Heart failure is a growing public health problem. Over the past 2 decades, considerable advancement has occurred in the understanding of the basic pathophysiologic mechanisms that underlie the clinical syndrome of heart failure (HF), the progressive nature of left ventricular (LV) remodeling, and the associated high mortality rates. Furthermore, randomized, controlled trials (RCTs) have demonstrated that medications such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), β-blockers, and aldosterone antagonists reduce mortality rates and improve functional status. Nonetheless, the morbidity associated with HF remains high, and many patients are not optimally treated. These observations have stimulated the formulation of specific guidelines for the management of patients with chronic HF. A major emphasis in the coming years will include not only a continued search for more effective therapies, but also a significant educational effort to assist health care providers in the increased utilization of existing therapies.
This chapter reviews current pharmacologic treatment strategies for ambulatory patients with chronic HF. In each section, the most pertinent information regarding pathophysiologic mechanisms is presented, along with data from important clinical trials that provide the scientific rationale for the treatment recommendations. For areas in which there is strong agreement on medical management, evidence-based recommendations from the American College of Cardiology/American Heart Association (ACC/AHA) and the Heart Failure Society of America (HFSA) are provided. For areas in which there are few data on mechanisms and treatment, the consensus opinion among HF specialists and empiric recommendations are discussed. In addition, each section includes practical recommendations that can be used in everyday clinical practice. A more detailed discussion of the drugs used in the treatment of HF can be found in Chapter 28 of the ninth edition of Braunwald’s Heart Disease .
Pathophysiology and Staging System: Targets of Therapy
The basic pathophysiology of HF—including short-term adaptive mechanisms; chronic ventricular and vascular remodeling; and neurohormonal, paracrine, and autocrine adjustments—is extensively discussed in Braunwald’s Chapter 25 and in other reviews. Three important pathophysiologic concepts have had a substantial impact on the overall treatment strategy. The first concept recognizes the systemic nature of the clinical syndrome of HF. Although the primary problem is related to an abnormality in the myocardium, many of the presenting signs and symptoms are related to dysfunction of end organs, including the lungs, liver, kidneys, and skeletal muscle. The fact that HF is a systemic process makes it unlikely that any single therapy will offer a complete treatment response. A second important concept involves the interactions among myocardial dysfunction, activation of neurohormonal systems, and disease progression ( Figure 12-1 ). This model emphasizes the fact that although HF is related to a primary abnormality in myocardial function, either genetic or acquired, further impairments in myocardial function and progressive hypertrophy, dilation, or both can occur in the absence of additional direct injury to the heart. This model can also help to explain the absence of signs and symptoms of HF in some patients who have significant ventricular dysfunction, and it provides the rationale for therapy with renin-angiotensin system inhibitors and β-blockers in patients with asymptomatic LV dysfunction. Finally, this model emphasizes the observation that treatments that do not have an intrinsic action on the primary myocardial abnormality can still have substantial benefits in HF. Thus, ACE inhibitors reduce vasoconstrictor tone and angiotensin-mediated toxicity in the heart, vasculature, and kidneys and are associated with marked improvement in symptoms and survival. In contrast, drugs that have been shown to activate neurohormonal pathways, such as oral positive inotropes, have a neutral or adverse effect on long-term survival.
A third concept that has evolved from randomized clinical trials is that all therapeutic interventions must be critically examined with respect to two different but equally important endpoints: 1) an improvement in symptoms or quality of life and 2) an improvement in survival. Although it is preferable that all interventions have a concordant effect on these endpoints, this is not always the case ( Table 12-1 ). For example, diuretics are very effective in reducing signs and symptoms of HF, but their effects on survival are unknown. In contrast, β-blockers reduce hospitalizations and prolong survival, but their effects on exercise tolerance and quality of life are less evident. The distinction between the two endpoints is also reflected in prioritization of treatment for different patient subgroups. For example, patients with asymptomatic LV dysfunction do not require therapy that will reduce symptoms, but they benefit from treatment that slows disease progression and prolongs life. In contrast, a patient with advanced HF is benefited by any treatment that relieves symptoms at the end of life.
| DRUG | MORTALITY RATE | EXERCISE TOLERANCE | QUALITY OF LIFE |
|---|---|---|---|
| ACE inhibitor | ↓ 20% | Mild improvement | Mild improvement |
| β-Blocker | ↓ 35% | Mild or no improvement | Mild or no improvement |
| Aldosterone antagonist | ↓ 30% | Mild or no improvement | Mild improvement |
| Digoxin | No effect | Mild improvement | Unknown |
| Diuretic | Unknown | Moderate improvement | Moderate improvement |
In 2001, the writing committee of the ACC/AHA guidelines proposed a new approach to the classification of HF that emphasized both the development and progression of the disease. Stage A and B patients are at high risk for developing HF; this includes patients without structural heart disease (stage A) and those with structural heart disease but without signs or symptoms of HF (stage B). Stage C and D patients have structural heart disease with prior or current symptoms of HF (stage C) or refractory HF requiring specialized interventions (stage D; Figure 12-2 ). This staging system recognizes that 1) established risk factors and structural prerequisites exist for the development of HF; 2) therapies used before LV dysfunction or symptoms develop can reduce morbidity and mortality rates; 3) patients are expected to progress from one stage to the next unless slowed by treatment; and 4) all patients benefit from risk factor management that includes blood pressure control, lipid management, exercise, and smoking cessation. This chapter focuses primarily on stage C patients with reduced ejection fraction, for whom there is a large base of evidence available to guide therapy ( Table 12-2 ). In contrast, a more limited discussion of empiric recommendations for patients with HF and preserved ejection fraction is presented.
