Ali Zentner, MD, FRCPC, Andrew Ignaszewski, MD, FRCPC

Dr Edward Freis: A pioneer in evidence-based treatment of hypertension

ing CV disease in patients with mod-

Dr Edward Freis: A pioneer in evidence-based treatment of hypertension

      health. But Mary Lasker, a philanthro-   ...
Dr Edward Freis: A pioneer in evidence-based treatment of hypertension

with diabetes and blood pressure            Tab...
Dr Edward Freis: A pioneer in evidence-based treatment of hypertension

      initial choice of medication is based    ...
Dr Edward Freis: A pioneer in evidence-based treatment of hypertension

    sient ischaemic attack. Lancet 2001;       ...
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British Columbia Medical Journal, April 2010 issue: Dr Edward Freis: A pioneer in evidence-based treatment of hypertension


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British Columbia Medical Journal, April 2010 issue: Dr Edward Freis: A pioneer in evidence-based treatment of hypertension

  1. 1. Ali Zentner, MD, FRCPC, Andrew Ignaszewski, MD, FRCPC Dr Edward Freis: A pioneer in evidence-based treatment of hypertension Our understanding of the need for antihypertensive therapy owes much to the work of Edward Freis. ABSTRACT reventive measures have P Dr Edward Freis (1912–2005) was a early 1990s. Currently there has been pioneer in answering the question a shift in this treatment paradigm played a major role in how of whether hypertension should be toward prevention. Prevention of patients are screened and treat ed. Freis contributed to the end organ dysfunction is a relatively treated for cardiovascular development of evidence-based new concept. Our treatment focus disease (CVD) over the last 30 years. medicine by conducting the first has shifted to include those patients Most of our previous clinical deci- double-blind RCT comparing the ef- with asymptomatic cardiovascular sions focused on treating the effects fectiveness of single agents vs com- risk factors such as hypertension. of atherosclerosis: coronary artery bination therapies in hypertension The current recommendations of the disease, cerebral vascular disease, from 1964–1969. Though the study Canadian Hypertension Education nephropathy, and peripheral vascular did not have an immediate impact, Program are to control blood pres- disease. Today our treatment focus has over time its value was recognized sure in diabetic patients; ensure all shifted to managing those patients and Freis continued his work, even- adults have regular blood pressure with asymptomatic cardiovascular tually publishing over 400 articles assessments; conduct overall assess- (CV) risk factors such as hyperten- on hypertension treatment. He was ments of patients’ CV risks; make sion1 in response to overwhelming instrumental in changing medical lifestyle modifications the corner- evidence showing the CV benefits and public attitudes toward hyper- stone of prevention and treatment; of antihypertensive therapy.2 Clinical tension screening and management, treat most patients to a target below research has prompted a revolution in and was a pioneer in public health 140/90; use combination therapies practice philosophy to include CV risk and preventive medicine. Hyperten- when necessary; and treat newly prevention. The randomized clinical sive medicine began its golden age diagnosed hypertension in patients trial (RCT) has been the catalyst for of evidence-based medicine in the older than 80. this change and has provided a scien- tific base for many modern treatment Dr Zentner is a specialist in internal med- decisions. icine with a special focus on obesity med- We have Dr Edward Freis, a pio- icine, the metabolic syndrome, and pre- neer in the application of evidence- vention medicine. She practises in West based medicine (EBM), to thank for Vancouver. Dr Ignaszewski is head of the making us more aware of the need for Division of Cardiology at St. Paul’s Hospital CV risk prevention. He completed the and is affiliated with the hospital’s Heart first double-blind RCT comparing the Transplantation Program and Heart Failure effectiveness of single agents and Program. He is also a clinical associate combination therapies in hyperten- professor in the Division of Cardiology at sion, and showed the benefit of anti- the University of British Columbia. hypertensive treatments for prevent- 144 BC MEDICAL JOURNAL VOL. 52 NO. 3, APRIL 2010
