Vasodilators in the treatment of acute heart failure: what we know, what we don’t

Vasodilators are recommended for the early treatment of AHF associated with elevated BP at presentation. What is the underlying pathophysiology in such patients that suggest that vasodilators may be useful? Most studies suggest that vasoconstriction plays a central role in the pathogenesis of AHF via multiple mechanisms (Fig. 1). One fundamental mechanism in AHF is the interaction between a progressive decrease in cardiac performance and an acute increase in systemic vascular resistance, the so-called “afterload mismatch”. This leads to a decrease in cardiac output and increase in left ventricular filling pressure. The increase in left ventricular filling pressure leads to a steep increase in pulmonary venous and hence pulmonary capillary pressure inducing exudation of fluid from the intravascular compartment into the lung interstitium and alveoli, resulting in pulmonary congestion and dyspnea.

There are multiple further mechanisms which may contribute to symptoms and the poor prognosis of patients with AHF, and they have been recently reviewed in detail [7, 9, 10]. First, as congestion increases, O₂ saturation deteriorates and systemic O₂ desaturation contributes to insufficient myocardial O₂ supply and possibly myocardial ischemia and damage. This mechanism may be further favored by concomitant coronary artery disease, coronary vasoconstriction, caused by neurohormonal activation, and by increased myocardial oxygen demand from increased wall stress secondary to the afterload mismatch. Second, the increased fluid content in the lungs and decreased O₂ saturation may induce pulmonary vasoconstriction with a further increase in RV pressure, again compromising left ventricular function through the ventricular interaction mechanism. Third, profound circulatory insufficiency results in metabolic acidosis, which further jeopardizes cardiac performance. Fourth, inflammatory and neurohormonal activation can lead to multiple consequences affecting cardiac and renal function as well as pulmonary membranes leading to increased “leak” of fluid into alveoli, further amplifying congestion. Finally, decreased forward perfusion, increased venous pressure, and neurohormonal-inflammatory activation lead to further impairment in renal function that in turn worsens heart failure.

As noted above, large registries such as ADHERE and OPTIMIZE demonstrate that most patients with AHF have either preserved or increased BP at presentation [5, 11]. These registries may actually underestimate the importance of hypertension, because the first BP recorded was usually a few hours after presentation and sometimes after initial treatment was administered. In a recent comprehensive small study that captured the initial BP in the emergency department or in the ambulance in all the patients admitted with AHF to a community hospital, the vast majority of patients were hypertensive at admission with only about 10% of patients having “normal” or low BP at presentation [12]. In a hemodynamic study where data were collected in patients admitted to the hospital with an AHF event, the most notable change in hemodynamic measures leading to heart failure was a very steep increase in vascular resistance and BP [13]. Patients admitted for AHF with high BP are more likely to be females, elderly, with a history of hypertension, and with a normal left ventricular ejection fraction [14, 15].

Taken as a whole, these data suggest that changes in vascular tone, possibly both on the arterial side (increasing afterload) and venous side (increasing pre-load), are important contributors to AHF and may be a crucial determinant of the AHF syndrome in patients with AHF and elevated BP (recently termed acute vascular or cardiovascular AHF).

Treatment goals in AHF should be aligned with the general principles of drug therapy—i.e., that interventions in any disease should make patients “feel better” and/or “live longer”. Vasodilators in AHF were traditionally developed to make patients “feel better”, which in AHF has typically been assessed as the early and sustained relief of dyspnea. As with all symptoms relief, however, it is crucial that such improvement is not achieved at the expense of greater “downstream” risks for outcomes such as end-organ damage, hospitalization, or death. Avoidance of hypotension and end-organ hypoperfusion seems to play a crucial role.

Despite their long history of use, the body of evidence to understand the safety profile of vasodilators in AHF remains limited. Retrospective analyses of pooled data for nesiritide suggested the possibility of worsening renal function and increased mortality, leading to substantial controversy about the safety of this agent [16, 17]. Of note, in the studies that were used for this meta-analysis, patients with systolic BPs <90 mmHg were allowed. In patients with low systolic BP, renal perfusion might be seriously jeopardized when a vasodilator is added, leading to increased risks of worsening renal function. In other groups of patients with systolic dysfunction, nesiritide treatment was not associated with worsening renal function nor was even related to improvement of renal dysfunction [18, 19].