| STAGE | DRUG | SELECTED INDICATIONS |
|---|---|---|
| A | ACE inhibitor or ARB | Vascular disease, diabetes, hypertension |
| B |
|
|
| C |
|
|
| D |
|
|
Diuretics and Sodium Restriction
Pathophysiologic Mechanisms
A common abnormality in patients with HF is an expanded extracellular volume that manifests as pulmonary congestion, peripheral edema, ascites, elevated jugular venous pressure, and symptoms such as ankle swelling, dyspnea on exertion, and abdominal bloating. These abnormalities are related in part to avid sodium retention by the kidney caused by a complex interaction among decreased cardiac output and renal perfusion, redistribution of intrarenal blood flow to the sodium-conserving medulla, systemic and local neurohormonal activation, and increased renal sympathetic nerve activity. Diuretics are a cornerstone in the pharmacologic management of patients with signs and symptoms related to an expanded extracellular volume. Although restriction of dietary sodium intake is universally recommended for patients with HF who are treated with diuretics, this recommendation is inadequately implemented in many clinical settings. The failure to correctly implement a sodium-restricted diet diminishes the effectiveness of diuretics, increases the dosage requirement, and aggravates potassium loss.
Sodium Restriction
Few contemporary studies have specifically assessed the effect of dietary sodium intake in HF. Cody and colleagues studied 10 patients with severe HF who were monitored in a clinical research center after all vasodilator and diuretic therapy was discontinued in conjunction with a diet containing very low sodium (~200 mg/day) or moderate sodium intake (~2000 mg/day). The very low sodium diet was associated with a significant reduction in weight, mean pulmonary artery pressure, and mean pulmonary capillary wedge pressure. In contrast, a high-salt diet in patients with mild HF has been shown to increase LV volumes, suppress renin and aldosterone concentrations, and reduce daily sodium excretion. Thus, even in patients without signs or symptoms of congestion, the ability to excrete a sodium load is reduced. Other studies in patients with hypertensive heart disease and HF with preserved ejection fraction suggest that sodium restriction may reduce natriuretic peptides, attenuate ventricular remodeling, and improve clinical status.
The recommended level of sodium restriction depends on the history and severity of edema formation. In patients with asymptomatic LV dysfunction, judicious sodium restriction to no more than 3500 mg/day is probably reasonable. Patients with mild HF typically require restriction to less than 2500 mg/day, but those with moderate to severe HF should reduce intake to less than 2000 mg/day. Important principles include substituting herbs and other spices for table salt, avoiding common foods that contain large amounts of sodium ( Table 12-3 ), reading food labels carefully, and cooking with fresh meats and vegetables. Keys to compliance are patient and family education by nurse specialists, referral to nutritionists, and use of patient-oriented texts and websites such as www.hfsa.org .
| FOOD | PORTION | SODIUM (MG) |
|---|---|---|
| American cheese | 1 oz | 406 |
| Tuna, canned | 3 oz | 288 |
| Ham | 3 oz | 1114 |
| Hot dog | 1 | 639 |
| Spaghetti, canned | 8 oz | 1124 |
| Bread, white | 1 slice | 114 |
| Corn chips | 2 oz | 462 |
| Chicken noodle soup | 1 cup | 1107 |
| Beans, canned | 1 cup | 326 |
| Soy sauce | 1 tbsp | 1029 |
| Italian dressing | 1 tbsp | 116 |
| Big Mac | 1 | 1010 |
| Whopper with cheese | 1 | 1450 |
Diuretics
Mechanisms of Action
Diuretics inhibit sodium reabsorption in the kidney and lead to increased urinary sodium and water excretion. Several diuretics are available ( Table 12-4 ), usually classified according to site of action in the kidney. Thiazide diuretics inhibit the sodium-chloride symporter in the distal convoluted tubule, where approximately 30% to 35% of the filtered load of sodium is reabsorbed. However, as cardiac function and renal perfusion decrease, proximal tubular sodium reabsorption increases from approximately 65% to 80% to 90% of the filtered load, making thiazide diuretics less effective. Therefore, for most patients with HF and edema, a loop diuretic is the preferred initial agent; it will inhibit the sodium-potassium-chloride symporter in the thick ascending limb of the loop of Henle and lead to a marked increase in the fractional excretion of sodium. In addition, loop diuretics inhibit solute concentration in the medullary interstitium and thereby decrease the driving force for water reabsorption in the collecting duct. Because both loop diuretics and thiazides also cause potassium excretion, adjunctive therapy with potassium-sparing diuretics that act in the distal tubule and collecting duct may be required to maintain normokalemia. (For a detailed discussion of the pharmacology of diuretics, see Braunwald, Chapter 28 ).
