INTRODUCTION
Even the language of “diastolic heart failure” is controversial. The phrase “heart failure with preserved left ventricular function” is preferred by many. When there is uncertainty about the name of a disorder and ambiguity regarding its pathophysiology, you can be almost certain that there will be little agreement about its treatment. However, there is general, although not universal, agreement that the fundamental problem of diastolic heart failure is impaired left ventricular (LV) filling. The left ventricle is often thickened and stiff, and the filling pressures are increased relative to the LV volume. This leads to the cardinal features of heart failure, including pulmonary congestion, dyspnea, exercise intolerance, and edema. In fact, systolic and diastolic failure are usually clinically indistinguishable at the bedside. In most cases, a detailed imaging or even a hemodynamic study is necessary to understand the underlying structural and functional distinction between systolic and diastolic heart failure. Moreover, systolic and diastolic functions are intertwined and usually don’t occur in isolation. These observations have in part obscured the development of a specific therapy designed to treat diastolic heart failure. There currently is no targeted therapy for diastolic heart failure. This may change as old concepts of pathophysiology are challenged.
BACKGROUND
There are several trials that are ongoing or under consideration to test different therapies in patients with diastolic heart failure. Only two large trials have been completed. The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM-Preserved) trial demonstrated a trend toward improvement as measured by fewer hospitalizations for heart failure when candesartan was added to conventional therapy. More recently, the perindopril in elderly people with chronic heart failure (PEP-CHF) study was published. This study did not show a mortality benefit with perindopril, but similarly, there was a significant reduction in heart failure related hospitalizations at one year. However, the cardiovascular event rate in patients with diastolic heart failure is relatively low compared with patients with systolic heart failure. There are more noncardiovascular deaths and non-heart failure hospitalizations in patients with diastolic heart failure, as they tend to be older and have more comorbid conditions. Elderly women with hypertension, LV hypertrophy (LVH), and ischemic heart disease are the prototypical patients. This makes it much more difficult to demonstrate a clear reduction in all-cause death and all-cause hospitalizations in a clinical trial that focuses on treatment of diastolic heart failure, unless the sample size is very large and the follow-up is quite long. Recognition of this problem has probably hampered the design and implementation of large clinical trials for the treatment of diastolic heart failure.
Because the language and pathophysiology of diastolic heart failure are complex, it is not unexpected that the treatment would also be ambiguous. Nevertheless, certain general principles of treatment can be applied. One should initially target therapy toward reducing pulmonary congestion, maintaining synchronous atrial contraction, and increasing the duration of diastole by reducing heart rate. Sodium restriction, reduction of total blood volume, and reduction of central blood volume are generally useful. Blunting neurohormonal activation (both the sympathetic nervous system [SNS] and the renin-angiotensin-aldosterone system [RAAS]) seems helpful. Hypotension should be avoided by cautious use of low-dose diuretics, so as to maintain blood pressure and cardiac output. Interventions should include drugs designed to prevent and treat myocardial ischemia and foster prevention and regression of LVH. Preservation of exercise tolerance is an important clinical goal. Nevertheless, it should be reiterated that there are no large randomized clinical trials to guide our therapy, with the exception of CHARM-Preserved and PEP-CHF, and both of these trials failed to show a survival benefit.
Despite a lack of clinical trial data, physicians are faced on a daily basis with patients who have severe diastolic heart failure. The question remains, how should we manage them? This chapter will outline a number of conventional treatment options currently available. We may lack objective data from large clinical trials, but we have years of observational data. These treatment options are outlined in Table 32-1 .
