All patients should keep a diary of daily weight and blood pressure. These two parameters are of extreme importance in evaluating for underdiuresis and overdiuresis. When patients are educated about looking for increased weight gain and increasing blood pressure, they can alert their health care provider in a timely fashion in order to allow for intervention prior to progression of HF, which invariably leads to hospitalization.
Several studies have now shown that patients with HFpEF benefit from exercise training. Thus, in symptomatic HFpEF patients who can exercise, prescribed exercise training should be considered.
An innovative wireless hemodynamic monitor (CardioMEMS), implanted percutaneously in the pulmonary artery, was shown in the CHAMPION trial (N = 550) to reduce HF hospitalizations compared to placebo in HFpEF (16% vs. 33%, P < 0.0001). The CHAMPION trial has been the only clinical trial to show a clear benefit in HFpEF, and although not yet U.S. Food and Drug Administration approved, devices like CardioMEMS may play a big role in HFpEF management in the future.
Finally, catheter-based renal denervation therapy has resulted in significant lowering in blood pressure and regression of LV hypertrophy in patients with resistant hypertension. Although clinical trials of renal denervation in HFpEF are lacking, this therapy may be very important in the future for prevention and treatment of HFpEF.
Abraham WT, et al. CHAMPION Trial Study Group. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet
. 2011; 377(9766):658–66.
Kitzman DW, et al. Exercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. Circ Heart Fail.
Sobotka PA, et al. The role of renal denervation in the treatment of heart failure. Curr Cardiol Rep
Taylor RS, et al. Effects of exercise training for heart failure with preserved ejection fraction: a systematic review and meta-analysis of comparative studies. Int J Cardiol
. 2012 Jun 2. [Epub ahead of print]
Treatment of HFpEF remains empiric. Compared to HFrEF, there is a relative paucity of randomized controlled trial data to guide treatment. To date, only few large randomized trials have specifically studied patients with HFpEF. The major trials include DIG-PEF, CHARM-Preserved, I-PRESERVE, PEP-CHF, and SENIORS.
In the DIG trial, digoxin did not decrease mortality, and although there was a trend toward decreased hospitalization, there was also a trend toward increased unstable angina. Digoxin increases systolic energy demand and adds to calcium overload in diastole and may be deleterious to patients with HFpEF; therefore, it is generally not recommended. If digoxin is necessary for rate control in patients with HFpEF who have atrial fibrillation, digoxin concentration should be kept at 0.5–0.9 ng/mL since higher concentrations were associated with increased mortality in the DIG trial.
In the CHARM-Preserved trial of mostly male patients with ejection fraction > 40%, candesartan, an angiotensin receptor blocker, was associated with a slight decrease in hospitalization but no difference in mortality when compared with placebo. The large I-PRESERVE trial (N = 4128) enrolled HFpEF patients who more closely matched with those encountered in clinical practice (60% female with a mean age of 72 years). However, I-PRESERVE, which studied irbesartan versus placebo, also found no improvement in outcomes with angiotensin receptor blocker therapy in HFpEF.
The PEP-CHF trial, which studied perindopril (an angiotensin-converting enzyme inhibitor [ACEI]), and SENIORS, which studied nebivolol (a vasodilating β-blocker), both included patients with HF and preserved or relatively preserved ejection fraction, and both did not show major benefits in terms of improved hard outcomes.
Despite these disappointing results, a few recent clinical trials in patients with HFpEF demonstrate that there may be beneficial therapies on the horizon. In a small randomized controlled trial (N = 44) of sildenafil in patients with HFpEF, pulmonary venous hypertension, and superimposed pulmonary arterial hypertension (ie, PADP-PCWP gradient > 5 mm Hg), sildenafil resulted in improved cardiac structure/function and improved exercise capacity. In PARAMOUNT, a phase 2 randomized controlled trial (N = 301) of a novel class of drug (angiotensin receptor neprilysin inhibitor LCZ696), patients with HFpEF randomized to the LCZ696 had greater reduction, compared to placebo, in N-terminal proBNP and left atrial volume at 3 months. LCZ696 was well tolerated, and there were also less serious adverse outcomes in the LCZ696 arm, although this finding did not reach statistical significance (15% vs. 30%, P = 0.32).
Since extensive randomized controlled trial data for HFpEF are not available, treatment of HFpEF relies on extrapolation of therapies for HFrEF, nonspecific relief of congestion, and ameliorating the underlying disease processes and comorbidities. Table 27–3 lists the most important treatment priorities for patients with HFpEF, as outlined below.
