Dhruva et al. FAQs

February 21, 2020
Dhruva et al Clinical Outcomes

What was the design and objective of Dhruva et al.?

Dhruva et al. is a retrospective, observational analysis of patients with acute myocardial infarction (AMI) complicated by cardiogenic shock undergoing percutaneous coronary intervention (PCI) between October 1, 2015 and December 31, 2017. Patient data came from hospitals participating in two registries (CathPCI and Chest Pain-MI) in the National Cardiovascular Data Registry (NCDR).1

The stated objective of Dhruva et al. was to examine outcomes among patients undergoing PCI for AMI complicated by cardiogenic shock treated with MCS devices. The primary outcomes were in-hospital mortality and in-hospital major bleeding. In a secondary analysis, patients receiving IABP were compared to patients receiving only medical therapy to determine whether outcomes using propensity matching were similar to those observed in the IABP-SHOCK II trial.1

Cardiogenic shock in the two patient registries was defined as one, two or all three of the following: systolic blood pressure (SBP) lower than 90 mmHg, cardiac index lower than 2.2 L/min/m2 for at least 30 minutes secondary to ventricular dysfunction, and/or requirement for parenteral inotropic, vasopressor, or MCS device therapy.2 However, the patient data from the registries lacked clinical and hemodynamic parameters, such as door-to-support time, duration of shock, severity of shock, or metabolic derangement, all of which are strong, well-known predictors of outcome.13,14

What patient populations were analyzed in Dhruva et al.?

This registry-based retrospective cohort included 3,360 propensity-matched patients undergoing PCI for AMI. Patients who required escalation in their hemodynamic support were excluded from the analysis.1 Previous studies have shown that patients escalated from IABP had higher costs of care, longer lengths of stay, and worse outcomes.15 As a result of this exclusion, patients treated with IABP as an only therapy were likely less critically ill, thus creating a selection bias. The authors of Dhruva et al. state that “there may be residual confounding whereby patients receiving intravascular microaxial LVADs had greater severity of illness than those receiving IABPs.”1

What results were reported by Dhruva et al. and how do these results compare to other published data?

A video reviewing the Dhruva et al. data is available on ProtectedPCI.com. Key results are presented below along with discussion of how the authors’ conclusions conflict with Impella best practice outcomes reported in more robust, previously published, contemporary, prospective studies such as the STEMI DTU Pilot RCT, the INOVA Study and the National Cardiogenic Shock Initiative (NCSI) Study.

In-hospital death and in-hospital bleeding
Dhruva et al. reported that treatment with intravascular microaxial LVAD (Impella) compared to IABP was associated with a significantly higher risk of in-hospital death (45% vs 34.1%) and in-hospital bleeding (31.3% vs 16.0%), but because the bleeding rate in the excluded group was 30%, bleeding may be associated with patient condition rather than the device. From these results, the authors state that the use of intravascular microaxial LVAD compared with IABP may be associated with worse in-hospital clinical outcomes among patients with AMI and cardiogenic shock undergoing PCI, although they also note that “study interpretation is limited by the observational design.”1

In an accompanying editorial by Holger Thiele, MD, and colleagues, they comment, “Despite propensity matching, the observed differences in outcomes between use of the microaxial LVAD and use of the IABP reported by Dhruva et al. may have been related to limitations in these registry-based analyses, and the findings should not be considered definitive. Since the indication for mechanical circulatory support strongly depends on the familiarity of the operator with the device and the severity of cardiogenic shock, findings derived from observational registries may be limited by selection bias and confounding, which cannot be completely accounted for even with sophisticated statistical matching and analyses.”3

Neither of the primary outcome results reported by Dhruva et al. are consistent with other published data. The bleeding data is inconsistent with results from prospective studies, RCTs, and real-world data. It also excludes best practices and outcomes being implemented in recent years.5,16,17,18,19 The 66% survival rate for cardiogenic shock patients who received IABP1 is inconsistent with published literature and FDA-audited clinical evidence, including IABP SHOCK II.6 This unusually high survival rate is likely  attributed to patients receiving IABP being in less severe shock, or perhaps not in shock, and the exclusion of IABP patients escalated to other therapies, which is a known predictor of higher cost and poorer outcomes.

Survival for medical therapy only
Dhruva et al. also reported that the mortality rate for the 16,227 patients receiving medical therapy only was 20%,1 a result substantially challenging the definition of shock in this dataset. These low mortality rates in the medical treatment and IABP arms may be explained by the fact that the analysis did not use the inclusion criteria for cardiogenic shock that has been established in multiple RCTs.

