August 22nd, 2013
Expert Perspective: Remote Ischemic Preconditioning for CABG
Zhe Zheng, M.D., Ph.D. and Shengshou Hu, M.D.
Dr. Zhe Zheng and Dr. Shengshou Hu, of Fu Wai Hospital in Beijing, discuss findings from a randomized trial, conducted in Germany and published in the Lancet, of remote ischemic preconditioning before coronary artery bypass graft surgery. (See CardioExchange’s news coverage here.)
THE LANCET STUDY
Thielmann and colleagues randomized 329 patients with triplevessel CAD undergoing elective, isolated first-time CABG to receive remote ischemic preconditoning (rIPC; consisting of 3 cycles of inflation of a blood-pressure cuff for 5 minutes, followed by 5 minutes of reperfusion) or no preconditioning. The rIPC group had significantly lower serum cardiac troponin I (cTnI) levels in the first 72 hours after CABG. Clinical benefits were not evident at 30 days, but rIPC was associated with significantly lower rates of MI and all-cause mortality at 1 year. The rIPC group’s hazard ratio for 1-year all-cause mortality, compared with the control group, was 0.27 (95% CI, 0.08–0.98; P=0.046).
EXPERT PERSPECTIVE
Reperfusion injury may be an important therapeutic target for improving clinical outcomes after acute myocardial infarction or open-heart surgery. Ischemic preconditioning, whereby the heart is subjected to brief cycles of ischemia and reperfusion, may help to limit damage from acute ischemia and reperfusion injury.First reported by Murry and colleagues in a dog model, ischemic preconditioning was then replicated in multiple in-vivo models. Mediators and pathways such as transcription factors, oxidative stress, humoral factors, neuronal communication, and systemic-inflammatory or apoptosis responses may interact dynamically in ischemic preconditioning, although the precise mechanisms are not yet clear.
Clinical application of ischemic preconditioning has been restricted to certain cardiovascular surgical procedures, primarily operations in which the ischemic period is predictable. In the past decade, randomized controlled trials of the effects of rIPC have had variable results (e.g., J Am Coll Cardiol 2006, 47:2277; Circulation 2007, 116:I-98; Heart 2009, 95:1567; J Thorac Cardiovasc Surg 2012, 144:178; and J Thorac Cadiovasc Surg 2013, in press). Postoperative cTnI levels, creatine kinase-MB levels, and inotropic requirements during the initial days after surgery have been identified as markers of myocardial protection, but the evidence on mortality and prognostic factors is extremely limited. Besides, this simple and safe technique has rarely been used during CABG, at least outside the context of research.
The study by Thielmann and colleagues provides useful perspective for further study, and even clinical application, of rIPC. Their intentiontotreat and perprotocol analyses both confirm the protective benefits. We know that the trial participants were low-risk patients, and the authors openly state the study’s limitations (single center, endpoints not intuitively related to cardioprotection, small number of secondary endpoints, etc.).
Notably, however, differences in study protocols, potentially confounding comorbidities, and surgical procedures might be responsible for inconsistent findings across the various published trials. For example, previously reported strategies for rIPC vary in the duration for cycles of ischemia and reperfusion (1, 5, or 10 minutes), as well as locations in the left upper arm, the right forearm, the lower limb, or the common iliac artery (according to the types of surgery and patient groups).
The findings from Thielmann and colleagues are certainly noteworthy, even though trigger mechanisms and possible pathways must be explored in further studies. Larger trials also will need to test the effectiveness of rIPC in surgical revascularization settings and in patients with comorbidities that affect tolerance of ischemia–reperfusion.
JOIN THE DISCUSSION
What’s your view on remote ischemic preconditioning, in light of findings from the trial in Germany and analysis from Dr. Zheng and Dr. Hu?
2 Responses to “Expert Perspective: Remote Ischemic Preconditioning for CABG”
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The Lancet is known to occasionally publish a catchy idea rather than true evidence – probably reflecting British humor.
It is a fact that a surgical revascularization procedure is generally intended to reduce myocardial ischemia. However, historically – in the 1950’s – the idea of remote treatment of angina pectoris by bilateral ligation of internal mammary arteries (known as bl-IMA) was a controversial topic, but was finally abolished after two randomized controlled trials demonstrated that bl-IMA was no better than a sham intervention.
Revisiting the story of bl-IMA offers valuable insights into the ethics of sham-controlled trials and the implications of the placebo effect in an otherwise irrational experimental situation. Please read the excellent paper from Miller FG (Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD) entitled “The enduring legacy of sham-controlled trials of internal mammary artery ligation” which was published in Prog Cardiovasc Dis. 2012 ;55:246-50.
Returning to British humor and given the numerous arteries of the human body and the already suggested rIPC-locations in the left upper arm, the right forearm, the lower limb, or the common iliac artery, I could easily imagine that innocent Rowan Atkinson – acting as Prince Edmund the Black Adder – would propose rIPC-experiments in the dorsal penile artery to publish his enlightening experiments in the Christmas edition of BMJ.
Humans tend to be seduced by the mystic, and some thinking of themselves as scientists are no less susceptible to such delusions.