Cardiogenic shock (CS) is a leading cause of mortality associated with acute myocardial infarction (AMI). , Improved prehospital emergency care and timely reperfusion from initially systemic lytics to now percutaneous coronary intervention have decreased the incidence of AMI-CS and associated mortality from 1970 through the early 21st century. Unfortunately, between 2003 and 2010, there was a possible near doubling in the incidence of AMI-CS in the United States. , Results from international randomized controlled trials (RCTs) including the Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock (IABP-SHOCK II) and PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock (CULPRIT SHOCK) show that 30-day mortality remains at 30%-40% and approaches 50% at 1 year. This is consistent with clinical practice data from a US national registry (the American College of Cardiology CathPCI Registry), which also showed rising mortality in patients with AMI-CS who are managed with invasive, contemporary therapeutics including timely revascularization and percutaneous mechanical circulatory support.
Clinical trials that evaluate drugs, devices, and best practices for CS have been challenging to conduct and slow to enroll. Since the “Early Revascularization in Acute Myocardial Infarction Complicated by Cardiogenic Shock” (SHOCK) trial opened enrollment in 1993, only 2,500 patients in total have been enrolled in prospective randomized trials worldwide; this represents 0.5% of estimated AMI-CS patients from Europe and North America. Moreover, it took nearly 40 years from development of the intra-aortic balloon pump (IABP) in the 1960s to the first appropriately sized RCT studying its efficacy. The “Intraaortic Balloon Pump in Cardiogenic Shock” (IABP-SHOCK II) trial demonstrated no survival benefit or improvement in measures of end-organ function.
The prevalence and persistently high mortality with CS have led to widespread use of novel mechanical circulatory support (MCS) devices for the management of CS despite the paucity of appropriately sized, prospective RCTs to support a beneficial effect on outcome. The Cardiac Safety Research Consortium ThinkTank “Defining the Clinical and Regulatory Landscape for Cardiogenic Shock” was therefore convened in September 2018 in Washington, DC, to attempt to address these issues. Physician experts, US and Canadian regulators, and industry leaders met to discuss current clinical best practices, barriers to generating prospective evidence, areas of CS care that have not been studied ( Table I ), and future directions for approaches to device and drug development evidence for therapies in CS.
| Revascularization |
| Revascularization strategy (percutaneous vs surgical bypass) |
| Access site (radial vs femoral) |
| Timing of complete revascularization (after treatment of culprit lesion at presentation) |
| Devices |
| Ventilation strategies |
| Use of invasive hemodynamics |
| Mechanical circulatory support (timing, device selection, patient selection) |
| Hypothermia |
| Optimal pharmacological therapies |
| Inotrope regimens |
| Vasopressor regimens |
| Antiplatelet therapies |
| Anticoagulant therapies |
| Anti-inflammatory agents |
| Immunomodulatory agents |
| Systems of care |
| Timing and frequency of invasive hemodynamic measurement |
| Target mean arterial blood pressure |
| Timing of mechanical circulatory support implantation |
| The role of specialized shock team |
| Transfusion strategy |
| Optimal blood glucose levels |
Addressing barriers to generating evidence in cardiogenic shock
Importance of a standardized definition of cardiogenic shock
There are currently multiple ongoing prospective studies of device therapies, pharmacologic therapies, and systems of care interventions for patients with a primary condition of “cardiogenic shock.” Outcomes of CS may relate to a matrix of critical features, including patient characteristics, severity of CS at time of recognition, clinical comorbidities, coronary anatomy, timing of intervention, support technologies, and postprocedural care. Current definitions of CS used in prospective trials and registries have varied and include combinations of clinical, hemodynamic, and metabolic profiles, as depicted in Table II .