| GENERIC NAME | USUAL ORAL DOSE | DURATION OF ACTION |
|---|---|---|
| Loop Diuretics | ||
| Furosemide | 40-160 mg/day | 6-8 hours |
| Bumetanide | 0.5-4 mg/day | 4-6 hours |
| Torsemide | 10-40 mg/day | 2-4 hours |
| Ethacrynic acid | 50-150 mg/day | 6-8 hours |
| Thiazide and Thiazide-Like Diuretics | ||
| Chlorothiazide | 500-1000 mg/day | 6-12 hours |
| Hydrochlorothiazide | 25-100 mg/day | >12 hours |
| Metolazone | 2.5-10 mg/day | 24-48 hours |
| Chlorthalidone | 100 mg/day | 24 hours |
| Indapamide | 1.25-5 mg/day | 24 hours |
| Potassium-Sparing Diuretics | ||
| Spironolactone | 25-100 mg/day | 3 days after starting |
| Triamterene | 100-200 mg/day | 8-16 hours |
| Amiloride | 5-10 mg/day | 24 hours |
Adverse Effects
Despite the wide acceptance of diuretics, they have a number of long-term adverse effects that include electrolyte depletion, neurohormonal activation, hypotension, and renal insufficiency. Chronic diuretic therapy can result in hypokalemia, hyponatremia, hypocalcemia, hypomagnesemia, and metabolic alkalosis. Hypokalemia and hypomagnesemia are of particular concern because they can precipitate arrhythmias in patients with HF. In addition to electrolyte depletion, diuretics may cause an increase in uric acid levels and contribute to the development or exacerbation of gout. An adverse effect of diuretics that may be particularly important in patients with HF is activation of neurohormonal pathways. The mechanisms by which diuretics stimulate renin and norepinephrine release have not been completely defined, but there are three important pathophysiologic consequences. First, renin secretion will result in increased secretion of aldosterone, which will promote sodium retention. Second, increased vasoconstriction secondary to increased levels of angiotensin II and norepinephrine may have a positive feedback effect, in which the increased impedance to ventricular emptying results in progressive ventricular dysfunction. Third, norepinephrine, angiotensin II, and aldosterone exert direct toxic effects on the myocardium that result in ventricular remodeling and proarrhythmia. Finally, neurohormonal activation is a strong predictor of increased mortality rate. Therefore, it is possible that diuretic-associated neurohormonal stimulation could be associated with an adverse effect on long-term survival.
The association of diuretic therapy with neurohormonal activation has an important influence on the optimal use of diuretics for patients with HF. As discussed, it is useful to reinforce dietary sodium restriction in patients who appear to require large doses of diuretics. Second, it is important to emphasize that many of the adverse effects of neurohormonal stimulation by diuretics can be blocked by the concomitant administration of an ACE inhibitor (or ARB) and β-blocker. With combination therapy, the beneficial effect of diuretics may be obtained but the increase in angiotensin II and aldosterone is blocked, and the effects of norepinephrine are inhibited. It is also important to understand the effects of secondary processes that can cause overall sodium balance to return to neutral despite continued diuretic administration. The response to a diuretic-induced reduction of extracellular volume is a further reduction in sodium and chloride excretion through stimulation of proximal tubular reabsorption, increased renal sympathetic nerve activity, and increased aldosterone. In addition, long-term diuretic treatment induces a number of changes in the collecting duct and distal tubule, including increases in mitochondrial volume, adenosine triphosphatase activity, and cellular hypertrophy, that increase distal tubular reabsorption.
The pharmacokinetics and pharmacodynamic effects of diuretics may be abnormal in patients with HF. In patients with bowel wall edema and splanchnic hypoperfusion, the absorption of orally administered drugs can be reduced, thereby delaying the time to appearance and peak concentration of the diuretic in the urine. Unless the glomerular filtration rate (GFR) is less than 30 mL/min, the pharmacokinetics of intravenous (IV) formulations are largely normal in HF, which explains the effectiveness of the IV route in patients with acute decompensated HF (see Chapter 14 ). Furthermore, the pharmacodynamic response is attenuated in HF so that the rate of sodium excretion is reduced at any given renal tubular diuretic concentration. Thus, the “ceiling” dose, or dose above which further sodium excretion is minimal, is typically double in patients with HF compared with normal subjects. For this reason, prescribing a larger dose of diuretic is commonly more effective than increasing the frequency of administration.
