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Nonpharmacologic Therapy
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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.
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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.
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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.
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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.
[PubMed: 21315441]
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. 2010;3(6):659–67.
[PubMed: 20852060]
Sobotka PA, et al. The role of renal denervation in the treatment of heart failure.
Curr Cardiol Rep. 2012;14(3):285–92.
[PubMed: 22392370]
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]
[PubMed: 22664368]
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Pharmacologic Therapy
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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.
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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.
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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.
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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.
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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).
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Categorization of HFpEF Subtype
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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.
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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.
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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.
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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.
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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. 2006;114(5):397–403.
[PubMed: 16864724]
Bennett KM, et al. Heart failure with preserved left ventricular systolic function among patients with non-ST-segment elevation acute coronary syndromes.
Am J Cardiol. 2007;99(10):1351–6.
[PubMed: 17493458]
Yusuf S, et al. Effects of
candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial.
Lancet. 2003;362(9386):777–81.
[PubMed: 13678871]