SHEP trial

SHEP trial

The SHEP trial was a multicenter randomized controlled clinical trial that evaluated treatment of isolated systolic hypertension in older adults. It demonstrated that antihypertensive therapy reduced risk of stroke and cardiovascular events, influencing guidelines and public health programs across North America and Europe. The trial involved collaboration among academic centers, federal agencies, and professional societies.

Background

The trial was designed during a period when hypertension management for older adults was debated among investigators at institutions such as the National Heart, Lung, and Blood Institute, Mayo Clinic, Johns Hopkins Hospital, Harvard Medical School, University of California, San Francisco, Massachusetts General Hospital, Stanford University, Cleveland Clinic, Columbia University, University of Pennsylvania, University of Michigan, Duke University School of Medicine, University of Pittsburgh Medical Center, Vanderbilt University Medical Center, University of Minnesota, McMaster University, University of Toronto, University of British Columbia, Mount Sinai Hospital (Toronto), Queen's University at Kingston, McGill University, University of Western Ontario, Dalhousie University, McMaster Health Sciences Centre, SickKids Hospital, City of Hope and other centers. Investigators sought to resolve controversies raised by prior studies such as the Framingham Heart Study, Multiple Risk Factor Intervention Trial, Hypertension Detection and Follow-up Program, Veterans Administration Cooperative Study Group, MRC trial of hypertension treatment, Consortium for Longitudinal Studies, and analyses by panels including the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Policy and guideline bodies like the World Health Organization, American Heart Association, American College of Cardiology, Canadian Cardiovascular Society, Royal College of Physicians (UK), European Society of Cardiology, National Institutes of Health, Food and Drug Administration, and the Centers for Disease Control and Prevention followed results closely. Influential clinicians and investigators associated with the trial included researchers who had worked with projects such as the Framingham Heart Study, Physicians' Health Study, Dunedin Multidisciplinary Health and Development Study, SHEET? and others focusing on vasculature aging, arteriosclerosis, and stroke epidemiology exemplified by work at Mayo Clinic, Johns Hopkins Hospital, Massachusetts General Hospital, and University College London.

Methods

The trial randomized approximately 4,736 participants aged 60 years or older with isolated systolic hypertension to active therapy versus placebo at centers across the United States and Canada. Centers involved included academic hospitals and clinical research units affiliated with Harvard Medical School, Yale School of Medicine, Columbia University, University of Chicago, Northwestern University, Mount Sinai Hospital (New York), Weill Cornell Medicine, NYU Langone Health, University of California, Los Angeles, University of Southern California, Rush University Medical Center, Oregon Health & Science University, University of Colorado School of Medicine, University of Iowa, University of Kansas Medical Center, University of Florida, University of Texas Southwestern Medical Center, Baylor College of Medicine, Emory University School of Medicine, Wake Forest School of Medicine, University of Alabama at Birmingham, University of North Carolina at Chapel Hill, University of Cincinnati, Indiana University School of Medicine, Temple University Hospital, Albert Einstein College of Medicine, University of Rochester Medical Center, Mayo Clinic Arizona, Scripps Research, Georgetown University Medical Center, Medical College of Wisconsin, University of Oklahoma Health Sciences Center, University of Maryland School of Medicine, SUNY Downstate Medical Center, University of California San Diego, University of Connecticut School of Medicine, Case Western Reserve University, and community clinics. The active regimen began with chlorthalidone, with atenolol or enalapril added per protocol for blood pressure control, using outcome adjudication committees modeled after practices from the Framingham Heart Study and Cardiovascular Health Study. Primary endpoints included stroke, myocardial infarction, and all-cause mortality. Statistical oversight was provided by data safety monitoring boards similar to those used in trials like the SOLVD trial, ALLHAT, and SALTIRE.

Results

The trial found a significant reduction in stroke incidence among treated participants, paralleling benefit signals for myocardial infarction and heart failure. Findings influenced guideline changes endorsed by organizations such as the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, American Heart Association, American College of Cardiology, European Society of Cardiology, and the Canadian Cardiovascular Society. The data were discussed at scientific meetings including the American Heart Association Scientific Sessions, European Society of Cardiology Congress, World Congress of Cardiology, International Stroke Conference, American College of Cardiology Annual Scientific Session, and were cited in reviews appearing in journals associated with the New England Journal of Medicine, The Lancet, Journal of the American Medical Association, Circulation, BMJ, and Annals of Internal Medicine.

Safety and Adverse Events

Adverse event profiling in the trial identified electrolyte disturbances and metabolic changes associated with diuretic therapy, heart rate and conduction effects with beta-blocker use, and considerations about renal function monitoring consistent with experiences reported in trials like ALLHAT and SOLVD. Safety monitoring involved procedures and committees analogous to those used by the National Institutes of Health, Data Safety Monitoring Board processes, and institutional review boards at participating centers such as Harvard Medical School, Johns Hopkins Hospital, Mayo Clinic, Massachusetts General Hospital, University of Toronto, McGill University, and Mount Sinai Hospital (New York).

Impact and Legacy

The trial had substantial impact on public health policy, clinical practice, and subsequent research, informing hypertension guidelines promulgated by entities including the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, American Heart Association, American College of Cardiology, European Society of Cardiology, Canadian Cardiovascular Society, and influencing later large-scale trials such as ALLHAT, SPRINT, HYVET, HOPE trial, PROGRESS, UKPDS, ASCOT, INVEST, VALUE trial, ONTARGET, TRANSCEND, LIFE trial, ADVANCE, ACCORD, HOT trial, SHEP follow-up studies and observational analyses from the Framingham Heart Study and Cardiovascular Health Study. The findings informed preventive programs run by the Centers for Disease Control and Prevention and screening initiatives in primary care settings across institutions like Kaiser Permanente, Veterans Health Administration, Group Health Cooperative, National Health Service (England), Health Canada, and influenced teaching at Harvard Medical School, Johns Hopkins University School of Medicine, Mayo Clinic Alix School of Medicine, Stanford University School of Medicine, University of Toronto Faculty of Medicine, and others. The trial remains cited in consensus statements and continues to appear in meta-analyses and systematic reviews alongside data from trials and cohorts including ALLHAT, SPRINT, HYVET, Framingham Heart Study, INTERHEART Study, MONICA Project, Global Burden of Disease Study, and guideline development by the World Health Organization and national academies.

Category:Clinical trials