| OBJECTIVE | TREATMENT | DAILY MEDICATION DOSE |
|---|---|---|
| Control congestion | Salt restriction | <2 g of sodium per day |
| Diuretics | Furosemide 10-120 mg | |
| Hydrochlorothiazide 12.5-25 mg | ||
| Control hypertension and regress LVH | Diuretics | Chlorthalidone 12.5-25 mg |
| Hydrochlorothiazide 12.5-25 mg | ||
| Beta blockers | Atenolol 12.5-100 mg | |
| Metoprolol 12.5-200 mg | ||
| Propranolol 20-80 mg | ||
| Carvedilol 3.126-50 mg | ||
| ACE inhibitors | Enalapril 2.5-40 mg | |
| Lisinopril 10–40 mg | ||
| Ramipril 5-20 mg | ||
| Captopril 25-150 mg | ||
| ARBs | Losartan 50-100 mg | |
| Candesartan 4-32 mg | ||
| Aldosterone blockers | Spironolactone 25-75 mg | |
| CCBs | Amlodipine 2.5-10 mg | |
| Felodipine 2.5-20 mg | ||
| Maintain sinus rhythm and control tachycardia | Cardioversion of atrial fibrillation | |
| Radiofrequency ablation of atrial fibrillation | ||
| Beta blockers | Atenolol 12.5-100 mg | |
| Metoprolol 12.5-200 mg | ||
| CCBs | Verapamil 120-360 mg | |
| Diltiazem 120-540 mg | ||
| Treat myocardial ischemia | Coronary revascularization (coronary artery bypass surgery or percutaneous coronary intervention) | |
| Nitrates | Isosorbide dinitrate 30-180 mg | |
| Isosorbide mononitrate 30-90 mg | ||
| Beta blockers | Atenolol 12.5-100 mg | |
| Metoprolol 12.5-200 mg | ||
| CCBs | Amlodipine 2.5-10 mg | |
| Verapamil 120-360 mg | ||
| Diltiazem 120-540 mg |
PATHOPHYSIOLOGY
To date, the pathophysiology of diastolic heart failure is incompletely understood and is not directly addressed by any drugs currently available. The core feature of diastolic heart failure is inadequate LV diastolic filling, which is a consequence of both impaired LV relaxation and increased LV stiffness. Several mechanisms contribute to these processes, including increased myocardial mass and changes in the extracellular matrix caused by excess fibrillar collagen. Ventricular relaxation is an energy-dependent process and is often impaired when myocardial ischemia is present. Hypertension, LVH, and fibrosis caused by scarring from myocardial infarction (MI), dilated cardiomyopathy, or aging all lead to increased myocardial stiffness. Additional etiologies include pericardial diseases, infiltrative cardiomyopathies, and hypertrophic cardiomyopathy. Each increases myocardial stiffness and produces diastolic dysfunction.
Just as in heart failure with impaired LV function, neurohormonal and endothelial activity play important roles in diastolic heart failure. Activation of the RAAS contributes to increased myocardial stiffness, partly by increasing reactive collagen deposition. The collagen matrix is particularly active in heart failure, leading to both enhanced collagen synthesis and a higher turnover of collagen. The ratio of myocardial fibroblasts to myocytes is 4 : 1, implying the important role of collagen in myocardial growth and hypertrophy. Angiotensin II and aldosterone stimulate hypertrophy and proliferation of cells and stimulate collagen synthesis by fibroblasts, leading to LV remodeling, including hypertrophy. Therefore, one could postulate that reducing RAAS activity with agents such as angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone receptor blockers is beneficial in patients with diastolic heart failure, just as in systolic heart failure.
Increased LV stiffness and decreased compliance of the ventricle are reflected in the pressure-volume loop curve such that for any given LV volume, a higher LV diastolic pressure is observed. Likewise, for any pressure, the LV end diastolic volume is much smaller. Pulmonary congestion ensues when the higher pressures are transmitted back to the lungs. All these lead to the typical symptoms of heart failure, including exertional dyspnea and diminished exercise tolerance. An exaggerated hypertensive response to exercise is often observed when patients with diastolic heart failure undergo exercise stress testing. This may be due to the high frequency of concomitant systemic hypertension.
CLINICAL RELEVANCE
General Treatment Guidelines
The goals of treatment of diastolic heart failure are similar to those of systolic heart failure. Not only do we seek to improve survival in our patients, but we also aim to improve our patients’ quality of life by reducing symptoms, increasing exercise tolerance, and decreasing hospitalizations. Like most disease states, treatment should be based on evidence derived from clinical trials. Practice guidelines are generally data driven, but when there are few data, consensus or expert opinion is provided. Most of the data from clinical trials have been exclusive to systolic heart failure. Although the mortality rate of patients with diastolic heart failure is not quite as high as that of systolic heart failure, it is nevertheless higher than in patients without heart failure. Moreover, there is significant morbidity associated with diastolic heart failure, and the hospitalization rate in the elderly remains close to that of systolic heart failure. Approximately one third to one half of all patients with manifest heart failure have preserved ejection fraction (EF). The incidence of diastolic heart failure depends on the local demographics. Hospitals in large inner-city neighborhoods will see much more diastolic heart failure, as poorly treated hypertension and elderly people are more common. Therefore it remains crucial that we learn more about effective treatment strategies for patients with diastolic heart failure. However, lack of data from large clinical trials is reflected in the practice guidelines set forth by the experts.
