The pandemic of cardiovascular disease has immense negative effects on global population health and life expectancy1 and accounts for 30% of the global cost of non-communicable diseases.2 Myocardial infarction and stroke are the most detrimental of the acute cardiovascular ischaemia-reperfusion syndromes, and are frequently followed by chronic organ failure which therefore results in a vast socio-economic burden. Worldwide, 17 million people are expected to die from cardiovascular diseases (7.4 million from ischaemic heart disease and 6.7 million from stroke). Attempts to modify risk factors and lifestyle-related growth in cardiovascular disease are important and have been successful in some parts of the world, but improved treatment of acute and chronic cardiovascular disease is crucial to alleviate the overall disease burden.
In myocardial infarction, early and successful restoration of tissue perfusion following an ischaemic event is the most effective strategy to reduce tissue injury and improve clinical outcomes. However, the return of oxygenated blood into ischaemic tissue during reperfusion may itself paradoxically induce further tissue damage (reperfusion injury), which can be responsible for ~35% of the infarct size.3,4 Therefore, despite the shortened ischaemia duration achieved with today’s improved logistic handling and advanced medical treatment of patients with myocardial infarction, and even with optimal acute reperfusion treatment by primary percutaneous coronary intervention (PCI) and up-to-date antithrombotic pharmacological therapy, myocardial infarction remains a leading cause of mortality and morbidity. Consequently, the focus in myocardial infarction treatment has now been directed towards reducing the reperfusion injury.
The development of effective drugs to target the detrimental effects of reperfusion injury, however, has proven to be a challenge. Several mechanical and pharmacologic strategies that showed convincing benefit in animal models of ischaemia-reperfusion injury have failed to translate into clinical improvements. One exception has been remote ischaemic conditioning.
Remote ischaemic conditioning
Based on the original ground-breaking observation by Murry et al. that the myocardium can be “trained” by brief ischaemic episodes to withstand a longer-lasting ischaemic insult5 (local ischaemic preconditioning), the concept of conditioning the myocardium from afar (remote ischaemic conditioning, RIC) was developed through a series of increasingly clinically applicable techniques6–8 culminating in the presently most widespread concept of achieving organ protection by inducing brief episodes of limb ischaemia9 by a blood pressure cuff or an automated device (the autoRIC® Device, CellAegis Devices Inc., Toronto, Canada).
While the concept of RIC was developed in models of myocardial ischaemia, the benefit provided by RIC has subsequently been shown to exert powerful protection against ischaemia-reperfusion injury in animal models of brain, kidney, lung, and liver injury, and RIC has successfully been translated into clinical use in clinical ischaemia-reperfusion scenarios such as abdominal aortic aneurysm repair10 and elective PCI.11
Notably, the most specific advantage of RIC is its easy applicability during ongoing ischaemia of the target organ, which has been exploited in animal models and clinical studies to show that RIC reduces injury during evolving myocardial infarction12,13 and stroke.14
RIC induces complex and diverse biological effects,15 and while all the mediators and mechanisms remain to be completely identified, in the heart RIC results in cytoprotection, improved endothelial function and microcirculation and reduced inflammation. These are three of the key players in the pathology underlying heart failure and suggest that RIC may be a powerful tool to counteract the multiple detrimental biological processes involved in the development of heart failure after MI.
Therefore, the benefits of RIC treatment in patients admitted with ST-elevation myocardial infarction (STEMI) appear to extend beyond the acute effects, which was recently shown in a follow-up study, where treatment of high-risk STEMI patients in the ambulance with RIC during hospital transport for primary PCI improved long-term clinical outcomes (Figure 1).13 While these promising results are awaiting confirmation in large-scale clinical trials (for example, the currently ongoing CONDI2/ERIC-PPCI trials), it is prudent to consider another important aspect of cardioprotection; RIC (and other means of mechanical cardioprotection) may provide a highly cost-effective adjunct to the current handling of patients with acute coronary syndromes.
Fig. 1: Cost-effectiveness plane.
