(1)
University of Ottawa The Ottawa Hospital, Ottawa, ON, Canada
The Size of the Problem
The world faces an epidemic of heart failure (HF). The plague of HF is common in developed and in developing countries.
Although treatment strategies have improved considerably over the past two decades, improvement in outcomes remains modest and the incidence of HF is increasing. Some of this increase is owing to an aging population in all countries and poor choice of optimal medications, particularly a reliance on angiotensin-receptor blockers (ARBs). In Val-HeFT, “valsartan when combined with a beta blocker caused significantly more cardiac events” (Val-HeFT, Cohn, and Tognoni 2001).
In patients with HF, a beta-blocker is needed as proven therapy. Thus an ACE inhibitor must be used, not an ARB; importantly, telmisartan failed in the HF trial. Telmisartan therapy for 56 months, although shown in ONTARGET to be equivalent to ramipril surprisingly, failed to decrease total mortality and had no significant effect on the primary outcome, hospitalizations for HF (TRANSCEND). See further discussion of ARB failures in HF randomized control trials (RCTs).
Caution: valsartan must not be combined with a beta-blocker.
In VALIANT (Pfeffer et al. 2003): a clinical trial of valsartan, captopril, or both in MI complicated by HF, left ventricular dysfunction, or both, during a median follow-up of 24.7 months, total mortality was not reduced by valsartan: 979 patients in the valsartan group died, as did 941 patients in the valsartan-and-captopril group and 958 patients in the captopril group. There was no placebo group.
Caution: Valsartan is not advisable in HF patients because in this large number of patients a beta-blocker is needed therapy.
Although medical therapy for acute HF has improved dramatically from 1990, unfortunately, more than 45 % of patients require readmission within 6 months of discharge.
A major advance may be on its way: a novel drug, LCZ696, a dual inhibitor of angiotensin II receptor and neprilysin proved to be more effective than enalapril, (Jessup 2014). Our current drugs are not used adequately. For example:
1.
Digoxin has been shown to significantly reduce readmissions and decreases mortality in patients with cardiomegaly or EF < 35 %, and is useful in most HF patients with atrial fibrillation, yet the drug is rarely used because of fear of digoxin toxicity, a complication that can be completely avoided by a watchful physician (see discussion under digoxin).
About 20 % of patients would not be able to use digoxin because of renal failure (GFR < 40 ml/min). More than 70 % of patients, however, can be given digoxin, but worldwide <15 % receive a useful inexpensive drug because of poor logic amongst those experts who formulate guidelines or prepare editorials.
Only those who had the pleasure of carefully dissecting the digoxin trial results and hearing an S3 gallop disappear after 3–4 days of digoxin administration would understand the salutary myocardial effects of this simple drug. Deaths and rehospitalizations continue with much outcry about health cost of HF.
Digoxin is best suited for the multitude of hearts that are genuinely failing with an ejection fraction (EF) < 40 % or with manifested mild or moderate cardiomegaly. In this large subset of patients worldwide, digoxin can be an asset to prevent some deaths but definitely prevent rehospitalization if used along with a beta-blocker and ACE inhibitor. Rosuvastatin in CORONA did not alter mortality and had a small significant effect in preventing rehospitalization; this is considered a breakthrough (Rogers et al. 2014).
Since the downfall of digoxin during the past 20 years inotropes have been developed and much research is presently under way. Yet none has emerged to save more than a few lives (see section entitled “New Developments”.) A new novel intravenous inotropic agent would have little impact on lives saved because that subset of nearly terminally ill patients require compassionate care and a transplant in some.
2.
Spironolactone and eplerenone are proven effective for selected patients, but the agents are rarely prescribed because of the fear of hyperkalemia. This complication can be prevented by a watchful clinician. More than 40 % of patients can be treated with these agents but <20 % receive them. If the patient is stable and free from pulmonary congestion, ACE inhibitor or ARB dose should be slightly reduced prior to discharge to allow the maintenance of an aldosterone antagonist.