  2. 2. Dr Edward Freis: A pioneer in evidence-based treatment of hypertension ing CV disease in patients with mod- Photo courtesy of the Albert and Mary Lasker Foundation. erate to severe hypertension.3 He also promoted patient screening and the use of antihypertensive medications for all patients with hypertension. Born in Chicago in 1912, the youngest of four sons, Edward Freis began his academic career at the Uni- versity of Arizona. He chose the drier climate in the hopes that it would help his asthma. He hoped to become an actor and took time off from universi- ty to study at the Pasadena Playhouse. Freis soon decided he was not tall enough to succeed in show business and returned to Arizona where he received his bachelor of science in 1936. Four years later he received a medical degree from Columbia Uni- versity. Following his internship and residency at Massachusetts Memorial Hospital, Freis joined the United States Army Air Forces (now known as the US Air Force) and served as chief of the laboratory service at the Lincoln Air Force Base in Lincoln, Nebraska. After the war, Freis began a cardiology residency at Evans Memo- rial Hospital in Boston. He followed this with a research fellowship focus- ing on hemodynamics and pharma- cotherapy for hypertension. Dr Edward Freis completed the first double-blind RCT comparing the effectiveness of In 1949 Freis was appointed assis- single agents and combination therapies in hypertension. tant chief of the medical service at the Veterans Administration (VA) hospi- tal in Washington, DC, with a joint that outpatient hypertension manage- ment of hypertension reduced the inci- appointment as adjunct clinical pro- ment began. In 1952 the VA conduct- dence of major hypertensive compli- fessor at Georgetown University School ed an RCT looking at the efficacy of cations. The treatment group showed of Medicine. From 1950 to 1960 he antifungal medications in tuberculo- a 50% reduction in the incidence of served as chief of the Hypertension sis. Dr Freis and his colleagues used stroke, congestive heart failure, and Clinic at Georgetown University. this study as a model for the first RCT progressive nephropathy. However, In the 1950s hypertension man- in hypertension using chlorothiazide the VA study failed to demonstrate a agement was vastly different from versus placebo.4 treatment benefit for prevention of what it is today. Treatment was confin- The study ran from 1964 to 1969 myocardial infarction and sudden car- ed to patients with malignant hyper- and was the first double-blind place- diac death.5 tension, who were hospitalized, treat- bo-controlled multicentre trial done in The VA study results were pub- ed with intravenous medications, and the United States. The study was done lished in 1970 to little fanfare. The often discharged home on salt restric- at 17 VA medical centres and involved medical community had yet to appre- tion and dietary management. It was 523 patients. It was the first study of ciate the impact of EBM in the areas only after the launch of chlorothiazide its kind to demonstrate that the treat- of preventive medicine and public VOL. 52 NO. 3, APRIL 2010 BC MEDICAL JOURNAL 145
  3. 3. Dr Edward Freis: A pioneer in evidence-based treatment of hypertension health. But Mary Lasker, a philanthro- who would directly benefit from his tension Education Program (CHEP) pist and health policy advocate, was research. was established as an offshoot of CHS not a member of the medical commu- Dr Freis published over 400 arti- in order to promote standards of clin- nity, and she believed that the VA study cles on hypertension treatment during ical care for the treatment of hyper- revealed a major public health problem his career and was instrumental in tension. Almost a decade later CHEP that should and could be addressed. changing medical and public attitudes is most widely known for its estab- She asked the then secretary of health, toward the screening and management lishment of annual evidence-based Elliot Richardson, to establish a hy- of hypertension. He received awards guidelines on the diagnosis and man- pertension education program to alert from the most respected CV centres in agement of hypertension. physicians and the general public to North America, including the Ameri- the significance of hypertension. With can Society of Hypertension, the Management of the support of Freis’s scientific proof American College of Physicians, and hypertension in 2009 and Mary Lasker’s political and finan- the American Heart Association. On Hypertension management in Canada cial influence, the National High his 90th birthday he played Chopin on has evolved and improved as a result Blood Pressure Education Program the piano and recited Hamlet from of the guidelines inspired by the work was launched in 1972. It was the first memory. He died at the age of 92 on of Dr Freis. The release of the CHEP program of its kind to unite the scien- 1 February 2005 in Washington, DC, recommendations for 2009 marked a tific community and public health pol- of multiorgan failure—ironically as a decade of Canadian evidence-based icymakers who