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OBITUARY

In memoriam Eivind Berge, MD, PhD, 1964–2020

cardiologist, trialist and hypertension/stroke researcher

Wyller, Torgeir Bruuna; Kjeldsen, Sverre E.b; Halvorsen, Sigrunb; Bath, Philip M.c; Sandercock, Peterd

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doi: 10.1097/HJH.0000000000002488
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With great sadness, we report the passing of Professor Eivind Berge, MD, PhD. He died from prostatic cancer on 6 February 2020. His early passing at the age of 55 shocked all of us in the Departments of Cardiology, Geriatrics and Neurology at Oslo University Hospital, Ullevål, and at the Faculties of Medicine at the Universities in Oslo and Tromsø, as well as his many research colleagues in the UK (Edinburgh, Nottingham and Oxford) and around Europe. We all mourn the loss of a wonderful colleague and a great friend. Eivind is survived by his physician wife Hilde, and three grown-up children Sindre, Trude Elisabeth and Sivert. He continued working with his research projects, returned E-mail and supervised his PhD fellows until just days before his passing.

Eivind was a brilliant clinician who served his patients in the Cardiology Outpatient Clinic or the Cardiology Ward almost to the last moment. He was the favourite physician of the nurses and other personnel because of his ever-friendly attitudes. He was always active in teaching and lecturing in Norway, Europe and in North America.

Eivind held many academic appointments in research projects and important scientific committees. Through his diverse and extensive research, Eivind undoubtedly made a major contribution to research in stroke as well as vascular medicine in general. A large number of researchers around the world will remember Eivind for decades to come.

One of Eivind's most important research achievements was in leading and delivering the Heparin in Acute Embolic Stroke Trial (HAEST), a randomized controlled, double-blind study of 14 days of treatment with low molecular weight heparin (dalteparin) vs. aspirin in 449 patients with acute ischemic stroke and atrial fibrillation [1]. The primary aim of the study was to investigate whether treatment with dalteparin was superior to aspirin for the prevention of recurrent strokes during the first 2 weeks after an acute ischemic stroke. The results showed similar rates of recurrent strokes in both groups; further, dalteparin was associated with a borderline significant increase in the secondary endpoint of ‘recurrence or progression of ischemic stroke, death or symptomatic cerebral haemorrhage’. HAEST is one of the largest studies focused on patients with acute ischemic stroke and atrial fibrillation. The study contributed significantly to the standardization of treatment of acute ischemic stroke in atrial fibrillation patients (approximately 20% of all cerebral stroke patients).

Eivind also did one of the largest and most important analyses of the prognostic significance of blood pressure variability, using data from The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial comprising more than 15 400 high-risk hypertensive patients [2]. He and colleagues found that higher ‘visit-to-visit’ blood pressure variability is associated with an increased risk of cardiovascular events, regardless of other risk factors. The associations were stronger in younger patients and in those with lower mean blood pressure. The work has attracted considerable international attention and created new interest in the importance of blood pressure variability.

Another example of Eivind's interest in hypertension research is his role as Nordic Coordinator and a driving force in the Optimal Blood Pressure and Cholesterol Targets for Preventing Recurrent Stroke in Hypertensives (SHOT) study, a large and ongoing European-Chinese collaborative RCT investigating different strategies for reducing blood pressure and serum cholesterol in the secondary prevention of stroke.

In the 35-year follow-up of the Oslo Ischemia Study, involving 2014 apparently healthy and employed middle-aged men from the general population in Oslo, Eivind and colleagues showed that improvement in physical exercise capacity, measured twice during ergometer exercise 7 years apart, rather strongly predicted lower risk of stroke with a 50% reduction compared to men who remained unfit, and vice versa for the men who lost physical exercise capacity [3]. Thanks to a British journalist who attended the original abstract presentation at the 2017 European Society of Cardiology scientific conference in Barcelona, the good news went viral and could be read in the Kathmandu Post; perhaps the Sherpas in the country who repeatedly climb in the Himalayas benefit from these important findings.

Eivind was the Chief Investigator of the Scandinavian Candesartan Acute Stroke Trial (SCAST), a large international randomized and placebo-controlled, double-blind study of modest blood pressure lowering treatment with the angiotensin receptor blocker candesartan in acute stroke [4]. The study included 149 hospital wards in nine European countries and recruited 2029 patients. The study showed no beneficial effects of antihypertensive therapy in the acute phase of stroke. On the contrary, the authors found that the treatment led to poorer functional levels after 6 months. The Third International Stroke Trial (IST-3) was a large, international randomized controlled trial of thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA, alteplase) in acute ischemic strokes (<6 h) [5]; Eivind developed a network of centres in Norway to contribute to the project, and led work on health economic analyses of the treatment. The study included 3035 patients and provided reliable evidence that alteplase was effective in people aged over 80 years, a group that had previously been excluded from trials of thrombolysis for stroke.

