID. Losartan was started at 12.5mg and increased to 50mg per day. Three hundred and fifty-two patients took losartan and 370 took captopril. At 48 weeks, fewer losartan patients died (5% versus 9%) and had fewer hospitalizations. Twelve percent of losartan patients versus 21% of captopril patients stopped treatment because of side effects. Cough occurred in 4% of captopril patients and none of the losartan patients. Losartan (an ARB) is a good alternative to ACE inhibitors for heart failure patients, especially in patients who get a bad cough on ACE inhibitors. The lower death rate of people taking losartan in this trial was unexpected and is unexplained. Title: Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE) Author: Pitt B et al, Lancet 1997 Mar 15; 349:747-752 Source: Journal Watch: Cardiology 28 April 1997

ELITE 2 Results
December 20, 1999 - The original ELITE trial showed 46% reduction in all-cause death and 64% reduction in SCD with losartan compared to captopril. ELITE 2 was done to study this. ELITE 2's primary endpoint was all-cause mortality. Secondary endpoints were SCD, all-cause hospitalizations, hospitalization for CHF, heart-related death, and heart attack - either fatal or nonfatal. There were 3,152 patients in the trial and 1,574 took 50mg captopril 3 times a day while 1,578 took 50mg losartan per day. In both groups, patients were mostly men with an average age of 72 years. Average EF was 31% in both groups. Eighty percent had ischemic CHF. About 25% in each group were taking a beta-blocker and 50% were on digoxin (Lanoxin). No difference was seen in SCD, heart failure deaths, heart attack, or stroke between the groups. The event rate was 16% in the captopril group and 18% in the losartan group. ELITE II did not confirm ELITE's finding that losartan is better than captopril for improving survival. No differences were seen in all-cause mortality, sudden cardiac death, resuscitated cardiac arrest, or hospitalizations. Title: ELITE II - Evaluation of Losartan in The Elderly Study, The Losartan Heart Failure Survival Study Presented by: Philip A. Poole-Wilson, MD and Betram Pitt, MD.

Losartan Lowers BP & Improves Heart Size

October 23, 2000 - Long-term losartan use reduces blood pressure and may improve heart function. Losartan also reduces left ventricular size in patients with enlarged hearts. Dr. Per Omvik studied the long-term effects of losartan in 28 patients with high blood pressure. Patients took 50mg to 100mg

losartan per day for 8 months. At follow-up, "intra-arterial pressure was reduced from 165/102mm Hg to 145/91mm Hg at rest; and from 193/104mm Hg to 179/96mm Hg during exercise." Total peripheral resistance was reduced 12 to 15%. Cardiac index and heart rate remained unchanged. During exercise, heart output increased 7% to 9% but was unchanged at rest. Blood pressure measured over 24 hours with patients moving around freely went down 10% to 13%. There was a 27% reduction in left ventricular size in 18 patients with enlarged hearts. Source: Am Heart J 2000;140:624-630

Blood ACE Levels Predictor

February 7, 2000 - Even while taking ACE inhibitors, CHFers may have high angiotensin II levels. High levels are linked to death or worsening heart failure. Dr. Eulalia Roig measured blood levels of aldosterone, norepinephrine, ANP, angiotensin II, and TNF in 70 CHFers after 6 months of ACE inhibitor use. The patients were taking either 20mg or more enalapril per day, or 150mg captopril or more per day. Angiotensin II levels increased in half the patients. Levels in the remaining patients stayed in a normal range. Increased angiotensin II meant higher risk for death or heart failure. "This study showed for the first time that chronic high blood levels of angiotensin II are linked to higher mortality and complications," Dr. Roig says. "This may explain why - despite ACE inhibitor therapy - many CHFers still have symptoms and poor outcomes,". The authors think that adding ARBs to ACE inhibitor therapy may benefit such patients. Source: Eur Heart J 2000;21:14-16,53-57