The practice guidelines on chronic heart failure of the American College of Cardiology/American Heart Association (ACC/AHA) were revised in 2005 and include a section on patients with heart failure and normal LVEF. The recommendations listed by the task force are presented in Table 32-2 .
| Class I | Level of Evidence |
|---|---|
| A |
| C |
| C |
| Class IIa | Level of Evidence |
|---|---|
| C |
| Class IIb | Level of Evidence |
|---|---|
| C |
| C |
| C |
Class I recommendations include control of hypertension, control of ventricular rate in patients with atrial fibrillation, and use of diuretics to control pulmonary congestion and peripheral edema. Coronary revascularization in patients with heart failure and normal EF and coronary artery disease is a class IIa recommendation. Restoration and maintenance of sinus rhythm in patients with atrial fibrillation, heart failure, and normal EF may improve symptoms and is a class IIb recommendation. Due to a paucity of data to guide management of patients with diastolic heart failure, a class IIb recommendation is given to beta blockers, ACE inhibitors, ARBs, and calcium channel blockers (CCBs). Efficacy of digitalis to minimize symptoms of heart failure in patients with a normal EF is not well established, and its use is also a class IIb recommendation. The task force emphasized the need to eliminate other conditions that may contribute to heart failure with a normal EF.
The Heart Failure Society of America (HFSA) also produced an executive summary on its Heart Failure Practice Guidelines. These too include a section on evaluation and management of patients with heart failure and preserved LVEF ( Table 32-3 ). The guidelines highlight the necessity to obtain a differential diagnosis in these patients, as treatment may vary for differing conditions. The HFSA recommendations are similar to those of the ACC/AHA task force and stress the importance of evaluating for myocardial ischemia, controlling blood pressure, and counseling on salt restriction. Diuretic therapy is recommended in those patients with evidence of volume overload. ACE inhibitors are recommended in all patients with heart failure and preserved EF who have diabetes or atherosclerotic cardiovascular disease and one additional risk factor. The guidelines recommend that ARBs be used in patients who are intolerant of ACE inhibitors. Beta blockers are recommended in patients who have a history of MI, hypertension, or atrial fibrillation with rapid ventricular rate. CCBs are recommended in those patients who have atrial fibrillation but are intolerant to beta blockers, those with symptom-limiting angina, and those with hypertension. Finally, the guidelines recommend that sinus rhythm be restored and maintained in patients who have symptomatic atrial fibrillation or flutter.
| RECOMMENDATION | STRENGTH OF EVIDENCE | |
|---|---|---|
| C | |
| C | |
| C | |
| C | |
| C | |
| B or C respectively | |
| C | |
| C | |
| ||
| C | |
| B | |
| B | |
| ||
| C | |
| A | |
| C | |
| C | |
These guidelines are essentially based on observational studies. Other than for the ACC/AHA and HFSA guidelines, there are few recommendations to offer patients with diastolic heart failure. While there is no standardized treatment, attention needs to be paid to the individual patient and to potential etiologies of diastolic heart failure. Since no patient is quite like another, treatment strategies should be targeted to underlying mechanisms that could be contributing to heart failure in each individual.
Treatment of Underlying Disease and Contributing Factors
There are several conditions that contribute to or exacerbate diastolic heart failure. These include hypertension, LVH, myocardial ischemia, increased vascular stiffness, diabetes mellitus, renal failure, anemia, obesity, and pulmonary diseases. Furthermore, there may be external constraints on the myocardium and pericardium that render the left ventricle incapable of filling adequately, thereby mimicking diastolic heart failure. It is crucial to consider these conditions, as treatment of constrictive pericarditis is obviously quite different than that of systemic hypertension with LVH.
Hypertension
Hypertension is associated with an increase in left atrial (LA) pressure that contributes to increased LV diastolic pressure and delays early diastolic filling (see Chapter 19 ). Lowering the blood pressure allows the ventricle to relax more adequately, thereby increasing early diastolic filling. Furthermore, treating hypertension may reduce myocardial ischemia, which can also contribute to diastolic heart failure. Chronic hypertension leads to LVH, causing impaired LV compliance because of a stiffer ventricle. Antihypertensive therapy is critical in diastolic heart failure, as it induces LVH regression, improving diastolic performance and LV distensibility.
Klingbeil et al. published a meta-analysis of the effects of treatment on LV mass in essential hypertension. This meta-analysis of 80 clinical trials and over 4000 patients showed that anti-hypertensive drug classes had differing effects on LV mass reduction. ARBs produced a 13% reduction of LV mass index; CCBs, 11%; ACE inhibitors, 10%; diuretics, 8%; and beta blockers, 6% ( Fig. 32-1 ). ARBs, CCBs, and ACE inhibitors all reduced LV mass index more significantly than beta blockers. It is intuitive that with LVH regression, diastolic function might improve; however, it remains to be determined whether a greater reduction in LV mass improves clinical outcomes. Nevertheless, in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study, regression of Cornell product LVH was associated with 35% to 45% reductions in the risk of cardiovascular death, stroke, or MI, a 37% reduction in the composite endpoint, and a 28% reduction in all-cause mortality. It is very infrequent that single drug therapy is effective in reducing blood pressure, and we are often left to employ multiple agents to achieve goal blood pressure, especially in patients with concomitant diabetes mellitus.
