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VOL 47: MARCH • MARS 2001Canadian Family PhysicianLe Médecin de famille canadien 499

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défi clinique clinical challenge

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Just the Berries

clinical challenge

défi clinique

Management of heart failure

Leslie Ruggles, MD

H

eart failure (HF) is associated with very high morbidity and mor tality. Until recently, patients with HF were managed with a combination of digoxin and diuretics. These drugs alleviated symptoms but were not shown to affect mortality.

In the last 10 years, many studies have shown evi- dence of decreased mortality among patients with HF using new (angiotensin II–converting enzyme [ACE] inhibitors, angiotensin I– or II–receptor blockers) and old (spironolactone, hydralazine, and nitrates) classes of drugs, as well as drugs previ- ously thought to be contraindicated (β-blockers).

A MEDLINE search using “heart failure” and the subheading “drug therapy” looked for large (> 1000 patients, where possible) double-blind, controlled studies. Those found were supplement- ed from the reference lists of previously published articles. This article discusses drugs considered to be standard of care in management of systolic hear t failure. Where applicable, the New York Heart Association (NYHA) classification for indi- cations for specific drug classes is noted.

This article will deal solely with systolic dys- function (left ventricular ejection fraction [LVEF]

< 40%); HF will refer only to systolic heart failure.

We know that patients with HF develop compen- sator y mechanisms in response to low cardiac output. The sympa-

thetic nervous system is activated, as is the r e n i n - a n g i o t e n s i n - aldosterone system.

Such activation even- tually worsens the load on the heart and worsens the HF. Most current therapies are aimed at these com- pensator y systems.1

Angiotensin II–converting enzyme inhibitors

Many trials2-4have produced level 1 evidence that ACE inhibitors significantly reduce mortality in HF. All patients with preser ved renal function should be started on ACE inhibitors. It is impor- tant to tr y to reach target doses (Table 1) for maximum benefit. These patients can often toler- ate a systolic blood pressure (BP) of 80 to 90 mm Hg. Serum creatinine and potassium levels should be checked before and 1 week after start- ing the drug because only small non-progressive elevations in levels are acceptable; creatinine should be kept lower than 220 µmol/L.

A recent review of the Studies of Left Ventricular Dysfunction5 database revealed that use of enalapril was associated with a 33% increase in risk of poorer renal function (increase in creati- nine of < 45 µmol/L). Diabetes, older age, and use of diuretics increased risk in all patients (treated and placebo). Enalapril, however, appeared to be renoprotective in diabetic patients. β-Blockade and increased ejection fraction were renoprotective in all patients.

-Adrenergic blockers

Patients with NYHA Class II or III HF who have been stable for at least 4 weeks should con- sider, based on level 1 evidence from two tri- als,6,7cautious intro- duction of a β-blocker to counteract the effects of an activated sympathetic ner vous system. Initially, patients will have a small drop in LVEF

“Just the Berries” for Family Physicians originated at St Martha’s Regional Hospital in 1991 as a newsletter for members of the Department of Family Medicine. Its purpose was to provide useful, practical, and current informa- tion to busy family physicians. It is now distributed by the Medical Society of Nova Scotia to all family physicians in Nova Scotia. Topics discussed are suggested by family physicians and, in many cases, articles are researched and written by family physicians.

Just the Berries has been available on the Internet for the past 3 years.

You can find it at www.theberries.ns.ca.Visit the site and browse the Archives and the Berries of the Week. We are always looking for articles on topics of interest to family physicians. If you are interested in contribut- ing an article, contact us through the site. Articles should be short (350 to 1200 words), must be referenced, and must include levels of evidence and the resources searched for the data. All articles will be peer reviewed before publication.

Dr Ruggles is a family physician at St Martha’s Regional Hospital in Antigonish, NS. She spends a good deal of her time in the emergency room.