Practical Considerations
Short-term studies have shown that diuretics reduce signs and symptoms of congestion and decrease cardiac filling pressures within hours to days of initiation, and intermediate-term studies demonstrate the beneficial effects of diuretics on exercise tolerance and quality of life. The effects of diuretics on morbidity and mortality in HF have not been tested. According to ACC/AHA guidelines, diuretics should be prescribed to all patients with current or prior symptoms of HF who have evidence of fluid retention and combined with an ACE inhibitor and β-blocker to maintain clinical stability. Furthermore, inappropriately low doses of diuretics will result in fluid retention, which can attenuate the response to ACE inhibitors and increase the risk of β-blockade. The first step is to identify patients with fluid retention based on symptoms (shortness of breath, orthopnea, paroxysmal nocturnal dyspnea), signs (rales, elevated jugular venous pressure, peripheral edema), and other clinical characteristics such as weight gain, frequent outpatient visits, or recurrent hospitalizations. Noninvasive tools that may be helpful in recognizing hypervolemia include chest radiographs, natriuretic peptide levels, and echocardiography, although the sensitivity and specificity of these tests are limited. Newer devices such as implantable hemodynamic and intrathoracic impedance monitors and noninvasive Valsalva response recorders have also been developed for use in HF. Direct assessment of blood volume using a radiolabeled albumin technique is available at specialized centers. If the clinical evaluation is equivocal, a right heart catheterization to measure intracardiac filling pressures should be considered.
For patients with HF, the most commonly prescribed loop diuretic is furosemide, which is usually started at a low dose (20 to 40 mg once daily) and increased until urine output increases and weight loss occurs. The dose or frequency of diuretics may be titrated while monitoring several endpoints. Because one of the primary goals of therapy is symptom relief, the dose of diuretics may be reduced to maintenance levels once a satisfactory reduction is seen in dyspnea, orthopnea, and edema. In addition, careful attention to normalizing the jugular venous pressure and eliminating congestive hepatomegaly are keys to achieving euvolemia, especially in patients with advanced HF. The development of symptomatic hypotension or azotemia often necessitates holding diuretic therapy, but diuretics can often be resumed at a lower dose after adjustment of other HF medications, such as ACE inhibitors and β-blockers. Once fluid retention has resolved, a maintenance dose of diuretics is recommended to prevent recurrent volume overload. Selected patients with mild HF or asymptomatic LV dysfunction may not require maintenance diuretics if the patient is able to reduce dietary sodium intake, although a strategy of diuretic withdrawal has not been tested in randomized clinical trials. In a short-term study, diuretic withdrawal resulted in subclinical increases in volume status and markers of tubular dysfunction. However, others have demonstrated stable clinical status with improved renal function and neurohormonal markers after 3 months of diuretic interruption.
Some patients have refractory signs and symptoms of HF and are labeled diuretic resistant. However, these patients may be nonadherent with their medication regimens or ineffective in limiting sodium and fluid intake, and they require reinforcement of education. In patients with biventricular or right HF, significant bowel wall edema may limit oral absorption, so that IV formulations (furosemide or chlorothiazide) or loop diuretics with increased oral bioavailability (torsemide) may be effective in initiating a diuresis. In patients with low cardiac output, the problem is inadequate sodium delivery to the tubular lumen because of reduced renal perfusion and impaired tubular secretion of diuretics. Most patients will respond to doubling the dose rather than giving the same dose twice daily.
In other patients the combination of a loop diuretic with a thiazide diuretic or metolazone, which facilitates the action of the loop diuretic, may be particularly effective. The mechanisms of diuretic synergism are not fully defined but are likely related to the fact that diuretics inhibit transport in different segments of the nephron. In addition, adding a thiazide diuretic may inhibit compensatory distal tubular adaptations and result in a sustained diuresis that would be much greater than simply increasing the dose of the loop diuretic. The addition of metolazone may also be used for transient episodes of fluid accumulation. This strategy maintains a constant dose of the loop diuretic, minimizes errors associated with frequent dosage changes, and reduces the long-term exposure to high-dose diuretics. However, close monitoring is required because this “booster pill” strategy can rapidly lead to overdiuresis with hypotension, hypokalemia, hyponatremia, and worsening renal function.
During long-term treatment, and particularly during changes in diuretic regimens, it is important to monitor levels of potassium, given the marked kaliuretic effects of diuretic drugs. Renal function as assessed by serum blood urea nitrogen (BUN) and creatinine levels should be monitored because they may be sensitive to changes in blood volume and/or vasoconstrictor hormones. Excessive volume depletion should be avoided because it may result in hypotension and renal dysfunction. In patients with coexistent HF and chronic kidney disease, the so-called cardiorenal syndrome, potential nephrotoxic agents should be used with extreme caution. Nonsteroidal antiinflammatory drugs (NSAIDs), including cyclooxygenase-2 inhibitors, should be avoided; these agents can inhibit the natriuretic effects of diuretics and impair renal function, thereby exacerbating fluid retention. Other agents—such as thiazolidinediones and pregabalin, which cause edema—are relatively contraindicated in HF.
Patients should weigh themselves on a daily basis; if they do not own a scale, one should be provided for them. This process engages patients in their medical care, alerts them to the effect of dietary indiscretions, and facilitates fine-tuning of medications. For selected patients, electronic scales that transmit daily information on weight, vital signs, and symptoms may help to maintain accuracy and compliance. In the case of a rapid weight gain of 2 to 3 pounds, a temporary increase in diuretic dosage or the addition of metolazone or a thiazide diuretic for 1 to 3 days is often sufficient to return the patient to “dry” weight. In patients with advanced HF, it is important to remember that dry weight may decrease over time with loss of skeletal muscle mass and adipose tissue as a result of cardiac cachexia. The use of IV diuretics and other fluid management strategies in hospitalized patients with acute decompensated HF is discussed in detail in Chapter 14 .
Renin-Angiotensin System Inhibitors
Pathophysiologic Mechanisms
Nearly 35 years ago, an important advance in the treatment of HF was the recognition that pump function was critically dependent on the outflow resistance, against which the ventricle must empty. Acute hemodynamic studies established that vasodilator drugs that relax peripheral arterioles shift the ventricular function curve upward and to the left, resulting in an increase in cardiac output without a large change in blood pressure. Moreover, drugs that increase venous capacitance redistribute blood volume from the central to peripheral reservoirs and therefore decrease the signs and symptoms of elevated cardiac filling pressures. Unlike hydralazine, which acts predominantly on the arterioles and leads to a reduction in impedance, or nitrates, which act on arterial compliance and venous tone, ACE inhibitors and ARBs have a balanced effect on arterioles, arteries, and veins.
The traditional view of ACE inhibitors was that their primary mechanism of action in HF was a reduction in angiotensin II–mediated vasoconstriction. In addition, the reduction of angiotensin II was noted to decrease the release of aldosterone from the adrenal gland and norepinephrine in the synaptic cleft. However, subsequent studies have shown that the actions of ACE inhibitors are considerably more complex than a simple effect on circulating levels of angiotensin II ( Figure 12-3 ). Because kininase is identical to converting enzyme, ACE inhibitors also reduce the metabolism of bradykinin, which can stimulate the release of nitric oxide and other endothelium-dependent vasodilators, including prostaglandins. More importantly, by inhibiting tissue renin-angiotensin systems in blood vessels, the kidney, and the heart, ACE inhibitors play a critical role in attenuating vascular and myocardial remodeling, reducing inflammation and the risk of thrombosis, and delaying the progression of renal disease. All these actions have an important impact on mediating the clinical efficacy of ACE inhibitors in HF.
Several nonenzymatic pathways independent of ACE exist for the conversion of angiotensin I to angiotensin II and may contribute to persistent availability of both circulating and tissue angiotensin despite treatment with ACE inhibitors (see Figure 12-3 ). This escape phenomenon may be due in part to non-ACE pathways of angiotensin I metabolism (e.g., myocardial chymase); this has provided the rationale for the development of ARBs, which bind competitively to, and dissociate slowly from, angiotensin II type 1 receptors. Circulating angiotensin II levels increase during therapy as a result of loss of negative feedback. Many ARBs are available, but only two are currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of HF ( Table 12-5 ). Valsartan is approved for the treatment of patients with New York Heart Association (NYHA) functional class II through IV heart failure and is indicated to reduce cardiovascular mortality in clinically stable patients with LV failure or dysfunction following myocardial infarction (MI). Candesartan is indicated to reduce cardiovascular mortality and hospitalizations in patients with NYHA functional class II through IV heart failure and reduced ejection fraction.
| GENERIC NAME | INITIAL DAILY DOSE | MAXIMUM DOSE |
|---|---|---|
| ACE Inhibitors | ||
| Captopril | 6.25 mg tid | 50 mg tid |
| Enalapril | 2.5 mg bid | 10-20 mg bid |
| Fosinopril | 5-10 mg qd | 40 mg qd |
| Lisinopril | 2.5-5 mg qd | 20-40 mg qd |
| Quinapril | 5 mg bid | 20 mg bid |
| Ramipril | 1.25-2.5 mg qd | 10 mg qd |
| Trandolapril | 1 mg qd | 4 mg qd |
| Angiotensin Receptor Blockers | ||
| Candesartan | 4-8 mg qd | 32 mg qd |
| Losartan | 12.5-25 mg qd | 100 mg qd |
| Valsartan | 40 mg bid | 160 mg bid |
| β-Blockers | ||
| Bisoprolol | 1.25 mg qd | 10 mg qd |
| Carvedilol | 3.125 mg bid | 25 mg bid |
| Metoprolol succinate | 12.5-25 mg qd | 200 mg qd |
Clinical Efficacy
Angiotensin-Converting Enzyme Inhibitors
Numerous prospective, placebo-controlled studies have demonstrated the beneficial effects of ACE inhibitors on exercise tolerance, salt and water balance, clinical signs and symptoms, neurohormonal stimulation, quality of life, and survival in patients with chronic HF ( Table 12-6 ). The concordance of findings in these multicenter trials provides a strong scientific basis for the use of ACE inhibitors in the management of HF. Several multicenter trials deserve comment.
