News:Cardiogenic Shock: New Treatment Options with Percutaneous Left Ventricular Assist Devices?

September 11, 2007 by Grendel Burrell [mailto:grendel.burrell@gmail.com]

While mortality improved in the 1990s for patients with cardiogenic shock, approximately half of patients still die within the first 30 days [4,5]. In 2005, the TRIUMPH (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock) study was undertaken to examine the effects of an isoform-nonselective nitric oxide synthase inhibitor in patients with MI and refractory cardiogenic shock despite establishment of a patent infarct-related artery. TRIUMPH was a multicenter, randomized, double blind, placebo-controlled trial with planned enrollment of 658 patients at 130 centers. TRIUMPH was terminated mid-2006 at approximately 50% of the planned enrollment due to analysis for futility. There was no difference in the primary outcome of all cause, 30-day mortality between patients who received tilarginine and those who received placebo (48% vs 42%; risk ratio, 1.14; 95% CI, 0.92-1.41; P=. 24) [6].

In the October issue of Current Opinion in Critical Care 2007 [7]. Dr. Stephan Windecker, MD, Professor and Head of Invasive Cardiology, Department of Cardiology, University Hospital Bern, Switzerland, undertakes a review of percutaneous left ventricular assist devices (pLVADS), the latest advance in the management of these challenging patients. The advent of percutaneous left ventricular assist devices may constitute a critical advance in the management of patients with cardiogenic shock to serve as a bridge to recovery or to transplant.

LVADs provide partial or total circulatory support in cases of severe left ventricular failure. Intra aortic balloon pumps (IABP) solely decrease preload and afterload, while LVADs augment cardiac output and may usurp left ventricular function. LVADs remove freshly oxygenated blood from the left atrium or ventricle.

There are two pLVADs available for utilization, the TandemHeart (Cardiac Assist Inc, Pittsburgh, PA) and the Impella Recover system (Impella Cardiosystems AG, Aachen, Germany). The TandemHeart employs a drainage cannula placed via transeptal puncture into the left atrium in order to aspirate oxygenated blood that is moved by centrifugal pump into the femoral artery to establish a left atrial to femoral arterial bypass (www.cardiacassist.com). The Impella Recover system (www.abiomed.com) utilizes a caped blood flow inlet that is placed retrogradely into the left ventricle to aspirate oxygenated blood. This oxygenated blood is then injected via microaxial pump into the ascending aorta to establish a left ventricular to aortic bypass. The TandemHeart requires both venous and arterial femoral access; however, the Impella Recover system needs only femoral access.

Percutaneous LVADs can be used in cases of reversible, severe left ventricular failure when circulatory support is required until recovery has occurred or revascularization has been performed, temporary circulatory support during high risk percutaneous or surgical revascularization, or as bridging therapy as a bridge to a permanent assist device or a heart transplant. Additionally, patients without shock but with a large ischemic area at risk, undergoing high-risk revascularization may have a LVAD placed prophylactically to provide circulatory support during the intervention.

In 18 patients with cardiogenic shock secondary to myocardial infarction, cardiac out put was improved with the TandemHeart device. Cardiac output (without support 3.5+/-0.8 l/min compared to those with support 4.8+/-1.1 l/min, P<0.001) and mean arterial blood pressure (without support 63.1+/-7.8 mmHg versus with support 80.2+/-8.9 mmHg, P<0.001) significantly increased. Circulatory support of vital organ perfusion was accompanied by a reduction in preload with a significant decrease of pulmonary capillary wedge pressure (without support 21+/-4mmHg versus with support 14+/-4 mmHg, P<0.001), mean pulmonary arterial pressure (without support 31+/-8 mmHg versus with support 23+/-6 mmHg, P<0.001), and central venous pressure (without support 13+/-4mmHg versus with support 9+/-3mmHg, P<0.001) [8].

In an investigation of 10 patients undergoing high risk PCI, the hemodynamic effect of the Impella Recover device showed an increase in left ventricular volume immediately after Impella device insertion in to the left ventricle. However, there was no significant unloading of the left ventricle and no significant change to stroke volume, cardiac output, and ejection fraction. (Valgimigli M, Steendijk P, Serruys P, et al. Use of Impella Recover LP 2.5 left ventricular assist device during high-risk percutaneous coronary interventions: clinical, haemodynamic and biochemical findings. EuroIntervention 2006; 2:91–100.).

A multicenter, randomized trial compared the safety and efficacy of the TandemHeart to IABP in 42 patients with cardiogenic shock [9]. The mean length of support was 2.5 days. Compared to IABP, the TandemHeart significantly improved cardiac output (1.2+/-0.8 l/min versus 0.6+/-0.6 l/min, P<0.05) and decreased pulmonary capillary wedge pressure. The number of studied patients is small and precludes firm conclusion; however, the overall clinical outcome between the two groups was not different at 30 days, mortality of 64% in the IABP group and 53% in the TandemHeart group. Adverse events were similar in both groups.

Clinical use of the Impella Recover device has also been reported in 19 patients undergoing high-risk percutaneous coronary intervention. The device was successfully placed in all patients without procedural deaths. The device did not result in aortic valve regurgitation and there were no device-related complications during the short period of left ventricular support [10]. Efficacy Study of LV Assist Device to Treat Patients With Cardiogenic Shock (ISAR-SHOCK), a Phase IV study to evaluate the efficacy and safety of a left ventricular assist device in comparison to a standard treatment with an intraortic balloon pump in patients with cardiogenic shock due to left ventricular failure following an acute myocardial infarction has also been completed (http://www.clinicaltrials.gov/ct/show/NCT00417378?order=1). 26 patients were enrolled in this randomized, open label, active control, and parallel-assignment study.

Percutaneous left ventricular assist devices may provide an advance in the management of patients with left ventricular dysfunction and cardiogenic shock. These devices may assist as a bridge to recovery or heart transplantation in selected patients. Improvement of hemodynamic parameters by these devices appears promising when compared with use of IABP alone; however, it is not yet clear whether this benefit translates into improved clinical outcome. Mortality in patients with cardiogenic shock remains high and complications including limb ischemia and severe bleeding must be considered in the further evaluation of these devices.

Another pharmacologic approach to the management of cardiogenic shock is being undertaken by Cardiome Pharma Corp. (NASDAQ: CRME / TSX: COM). On April 30, 2007, Cardiome announced (http://cardiome.com/wordpress/?p=350) that it has signed an exclusive in-licensing agreement with Eli Lilly and Company for LY458202 (GED-aPC), a clinical-stage drug candidate. Cardiome was granted exclusive worldwide rights to GED-aPC for all indications. According to the Cardiome web site, GED-aPC is an engineered analog of recombinant human activated Protein C (aPC) with enhanced anti-inflammatory, anti-thrombotic and strong binding to endothelial protein C receptor properties, and has broad potential across multiple indications. Cardiome intends to initially develop GED-aPC in cardiogenic shock, as stated in the April 30, 2007 press release. There are few medical conditions with a 30-day mortality of approximately 50%. Clearly, further clinical investigations are required to precisely identify the risks and benefits associated with new drugs and devices for cardiogenic shock.

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