Management of Hypertension in Chronic Heart Failure

Saraswathy Manickavasagam; Ramanna Merla; Michael M Koerner; Ken Fujise; Sanjay Kunapuli; Salvatore Rosanio; Alejandro Barbagelata

Disclosures

Expert Rev Cardiovasc Ther. 2009;7(4):423-433. 

In This Article

Management of HTN in Patients with Reduced Ejection Fraction

Patients with HF may present either with reduced or normal ejection fraction. Despite the difference in ejection fraction, both groups have similar symptoms and signs. HFREF has been well studied but little is known about the benefits of treating coexisting HTN because blood pressure usually decreases as cardiac function declines and many patients do not live to see the benefits of long-term antihypertensive therapy.[19] HTN further worsens the loading conditions of the failing ventricle, and small increases in afterload can produce large decreases in stroke volume. For this reason, the blood pressure goal is less than 130/80 mmHg in these patients.[19] Many experts go further and suggest that patients reach the lowest blood pressure possible without symptoms or signs of hypoperfusion. Acceptable systolic blood pressures may be as low as 90 mmHg without symptoms or signs of hypoperfusion. However, a prospective study of 24-h blood pressure control in patients with HFREF demonstrated a high prevalence of significant daytime and nocturnal hypotension with the use of additional medical therapy. Over a 2-year follow-up, the group with the greatest burden of diastolic hypotensive events experienced more HF admissions, mortality and emergency admissions.[50]

Renin-angiotensin Inhibitors

Renin-angiotensin inhibitors include drugs that inhibit conversion of angiotensin I to angiotensin II (ACE inhibitors), block the angiotensin receptor (ARB) or block aldosterone receptors. A large body of data indicates that ACE inhibitors decrease the morbidity of patients with LV dysfunction, reduce hospitalization rates and reduce the risk of death by 1-4 years in patients at any stage of HF, including those who are asymptomatic and those who develop HF early after a myocardial infarction, making these agents first-line therapy for all categories of HF.[10,11,12,13,14] ACE inhibition also alleviates symptoms, improves clinical status and enhances the sense of wellbeing in patients with HF.[10] Mechanisms responsible for these beneficial effects include limitation of cardiac hypertrophy and fibrosis, reduction of ventricular wall stress and decreased efferent sympathetic traffic from the brain.[51]

Fortunately, although ACE inhibitors remain first choice, ARBs are an acceptable alternative, as shown in the Valsartan Heart Failure Trial (VAL-HeFT) and Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Alternative trials.[15,16]

The CHARM-Added and Val-HeFT trials also demonstrated that combining an ARB with ACE inhibitor reduces hospitalizations[52,53] but a more recent meta-analysis suggested that, when used together, these drugs may markedly increase adverse effects, such as renal dysfunction, hyperkalemia and symptomatic hypotension.[49,54] Thus, such combination therapy is not recommended at this time except in rare circumstances of refractory HTN.

β-adrenergic Receptor Blockade

Owing to their favorable effects on survival and disease progression, the Heart Failure Society highly recommends the use of β-adrenergic receptor blockers for patients whose ejection fraction is less than 40%, unless there is a contraindication (Figure 1) or intolerance to the drug.[8,55] The administration of β-blockers should be started as soon as possible after the diagnosis systolic dysfunction and may be used in patients with compensated class II, III or IV HF. Carvedilol, sustained-release metoprolol and bisoprolol have been shown to improve overall and event-free survival of patients with mild-to-advanced HF and, thus, are approved for treating HF in the USA.[26,27,28] Carvedilol is distinguished by its blocking of β2- and α1-adrenergic receptors, in addition to β1-receptors, and by its antioxidant properties. The administration of β-receptor blockers with intrinsic sympathomimetic activity, such as pindolol and acebutolol, should be avoided.

β-receptor blockers are especially appropriate in HF patients with HTN. Unlike their performance in patients with HTN only, β-blockers improve overall and event-free survival in HF patients.[56] Improvement in survival with β-blockade and ACE inhibition appears to be additive and, in seeking their blood pressure goal, hypertensive patients with HF should start β-blocker therapy without waiting to maximize the dose of ACE inhibitor. A meta-analysis including 22 trials and more than 10,000 patients demonstrated the benefit of β-receptor blockade in HF patients with HTN.[55] β-blockers significantly reduced mortality at 1 and 2 years compared with placebo. The study estimated that, during the first year, β-blockade saved 3.8 lives per 100 treated patients and reduced hospitalizations by four per 100 treated patients. Since the improvement appears to be dose related, the aim in stable HF patients with HTN is to eventually maximize both β-blocker therapy and ACE-inhibition (or angiotensin receptor blockade).