| TRIAL | N | AGENT | ENTRY CRITERIA | FOLLOW-UP PERIOD | PRIMARY ENDPOINT | FINDINGS* |
|---|---|---|---|---|---|---|
| Heart Failure Trials | ||||||
| CONSENSUS | 253 | Enalapril vs. placebo | NYHA IV | 188 days | Death | Placebo 52% Enalapril 36% (40% ↓) |
| V-HeFT II | 804 | Hydralazine/ isosorbide dinitrate vs. enalapril | CTR >0.55 LVID >2.7 cm/m 2 LVEF <45% VO 2 <25 mL/kg/min | 2.5 years | Death | Hyd/ISDN 25% Enalapril 18% (28% ↓) |
| SOLVD Treatment | 2569 | Enalapril vs. placebo | LVEF ≤35% NYHA II-III | 41 months | Death | Placebo 40% Enalapril 35% (16% ↓) |
| SOLVD Prevention | 4228 | Enalapril vs. placebo | LVEF ≤35% No or minimal symptoms | 37 months | Death | Placebo 16% Enalapril 15% (8% ↓, P = .30) |
| ATLAS | 3164 | High-dose vs. low-dose lisinopril | LVEF ≤30% NYHA II-IV | 39 to 58 months | Death | Low-dose 45% High-dose 43% (8% ↓, P = .13) |
| ELITE-II | 3152 | Losartan vs. captopril | Age ≥60 years LVEF ≤40% NYHA II-IV | 1.5 years | Death | Losartan 18% Captopril 16% (13% ↓, P = .16) |
| Val-HeFT | 5010 | Valsartan vs. placebo | LVEF <40% LVID >2.9 cm/m 2 NYHA II-IV | 23 months | Death | Placebo 19% Valsartan 20% ( P = .80) |
| Death and complications | Placebo 32% Valsartan 29% (13% ↓) | |||||
| CHARM-Added | 2548 | Candesartan vs. placebo | LVEF ≤40% NYHA II-IV Treatment with ACE inhibitors | 41 months | CV death or HF hospitalization | Placebo 42% Candesartan 38% (15% ↓) |
| CHARM-Alternative | 2028 | Candesartan vs. placebo | LVEF ≤40% NYHA II-IV Intolerance to ACE inhibitors | 34 months | CV death or HF hospitalization | Placebo 40% Candesartan 33% (23% ↓) |
| Postinfarction Trials | ||||||
| SAVE | 2231 | Captopril vs. placebo | LVEF ≤40% 3-16 days after MI | 42 months | Death | Placebo 25% Captopril 20% (19% ↓) |
| CONSENSUS II | 6090 | Enalapril IV/PO vs. placebo | 24 hours after MI | 6 months | Death | Placebo 10% Enalapril 11% (10% ↑, P = .26) |
| AIRE | 2006 | Ramipril vs. placebo | HF 3-10 days after MI | 15 months | Death | Placebo 23% Ramipril 17% (27% ↓) |
| GISSI-3 | 19,394 | Lisinopril vs. placebo | 24 hours after MI | 6 weeks | Death | Placebo 7.1% Lisinopril 6.3% (12% ↓) |
| SMILE | 1556 | Zofenopril vs. placebo | 24 hours after MI | 6 weeks | Death or severe heart failure | Placebo 10.6% Zofenopril 7.1% (34% ↓) |
| TRACE | 1749 | Trandolapril vs. placebo | LVEF ≤35% 3 days after MI | 4 years | Death | Placebo 42% Trandolapril 35% (22% ↓) |
| ISIS-4 | 58,050 | Captopril vs. placebo | 24 hours after MI | 5 weeks | Death | Placebo 7.7% Captopril 7.2% (7% ↓) |
| VALIANT | 14,808 | Valsartan vs. valsartan plus captopril vs. captopril | 0.5-10 days after MI HF, LVEF ≤35%, or both | 25 months | Death | Valsartan 20% Valsartan plus captopril 19% Captopril 20% |
Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)
CONSENSUS randomized 253 hospitalized patients with NYHA functional class IV symptoms to either enalapril or placebo in addition to treatment with digoxin, diuretics, and non-ACE vasodilators. Based on an interim analysis, enalapril was associated with a highly significant survival benefit compared with placebo (52% vs. 36%), although no difference was reported in the combined risk of death or hospitalization for HF. The CONSENSUS trial was prematurely terminated, because it was deemed unethical to continue a trial in which half of the participants were randomized to placebo.
Vasodilator Heart Failure Trial (V-HeFT) II
V-HeFT I was the first placebo-controlled trial to demonstrate that vasodilators could prolong survival in patients with HF. V-HeFT II was designed to compare treatment with hydralazine–isosorbide dinitrate, the superior drug combination in V-HeFT I, to enalapril in patients with mild to moderate HF as a result of ischemic or nonischemic cardiomyopathy. The enalapril group had a lower 2-year mortality rate compared with those patients randomized to hydralazine–isosorbide dinitrate (18% vs. 25%; mortality reduction, 28%; P = .016). Interestingly, exercise time and LV function improved to a greater degree in the patients randomized to hydralazine–isosorbide dinitrate.
Studies of Left Ventricular Dysfunction (SOLVD)
SOVLD was a prospective, double-blind placebo-controlled trial in patients with an ejection fraction of 35% or less. The SOLVD Treatment trial randomized 2569 patients with NYHA functional class II or III heart failure, treated with digitalis and diuretics, to enalapril or placebo. After a mean follow-up of 41 months, significantly more deaths were reported in the placebo group compared with the enalapril group (510 vs. 452; mortality reduction, 16%; P = .0036). Furthermore, enalapril was associated with a 30% reduction in hospitalizations for HF.