HOPE Trial Results

January 20, 2000 - Dr. Salim Yusuf studied 9,297 high-risk patients age 55 or older who had a history of coronary artery disease, peripheral vascular disease, stroke, or diabetes, plus another risk factor for heart disease. None had a low ejection fraction or heart failure. Patients took either 10mg ramipril or placebo once daily in the evening and 400 IU vitamin E or placebo daily. Follow-up visits were at one month and then every 6 months. Six hundred and fifty-one patients took 10mg ramipril once per day and the rest took placebo in the 4-1/2 year trial. Ramipril reduced rates of death from heart-related causes - 6% in Ramipril group versus 8% in placebo group. Heart attack rates were 10% in the ramipril group and 12% in the placebo group. Death rates from any cause were 10% in the ramipril group and 12% in the placebo group. Risk of stroke, need for procedures like bypass or angioplasty, and risk of heart attack were all reduced in the Ramipril group. Ramipril reduced diabetic complications from 7.6% to 6.4%. Vitamin E supplements did not change risk of adverse heart-related outcomes. Source: N Engl J Med 2000;342:145-153,201-202

HOPE Trial: Diabetic Subgroup

January 22, 2000 - The ACE inhibitor ramipril definitely lowers risk of heart-related events and kidney disease in diabetic patients. The HOPE study treated 3,577 diabetic patients aged 65 years and older, who had heart disease. None of the patients had a low ejection fraction or heart failure. Patients took 10mg of ramipril or a placebo daily, along with 400 IU of vitamin E or placebo, and were followed for 4-1/2 years. Combined outcome of heart attack, stroke, or heart-related death was 25% lower in the ramipril diabetic group than in the placebo diabetic group. Ramipril also lowered risk of heart attack by 22%, stroke by 33% and heart-related death by 37% (relative risk). Ramipril patients also showed a 24% reduction in overall risk of death, a 17% reduction in need for procedures like bypass or angioplasty, and a 24% reduction in nephropathy (common in diabetics) [relative risk]. "Ramipril's benefit was seen regardless of whether patients had a history of heart-related events, high blood pressure, or stroke; whether or not they had type one or type two diabetes; and regardless of current treatment for high blood sugar," the investigators say. Source: Lancet 2000;355:246-247,253-259

ARBs Slow Diabetic Nephropathy

May 21, 2001 - Results from 3 clinical trials now show that the ARBs irbesartan (Avapro) and losartan (Cozaar) slow diabetic kidney failure (nephropathy) in patients with type 2 diabetes. The IRMA 2, IDNT and RENAAL trials combine to show that regardless of blood pressure reduction, using an ARB can reduce worsening of kidney function by 70%.. In the IRMA 2 trial, Dr. Parving in Denmark studied 590 patients from 30 to 70 years of age who had microalbuminuria. Patients took either 150mg or 300mg irbesartan per day, or placebo. During 2 years of follow-up, 15% of placebo patients progressed to diabetic nephropathy, compared to 10% in the 150mg irbesartan group and 5% in the 300mg irbesartan group. Also, 9% of placebo patients suffered heart-related events compared to 5% in the 300mg irbesartan group. Dr. Parving said, "Irbesartan should be given as soon as you detect microalbuminuria, because these patients have a 10 to 25% higher risk of developing kidney dysfunction," Dr. Parving said he would start all type 2 diabetics with high blood pressure on irbesartan anyway, to protect against kidney disease. In the IDNT trial, Dr. Edmund Lewis in Chicago studied 1,715 men and women with high blood pressure from 30 to 70 years of age. All had type 2 diabetes and established kidney disease. Patients took either irbesartan, the calcium channel blocker amlodipine, or placebo. With 2-1/2 years average follow-up, kidney disease did not progress nearly as far in the irbesartan group, said Dr. Lewis - only 33% as often as the placebo group and only 37% as often as the amlodipine group. "Irbesartan protects the kidneys in these patients," Dr. Lewis said. The RENAAL trial compared 50mg or 100mg losartan per day and placebo in 1,513 type 2 diabetic patients. All patients had established kidney disease and 94% had high blood pressure, said Dr. Barry Brenner in Boston. Most patients taking losartan needed to also take another drug to bring their blood pressure under 140/90 mmHg. Losartan reduced progression of kidney disease to end-stage kidney failure by 28%. Losartan also reduced the risk of endstage kidney disease or death by 20%. There was a 32% reduction in the development of new heart failure, and a 28% reduction in heart attack. "Losartan should be a first-line drug for treating high blood pressure patients with type 2 diabetes," Dr. Brenner said.

