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CardioPulse ArticlesFirst Symposium of ESC Working Group on e-CardiologyCardiac electrophysiology in New Zealand: a small but vital specialityNovel oral anticoagulants for stroke prevention in atrial fibrillationThe Polish Cardiac SocietySouth Africa Heart JournalRemote ischaemic preconditioning for heart surgery

DOI: http://dx.doi.org/10.1093/eurheartj/ehs131 1417-1425 First published online: 14 June 2012

First Symposium of ESC Working Group on e-Cardiology

An ESC WG symposium to promote and support the use of information technology in cardiology has recently taken place in Croatia

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ESC booth, left to right: Enno van der Velde, chairman ESC WG e-Cardiology; Mrs Céline Serio, ESC Heart House staff, who supports the WG from within the ESC; and Goran Krstacic, WG current secretary, chairman-elect and local organizer of this first e-Cardiology symposium.

On 15–17 March 2012, the ESC Working Group (WG) on e-Cardiology held their first independent symposium in Osijek, Croatia. The symposium was co-organized with the Croatian Cardiac Society. During the past few years, the ESC WG on e-Cardiology has intensified their work and their collaboration with other communities within the ESC.

Besides the usual participation and organization of symposia at the annual ESC Congress, the WG has organized joint symposia at other congresses, e.g. during ‘EuroEcho & other imaging modalities’ congress with the EAE, during the EuroPCR with the EAPCI and during EuroPace with the EHRA. Because those joint symposia were very successful, the WG felt that it was time to organize an independent symposium. Prof. Goran Krstacic, recently elected vice-chairman of the WG and president of the WG on e-Cardiology of the Croatian Cardiac Society, and Dr Enno van der Velde, President of the ESC WG on e-Cardiology, undertook the challenging task of organizing ‘the First Symposium on e-Cardiology’ in Osijek, Croatia. After more than a year of hard work, this symposium with 144 registered participants and representation from industry was a great success for one of the smaller WGs within the ESC (∼200 members). The meeting was covered by both national Croatian television and radio, which reflected a large regional interest thanks to the efforts and promotion by the symposium organizing committee. It shows that locations outside Western Europe can be a very good choice and provides the opportunity to organize and participate in such an event for those who might not have the possibility to travel to locations further away.

For more information about the specific objectives of the WG and a review of the abstracts, visit the website at http://ekardiologija.kardio.hr. As a brief overview, the WG has a wide scope of interest promoting and supporting the use of information technology within cardiology. It approximately covers the areas of biomedical signal processing, image processing, and medical informatics. It integrates information technology with Clinical Cardiology: the main objective being the improvement of patient care in all its aspects. This mix was very well reflected in the presentations given at the symposium. The presentations were given by all the nucleus members of the WG, two regular members of the WG, and five cardiologists from Croatia. In addition, there was a poster session which could be visited during the coffee and lunch breaks.

All the presentations showed the widespread use of informatics in Cardiology. The symposium started off with an impressive opening ceremony on Thursday evening, with music, opening words from local administrators, and a presentation by the Symposium Director. The second day began with presentations covering the applications of telecardiology and health information standards and digital exchange of medical data and how complicated that can be. This area is becoming more and more important as the change occurs to a complete digital reporting and storage environment in medicine and cardiology. This was followed by presentations showing new software approaches/algorithms for both signal processing (e.g. electrocardiograms) as well as, for imaging, both invasive and non-invasive, for improved diagnosis, and for evaluation of new treatment methods. Abstracts of all invited presentations, presented posters, and other information related to the symposium can be seen at http://ekardiologija.kardio.hr. All the presentations are available on the website of the congress and the website of the WG as webcasts. The symposium ended with a dinner party for all participants.

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Members of the ESC Working Group on e-Cardiology, ESC Heart House staff and nucleus members [from left to right: Catherine Chronaki (member); Guy Garrault (nucleus); Céline Serio (Heart House); Enno van der Velde (chairman); Nico Bruining (past-chairman); Niek van der Putten (nucleus); Marek Malik (vice-chairman); Goran Krstacic (secretary and vice-chairman elect); Philippe Chevalier (nucleus); Alberto Macereta (nucleus); and Enrico Caiani (nucleus)].

The WG nucleus members look back on a very successful meeting and are already discussing when and where the second symposium on e-Cardiology will be held. Regular WG members are also requested to present ideas and suggestions. And of course, persons who are not yet members of our WG and who are interested in joining should visit the ESC website and WG web pages: http://www.escardio.org/communities/Working-Groups/e-cardiology/Pages/welcome.aspx.