Long-term effects of RIC
While the long-term clinical effects of RIC await the completion of currently ongoing multicentre trials, follow-up data from early proof-of-concept trials have recently emerged. A study by Davies et al. of patients undergoing elective PCI with or without RIC preconditioning, showed a 35% reduced rate of major adverse cardiac and cerebral events (MACCE) at six years follow-up in the group pretreated with RIC.16
Similarly, Sloth et al. showed that the MACCE rate after primary PCI for STEMI at four years follow-up was 13.5% among patients treated with RIC during transport to hospital compared to 25.6% in the control group, yielding a hazard ratio of 0.49 (p=0.018). Furthermore, only five deaths (4%) occurred in the intervention group compared with 15 (12%) in the control group, yielding a hazard ratio 0.32 (95% confidence interval (CI) 0.12–0.88, p=0.027).17
Cost-effectiveness of RIC
Several trials have shown that RIC conducted in patients admitted with STEMI reduces myocardial injury.12,19–21 Myocardial injury is a predictor of long-term clinical outcomes, so the improvement in MACCE rate as reported by Sloth et al. in STEMI patients would naturally be expected and the MACCE rate improvement would also be expected to result in cost-effectiveness of the therapy. In this commentary, we discuss novel data presented by Sloth et al. at the European Society of Cardiology conference 201518 suggesting that RIC may disrupt the usual cost–benefit relationship of novel (pharmacological) therapies – “the more you pay, the healthier you’ll get” – and for once, a low-cost treatment may improve outcomes in myocardial infarction, which remains a leading cause of morbidity and mortality.
The cost–benefit analysis discussed below is based on a trial conducted at our institution where 333 patients admitted with STEMI for primary PCI were randomised to either standard treatment or RIC performed in the ambulance during transportation to primary angioplasty. The original trial showed that RIC improved myocardial salvage index (0.75 in the RIC group versus 0.55 in the control group, p=0.033) as measured by SPECT.12
In contrast to most novel pharmacological advances in the treatment of the patient with acute coronary syndromes, RIC is either free (when conducted by simple inflation of a blood pressure cuff) or relatively inexpensive when performed using a commercially available automatic device (autoRIC Device). We set the cost of an intervention at €75 ($82) per patient.
Of the 333 randomised in the original study, 251 fulfilled the study criteria (82 patients were excluded because STEMI was not confirmed, onset of chest pain >12 hours before, prior coronary artery bypass surgery or prior myocardial infarction).12
The primary outcome measure was cost-effectiveness of RIC after four years of follow-up, presented in the cost-effectiveness plane as the difference in cardiovascular medical care costs and MACCE-free survival between RIC and control groups.
Cardiovascular medical care costs were based on standardised estimates from Danish diagnosis-related groups calculated using an event-based method and included cardiovascular re-admissions, outpatient contact for heart failure, and cardiovascular medications. MACCE-free survival was defined as the absence of any of the following events during follow-up: death, myocardial infarction, re-admission for heart failure and cerebral ischaemic event.
Mean cumulative medical care costs were €2896 (95% CI: 113; 5679, p=0.034) lower in the RIC group than in the control group (€12,404 versus €15,300).
Mean MACCE-free survival time was 0.31 years (95% CI: 0.03; 0.60, p=0.032) higher in the RIC group than in the control group (3.66 versus 3.35 years). The reduction in cardiovascular medical care costs was most pronounced in year one and mainly driven by lower device implantation costs in the RIC group. Plotted on the cost-effectiveness plane, the RIC strategy was dominant (less costly, more effective) in 97.26% of 10,000 bootstrap replications (Figure 1).
The RIC strategy remained dominant in sensitivity analyses based on different assumptions regarding discount rates (0% and 6%) and intervention costs (€0 and €50).
