Un-Break My Heart

Abstract

Recently Gustafsson et al published guidelines for “Inotropic therapy in patients with advanced heart failure. A clinical consensus statement from the Heart Failure Association of the ESC.”1 This can be seen as an addendum to the more extensive ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure published in 20212, and indeed these two documents share some of the same authors. What Gustafsson et al have tried to do is create some guidance for the use of inotropes in advanced heart failure (table 1) which really lies outside the recommendations of the more solidly evidence based guidelines from 2021. In fact, the 2021 guidelines recommend inotropes only in the setting of acute heart failure, due to insufficient evidence to recommend inotropes in the setting of advanced heart failure.Table 1Patient characteristics in the control (post-amputation surgically sited perineural sciatic catheters) and intervention (pre-operative sciatic nerve block) groups. Values are mean (SD), number (proportion) or median (IQR [range]).Control n = 40Intervention n = 40Total n = 80Age66.0 (10.4)61.8 (12.3)63.9 (11.5)Sex; female12 (30%)12 (30%)24 (30%)Weight; kg84.3 (21.4)88.0 (25.1)86.1 (23.2)Ethnicity European27 (67.5%)22 (55.0%)49 (61.2%) Māori9 (22.5%)18 (45.0%)27 (33.8%) Indian1 (2.5%)01 (1.2%) Not stated3 (7.5%)03 (3.8%)Indication Ischaemia27 (67.5%)21 (52.5%)48 (60.0%) Infection11 (27.5%)14 (35.0%)25 (31.2%) Emboli2 (5.0%)3 (7.5%)5 (6.2%) Chronic pain01 (2.5%)1 (1.2%) Neoplasm01 (2.5%)1 (1.2%)Diabetes mellitus22 (55.0%)27 (67.5%)49 (61.2%)Peripheral vascular disease29 (72.5%)23 (57.5%)52 (65.0%)Chronic kidney disease13 (32.5%)16 (40.0%)29 (36.2%)Anaesthetic technique General26 (65.0%)32 (80.0%)58 (72.5%) Spinal14 (35.0%)3 (7.5%)17 (21.2%) Sedation05 (12.5%)5 (6.2%)Concurrent regional analgesia None29 (72.5%)24 (60.0%)53 (66.2%) Femoral5 (12.5%)13 (32.5%)18 (22.5%) Sciatic3 (7.5%)03 (3.8%) Adductor canal2 (5.0%)3 (7.5%)5 (6.2%) Tibial1 (2.5%)01 (1.2%)Pre-operative pain (NRS)4.5 (3.0–6.0[0-10])4.5 (0.0–7.2[0-10])4.5 (2.0-6.0[0-10]) Open table in a new tab While the stated aim of the consensus statement is “to provide a review of the literature related to inotropic therapy in patients with advanced chronic HFrEF(heart failure with reduced ejection fraction) and to describe a strategy for inotrope use in the care of this population”1 the fact that the 2021 guidelines do not recommend inotropic therapy for advanced heart failure, makes a further review of the literature likely to be futile. Hence, these guidelines consist essentially of expert opinion with a brief nod to the literature. Whilst guidelines and consensus statements are a convenient way for anesthesiologists to keep abreast of progress in other fields, treatment of chronic heart failure is fairly squarely in cardiology territory and something that most of us are unlikely to become involved in. Having said that, at least two of the scenarios they describe; evaluation of reversibility of end-organ dysfunction prior to a decision about durable left ventricular assist device (LVAD) implantation or heart transplant listing and inotropic support to stabilize clinical condition prior to heart transplantation (HTx) or LVAD implantation may well involve anesthesiology input in the decision making process. Therefore, knowledge of this consensus statement and the fairly flimsy evidence that is based-on might well be useful in the clinical practice of the cardiac anesthesiologist. Of the other clinical scenarios that they put forward figure 1), persistent congestion refractory to loop or combination diuretic therapies, and palliative or supportive therapy for advanced HF in patients not eligible for HTx or LVAD implantation, the first seems to be in the domain of cardiology and the second should really be a question for the local community as a whole. Palliating patients in the community with continuous or repeated infusions of inotropes is undoubtedly possible, but whether it should be done or not is highly dependent on the resources and values of the local community. Avoiding a difficult or uncomfortable conversation with the patient may well be the motivation behind this treatment. To paraphrase an intensive care colleague “no difficult conversation can't be avoided with a futile two week intensive care admission”. Having said that, providing