Three Critiques of the DanGer-Shock Trial

Two Spanish authors wrote a letter-to-the-editor but NEJM chose not to publish it. We will publish it here on Sensible Medicine.

This is a first for Sensible Medicine. For the study-of-the-week, we will publish a criticism of the DanGer-Shock trial.

Dr. Guillermo Aldama is an interventional cardiologist in a university hospital in Northwestern Spain. He and colleagues sent me sharp critiques of the DanGer-Shock trial, which compared the micro-axial flow pump (brand name Impella) vs standard care in patients who had cardiogenic shock due to myocardial infarction.

Aldama sent the criticisms in a letter-to-the-editor but the NEJM editors rejected the letter. I circulated the contents of the letter to colleagues and both they and I consider these reasonable concerns. We will publish their letter.

A brief intro to DanGer-Shock. The Impella device is placed across the aortic valve into the left ventricle. It takes blood from the failing LV and pumps it into the aorta. We call this a ventricular support device. Ventricular support makes sense in patients who have a failing ventricle due to an occluded coronary artery. The idea is that the artery will be opened, the heart will heal, but the heart needs support during the period of acute injury.

Previous clinical trials of other ventricular support devices have shown no benefits. Impella is a unique kind of support device. FDA had approved Impella many years ago, and the device gained acceptance—despite a lack of evidentiary support.

DanGer-Shock, therefore, was a major trial. Had it shown no benefit for Impella, like other types of support devices, the consequences would have been dire. Dire because we would have been using a costly invasive and non-beneficial device for years.

But DanGer-Shock was positive. Patients in the Impella arm had a 26% lower rate of death at 180 days vs standard care. I wrote (and spoke) in support of the trial, though I noted the careful selection of patients. I also covered the trial on Sensible Medicine and Stop and Think. Vinay Prasad offered sharp criticisms of the trial.

Adam, Vinay and I consider the publication of a rejected letter-to-the-editor an experiment. We have wide readership; we are on open and free platform. And we can offer rapid publication. Had the authors pursued an academic publication it would be many weeks to months, and would likely be behind a paywall. Let us know what you think.

---

Here is the correspondence from Dr. Aldama to me:

“We are concerned about three aspects of this work that could invalidate the results, which we illustrate in Figure 1:

First, given the long recruitment period (10.5 years) and the low inclusion rate (29%), there appears to be a a high degree of selection compared with other trials in similar settings such as IABP-SHOCK II,^2,3 (3.75 years/75.9%) or ECLS-SHOCK⁴ (3.42 years/47.5%).

As the DanGer-Shock authors reported in a 2019⁵ publication, the study, initially funded by the Danish Heart Foundation, started in January 2013. They determined that 4 years would be sufficient to recruit the estimated 360 patients out of the 3000 infarcts treated at the 4 Danish centres participating in the study, taking into account that approximately 5% would present with cardiogenic shock.

However, in October 2018, 5.5 years later, only 133 patients out of the 825 potential cardiogenic shocks had been included. What is the reason for this low inclusion?

If the device is so useful, why did the Danish hospitals not recruit patients? 

Abiomed, the manufacturer of the device, joined the trial at that time (2018). The trial was expanded to German hospitals (and one in the UK). The study was renamed DanGer Shock. We would still have to wait 5 more years for the results.

Therefore, although the authors in their flow chart state that they evaluated 1211 patients as eligible, just in Denmark, during the 10.5 years of follow-up, 1575 patients should have been evaluated. To this should be added the patients evaluated by the German centers and the British center.

The second aspect of concern is the disproportionate mortality in the control group. DanGer Shock was intended to be an IABP versus IMPELLA™ trial, but after the publication of IABP-SHOCK II, the authors decided to randomize the control group to amines (editor’s note: amines = vasopressors) and to evaluate escalation to another type of device other than IMPELLA in case of deterioration.

We know that amines are harmful in this context, and it is possible that this strategy was detrimental to the patients randomized to this arm, since almost 80% of them were treated with amines only. In fact, if we compare the mortality of the control groups of other trials in the same field with the mortality of the DanGer Shock control patients (Figure 1A), we will see that the mortality of the latter is unusually high. Would this strategy explain the reluctance to randomize patients? Have these patients been exposed to harmful management? Is it possible that the results in favor of the intervention group are really due to the poor results of the control arm? 

It would be very useful if the authors had reported the time that elapsed from randomization until the decision to escalate to a device was made in both groups. If the control group was mostly treated with a noxious strategy (amines) and in the 20% that were escalated to an assist device, this escalation was delayed, this could explain the high mortality recorded in this arm.

Finally, since heart transplantation is one of the components of the composite secondary endpoint, it would be mandatory for the authors to report the number of transplants performed in each of the groups. These data are important because a higher rate of transplantation in the IMPELLA™ group could explain the striking flattening of the mortality curve observed in this arm after month 2 (Figure 1B). The behavior of this curve is striking considering that the IMPELLA™ device was used only during the first 5 days of treatment and that patients assigned to this arm had many more complications than their counterparts in the control group.

We wrote a letter to the NEJM expressing these concerns and suggesting that they request this information from the authors. However, The Journal replied that they could not publish it due to lack of space.

We have also requested this information from primary investigators, Dr. Moller, by e-mail but have not received a response.”

REFERENCES

1.         Moller JE, Engstrom T, Jensen LO, et al. Microaxial Flow Pump or Standard Care in Infarct-Related Cardiogenic Shock. N Engl J Med 2024;390:1382-1393. doi: 10.1056/NEJMoa2312572

2.         Thiele H, Zeymer U, Neumann FJ, et al. Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial. Lancet 2013;382:1638-1645. doi: 10.1016/S0140-6736(13)61783-3

3.         Thiele H, Zeymer U, Neumann FJ, et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med 2012;367:1287-1296. doi: 10.1056/NEJMoa1208410

4.         Thiele H, Zeymer U, Akin I, et al. Extracorporeal Life Support in Infarct-Related Cardiogenic Shock. N Engl J Med 2023;389:1286-1297. doi: 10.1056/NEJMoa2307227

5.         Udesen NJ, Moller JE, Lindholm MG, et al. Rationale and design of DanGer shock: Danish-German cardiogenic shock trial. Am Heart J 2019;214:60-68. doi: 10.1016/j.ahj.2019.04.019

-- 

Guillermo Aldama López
Unidad de Cardiología Intervencionista
Servicio de Cardiología 
Complexo Hospitalario Universitario A Coruña
As Xubias s/n. 15006. A Coruña.