FOR PRESCRIBING INFORMATION SEE PAGE 648

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500 Canadian Family PhysicianLe Médecin de famille canadienVOL 47: MARCH • MARS 2001

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and consequently might deteriorate in the first 1 or 2 months. Car vedilol, a third-generation β-blocker and the drug first studied,6has mostly β-adrenergic effects but also some α-adrenergic effects and is an antioxidant as well. All-cause mor tality was decreased by 65% (from 7.8% to 3.2%)in that trial.

Subsequently, metoprolol, a second-generation β-blocker with mostly β-adrenergic effects and no antioxidant effect, has also been shown to benefit patients with NYHA Class II to IV HF.7 All-cause mortality was decreased by 34% (Table 1).

Aldosterone receptor blocker (spironolactone)

Recently, the Randomized Aldactone Evaluation Study (RALES)8has produced level 1 evidence that adding merely 25 mg of spironolactone to a regimen involving ACE inhibitors, with or without digoxin or furosemide, improves the sur vival rate of patients with NYHA Class III and IV HF with a significant reduction in deaths (30%) from HF and sudden death. We now believe that ACE inhibition does not entirely suppress production of aldosterone, which af fects atrial natriuretic peptide levels, causes myocardial fibrosis, and damages the vascular sys- tem. Spironolactone’s benefits are likely due to blocking these processes.

Patients with moderate to severe HF should be taking spir onolactone even if diur esis is not required. Creatinine levels higher than 220 µmol/L or potassium levels higher than 5.0 mmol/L are contraindications. Gynecomastia is the most com- mon side effect. Serum potassium levels should be monitored, although this was not found to be a problem at study doses. Loop diuretics can be titrat- ed accordingly.

The small subset of patients taking β-blockers upon entry into this trial did not show benefit (level 2 evidence), although the trial might not have gone on long enough to demonstrate it. The trial was discon- tinued early because of the decrease in mortality of the whole spironolactone group (Table 1).

Hydralazine and nitrates

If patients have renal dysfunction and, therefore, can- not take ACE inhibitors, then a combination of hydralazine and isosorbide dinitrate decreases mor- tality rates (as shown by level 1 evidence from the Vasodilator in Heart Failure Trials9), although not to the same degree as ACE inhibitors do.4 The four

times daily dosing regimen could af fect some patients’ compliance (Table 1).

Angiotensin I– or II–receptor blockers

If renal function is preserved and patients are intoler- ant of ACE inhibitors (usually because of cough or Table 1.Target doses

DRUG NAME DOSAGE

ANGIOTENSIN II–CONVERTING ENZYME INHIBITORS

Captopril (Capoten) 50 mg thrice daily Enalapril (Vasotec) 10 mg twice daily Fosinopril (Monopril) 30 mg once daily Lisinopril (Zestril, Prinivil) 10-40 mg once daily5 Perindopril (Coversyl) 8 mg once daily Quinapril (Accupril) 40 mg once daily Ramipril (Altace) 10 mg once daily -ADRENERGIC BLOCKERS

Carvedilol (Coreg) 3.125 mg twice daily titrated (doubled) every 4 weeks to a target dose of 25 mg twice daily Metoprolol XL/CR (Betaloc,

Lopresor)

12.5-25 mg titrated to 200 mg once daily ALDOSTERONE RECEPTOR BLOCKER

Spironolactone (Aldactone) 25 mg once daily. Dose was titrated to 50 mg at 8 weeks if diuresis was required

HYDRALAZINE OR NITRATES

Hydralazine (Apresoline) 75 mg four times daily Isosorbide dinitrate (Isordil) 40 mg four times daily ANGIOTENSIN I– OR II–RECEPTOR BLOCKERS

Candesartan (Atacand) 16 mg once daily Irbesartan (Avapro) 160 mg once daily Losartan (Cozaar) 100 mg once daily Valsartan (Diovan) 300 mg once daily

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VOL 47: MARCH • MARS 2001Canadian Family PhysicianLe Médecin de famille canadien 501

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angioedema), angiotensin I– or II–receptor blockers (ARB) are a good alternative. Each of these drugs blocks one of the seven known angiotensin receptors (either receptor 1 or 2). They have no effect on the bradykinin system so do not cause cough.

