Associate Professor of Cardiology
Consultant for Heart Failure
Karolinska University Hospital
Gianluigi Savarese is currently Associate Professor of Cardiology at the Karolinska Institute and Consultant for Heart Failure at the Karolinska University Hospital in Stockholm, Sweden. He received his MD from Federico II University in Naples, Italy, in 2010 and completed cardiology residency (2011-2016) at the same Institution. In 2013-2014 he was a guest fellow at the Center for Molecular Cardiology of the University of Zurich. In 2017 he obtained the title of heart failure specialist from the University of Zurich and the Heart Failure Association of the European Society of Cardiology. In 2018 he received his PhD from the Karolinska Institute. He is currently Board member of the Heart Failure Association and of the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology. Over the last five years he has published around 150 scientific works in leading peer-reviewed journals focusing mainly on heart failure, epidemiology, and cardiovascular pharmacotherapy. He is an expert in registry-based studies and trials.
Q: A recent study you led, based on data from the Swedish National Patient Registry, demonstrated that a common group of medications were not linked to an increased risk of death from COVID-19. Can you explain how the study was conducted and its relevant conclusions?
A: This has been an important topic of research over the last year. Based on the mechanism of infection of SARS-CoV-2, Covid-19 was hypothesized to be more severe and frequent in patients receiving angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), which are key treatments for heart failure, hypertension, and other cardiovascular and non-cardiovascular diseases.
Therefore, we investigated the association between the use of ACEI, ARB, and mineralocorticoid receptor antagonists (MRA) on the one hand, and Covid-19-associated mortality, incident hospitalization, or death on the other, in patients with heart failure, hypertension, kidney disease, ischemic heart disease, or diabetes who are enrolled in the Swedish National Patient Registry. By Cox regression models, after extensive adjustments, we could not observe any higher risk of outcomes associated with the use of ACE, ARB or MRA in these patients. Since in observational studies it is possible to adjust for known or measured, but not for unknown or unmeasured, confounders, we simulated the impact of residual confounding on our results and concluded that an unmeasured or unknown confounder would need to be both more common in patients not receiving the treatments and more strongly associated with Covid-19 than is clinically realistic in order to show any harmful association. These results have contributed to reassure the scientific community about the potential harm associated with ACE, ARB, and MRA during the Covid-19 pandemic.
Q: Was it difficult to have access to the data? How did that compare to other studies in which you have participated, where you have needed access to data?
A: During the Covid-19 pandemic, Swedish authorities have prioritized research on Covid-19 and therefore gaining access to data from national registries and ethical approval for their use has been surprisingly fast, even by national standards. Applying for access to registry data in Sweden is not difficult or particularly time-consuming. Data management might require some time, considering the number of national registries which the researcher aims to link in order to get more information about the patients, and the needed data cleaning.
Q: Sweden has an established tradition in population-based registries. Why are they important for research?
A: In cardiovascular sciences the importance of registries is highly recognised. Registries provide important information to phenotype populations with specific diseases, monitor the implementation of new and old treatments and help researchers understand the reasons for their underuse in daily clinical practice, facilitate trial design by providing useful evidence to set inclusion and exclusion criteria, identify appropriate surrogate endpoints for phase 2 trials, and assess the safety and effectiveness of drugs.
Q: How representative are the data you worked with for Sweden, Europe, and the rest of the world? Is it important that they be representative?
A: Representativeness is an important factor in registry-based research. A key word which is often used for these studies is “real-world,” meaning that findings come from populations which are not highly selected as in randomized clinical trials and therefore tend to be more generalisable to the entire population with that specific disease. When registries are nationwide, as the Swedish ones are, generalisability issues could be raised. However, for example, whether implementation of use of a drug is investigated together with the factors linked with poor use at a national level, these data might be at least representative for similar healthcare systems. For studies focusing on disease phenotypization, supporting trial design, assessing effectiveness and safety, representativeness of national data will not represent a limitation.
Q: In your opinion, what are the challenges ahead for an effective use of registries data in Europe? What is the role of clinicians, patients, and regulators?
A: Important challenges include low enrolment rates; finding the right balance between data quality, sample size, and missing data; privacy issues; and feasibility of enrolment. Representativeness is sometimes an issue for national data, which might be mitigated by the possibility of sharing, pooling, or harmonising data at an international level. Multinational registries represent the ideal setting for pragmatic registry-based randomised controlled trials. However, there is a strong need for clearer guidance by regulators on how to make this possible in the era of GDPR.
Q: You are a heart failure cardiologist. How do you expect your role to evolve in the coming years (e.g. multidisciplinary work, digital skills, evidence-based clinical practices, patient-centered strategies, communication with patients, regulatory framework)?
A: I think we have already entered the era of multidisciplinary work. There is still much to do in terms of patient-centred strategies and precision medicine. To move in this direction, registry-based research will be key, since patient profiling in large and unselected populations will help to identify the different needs of patients with a specific disease and to identify potential different treatments for different phenotypes. For example, at the moment this is the greatest challenge in heart failure with preserved ejection fraction. Digital medicine might support collection of important data to use for research purposes but also to directly treat patients.
Q: The European Health Data Space (EHDS) is an important EU priority which should promote access to health data for research and innovation through the secondary use of health data. How do you envisage EHDS will faciliate or contribute to CVD research and innovation? Could it improve data-driven CVD research and innovation using registry and electronic health records data, and if so – how?
A: It is very important that EHDS is considered as a priority by the European Union. This would create the perfect environment where to conduct research on representative, well-characterized, large samples of patients, but, even more importantly, will facilitate the design of large pragmatic registry-based randomized controlled trials involving many countries