Nico Bruining, PhD, FESC

Cardiac electrophysiology in New Zealand: a small but vital speciality

Dr Martin Stiles talks about the Electrophysiology scene in NZ with Iona MacDonald

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Dr Martin Stiles

Just 11 electrophysiologists operate out of Auckland, Hamilton, and Christchurch (1/12th is about to begin in Wellington), servicing a population of four million New Zealanders. An active member of this group is cardiologist Dr Martin Stiles, at Waikato Hospital in Hamilton, where he established a programme of atrial fibrillation ablation and facilitated the expansion of the service to include further complex ablations including the treatment of ventricular tachycardia.

New Zealand's electrophysiologists undertake a full range of procedures including diagnostic studies and ablation treatment for supraventricular tachycardia, atrial flutter, atrial fibrillation, and ventricular tachycardia. In addition, they are responsible for the implantation of devices such as pacemakers, defibrillators, and cardiac resynchronization therapy. As in the UK, healthcare in New Zealand is publicly funded, and currently, insurance companies fund procedures but not the devices.

Dr Stiles is Chair of Heart Rhythm New Zealand, members being physicians, physiologists, and scientists working with heart rhythm disorders. The group is affiliated to the Cardiac Society of Australia and New Zealand (which alternates its annual scientific meetings between Australia's states and New Zealand). He is a board member of the Asia Pacific Heart Rhythm Society (APHRS) and of the US-based Heart Rhythm Society (HRS). His view of the global electrophysiology community is that New Zealand and Australia form an Australasian body which sits alongside the Asia-Pacific electrophysiology community, with strong links to the HRS and the European Heart Rhythm Association (EHRA).

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Heart Rhythm NZ

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Asia Pacific Heart Rhythm Society

Australia has more electrophysiologists than New Zealand per head of population and their defibrillator implant rate is double that of New Zealand; the reason for this disparity being unclear. Dr Stiles believes that this indicates a significant unmet need. The waiting time of atrial fibrillation ablation in New Zealand is up to 8 months, but other procedures have much shorter times. The 13 cardiologists at the Waikato Hospital have formed strong departments in electrophysiology and structural heart disease and are heavily involved in clinical trials, many of which are multinational. Travel to clinical trial sites requires long flying times which could be replaced by video conferences, but Dr Stiles believes that there is no substitute for face-to-face communication, which makes the travelling commitment worthwhile.

Electrophysiology skills are sought after worldwide and there are opportunities to work in large centres in Europe and America. However, the electrophysiologists who choose to work in New Zealand are trading off those opportunities with an enviable lifestyle. For instance, Dr Stiles enjoys generous annual leave, with some paid educational expenses. Another attraction for him is living on a 1 ha lifestyle block only 9 km from a tertiary hospital, and able to cycle home from work on a 47 km route via the picturesque township of Cambridge.

Waikato Hospital serves a population of ∼850 000 people in the Waikato and Bay of Plenty provinces in the North Island and undertakes travelling clinics. The cardiologists also conduct outreach pacemaker clinics throughout the provinces. They see cases of rheumatic heart disease, which is prevalent among rural Māori in the Gisborne area, but otherwise, the patient composition is similar to that of Europe. Interestingly, a recent survey of attitudes towards atrial fibrillation revealed that while many physicians in Australia and New Zealand were happy using European and American guidelines, other parts of the Asia-Pacific thought that more local guidelines would be useful. However, Dr Stiles considers that the Australasian region will be increasingly looking towards Asia. One of the benefits he sees with the APHRS is that New Zealand and Australia are strengthening links through Asia and on from there to Europe and America.

Dr Stiles and many of his colleagues trained in Europe and he praises the APHRS and EHRA for setting up a clinical electrophysiology fellowship training programme to assist Asian-Pacific trainees train in Europe. This gives them the opportunity to form enduring relationships in the international electrophysiology community, an aspect of his work that Dr Stiles cherishes.

Iona MacDonald, MA

Novel oral anticoagulants for stroke prevention in atrial fibrillation

The availability of novel oral anticoagulants and an improved ability to manage warfarin has shifted the focus towards treating AF patients with one or more stroke risk factors

Oral anticoagulant therapy is the best way to prevent strokes. Warfarin use has been shown to decrease the burden of ischaemic strokes, but it is difficult to keep patients within the narrow therapeutic international normalised ratio (INR) range (2.0–3.0) required of warfarin. Indeed, good-quality INR control is associated with less stroke and significantly less bleeding, but if anticoagulation is very poorly controlled, patients do worse than if they are on no treatment at all. The limitations of warfarin have resulted in many patients declining such therapy and led some doctors to avoid prescribing warfarin, even among high-risk patients with atrial fibrillation (AF).