While medical therapy and lower blood pressure contribute to LVH regression, one must not forget that weight loss, reduced salt intake, and exercise can also play roles in managing hypertension. A recent cross-sectional study showed that long-term caloric restriction ameliorates the decline in diastolic function in humans. Twenty-five patients with caloric restriction were compared with 25 age- and gender-matched healthy subjects on a standard Western diet and were found to have lower body mass index, systolic and diastolic blood pressures, and levels of inflammatory markers. Indices of diastolic function were improved in patients with caloric restriction compared with the matched controls on a Western diet; however, no change was found with respect to systolic function. It is unclear whether the effect of caloric restriction on diastolic function is independent of blood pressure; nevertheless, emphasis should be placed on targeting dietary modifications when advising patients.
Coronary Artery Disease
Myocardial ischemia or infarction is a major contributor to diastolic heart failure (see Chapter 22 ). One of the first hemodynamic parameters observed when a coronary artery is acutely occluded by angioplasty is a reduction in negative change in pressure versus time (−dp/dt). This change is manifested by an abrupt increase in LV end diastolic pressure before there are any changes in systolic function. These observations suggest that diastolic relaxation, known to be energy dependent, is exquisitely sensitive to myo-cardial ischemia, even more so than systolic function. The pressure-volume relationship is shifted up and to the left. The chamber stiffness constant, k , achieves a greater slope. Fibrosis produced by scarring from a prior infarction also contributes to LV stiffening. Diastolic heart failure is primarily a disease of the elderly, and it is in this population that the prevalence of coronary artery disease is most high. There are no data demonstrating that coronary revascularization leads to an improvement in diastolic heart failure outcomes. Revascularization alone, without further medical therapy, has not been shown to reduce the incidence of pulmonary edema. In fact, one study showed that pulmonary edema occurred in 50% of patients within 6 months after revascularization. Despite this, it is essential that screening for coronary artery disease be performed, either by invasive or noninvasive techniques, as myocardial ischemia is a well-established cause of diastolic heart failure.
Diabetes
Diabetes mellitus and impaired glucose metabolism contribute to LVH and arterial stiffness, which impair LV relaxation and distensibility (see Chapter 26 ). Furthermore, the prevalence of coronary artery disease is higher in patients with diabetes, and there may be more underlying microvascular disease. The advanced glycation of proteins forms complex compounds known as advanced glycation end-products (AGEs), which cross-link and polymerize with other proteins. These cross-links with collagen alter vascular compliance, resulting in loss of elasticity and increased vascular stiffness. This process occurs with normal aging but is often accelerated in the presence of diabetes. In hypertensive patients without diabetes, fasting plasma glucose is associated with adverse diastolic function independent of LVH. Several studies have reported that insulin resistance in nondiabetic patients with hypertension is associated with diastolic dysfunction. In fact, hypertension and diabetes mellitus are a dominant force in the development of systolic and diastolic heart failure, and the combination of the two is associated with more severe abnormal LV relaxation.
It is not unreasonable to conclude that treating diabetes and improving glucose control may be favorable in patients with diastolic heart failure. Nevertheless, some studies have shown that an improvement in glycemic control in patients with type II diabetes mellitus does not ameliorate diastolic function in spite of regression of LVH. It may be that improved glycemic control has little effect on the already present AGEs responsible for collagen cross-linking and fibrosis. The LIFE study noted that patients with diabetes have less regression of LVH than those without diabetes in response to antihypertensive therapy. Additionally, regression of Cornell product LVH with antihypertensive therapy was associated with a reduction in the composite endpoint in the nondiabetic population, but this did not appear to be the case in patients with diabetes. These observations stress the importance of prevention, early strict glycemic control, and blood pressure control.
Some experimental studies have been conducted on diabetic animal models. Studies in prediabetic rats as well as in advanced diabetic rats have consistently demonstrated that peroxisome proliferator-activated receptor (PPAR) ligands improve glucose and lipid metabolism, as well as prevent LV diastolic dysfunction. PPAR-α agonists such as pioglitazone or rosiglitazone not only improve insulin resistance but facilitate endothelial function. Recent studies have confirmed the existence of endothelial dysfunction in patients with systolic heart failure, and we can perhaps assume that this is altered in patients with diastolic heart failure as well. Nonetheless, endothelial dysfunction has been implicated in the pathophysiology of hypertension, which is closely associated with development of diastolic heart failure. It is plausible that PPAR ligands may be useful in diabetic patients with diastolic heart failure, although randomized double-blind studies are needed, especially since PPAR agonists have been noted to promote fluid retention and exacerbation of heart failure.
