Optimal Use of Multi-Drug Therapy

Multi-drug therapy is required for optimal management to slow progression and improve outcome in patients with HF and reduced LVEF. An ACE inhibitor plus a beta blocker is standard background therapy. An ARB can be substituted for an ACE inhibitor if clinically indicated. An ARB can be added to an ACE inhibitor in individuals in whom beta blocker is contraindicated or not tolerated. The optimal choice of additional drug therapy to further improve outcome in patients already treated with 2 of these 3 drugs is not firmly established. An aldosterone inhibitor, an ARB (if the patient is already on an ACE inhibitor) and the combination of isosorbide dinitrate and hydralazine have all been shown to exert further benefit in controlled trials, but have not been the subject of comparative trials. The choice among these agents may be influenced by the patient's age, renal function, serum potassium, racial background, and severity of the clinical syndrome. Certain combinations would require careful monitoring. For example, if an ARB or aldosterone antagonist were combined with an ACE inhibitor, with or without beta blocker therapy, elderly patients would require close monitoring of serum potassium, especially those with diabetes or renal insufficiency.

The use of 4 or more of these drugs in combination cannot be recommended on the basis of clinical trial evidence for additional efficacy, but such combinations have been used in subsets of patients enrolled in clinical trials. In the CHARM-Added trial, an ARB was safely administered to patients receiving an ACE inhibitor, beta blocker and aldosterone inhibitor, when patients were closely monitored for hyperkalemia and worsening renal function.82 Non-significant increases in serum creatinine and serum potassium have been observed in clinical trials, and clinicians must closely monitor patients for these adverse effects when using these drugs in combination. In the A-HeFT study, black patients were given isosorbide dinitrate-hydralazine in addition to an ACE inhibitor, an ARB, and an aldosterone inhibitor with no apparent adverse effect.81 Nonetheless, the use of combinations of 4 or more of these drugs would not be based on evidence for further efficacy and should mandate close monitoring of blood pressure, renal function, and serum potassium.

As discussed previously in this section, ARBs, aldosterone antagonists, and hydralazine/isosorbide dinitrate all have been shown to be beneficial in patients with chronic HF with or without beta blocker therapy. However, no study has specifically evaluated patients who are intolerant to beta blockers. Those who are intolerant due to hypotension or worsening HF are likely to have more severe HF and to be at higher risk of hypotension, worsening renal function, or hypokalemia with additional medical therapy. Thus closer clinical and laboratory monitoring is important.