Table 27–3. Treatment of Heart Failure with Preserved Ejection Fraction: General Principles ||Download (.pdf)
Table 27–3. Treatment of Heart Failure with Preserved Ejection Fraction: General Principles
Treat underlying causes and precipitating factors
Treat congestion and edema
Ultrafiltration or dialysis (when diuretics are insufficient)
Aggressively treat hypertension
Use vasodilating β-blockers (eg, carvedilol), ACEIs or angiotensin receptor blockers, and thiazide diuretics whenever possible
Control heart rate and rhythm
Goal heart rate ∼60 bpm (use caution in patients with advanced diastolic dysfunction or restrictive cardiomyopathy who require increased heart rates to maintain cardiac output because of fixed stroke volume, and also consider the diagnosis of chronotropic incompetence in patients who do not tolerate heart rate–lowering agents)
Maintain sinus rhythm (cardioversion, ablation)
Pacemaker therapy (when necessary) to maintain atrioventricular synchrony or for patients who have chronotropic incompetence
Myocardial ischemia (medications, revascularization)
Dyslipidemia (preferably with statins for pleiotropic benefit)
Chronic kidney disease
Instruct patients to keep diary of daily weight and blood pressure
Prescribe exercise training (cardiac rehabilitation) in mild-to-moderate heart failure to improve functional status and decrease symptoms
Treat obstructive sleep apnea, sleep-disordered breathing, and nocturnal hypoxia
For symptomatic relief, the most important first step is to reduce the congestive state. Salt restriction and vasodilator therapy (ACEI, angiotensin receptor blockers, or hydralazine/nitrates) make up the cornerstone of treatment. Diuretics and other forms of fluid removal (eg, dialysis, ultrafiltration) are often needed, but as the acute congestive episode resolves, it is important to minimize diuretic therapy, since overdiuresis activates a heightened neurohormonal response and aggravates the cardiorenal syndrome.
From an electrophysiologic standpoint, it is important, whenever possible, to maintain atrial contraction and atrioventricular synchrony. Therefore, patients with atrial fibrillation or atrial flutter should undergo cardioversion or ablation. When necessary, patients should undergo pacemaker therapy to ensure atrioventricular synchrony or to treat chronotropic incompetence.
In some patients with HFpEF, it is ideal to promote bradycardia and avoid tachycardia. Tachycardia increases myocardial oxygen demand and decreases coronary perfusion time, which promotes diastolic dysfunction due to ischemia even in the absence of epicardial coronary disease. In addition, the time allotted for LV relaxation is decreased and diastolic filling time is decreased when tachycardia is present. By inducing relative bradycardia (eg, heart rate 50–60 bpm), coronary perfusion is optimized, and LV relaxation and diastolic filling time are both increased. Patients who benefit most from this type of treatment are most likely those who have impaired LV relaxation and prolonged early mitral inflow deceleration times. In patients with more severe, end-stage HFpEF, such as severe restrictive cardiomyopathy, increased heart rate may be the most important factor maintaining cardiac output, since stroke volume is often decreased and fixed. These patients invariably have a very high early mitral inflow velocity and short deceleration time. Although tachycardia should be avoided, heart rates of 80–90 bpm are often required in order to maintain adequate cardiac output. In these patients, overzealous β-blockade or nondihydropyridine calcium channel blocker therapy can result in a precipitous decline in cardiac output.
Most patients with HFpEF will benefit from rate control therapy with medications such as β-blockers and nondihydropyridine calcium channel blockers (verapamil, diltiazem). A good rule of thumb to follow when choosing β-blockers is that metoprolol succinate is a good agent in patients who have problems with rate control (eg, atrial fibrillation) and those with low or normal blood pressure. In patients who have severe hypertension, carvedilol is the agent of choice since it has potent antihypertensive effects due to its α-adrenergic blockade properties. Most patients with HFpEF have significant hypertension; thus carvedilol is typically a first-line drug for most HFpEF patients. In the COHERE registry, which was an observational study, treatment with carvedilol resulted in improved outcomes compared to other β-blockers, regardless of the underlying LV ejection fraction.