| Clinical criteria | Hemodynamic criteria | |
|---|---|---|
| Califf et al (1994) | SBP < 90 mm Hg or 30 mm Hg below baseline for at least 30 min | AVO2 difference > 5.5 mL/dL |
| Cardiac Index <2.2 L/min/m 2 AND | ||
| PCWP >15 mm Hg | ||
| (S)MASH (1999) | 1. SBP < 90 mm Hg despite inotropic support | 1. PCWP >15 mm Hg* |
| 2. AMI < 48 h prior to presentation | 2. Thermodilution CI < 2.2 L/min/m 2 * | |
| SHOCK (1999) | 1. SBP < 90 mmHg for at least 30 min OR | Cardiac index </= 2.2 L/min/m 2 AND |
| 2. Need for supportive measures to maintain SBP >/= 90 mm Hg | PCWP >/= 15 mm Hg | |
Signs of end-organ dysfunction | ||
| 1. Cool extremities | ||
| 2. UOP <30 mL/h AND | ||
| 3. HR >/= 60 beat/min | ||
| TRIUMPH (2007) | 1. <100 mm Hg despite vasopressor therapy 2. LVEF <40% | Elevated left ventricular filling pressures |
| IABP SHOCK (2010) | 1. SBP < 90 mm Hg for at least 30 min OR | CI < 2.2 L/min/m 2 |
| 2. Need for inotropic/vasopressor to maintain SBP >/= 90 mm Hg | ||
| IABP-SHOCK II (2012) 50 | 1. SBP < 90 mm Hg for at least 30 min OR | |
| 2. Infusion of catecholamines to maintain SBP > 90 mm Hg AND | ||
| 3. Impaired organ perfusion | ||
| A. Altered mental status | ||
| B. Cold/clammy skin | ||
| C. UOP < 30 mL/h | ||
| D. Serum lactate >2.0 mmol/L | ||
| CULPRIT-SHOCK (2017) | 1. SBP < 90 mm Hg for at least 30 min OR 2. Infusion of catecholamines to maintain SBP > 90 mm Hg 3. Impaired organ perfusion A. Clinical signs of pulmonary congestion B. Altered mental status C. Cold and clammy skin/limbs D. UOP (<30 mL/h) E. Arterial lactate >2.0 mmol/L |
Heterogeneity of inclusion criteria for CS trials reduces external validation and makes it difficult to generalize results to larger patient populations. As was the case with the Bleeding Academic Research Consortium’s (BARC) definition, development and use of an accepted definition of CS for future cardiovascular clinical research (trials and registries) would likely lead to more consistent, efficient, and interpretable evidence for specific devices and drug interventions and for accrual of knowledge in CS overall. In addition, structured classification of the severity of shock may enhance interpretation of results from different data sets.
Role of speed and triage of shock patients
The ThinkTank participants believe that there is a critical time, referred to as “preshock,” during which a potentially reversible hemodynamic state exists, and if not quickly intervened upon, preshock can rapidly progress to systemic shock with multiorgan failure and nearly universal mortality. The consensus of the ThinkTank participants is that such time dependence makes early recognition of shock states critical to their optimal care and that this time dependence has substantial implications for clinical trials that measure outcomes from investigational interventions. As such, the rapid identification of shock patients should constitute a critical metric for advancing both clinical care and research in therapies for shock.
There was strong consensus that once the hemodynamics of shock are identified, a multidisciplinary approach to stratifying different causes of shock with concomitant triage to surgical, cardiac, or other procedures is also of paramount importance in ultimately defining, or improving, outcomes in these patients. In the case of device interventions, the CSRC ThinkTank felt that the differentiation of non-CS from CS, further followed by the identification of CS due to acute ischemic (non–ST-elevation myocardial infarction [non-STEMI or STEMI), might all be relevant to the feasibility of conducting informative clinical trials.
Delineating populations of intended use and outcomes
Regulatory authorities require device labeling to give a clear and clinically relevant definition of the population of intended use. Typically, this population is derived from the characteristics of patients in whom the therapy has been studied investigationally. To date, the vast majority of research in CS has focused on patients with concurrent AMI or other hemodynamic embarrassment potentially due to a reversible coronary mechanism. There are, however, other cohorts of CS patients with similarly poor outcomes who are not as well studied but for whom MCS may have a role ( Table III ). Despite a paucity of high-quality data including RCTs supporting their use, MCS devices are regularly deployed in these patients. In addition to defining the cohorts for future research, discerning the relationship between a given device and its appropriate duration of use is also necessary. Clinical context should be taken into account, including periprocedural use, shorter-term use as a “bridge,” or longer-term support such as definitive “destination therapy” ( Table IV ).
| Acute on chronic left ventricular /biventricular heart failure |
| Bridge to durable mechanical circulatory support |
| Bridge to orthotopic heart transplantation |
| Bridge to bridge |
| Postcardiotomy |
| Acute myocarditis |
| Primary graft dysfunction following orthotopic heart transplantation |
| Acute pulmonary embolism |
| Valvular cardiomyopathy |
| Left ventricular outflow obstruction |
| Peripartum cardiomyopathy |
| Refractory arrhythmia |
| Takotsubo syndrome |
| Acute on chronic right ventricular failure |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