Spironolactone and ACE inhibitors or ARBs, however, have been shown to be noneffective for HF with preserved EF (HFPEF), a large subset of HF patients in whom no decisive therapy is available.
Digoxin and nebivolol are the two agents that have shown some salutary effects, but this information remains hidden
3.
4.
Beta-blockers are proven to be most effective and equal to ACE inhibitor therapy, yet many patients are denied for various reasons, particularly a fear for beta-blocker use in the elderly. But HF is a disease of the elderly age over 65.
In addition the correct choice of a beta-blocking drug is crucial: carvedilol, bisoprolol, and nebivolol are the beta-blockers to choose; also (metoprolol succinate (Toprol XL) if available).
Atenolol is commonly used worldwide but is not recommended by the author (see Chap. 1 for reasons).
5.
Furosemide dosing is often inadequate: a single dose of 160 mg on an empty stomach is more effective than 80 mg twice daily (see Chap. 7). Salutary effects are much enhanced with the addition of spironolactone, eplerenone, or amiloride and in selected cases metolazone. The combination of furosemide and metolazone decreases hyperkalemia when an aldosterone antagonist is added to the HF regimen. See later section under Diuretics.
6.
Metolazone has a role in patients with a GFR < 50, and is underused.
7.
Acetazolamide is rarely indicated and proved useful in patients with refractory HF complicated by diuretic-induced normokalemic hypochloremic metabolic alkalosis (Khan 1980).
Prevention of HF is crucial, and physician education concerning the most appropriate drug cocktail to prescribe is vital.
Causes of Heart Failure
The many diseases causing HF must be sought (see Table 12-1) and treated aggressively prior to symptomatic HF.
Table 12-1
Causes of systolic heart failure and diastolic heart failure
Systolic heart failure |
Coronary heart disease ~40 %a |
Hypertensive heart disease ~40 % |
Valvular heart disease ~15 % |
Other causes ~5 % |
Diabetes |
Dilated cardiomyopathy |
Myocarditis |
Cardiotoxins |
Diastolic heart failure: HFPEF |
Left ventricular hypertrophy |
Hypertensive heart disease (systolic and diastolic HF) |
Chronic CHD |
Diabetes |
Myocardial fibrosis |
Cardiomyopathy |
Hypertrophic and restrictive |
Amyloid heart disease |
Sarcoidosis, Hemochromatosis, metabolic storage disease |
Hypertensive hypertrophic “Cardiomyopathy” of the elderly: aging heart (particularly woman) |
Arrhythmogenic right ventricular dysplasia |
Constrictive pericarditis, pericardial effusion, and tamponade |
Atrial myxoma |
Systolic dysfunction is a principal cause of diastolic dysfunction |
Basic Cause
Determine the basic cause of the heart disease. If the specific cause is present but is not recognized (e.g., surgically correctable causes: significant mitral regurgitation may be missed clinically; atrial-septal defect, arteriovenous fistula, constrictive pericarditis, and cardiac tamponade are important considerations), the possibility of achieving a complete cure, although rare, may be missed or the HF may become refractory.
Note: Pulmonary edema and HF are not complete diagnoses; the basic cause and precipitating factors should be stated.
The search for the etiology must be systematic, and the following routine check is suggested:
1.
Myocardial damage:
Ischemic heart disease and its complications
Myocarditis
Cardiomyopathy
2.
Ventricular overload:
Pressure overload.
(a)
Systemic hypertension
(b)
Coarctation of the aorta
(c)
Aortic stenosis
(d)
Pulmonary stenosis
Volume overload
(a)
Mitral regurgitation
(b)
Aortic regurgitation
(c)
Ventricular septal defect
(d)
Atrial-septal defect
(e)
Patent ductus arteriosus
3.
Restriction and obstruction to ventricular filling:
Mitral stenosis
Cardiac tamponade
Constrictive pericarditis
Restrictive cardiomyopathies
Atrial myxoma
4.
Cor pulmonale
5.
Others:
Arteriovenous fistula
Thyrotoxicosis
Myxedema
Factors precipitating heart failure:
1.