After IST-3, the next big question was whether people with ‘wake-up’ stroke (whose time of onset is unknown) benefit from thrombolysis with intravenous tenecteplase. In collaboration with colleagues at the University of Tromsø, Eivind developed the Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST) that started in June 2017; the first patient in the trial was included in Norway in July 2017. The trial involves centres in Norway, Sweden, Denmark, Finland, Estonia, Lithuania, Switzerland and UK.

Eivind was a stalwart in supporting the Efficacy of Nitric Oxide in Stroke Trial (ENOS) trial, another large international randomized single blind study of blood pressure lowering treatment with transdermal glyceryl trinitrate (GTN) in acute stroke [6]. The ENOS Trial showed no beneficial effects of antihypertensive treatment in the acute phase of stroke, thus replicating the SCAST results.

Eivind initiated and organized the Study of Antithrombotic Treatment after Intracranial Haemorrhage (STATICH), which aims at randomizing 500 patients with a recent intracerebral haemorrhage and indication for antithrombotic treatment to stop or restart such treatment after the acute event (http://statich.no/). The study will address an unsolved clinical dilemma, and it was until his very end a must for Eivind that this project had to be carried through.

Eivind was very generous in sharing research ideas with clinical research fellows involved and often they took the first author spot on his top international publications [1–3], thus helping them to defend their PhD degrees. He authored or coauthored Cochrane systematic reviews, health economic analyses, clinical guidelines, papers on cardiac arrest in athletes and more research administrative issues [7]. He was a member of the editorial boards of several prestigious journals, played important roles within the European Stroke Organization and was widely respected for this work.

As a successful clinical investigator, Eivind received many medical prizes and awards. Maybe he was most proud of winning the prize for the ‘Best Clinical Study’ at the 6th International Symposium on Thromboembolic Diseases, Lisbon, Portugal, in June 1999 for the main paper in his doctoral thesis work ‘Heparin in Acute Embolic Stroke Trial (HAEST)’ [1].

Eivind was born in Fredrikstad, a suburban small town south-east of Oslo in Norway. He graduated from the University of Oslo in 1990 (MD) and acquired his PhD on the HAEST study [1] in the Department of Hematology, Ullevål Hospital in 2001 at a time when he was already a postdoctoral research fellow at the Department of Clinical Neurosciences, Western General Hospital, University of Edinburgh, UK. In the early 1990s and before he got deeply into research, he received his medical training as a resident and fellow at various departments in the Oslo University Hospital System until his tenure and staff membership in the Department of Cardiology, Ullevål hospital in 2008. In 2012, in recognition of his work, he was appointed Fellow of the Royal College of Physicians of Edinburgh. His strong grant support connected him also to the Artic University of Norway in Tromsø where he became professor at the Institute of Clinical Medicine in 2015.

In an unexpected way, we have lost a colleague and good friend. On behalf of all colleagues and friends who worked with Eivind Berge in Norway and around the world, we not only express our sadness over this irreversible fact but also express our optimistic view that his research and discoveries have improved the treatment of stroke and other vascular disorders to the benefit of many patients.

ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

REFERENCES

1. Berge E, Abdelnoor M, Nakstad PH. Sandset PM, on behalf of the HAEST Study Group. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind, randomised study. Lancet 2000; 355:1205–1210.
2. Mehlum MH, Kjeldsen SE, Liestøl K, Hua TA, Julius S, Berge E. Blood pressure variability and long-term risk of stroke in the VALUE trial. Eur Heart J 2018; 39:2243–2251.
3. Prestgaard E, Mariampillai J, Engeseth K, Erikssen J, Bodegård J, Liestøl K, et al. Change in cardiorespiratory fitness and risk of stroke and death. Long-term follow-up of healthy middle-aged men. Stroke 2019; 50:155–161.
4. Sandset EC, Bath PMW, Murray GD, Boysen G, Jatuzis D, Kõrv J, et al. on behalf of the SCAST Study Group. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial. Lancet 2011; 377:741–750.
5. The IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet 2012; 379:2352–2363.
6. The ENOS Trial InvestigatorsEfficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomised controlled trial. Lancet 2015; 385:617–628.
7. Slot KB, Berge E, Sandercock P, Lewis SC, Dorman P, Dennis M, et al. No evidence of bias in the process of publication of diagnostic accuracy studies in stroke submitted as abstracts. Stroke 2009; 40:1585–1589.
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