As stated earlier, all patients should be evaluated for myocardial ischemia, and when present, ischemia should be treated aggressively with revascularization, β-blockers, nitrates, and dihydropyridine calcium channel blockers. Hypertension should be treated aggressively with goal blood pressure < 130/80 mm Hg. Control of hypertension is the only proven therapy for prevention of HFpEF, and therefore is essential in all patients. HFpEF patients commonly have severe hypertension, and when they are referred, they may be taking four or five or more antihypertensive medications. The number of medications should be kept to a minimum in order to avoid the dangers of polypharmacy and adverse drug–drug interactions. In addition, minimizing medications will often promote increased patient compliance. Patients with HFpEF and severe hypertension are often taking medications such as clonidine and minoxidil, while other medications with proven cardiovascular benefits, such as β-blockers and ACEIs, are not titrated to maximum doses. Therefore, patients with significant hypertension should ideally be treated with a vasodilating β-blocker and maximum dose of an ACEI or angiotensin receptor blocker, unless contraindicated. Most patients will also benefit from a thiazide diuretic such as chlorthalidone. Routine use of more potent thiazides, such as metolazone, should be avoided since these medications often exacerbate the cardiorenal syndrome. Aldosterone antagonists can be very useful in HFpEF patients both for controlling blood pressure and for improving diuresis. However, these patients should be monitored closely for hyperkalemia. The utility of spironolactone in HFpEF is currently being evaluated in the TOPCAT randomized controlled trial.
In patients with severe, resistant hypertension who cannot be treated adequately with a combination of β-blockers, ACEIs, and thiazide diuretics, the following steps should be taken: (1) ensure medication compliance, (2) ensure euvolemia since fluid overload will exacerbate hypertension, and (3) look for causes of secondary hypertension. Using these steps, most patients will have adequately controlled blood pressure with two or three medications. In patients who need an additional agent, the combination of hydralazine and nitrates is a good option given their beneficial effects in HF. If tolerated and not associated with increased lower extremity edema, dihydropyridine calcium channel blockers may also be used to treat severe hypertension. These agents are often useful in patients who have significant chronic kidney disease since they may not be able to take ACEIs, angiotensin receptor blockers, or aldosterone antagonists.
Besides beneficial antihypertensive effects, β-blockers, ACE inhibitors, and angiotensin receptor blockers attenuate neurohormonal activation, which may be beneficial in HFpEF. In addition, ACEIs, angiotensin receptor blockers, and spironolactone may prevent fibrosis and may promote regression of LV hypertrophy. Statins may have pleiotropic benefit in HF, and all HFpEF patients with dyslipidemia or coronary risk factors should be treated with a statin. Interestingly, in a large study of Medicare beneficiaries discharged with a primary diagnosis of HF and documentation of preserved ejection fraction, statins were associated with increased survival irrespective of total cholesterol, coronary disease, diabetes, hypertension, or age.
Categorization of HFpEF Subtype
As stated earlier, HFpEF is a heterogeneous syndrome. Once the HFpEF syndrome is diagnosed, patients can be further categorized clinically into etiologic and pathophysiologic subtypes in order to help guide therapy above and beyond the recommendations listed above. Table 27–4 summarizes these HFpEF subtypes and provides guidance to HFpEF subtype-specific treatment options.
Table 27–4. Treatment of Heart Failure with Preserved Ejection Fraction: Treatment Approaches by Subtype ||Download (.pdf)
Table 27–4. Treatment of Heart Failure with Preserved Ejection Fraction: Treatment Approaches by Subtype
“Garden variety” HFpEF: See Table 27–3 for general recommendations; several medications are often required for control of blood pressure. Treatment of comorbidities is essential.
Coronary artery disease HFpEF: These patients typically have multivessel coronary artery disease and/or a history of prior coronary artery bypass graft. Treatment of these patients involves revascularization (if indicated to improve symptoms), β-blocker, ACEI or angiotensin receptor blocker, statin, nitrate, and antiplatelet therapy.
Atrial arrhythmia-predominant HFpEF: In these patients, blood pressure is typically easy to control, but atrial arrhythmias can be difficult to control and result in HF exacerbations. Here, treatment with long-acting metoprolol succinate, a nondihydropyridine calcium channel blocker, and/or amiodarone (or other antiarrhythmic, if not contraindicated) can be helpful. Some patients may require further intervention with either catheter-based or surgical treatment of atrial arrhythmias.
Right heart failure HFpEF: These patients typically have right ventricular dysfunction and pulmonary hypertension that predominates their clinical course. Right heart catheterization should be performed to exclude pulmonary arterial hypertension or superimposed pulmonary arterial hypertension (on top of pulmonary venous hypertension). In patients with advanced right ventricular failure, cardiac output is reduced and systemic blood pressure can be low. Treatment is challenging and often requires a combination of diuretics (or ultrafiltration for refractory cases), digoxin (for right ventricular inotropy), and phosphodiesterase-5 inhibition (eg, sildenafil). Midodrine, an α-agonist, can be useful to support the systemic blood pressure if hypotension occurs during diuresis.