The SOLVD Prevention trial was run concurrently with the treatment trial and utilized the same experimental design except for the restriction to patients with minimal to no symptoms of HF who were on no treatment for overt HF. After an average follow-up of 37 months, 334 deaths were reported in the placebo group compared with 313 in the enalapril group. This 8% mortality reduction approached but did not achieve statistical significance ( P = .30). More impressive were the highly significant reductions in the first hospitalization for HF (36%) and in the onset of HF requiring pharmacologic therapy (37%).
Assessment of Treatment with Lisinopril and Survival (ATLAS)
Despite controlled trials demonstrating the benefits of high-dose ACE inhibitor therapy (e.g., captopril 50 to 100 mg three times daily, enalapril 10 to 20 mg twice daily), much lower doses are used in clinical practice because of concerns regarding patient tolerance. The ATLAS study randomized 3164 patients with NYHA functional class II to IV heart failure and an ejection fraction of 30% or less to low-dose (2.5 to 5 mg/day) or high-dose (32.5 to 35 mg/day) lisinopril. After a median follow-up of 46 months, high-dose lisinopril was modestly superior in decreasing the combined risk of death or hospitalization (12% reduction; P = .0002), but it had no significant effect on all-cause mortality. Although dizziness and renal insufficiency were more common in the high-dose group, the rate of drug withdrawal because of adverse effects (18%) was similar in the two groups.
Angiotensin Receptor Blockers
In early clinical studies in patients with chronic HF as a result of LV systolic dysfunction, angiotensin receptor blockade produced beneficial hemodynamic effects and was generally well tolerated. The Evaluation of Losartan in the Elderly (ELITE) I study randomly assigned 722 patients aged 65 years or older with NYHA functional class II to IV heart failure and an ejection fraction of 40% or less to receive losartan or captopril for 48 weeks. Although no difference was found between the drugs with regard to the primary safety endpoint (i.e., treatment effect on renal function), losartan unexpectedly decreased mortality rate by 46%. With a similar design as ELITE I, but powered to detect a difference in all-cause mortality, ELITE II randomized 3152 patients with mild to moderate HF to losartan (target dose 50 mg once daily) or captopril (target dose 50 mg three times daily) and demonstrated a nonsignificant 13% reduction in mortality rate in favor of captopril. Trends were also seen in favor of ACE inhibitor therapy for the secondary endpoint of sudden cardiac death and the combined endpoint of death and hospitalization. Fewer patients randomized to losartan discontinued therapy because of side effects (9% vs. 15%; P < .001). The inferiority of losartan in ELITE II was likely due to underdosing; although losartan is not approved for the treatment of HF, the recommended daily dose in this setting is 100 mg.
There is theoretical reason to suggest that combined therapy with an ARB and an ACE inhibitor would be more clinically effective than therapy with either alone; this thesis has been tested in several clinical trials. In a small pilot study, the addition of losartan to maximally tolerated doses of ACE inhibitors was associated with a lower NYHA class and higher peak oxygen consumption. The Valsartan in Heart Failure Trial (Val-HeFT) randomized 5010 patients with NYHA functional class II to IV heart failure to receive valsartan (target dose 160 mg twice daily) or placebo in addition to usual therapy that included ACE inhibitors in 93% and β-blockers in 36%. Valsartan significantly reduced the combined endpoint of mortality and morbidity by 13% ( P = .009), including a 28% reduction in HF hospitalization, but it had no effect on all-cause mortality. Despite post hoc analysis raising concern about adverse outcomes in patients receiving an ACE inhibitor, ARB, and β-blocker—so-called triple therapy —similar efficacy and safety results were reported from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Added study. In CHARM-Added, 2548 patients with mild to moderate HF and reduced ejection fraction who were being treated with ACE inhibitors were randomized to receive candesartan (target dose 32 mg once daily) or placebo. During a median follow-up of 41 months, candesartan reduced the combined endpoint of cardiovascular death or HF hospitalizations by 15% ( P = .01). Importantly, candesartan reduced this risk in patients treated with β-blockers in addition to an ACE inhibitor and was as effective among patients taking a recommended dose of ACE inhibitor as in those taking lower doses; however, the risk of worsening renal function and hyperkalemia were higher with add-on therapy.
For patients who are intolerant to ACE inhibition, angiotensin receptor blockade has proven effective as an alternative therapy. In the CHARM-Alternative study, 2028 patients with symptomatic LV dysfunction who were not receiving ACE inhibitors because of cough (72%), hypotension (13%), or renal dysfunction (12%) were randomized to receive candesartan (target dose 32 mg once daily) or placebo. During a median follow-up period of 34 months, candesartan reduced the risk of cardiovascular death or HF hospitalization by 23% ( P = .004). In addition, a trend was seen toward a decrease in all-cause mortality with candesartan (hazard ratio [HR], 0.87; 95% CI, 0.74 to 1.03; P = .11). A subgroup of 366 patients in the Val-HeFT study who were not taking ACE inhibitors at baseline also experienced a significant reduction in morbidity and mortality with angiotensin receptor blockade.
