Between 5% and 10% of patients experiencing ST-segment elevation myocardial infarction (STEMI) develop cardiogenic shock (CS), over half of whom die during hospitalization. To date, no mechanical circulatory support (MCS) device has shown improved outcomes in clinical trials for these patients. This study aims to determine whether the routine use of a microaxial flow pump brings significant benefits in terms of reducing mortality among patients with STEMI complicated by CS.
The DanGer study (Danish-German Shock Trial) is an international, multicenter, randomized trial that enrolled STEMI patients with CS (stage C, D, or E). One group received standard care with an additional microaxial flow pump (Impella CP®), while the other received only standard treatment. The primary outcome assessed was all-cause mortality at 180 days, with secondary analysis including adverse events such as severe bleeding, limb ischemia, hemolysis, device failure, and worsening aortic regurgitation.
A total of 360 patients participated, with 355 included in the final analysis (179 in the microaxial flow pump group and 176 in the standard care group). The median age was 67 years, and 79.2% were men. All-cause mortality was 45.8% in the microaxial pump group and 58.5% in the standard care group (hazard ratio = 0.74; 95% confidence interval [CI]: 0.55-0.99; p = 0.04). Regarding adverse events, the composite safety event occurred in 24.0% of patients in the microaxial flow pump group versus 6.2% in the standard care group (relative risk, 4.74; 95% CI: 2.36-9.55). Additionally, renal replacement therapy was needed in 41.9% of patients in the microaxial flow pump group versus 26.7% in the standard care group (relative risk 1.98; 95% CI: 1.27-3.09).
The investigators concluded that routine use of a microaxial flow pump alongside conventional treatment in patients with STEMI-associated CS led to reduced all-cause mortality at 180 days compared to those receiving standard care alone. However, a higher incidence of composite adverse events was noted in the microaxial flow pump group.
COMMENTARY:
The DanGer study results mark a milestone as the first to show significant mortality reduction through the routine implantation of an MCS device for STEMI-associated CS. This study provides a solid scientific basis supporting routine MCS use in STEMI-related CS. The lack of clear evidence to date, disappointing and surprising to many, could largely be attributed to inadequate study designs in previous trials.
The DanGer study stands out due to its sound design, which resulted in a low crossover rate between groups, inclusion of less critical CS patients, exclusion of patients in a coma, evaluation of study endpoints over a more extended period (180 days instead of 30 days), and a higher rate of pre-Impella® percutaneous revascularization, among other factors. As discussed below, these features clearly favor the Impella®.
Before delving into a detailed analysis, it is essential to review and contextualize available evidence. For over two decades, researchers have sought a strategy (pharmacological, surgical, interventional, device use, etc.) to reduce the high mortality associated with STEMI-related CS (approximately 50%). Only the 1999 SHOCK study and the 2017 CULPRIT-SHOCK trial demonstrated mortality improvements by establishing early culprit-lesion coronary revascularization as the fundamental treatment. Other studies have attempted to achieve similar results using pharmacologic strategies (TRIUMPH, PRAGUE-7, SOAP-2) or non-pharmacologic approaches, like the SHOCK COOL trial exploring hypothermia. Despite the advent and growing use of MCS devices, attempts to prove their efficacy in this context have been unsuccessful, as evidenced by trials such as IABP-SHOCK II with intra-aortic balloon pumps (IABP), ISAR-SHOCK with Impella 2.5®, IMPRESS with Impella CP®, and studies like EURO-SHOCK and ECLS-SHOCK with VA-ECMO, where none achieved the expected benefits. Nevertheless, based on positive results from non-randomized studies and expert group experiences, the 2021 clinical guidelines justifiably maintained a class IIa recommendation with a level C evidence for MCS devices, relegating IABP to a IIIB indication.
The DanGer study took ten years to recruit 360 patients, highlighting the dedication and perseverance of the investigators. This is particularly noteworthy given that microaxial flow pumps were not widely used, and evidence was limited at the time. Additionally, it underscores the challenges of conducting such studies, including patient selection and informed consent. Notably, no differences in observed mortality occurred over this long period among Impella® patients.