together focused on result of the hypertension he had diag- approaches to hypertension manage- the idea that CVD was preventable nosed in himself 40 years earlier. ment. The current guidelines reflect and something patients should be the need to target specific populations screened for.6 The program was the Freis’s Canadian legacy for screening, treatment, and adher- first of many initiatives that today EBM, preventive medicine, and patient ence.9 The key points (“red flags”) of encourage a partnership between education have been the cornerstones CHEP 2009 are as follows. patient and physician in the screening of hypertension management in Ca- and treatment of preventable diseases. nada. In 1977 a national committee Ensure blood pressure in diabetic Dr Edward Freis was given the sponsored by Health and Welfare patients is below 130/80 mm Hg. The Lasker Award for clinical research in Canada met to review the evidence for latest CHEP guidelines emphasize 1971 for his leadership in the VA the usefulness of pharmacotherapy the need to improve control of hyper- study. At the time, Lasker Award and a stepped-care approach to the tension in people with diabetes. Sixty- recipients were considered to be treatment of hypertension. The VA five percent of diabetic deaths can be Nobel Prize hopefuls. For the next study and other RCTs undertaken by attributed to the CV complications.10-18 decade Freis continued to direct coop- Dr Edward Freis provided a small Several large-scale RCTs have con- erative studies on hypertension, to body of evidence used to form the first firmed the morbidity and mortality advocate for antihypertensive treat- Canadian guidelines. In 1979 the Cana- benefits of blood pressure reduction ment in all patients, and to become dian Hypertension Society (CHS) was in this high-risk population. In 2008 recognized as one of the world’s fore- established to act as the professional data from ACCORD and ADVANCE most authorities in the area of hyper- voice for hypertension treatment in confirmed that intensive reduction in tension medicine. In 1977 he was hon- Canada and to promote research and blood pressure (below 130/80 mm Hg) ored by the American College of teaching in the disease.8 The CHS pro- in people with diabetes leads to sig- Physicians with the James D. Bruce duced several guidelines throughout nificant reductions in overall mortali- Award in preventive medicine. In 1979 the 1980s. The development of these ty rate and CV events.18,19 Further- Freis coauthored The High Blood recommendations was primarily fund- more, the ADVANCE trial showed an Pressure Book, A Guide for Patients ed by national and provincial grants additional CV mortality benefit when and Their Families.7 The publication and used a panel consensus approach. two agents were used as initial thera- proved Freis to be a “patient’s phy- Over the next decade it was agreed py in diabetic patients with blood pres- sician,” able to contribute to publi- that for any guidelines to be success- sure above 150/90 mm Hg.18 cations for his colleagues in the scien- ful, they had to be current, based on The CHEP 2009 guidelines now tific community and able to create evidence, and from a credible, national recommend initial therapy with two reference material for the patients source. In 2000 the Canadian Hyper- antihypertensive drugs for people 146 BC MEDICAL JOURNAL VOL. 52 NO. 3, APRIL 2010
  4. 4. Dr Edward Freis: A pioneer in evidence-based treatment of hypertension with diabetes and blood pressure Table. Lifestyle modification and impact on blood pressure. above 150/90 mm Hg. The use of ACE inhibitors and angiotensin receptor Reduction in systolic blood Intervention Comments pressure blockers (ARBs) as first-line therapy in diabetes is again a reflection of the Adopting a Dietary Approach to Stop Diet Hypertension (DASH): A diet rich in fibre, 8–14 mm Hg last decade’s evidence.20,21 fruits, and vegetables and low in fat and salt. Losing as little as 4 kg or maintaining a BMI 3–20 mm Hg depending on All Canadian adults need to have Weight loss between 20–29 kg/m.2 amount of weight lost blood pressure assessed at all ap- Undertaking 30–60 minutes of moderate propriate clinical visits. CHEP 2009 Regular intensity dynamic exercise 4–7 days per 4–9 mm Hg exercise emphasizes that 90% of Canadians week in addition to daily activities. will develop hypertension in their life- Restricting Limiting total sodium consumption to less 2–8 mm Hg times.22 At a time when antihyper- sodium than 2 g per day. tensive treatment is so available and Reducing Consuming <2 standard drinks per day and alcohol <14 per week for men and 9 per week for 2–4 mm Hg so varied, screening and diagnosis consumption women. remain the key to adequate care. Optimum management of BP re- guidelines