The Population Health Research Institute

The PHRI in Hamilton, Canada: a leader in global health research With over 90 active trials and studies in 101 countries involving over 1600 centres in all 6 inhabited continents of the world, (Figure 1) the Population Health Research Institute (PHRI) in Canada is committed to generating the evidence that can facilitate control of cardiovascular disease and other non-communicable diseases globally. Indeed, very few organizations in the world can match the Institute’s capacity. Our motto is ‘Health through Knowledge’, and we believe in global partnerships, global studies, and global impact. Six continents/101 countries. Population Health Research Institute conducts collaborative studies examining the biological, genetic, social, environmental, and policy determinants of health, and how they are affected by health systems. The foci of these investigations are as broad as their global reach, with special attention paid to understanding the risk factors and prevention of myocardial infarction (MI), stroke, diabetes, kidney disease, and cognitive decline. By bringing together a multidisciplinary team of leading investigators, and using a range of research methods (probing biologic mechanisms, large randomized clinical trials, varied approaches for epidemiologic studies, new methods to study the environment and societal influences, and assessing health systems) in a large number of countries, PHRI studies inform the causes, prevention, and control of cardiovascular disease (CVD) and non-communicable diseases (NCDs) by developing a comprehensive and multi-pronged knowledge base. Today, PHRI enjoys a strong reputation for its major clinical trials and population studies which range in size from 100 patients to more than 200 000 people in any one study. To date over 1 million participants have participated in PHRI studies. The success of PHRI is due to its founder and Executive Director, Dr Salim Yusuf, and several other scientific program leaders (Figure 2) who have worked collaboratively to develop high impact studies tackling a range of health conditions. The institute has grown dramatically in 25 years and now hosts 330 staff and an additional 49 scientists. Population Health Research Institute also has 20 International Fellows who collaborate closely on our research, many of whom trained at PHRI early in their research career and have returned to their home institutions. PHRI Scientific Program Leadership. Originally established with a focus on CVD and diabetes, the scope of the programmes at PHRI has expanded over the years. Exploring diverse populations around the world defined by ethnicity, economic status, and geography; the Institute’s research is now broad based and additionally includes many associated disease and injury areas as well as being committed to translating knowledge into practice and policy. Unique to PHRI, it also has a focus on neglected diseases and neglected populations. Several of PHRI’s global trials, have established the current standards of prevention and treatment in a range of CVD conditions. These include the primary and secondary prevention of athero-thrombotic CVD, management of acute coronary syndromes, arrhythmia, strokes, and preventing CV complications of surgery (see Table 1). The Heart Outcomes Prevention Evaluation (HOPE) trial completed in 2000, demonstrated that the angiotensin-converting enzyme (ACE) inhibitor, Ramipril reduced heart attacks, strokes, and deaths in patients with chronic stable vascular disease or diabetes, and its findings have been widely adopted worldwide and incorporated into numerous guidelines. Following that, the HOPE-3 trial evaluated the role of statins in primary prevention and showed benefits in intermediate risk people without CVD irrespective of lipid levels and that blood pressure lowering provided added benefit in those with hypertension but not in those with lower BP. The combination of statins and lowering of BP reduced CVD by 40% in those with hypertension and was cost effective worldwide. PHRI High Impact Studies PHRI High Impact Studies The concept of combination therapy is now being further tested in The International Polycap Study (TIPS) program. This is a series of three trials which aim to assess whether a polypill (polycap consisting of a statin, and three BP lowering drugs) will reduce CVD to a large extent in moderate risk individuals who do not have CVD. If successful and widely implemented, the polypill has the potential to reduce CVD globally by over 50% thereby avoiding several millions of premature CVD events each year. The recent COMPASS trial has established the added value of a new oral anticoagulant (rivaroxaban) in secondary prevention by demonstrating an additional reduction in risk of CVD compared to aspirin alone by 25% in those with coronary artery disease and peripheral artery disease. Population Health Research Institute-led clinical research has established the importance of both diabetes and lesser elevations in glucose levels above normal (dysglycaemia) for predicting major cardiovascular events and demonstrated that diabetes can be delayed or safely prevented with temporary use of exogenous basal insulin glargine or thiazolidinediones (rosiglitazone). Ongoing trials are systematically testing whether and how remissions of type 2 diabetes can be achieved and the cardiovascular