Does ivabradine balance dobutamine effects in cardiogenic shock? A promising new strategy

Cardiogenic shock (CS) is associated with a high rate of in-hospital mortality and a poor prognosis. Inotropic agents, used in clinical practice, remain the cornerstone of the management of CS. Dobutamine is the most usually preferred in this indication. Despite its benefit effects, this drug also exerts adverse effects as sinus tachycardia, possibly deleterious in this context. In the recent ESC guidelines (Ponikowski et al. 2016), inotropic agents are clearly not recommended for the management of a patient with acute HF unless the patient is symptomatically hypotensive or hypoperfused because of safety concern (class III, A). Shortterm, intravenous infusion of inotropic agents may be considered in patients with hypotension (SBP < 90 mmHg) and/or signs of hypoperfusion (despite adequate volemia), in order to maintain and improve the cardiac outflow, peripheral perfusion and maintain end-organ function (class IIb, level C). Dobutamine has even been suggested to increase mortality (O’Connor et al. 1999, Wang et al. 2015). The level of recommendation and the years of publications of main trials in the field underline that we lack data, regarding both basic models and clinical trials. We lack strong clinical data in the field. Only few trials are currently studying CS (Table 1). As indicated in the Table 1, there are some epidemiological or prognostic evaluations, some trials on mechanical assistances and devices, but surprisingly few studies with drugs (and none evaluating ivabradine in this context to our knowledge). A few years ago, the interest of intra-aortic balloon support for patients with acute myocardial infarction leading to CS has been definitely challenged (Thiele et al. 2012, 2013), reinforcing the lack of trials and recommendations with strong level of evidence. Even epidemiological data are rather scarce and local uses are heterogeneous. Recently, a multi-centre study (Harjola et al. 2015) included in nine centres representing eight countries. A total of 219 patients were included over 2 years, underlining the high difficulties to conduct a trial in the field. Consistently, FRENCHSHOCK, a French nationwide registry, is currently ongoing (NCT02703038). Its aim is to reflect the current practice in the field, including the likely heterogeneous clinical strategies, in a nationwide registry, in the as short as possible framework (>500 patients in less than 6 months). Importantly, this registry aims to present real-life clinical features and management of more than 500 patients in various centres. The current management of CS is indeed crucial including the real use of inotropic drugs and their prognostic impact. We lack basic data in the field. In the study published in this journal, Bakkehaug et al. (2016) reported a basic model of CS (Bakkehaug et al. 2016). The aim of the authors was to evaluate the effect of a combined therapy by dobutamine and ivabradine in a model of post-ischaemic low cardiac output. Indeed, both inotropic impact and induced tachycardia by dobutamine participate to increase the cardiac output in CS. On the other hand, the induced sinus tachycardia could exert in turn deleterious effects (we could also cite other side effects such as arrhythmias). Indeed, increased tachycardia may increase left ventricular work inducing myocardial ischaemia and shortening diastole period and then efficient ventricular filling. Ivabradine is a specific blocker of the If funny current supported by the hyperpolarization-activated cyclic nucleotide-gated channels. This ionic current is involved in activity of the sinoatrial node. The interest of ivabradine is the reduction of heart rate without depressing myocardial inotropism or decreasing cardiac output (Roubille & Tardif 2013). This reduction remains mild (about 9 bpm in the clinical trials in patients with HF), which appears compatible with haemodynamics adaptation and not compromising this adaptive tentative, hence its theoretical interest in this setting (Roubille et al. 2013, Lattuca&Roubille 2015). Ivabradine is currently indicated in chronic heart failure (class IIa, level B), in patients in sinus rhythm with a left ventricular ejection fraction <35% and heart rate <70% despite treatment with an evidence-based dose of beta-blockers, angiotensin-converting enzyme inhibitor and a mineralo-corticoid receptor antagonist (Ponikowski et al. 2016). Importantly, it is currently not recommended in patients with acute HF as no randomized large trials addressed this issue. Only few data are available concerning its indication in CS.