recommend a target below suggested cautionary use of pharma- quires assessment of overall CV risk. 130/80 mm Hg in patients with dia- cotherapy in this patient population. Ninety percent of all patients with betes and those with chronic renal The Hypertension in the Very Elderly hypertension will have another risk failure. Trial (HYVET), which showed an factor for CVD.23 The paradigm of absolute reduction in the primary end- antihypertensive management should Combinations of therapies (both point of fatal and nonfatal stroke of therefore shift to one of CV risk man- lifestyle and drug) are generally 18% in octogenerians treated with agement, making the diagnosis of necessary to achieve target blood indapamide (with possible addition of hypertension in any patient the start of pressures. A variety of trials have perindopril) over placebo,36 has now CV risk reduction in general. Risk cal- confirmed the need for combination settled the argument of whether to culators such as the Framingham and therapy to manage hypertension. The treat newly diagnosed hypertension in Reynolds risk scores have proven to more recent CHEP guidelines have patients over the age of 80. The CHEP be useful tools for assessing global advocated the use of combination 2009 guidelines echo this with the rec- CV risk and should be used to guide therapy as initial therapy in patients ommendation to initiate diuretics in patients’ therapy.24,25 with blood pressure above 160/100 mm these patients. Dr Edward Freis would Hg. Based on the newest ONTARGET be pleased indeed. Lifestyle modifications are effective data, CHEP 2009 now specifically in preventing hypertension, treat- recommends that an ACE inhibitor not The future ing hypertension, and reducing CV be combined with an ARB in people Hypertension medicine has enjoyed a risk. Although lifestyle modification with uncomplicated hypertension, golden age from the early 1990s to the remains the most difficult treatment to diabetes (without micro- or macro- present day. From the outset Dr enforce with patients, it is still the albuminuria), chronic kidney disease Edward Freis helped answer the ques- most effective way to prevent hyper- (without micro- or overt proteinuria), tion, Should hypertension be treated? tension. The benefits of a healthy diet, or ischemic heart disease (without Over the last two decades, the great regular exercise, and weight loss have heart failure).35 debate in hypertension medicine has been proven in a variety of trials to shifted away from whether to treat this confer significant benefit on the treat- Treat newly diagnosed hyperten- disease. Now researchers and physi- ment and management of hyperten- sion in patients older than 80. Prior cians are trying to determine exactly sion ( Table ).26-34 to October 2008, controversy sur- how to treat. rounded the use of antihypertensive The current CHEP 2009 guide- Treat to target. Blood pressure should medications in patients older than 80 lines advocate a target blood pressure be lowered to below 140/90 mm Hg who were newly diagnosed with hy- in patients without compelling indica- in most patients. The CHEP 2009 pertension. Meta-analysis data in fact tions to be below 140/90 mm Hg. The VOL. 52 NO. 3, APRIL 2010 BC MEDICAL JOURNAL 147
  5. 5. Dr Edward Freis: A pioneer in evidence-based treatment of hypertension initial choice of medication is based he also contributed to by completing Joint National Committee on Prevention, on evidence from the trials published clinical trials. His publications span- Detection, Evaluation, and Treatment of in the last decade. There is over- ned the clinical, basic science, and High Blood Pressure. National Heart, whelming data supporting the use popular medical databases, yet he also Lung, and Blood Institute; National High of ACE inhibitors and ARBs as one made significant contributions to pub- Blood Pressure Education Program Coor- of the possible first-line choices. In lic health and patient education. dinating Committee. Seventh report of a tribute to Freis’s work, ALLHAT Freis changed the way we deliver the Joint National Committee on Pre- showed the superiority of thiazide care. He gave us the scientific evi- vention, Detection, Evaluation, and Treat- diuretics.37 Long-acting calcium chan- dence to support preventive medicine ment of High Blood Pressure. Hyperten- nel blockers also show benefit and as and was a driving force behind the sion 2004;42:1206-1252. such are included among the choices public programs that allow such infor- 7. Freis ED, Kolata GB. The High Blood Pres- for first-line therapy.38 Beta blockers mation to be adopted by and dissemi- sure Book: A Guide for Patients and Their are no longer recommended as first- nated to the public. Dr Edward Freis’s Families. Sausalito, CA: Painter Hopkins; line therapy for uncomplicated hyper- legacy is both the breadth of his sci- 1979. tension in patients over the age of 60 entific publications about medicine 8. Logan A. Report of the Canadian Hyper- based on recent data.39 for hypertension and the impact this tension Society’s consensus conference The scientific community has spent body of work has had on the public on the management of mild hyperten- the last two decades determining the health movement in North America sion. CMAJ 1984;131:1053-1057. best method for treating the most com- and on disease prevention worldwide. 