Patients with impaired diastolic function can remain asymptomatic for years without evident heart failure. LA hypertrophy and forceful LA contraction can augment late diastolic filling. However, in patients with atrial fibrillation, this useful mechanism is absent, invoking an augmentation of LA pressure. The left atrium then acts more as a simple conduit and cannot propel blood easily into the thickened, nondistensible left ventricle. Pulmonary congestion ensues and consequently symptomatic heart failure. Therefore, it is usually advantageous to restore and maintain sinus rhythm in patients with diastolic heart failure. When this is not feasible, it is important to at least control ventricular rate, as tachycardia reduces the time for complete relaxation and may be hazardous to patients with diastolic dysfunction. Slowing the heart rate enables more time for diastolic filling and thus better coronary perfusion and LV performance.
Specific Therapies
Diuretics
Life-threatening pulmonary edema can occur in patients with diastolic heart failure. It can be a dramatic presentation and should be promptly treated, as in any case of acute pulmonary edema. Severe systemic hypertension is frequently present and must be aggressively treated. Acute myocardial ischemia, mycardial infarction, and rapid atrial fibrillation must also be identified, and if evident, promptly treated. Intravenous diuretics, nitrates, oxygen, and in some cases morphine sulfate are frequently employed. Intubation and ventilatory support may be necessary, and patients with chronic or acute renal failure may sometimes need urgent dialysis. Intravenous furosemide and nitrates should be employed judiciously, as patients with diastolic heart failure and small LV chambers may be more easily volume depleted than patients with large, dilated, poorly contracting hearts. This is particularly the case when there is an absence of systemic hypertension, making diastolic heart failure difficult to treat. The diastolic pressure-volume curve is steep, implying that small changes in volume result in large changes in pressure, and therefore a significant drop in cardiac volume can produce hypotension and reduced cardiac output.
Diuretics have no direct effect on actual diastolic function, but they can reduce central blood volume. Loop diuretics preferentially are utilized in treating volume overload, whereas thiazide diuretics are more useful for control of blood pressure. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) demonstrated that chlorthalidone was superior to both amlodipine and lisinopril in hypertensive patients. Interestingly, this benefit was even more prominent in African-American participants. Several studies have confirmed that African-American patients do not respond as well to blockers of the RAAS; this may be due to inherent lower plasma renin levels. However, a substantial number of patients with heart failure have some degree of renal insufficiency, and thiazide diuretics are well known to be ineffective when there is reduced glomerular filtration.
Nitrates
Nitrates are frequently used along with diuretics in the treatment of acute pulmonary edema. They assist in alleviating pulmonary congestion while acting primarily as venodilators. Unlike diuretics, however, nitrates may also exert their action on the ventricle by releasing endothelial nitric oxide, thereby improving ventricular distensibility. Nitrates are predominantly useful in cases of hypertensive pulmonary edema and are often used either sublingually or intravenously. Like diuretics, nitrates must be cautiously used, as hypotension can occur. Large doses of nitroglycerin must be given to achieve arteriolar dilation (i.e., to lower blood pressure), whereas smaller doses of nitroglycerin (i.e., 40 μg/min) lower venous pressure through dilation of large-capacitance veins and thereby reduce pulmonary congestion without reducing blood pressure.
Beta Blockers
It has become standard practice to incorporate beta blockers into the treatment of coronary artery disease, hypertension, and more recently systolic heart failure. Prior studies have shown that beta blocker treatment in patients with systolic heart failure is associated with improved ventricular performance, a higher EF, and increased survival. Despite the paucity of data with beta blockade and diastolic heart failure, it is not unreasonable to infer that beta blockade is also valuable in the treatment of diastolic heart failure.
Beta blockade may exert its actions on diastolic heart failure via several distinct mechanisms. Coronary artery disease is a common comorbidity in the elderly hypertensive patient manifesting with heart failure and a preserved EF. Myocardial ischemia may instigate heart failure, and it has been shown that beta blockers improve symptoms and survival in patients with coronary artery disease. Administration of beta blockers likely relieves ischemia and may play a role in preventing diastolic heart failure. Additionally, beta blockers are effective in reducing tachycardia. Tachycardia is generally not well tolerated in patients with diastolic dysfunction, as it reduces diastolic time, thereby reducing the time for complete relaxation and LV filling, thus contributing to elevated diastolic pressure. Furthermore, tachycardia is not well tolerated in myocardial ischemia, due to increased myocardial oxygen demand and decreased time allowed for coronary perfusion. For these reasons, beta blockers are also advantageous in the setting of atrial fibrillation and a rapid ventricular rate.