In addition to targeting patients with HF, several large trials have studied the effects of ACE inhibitors and ARBs on mortality in patients following acute MI (see Table 12-6 ). These trials focused on a patient population that is not comparable to patients with chronic HF and reduced ejection fraction that were enrolled in the V-HeFT, CONSENSUS, SOLVD, and CHARM trials. In addition, background drug therapy and study drug dosing differed significantly from the chronic HF trials. Nevertheless, the results of the postinfarction trials have several important implications when considering treatment for patients with LV systolic dysfunction and/or HF.
First, the majority of these trials demonstrated that treatment with an ACE inhibitor initiated early after MI had a small but significant benefit in reducing short-term mortality. This finding is significant because most of the patients enrolled in the postinfarction trials did not have HF. Furthermore, the Heart Outcomes Prevention Evaluation (HOPE) study demonstrated a reduction in mortality from the ACE inhibitor ramipril in patients with atherosclerosis in the absence of HF, and the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) confirmed the vasculoprotective effect of ACE inhibitors in even lower risk patients.
A second and more compelling issue is that early intervention with an ACE inhibitor can prevent or delay the onset of HF. In the Survival and Ventricular Enlargement (SAVE) trial, captopril was associated with a 37% reduction in the development of HF and a 22% reduction in hospitalizations for HF. CONSENSUS II demonstrated that enalapril reduced the need to change therapy for HF by 10%, and the Survival of Myocardial Infarction Long-term Evaluation (SMILE) study demonstrated that early use of zofenopril reduced the likelihood of developing severe HF within 6 weeks of MI. These data are consistent with the results of the SOLVD Prevention trial, which demonstrated a 20% reduction in hospitalizations for HF and a 29% reduction in the development of HF. In the HOPE study, ramipril reduced the risk of developing HF by 23%; and in EUROPA, perindopril reduced HF hospitalizations by 39%. These cumulative data suggest that ACE inhibitors have a significant clinical benefit even in relatively low-risk patients.
Third, results from the Valsartan in Acute Myocardial Infarction (VALIANT) trial suggest that although ACE inhibitors and ARBs are equally effective at reducing morbidity and mortality in patients with acute MI and HF, LV systolic dysfunction, or both, combined therapy offers no advantages over ACE inhibition or angiotensin receptor blockade alone and increases the rate of adverse events. These findings appear to be at odds with results from the Val-HeFT and CHARM studies demonstrating further cardiovascular risk reduction (RR) with the addition of angiotensin receptor blockade to background ACE inhibition; however, differences in patient population, drug regimens, and patterns of cardiovascular risk between patients with stable HF and those with acute MI likely explain these divergent results.
Practical Considerations
Angiotensin-Converting Enzyme Inhibitors
Despite the overwhelming database from clinical trials and the adoption of consensus guidelines, the application—including utilization and dosing—of ACE inhibitors to the broad population of patients with HF remains suboptimal. Several factors are responsible for this. First, the use of ACE inhibitors appears to vary among different specialties, as evidenced by the fact that cardiologists are more likely to prescribe ACE inhibitors than are primary care physicians. Second, it is a common perception that ACE inhibitors are associated with a high frequency of adverse effects when used at higher doses and/or in the elderly. However, the early experience from CONSENSUS and SOLVD in a large population of ambulatory patients suggests that the incidence of these complications is acceptably low given the potential benefit, and ATLAS demonstrated no increased risk of drug withdrawal with high-dose therapy. Finally, management and avoidance of ACE inhibitor–related complications can be facilitated by knowledge of certain predisposing factors and by institution of precautionary measures. Other patient-related factors associated with physician underutilization of ACE inhibitors include older age, renal dysfunction, and preserved ejection fraction.
The most important adverse effect to monitor for during the initiation of ACE inhibitors is hypotension ( Table 12-7 ), although the decrease in blood pressure is usually minor and the patient is often asymptomatic. Patients who are at highest risk for symptomatic hypotension are those who are volume depleted, receiving high doses of diuretics or concomitant vasodilator therapy, or older than 75 years. Patients with increased activation of the renin-angiotensin-aldosterone system, manifest by increased levels of plasma renin activity, are those who have angiotensin-mediated vasoconstriction and who are also at risk for hypotension. Because measurements of plasma renin activity are not readily available, clinicians can take advantage of the relatively tight inverse correlation between plasma renin activity and serum sodium. Patients with low serum sodium (<130 mmol/L) are more likely to develop hypotension during the initiation of therapy. Useful strategies in these patients include temporary withholding of diuretics, liberalizing of salt intake, and the use of a test dose of a short-acting ACE inhibitor (e.g., captopril 6.25 mg) followed by gradual uptitration over several weeks. If symptomatic hypotension occurs with the first dose, it may not recur with subsequent dosing.
| ADVERSE EFFECT | ACE INHIBITOR | ANGIOTENSIN RECEPTOR BLOCKER | ALDOSTERONE ANTAGONIST |
|---|---|---|---|
| Hypotension | ++ | ++ | + |
| Renal insufficiency | ++ | ++ | +/− |
| Hyperkalemia | + | + | ++ |
| Cough | + | − | − |
| Angioedema | ++ | + | − |
| Skin rash | + | +/− | − |
| Neutropenia | + | + | +/− |
| Gynecomastia | − | − | + * |
| Impotence | − | − | + * |
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