9. Canadian Hypertension Education mon disease in North America. Program. Recommendations—2009. Through these years the evidence has Competing interests shaped our appreciation for this dis- None declared. recommendations-2009 (accessed 12 ease and its management. The future February 2010). of hypertension medicine lies not in References 10. UK Prospective Diabetes Study Group. the development of newer agents to 1. Pearson TA, Blair SN, Daniels SR, et al. Tight blood pressure control and risk of treat this disease. Nor does it lie in the AHA guidelines for primary prevention of macrovascular and microvascular com- evidence-based pursuit of the “best cardiovascular disease and stroke: 2002 plications in type 2 diabetes: UKPDS 38. drug” for the management of high update: Consensus panel guide to com- BMJ 1998;317:691-692. blood pressure. The future lies in the prehensive risk reduction for adult 11. Tuomilehto J, Rastenyte D, Birkenhager prevention of this disease. The CHEP patients without coronary or other ather- WH, et al.; Systolic Hypertension in 2009 guidelines strongly advocate the osclerotic vascular diseases. Circulation Europe Trial Investigators. Effects of cal- screening of patients for hypertension 2002;106:388-391. cium-channel blockade in older patients and the use of lifestyle modification 2. Grundy SM, Balady GJ, Criqui MH, et al. with diabetes and systolic hypertension. both in the treatment and prevention Guide to primary prevention of cardio- N Engl J Med 1999;340:677-684. of disease. It cannot be denied that vascular diseases. A statement for 12. Hansson L, Zanchetti A, Carruthers SG, prevention of hypertension is an ambi- healthcare professionals from the Task et al. Effects of intensive blood-pressure tious and perhaps unrealistic pursuit. Force on Risk Reduction. Circulation lowering and low-dose aspirin in patients Whether it can be achieved in a scien- 1997;95:2329-2331. with hypertension: Principal results of tific laboratory or through a commu- 3. Oransky I. Edward D Freis. Lancet 2005; the Hypertension Optimal Treatment nity’s pursuit of lifestyle modification 365(9462):840. (HOT) randomised trial. Lancet 1998; remains to be seen. 4. Freis ED. Hypertension: Current status 351(9118):1755-1762. of therapy—Hope for the future. J Nat 13. Brenner BM, Cooper ME, de Zeeuw D, A final word Med Assoc 1956;48:252-263. et al. Effects of losartan on renal and car- At the time of his death, Dr Freis was 5. Poblete PF, Kyle MC, Pipberger HV, et al. diovascular outcomes in patients with working on a second book about hy- Effect of treatment on morbidity in hyper- type 2 diabetes and nephropathy. N Engl pertension for a popular audience. His tension. Veterans Administration Co- J Med 2001;345:861-869. career was a true marriage of clinical operative Study on Antihypertensive 14. PROGRESS Collaborative Group. Ran- and academic medicine. He treated Agents: Effect on the electrocardiogram. domised trial of a perindopril-based blood- hundreds of thousands of patients with Circulation 1973;48:481-490. pressure-lowering regimen among 6,105 the help of EBM, a medical approach 6. Chobanian AV, Bakris GL, Black HR, et al.; individuals with previous stroke or tran- 148 BC MEDICAL JOURNAL VOL. 52 NO. 3, APRIL 2010
  6. 6. Dr Edward Freis: A pioneer in evidence-based treatment of hypertension sient ischaemic attack. Lancet 2001; vascular disease in Canada: Temporal, Brief physician advice for problem alco- 358:1033-1041. socio-demographic and geographic fac- hol drinkers. A randomized controlled trial 15. Heart Outcomes Prevention Evaluation tors. CMAJ 2009;181:E55-66. in community-based primary care prac- Study Investigators. Effects of an angio- 23. Neal B, MacMahon S, Chapman N. tices. JAMA 1997;277:1039-1045. tensin-converting-enzyme inhibitor, rami- Effects of ACE inhibitors, calcium antag- 33. Elmer PJ, Obarzanek E, Vollmer WM, et pril, on cardiovascular events in high-risk onists, and other blood-pressure-lower- al. Effects of comprehensive lifestyle patients. N Engl J Med 2000;342:145-153. ing drugs: Results of prospectively modification on diet, weight, physical fit- 16. Yusuf S, Teo K, Anderson C, et al. Effects designed overviews of randomised tri- ness, and blood pressure control: 18- of the angiotensin-receptor blocker tel- als. Lancet 2000;356(9246):1955-1964. month results of a randomized trial. Ann misartan on cardiovascular events in high- 24. Wilson PW, D’Agostino RB, Levy D, et al. Intern Med 2006;144:485-495. risk patients intolerant to angiotensin- Prediction of coronary heart disease 34. Appel LJ, Champagne CM, Harsha DW, converting enzyme inhibitors: A rand- using risk factor categories. Circulation et al. Effects of comprehensive lifestyle omised controlled trial. Lancet 2008; 1998;97:1837-1847. modification on blood pressure control: 372(9644):1174-1183. 