some time to assess the options and assemble the support people of the patient may well have some benefit, fitting into the “bridge to a decision” treatment category. Taking a step back and considering the place of inotrope therapy in heart failure is useful when considering the value of this consensus statement. Broadly speaking, the treatments for heart failure fall into 2 categories, inotropes, lashing the heart to work harder, and drugs that reduce the work of the heart, beta-blockers, angiotensin-converting-enzyme inhibitors (ACE inhibitors) and their derivatives, diuretics and SGLT-2 inhibitors. Despite the attractiveness of making the heart work harder to overcome heart failure, the brief summary would be that this has never been shown to reduce mortality. Instead, the drugs that reduce the work of the heart, have in general shown mortality benefits. This contrasts with mechanical support, which makes pathophysiological sense, having something working alongside the heart, rather than forcing the heart to work harder. Indeed, the literature is strongly supportive of the benefits of mechanical support in advanced heart failure in the form of durable left ventricular assist devices(LVADs). The key trial evidence for LVAD's comes from the REMATCH study as destination therapy for advanced heart failure3. There was a 48% relative risk reduction and a whopping 27% absolute risk reduction in the chance of death at one year when compared to optimal medical therapy. Bearing in mind that even in the LVAD group survival at one year was only 52%. Since this trial, there have been advances in technology (fully magnetic levitated centrifugal-flow pumps) with fewer associated complications compared with axial flow pumps4,5 the benefit from LVAD compared with medical therapy is likely to be increasing. There is also registry data indicating that both early or late LVAD implantation is superior to optimal medical therapy6,7. Ongoing research will clarify the situation further with randomized control trials underway comparing modern LVAD with medical therapy for destination therapy (SweVAD)8 and as a bridge to transplant(EARLY-VAD)9. The evidence for short term mechanical support over inotropic support is less clear. The ESC guideline2 recommends short term mechanical support for those patients in critical cardiogenic shock through to those who are inotrope dependent (Interagency Registry for Mechanically Assisted Circulatory Support(INTERMACS) Profiles 1-3). The options suggested range from intra-aortic balloon pump(IABP), Impella devices to Tandem Heart and extracorporeal membrane oxygenation(ECMO) as options for a bridge to decision, recovery or to long term LVAD or transplant. The current evidence available has not been in favour of short-term IABP or veno-arterial ECMO10,11. However, the patient populations that these have been studied are those with cardiac arrest or acute cardiogenic shock and are a different population from those with advanced heart failure. It is probably reasonable to assume that in patients with decompensated advanced heart failure that inotropes or short term mechanical support(VA-ECMO, IABP, Impella, Tandem Heart) will provide equivalent results as a bridge to a decision, though neither are destination therapies, but this remains to be confirmed by trial evidence. There are clearly times when inotropic support is warranted and these scenarios are unlikely to ever been supported by randomized controlled trial evidence. These consensus guidelines outline some of those scenarios and are likely to reflect practice current practice in many countries around the world. As a bridge to transplant where the period of waiting for an organ is likely to be short or in countries where mechanical support is not readily available, of course longer-term inotrope therapy is justified. As is the scenario where reversibility of organ dysfunction before considering transplant or LVAD or for stabilisation of the patient prior to these procedures. There is evidence supporting poorer outcomes from mechanical support in the presence of organ dysfunction, so if this can be reversed prior to LVAD implantation then it is likely to improve outcomes. Considering the evidence, is it likely that milrinone or levosimendan are the inotropes of choice in this setting. Evidence from Lee et al12, suggest that patients