References for Medications

Treatment: Medications references

The medications below are considered beneficial for all patients with heart failure, including women unless future research proves otherwise. Any information that appears discouraging should be interpreted with caution since studies involving women have been quite limited. The intention of this review is to recognize how little research has been done with women and heart failure, and to encourage more research specifically for women so that women continue to receive the best care. Please review this information with your physician to assist in planning your treatment. Most patients require a combination of these drugs:

• Angiotensin Converting Enzyme Inhibitors
• Angiotensin Receptor Blockers
• Aldosterone Antagonists
• Digoxin
• Isorbide Dinitrate and Hydralazine
• ß-blockers
• Anticoagulation
• Diuretics
• Herbal or other nutritional supplements

Angiotensin Converting Enzyme Inhibitors

(i.e enalapril, captopril)

Angiotensin Converting Enzyme Inhibitors (ACE I) have been shown in men to improve survival and reduce hospitalization. However, the benefits in women remain unclear and may only be present if patients are symptomatic ¹. Data combining 30 ACE I studies involving a total of 1,587 women with heart failure demonstrated a trend towards improved survival in the group taking ACE I compared to those not taking the drug (13.4% death with use of ACE I vs 20.1% death without ACE I) and a favorable trend in the combined endpoint of survival and hospitalization in the group of women taking an ACE I (20.2% vs 29.5%). ² Another meta-analysis involving 2,373 women revealed similar trends. ¹ However, there is some doubt regarding the actual benefit of the drug since both studies had wide confidence intervals that crossed 1.0.

Angiotensin Receptor Blockers

(i.e. Candesartan, Valsartan)

Angiotensin Receptor Blockers (ARBs) are often used by heart failure patients when they do not tolerate an angiotensin converting enzyme inhibitor (ACE I). However, candesartan was found recently to be safe for symptomatic heart failure patients when added to an ACE I. Both men and women with weak hearts (left ventricular ejection fraction (LVEF) < 40%) had improved survival and reduced hospitalization for heart failure with usage of candesartan +/- an ACE I. ¹ Unfortunately, in the subgroup of women (1,212 women) with relatively preserved heart function LVEF > 40%) the data was not analyzed with regard to gender ^1,2. Although other ARBs have been studied, the benefit in women remains unclear because of wide confidence intervals and hazard ratios crossing 1.0 ^3,4.

1. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S; CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003 Sep 6;362(9386):759-66.
2. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003 Sep 6;362(9386):777-81.
3. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001 Dec 6;345(23):1667-75. Summary for patients in: J Card Fail. 2002 Apr;8(2):56-8.
4. Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, Konstam MA, Riegger G, Klinger GH, Neaton J, Sharma D, Thiyagarajan B. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial--the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000 May 6;355(9215):1582-7.

Aldosterone Antagonists

There are two drugs available which are aldosterone antagonists: spironolactone and eplerenone. Both appear to be beneficial in women based on one study for each drug. In the RALES study which analyzed 446 women participants retrospectively, women lived longer with usage of spironolactone. The women participants had very weak hearts (i.e.. left ventricular systolic ejection fraction < 35%) and moderate to severe symptoms (NYHA class IIII or IV). Spironolactone was used in that study as therapy for chronic heart failure from many different causes including old heart attacks and those with weak hearts of unknown cause. ¹ In the EPHESUS study, eplerenone was used in a very select population which included 1918 women. All patients were given the drug 3-14 days after a heart attack if their heart function was weak (i.e.. left ventricular systolic ejection fraction < 40%) and they had signs of heart failure. The women participants taking eplerenone had a better survival than those not using the study drug. However, the EPHESUS study did not clearly show a benefit in women using eplerenone for the combined endpoint of preventing hospitalization for heart disease and death specifically due to heart disease. (i.e.. wide confidence interval and hazard ratio crossing 1.0) ²

1. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. NEJM. 1999; 341: 709-717.
2. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. NEJM. 2003. 348: 1309-1320.*

Digoxin

There is very little data regarding the usage of digoxin in women with heart failure. One study (Digitalis Investigation Group trial, DIG) suggested a higher rate of death in women with weak hearts (1,519 women with left ventricular ejection fraction < 45%) ¹ but no increased risk of death with normal heart function (405 women) ². Interpreting this data should be done with great caution since there are many limitations with the design of this study.

1. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure NEJM. 2002; 347: 1403-1411.
2. Jones RC, Francis GS, Lauer MS. Predictors of mortality in patients with heart failure and preserved systolic function in the Digitalis Investigation Group trial. J Am Coll Cardiol. 2004 Sep 1;44(5):1025-9.