For a long time, it was perceived that it would be difficult to develop drugs that were more effective (and safer) than warfarin but the availability of new oral anticoagulants (either oral direct thrombin inhibitors or oral Factor Xa inhibitors) has changed the treatment landscape. These drugs are given in a fixed dose and there is no need for monitoring and dose adjustment.

In the Randomised Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, the oral direct thrombin inhibitor, dabigatran 150 mg bid, showed superiority compared with warfarin for stroke prevention but a similar rate of major bleeding. Dabigatran 110 mg bid showed a similar efficacy to warfarin and 20% less major bleeds. Both dabigatran doses were associated with significantly less intracranial bleeding compared with warfarin.

‘This landmark trial changed the whole concept of how we are approaching these patients’, says Professor Gregory YH Lip, professor of cardiovascular medicine at the University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK. ‘These drugs still have relatively good safety and potential advantages’.

RE-LY also showed that dabigatran works for patients over a wide spectrum of stroke risk, as evaluated by the CHADS2 and CHA2DS2-VASc scores, which are used within the 2010 European Society of Cardiology (ESC) Guidelines to evaluate stroke risk in AF.

Because the RE-LY trial compared dabigatran with warfarin, the next question was how dabigatran performs against placebo and against antiplatelet therapy. An indirect analysis showed that dabigatran 150 mg produced a 75% reduction in stroke vs. placebo and a 63% reduction in stroke vs. aspirin. There was a 36% reduction in all-cause mortality vs. placebo and a 17% reduction vs. aspirin.

‘When people look at anticoagulation in AF they tend to focus just on the stroke reduction and forget about the significant reduction in mortality’, says Lip. ‘Even in the original historical trials comparing warfarin versus placebo or control, there was a 64% reduction in stroke and a 26% significant reduction in mortality’.

The Apixaban versus Acetylsalicylic Acid to Prevent Strokes (AVERROES) trial in patients with AF for whom warfarin was unsuitable found that the oral Factor Xa inhibitor, apixaban, was superior to aspirin for stroke reduction, with no difference in major bleeding and, surprisingly, aspirin was less well tolerated than the anticoagulant.

A Markov decision analysis model by Dr Mark Eckman at the University of Cincinnati, OH, USA, showed that anticoagulation with the new ‘safer’ anticoagulants drugs is preferred in AF patients with an annual stroke rate of 0.9% per year and above. Lip says: ‘It's shifting the balance towards anticoagulating more patients with AF, which at least is effective therapy in reducing stroke and mortality, with only a minimal role for aspirin, given its inferior efficacy’.

In the past, stroke risk factor scoring methods like CHADS2 were used to pick out ‘high-risk’ AF patients, who would be prescribed warfarin. Today, with the new oral anticoagulants and the ability to better control warfarin, the focus has shifted towards identifying ‘truly low-risk’ AF patients (essentially, a CHA2DS2-VASc score of 0) who preferably do not need any antithrombotic therapy. In such patients, the available evidence suggests that aspirin does not reduce thrombo-embolism but seems to increase bleeding.

Atrial fibrillation patients with one or more stroke risk factors should be considered for oral anticoagulation therapy, and whether this is delivered as well-controlled warfarin or one of the new anticoagulant drugs is up to the clinician or health-care system.

Three studies have shown that dabigatran is cost effective in the AF setting. ‘There is a tendency to compare the cost of that new drug, which is expensive, directly against the cost of warfarin, which is cheap’, says Lip. ‘People forget the monitoring, the inconvenience of dose adjustment, [and] the additional advantages of the new drug such as a superior reduction in stroke, a significant reduction in intracranial haemorrhage [and a] significant reduction in major bleeding’.

He adds that warfarin clinics will not vanish overnight. An evidence base for the new oral anticoagulants is still lacking in some situations such as prosthetic heart valves, thrombophilic states, and AF patients requiring a stent. But these are specific and fairly small subgroups of patients where management can be complex.

Atrial fibrillation is the commonest heart rhythm disorder and the main message is that oral anticoagulation should be given to AF patients with one or more stroke risk factors. This change of thinking is outlined in the 2010 ESC Guidelines for the management of AF. They advocate a more comprehensive stroke risk assessment using CHA2DS2-VASc and an assessment of bleeding risk using the HAS-BLED score. The net clinical benefit balancing the risk of ischaemic stroke against intracranial haemorrhage seems to be a neutral or positive net clinical benefit with oral anticoagulation in patients with a CHADS2 score of ≥0, and CHA2DS2-VASc score of ≥1, while there was a negative net clinical benefit at a CHA2DS2 -VASc score of 0 (reflecting the ‘truly low risk’ status of these patients). Indeed, the net clinical benefit was even greater at HAS-BLED scores of ≥3.