Patient–physician problems:
Reduction or discontinuation of medications
Salt binge
Increased physical or mental stress
Obesity
2.
Increased cardiac work precipitated by:
Increasing hypertension (systemic or pulmonary)
Arrhythmia; digoxin toxicity
Pulmonary embolism
Infection, e.g., bacterial endocarditis, chest, urinary, or others
Thyrotoxicosis or myxedema
3.
Progression or complications of the basic underlying heart disease:
Ischemic heart disease—acute MI, left ventricular aneurysm, papillary muscle dysfunction causing mitral regurgitation
Valvular heart disease—increased stenosis or regurgitation
4.
Blood problems:
Increased volume—transfusions of saline or blood
Decreased volume—overzealous use of diuretics
Anemia: hemoglobin in cardiacs <10 g/100 mL (100 g/L)
Electrolytes and acid–base problems (potassium, chloride, magnesium)
5.
Drugs that affect cardiac performance and may precipitate HF:
Nonsteroidal anti-inflammatory drugs (NSAIDs):
Alpha-blockers are contraindicated all patients at risk for heart failure
Beta-blockers: uncommon if used appropriately
Corticosteroids
Disopyramide, procainamide
Calcium antagonists: verapamil, diltiazem, nifedipine, and amlodipine commonly used to treat hypertension (see Table 9-2)
Digitalis toxicity
Vasodilators and antihypertensive agents that cause sodium and water retention. These agents are further likely to precipitate HF if they cause an inhibition of increase in heart rate, which is especially important in patients with severe bradycardia or sick sinus syndrome.
Drugs that increase afterload and increase blood pressure
Adriamycin, daunorubicin, and mithramycin
Alcohol, acute excess (e.g., 8 oz of gin in a period of less than 2 h causes cardiac depression and a fall in the ejection fraction [EF]).
Antidepressants: tricyclic compounds
Ephedra can cause HF
Diagnosis
1.
Ensure that the diagnosis is correct by critically reviewing the history, physical exam, and posteroanterior (PA) and lateral chest radiographs. Many patients are incorrectly treated for HF on the basis of the presence of crepitations at the lung bases or peripheral edema. Crepitations may be present in the absence of HF and may be absent with definite LV failure. Edema is commonly owing to causes other than cardiac. The chest radiograph may be positive before the appearance of crepitations. Edema or raised jugular venous pressure (JVP) may be absent or incorrectly assessed.
2.
Chest radiograph confirms the clinical diagnosis. It is most important to recognize the radiologic findings of HF, listed as follows:
Obvious constriction of the lower lobe vessels and dilation of the upper vessels related to pulmonary venous hypertension are commonly seen in left HF, in mitral stenosis, and occasionally with severe chronic obstructive pulmonary disease (COPD).
Interstitial pulmonary edema: pulmonary clouding; perihilar haze; perivascular or peribronchiolar cuffing; septal Kerley A lines and more commonly B lines.
Effusions, subpleural or free pleural; blunting of the costophrenic angle, right greater than left.
Alveolar pulmonary edema (butterfly pattern).
Interlobar fissure thickening related to accumulation of fluid (best seen in the lateral film).
Dilation of the central right and left pulmonary arteries. A right descending pulmonary artery diameter >17 mm (normal 9–16 mm) indicates an increase in pulmonary artery pressure.
Cardiac size: cardiomegaly is common; however, a normal heart size can be found in several conditions causing definite HF:
(a)
Acute myocardial infarction (MI).
(b)
Mitral stenosis.
(c)
Aortic stenosis.
(d)
Acute aortic regurgitation.
(e)
Cor pulmonale.
Cardiomegaly lends support to the diagnosis, severity, and etiology of HF but has been overrated in the past. Such phrases as “no HF if the heart size on PA film is normal” are to be discarded. The heart size may be normal in the presence of severe cardiac pathology, that is, an LV aneurysm or repeated MIs that can cause hypokinetic, akinetic, or dyskinetic areas that may be observed on inspection of the chest wall but may not be detectable on PA chest radiographs. Echocardiography is often necessary as it provides the most useful information on the severity of valvular lesions, LV contractility, EF, and verification of causes of HF.
