The broken promise of remote ischaemic conditioning
Authors: Andrew Peter Vanezis
Journal: The Lancet (2019)

Intermittent ischaemia and reperfusion cycles, or ischaemic conditioning, has been viewed as a promising potential cardioprotective technique since its first description by Murry and colleagues in 1986.1Murry CE Jennings RB Reimer KA Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.Circulation. 1986; 74: 1124-1136Crossref PubMed Scopus (7016) Google Scholar The most encouraging iteration of this technique to emerge over the past three decades has been the application of a modified blood pressure cuff placed on the upper arm to induce cycles of remote, transient ischaemia that relay protection to the heart via predominantly neurohormonal mechanisms.2Davidson SM Arjun S Basalay MV et al.The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection-evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology.Basic Res Cardiol. 2018; 113: 43Crossref PubMed Scopus (65) Google Scholar Remote ischaemic conditioning showed early potential in reducing infarct size after myocardial infarction in animal models.3Kerendi F Kin H Halkos ME et al.Remote postconditioning. Brief renal ischemia and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors.Basic Res Cardiol. 2005; 100: 404-412Crossref PubMed Scopus (261) Google Scholar, 4Andreka G Vertesaljai M Szantho G et al.Remote ischaemic postconditioning protects the heart during acute myocardial infarction in pigs.Heart. 2007; 93: 749-752Crossref PubMed Scopus (170) Google Scholar The initial CONDI-1 trial, although small (n=333), suggested that remote ischaemic conditions used as an adjunct to the gold standard therapy of primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) improved the myocardial salvage index5Bøtker HE Kharbanda R Schmidt MR et al.Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial.Lancet. 2010; 375: 727-734Summary Full Text Full Text PDF PubMed Scopus (810) Google Scholar as well as left ventricular systolic function at 30 days in patients at risk of large infarcts.6Munk K Andersen NH Schmidt MR et al.Remote ischemic conditioning in patients with myocardial infarction treated with primary angioplasty: impact on left ventricular function assessed by comprehensive echocardiography and gated single-photon emission CT.Circ Cardiovasc Imaging. 2010; 3: 656-662Crossref PubMed Scopus (106) Google Scholar The results of the RIC-STEMI trial (n=258) echoed those of CONDI-1, with remote ischaemic conditioning showing additional benefits in reducing cardiac deaths and hospitalisations and increasing the overall mean improvement of ejection fraction after 1 year.7Gaspar A Lourenço AP Pereira MÁ et al.Randomized controlled trial of remote ischaemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty (RIC-STEMI).Basic Res Cardiol. 2018; 113: 14Crossref PubMed Scopus (109) Google Scholar Medium-term follow-up data (at a median 3·6 years) from the LIPSIA CONDITIONING study (n=696) showed that remote ischaemic conditioning combined with post-conditioning reduced new heart failure diagnoses compared with remote ischaemic conditioning alone.8Eitel I Stiermaier T Rommel KP et al.Cardioprotection by combined intrahospital remote ischaemic perconditioning and postconditioning in ST-elevation myocardial infarction: the randomized LIPSIA CONDITIONING trial.Eur Heart J. 2015; 36: 3049-3057Crossref PubMed Scopus (170) Google Scholar None of these trials showed a reduction in infarct size when remote ischaemic conditioning was applied; however, cardiac MRI data suggest the ability of remote ischaemic conditioning to induce positive ventricular remodelling in the absence of absolute infarct size reduction.9Traverse JH Swingen CM Henry TD et al.NHLBI-sponsored randomized trial of postconditioning during primary percutaneous coronary intervention for ST-elevation myocardial infarction.Circ Res. 2019; 124: 769-778Crossref PubMed Scopus (28) Google Scholar In The Lancet, Derek Hausenloy and colleagues10Hausenloy DJ Kharbanda RK Møller UK et al.Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.Lancet. 2019; (published online Sept 6.)http://dx.doi.org/10.1016/S0140-6736(19)32039-2Summary Full Text Full Text PDF PubMed Scopus (173) Google Scholar report the findings of the combined CONDI-2/ERIC-PPCI trial, a large and appropriately powered randomised controlled trial to address whether remote ischaemic conditioning as an adjunct to PPCI can improve the clinical outcomes of patients with STEMI when compared with PPCI alone. The trial was a pragmatic combination of two very similar protocol designs. Between 2013 and 2018, 5401 patients undergoing PPCI for STEMI across four European countries were randomly allocated (1:1) to PPCI alone (mean age 63·1 years [SD 12·2], 576 [22·4%] women) or PPCI plus remote ischaemic conditioning (63·9 years [12·1], 611 [24·0%] women). Remote ischaemic conditioning was administered either in the ambulance en route to the hospital or in the hospital, before or during the PPCI procedure. The combined primary endpoint, cardiac death or hospitalisation for heart failure within 1 year, did not differ between groups, occurring in 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio [HR] 1·10 [95% CI 0·91–1·32], p=0·32). This finding was consistent in prespecified subgroup analyses by age, presence of diabetes, pre-PPCI TIMI flow, ischaemia time, or infarct location. Furthermore, the 12-month incidence of major adverse cardiac and cerebrovascular events (a composite of all-cause death, reinfarction, unplanned revascularisation, and stroke) did not differ significantly between the groups (HR 1·09 [95% CI 0·90–1·32], p=0·38). Hausenloy and colleagues should be praised for their robust and clinically relevant trial to assess the role of remote ischaemic conditioning in the current landscape of STEMI management. The findings show clearly that the use of remote ischaemic conditioning around the time of PPCI for STEMI adds no clinical benefit for outcomes assessed within 1 year of the procedure.10Hausenloy DJ Kharbanda RK Møller UK et al.Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.Lancet. 2019; (published online Sept 6.)http://dx.doi.org/10.1016/S0140-6736(19)32039-2Summary Full Text Full Text PDF PubMed Scopus (173) Google Scholar A cautionary note pertains to the follow-up time of only 1 year: our current understanding of cardiac remodelling post-STEMI is that the clinical benefits derived from cardioprotective interventions might not manifest until after 2 years, or perhaps longer,11Hassell ME Vlastra W Robbers L et al.Long-term left ventricular remodelling after revascularisation for ST-segment elevation myocardial infarction as assessed by cardiac magnetic resonance imaging.Open Heart. 2017; 4e000569Crossref PubMed Scopus (14) Google Scholar and as such the trial could have benefited from a longer follow-up time. The authors also acknowledge that the remote ischaemic conditioning protocol used (four 5-min cycles of upper arm cuff inflations and deflations applied before PPCI) might have been insufficient to induce an adequate neurohormonal response in some patients, although this protocol has been shown to be the most efficacious one in animal and subsequent clinical studies.12Johnsen J Pryds K Salman R Løfgren B Kristiansen SB Bøtker HE The remote ischemic preconditioning algorithm: effect of number of cycles, cycle duration and effector organ mass on efficacy of protection.Basic Res Cardiol. 2016; 111: 10Crossref PubMed Scopus (101) Google Scholar The role of remote ischaemic conditioning in improving the lives of patients with STEMI has been thrown sharply into question. Despite the early promise of a number of preclinical and smaller proof-of-principle clinical trials, this large and adequately powered trial points to a lack of clinical efficacy for remote ischaemic conditioning in this setting. As such, it might be time to abandon this form of cardioprotection in favour of more effective therapies to extend and improve the lives of these patients. I declare no competing interests. Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trialRemote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. Full-Text PDF Open Access