The ESC Guidelines are there with evidence to back them up, but some clinicians have yet to update their practice. As Lip says: ‘It's hard to change people's perceptions because for so many years people were obsessed with trying to pick out high risk patients and give them this inconvenient drug called warfarin’.

Jennifer Taylor, MPhil

The Polish Cardiac Society

The president discusses the aims and achievements of one of the largest national societies in the ESC

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Polish Cardiac Society

The Polish Cardiac Society (PCS) is one of the largest and most active national societies within the European Society of Cardiology (ESC), with over 6000 members. The main goal of the PCS is to combat cardiovascular diseases by promoting education, research, and international collaboration. PCS provides an array of scientific and educational activities. The Society is composed of one Association, 20 Working Groups, and 19 Regional Councils, and its acting president for 2011–13 is Professor Janina Stępińska. The PCS actively implements ESC Guidelines in Poland: the last three issued in 2011 have already been translated into Polish and were actively promoted at the Spring Conference of the PCS on 21 April 2012, as they will also be at the 16th International PCS Congress on 20–22 September 2012 in Poznań. The annual International Congresses of the Polish Cardiac Society gather over 5000 participants, mainly cardiologists from Poland, the European Union, and Eastern European countries. The Polish Heart Journal is the official journal of the society, with an Impact Factor of 0.523, and has been published for 45 years. The PCS strongly supports Polish cardiology to further improve its standards in clinical services and research. The Society has developed a range of grants to help young professionals in the field of cardiology to develop research projects and helps them present their research results at international congresses.

Club 30 of the Polish Cardiac Society is an official unit within our structure. The initiative was introduced in 1994 by Prof. Leszek Ceremużyński to provide an interactive forum for young Polish cardiologists actively involved in research and clinical practice, who have had significant achievements, including scientific publications in international medical journals before the age of 40. The main goal of the Club is to integrate the community of young cardiologists through meetings, to share medical expertise and exchange inspiring research ideas. The members of Club 30 are notably involved in scientific studies, education, and clinical activities related to each field of cardiology.

Our Society initiated the Polish Forum of Prevention, which consolidated the national society's active in the field of cardiovascular diseases. Moreover, PCS supports various clinical registries, e.g. Polish Registry of Acute Coronary Syndromes, Polish Registry of Percutaneous Interventions, and Polish Registry of Pulmonary Embolism.

The new aim in 2012 to promote and strengthen high-quality education and training is to establish the E-Learning Platform. PCS also recently designed, conducted, and sponsored the Electrical Storms Trial.

The ongoing Presidency is particularly focused on intensive cardiac care. On the initiative of the Polish Cardiac Society, a national registry of intensive cardiac care units (diagnostic and therapeutic capabilities, the training of medical professionals) is currently running. Moreover, measures are underway to strengthen the primary role of intensive cardiac care in the health-care system with a systematic revision of running and updating doctors' training. The aim of these efforts would lead to enhancing the qualification of the cardiac intensivist and even to legitimize the speciality of intensive cardiac care.

Janina Stępińska, President Polish Cardiac Society

South Africa Heart Journal

Striving to be the best cardiovascular medicine journal on the African continent

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Anton Doubell

SA Heart Journal was founded as a scientific, peer-reviewed print journal in 2006. Electronic publication started in 2008.

It is the official publication of the South African Heart Association, which was established in 2000 after the merger of two cardiac societies representing private practice and academic medicine.

The Association's first president was Professor Anton Doubell, head of the Division of Cardiology, Department of Medicine, Faculty of Health Sciences at Stellenbosch University, South Africa, and editor-in-chief of SA Heart Journal. ‘During my tenure as president we identified the need for a journal that reflects the opinions of the South African Heart Association’, he says.

During 2004–06, the Association used Cardiology Forum as a vehicle for publication but it was sponsor-driven and not peer-reviewed, so the arrangement was temporary.

Doubell became editor in 2006 when the journal took its current format. His goal was to establish a top class national and international journal that provides the current information to members and is a high-quality venue for local manuscripts.

‘We wanted to be the best journal in cardiovascular medicine on the continent’, says Doubell. ‘I think there's room for that because apart from us in the south and maybe one or two cardiovascular societies in the north, Africa is not producing high quality scientific information’.