As previously mentioned, a standout feature of the study was its well-structured protocol, which minimized disproportionate crossovers between groups. Escalation of support was permitted in both groups, but Impella CP® use in the control group was kept to a minimum. In the control group, 37 patients (20.7%) ultimately needed additional support: 28 chose VA-ECMO (seven transferred from Impella®), five received a long-term LVAD (three after VA-ECMO, one after Impella 5.0® implantation, and another with direct implant), and one received Impella 5.0®. Three patients in the control group transitioned to the Impella CP® treatment group. In the Impella-treated group, 28 patients (15.6%) required escalated support: 14 opted for VA-ECMO, four for VA-ECMO + Impella 5.0®, and ten for a long-term LVAD.
The inclusion and exclusion criteria were similar to previous studies. However, previous studies reported a significantly higher percentage of patients with prior cardiopulmonary resuscitation: 45% in IABP-SHOCK II and 77.7% in ECLS-SHOCK, compared to 20.3% in DanGer Shock. Additionally, DanGer Shock excluded patients who, post-resuscitation, presented with a Glasgow score <8, an exclusion not applied in other MCS studies like IMPRESS, where this exclusion might have yielded benefits. Consequently, DanGer included patients with higher neurological recovery potential and a greater likelihood of benefiting from MCS. Furthermore, these patients were less critical than those in ECLS-SHOCK, as indicated by the average initial lactate levels (4.5 mmol/L vs. 6.9 mmol/L).
Furthermore, it is essential to note that the primary endpoint of mortality was assessed at 180 days, unlike IABP-SHOCK II or ECLS-SHOCK, which did so at 30 days. Although the SHOCK study showed no benefit at 30 days, it did at 180 days. The physiopathological potential of left ventricular unloading, demonstrated in animal studies, might partly account for this improvement beyond 30 days. This suggests that assessing mortality at 30 days might be premature for determining the benefits of MCS interventions.
Additional positive characteristics of this study include the high rate of primary angioplasty performed in 85% of cases, which helps reduce ischemic injury. The study also highlighted the mandatory use of a Swan-Ganz catheter and MCS for a minimum of 48 hours before beginning weaning, ensuring adequate ventricular rest and avoiding excessive vasopressor use.
While 180-day mortality improved significantly with microaxial flow pumps, complications like moderate to severe bleeding and limb ischemia were more common. It is crucial to note that patients with peripheral artery disease were excluded, implying that these complications could be even higher in real clinical practice without appropriate preventive measures. Vascular ultrasound to aid vascular access, distal perfusion catheters, or even Impella® implantation through the subclavian artery using a Dacron graft, as performed at our Cardiac Surgery Department in A Coruña, could help reduce these complications.
This study’s importance is highly relevant, as it surpasses the “no benefit” barrier for routine MCS use in STEMI-related CS, potentially marking the beginning of a new era in managing this condition. We await results from ongoing observational studies and the RECOVER IV trial (comparing Impella® use before percutaneous intervention to conventional treatment), expected to conclude in 2027, to confirm these findings.
Nonetheless, several unresolved uncertainties and complex questions remain:
What is the optimal timing for device implantation? Before or after percutaneous coronary intervention for the culprit STEMI lesion?
Are clear protocols or even dedicated CS teams needed? Undoubtedly, many hospitals will adopt this approach.
In which cases is combining microaxial flow pumps with other MCS devices like VA-ECMO appropriate?
Is it cost-effective? With an NNT of 8 and an Impella CP costing approximately €15000, saving a life would cost at least €120000. Before routinely implementing these devices, we must ensure they are effective. Inappropriate use not only adds unnecessary costs but is associated with severe complications, potential device shortages, and ICU bed scarcity.
Who should implant these devices? The on-call interventionalist before or after percutaneous intervention, or the cardiac surgeon in an urgent or semi-scheduled operating room using alternative access routes like the subclavian artery, as done in our hospital when cardiac surgeons perform the procedure.
REFERENCE:
Møller JE, Engstrøm T, Jensen LO, Eiskjær H, Mangner N, Polzin A, et al. DanGer Shock Investigators. Microaxial Flow Pump or Standard Care in Infarct-Related Cardiogenic Shock. N Engl J Med. 2024 Apr 18;390(15):1382-1393. doi: 10.1056/NEJMoa2312572.
