Cardiovascular Disease Prevention Research at the National Heart, Lung, and Blood Institute

Cardiovascular Disease Prevention Research at the National Heart, Lung, and Blood Institute Denise G. Simons-Morton, MD, PhD, Jeffrey A. Cutler, MD, MPH

Medical Subject Headings (MeSH): National Institutes of Health, cardiovascular diseases, prevention, research, intervention studies, primary prevention, risk factors. (Am J Prev Med 1998;14:317–330) © 1998 American Journal of Preventive Medicine

Introduction

P

revention research at the National Heart, Lung, and Blood Institute (NHLBI) consists of research testing effects of interventions in humans, including both behavioral and medical interventions, to answer questions relevant to the primary and secondary prevention of heart, lung, and blood diseases. The purpose of this paper is to present the context of prevention research at NHLBI, to summarize major past and current cardiovascular disease (CVD) prevention research studies, and to discuss current and future research directions and issues. The paper focuses on CVD because studies targeting CVD factors represent the most extensive and long-standing area of NHLBI prevention research activity. Forty-two selected major studies, both completed and current, are presented to illustrate the type and range of research studies funded by NHLBI for prevention research.

The Context of Prevention Research at NHLBI Prevention research at NHLBI should be viewed in the broader context of a sequence of research (Figure 1). Basic research, which includes epidemiology, human pathophysiology, and animal experimental studies, provides evidence that a specified factor increases or decreases the risk of disease incidence or mortality. The NHLBI funds a wide range of laboratory, clinical, and epidemiologic studies examining potential etiologic factors for diseases of the cardiovascular, respiratory, and hematologic systems. These studies provide a rich source of information for specific questions addressed by prevention research. The specific research question drives all other aspects of a prevention study including selection of Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892. Address correspondence to: Denise G. Simons-Morton, MD, PhD, Prevention Scientific Research Group, National Heart, Lung, and Blood Institute, II Rockledge Centre, MSC 7936, 6701 Rockledge Drive, Room 8138, Bethesda, MD 20892.

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participants, setting, intervention, and outcomes. Prevention studies can be characterized as addressing two main prototypes of research questions: efficacy and effectiveness. Efficacy studies attempt to determine the effects of altering a putative causal factor on pathophysiologic or clinical outcomes by implementing a specified intervention in a well-controlled manner with high compliance in a highly selected group of participants. Once the efficacy of an intervention is shown, prevention research asks more applied questions, i.e., whether under more generalizable situations an efficacious intervention will be feasible and effective in improving outcomes. Effectiveness is a function of several things, including the efficacy of the intervention, the adherence to its implementation, and its effects in the broader population to which it is delivered (in which biological heterogeneity may well be greater). The term “demonstration and education research” refers to effectiveness studies that are implemented in communitybased settings, such as schools, worksites, health care offices, or whole communities. Effectiveness studies provide important information applicable to the dissemination of programs to the broader population. Efficacy and effectiveness studies form a continuum from studies of more controlled interventions with selected populations to studies of more feasible interventions with representative populations. The conceptual framework for prevention research is the natural history of disease (Figure 2). Preventing risk factors from developing has been termed “primordial prevention”1; such studies are often conducted in children or youth. One example is the Children and Adolescent Trial for Cardiovascular Health (CATCH), a school-based study of interventions to prevent elevated cholesterol and other CVD risk factors in children.2 Primary prevention focuses on preventing disease, and primary prevention studies are aimed at reducing identified risk factors for disease. One example is the Multiple Risk Factor Intervention Study (MRFIT), which tested interventions to reduce high blood cholesterol, hypertension, and smoking preva-

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Figure 1. The sequence of research in prevention.

lence to prevent CHD.3,4 Primordial and primary prevention both are addressed in community intervention studies to reduce CVD risk factors in a population. Secondary prevention focuses on preventing subsequent morbidity and mortality and improving health outcomes in persons with disease. One example is the Beta-Blocker Heart Attack Trial (BHAT), which tested the impact on mortality of beta-blocker treatment following myocardial infarction.5 Primordial, primary, and secondary prevention form a continuum, so the distinction among the three is somewhat arbitrary, and the designation of level of prevention depends on the definitions of “risk factor” and “disease.” For example, blood pressure (BP) affects CHD mortality over a broad range of BP values, yet a cutoff value is used to define hypertension; therefore, high BP can be considered a risk factor for cardiovascular disease, or hypertension can be considered a disease. Studies in children to lower BP (or to prevent BP increases) can be called either primordial prevention of high BP or primary prevention of hypertension, and studies to lower elevated BP in adults to reduce risk of CHD can be called either primary prevention of CHD or secondary prevention of hypertension. We consider hypertension to be a risk factor for CHD and stroke.