Four issues are published each year, around three of which are produced with a guest editor. Past guest editors have included Professor Lionel H. Opie in Cape Town and Professor Bernard J. Gersh in Rochester, M N, USA. In most cases, guest editors invite five to six reviews on a particular topic and the remaining two articles in the issue are original submitted work.

All articles (both invited and submitted) are subject to peer review. ‘It's placed me in a few tough spots [when] we've invited prominent people and the editorial review turns down the paper’, says Doubell. ‘But that's just the nature of the beast’.

Guest editors focus on their area of expertise. Similarly, when Doubell invites members of special interest groups in the South African Heart Association to be guest editors, the issue covers that topic. He aims for a regular contribution from the different areas of cardiovascular medicine when sending invitations for guest editorship.

The objective is to provide readers an overview of what's current in general cardiology. ‘Most cardiologists in South Africa are practising general cardiology and cannot afford the luxury of focusing on being just an electrophysiologist or just a valve specialist’, explains Doubell.

The South African Heart Association's members are cardiologists, cardio-thoracic surgeons, and physicians with a special interest in cardiology. Associate members include cardiac technologists (they do haemodynamic monitoring in the operating room and test pacemakers), coronary care nurses, nurses in preventive cardiology, and people from affiliated countries.

The journal targets the Association's members and associate members as well as all practising clinicians in South Africa with an interest in cardiology. One way of reaching the latter is by distributing the journal to delegates at the Association's annual congress.

The journal receives up to 30 manuscripts per year, of which 20 are invited. About 20% of original submissions are rejected. Submissions come from a wide spectrum. Students and cardiac technicians in South Africa submit articles, as do researchers from other African countries. Doubell encourages such submissions but in the process gets articles of varying quality and some are of insufficient standard for publication. But, he believes that the submission process can be educational and tries to assist aspiring authors.

The day-to-day running of the journal is a one man show, and for that reason, Doubell has set targets in a step-wise fashion. The first target was to ensure that all articles were peer-reviewed. Second was to publish electronically. The third target, which was achieved last year, was to be listed as an accredited journal by the South Africa Department of Education. It means that universities receive a subsidy when their employees publish in the journal.

The next target is to be listed in Pubmed and other international indices and to obtain an impact factor.

The journal has a 12-strong editorial board who advise on strategy and vision, and a bank of reviewers. There are plans to build up the operational side by hiring an assistant to take on the general logistics. In addition, they would like to instigate the Association's structure for succession planning (it has a president, vice-president, and past-president on the national executive committee) by taking on an assistant editor.

Doubell is keen to increase the number of original research articles, but there is a balance to be achieved. He encourages colleagues to submit to top international journals but believes that SA Heart Journal should be an important target for up-and-coming scientists in Africa. He says: ‘If it's good quality research then we're a good vehicle’.

Jennifer Taylor, MPhil

Remote ischaemic preconditioning for heart surgery


Aims Transient ischaemia of non-vital tissue has been shown to enhance the tolerance of remote organs to cope with a subsequent prolonged ischaemic event in a number of clinical conditions, a phenomenon known as remote ischaemic preconditioning (RIPC). However, there remains uncertainty about the efficacy of RIPC in patients undergoing cardiac surgery. The purpose of this report is to describe the design and methods used in the ‘Remote Ischaemic Preconditioning for Heart Surgery (RIPHeart)-Study’.

Methods We are conducting a prospective, randomized, double-blind, multicentre, controlled trial including 2070 adult cardiac surgical patients. All types of surgery in which cardiopulmonary bypass is used will be included. Patients will be randomized either to the RIPC group receiving four 5 min cycles of transient upper limb ischaemia/reperfusion or to the control group receiving four cycles of blood pressure cuff inflation/deflation at a dummy arm. The primary endpoint is a composite outcome (all-cause mortality, non-fatal myocardial infarction, any new stroke, and/or acute renal failure) until hospital discharge.

Conclusion The RIPHeart-Study is a multicentre trial to determine whether RIPC may improve clinical outcome in cardiac surgical patients.

This trial is registered at www.clinicaltrials.gov (Identifier: NCT01067703).ischemic preconditioning, clinical study.


Transient ischaemia of non-vital tissue (e.g. skeletal muscles) has been shown to enhance the tolerance of remote vital organs (heart, brain, and kidney) to cope with a subsequent prolonged ischaemic event in a number of clinical conditions, a phenomenon known as remote ischaemic preconditioning (RIPC).