Aldosterone Antagonists

Aldosterone can adversely affect the heart's structure and function.[57,58,59] Blocking its effects can improve survival of patients with moderate-to-severe HF symptoms with recent decompensation,[60] and recent myocardial infarction with LV dysfunction.[61] Aldosterone-blocking agents may also reduce arrhythmic death in patients with mild-to-moderate HF.[62] The Randomized Aldactone Evaluation Study (RALES) trial found that when added to an ACE inhibitor and a loop diuretic, spironolactone significantly reduced mortality at 24 months in patients with class IV HF, and in those with class III HF who had had class IV HF within 6 months.[32] The Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial showed that eplerenone was associated with a 15% reduction in overall mortality at 16 months if started within 2 weeks of a myocardial infarction in patients with a low ejection fraction and evidence of HF and/or diabetes.[33] Both spironolactone or epleronone therapy significantly decreased both systolic and diastolic arterial pressure compared with placebo and can be of additional aid in the management of HTN in these HF population.[32,33]

Diuretics

Although diuretics are the mainstay of treating acutely decompensated HF, no long-term, randomized clinical trial has shown that they reduce morbidity or mortality, despite their relief of pulmonary and systemic venous congestion. Loop diuretics (e.g., furosemide, bumetenide, torsemide and ethacrynic acid) are used most commonly in HF patients, followed by thiazide and thiazide-like diuretics (e.g., chlorthalidone, hydrochlorothiazide, indapamide and metolazone), which are usually less effective in this setting. Treating volume overload with a loop diuretic reduces intracardiac filling pressure and cardiac output and, in hypertensive patients, may decrease systolic and diastolic blood pressures by as much as 15.8 and 8.2 mmHg, respectively.[63] Even if this fall in output is tolerated symptomatically, a consequent rise in blood urea nitrogen (BUN) may represent tissue hypoperfusion that warrants a reduction in dose.

Thiazides can reduce the incidence of HF in patients with HTN and prevent HTN-related mortality and morbidity but fail to prolong survival if patients already have HF. Recent guidelines suggest using thiazide diuretics in hypertensive HF patients with mild fluid retention because of their persistent antihypertensive action.[19] The Heart Failure Society suggests adding chlorothiazide or metolazone to a loop diuretic if the latter is unsuccessful in reduce fluid retention alone.[8] One may fully block the distal convoluted tubule by administering a diuretic that affects the distal tubule, followed by a loop diuretic. This may increase the natriuresis in chronic renal failure patients, in whom thiazides alone are much less effective. However, this combination may not significantly reduce blood pressure.

Hydralazine & Nitrates

Combining isosorbide dinitrate and hydralazine with standard therapy is especially effective in prolonging the survival of African-American patients with moderate-to-severe HF,[64] and may provide good blood pressure control in those already taking an ACE inhibitor, β-blocker and, perhaps, also an aldosterone antagonist. The African-American Heart Failure Trial (AHeFT) showed that a fixed-dose combination of isosorbide dinitrate and hydralazine improved the survival of African-American patients with class III or IV HF by 43%.[64,65] The combination's reduction of blood pressure may have helped improve survival. Since this regimen calls for multiple daily doses, is less efficient in reducing mortality and blood pressure and causes more side effects than ACE inhibition alone and, therefore, it is usually added to ACE inhibitor and β-blocker therapy (Figure 2).[14]

Figure 2.

Choice of agents in treatment of hypertension in patients with low ejection fraction. ACE-I = Angiotensin-converting enzyme inhibitor; ARB = Angiotensin receptor blocker; HF = Heart failure; I/H = Isosorbide dinitrate and hydrazine; LVD = Left ventricular dysfunction; MI = Myocardial infarction.

Less-ideal Agents

Some drugs are not recommended for HF patients. Calcium channel blockade does not improve symptoms and can worsen CHF and the risk of death in these patients. Amlodipine and felodipine neither improve nor worsen the survival of HF patients[66,67] and, generally, would not be chosen before other drugs of known survival benefit. However, the American College of Cardiology (ACC), American Heart Association (AHA) and Heart Failure Society accept using amlodipine in HF patients with HTN because it may be safe and well tolerated.[19] Limited trials have reported that reducing central sympathetic outflow (clonidine) and blocking peripheral α-receptors (prazosin) can benefit CHF patients.[29,30] These agents are not recommended for CHF at this time. Potent vasodilators (minoxidil) are avoided in HF patients because they promote sodium retention (Table 1).[19]

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