Pre-PCI vs Post-PCI Impella use
Dhruva et al. attempted to evaluate pre- and post-PCI use of Impella as a predictor of outcome. However, their data does not reflect the standard definitions in which pre-PCI Impella use includes only patients who receive Impella to achieve hemodynamic stabilization prior to the angiogram or PCI and post-PCI includes all Impella use after the initiation of the PCI. Instead, the pre-PCI group in Dhruva et al. includes both patients who received Impella prior to PCI and patients who received Impella as bailout during PCI, likely worsening Impella outcomes. The conclusion in Dhruva et al. that better outcomes are associated with MCS placement post-PCI is inconsistent with published literature and FDA-audited data. Multiple datasets and subset analyses of RCTs have consistently demonstrated the association of survival with pre-PCI Impella use.14,20-28

Results summary
The results presented by Dhruva et al. conflict with more than 10 years of outcomes data on Impella reported in robust, FDA-audited, peer-reviewed, real-world published studies and RCTs. Based on the Dhruva et al. headlines alone, this analysis has the potential to impact patient access to Impella. Thus, Seth Bilazarian, MD warns, “Caution is recommended in making important patient management decisions for the patient you may be seeing today when data that conflicts with more than a decade of publications is presented from observational databases.”

What do clinical guidelines say about IABP use?

It has been well known since the publication of the IABP-SHOCK II trial that IABP support is not associated with better outcomes than optimal medical treatment.4-6 In 2013, guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) include a Class IIa level of evidence recommendation for use of IABP in patients with cardiogenic shock.9 In Europe and Japan, IABP has received a Class III recommendation (not recommended, may be harmful).7,8 Thiele et al. write, “Against this background, a 30% rate of IABP use in the United States between 2015 and 2017 is surprising, and by comparison, adoption of the latest scientific evidence has been seemingly faster in European countries, as shown in several European registries with rates of IABP use of less than 10%, from 2012 to 2017.”10-12

Is Abiomed conducting randomized controlled trials (RCTs) of Impella for cardiogenic shock?

Abiomed has made a broad commitment to evidence generation for Protected PCI and cardiogenic shock with RCTs and large real-world data collections. Abiomed is sponsoring the Danish-German (DanGer) Shock RCT of Impella in cardiogenic shock in Europe and has recently begun the STEMI DTU RCT. On February 6, 2020, Abiomed announced its intention to conduct another cardiogenic shock RCT in the United States, the RECOVER IV RCT, in which patients with cardiogenic shock will be randomized to receive either Impella pre-PCI or other treatment protocols, which can include any kind of non-Impella mechanical circulatory support. To learn more about Abiomed’s ongoing clinical trials, visit this page.  Visit this page to learn about Abiomed’s previous attempts to randomize patients in cardiogenic shock.

References

  1. Dhruva SS, Ross JS, Mortazavi B, et al. Association of use of an intravascular microaxial left ventricular assist device vs intra-aortic balloon pump with in-hospital mortality and major bleeding among patients with acute myocardial infarction complicated by cardiogenic shock. JAMA. Published online February 10, 2020. doi:10.1001/jama.2020.0254.
  2. Cannon CP, Battler A, Brindis RG, et al. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes: a report of the American College of Cardiology Task Force on Clinical Data Standards (Acute Coronary Syndromes Writing Committee). J Am Coll Cardiol. 2001;38(7):2114-2130. doi:10.1016/s0735-1097(01)01702-8.
  3. Thiele H, Desch S, Freund A. Microaxial left ventricular assist devices: in search of an appropriate indication. JAMA. Published online February 10, 2020. doi:10.1001/jama.2020.0254.
  4. Thiele H, Zeymer U, Neumann FJ, et al; Intraaortic Balloon Pump in cardiogenic shock II (IABP-SHOCK II) trial investigators. Intraaortic 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(9905):1638-45. doi:10.1016/S0140-6736(13) 61783-3.
  5. Thiele H, Zeymer U, Neumann F-J, et al; IABP-SHOCK II Trial Investigators. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012;367(14):1287-96. doi:10.1056/NEJMoa1208410.
  6. Thiele H, Zeymer U, Thelemann N, et al; IABP-SHOCK II Investigators. Intraaortic balloon pump in cardiogenic shock complicating acute myocardial infarction: long-term 6-year outcome of the randomized IABP-SHOCK II Trial. Circulation. 2018;139(3):395-403. doi:10.1161/ CIRCULATIONAHA.118.038201.
  7. Neumann FJ, Sousa-Uva M, Ahlsson A, et al; ESC Scientific Document Group. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J. 2019;40(2):87-165. doi:10.1093/eurheartj/ ehy394.
  8. Ibanez B, James S, Agewall S, et al; ESC Scientific Document Group. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119-77. doi:10.1093/eurheartj/ ehx393.
  9. O’Gara PT, Kushner FG, Ascheim DD, et al; American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362-e425. doi:10.1161/CIR.0b013e3182742c84.
  10. Helgestad OKL, Josiassen J, Hassager C, et al. Temporal trends in incidence and patient characteristics in cardiogenic shock following acute myocardial infarction from 2010 to 2017: a Danish cohort study. Eur J Heart Fail. 2019;21(11):1370-78; epub ahead of print. doi:10.1002/ejhf.1566.
  11. Rathod KS, Koganti S, Iqbal MB, et al. Contemporary trends in cardiogenic shock: incidence, intra-aortic balloon pump utilisation and outcomes from the London Heart Attack Group. Eur Heart J Acute Cardiovasc Care. 2018;7(1):16-27. doi: 10.1177/2048872617741735.
  12. Backhaus T, Fach A, Schmucker J, et al. Management and predictors of outcome in unselected patients with cardiogenic shock complicating acute ST-segment elevation myocardial infarction: results from the Bremen STEMI Registry. Clin Res Cardiol. 2018;107(5):371-79. doi:10.1007/s00392-017-1192-0.
  13. Valente S, Lazzeri C, Vecchio S, et al. Predictors of in-hospital mortality after percutaneous coronary intervention for cardiogenic shock. Int J Cardiol. 2007;114(2):176-82.
  14. Basir MB, Schreiber TL, Grines CL, et al. Effect of early initiation of mechanical circulatory support on survival in cardiogenic shock. Am J Cardiol. 2017;119(6):845-51.
  15. Stretch R, Sauer CM, Yuh DD, Bonde P. National trends in the utilization of short-term mechanical circulatory support. Journal of the American College of Cardiology. 2014;64(14):1407-15.
  16. FDA PMA Submission, Data on file (bleeding requiring transfusion).
  17. FDA Post-Approval Study, Data on file (bleeding requiring transfusion).
  18. Burkhoff D, Cohen H, Brunckhorst C, O’Neill WW., A randomized multicenter clinical study to evaluate the safety and efficacy of TandemHeart percutaneous ventricular assist device versus conventional therapy with intraaortic balloon pumping for the treatment of cardiogenic shock. Am Heart J. 2006;152(3):469.e1-469.e8.
  19. Cheng R, Hachamovitch R, Kittleson M, et al., Complications of extracorporeal membrane oxygenation for treatment of cardiogenic shock and cardiac arrest: a meta-analysis of 1,866 adult patients. Annals Thoracic Surgery. 2014;97(2):610-616.
  20. O’Neill WW, Grines C, Schrieber T, et al. Analysis of outcomes for 15,259 US patients with acute myocardial infarction cardiogenic shock (AMICS) supported with Impella device. Am Heart J. 2018;202:33-8.
  21. O’Neill WW, Schreiber T, Wohns DH, et al. The current use of Impella 2.5 in acute myocardial infarction complicated by cardiogenic shock: results from the USpella Registry. J Interv Cardiol. 2014;27(1):1-11.
  22. Meraj PM, Doshi R, Schreiber T, et al. Impella 2.5 initiated prior to unprotected left main PCI in acute myocardial infarction complicated by cardiogenic shock improves early survival. J Interv Cardiol. 2017;30(3):256-63.
  23. Schroeter MR, Köhler H, Wachter A, et al. Use of the Impella device for acute coronary syndrome complicated by cardiogenic shock – experience from a single heart center with analysis of long-term mortality. J Invasive Cardiol. 2016;28(12):467-72.
  24. Thiele H, Akin I, Sandri M, et al. PCI strategies in patients with acute myocardial infarction and cardiogenic shock. N Engl J Med. 2017;377:2419-32.
  25. Ouweneel DM, Eriksen E, Sjauw KD, et al. Percutaneous mechanical circulatory support versus intra-aortic balloon pump in cardiogenic shock after acute myocardial infarction. J Am Coll Cardiol. 2017;69(3):278-87.
  26. Schrage B, Ibrahim K, Loehn T, et al. Impella support for acute myocardial infarction complicated by cardiogenic shock. Circulation. 2019;139(10):1249-58.
  27. Dhruva SS, Ross JS, Mortazavi B, et al. Utilization and outcomes of Impella vs IABP among patients with AMI complicated by cardiogenic shock undergoing PCI. Presented at: American Heart Association Scientific Sessions; November 17, 2019; Philadelphia, PA.
  28. Stretch R, Sauer CM, Yuh DD, Bonde P. National trends in the utilization of short-term mechanical circulatory support. Journal of the American College of Cardiology. 2014;64(14):1407-15.

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