In previous pilot studies, RIPC has been shown to reduce myocardial injury in coronary artery surgery,1,2 congenital heart surgery,3 and non-cardiac surgery of high-risk patients.4 Nevertheless, this may not necessarily translate into a readily demonstrable clinical benefit. Thus, a large randomized study with a robust and relevant clinical endpoint is required.5


This is a prospective, randomized, double-blind, multicentre, parallel group controlled trial in 2070 adult cardiac surgical patients. All types of elective surgery in which cardiopulmonary bypass is used will be included. The trial work flow is presented in Supplementary material online, Figure S1.

Study population

Patients (age ≥18 years) after written informed consent scheduled for all types of elective cardiovascular surgery in which cardiopulmonary bypass is used are included. Exclusion criteria comprise surgery-related criteria (off-pump heart surgery, concomitant carotid surgery, minimal-invasive surgery, selective antegrade cerebral perfusion, previous heart surgery, aorta descendent surgery), cardiac conditions (myocardial infarction up to 7 days, ejection fraction <30%, previous atrial fibrillation up to 6 months, drug therapy with antiarrhythmic agents, implanted pacemaker or defibrillator, instable angina pectoris), and others [stroke up to 2 months, renal failure, liver failure, severe alcohol abuse, severe chronic obstructive pulmonary disease, drug therapy with sulfonylureas and nicorandil (preconditioning-blocking and preconditioning-mimetic medication, respectively), acute infection with antibiotic therapy, severe peripheral artery occlusive disease (Fontaine stages 3 and 4), previous serious neurological illness, and/or heparin-induced thrombocytopenia Type II].

Anaesthesia and management of cardiopulmonary bypass

Total intravenous anaesthesia will be performed in all patients, as volatile anaesthetic agents have been shown to induce preconditioning-like effects, thereby reducing myocardial ischaemia.6,7 As only 7 out of 14 recruiting centres are able to run a vaporizer attached to the cardiopulmonary bypass circuit to administer volatile anaesthetics, we use a total intravenous anaesthesia technique to avoid a potential impact on generalizability of our data. According to a recent review,8 we standardize the management of cardiopulmonary bypass as follows: the use of non-pulsatile cardiopulmonary bypass, the mean arterial blood pressure of 60–70 mmHg, haematocrit values 25–30%, α-stat acid–base management to regulate carbon dioxide tension, the use of arterial line filters, and blood glucose levels <200 mg/dL.


Patients are randomized to the RIPC or the control group. Randomization is performed centrally by the Clinical Trial Centre Leipzig. The randomization is stratified for (i) centres and (ii) individual risk for perioperative mortality using the European System for Cardiac Operative Risk Evaluation (EuroSCORE).9 We use a cut-off value of higher than 5% for a ‘Predicted mortality by logistic EuroSCORE’ to stratify randomization of so-called ‘high-risk patients’.10 An online checklist for individual risk factors is used to calculate the logistic EuroSCORE at the time of registration. After written informed consent, the Data Management (Clinical Trial Centre Leipzig) is contacted via an Internet-based randomization tool.


To ensure blinding, surgical drapes are used to cover both blood pressure cuffs of the patient's arm and the dummy arm. Blinding concerns (i) the individual patient, (ii) staff involved in intraoperative (anaesthesia and cardiac surgery team) and perioperative care (intensive care unit), (iii) investigators obtaining data, performing neurocognitive assessment, follow-up visits, and documentation, and (iv) the endpoint committee. Study intervention (RIPC or control) is performed by un-blinded staff. RIPC will be induced by four cycles of upper limb ischaemia (5 min blood pressure cuff inflation to 200 mmHg, at least a pressure 15 mmHg higher than the systolic arterial pressure and 5 min cuff deflation). In patients assigned to the control group, a dummy arm will be used for four cycles of 5 min blood pressure cuff inflation to 200 mmHg and 5 min cuff deflation.


Primary endpoints

The primary endpoint is defined as a composite of all-cause mortality, non-fatal myocardial infarction, any new stroke, and/or acute renal failure until hospital discharge (with a maximum period of 14 days after surgery).

  1. All-cause mortality.

  2. According to the ESC/ACC/AHA/WHF Task Force for the Redefinition of Myocardial Infarction,11 non-fatal myocardial infarction is considered according to a Type V myocardial infarction as follows: biomarker values more than five times the 99th percentile of the normal reference range combined with new pathological Q-waves or new left bundle branch block within the first 72 h, standard clinical criteria for myocardial infarction from 72 h on, or myocardial infarction diagnosed at autopsy.

  3. Stroke is defined by any new, temporary or permanent, focal or global neurological deficit,12 or evidence of stroke on autopsy and will be evaluated according to the NIH stroke scale (≥4 points) documented preoperatively and at hospital discharge.