Source: Reuters Health and The 16th annual meeting of the American Society of Hypertension

ACE Inhibitors Reduce Complications & Mortality

May 8, 2000 - ACE inhibitors improve many outcome measures in heart failure patients, according to two reports in the May 6th issue of The Lancet. In the first report, Dr. Salim Yusuf and associates analyzed 5 long-term, placebo-controlled ACE inhibitor trials in patients with reduced left ventricular function. Death rate for ACE inhibitor patients (23%) was lower than for placebo patients (27%). In the 3 post-MI trials, the difference was even bigger (23% versus 29% in placebo patients). ACE inhibitor patients were hospitalized less for heart failure (14%) than placebo patients (19%), and they had fewer repeat heart attacks (9% versus 11%). The authors conclude that "ACE inhibitors should be routinely used long-term in all eligible high-risk patients." In a second report, Dr. Bertram Pitt compared the effects of the ARB losartan to the ACE inhibitor captopril in 3,152 elderly CHF patients. Overall death rates, sudden death rates, and number of hospital admissions were about the same in both groups. Fewer patients taking losartan stopped treatment because of cough, but there were no other real differences. "We believe that ACE inhibitors should be the main treatment for heart failure," the authors say, "although ARBs may be useful when ACE inhibitors are not tolerated." Source: Lancet 2000;355:1568-1569,1575-1587, Reuters Health

ACE Inhibitors In CHFers With Low Blood Pressure

October 26, 2000 - Heart failure patients with low blood pressure can benefit from ACE inhibitor use, according to researcher Dr. Kwame Akosah. Low blood pressure patients have been kept out of ACE inhibitor trials for CHF, and that low BP "may be the single most important reason why doctors don't prescribe ACE inhibitors." "We studied ACE inhibitor use in CHF patients who were denied this medication based just on the complexity of their illness," Dr. Akosah said. The team studied 100 CHF patients, 18 of whom had low BP, with systolic blood pressures ranging from 60 to 100 mmHg. The researchers raised lisinopril doses to pre-determined "best" or "maximum" doses. At 4 weeks, 83% of the 18 low BP patients were tolerating 20mg of lisinopril or equivalent. At 8 weeks, 82% were taking the maximum dose of 40mg. Three patients stayed at 20mg. The average systolic blood pressure was 86mm Hg at start, 98mm Hg at optimum dose, and 107mm Hg at maximum lisinopril dose. Dr. Akosah noted that "not only were ACE inhibitors well tolerated, but low blood pressure symptoms actually got better. All patients saw symptoms improve, with better heart class ." Source: Reuters Health

Artery Flexibility Better With ACE Inhibitor

August 25, 2000 - In heart failure patients, artery stiffness can be reversed by ACE inhibitors, according to a report at a meeting of the International Society of Hypertension. Dr. C. Giannattasio gave results from a study of 30 CHF patients. In these patients and in 30 control patients, researchers measured the diameter and stretchability of the radial artery (in the arm), carotid artery (in the neck) and the abdominal aorta. The patients were divided into 3 groups. After a treatment period with diuretics, digoxin and low-dose ACE inhibitors, group A continued standard treatment, group B took a high-dose ACE inhibitor, and group C continued standard therapy with an ARB added. At study start, diameter of the radial and carotid artery were similar in all patients but the diameter of the abdominal aorta was higher in CHFers. The radial artery and abdominal aorta of CHF patients were much stiffer than in healthy control patients. After 8 weeks of treatment, artery diameters remained the same in all 3 groups. Stretchability (distensibility) was also unchanged in all 3 arteries in group A. However, stretchability "significantly" increased in groups B and C. In group B, patients showed a 99% improvement in radial artery flexibility, 45% in the carotid artery and 33% in the aortic artery. In group C, patients showed a 75% improvement in radial artery flexibility, 65% in the carotid artery and 90% in the aortic artery. Source: Reuters Health

ACE Inhibitor Side Effect Under-diagnosed

November 28, 2000 - A report of 2 patients who suffered swelling of internal organs after taking ACE inhibitors suggests that this complication may be an under-recognized cause of stomach pain. The first was a 67 year old woman who came to the emergency room with severe stomach pain, nausea and vomiting. Dr. David Douglas said that a CT scan showed a swollen and thickened small bowel and ascites. The woman had a history of high blood pressure and had suffered similar pain during previous Monopril treatment. Her gallbladder had been removed trying to fix the pain. She restarted Monopril 3 days before this episode. The researchers stopped her Monopril, which completely stopped her symptoms and led to normal bowel tests. The second case was a 41 year old woman who came to the emergency room with cramp-like stomach pain, nausea, and vomiting. Her gallbladder had also been removed a month earlier for similar symptoms, and her only medication was Prinivil for high blood pressure. A stomach CT scan showed thickening of the small bowel and ascites. During surgery, Dr. Douglas found an inflamed, swollen small intestine. He stopped her Prinivil and her symptoms disappeared. Eight cases of this "visceral angioedema" after ACE inhibitor treatment have been reported, mostly involving women. "Visceral angioedema should be considered in patients with unexplained stomach pain who take ACE inhibitors." Such symptoms are reason to stop ACE inhibitor treatment. Failure to consider this condition may lead to unnecessary surgery. Source: Mayo Clin Proc 2000;75:1201-1204

Indomethacin & ACE Inhibitors Don't Mix

October 9, 2000 - Taking indomethacin and either captopril or losartan greatly reduces the heart drug's effectiveness. Dr. Paul Conlin's team studied 281 high blood pressure patients. The patients either took 50mg losartan once a day or 25mg captopril twice a day, which was increased to 50mg twice a day after one week. After 6 weeks, patients were also given 75mg of indomethacin per day. To test the effect of taking indomethacin, researchers measured the change in average 24 hour diastolic blood pressure.

While both heart drugs lowered diastolic blood pressure, indomethacin "significantly reduced their effectiveness." High blood pressure patients taking these drugs along with indomethacin need to be monitored for proper blood pressure control. Source: Hypertension 2000;36:461-465.

NSAIDs Raise Blood Pressure

December 28, 2000 - Elderly patients taking an ACE inhibitor are at risk of high blood pressure if they also take NSAIDs. Dr. Trefor Morgan studied 30 patients averaging 72 years old on Vasotec (enalapril) and 31 patients averaging 69 years old on Norvasc (amlodipine). The patients were randomized to either placebo or indomethacin for 3 weeks. All had high blood pressure being effectively controlled by the drug they were taking. Indomethacin significantly raised blood pressure and lowered pulse rate in patients taking Vasotec. This was not seen in patients taking Norvasc. Adding indomethacin to either drug caused weight gain, and lowered blood levels of renin. "The major problem is the patient who takes indomethacin or other NSAIDs off and on," Dr. Morgan points out. If the patient is also taking an ACE inhibitor, this will cause "blood pressure to go out of control. In such patients amlodipine may be a better choice than enalapril." Researchers think that indomethacin causes a CHFer's body to retain sodium. The lower renin level overcomes this in patients taking amlodipine, but not in patients taking enalapril. Source: Am J Hypertens 2000;13:1161-1167

ARBs and Sexual Performance

February 1, 2001 - While the beta-blocker Coreg may worsen sexual function in men treated for high blood pressure, valsartan an ARB - does not. In fact, valsartan (Diovan) may actually improve sexual function in such men. Dr. Roberto Fogari studied the impact of valsartan and Coreg on sexual activity. This was a crossover study of 120 newly diagnosed men never before treated for high blood pressure. The patients took either valsartan or Coreg, and were then crossed over to the other drug. Forty similar men took placebo. After 16 weeks, sexual activity was measured by questionnaire. Both treatments lowered blood pressure, but Coreg was linked to fewer episodes of sexual intercourse during the first month of therapy. Coreg also gave worsening results. Howevere, sexual activity rebounded and actually improved with valsartan. Only one man on valsartan complained of not being able to get an erection, while 15% of Coreg-treated patients reported this problem. The researchers are not sure why this ocurred but there you have it, guys! Please note though, that these men did not have CHF. Source: Am J Hypertens 2001;14:27-31,70-73

More Patients Need ACE Inhibitors

October, 2002 - Dr. Ali Ahmed studied 295 older patients hospitalized for CHF. At hospital discharge, 63% of patients began taking an ACE inhibitor. Eighteen percent had conditions like low blood pressure, high potassium levels, or weak kidney function. Such patients were 65% less likely to get an ACE inhibitor than patients without such problems. Patients with such conditions who took ACE inhibitors did well despite doctors' views that such conditions prohibit ACE inhibitor use. These patients had a 31% reduction in absolute risk of death in the year after hospital discharge, compared to a 15% reduction in patients without these problems. In other words, they got a bigger benefit than patients who usually get ACE inhibitors! The researchers say "life-saving therapy is being withheld on the basis of questionable evidence" and suggest that ACE inhibitors be given to more patients. Source: J Am Geriatr Soc 2002;50.

ACE Inhibitors To Prevent CHF

February, 2003 - Ramipril may lower risk of heart failure in people at high risk for it, but who still have a normal EF. Dr. Malcolm Arnold randomly assigned 9,297 patients to take 10mg ramipril daily or placebo for 4-1/2 years. Patients were not included if they had a history of heart failure, known low ejection fraction or uncontrolled high blood pressure. However, patients with coronary artery disease, peripheral artery disease, stroke, or diabetes plus one other risk factor, were included. Ramipril patients went into heart failure 23% less often and had 24% less heart-related death and heart failure. In those with normal EF there was 22% less heart failure and 15% less hospitalizations for heart failure. Ramipril reduced the rate of heart failure by 13% in 1,029 patients who had a heart attack during the study. Dr. Arnold said, "Patients over 55 years with heart disease should be considered for ramipril to lower their risk of serious events." Source: Circulation 2003;107:1278-1284,1230-1232

The CHARM Trial For ARBs In CHF

September, 2003 - The CHARM trials showed that the long-acting ARB candesartan reduces heart-related deaths and CHF hospital admissions. This was seen "on top" of standard therapy including beta-blockers and ACE inhibitors. CHARM had 3 subtrials in specific groups of heart failure patients: CHARM-Alternative Patients with EF less than 41% who could not tolerate ACE inhibitors CHARM-Added Patients with EF less than 41% who were also taking an ACE inhibitor chosen by their doctor CHARM-Preserved Patients with EF greater than than 40%, who may or may not have taken an ACE inhibitor CHARM Overall All the above trials, combined for analyzing overall mortality Patients took either candesartan or placebo. Starting candesartan dose was 4mg or 8mg once a day, increased up to a maximum

dose of 32mg a day, as patients tolerated it. Patients were seen at 2, 4, and 6 weeks; at 6 months and then every 4 months. Primary end point for each sub-trial was heart-related death or CHF hospitalization. Primary outcome for the overall program (CHARM-Overall) was all-cause death. CHARM included 7,601 CHFers. Patients with kidney failure, high potassium, high blood pressure, heart attack, stroke, or open-heart surgery in the previous 4 weeks were not included in the trial. Patients were being treated with standard therapy including beta-blockers, diuretics, digoxin (Lanoxin), Aldactone (spironolactone), and sometimes ACE inhibitors, at close to target doses.

CHARM-ALTERNATIVE
CHARM-Alternative included 2,028 CHFers who did not tolerate ACE inhibitors. They got standard therapy, or standard therapy plus candesartan. The most common reasons for ACE inhibitor intolerance was cough (72%), low blood pressure (13%), and kidney dysfunction (12%). Candesartan reduced relative risk of heart-related death or CHF hospitalization 23%. This is similar to the risk reduction seen in the SOLVD ACE inhibitor trial. With an average follow-up of 34 months, 33% of candesartan patients had reached the end point versus 40% of placebo patients. That means you need to treat 14 patients with candesartan to prevent one patient from having heart-related death or CHF hospitalization. Candesartan was well tolerated by these ACE inhibitor-intolerant patients: 22% dropped out versus 19% of placebo patients. Four percent of candesartan patients stopped taking the drug due to low blood pressure versus 1% of placebo patients, decreased kidney function (6% versus 3%), and high potassium levels (2% versus 0.3%). Angioedema was rare in CHARM-Alternative, with only one of 39 patients with a history of it having an episode that made them quit taking candesartan. So angioedema on an ACE inhibitor should not prevent a CHFer from trying an ARB.

CHARM-ADDED
CHARM-Added included 2,548 CHFers taking an ACE inhibitor. Ninety-six percent were at target dose. Fifty-five percent were also taking a beta-blocker and 17% took spironolactone. Candesartan reduced relative risk of heart-related death or CHF hospital admission 15%. With an average 41 months followup, primary end point was reached in 42% of placebo patients and 38% of candesartan patients. There were relatively few side effects when the ARB was added to ACE inhibitor therapy. However, blood potassium level and kidney function need to be monitored. Eight percent of candesartan patients stopped due to worsening kidney function versus 4% of placebo patients. Three percent withdrew due to low potassium levels versus less than 1% of placebo patients.

CHARM-PRESERVED
CHARM-Preserved included 3,023 CHFers. The lead researcher for this sub-trial said that although almost half of all CHFers seen in the "real world" have normal LV systolic function, there are few trials done with just these patients - diastolic heart failure. After an average 37 months follow-up, there was no difference in risk of heart-related death, but fewer candesartan patients were hospitalized for CHF (402) than placebo patients (566). A 40% relative risk reduction was seen in development of new diabetes in candesartan patients. This is similar to the HOPE and LIFE trials and suggests that blocking the renin-angiotensin system with ACE inhibitors or ARBs helps prevent diabetes.

CHARM-OVERALL
Summarizing CHARM-Overall, Dr. Marc Pfeffer said that after an average follow-up of 38 months, analyzing the 3 studies showed a 9% relative reduction in all-cause death. In absolute terms, that is 23% of patients dying versus 25% in the placebo group. With candesartan, relative risk of heart-related death was reduced 12%, hospital admission for CHF 21%, and combined heartrelated death or hospital admission for CHF 16%. These results were similar in men and women, and in CHFers of all ages. Benefit was seen when added to current therapy of ACE inhibitors and beta-blockers. This means that 23 patients need to take candesartan for 3 years in order to prevent one heart-related death or CHF hospitalization. CHARM-Overall showed that candesartan did not greatly reduce risk of heart attack, stroke, or need for procedures like bypass or angioplasty, but new-onset diabetes was reduced (163 cases or 6%) versus placebo (202 or 7%). In CHARM-Overall, candesartan did cause low blood pressure in 4% of CHFers versus 2% of placebo patients, reduced kidney function in 6% versus 3% of placebo patients, and high potassium level in 2% versus less than 1%. This shows that ARB patients need routine blood testing.

What Does It Mean?

Dr. Philip Poole-Wilson was invited by the European Cardiology Society to interpret CHARM results. He said that before CHARM, ELITE II showed no real differences between an ARB (losartan) and an ACE inhibitor (captopril), except that significantly fewer patients on the ARB stopped treatment due to side effects. (Jon's Note - Captopril may not be the best ACE inhibitor to use in such studies.) Dr. Poole-Wilson said the results of CHARM-Added were "reasonably convincing." He believes adding candesartan to other CHF meds will benefit patients. "The only problem," he said, "is that this is the 8th drug heart failure patients are going to be taking." Proper doses and drug combinations are becoming tough to figure. (Jon's Note - it's getting too expensive to afford as well!) Dr. Poole-Wilson Dr. Poole-Wilson cited 4 points from CHARM that he considers important: 1. CHARM-Overall showed an increase in fatal cancer, but this was probably due to chance. 2. CHARM-Added showed benefit in patients already on a beta-blocker and an ACE inhibitor. This contradicts ValHeFT. 3. CHARM-Added showed benefit in patients on target dose of an ACE inhibitor, so the ARB benefit isn't because patients were not taking a high enough dose of ACE inhibitor. 4. CHARM-Alternative found only one case of angioedema on candesartan in the 39 patients intolerant of ACE inhibitors because of angioedema. Source: Medscape Title: CHARM: Candesartan in Heart Failure - Assessment of Reduction in Mortality and Morbidity. Author: Linda Brookes, MSc.

ARB Plus ACE Inhibitor FDA-Approved For Heart Failure

May 19, 2005 - Adding the ARB Atacand (candesartan cilexetil) to ACE inhibitor therapy was FDA approved May 18, 2005 for treating class 2 to class 4 CHFers. The official recommendation is for CHFers with an EF of 40% or less. This came from CHARM-Added trial results. The ARB was already FDA-approved for CHFers who can't tolerate ACE inhibitors, based on another part of the CHARM trial called CHARM-Alternative. When used with an ACE inhibitor for heart failure, Atacand's dose is FDA-recommended to start at 4 mg once a day and rise to a target dose of 32 mg once a day. Source: www.fda.gov/cder/foi/label/2005/020838s022lbl.pdf Source: www.fda.gov/cder/foi/appletter/2005/020838s022ltr.pdf Source: Heartwire.
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 Jon C.

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