Further concerns are related to the effects of vasodilators on coronary perfusion and myocardial damage. Studies based on serial measurements of serum troponin levels have shown that a consistent proportion of AHF patients, also including patients with idiopathic dilated cardiomyopathy, develop myocardial damage at the time of their admission. In a study by Metra et al., detectable serum troponin T levels were found in 48% of the patients admitted for AHF (54% of the patients with coronary artery disease and 40% of those with idiopathic dilated cardiomyopathy) [20]. Excessive hypotension may lead to coronary hypoperfusion and cause myocardial damage. Further, although this is not the case for nitrates, vasodilators may preferentially dilate normal coronary vessels causing “coronary steal” with further decline of blood flow in diseased vessels.

The results of one of the earliest randomized, placebo-controlled, double-blind trials of vasodilators in patients with left ventricular dysfunction were actually consistent with the hypothesis that vasodilators may be detrimental in patients with ongoing myocardial ischemia. In this trial, Cohn et al. randomized 812 men with presumed acute myocardial infarction and left ventricular filling pressure ≥12 mmHg to a placebo or sodium nitroprusside 48 h infusion. Results on mortality were strongly affected by the time of treatment with a deleterious effect of sodium nitroprusside when infusion was started at <9 h from the onset of symptoms (mortality at 13 weeks, 24.2% vs. 12.7%; P = 0.025) and a beneficial effect in those whose infusion was begun later (mortality at 13 weeks, 14.4% vs. 22.3%; P = 0.04) [21]. These results are consistent with the hypothesis that vasodilator therapy may aggravate coronary hypoperfusion and, when associated with hypotension, may be deleterious in the setting of myocardial ischemia. They, however, also show that vasodilator treatment may favorably affect outcomes when used appropriately in patients with cardiac dysfunction.

More recent data also indicate that excessive peripheral vasodilatation may be deleterious in patients with AHF. A retrospective analysis of data from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) has shown that the combination of intravenous vasodilators and inotropes is associated with a risk-adjusted increased mortality which is even higher (hazard ratio, HR, 4.81, 95% confidence intervals, CI, 2.34–9.90) than with inotropes alone (HR, 2.14, 95% CI 1.10–4.15). Vasodilators alone, however, were not associated with a significant increase in the risk of death (HR, 1.39, 95% CI 0.64–3.00). Similar data were found when the combined end-point of death plus rehospitalizations were considered [22]. Consistently, the lack of improvement in outcomes with levosimendan, compared to dobutamine, in SURVIVE has been ascribed also to the vasodilatatory effects and hypotension associated with levosimendan administration as observed in this trial [23].

Thus, we are left with doubts regarding the effects of vasodilators on outcomes, and even symptoms, in the patients with AHF. No single study of vasodilators in AHF has been sufficiently powered to carefully evaluate safety, and in particular, no adequately powered prospective studies have been performed with nitrates or sodium nitroprusside, the most commonly used vasodilators in AHF. Do vasodilators as a class lead to worsening renal function, end-organ damage, or increase the rate of post-discharge re-admission and death in AHF? Although currently available data do not permit a definitive answer to this question, we believe that the answer is no. First, we believe that safety of vasodilator therapy can be significantly increased by focusing on those patients most likely to benefit: patients with AHF and normal or elevated BP. In addition, careful monitoring of BP during treatment and down titration or discontinuation of vasodilator therapy, if BP drops significantly, may improve the safety profile of these agents. Finally, these agents may have U-shaped dose–effect relationships. While it is widely recognized that sub-optimal doses of vasodilators may have a limited effect, administration of high doses might also reduce their effectiveness because of counter regulatory mechanisms. In some cases, vasodilators doses were chosen based on small hemodynamic studies largely confined to patients with stable severe chronic heart failure with systolic dysfunction. The doses chosen were those achieving the maximal possible vasodilatation, or largest increase in cardiac index and decrease in pulmonary wedge pressure (PWP). However, in patients with AHF in whom cardiac reserve is reduced, inappropriate vasodilatation may induce a steep reduction in BP, resulting in hemodynamic instability, ischemia, renal failure, and sometimes frank shock. In addition, high-dose vasodilators can induce rebound neurohormonal activation potentially limiting short- and long-term efficacy [24‐26]. Therefore, the administration of these drugs should be done with caution, to the patients who really deserve them, using the right doses, under careful BP monitoring, and with careful titration of the dose according to changes in BP. Large, carefully controlled prospective studies will be required to provide conclusive evidence of the safety and efficacy of vasodilator therapy in AHF.