It is necessary to exclude radiologic mimics of cardiogenic pulmonary edema:
(a)
Circulatory overload.
(b)
Lung infection—viral and other pneumonias.
(c)
Allergic pulmonary edema: heroin and nitrofurantoin.
(d)
Lymphangitic carcinomatosis.
(e)
Uremia.
(f)
Inhalation of toxic substances.
(g)
Increased cerebrospinal fluid (CSF) pressure.
(h)
Drowning.
(i)
High altitude.
(j)
Alveolar proteinosis.
3.
BNP: Rapid testing of brain natriuretic peptide (BNP) in the emergency room helps differentiate cardiac from pulmonary causes of acute dyspnea and has proved useful (Maisel et al. 2002). The popularity of BNP or amino-terminal pro-BNP as an aid to the diagnosis of HF continues to increase.
4.
Echocardiography is the single most useful diagnostic test to evaluate the causes of HF and the heart function in patients confirmed to have HF clinically radiologically or by BNP (see Table 12-2). The echocardiographic measurement of EF carries a substantial error but is sufficient for patient management and comparison.
Table 12-2
Echocardiography, the most useful test to evaluate patients with proven heart failure
Asses left ventricular (LV) function and provide a sufficiently accurate ejection fraction (EF)a for guidance of therapy |
Screen for regional or global hypokinesis |
Gives accurate cardiac dimensions; replaces radiology for cardiac chamber dilation |
Assess regional LV wall motion abnormalities that indicate ischemia and significant coronary heart disease |
Asses hypertrophy, concentric or other |
Left atrial enlargement common with valvular heart disease and early sign of LV hypertrophy |
Assess valvular heart disease |
Congenital heart disease |
Diastolic dysfunction: assess after confirmation of normal systolic function and absence of valvular disease |
Pericardial disease, effusion, tamponade |
Myocardial disease |
In patients in whom it is crucial to obtain an accurate EF, a gated radionuclide study should be requested after the results of echocardiography, except in patients with atrial fibrillation. Echocardiography is the key investigation because correctable causes of HF such as valvular disease, pericardial, and other problems can be rapidly documented. Adequate information on LV function is provided, e.g., a poorly contractile ventricle, and fractional shortening should suffice. An EF < 45 % is in keeping with decreased LV systolic function. Values of 20–30–35–40–% have some meaning to those who are used to these numbers. Also, the numbers assist with reference to published articles that do not use fractional shortening. A radionuclide cardiac scan is more accurate for the determination of EF but does not evaluate hypertrophy or valvular, pericardial, and other diseases. The cost of a second test is not justifiable.
Pathophysiology
It is most important to have a clear knowledge of the pathophysiology of HF, in particular how LV work is dictated by systemic vascular resistance (SVR; see Fig. 12-1).
Fig. 12-1
Pathophysiology of heart failure.
Decrease neurohormonal activation; inhibition of the renin–angiotensin–aldosterone system.
Inhibit LV remodeling.
Improve myocardial hemodynamics.
Increase cardiac output to deliver oxygenated blood to vital organs and to meet the metabolic needs of the tissues, especially during normal activities and exercise.
The cardiac output (CO) is reduced and filling pressure is increased. The low CO results in a number of compensatory responses, as outlined in Fig. 12-1.
The following definitions are relevant:
Cardiac output = stroke volume × heart rate (HR). Stroke volume is a reflection of preload (filling pressure), myocardial contractility, and afterload (arterial impedance).
LV work and myocardial oxygen consumption depend on
(a)
HR × blood pressure (BP) (rate-pressure product).
(b)
BP = cardiac output × SVR.
The resistance or arterial impedance (afterload) against which the left ventricle must eject is an important determinant of LV workload. A reduced SVR requires less energy and less force of myocardial contraction to produce an increase in stroke volume.
SVR is automatically increased early in the development of HF and remains unchanged or increases with increasing HF. This reaction is a necessity and is a normal compensatory adjustment to maintain blood pressure and vascular homeostasis.
The compensatory adjustments are initiated by:
Sympathetic stimulation that causes an increase in
(a)
Heart rate
(b)
The force of myocardial contraction
(c)
SVR
Activation of the renin–angiotensin–aldosterone system (RAAS), which causes
(a)
Intense arterial constriction and therefore an increase in SVR and blood pressure
(b)
An increase in aldosterone, which produces distal sodium and water retention
The important proximal tubular reabsorption of sodium is believed to be caused by a combination of the preceding points and other as yet undetermined mechanisms (see Fig. 12-1).
The renal response to a low CO in the normal subject is to maintain the blood pressure by causing vasoconstriction and sodium and water reabsorption (saline autotransfusion). We cannot expect the kidney to change its program when HF occurs. The kidney is behaving appropriately in the wrong circumstances. Clearly, we can prevent the kidney from carrying out its program only if we switch off the initiating cause of the renal reflex, that is, by increasing the cardiac output. Therefore, any drug that will increase CO will reduce the renal response and lower SVR and further improve CO. An alternative strategy is to reset the neurohormonal imbalance by the use of ACE inhibitors and aldosterone antagonists.
Note: Inotropic agents, digoxin or dobutamine, improve cardiac output and, therefore, cause a fall in SVR. Similar acting agents, but with minimal side effects, are needed.
Management Guide
Four golden rules dictate the efficient management of HF:
1.
Ensure that the diagnosis of HF is correct, eliminating conditions that may mimic HF.
2.
Determine and treat the basic cause of the heart disease. The rare surgical or medical cure is worth the effort.
3.
Search for the precipitating factors; remove or treat and prevent their recurrence to avoid further episodes of HF. Withdraw drugs known to worsen HF: NSAIDs and notably calcium antagonists commonly administered to patients with hypertension and CHD.
4.
The specific treatment of HF requires sound and up-to-date knowledge of the pathophysiology of HF and the actions, indications, and side effects of the pharmacologic agents used in its management.
Relieve symptoms and signs of HF by reducing raised filling pressures to near normal. Therapeutic goals:
Shift the cardiac function curve to the left and upward, decreasing the filling pressure yet increasing stroke volume.
Arrest or cause amelioration of the disease process.
This can be achieved by the judicious use of
Loop diuretics.
Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).
Beta-blockers.
Digoxin: this old drug still has a role and is underused; toxicity is very rare if used by a watchful physician: keep levels 0.6–1.0 nmol/l (0.5–0.9 ng/ml). See later discussion.
Aldosterone antagonists: eplerenone, if not available use spironolactone or amiloride.
Vasodilators
ACE Inhibitors/Angiotensin II Receptor Blockers
These agents are discussed in Chap. 3. ACE inhibitors play a major role in the management of HF. When there is intolerance to ACE inhibitor therapy, selected ARBs are administered.
Activation of the RAAS is an early manifestation of HF. The prime role of angiotensin II is to support systemic blood pressure by:
Causing systemic vasoconstriction, and increase in SVR.
Stimulation of the central and peripheral effects of the sympathetic nervous system (NOVEL DRUG 2014).
Causing retention of sodium and water in the proximal nephron and directly by stimulation of aldosterone production.
Stimulating thirst and enhancing synthesis of vasopressin, thereby increasing total body water.
In addition, angiotensin II preserves cerebral blood flow. Renal blood flow is preserved by selective vasoconstriction of the postglomerular (efferent) arterioles. Thus, the influence of angiotensin II allows patients with severe HF to maintain blood pressure for cerebral, renal, and coronary perfusion, and relatively normal values for serum creatinine and blood urea nitrogen concentration also prevail. ACE inhibitors may cause a dramatic decrease in glomerular filtration rate and increase azotemia in patients with HF and hypotension. This deleterious effect can be minimized by reducing the patient’s dependence on the renin–angiotensin system by reducing the dose of diuretic used. Initially it is best to choose an ACE inhibitor with a short action so as to allow brief restoration of the normal homeostatic actions of the renin–angiotensin system (Packer 1985). Long-acting agents may produce prolonged hypotensive effects that may compromise cerebral and renal function and thus may have disadvantages in such cases compared with short-acting agents. Initial low-dose enalapril, 2.5 mg, caused a low 3.2 % incidence of hypotension in a Scandinavian study, proving the drug’s safe profile (CONSENSUS 1987).
If ACE inhibitors or ARBs are not tolerated or are contraindicated, the combination of hydralazine/isosorbide dinitrate (ISDN) should be tried; this combination is preferred over ACE inhibitors in black patients as indicated in the Veterans Administration Heart Failure Trial (A-HeFT et al. 2004).
Data from the Veterans Administration Vasodilator Heart Failure Trial (V-HeFT) suggested that patients with chronic HF could be considered for treatment with hydralazine (25 mg three or four times daily) and ISDN (Cohn et al. 1987), but use of captopril or enalapril is preferred. In V-HeFT, the 2-year reduction in mortality rate was 25 %. Hydralazine and ISDN were poorly tolerated and were withdrawn in 19 % of patients. Only 55 % of patients were taking full doses of both drugs 6 months after randomization (Cohn et al. 1986). Improvement in survival was observed mainly in patients with New York Heart Association (NYHA) class II HF. In this subset, 48 (24 %) of 200 patients treated with enalapril and 66 (31 %) of 210 patients treated with hydralazine/ISDN died (V-HeFTII et al. 1991).
The following studies have tested the effect of ACE inhibitors:
CONSENSUS 1987: The Cooperative North Scandinavian Enalapril Survival Study showed that 6 months of enalapril therapy produced a reduction in mortality rate in patients with NYHA class IV, severe HF. Total mortality 68 in the placebo arm and 50 in the treated subjects (P = 0.003). This is significant but a modest effect.
The drug, when given as a 2.5-mg initial dose, was well tolerated. Patients were receiving optimal treatment with digitalis (~94 % of subjects) and diuretics. Treatment with enalapril or an identical placebo was started in the hospital with a dose of 5 mg twice a day. After 1 week, the dosage was increased to 10 mg twice a day if the patient did not have symptoms of hypotension or other side effects. According to the clinical response, a further increase in dosage could occur up to a maximal dose of 20 mg twice a day.
SOLVD 1991 studied the effect of the ACE inhibitor, enalapril, on mortality and hospitalization in patients with chronic heart failure and ejection fractions ≤0.35. Patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n = 1,284) or enalapril (n = 1,285) at doses of 2.5–20 mg per day in a double-blind trial. Approximately 90 % of the patients were in New York Heart Association functional classes II and III. The follow-up averaged 41.4 months. Only about 8 % received beta-blockers and 68 % digoxin.
Results. There were 510 deaths in the placebo group (39.7 %), as compared with 452 in the enalapril group (35.2 %). A modest reduction in risk, 16 %, was observed (P = 0.0036).
SAVE 1992 In the Survival and Ventricular Enlargement trial, 36,630 post-MI patients were screened. Within 3–16 days after MI 2,231 patients with ejection fractions of 40 % or less but without overt heart failure or symptoms of myocardial ischemia were randomly assigned to receive double-blind treatment with either placebo (1,116 patients) or captopril (1,115 patients) and were followed for an average of 42 months.
275 of the 1,116 patients (25 %) in the placebo group and 228 of 1,115 (20 %) in the captopril group died; the reduction in the risk of death from all causes was small 19 % ( P = 0.019). Follow-up at 3.5 years showed a 22 % decrease in the risk of requiring hospitalization for HF. But only ~36 % of subjects received a beta-blocker (thus current optimal therapy was lacking).
AIRE (1993): In the Acute Infarction Ramipril Efficacy study, ramipril was shown to improve prognosis in post-MI patients with clinical evidence of HF.
Drug name: | Captopril |
Trade name: | Capoten |
Supplied: | 12.5, 25, 50, 100 mg |
Dosage: | See text |
In renal failure, the dose interval is increased according to the creatinine clearance (see Chap. 3 for a detailed account of adverse effects, cautions, interactions, and pharmacokinetics).
Drug name: | Enalapril: Vasotec, Innovace (UK) |
Supplied: | 2.5, 5, 10, 20 mg |
Dosage: | 2.5-mg test dose; 8–12 h later start 2.5 mg twice daily, increasing over days to weeks to 10–20 mg once or twice daily |
Contraindications, side effects, and other considerations are discussed in Chap. 3 (see Table 3-1). Notably, the drug’s onset of action is delayed 2–4 h as opposed to captopril (½–l h). Withdrawal of diuretics does not always prevent marked hypotension or syncope (Cleland et al. 1985), so caution is required with captopril and enalapril. A RCT indicates that 20 mg of enalapril is as beneficial as 40 mg daily for HF treatment (Nanas et al. 2000).
Drug name: | Lisinopril |
Trade names: | Prinivil, Zestril, Carace (UK) |
Supplied: | 5, 10, 20, 40 mg |
Dosage: | 2.5-mg test dose, then titrate dosage; 5–10 mg once daily, average 10–20 mg daily. If no hypotension or adverse effects, the dose may be increased to 30–35 mg daily |
The high dose was used in the Assessment of Treatment with Lisinopril and Survival (ATLAS 1999) study. Unfortunately, the ATLAS study compared 2.5–5 mg with 32.5–35 mg lisinopril daily. It would make more clinical sense to have compared the dose commonly used in clinical practice (i.e., 10–20 mg) as the low dose. The results of the study showed a marginal difference; the high dose decreased modestly the risk of hospitalization but not total mortality.
Drug name: | Ramipril |
Trade names: | Altace, Tritace (UK) |
Supplied: | 1.25, 2.5, 5, 10 mg |
Dosage: | 1.25–2.5 mg daily, increasing over weeks to 5–10 mg once daily or two divided doses |
For other ACE inhibitors and ARBs, see Chap. 3.
In the AIRE (1993) trial, ramipril administered to patients within 3–10 days of acute MI with transient signs and symptoms of HF caused a significant 27 % reduction in the risk of death at 15 months, a benefit that was maintained for 5 years.
Angiotensin-Receptor Blockers
ARBs are advisable if ACE inhibitors are not tolerated, but they have not been shown to significantly decrease total mortality. These agents are overused; trial results are as follows:
CHARM (2003). In this study, 2,028 patients were studied to examine the effects of the ARB candesartan in patients with reduced left ventricular ejection fraction (<40 %) who were intolerant of ACE inhibitors. Treated patients received candesartan 4–8 mg titrated to 32 mg once daily plus the treatment given to placebo patients. Standard heart failure therapy included diuretics, beta-blockers, digoxin, and spironolactone (85 %, 54 %, 45 %, and 24 %, respectively).
Results: Total mortality was not significantly reduced by the ARB candesartan. There were 265 deaths from any cause in the candesartan group and 296 in the placebo group.
P = 0.11. Hospitalization for heart failure occurred in 207 (20.4 %) in the candesartan group and 286 (28.2 %) in the placebo group, a modest 27 % reduction in admissions to hospital, P = 0.0001. Digoxin and beta blockers were underused.
In CHARM—Alternative (2003). 7,599 patients [with left-ventricular ejection fraction (LVEF)] 40 % or less, and mainly class 11 and 111 HF, who were not receiving ACE inhibitors because of previous intolerance were randomly assigned candesartan (n = 3,803, titrated to 32 mg once daily) or matching placebo. Median follow-up was 37.7 months. Total mortality was not reduced: 886 (23 %) patients in the candesartan and 945 (25 %) in the placebo group died p = 0.055. In this negative trial ~50 % of subjects had a previous MI.< div class='tao-gold-member'>Only gold members can continue reading. Log In or Register to continue
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