25. Ridker P, Buring JE, Rifai N, et al. Devel- Main results of the PREMIER clinical trial. 17. Fox KM. EURopean trial On reduction of opment and validation of improved algo- JAMA 2003;289:2083-2093. cardiac events with Perindopril in stable rithms for the assessment of global car- 35. Mann JF, Schmieder RE, McQueen M, et coronary Artery disease Investigators. diovascular risk in women: The Reynolds al. Renal outcomes with telmisartan, Efficacy of perindopril in reduction of car- Risk Score. JAMA 2007;297:611-619. ramipril, or both, in people at high vascu- diovascular events among patients with 26. He FJ, MacGregor GA. Effect of longer- lar risk (the ONTARGET study): A multi- stable coronary artery disease: Random- term modest salt reduction on blood centre, randomised, double-blind, con- ised, double-blind, placebo-controlled, pressure. Cochrane Database Syst Rev trolled trial. Lancet 2008;372(9638): multicentre trial (the EUROPA study). 2004;(3):CD004937. 547-553. Lancet 2003;362(9386):782-788. 27. Joffres M, Campbell NR, Manns B, et al. 36. Beckett N, Peters R, Fletcher AE, et al.; 18. Patel A; ADVANCE Collaborative Group, Estimate of the benefits of a population- HYVET Study Group. Treatment of hyper- MacMahon S, Chalmers J, Neal B, et al. based reduction in dietary sodium addi- tension in patients 80 years of age or Effects of a fixed combination of perindo- tives on hypertension and its related older. N Engl J Med 358:1887-1898. pril and indapamide on macrovascular health care costs in Canada. Can J 37. ALLHAT Officers and Coordinators for and microvascular outcomes in patients Cardiol 2007;23:437-443. the ALLHAT Collaborative Research with type 2 diabetes mellitus (the 28. Penz ED, Joffres MR, Campbell NR. Group. Major outcomes in high-risk ADVANCE trial): A randomised controlled Reducing dietary sodium and decreases hypertensive patients randomized to trial. Lancet 2007;370(9590):829-840. in cardiovascular disease in Canada. Can angiotensin-converting enzyme inhibitor 19. Action to Control Cardiovascular Risk in J Cardiol 2008;24:497-501. or calcium channel blocker vs diuretic: Diabetes Study Group. Effects of inten- 29. Appel LJ, Moore TJ, Obarzanek E, et al.; The Antihypertensive and Lipid-Lower- sive glucose lowering in type 2 diabetes. DASH Collaborative Research Group. A ing Treatment to Prevent Heart Attack N Engl J Med 2008;358:2545-2559. clinical trial of the effects of dietary pat- Trial (ALLHAT). JAMA 2002;288:2981- 20. Schrier RW, Estacio RO, Esler A, et al. terns on blood pressure. N Engl J Med 2997. Effects of aggressive blood pressure 1997;336:1117-1124. 38. Dahlof B, Devereux RB, Kjeldsen SE, et control in normotensive type 2 diabetic 30. Whelton SP, Chin A, Xin X, et al. Effect of al.; LIFE Study Group. Cardiovascular patients on albuminuria, retinopathy and aerobic exercise on blood pressure: A morbidity and mortality in the Losartan strokes. Kidney Int 2002;61:1086-1097. meta-analysis of randomized, controlled Intervention For Endpoint reduction in 21. Heart Outcomes Prevention Evaluation trials. Ann Intern Med 2002;136:493-503. hypertension study (LIFE): A randomised Study Investigators. Effects of ramipril 31. Trials of Hypertension Prevention Collab- trial against atenolol. Lancet 2002; on cardiovascular and microvascular out- orative Research Group. Effects of 359(9311);9311:995-1003. comes in people with diabetes mellitus: weight loss and sodium reduction inter- 39. Jamerson K, Weber MA, Bakris GL, et Results of the HOPE study and MICRO- vention on blood pressure and hyperten- al.; ACCOMPLISH Trial Investigators. HOPE substudy. Lancet 2000;355(9232): sion incidence in overweight people with Benazepril plus amlodipine or hydro- 253-259. high-normal blood pressure. The Trials of chlorothiazide for hypertension in high- 22. Lee DS, Chiu M, Manuel D, et al.; Cana- Hypertension phase II. Arch Intern Med risk patients. N Eng J Med 2008; dian Cardiovascular Outcomes Research 1997;157:657-667. 359:2417-2428. Team. Trends in risk factors for cardio- 32. Fleming MF, Barry KL, Manwell LB, et al. VOL. 52 NO. 3, APRIL 2010 BC MEDICAL JOURNAL 149