  4. Acute renal failure is defined by any serum creatinine greater than or equal to two-fold increase from baseline within the first 48 h, urine output <0.5 mL/kg/h for >12 h within the first 48 h (RIFLE injury),13 use of renal replacement therapy, or evidence of renal failure on autopsy.

Secondary endpoints

  • The occurrence of any individual component of the composite at 30 days and 3 and 12 months after surgery (phone interview).

  • The duration of ventilator support, length of stay on the intensive care unit, and total hospital stay.

  • Troponin T and serum creatinine (preoperative, 6, 12, 24, and 48 h after surgery).

  • Cumulative vasopressor dose and inotropic support (within max. 7 days after surgery).

  • New onset of atrial fibrillation (within 4 days after surgery).

  • Incidence of postoperative delirium will be assessed with the CAM-ICU score14 (preoperative, 24, 48, 72, and 96 h after surgery).

  • Optional: in a subgroup of patients, myocardial function will be assessed by intraoperative transoesophageal echocardiography 30 ± 5 min before and 30 ± 5 min after cardiopulmonary bypass.15

  • Optional: neurocognitive function—a subgroup of patients will undergo robust neuropsychological tests preoperative, 5–7 days, and 3 months after surgery.16 A ‘core battery’ of 10 tests will include four main domains: (i) memory, (ii) attention, (iii) motor skills, and (iv) executive function.


Study protocol, patient information, and informed consent were approved by the Ethics Committees of the University of Kiel and of all participating centres. Each patient must give written informed consent to participate in the study. Data collection is performed pseudonymously.

Statistical analysis

Assumed event rates in the control group are based on the German data by the ‘Bundesgeschäftsstelle für Qualitätssicherung GmbH’ (www.bqs-outcome.de/2007/ergebnisse/leistungsbereiche; assessed 3 May 2009) for all-cause mortality (ranging from 3.2 to 6.1%), any new stroke (1.3–2.3%), and acute renal failure (3.8–6.9%) depending on the type of surgery. Assuming a case-mix in the registry (72% isolated coronary artery graft surgery, 17% isolated aortic valve replacement, and 12% combined operations), we calculated a weighted mean of 3.7% for all-cause mortality, 1.5% for any new stroke, and 4.2% for acute renal failure. The non-fatal myocardial infarction event rate was not reported in the above data registry. A compilation of relevant studies that reported myocardial infarction event rates from 2.4 to 5.1,7 2.8 to 5.4,17 3.9 to 4.2,18 and 6.2 to 7.919 results in a median rate of 4.7%. The sum of the four components for the composite endpoint is 14.1%. Considering the fact that a small proportion of patients dying after stroke or myocardial infarction count more than once in these figures and that study populations tend to be at lower risk than unselected patient populations, we conservatively assume a baseline rate of 12% for the primary endpoint in the control group. Pharmacological studies in the field of cardiac surgery reported risk reductions ranging from 25 to 70%.17,2022 As a cheap, simple, and safe intervention is investigated in our study, we target at 33% risk reduction to an event rate of 8% in the RIPC group.

Group sample sizes of 931 and 931 achieve 80% power to detect a difference of 4% using a two-sided χ2 test with continuity correction and with a significance level of 0.05. We used a commercial available statistic software (NCSS 2007 and Power Analysis and Sample Size 2008; Kaysville, UT, USA) for sample size and power calculation. To account for 10% follow-up loss, 104 patients per group will be additionally enrolled, resulting in a total of 1.035 patients per group.

Logistic regression adjusting for EuroSCORE, diabetes mellitus status, concomitant treatment with statins, and incorporating centres as random effect will be used to estimate the treatment effect on the odds ratio scale with two-sided 95% confidence intervals provided. Additionally, the endpoints of the study will be evaluated by multiple regression modelling techniques to assess/adjust associations with other baseline clinical factors. No formal interim analyses are planned.

Clinical study monitoring

Pre-study, initiation, and close-out visits will be performed in all trial sites. The trial sites will be regularly visited approximately every 3 months during the recruitment and follow-up. The scope of these visits is to check compliance of the trial sites with the study protocol and good clinical practice rules. In addition, source data verification of the key data (eligibility criteria, intervention, outcome measures) will be performed routinely in a random sample of 50% of the patients. Central monitoring will include a timely query management process based on consistency and plausibility checks supervised by the trial biometrician.


Cardiac surgery with cardiopulmonary bypass is generally associated with a predictable incidence of myocardial, neurological, and renal ischaemia/reperfusion injury leading to an increased risk of post-operative myocardial stunning, neurological deficits, and acute renal failure.