As with systolic heart failure, beta blockers can suppress the deleterious effects of chronic activation of the sympathetic nervous system, thereby improving autonomic balance and reducing ventricular wall stress. Beta blockers, still useful as effective anti-hypertensive agents, elicit LVH regression, though not to the same degree as other antihypertensive agents. The analysis of the LIFE study, in which atenolol was shown to be inferior to losartan with regard to the composite primary endpoint of cardiovascular death, stroke, and MI, supports the contention that beta blockers are less effective in LVH regression than ARBs.
Although there are no large-scale randomized trials assessing the efficacy of beta blockers in patients with heart failure and preserved EF, a few smaller-scale trials have been performed. Differing patient populations and small sample sizes have produced conflicting results, and there are essentially no serious outcomes data.
One of the earlier studies randomized 158 elderly patients with a prior history of MI, heart failure, and an EF greater than 40% to propranolol or placebo. All patients were treated with ACE inhibitors and diuretics and followed for 32 months. The authors demonstrated that there was a 35% reduction in total mortality and a 37% reduction in combined total mortality and nonfatal MI in patients randomly allocated to propranolol. The mortality reduction seems quite high in the face of the small sample size and portrays a higher benefit of beta blockers than was reported in the larger-scale Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalizations in Seniors with Heart Failure (SENIORS). It may very well be that the mortality benefit observed with propranolol is attributable to these patients having underlying coronary artery disease, with improvement of myocardial ischemia driving the benefit rather than direct improvement in actual diastolic function.
The SENIORS trial randomized 2128 elderly patients with heart failure to nebivolol versus placebo. Nebivolol is a beta-1-selective blocker that modulates nitric oxide and serves as a vasodilator but is not yet approved for use in the United States. This study was not exclusive to diastolic heart failure, with a mean EF of 36%. Only 35% of patients had an EF greater than 35%. The primary outcome consisted of a composite of all-cause mortality or cardiovascular hospitalizations. These endpoints occurred in 31.1% of patients receiving nebivolol compared with 35.3% of patients receiving placebo. The hazard ratio in favor of nebivolol was 0.86, with a p value of nominal significance ( p = 0.039). In SENIORS, 68% of patients had documented coronary artery disease. Subgroup analyses were performed in patients with EFs less than and greater than 35%. The hazard ratios for the primary outcome were 0.87 and 0.82, respectively, indicating no differential effect on preserved or low EF. The benefit of nebivolol was not as robust as that observed with beta blockers in systolic heart failure, such as was demonstrated with carvedilol in the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) and bisoprolol in the Cardiac Insufficiency Bisoprolol Study (CIBIS) II. The population studied in the SENIORS trial was older; the inclusion criteria was age older than 70 years, which produced a mean age of 76 years. Subgroup analysis demonstrated that patients younger than 75 years had a greater reduction in all-cause mortality or cardiovascular hospitalizations with nebivolol (17.4%) than placebo (22.5%) compared with those older (24.6% vs. 26.7%). These observations support the contention that large clinical trials in older patients will have many noncardiovascular deaths, making “all-cause mortality” a poor choice for an endpoint.
These studies looked primarily at clinical outcomes of patients with diastolic heart failure and did not focus on actual diastolic function. However, there are studies that sought to ascertain this notion. Echocardiographic parameters are utilized to determine stages of diastolic dysfunction, and studies have consistently confirmed that beta blocker usage is associated with improved diastolic function. A study published in 2000 showed that in 45 patients with depressed EF, administration of carvedilol significantly increased deceleration time of early diastolic filling. The authors demonstrated an improvement in diastolic function: 77% of patients with a baseline restrictive filling pattern reverted to normal or pseudonormal filling patterns after carvedilol therapy, and 71% of patients with an abnormal relaxation pattern changed to a normal filling pattern. The Swedish Doppler-echocardiographic study (SWEDIC) was comprised solely of patients with heart failure and preserved systolic function. In this study, 113 patients were randomized to carvedilol or placebo for 6 months. The primary endpoint was change in the integrated quantitative assessment of all four Doppler variables of diastolic function. These are (1) E/A ratio (early diastolic filling velocity to atrial late diastolic filling velocity), (2) mitral atrial (A)-wave duration compared with pulmonary venous atrial duration, (3) isovolumic relaxation time, and (4) pulmonary venous systolic/diastolic velocity. Although there was no effect on the primary endpoint, there appeared to be a trend toward improved diastolic function in patients treated with carvedilol. A statistically significant improvement in E/A ratio was found in patients treated with carvedilol ( p = 0.046). This finding may be purely a result of lowering the heart rate. As expected, heart rate decreased significantly in the carvedilol group (from 74 to 60 bpm), although there was no significant reduction in systolic and diastolic blood pressure. When subgroup analysis was performed, the benefit of carvedilol on E/A ratio was exclusive to patients with baseline heart rates greater than 71 bpm ( p = 0.002). In those with low heart rates (<71 bpm), there was no effect. Although the study was not powered for mortality, other measurements were assessed. A trend toward worsening New York Heart Association (NYHA) class with carvedilol treatment was observed, though it was not statistically significant.