on long term milrinone do better if they have an implantable defibrillator in situ and are able to follow the best practice guidelines for the treatment of heart failure (e.g. treatment with beta-blockers). This suggests that arrhythmias are a significant cause of morbidity and maybe mortality with long term inotropes. Treating with a beta-blocker and a beta-agonist at the same time seems counter-intuitive, so that leaves milrinone and levosimendan as the first choice inotropes for long term use. A lot has been written about the potential benefits of levosimendan in advanced heart failure, which has not been borne out by the trial evidence. A 2012 meta-analysis showed a reduction in mortality for the use of levosimendan vs placebo and vs dobutamine13, but as pointed out by Abbate and Tassell in an excellent editorial in 201814 “These mortality benefits occurred even though no mortality effect was observed in either of the 2 pivotal trials that constituted approximately 50% of the weight in the meta-analysis.” Therefore, the meta-analysis seemed to be biased by the strongly positive effects seen in the remaining 43 small or moderate sized trials include in the meta-analysis. While levosimendan has a novel and attractive mechanism of action, it is still making the heart work harder and given what we know about other inotropes, it seems unlikely that levosimendan will improve mortality. In summary, this consensus guideline outlines scenarios where long-term inotropic therapy might be useful despite there being little evidence in the literature for these indications, and the guidelines probably reflect how these drugs are being used around the world currently. Due to the nature of the scenarios, it is unlikely that there will ever be strong evidence in the literature for these indications, so we are left practicing in a pragmatic fashion, now with support from major guidelines suggesting these as acceptable indications according to expert opinion. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.1Gustafsson F, Damman K, Nalbantgil S, et al: Inotropic therapy in patients with advanced heart failure. A clinical consensus statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail20232McDonagh TA, Metra M, et al: 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 24:4–131, 20223Rose EA, Gelijns AC, Moskowitz AJ, et al: Long-Term Use of a Left Ventricular Assist Device for End-Stage Heart Failure. New Engl J Medicine 345:1435–43, 20014Mehra MR, Goldstein DJ, Uriel N, et al: Two-Year Outcomes with a Magnetically Levitated Cardiac Pump in Heart Failure. New Engl J Medicine 378:1386–95, 20185Slaughter MS, Rogers JG, Milano CA, et al: Advanced Heart Failure Treated with Continuous-Flow Left Ventricular Assist Device. New Engl J Med 361:2241–51, 20096Kitada S, Schulze PC, Jin Z, et al: Comparison of early versus delayed timing of left ventricular assist device implantation as a bridge-to-transplantation: An analysis of the UNOS dataset. Int J Cardiol 203:929–35, 20167Barge‐Caballero E, Almenar‐Bonet L, Gonzalez‐Vilchez F, et al: Clinical outcomes of temporary mechanical circulatory support as a direct bridge to heart transplantation: a nationwide Spanish registry. Eur J Heart Fail 20:178–86, 20188Karason K, Lund LH, Dalén M, et al: Randomized trial of a left ventricular assist device as destination therapy versus guideline‐directed medical therapy in patients with advanced heart failure. Rationale and design of the SWEdish evaluation of left Ventricular Assist Device (SweVAD) trial. Eur J Heart Fail 22:739–50, 20209Retrieved from: https://clinicaltrials.gov/ct2/show/NCT02387112 Accessed 18/04/2023.10Thiele H, Zeymer U, Werdan K: Intraaortic Balloon Support for Cardiogenic Shock. New Engl J Medicine 368:80–1, 201311Ostadal P, Rokyta R, Karasek J, et al: Extracorporeal Membrane Oxygenation in the Therapy of Cardiogenic Shock: Results of the ECMO-CS Randomized Clinical Trial. Circulation 147:454–64, 202212Lee EC, McNitt S, Martens J, et al: Long-term milrinone therapy as a bridge to heart transplantation: Safety, efficacy, and predictors of failure. Int J Cardiol 313:83–8, 202013Landoni G, Biondi-Zoccai G, Greco M, et al: Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies* Crit Care Med 40:634–46, 201214Abbate A, Tassell BWV: Levosimendan in Advanced Heart Failure. J Cardiovasc Pharm 71:127–8, 2018 None.