Vasodilators
According to recent guidelines,27 vasodilators may be considered as an adjuvant to diuretic therapy for dyspnea relief when SBP remains >110 mmHg. Interestingly, SBP is used as a safety signal and not as marker of efficacy. IV nitroglycerin (NTG) is primarily a venodilator that lowers preload and reduce pulmonary congestion.48 The hemodynamic benefit of NTG is produced by activation of cyclic guanosine monophosphate (cGMP)-dependent protein kinases.49
NTG produces redistribution of blood from the central circulation into larger capacitance veins, decreasing pulmonary venous congestion and decreasing LV impedance, which results in a decrease in left atrial pressure.50 Concomitant high-dose nitrate therapy and low-dose IV furosemide51 was associated with a reduced need for intubation and a lower risk of other cardiovascular events compared with highdose IV furosemide in PO patients. Utilisation of IV nitrates in AHF is limited by reactive neurohormonal activation and tolerance. Nitrate tolerance,50 defined as a loss of hemodynamic effect despite dose escalation, may develop within hours, and may contribute to the pattern of IV nitrate utilisation observed in registries.
Nesiritide, a recombinant B-type natriuretic peptide (BNP) with vasodilatory properties, is associated to significant decrease of pulmonary capillary wedge pressure (PCWP).52,53 Compared with NTG, nesiritide resulted in significant decrease of filling pressure but there was no difference between nesiritide and NTG in terms of dyspnea improvement.54 In the pivotal ASCEND-HF trial,55 nesiritide showed moderate dyspnea improvement, but neutral effects on mortality and re-hospitalisations and was associated with an increase in rates of hypotension.
Relaxin is a hormone that induces NO activation of guanylate cyclase (GC) and triggers haemodynamic adaptive changes that occur during pregnancy. The recombinant human form, serelaxin, demonstrated potential hemodynamic benefits for AHF patients. In experimental studies,56,57 serelaxin decreased SVR concomitant to increase (CO) and renal blood flow. In a phase III placebo-controlled trial, which enrolled patients within 16 hours of presentation,58 serelaxin improved visual analog scale (VAS)-assessed dyspnea, but did not significantly improve dyspnea as measured by a Likert scale. In spite of the lack of benefit on in-hospital mortality, serelaxin significantly improved 180-day allcause mortality. A recent exploratory analysis of the mortality benefit in RELAX-AHF suggested serelaxin improved markers of cardiac, renal, and hepatic function early during AHF hospitalisation.59 Hence, improved dyspnea relief, preserved end-organ function, and less use of concomitant IV therapies may support improved long-term outcomes with novel agents in AHF.
Although, some studies have shown that soluble guanylyl cyclase (sGC) activators may offer organ-protective qualities,60,61 particularly for renal function, a recent study with cinaciguat suggested no clear symptomatic benefit of this therapy.62 In spite of decreasing PCWP, cinaciguat decreased SBP without improving dyspnea or cardiac index.
Clevipidine, an ultra-short-acting dihydropyridine calcium antagonist with a high degree of vascular selectivity, has been studied in hypertensive AHF in an open-label design study.36 Clevidipine was initiated very shortly after presentation (i.e. median time 149 minutes) and was associated with marked improvement of dyspnea, lower rates of ICU admissions, and reduced length of stay compared with usual care supporting a new model of intervening within the first few hours after presentation.
Inotropes
The majority of patients admitted with PO have pulmonary congestion related to high LV filling pressures. Although most are hypertensive or normotensive on admission, approximately 10–15 % of PO patients present with low SBP as a result of low CO6,11 and inotropic agents are required. Other PO patients may experience an unexpected and abrupt decrease of SBP during hospitalisation as result of aggressive treatment of pulmonary congestion or resolution of a reactive stress response. This subset subsequently requires IV inotropes to maintain CO and perfusion pressure. Low SBP at presentation or signs of tissue hypoperfusion, as well as need of inotropic therapies, were all variables associated with short-term mortality in registries enrolling PO patients (see Table 2). The most commonly used inotropes are sympatomimethic agents (i.e. dobutamine and dopamine). These agents have been associated with adverse events such as ischemia, tachyarrhythmias, and hypotension, and may increase in-hospital and postdischarge mortality.63,64 However, as systemic hypoperfusion in the setting of low CO occurs, sympathomimetic agents remain a mainstay of therapy, despite their associated long-term adverse events, probably mediated through worsening myocardial injury. For sympathomimetic agents, previous treatment with beta-blockers may greatly influence the anticipated clinical response. Other inotropic agents, non-AmpC dependent, have been tested in clinical trials but with unfavourable results. The short-term use of milrinone, an IV inotrope with vasodilatory properties, has been associated with an increase in postdischarge mortality.65,66 The negative impact on mortality of these agents is considered to be related to myocardial injury as a result of a reduction in SBP and subsequently in coronary perfusion.
Levosimendan exerts positive inotropic effects by enhancing calcium sensitivity of the cardiac contractile elements and exerts direct peripheral vasodilator effects by blocking ATP-dependent potassium channels in vascular smooth muscle.67 These effects are not attenuated by concomitant treatment with beta-blockers and are sustained beyond the duration of the drug infusion because levosimendan has an active metabolite with a long half-life.1,63,64,66,67 Levosimendan demonstrated a favorable haemodynamic profile in preclinical and clinical studies63 as it reduced PCWP and increased CO, suggesting potential benefit for patients with PO with low or normal SBP. However, when tested in rigorous randomized double-blind trials,68,69 levosimendan showed only modest clinical improvement, and was associated with hypotension, atrial and ventricular arrhythmias, and, in one trial, a trend toward an increase in early mortality.68
Istaroxime is a new agent with dual inotropic and lusitropic properties. Istaroxime inhibits Na/K ATPase and stimulates sarcoplasmic reticulum calcium ATPase.70 In patients hospitalized with HF, istaroxime decreased PCWP and improved diastolic function. Compared with sympathomimetic agents, istaroxime increased SBP and decreased HR and myocardial oxygen demand, characteristics suggesting a possible role in preventing myocardial injury.71 Although this agent was studied only in chronic HF: reduced ejection fraction (HFrEF), it seems to be an ideal agent for PO patients presenting with low or normal SBP.
Stresscopin, a corticotropin-releasing factor type 2 receptor (CRFR2) selective agonist,71 has intrinsic inotropic properties via stimulation of G-protein family. In a recent trial,72 stresscopin increased CO and decreased SVR without significantly affecting HR or SBP, highlighting its potential advantage over standard inotropic agents. However, there was a significant decrease in DBP, which could have an unfathomable effect on coronary perfusion pressure.72