effects of a once-weekly GLP1 receptor agonist (dulaglutide). In addition, PHRI research has identified and validated novel biomarker panels for predicting cardiovascular events and death in people with diabetes and a unique biomarker (growth differentiation factor 15) for the presence of metformin. Other PHRI research has demonstrated that renin–angiotensin system inhibitor drugs prevent major cardiovascular events in people with diabetes; that long-acting basal insulin glargine has a neutral effect on all of the chronic consequences of diabetes; that targeting perfectly normoglycaemic and normotensive HbA1c and blood pressure levels, and adding a fibrate to a statin is not necessary to reduce cardiovascular events in people with diabetes and cardiovascular risk factors; and that Vitamin E, homocysteine lowering with vitamins and omega 3 fatty acid supplements do not reduce cardiovascular outcomes. In acute coronary syndrome (ACS) a series of large trials (OASIS and others) have established the added benefits of Clopidogrel (with Aspirin) in preventing major cardiovascular events; that Fondaparinux is as effective as established agents such as low-molecular weight heparins but caused substantially less bleeding and so reduced mortality; that early coronary interventions were only effective in high risk people with ACS and so could be selectively targeted; and that the radial approach to vascular access as compared with the standard femoral approach for angiography and angioplasty reduced complications and death. Research continues in the STEMI population to determine the optimal reperfusion strategy looking at single-culprit or multi-vessel PCI approach. In other areas of interventional cardiology the researchers are integrating device and digital technologies in various aspects of their research for detection, treatment, and monitoring. In patients with atrial fibrillation (AF) the RELY and AVERROES trials demonstrated the efficacy and safety of the new oral anticoagulants Dabigatran and Apixaban to reduce the risk of stroke and the ACTIVE trial showed the efficacy of dual antiplatelet therapy. Large trials of pacemakers and defibrillators have enhanced care of patients with brady- and tachy-arrhythmias, and PHRI scientists are now conducting studies to detect subclinical AF also with the aim to reduce the risk of stroke. Trials in surgery have demonstrated similar effects of on-pump vs. off-pump surgery and the risks of steroids in on-pump cardiac surgery. Trials in non-cardiac surgery have evaluated beta-blockers, alpha-blockers, and aspirin in preventing perioperative complications and have changed clinical care globally. Large prospective studies have demonstrated that 65% of perioperative myocardial infarction will go unrecognized without monitoring of troponin measurements and that expensive preoperative non-invasive tests do not improve overall risk prediction but a relatively inexpensive biomarker (NT-pro BNP) dramatically improves perioperative risk prediction. Ongoing trials are testing whether outcomes in individuals with perioperative myocardial damage can be improved by using new anticoagulants and whether accelerated surgery for a hip fracture may improve outcomes compared to standard care (i.e., surgery typically 24 h after the diagnosis). The INTERHEART and INTERSTROKE studies conducted in 52 and 33 countries respectively uncovered that over 90% of the risk of heart attacks and strokes could be explained by just nine risk factors and that these risk factors had generally similar effects in most ethnic groups and in all regions of the world. These risk factors include tobacco smoking, abnormal lipids, hypertension, diabetes, lack of exercise and lack of fruits and vegetables, stress and psychosocial factors, and alcohol consumption. The INTERHEART and INTERSTROKE studies have provided vital groundwork for the current large cohort study [the Prospective Urban Rural Epidemiology (PURE study)] involving 200 000 people from about 700 communities (half urban and half rural) from more than 25 low, middle, and high-income countries examining the effects of lifestyle, environmental factors, and health systems on mortality and morbidity from CVD, pulmonary and renal diseases, cancers, and injuries. This study has described the elements and causes of the epidemiologic and social transitions globally including the varying effects of nutritional inadequacy and excess (including impact of both high and low sodium consumption); of different forms of alcohol and tobacco use and; of different forms of physical activity (recreational and obligatory) on CVD, and diet on health and mortality. It is clear that PHRI has been a formative leader in establishing the foundation for today’s clinical practice in cardiovascular prevention and continues to discover and write the road-map for continued advancements. With data and specimens from the studies described, research continues to discover novel biologic and genetic biomarkers and determinants. This, and digital health are the next realms PHRI is navigating to continually advance research. The global epidemiologic studies and trials are informing practice and policy to improve health globally. Conflict of interest: J.P. is COO of PHRI but has no conflict of interest or personal gain from contents of article.

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