Hypertrophic cardiomyopathy (HCM)-like HFpEF:These patients are typically elderly with long-standing hypertension. They have echocardiographic characteristics that mimic HCM (moderate or severe LV hypertrophy [with or without asymmetric septal hypertrophy] and LV outflow tract or intracavitary obstruction). These patients should be treated like younger patients with genetic HCM. Treatment includes metoprolol succinate and/or nondihydropyridine calcium channel blockers, control of atrial arrhythmias, and avoidance of vasodilators. Diuretics should be used sparingly and with caution to avoid hypotension or syncope.
High-output HFpEF: Treatment of the underlying cause of the high-output state is essential. Diuretics will be the mainstay of treatment for fluid overload.
Rare causes of HFpEF: Treat the underlying cause of HFpEF, and understand the caveats of treatment (eg, for cardiac amyloidosis, the most common cause of infiltrative cardiomyopathy, besides working up and treating the underlying type of amyloidosis, certain drugs [eg, digoxin, nondihydropyridine calcium channel blockers, ACEIs/angiotensin receptor blockers] should be avoided, and all patients should be evaluated for anticoagulation given the high risk of atrial thrombi).
Some patients with HFpEF live a delicate balance between symptomatic congestion (due to inadequate diuresis) and poor cardiac output (due to overdiuresis). The latter causes lightheadedness, dizziness, fatigue, and worsening renal dysfunction due to decreased renal perfusion. Patients with HFpEF who have a classic physiologic picture of isolated “diastolic HF” rely on increased LV filling pressures to maintain cardiac output, and they tend to be very sensitive to overdiuresis, with small decreases in LV diastolic pressure resulting in large decreases in stroke volume. Therefore, it is important to start low and go slow with diuretic therapy. Many patients typically require frequent visits in order to find a diuretic regimen that results in optimal symptom control without exacerbating the cardiorenal syndrome.
In patients with hypertrophic cardiomyopathy, nondihydropyridine calcium channel blockers (verapamil, diltiazem) can be beneficial and therefore may be used as first-line therapy before β-blockade. Thiazide diuretics can exacerbate hyperglycemia and hyperuricemia, which are often present in elderly patients with HFpEF. Positive inotropes should be avoided in general because they promote calcium influx into cardiac myocytes, which worsens diastolic function. In addition, many of these patients have hypercontractile ventricles with small LV volumes. Therefore, positive inotropes frequently cause cavity obliteration with resultant obstruction of forward flow and decreased cardiac output. In patients with HFpEF who have non-ST elevation acute coronary syndromes, mortality is increased and patients are often undertreated. Therefore, all efforts should be made to treat this high-risk group (including an early invasive approach) using evidence-based guidelines.
Aside from treatment of hypertension, coronary disease, and atrial fibrillation (as listed earlier), it is important to treat other underlying comorbidities such as diabetes, metabolic syndrome, obesity, chronic kidney disease, and anemia. In addition, many patients with HFpEF have concomitant chronic obstructive pulmonary disease, which should also be treated aggressively in order to improve symptoms of breathlessness.
In all patients with HFpEF, it is important to avoid polypharmacy at all costs since adverse events increase and compliance decreases with increased numbers of medications. In addition, medications should always be carefully scrutinized as causes of signs and symptoms of HF. For example, calcium channel blockers and thiazolidinediones (eg, pioglitazone) can cause significant edema, nonsteroidal anti-inflammatory drugs (NSAIDs) can cause renal failure, and hydroxychloroquine (which is frequently used in rheumatologic diseases such as systemic lupus erythematosus and rheumatoid arthritis) can cause a restrictive cardiomyopathy. In the elderly cohort of patients with HFpEF, medications for Parkinson disease are common, and these agents have been shown to cause valvular disease. Certain foods and herbal supplements can also be deleterious in patients with HFpEF. Licorice can cause mineralocorticoid excess, ginseng interferes with warfarin, and ginseng also falsely elevates digoxin levels. Treatment of gout is difficult since NSAIDs are contraindicated in patients with HFpEF and colchicine is dangerous because many of these patients are elderly and have abnormal kidney function. In these patients, corticosteroid injection directly into the involved joint, a short pulse of oral corticosteroids, and colchicine 0.6 mg three times a week or allopurinol for maintenance therapy may be the best treatment options.
Ahmed A, et al. Effects of digoxin
on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation
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Yusuf S, et al. Effects of candesartan
in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet