Why did remote ischaemic conditioning not improve clinical outcomes in acute myocardial infarction in the CONDI-2/ERIC-PPCI trial?

New treatments are needed to reduce myocardial infarct (MI) size and preserve left ventricular (LV) function, in order to improve clinical outcomes in patients presenting with acute ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PPCI).1 Remote ischaemic conditioning (RIC), in which brief cycles of ischaemia and reperfusion are applied to an organ or tissue (including a limb) away from the heart, has been shown to reduce MI size in animal models of acute myocardial ischaemia/reperfusion injury (IRI).2 The ability to deliver the cardioprotective RIC stimulus by simply inflating and deflating a pneumatic cuff placed on the upper arm or thigh, to induce brief cycles of ischaemia and reperfusion3 has facilitated the translation of RIC into the clinical setting. The majority of clinical studies have demonstrated improved myocardial salvage [assessed by myocardial nuclear and cardiovascular magnetic resonance imaging (MRI)]4–7 and/or 20–30% reductions in MI size (quantified by cardiac biomarkers and cardiac MRI)8–10 with RIC administered as an adjunct to PPCI in STEMI. Furthermore, two follow-up studies,11,12 and a single prospective study13 have suggested that RIC may improve clinical outcomes in STEMI. However, a large, sufficiently powered, prospectively designed multicentre clinical outcome study has been lacking. Therefore, we conducted the CONDI-2/ERIC-PPCI trial. The study was an international, multicentre, single-blinded, randomized controlled trial comprising 5401 STEMI patients recruited through 36 centres in the United Kingdom, Denmark, Spain, and Serbia. Patients were randomly assigned to receive either standard (control) treatment or RIC, initiated prior to PPCI. RIC was administered using an automated AutoRIC™ cuff device (CellAegis Devices Inc., Toronto, Canada) placed on the upper arm to deliver four alternating cycles of inflation for 5 min to 200 mmHg and deflation for 5 min. The primary combined endpoint was cardiac death or hospitalization for heart failure (HHF) at 12 months post-randomization. Secondary endpoints included major cardiovascular and cerebral adverse events (MACCE, comprising all-cause death, re-infarction, repeat coronary revascularization, and stroke) at 30 days and 12 months, and MI size in a subset of 2662 patients [quantified as area under the curve (AUC) high-sensitivity Troponin T measured 0–48 h after PPCI]. A limited number of pre-specified subgroup analyses [age, diabetic status, left anterior descending (LAD) vs. non-LAD STEMI, pre-angioplasty TIMI flow (0–1 and 2–3), and time elapsed between first medical contact and PPCI] were performed on the primary outcome. The results of the CONDI-2/ERIC-PPCI trial were presented in a Hot Line Session at the European Society of Cardiology Congress in Paris 2019, and simultaneously published in the Lancet.14 Unfortunately, there was no difference between the control group [8.6% (n = 220)] and the RIC group [9.4% (n = 239)] with respect to the combined primary endpoint of cardiac death or HHF at 12 months [hazard ratio 1.10; 95% confidence interval (CI) 0.91–1.32; P = 0.32], demonstrating that RIC, applied as an adjunct to PPCI, did not improve clinical outcomes in STEMI patients. Similarly, there was no difference between the control group [7.8% (n = 197)] and the RIC group [8.4% (n = 212)] with respect to MACCE within 12 months of follow-up (hazard ratio, 1.09; 95% CI 0.90–1.32; P = 0.38). These findings are in direct conflict with the CONDI-1 and LIPSIA CONDITIONING follow-up studies. CONDI-1 reported less MACCE (all-cause mortality, myocardial infarction, readmission for heart failure, and ischaemic stroke/transient ischaemic attack) with RIC vs. control at a median follow-up of 3.8 years (13.5% vs. 25.6%).11 LIPSIA CONDITIONING reported MACE (cardiac death, re-infarction, and new congestive heart failure) with a combination of RIC and post-conditioning vs. control at a median follow-up of 3.6 years (10.2% vs. 16.9%).12 Similarly, the single-centre prospective RIC-STEMI trial reported less cardiac death or HHF at a median follow-up of 2.1 years with RIC vs. control (hazard ratio 0.35; 95% CI 0.15–0.78).13 All three studies had extended follow-up, whereas the CONDI-2/ERIC-PPCI trial had a relatively short-term follow-up period of 12 months, which may not have been long enough to observe any effect of RIC on clinical outcomes. In the CONDI-2/ERIC-PPCI trial there was also no effect of RIC on MI size when compared with control (evaluated by high-sensitivity Troponin T—ratio of means 1.05, 95% CI 0.92–1.18; P = 0.48). This finding confirms that RIC appeared to have no biological effect—a finding, which is consistent with the observed lack of effect of clinical outcomes at 12 months. Several other studies have failed to demonstrate a beneficial effect of RIC on MI size when quantified by cardiac biomarkers despite salutatory effects on myocardial salvage and clinical outcomes,4,5,11–13 questioning the reliability of using MI size quantified by cardiac biomarkers to assess cardioprotective efficacy. Because cardiac MRI is a more sensitive technique for assessing cardioprotective efficacy, the results of the cardiac MRI study from the CONDI-2/ERIC-PPCI trial, which will report the effect of RIC on MI size and myocardial salvage, are eagerly awaited. Even though MI size is known to be a critical determinant of clinical outcomes post-PPCI in STEMI, it has not been conclusively shown that a reduction in MI size by a cardioprotective intervention applied as an adjunct to PPCI, can be translated into improved clinical outcomes within the range of infarct sizes achieved with contemporary reperfusion therapy. Interestingly, the RIC-STEMI trial failed to demonstrate a reduction in MI size (using 48 h AUC Troponin I) but still found improved clinical outcomes after 2 years’ follow-up.13 The unexpected and discordant effects of RIC on MI size and clinical outcomes in the RIC-STEMI trial may have been due to a Type 1 error, as only 516 STEMI patients were randomized, and the number of events was relatively small (three RIC vs. 11 control for cardiac mortality and eight RIC vs. 17 control for HHF). An alternative explanation may be that the primary effect of RIC was on post-STEMI LV remodelling rather than acute MI size—but this is not supported by experimental animal studies, which have shown RIC reducing acute MI size.2 Other reasons why RIC may have failed to reduce MI size and improve clinical outcomes in the CONDI-2/ERIC-PPCI trial include: The RIC protocol itself: In the CONDI-2/ERIC-PPCI trial, four 5-min cycles of upper arm cuff inflations/deflations were used, a RIC protocol which has been shown in prior studies to increase myocardial salvage index4 and reduce MI size6. However, the optimal RIC protocol in terms of arm vs. leg, number of cycles, duration of ischaemia/reperfusion cycles, and unilateral vs. bilateral limbs, has not been established in humans. Interestingly, the RIC-STEMI study, which showed improved clinical outcomes with RIC, used three cycles of inflation/deflation of a pneumatic cuff placed on the thigh.13 Timing of the RIC protocol: Clinical studies have reported efficacy with RIC administered in the ambulance or on arrival at the hospital (prior to PPCI), during PPCI, and even at the onset of reperfusion after PPCI. In the CONDI-2/ERIC-PPCI trial, there were no differences in clinical outcomes whether the RIC protocol was performed in the ambulance or at the hospital. Furthermore, there was no difference in clinical outcomes whether the full four cycles of the RIC protocol were completed prior to onset of PPCI or not. Comedications and comorbidities: Experimental studies have shown that certain comorbidities (such as age and diabetes) and comedications (such as platelet P2Y12 inhibitors) can attenuate the cardioprotective efficacy of ischaemic conditioning strategies, although specific evidence for RIC is limited.15 However, in the CONDI-2/ERIC-PPCI trial, age, the presence of diabetes, or the administration of the P2Y12 receptor antagonist, ticagrelor, did not interfere with clinical outcomes between the control and the RIC groups. Pre-PPCI TIMI flow and coronary artery territory: The efficacy of cardioprotective interventions applied at reperfusion in STEMI patients is closely related to MI size and pre-PPCI TIMI flow with most benefit reported for patients with anterior infarcts and an occluded artery on presentation (pre-PPCI TIMI flow ≤1).4 However, prespecified subgroup analyses in the CONDI-2/ERIC-PPCI revealed no differences in clinical outcomes with RIC vs. control when considered according to MI location and pre-PPCI TIMI flow. In summary, the findings from the CONDI-2/ERIC-PPCI trial provide definitive and conclusive evidence that RIC offers no benefits on either MI size or clinical outcomes in STEMI patients treated by PPCI. This is unfortunate as RIC had been the most promising cardioprotective strategy for improving clinical outcomes following STEMI, and few other therapeutic options exist. Our stemi population were low-risk patients. RIC may be beneficial in higher risk patient with heart failure and less optimal reperfusion. Further studies are needed to identify novel cardioprotective targets and innovative approaches to cardioprotection such as combination multi-target therapy. RIC may still have benefit in other condition such as renal transplantation, stroke, and elective PCI. The authors thank all patients for participating in this study and all study personnel for their invaluable assistance. Conflict of interest: H.E.B. is a shareholder in CellAegis Inc. D.J.H. has no conflict of interest to declare. The ERIC-PPCI trial was funded by a British Heart Foundation Clinical Study Grant [CS/14/3/31002] and a University College London Hospital/University College London Biomedical Research Clinical Research grant. The CONDI-2 trial was funded by Danish Innovation Foundation grants [11-108354 and 11-115818], Novo Nordisk Foundation [NNF13OC0007447], and Trygfonden [109624]. D.J.H. was supported by the British Heart Foundation [FS/10/039/28270], National Institute for Health Research University College London Hospitals Biomedical Research Centre, Duke-National University Singapore Medical School, Singapore Ministry of Health’s National Medical Research Council under its Clinician Scientist-Senior Investigator scheme [NMRC/CSA-SI/0011/2017] and its Collaborative Centre Grant scheme [NMRC/CGAug16C006], and the Singapore Ministry of Education Academic Research Fund Tier 2 [MOE2016-T2-2-021]. H.E.B. was supported by the Novo Nordisk Foundation [NNF14OC0013337, NNF15OC0016674]. This article is based upon the work of COST Action EU-CARDIOPROTECTION [CA16225] and supported by COST [European Cooperation in Science and Technology]. Biography: Derek Hausenloy, PhD, FESC is professor at Duke-National University of Singapore Medical School and University College London. He is a Senior Consultant Cardiologist at the National Heart Centre, Singapore. He conducts both basic and clinical research in the area of ischaemic heart disease, heart failure, cardioprotection, and cardiac MRI. His research focus is on discovering novel therapies for protecting the heart against the detrimental effects of acute ischaemia/reperfusion injury in order to prevent the onset of heart failure. He uses a translational approach to cardioprotection ranging from cellular and animal models of acute IRI to proof-of-concept clinical studies in acute myocardial infarction and cardiac bypass surgery patients, and finally to large multicentre randomized clinical trials focused on clinical outcomes. He is also interested in both small animal and clinical cardiac PET and MRI imaging in the context of acute myocardial infarction and cardioprotection. Prof Hausenloy has been PI on over 30 research grants, and he has authored over 250 papers and his H-index is 80. In 2018, he was named Highly Cited Researcher. Biography: Hans Erik Bøtker, MD, PhD, FESC, FACC is an interventional cardiologist and professor of Cardiovascular Medicine and Interventional Cardiology and co-director of Department of Cardiology, Aarhus University Hospital, Denmark. He is past president of the Danish Society of Cardiology and nucleus member of the Working Group of Cellular Biology in the European Society of Cardiology. His research has focused on ischaemic heart disease, interventional cardiology, and myocardial metabolism during research conducted at Aarhus University Hospital and as visiting professor at University of Texas, Houston Medical School. He uses a translational approach to cardioprotection ranging from cellular and animal models, over proof-of-concept to clinical outcome studies in acute myocardial infarction. Together with his team, he has initiated a research programme that aims to optimize the whole chain of events involved in admission of patients with acute coronary syndrome for urgent treatment. Prof Bøtker has been PI on more than 20 research grants, among others from The Danish Research Council, The Danish Heart Foundation and Fondation Leducq. He has published more than 460 peer-review papers and his H-index is 58.

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