Patients likely to benefit from beta blocker therapy include those with known coronary artery disease, myocardial ischemia, and tachycardia. Lowering the heart rate to less than 71 bpm may not provide any incremental benefit of improved diastolic filling and diastolic function as seen in the SWEDIC trial. Beta blockers may also be valuable in patients with atrial fibrillation to control heart rate, lower blood pressure, and alleviate myocardial ischemia. Finally, beta blockers are still widely used in the treatment of hypertension, though other agents have been shown to provide more LVH regression.
Angiotensin-Converting-Enzyme Inhibitors
It has been well established that ACE inhibitors are beneficial in patients with chronic heart failure and reduced EF. Landmark trials such as the Studies of Left Ventricular Dysfunction (SOLVD) and the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) demonstrated that ACE inhibitors improve survival as well as slow the progression of heart failure in patients with depressed EF. Most of the clinical trials that have shown a benefit in patients with heart failure have excluded those with preserved EF, as a low EF was usually a criteria for entry. Several randomized studies have also shown a benefit of ACE inhibitors in patients post-MI, as in the Survival and Ventricular Enlargement (SAVE) trial, as well as in patients with high-risk factors, as in the European Trial of Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) and the Heart Outcomes Prevention Evaluation (HOPE) study. These trials have consistently demonstrated an improvement in survival and EF and a reduction in heart failure. ACE inhibitors may be beneficial in that they improve compliance of blood vessels, cause regression of LVH, restore flow-mediated dilation in blood vessels, and improve endothelial function in patients with heart failure. Additionally, ACE inhibitors play a vital role in modifying myocardial remodeling that occurs with systolic heart failure, LVH, post-MI, and activation of the RAAS. Theoretically, agents that block the RAAS should likewise be beneficial in patients with heart failure and preserved EF.
Very little data exist on the utility of ACE inhibitors in heart failure patients with preserved EF. Despite this, several observational studies have demonstrated that patients with diastolic heart failure prescribed ACE inhibitors had longer survival as well as a shorter length of stay during index hospitalization.
To address this issue, the Perindopril for Elderly People with Chronic Heart Failure (PEP-CHF) clinical trial is under way. In the PEP-CHF study, 850 elederly patients with LVEF between 40% and 50% and a history of heart failure and abnormal diastolic dysfunction were randomized either to perindopril or to placebo. The primary endpoint was a composite of all-cause mortality and heart failure hospitalizations and was achieved in 25.1% of patients randomized to placebo versus 23.6% of patients randomized to perindopril ( p = 0.545). However, when analysis was conducted at one-year follow-up, patients randomized to perindopril had significantly fewer heart failure hospitalizations, improvement in NYHA class, and an increase in six minute walking distance. The mean follow-up of the study was 26.2 months; however, after one year, a large percentage of the patients were unblinded, and over one third of patients were taking open-label ACE inhibitors by the end of the study. This could explain why there was no statistical difference in the overall primary endpoint in spite of a difference in subgroup analysis at one year follow-up.
A small study conducted in 1993 examined the effect of enalapril on congestive heart failure in elderly patients with prior MI and normal LVEF. In this study, 21 patients with NYHA class III heart failure who required diuretics were randomized to 3 months treatment with enalapril or placebo. Enalapril was found to significantly improve NYHA functional class, systolic and diastolic blood pressure, EF, and exercise tolerance and to reduce LV mass. Enalapril also led to improvement in diastolic parameters such as increased peak mitral E/A ratios.
Another trial examined the long-term Effects of Amlodipine and Lisinopril on LV Mass and Diastolic Function: E/A Ratio (ELVERA) in elderly, previously untreated hypertensive patients. This study randomized 166 patients to either amlodipine or lisinopril. Both drug therapies led to equivalent reductions in systolic and diastolic blood pressures, reduction in the LV mass index, and improvement in the E/A ratio. The authors demonstrated that even when blood pressures were stabilized in the second year of drug treatment, reduction of LV mass continued to take place. Although there appeared to be an improvement in diastolic function based on echocardiographic parameters, clinical outcomes were not assessed in this study.