The reduction in cardiovascular medical care costs in patients receiving RIC prevailed during the first two years of follow-up and was mainly driven by lower re-admission costs for heart failure including device implantations. Importantly, this finding may reflect that most medical care costs are due to post-infarction heart failure when patients are stabilised on heart failure therapy. RIC seemed to be more effective and more cost-saving in patients with LAD infarcts than in patients with non-LAD infarcts, which is consistent with our previous findings demonstrating that RIC improved myocardial salvage index and left ventricular ejection fraction predominantly in patients with LAD infarcts, which are prone to developing large myocardial injury.12,22
Animal experiments suggest that daily repeated RIC for four weeks after (induced) myocardial infarction prevents post-MI adverse cardiac remodelling,23 raising the intriguing question whether daily repeated RIC after MI would be even more efficient in antagonising the development of post-MI heart failure (with consequently improved cost-effectiveness). Proof-of-principle trials in post-MI, post-PCI patients are currently ongoing, examining the effect of such daily RIC treatment on the progression to heart failure.
Large clinical trials are needed to confirm the apparent clinical and economical beneficial effects of RIC in STEMI patients as all currently available data are derived from studies not sufficiently sized for such calculations. These confirmatory multicentre trials are currently ongoing.
Remote ischaemic conditioning as an adjunct to primary PCI seems to be a cost-effective treatment strategy in patients with STEMI.
- Roger VL et al. Heart Disease and Stroke Statistics–2012 Update: A Report From the American Heart Association. Circulation 2012;125:188–97.
- WHO. Global status report on noncommunicable diseases. 2010.
- Hausenloy DJ, Yellon DM. Myocardial ischaemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 2013;123:92–100.
- Heusch G. Cardioprotection: chances and challenges of its translation to the clinic. Lancet 2013;381:166–75.
- Murry CE, Jennings RB, Reimer KA. Preconditioning with ischaemia: a delay of lethal cell injury in ischaemic myocardium. Circulation 1986;74:1124–36.
- Przyklenk K et al. Regional ischaemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 1993;87:893–9.
- Birnbaum Y, Hale SL, Kloner RA. Ischaemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation 1997;96:1641–6.
- Gho BC et al. Myocardial protection by brief ischaemia in noncardiac tissue. Circulation 1996;94:2193–200.
- Kharbanda RK et al. Transient limb ischaemia induces remote ischaemic preconditioning in vivo. Circulation 2002;106:2881–3.
- Ali ZA et al. Remote ischaemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circulation 2007;116:98–105.
- Hoole SP et al. Cardiac Remote Ischaemic Preconditioning in Coronary Stenting (CRISP Stent) Study: a prospective, randomized control trial. Circulation 2009;119:820–7.
- Botker HE 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;375:727–34.
- Sloth AD et al. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J 2014;35(3):168–75.
- Hougaard KD et al. Remote ischaemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischaemic stroke: a randomized trial. Stroke 2014;45:159–67.
- Schmidt MR, Redington A, Botker HE. Remote conditioning the heart overview: translatability and mechanism. Brit J Pharmacol 2015;172:1947–60.
- Davies WR et al. Remote ischaemic preconditioning improves outcome at 6 years after elective percutaneous coronary intervention: the CRISP stent trial long-term follow-up. Circulation Cardiovasc Intervent 2013;6:246–51.
- Sloth AD et al. Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention. Eur Heart J 2014;35:168–75.
- Sloth AD et al. Remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction is a cost-effective strategy. Eur Heart J 2015;36:2.
- Rentoukas I et al. Cardioprotective role of remote ischaemic periconditioning in primary percutaneous coronary intervention: enhancement by opioid action. JACC Cardiovasc Intervent 2010;3:49–55.
- Prunier F et al. The RIPOST-MI study, assessing remote ischaemic perconditioning alone or in combination with local ischaemic postconditioning in ST-segment elevation myocardial infarction. Basic Res Cardiol 2014;109:400.
- White SK et al. Remote ischaemic conditioning reduces myocardial infarct size and edema in patients with ST-segment elevation myocardial infarction. JACC Cardiovasc Interv 2015;8(1 pt B):178–88.
- Munk K et al. Remote Ischaemic 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. Circulation Cardiovasc Imaging 2010;3:656–62.
- Wei M et al. Repeated remote ischaemic postconditioning protects against adverse left ventricular remodeling and improves survival in a rat model of myocardial infarction. Circ Res 2011;108:1220–5.