Small studies such as the Evaluation of Losartan in the Elderly (ELITE) trial involving 722 patients10 provide level 2 evidence that losartan and captopril have equivalent effects (losartan has marginally bet- ter outcomes). There are, however, many large trials with overwhelming evidence supporting use of ACE inhibitors. Therefore, until further studies back up ARB trials, patients with a nuisance cough should be encouraged to continue taking their ACE inhibitors.

If they cannot tolerate the cough, switching to an ARB is appropriate. Ver y small studies11suggest a benefit in adding an ARB to maximal ACE inhibition to more completely suppress the renin-angiotensin- aldosterone system (Table 1).

Loop diuretics and digoxin

These medications have not been shown to reduce mortality, but can be used effectively for relief of acute or chronic symptoms. Proper dosing with loop diuretics is important to resolve edema and improve symptoms. Underdosing reduces the efficacy of ACE inhibitors and increases risk of β-blocker side ef fects. Overdosing can lead to ar rhythmias if digoxin is used. Digoxin is especially useful for patients with atrial fibrillation. As ACE inhibitors and spironolactone are used and titrated to target doses, loop diuretics can be decreased; serum potassium should be monitored closely.

Acetysalicylic acid and warfarin

All patients with HF should receive 325 mg of ASA once daily for cardioprotection. Rapid atrial fibrilla- tion should be treated quickly because these patients need their atrial kick and do not tolerate rapid heart rates. Atrial fibrillation is common; patients who have it should receive anticoagulation therapy with war- farin to attain an international normalized ratio (INR) of 2.0 to 3.0.

Patients with HF have comorbid diseases, and risk reduction with management of diabetes, lipids, and ischemia has positive ef fects on the hear t.

Patients should be made aware of the signs of wors- ening HF (increased fatigue, dyspnea, ankle swelling, weight gain); of the impor tance of diet, daily weight monitoring, medication compliance, and limitation of alcohol; and of the benefits of staying physically active. Understanding that the numerous, often expensive medications should both make them feel better and improve sur vival might help to increase their compliance.

Acknowledgment

We thank the cardiologists at the Queen Elizabeth II Health Sciences Centre in Halifax, NS, for reviewing the draft of this article.

References

1. Cohn JN. Drug therapy: the management of congestive heart failure. N Engl J Med1996;335:490-8.

2. Pleffer MA, SAVE study group. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1992;327:669-77.

3. The SOLVD investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.

4. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, et al. A comparison of enalapril with hydralazine–isosorbide dinitrate in the treatment of chronic con- gestive heart failure. N Engl J Med 1991;325:303-10.

5. Knight EL, Glynn RJ, McIntyre KM, Mogun II, Avorn J. Predictors of decreased renal function in patients with heart failure during angiotensin-converting enzyme inhibitor therapy: results from the studies of left ventricular dysfunction.

Am Heart J1999;138(5 pt 1):849-55.

6. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart fail- ure. US Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349-55.

7. Goldstein S, Hjalmarson A. The mortality effect of metoprolol CR/XL in patients with heart failure; results of the MERIT HF Trial. Clin Cardiol 1999;22 (Suppl 5):30-5.

8. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure.

Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-17.

9. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FF, et al.

Effect of vasodilator therapy on mortality in chronic congestive heart failure.

Results of a Veterans Administrative Cooperative Study. N Engl J Med 1986;

314:1547-52.

10. Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, et al.

Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997;349:747-52.

11. Hamroff G, Katz SD, Mancini D, Blaufarb I, Bijou R, Patel R, et al. Addition of angiotensin II receptor blockade to maximal angiotensin-converting enzyme inhi- bition improves exercise capacity in patients with severe congestive heart failure.

Circulation1999;99(8):990-2.

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