It is well known that patients with chronic kidney disease have a propensity to develop LVH and diastolic heart failure. In fact, several reports have documented that diastolic dysfunction exists in children with chronic kidney disease on hemodialysis. Diastolic dysfunction poses a problem for the individual with chronic kidney disease, since hypotension during dialysis is a common occurrence. There are conflicting reports on whether kidney transplantation serves to improve diastolic dysfunction or not. Nevertheless, there may be a role for drug therapy. ACE inhibitors have been shown to be effective in slowing the progression of renal disease in both the diabetic and nondiabetic populations, as well as reducing protein excretion in diabetics by 35% to 40%. Additionally, ACE inhibitors have been shown to induce regression of LVH that is associated with a significant improvement in diastolic function in hypertensive patients with chronic renal failure. It may be challenging to interpret diastolic dysfunction in patients with renal failure because the Doppler indices of diastolic dysfunction are preload dependent and have been known to change during hemodialysis. Controversy exists over whether ACE inhibitors are equally efficacious in differing population subgroups. Most of the patients enrolled in clinical trials are Caucasian males, and we should not assume that these benefits will apply to women and non-Caucasians. Several studies have indicated that African-American patients are less likely to benefit from monotherapy with ACE inhibitors and ARBs than diuretics and CCBs compared with Caucasians. A pooled analysis from the SOLVD prevention and treatment trials demonstrated that enalapril therapy was associated with a significant reduction of heart failure hospitalizations among Caucasian patients with LV dysfunction, but not among African-American patients. Additionally, this analysis showed that both systolic and diastolic blood pressure reduction was more effective in Caucasian patients, whereas there was no significant difference in African-American patients.
A meta-analysis of the ACE inhibitor trials indicates that women are not as likely to benefit from these agents as men. It appears that men have a significant mortality reduction from treatment with ACE inhibitors (relative risk, 0.82), whereas women have a more modest mortality benefit (relative risk, 0.92). Women with symptomatic LV dysfunction have a slight mortality benefit (relative risk, 0.90), although not to the same degree as men. Mortality benefit is not observed in women with asymptomatic LV dysfunction (relative risk, 0.96). In men, there is a significant mortality benefit in both symptomatic and asymptomatic LV dysfunction groups. It is unclear why these differences exist, and evidently future studies are warranted.
Despite the paucity of data on ACE inhibitors in patients with heart failure and preserved EF, we still advocate their use in the treatment of diastolic heart failure. ACE inhibitors are effective in patients with hypertension as well as in those with vascular disease, both of which associate with diastolic heart failure. ACE inhibitors may be effective tools for primary prevention in that their use has been related to prevention of heart failure, diabetes, and even new or recurrent atrial fibrillation. Efficacy of ACE inhibitors is related to higher dosages. However, it is best to start at a lower dose and carefully uptitrate monthly, as hypotension continues to remain a risk in patients with diastolic heart failure receiving vasodilator therapy. Similarly, renal function must be closely monitored, as a substantial rise in blood urea nitrogen (BUN) and creatinine can occur when there is baseline renal insufficiency or simultaneous renovascular disease. Serum potassium should also be monitored frequently as hyperkalemia can frequently occur. Special consideration should be given in the elderly, as their creatinine clearance is usually lower, with even mild elevations in serum creatinine levels.
Angiotensin Receptor Blockers
ACE inhibitors are historically preferred over ARBs when treating patients with heart failure and depressed EF because the former have been available longer. ARBs are usually reserved for use in those who are intolerant of ACE inhibitors. There is little evidence to support one or the other in heart failure with preserved EF. The ACC/AHA guidelines give both drug classes a class IIb recommendation. To date, the largest randomized clinical trial in patients with heart failure and preserved EF conducted is the CHARM-Preserved trial.
CHARM-Preserved examined the effects of candesartan in patients with chronic heart failure and preserved LVEF. This trial was part of the overall CHARM program. CHARM-Preserved enrolled 3023 patients, randomizing them to either candesartan or placebo with a mean follow-up of 36.6 months. The primary endpoint consisted of combined cardiovascular death and hospitalizations related to heart failure. There was a slight relative risk reduction of 11% in the primary outcome among LV preserved patients treated with candesartan; however, this improvement was marginal (unadjusted p = 0.118, covariate adjusted p = 0.051) ( Fig. 32-2 ). Although cardiovascular death did not differ between the two groups, there did appear to be a significant reduction in heart failure hospitalizations with use of candesartan ( p = 0.017). There was also a trend toward reduced cardiovascular events with candesartan, although the results were not significant.