In the last 6 years, RIPC has been rapidly translated from experimental discovery to encouraging proof-of-principle human studies demonstrating the protection of the heart, lung, and kidney by using surrogate endpoints.1,35,2333 Despite these early promises, two recent trials of RIPC in cardiac surgery failed to demonstrate a significant effect of RIPC on troponin release.34,35 So far, there remains uncertainty about the efficacy of RIPC in cardiovascular surgical patients. Importantly, most of the previous clinical studies that showed beneficial effects of RIPC were single-blinded (lacking blinding members of the anaesthesia and cardiac surgery team), included mainly patients with isolated coronary artery bypass surgery, and were not standardized in terms of the anaesthesia regime. In contrast, in our study, we use a double-blind design with a dummy arm for control intervention, allow a much more generalizability to patients with isolated coronary surgery and complex heart surgery, and use total intravenous anaesthesia to avoid a potential impact of volatile anaesthetic.

In conclusion, the RIPHeart-Study is a prospective, randomized, double-blind, multicentre trial to determine whether RIPC may improve clinical outcome in more than 2000 cardiovascular surgical patients.


This work is supported by the German Research Foundation (grant no. ME 3559/1-1).

Conflict of interest: none declared.


Patrick Meybohm1, 18, Kai Zacharowski1, Jochen Cremer2, Jan Roesner3, Frank Kletzin3, Gereon Schaelte4, Marc Felzen4, Ulrich Strouhal5, Christian Reyher5, Matthias Heringlake6, Julika Schön6, Ivo Brandes7, Martin Bauer7, Pascal Knuefermann8, Maria Wittmann8, Thomas Hachenberg9, Thomas Schilling9, Thorsten Smul10, Sonja Maisch10, Michael Sander11, Tobias Moormann11, Andreas Boening12, Markus A. Weigand12, Rita Laufenberg13, Christian Werner13, Michael Winterhalter14, Tanja Treschan14, Sebastian N. Stehr15, Konrad Reinhart15, Dirk Hasenclever17, Oana Brosteanu17, Berthold Bein18, and the RIP Heart-Study Investigator Group*

Authors' Affiliations:

1Clinic of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany

2Department of Cardiovascular Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Germany

3Clinic of Anaesthesiology and Intensive Care Medicine, University Hospital Rostock, Rostock, Germany

4Department of Anaesthesiology, University Hospital Aachen, Aachen, Germany

5Department of Anaesthesiology, University Hospital Luebeck, Luebeck, Germany

6Department of Anaesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, Germany

7Department of Anaesthesiology and Intensive Care Medicine, University Hospital Goettingen, Germany

8Department of Anaesthesiology and Intensive Care Medicine, University Hospital Duesseldorf, Germany

9Department of Anaesthesiology, University Hospital Magdeburg, Germany

10Department of Anaesthesiology, University Hospital Wuerzburg, Wuerzburg, Germany

11Department of Anaesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany

12Department of Cardiovascular Surgery, University of Giessen, Germany

13Department of Anesthesiology, Medical Center of Johannes Gutenberg-University, Mainz, Germany

14Department of Anesthesiology University Düsseldorf, Germany

15Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany

16Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig, Germany

17Clinical Trial Center, University Leipzig, Leipzig, Germany

18Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Germany

*RIPHeart-Study Investigators: Christian Stoppe, Bernadette Krauss, Georg-Friedrich Eberhardt, Marc Coburn (Aachen), Katharina Chalk (Berlin), Georg Baumgarten, Olaf Boehm, Thomas Recht, Kerstin Köhlhoff, Florian Kessler, Thorsten Bähner, Eli Awlakpui (Bonn), Bertram Scheller, Alexander Koch, Tobias Bingold, Gerda Fingerhut (Frankfurt), Gerold Goerlach, Matthias Wollbrueck (Giessen), Julia Strauchmann (Goettingen), Kai U. Morsbach (Jena), Jens Scholz, Jochen Renner, Ole Broch, Matthias Gruenewald, Martin Albrecht, Martina Green, Carola Wehlen, Corina Messmer, Christina Schuldt (Kiel), Vera Schleicher, Silke Hauer, Holger Bogatsch, Bianca Scholze (Leipzig), Hans-Hinrich Sievers, Thorsten Hanke, Hermann Heinze, Silke Olsson, Joachym Ettel, Michael von der Ecken, Pascal Stitz, Joachim Bremer (Luebeck), Susanne Mauff (Mainz), Angela Alms, Stefan Bergt (Rostock).

Corresponding author: Patrick Meybohm, Clinic of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Tel: +49 69 6301 5998, Fax: +49 69 6301 5881, Email: patrick.meybohm{at}kgu.de


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