Potentially deleterious effects of long-term vasodilator therapy in patients with heart failure.

SUMMARY It is clear that we clinicians have accepted a philosophy of treating heart failure with vasodilator compounds, and we are fortunate to have a variety of pharmacotherapeutic agents from which we can choose. Each group has certain advantages and potentially deleterious effects, and as a general class of compounds, it is critical to remember the hemodynamic effects of these drugs. The advantages of the angiotensin-converting enzyme inhibitors include well-documented long-term efficacy with significant reduction in symptoms, improved exercise tolerance, and amelioration of detrimental hemodynamics. There is a large clinical experience with both captopril and enalarpril, with one agent, captopril, currently having the blessing of the Food and Drug Administration for use in congestive heart failure. Enalapril may have fewer side effects than captopril because of the absent sulfhydryl group and is suitable for once or twice daily dosing because of prolonged activity. The major disadvantages of the angiotensin-converting enzyme inhibitors include hypotension and pre-renal azotemia, but other potentially serious side effects such as neutropenia and proteinuria seem, fortunately, to be rare. Other vasodilators, such as hydralazine, prazosin, and nitrates, have some potential advantages, including the long-term demonstrated efficacy of nitrates in terms of hemodynamic and symptomatic improvement and relative freedom from serious side effects. Of additional importance are the recently published data from the VA cooperative study of vasodilators in heart failure, which demonstrated an attentuation of mortality in patients receiving the combination of oral isosorbide dinitrate and hydralazine (Apresoline). 8 This reduction in mortality was seen despite a complicated regimen of drug administration (300 mg of hydralazine per day and 160 mg of isosorbide dinitrate per day) and a 22 percent discontinuation of treatment in this group (usually because of deleterious effects). The major disadvantage of prazosin, which did not have the same effect on mortality as the combination of hydralazine and isosorbide dinitrate, seems to be the lack of demonstrated long-term efficacy. Still, the possibility of serious side effects from hydralazine (lupus syndrome), the requirement for frequent dosing (at least thrice daily), and the necessity of combining the agent with other vasodilators to achieve concomitant reduction in preload, remain disadvantages for hydralazine. Calcium-channel blocking agents have several physiologic properties, including peripheral and coronary vasodilation, electrophysiologic and antiarrhythmic effects, and the tendency to increase diastolic compliance, which, theoretically, make them beneficial drugs in certain patients with heart failure. The potential cardiodepressant effects and the limited clinical experience with calcium-channel blockers in congestive heart failure make for difficult titration, but, clearly, patients with ischemic heart disease and moderately depressed left ventricular function might benefit from them without developing serious deleterious consequences during long-term therapy. Also, patients who have heart failure with diastolic dysfunction such as hypertrophic cardiomyopathies would probably improve more predictably with these vasodilators than others. The use of combined vasodilator drugs may offer distinct advantages to the patient with heart failure, and the best example of this is the combination of nitrate therapy with hydralazine (Apresoline). Theoretically, nitrates and nifedipine or any of the other calcium-channel blockers would also be beneficial because the primary preload-reducing effects of nitrates would ameliorate one aspect of hemodynamic abnormality not affected by the relatively pure after-load-reducing advantage of the other. Results of combining two vasodilators effecting similar hemodynamic responses in patients with heart failure is unknown. Thus, combinations of angiotensin-converting enzyme inhibitors and prazosin or of hydralazine and nifedipine should not routinely be designed. It is possible that no additive vasodilator effects would be evident, but the patient might be exposed to an additional burden of toxic effects, particularly with respect to idiosyncratic reactions. It certainly might be appropriate to combine vasodilator drugs if the patient's condition was refractory to manipulation with one compound, but precise hemodynamic characterization of the clinical state would be mandatory. Should a decision be made to combine two or more vasodilators, choosing agents from disparate classes seems most logical. The choice of which single vasodilator agent to use clinically in patients with left ventricular dysfunction is one that must be individualized, juxtaposing the pharmacologic properties of agents with the hemodynamic, neurohumoral, and clinical characteristics of particular patients, always weighing the possibility of deleterious effects in the decision-making matrix. This demands beng cognizant of whether the patient is relatively well compensated and asymptomatic or whether symptoms are present that relate to low-output syndrome or the congestive state of heart failure.