Isosorbide Dinitrate and Hydralazine

There is insufficient data to comment on the use of the drug combination of isosorbide dinitrate and hydralazine for women with heart failure. The initial studies evaluating hydralazine and isosorbide dinitrate in patients with heart failure (Veterans Administration Cooperative Study I, II, and III) excluded women from the trials ^1,2,3. Recently an article was published regarding the beneficial use of hydralazine and isosorbide dinitrate in African American heart failure patients which included 40% women. The African American patients had moderate to severe heart failure symptoms and either a significantly weak heart (LVEF < 35%) or a heart with significant dilation and some degree of weakness (LVEF <45%) ⁴ . The combination drug (hydralazine/isordil) was shown to improve survival for the group but, the data specific for women has not been published yet. ⁴

1. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. NEJM. 1986; 314: 1547-1552.*
2. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G, Shabetai R, Haakenson C. A Comparison of Enalapril with Hydralazine-Isosorbide Dinitrate in the Treatment of Chronic Congestive Heart Failure. NEJM. 1991; 325: 303-310.*
3. Cohn J, Ziesche S, Smith R, Anand I, Dunkman B, Loeb H, Cintron G, Boden W, Baruch L, Rochin P, Loss L,. Effect of the Calcium Antagonist Felodipine as Supplementary Vasodilator Therapy in Patients with Chronic Heart Failure Treated with Enalapril. Circulation. 1997; 96:856-863.*
4. Taylor Anne, Ziesche S, Yancy C, Carson P, D'Argostino R, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn J. Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure. NEJM. 2004; 351: 2049-2057.*

ß-blockers

(i.e.. metoprolol XL, carvedilol)

ß-blockers when added to an angiotensin converting enzyme inhibitor appear to be beneficial in women with heart failure. For instance, bisoprolol which is a ß1-selective adrenergic antagonist significantly improved survival in the 515 women studied with weak hearts (left ventricular ejection fraction (LVEF) < 35%) and moderate to severe symptoms (NYHA class III or IV). ¹ Metoprolol CR/XL which is a less potent but still ß1-selective adrenergic antagonist reduced hospitalization for heart failure by 42% (P=0.021) in the 898 women studied with weak hearts (LVEF < 40%) and moderate to severe symptoms (NYHA class III or IV). This effect was even more dramatic (72% reductions in hospitalization for heart failure) in the subgroup of women (183 patients) with severely weak hearts (LVEF < 25%). ² And finally, carvedilol which is a non-selective ß-adrenergic antagonist with a-blocking and anti-oxidant properties reduced the combined endpoint of death or hospitalization in the 469 women studied with severely weak hearts (LVEF < 25%) and severe symptoms. ³ Combining the data of all the ß-blocker studies reviewed above (1-3) revealed a survival benefit for women similar to men (RR 0.69; 95% CI 0.51-0.93 in women vs. RR 0.66; 95% CI 0.58-0.75).

1. Tabassome Simon, Murielle Mary-Krause, Christian Funck-Brentano, and Patrice Jaillon. Sex Differences in the Prognosis of Congestive Heart Failure : Results From the Cardiac Insufficiency Bisoprolol Study (CIBIS II) Circulation. 2001; 103: 375-380.
2. Jalal K. Ghali, Ileana L. Piña, Stephen S. Gottlieb, Prakash C. Deedwania, and John C. Wikstrand. Metoprolol CR/XL in Female Patients With Heart Failure: Analysis of the Experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF). Circulation. 2002; 105: 1585-1591
3. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL; Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. NEJM. 2001; 344: 1651-1658.

Anticoagulation

There is a concern that women with weak hearts (LVEF < 35%) have an increase risk compared to men of developing blood clots which then dislodge (called thromboembolism) to the brain (stroke), lungs (pulmonary embolism), or arms/legs (peripheral embolism). This risk is still very low and is based on one study (SOLVD trial) which reviewed the number of thromboembolic events retrospectively in men and women with weak hearts and normal heart rhythm. Although women had a higher tendency to develop strokes, pulmonary embolisms, and peripheral embolisms, they were also less likely then men to be taking blood thinners (i.e. aspirin, plavix, coumadin) at the start of the study. In fact the usage of aspirin significantly reduced the likelihood of a women having a thromboembolic event. ¹

1. Dries DL, Rosenberg YD, Waclawiw MA, Domanski MJ. Ejection fraction and risk of thromboembolic events in patients with systolic dysfunction and sinus rhythm: evidence for gender differences in the studies of left ventricular dysfunction trials. J Am Coll Cardiol. 1997 Apr;29(5):1074-80.

Diuretics

There is not enough data to comment on the usage of diuretics (i.e.. Lasix, hydrochlorothiazide) in women with heart failure except for spironolactone which appears to be beneficial. (See Spironolactone). At this time diuretics are used for symptoms and have not been proven to increase survival.

Herbal or other nutritional supplements

Do not take herbals or other nutritional supplements without talking to your physician.

A note about medications:

Check the drug search to find out more about your medications. It is important to know:

• the names of your medications
• what they are for
• how often and at what times to take them.

Keep a list of your medications and bring them to each of your doctor visits.

Never stop taking your medications without discussing it with your doctor. Even if you have no symptoms, your medications decrease the work of your heart so that it can pump more effectively.

• Find a Cleveland Clinic heart doctor who specializes in heart failure in women

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written with Dr. Eileen Hsich, specialist in Women & Heart Failure