Funding Avenues and the NHLBI Initiative Process Prevention research, as all other research funded by NIH, can be either investigator-initiated where investigators submit unsolicited applications, or Instituteinitiated where the NHLBI solicits applications or proposals. The majority of funded research projects at NHLBI, as at NIH as a whole, are investigator-initiated. Applications are reviewed for quality through the NIH peer-review process and funded based primarily on priority score and available dollars, with Institute priorities a consideration. The National Heart, Lung, and Blood Advisory Council approves applications for fund-

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ing and provides direction to the Institute regarding funding decisions. A researcher can increase his or her chances of a successful grant application by a variety of means: building a track record of experience and publications through working on smaller studies funded by other sources or serving as a co-investigator on studies with an experienced principal investigator; addressing a well-conceived and timely research question; conducting a pilot study prior to submission; discussing potential applications with Institute staff; and being proactive in submitting applications. The NHLBI develops initiatives when the Institute determines that an area of research is not being addressed adequately by currently funded projects, which may occur when a large-scale multicenter study is needed to address a particular research question. Figure 3 shows the NHLBI process of planning, developing, and implementing Institute initiatives. The origins of initiative concepts are through an ongoing process of scientific exchange among NHLBI scientists and the biomedical community and also through Institute-organized task forces, workshops, and advisory groups. Recommendations are developed into specific research questions and specific initiatives by NHLBI staff, which are then reviewed and prioritized through interaction between senior scientific staff of the NHLBI divisions and the Institute Director. Selected initiatives are presented for concept approval to the National Heart, Lung, and Blood Advisory Council during open sessions at its regular meetings. Upon approval by the Institute Director and identification of set-aside funds, solicitation documents are developed and released: Requests for Applications (RFAs) for grants and cooperative agreements, and Requests for Proposals (RFPs) for contracts. Responses to RFAs and RFPs are usually due within 3 to 5 months. The peer-review process, which takes another 4 to 6 months, is conducted by a standing committee or an ad hoc committee. The top-ranked applications are presented to the Advisory Council for secondary review and funding recommendations, while contract proposals undergo secondary review by Institute staff. Successful applicants to RFAs or RFPs are experienced investigators with strong research background in areas relevant to the research question. The portion of Advisory Council meetings where potential initiatives are reviewed is open to the public, and investigators can obtain summaries of these deliberations. Despite the extensive approval process, many large NHLBI preventive intervention trials have been undertaken over the past 30 years, mostly Institute-initiated. These trials have made major contributions to the knowledge base for prevention activities in clinical and community settings. The Division of Epidemiology and Clinical Applications (DECA), where most of the NHLBI prevention

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Figure 2. The natural history of cardiovascular disease and levels of prevention.

research is located, spent over $75 million on prevention-related intervention studies (grants and contracts combined) in FY 1996. About half of the intervention research funding in DECA was for investigator-initiated

research, where currently over one hundred investigator-initiated intervention studies (new and continuing) are funded. These studies address specific questions in CVD-prevention-related areas such as nutrition, physical activity, obesity, blood pressure, smoking, blood cholesterol, and stress; they are conducted in clinical settings, worksites, schools, or communities; and they include children and/or adults, with appropriate female and minority representation. Although a substantial amount of research activity occurs in these smaller studies, the remainder of this paper focuses on large, multicenter research endeavors.

Primordial and Primary Prevention Studies

Figure 3. The process of planning, developing, and implementing NHLBI research initiatives.

Fifteen major NHLBI primordial and primary prevention studies that have been completed, selected to illustrate the range of studies funded by NHLBI in this area, are summarized in Table 1. The Physicians’ Health Study,6 the Treatment of Mild Hypertension Study (TOMHS),7 Trial of Nonpharmacologic Interventions in the Elderly (TONE),8 and the three community intervention studies9 –11 were investigator-initiated; the others were Institute-initiated. Several of the studies focused on hypertension as a risk factor for CVD. The Hypertension and Detection Follow-up Program (HDFP) tested a systematic approach to treating hypertension to determine effects on mortality.12 The Systolic Hypertension in the Elderly Program (SHEP) tested the efficacy of drug treatment of isolated systolic hypertension in the elderly in reducing stroke and cardiovascular events.13 The HDFP provided evidence that lowering BP in hypertensives,

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Table 1. Selected major completed primordial and primary prevention studies funded by NHLBI Study

Purpose

Design

Years

Participants

Interventions

Outcomes

HDFP12

Efficacy of a systematic hypertension treatment program in lowering BP and reducing mortality

Randomized controlled trial: 1 intervention and 1 usual-care control group 14 centers

1973–1979

10,940 adults with hypertension

Stepped-care drug treatment of hypertension

Intermediate: SBP/DBP Primary: all-cause mortality Secondary: CHD and stroke (fatal and nonfatal)

MRFIT3,4

Efficacy of multifactor intervention on CHD mortality in high-risk men

Randomized controlled trial: 1 intervention and 1 usual-care control group 22 centers

1973–1982

12,866 men highrisk by serum cholesterol, BP, and/or smoking

Drug treatment of hypertension, dietary control of cholesterol, behavioral approaches to smoking cessation

Primary: CHD mortality Secondary: all cause mortality, CVD mortality, CHD morbidity

LRC-CPPT17

Efficacy of cholesterol lowering in reducing risk of CHD

Randomized controlled trial: 1 intervention and 1 placebo control group 12 centers

1973–1983

3,806 asymptomatic men with high LDL cholesterol

Cholestyramine

Primary: CHD mortality and/or nonfatal MI

Stanford Five-City Project9

Effectiveness of community-wide health education on reducing stroke and CHD rates

Quasi-experimental design: 2 intervention cities, 3 control cities 1 center

1978–1992

5 cities: 2 intervention cities of 122,800 residents, 3 control cities of 197,500 residents

5-year comprehensive program of education and behavioral approaches to risk reduction for blood cholesterol, BP, smoking, weight, physical activity

Intermediate: knowledge, CVD risk factors Primary: fatal and nonfatal CVD rates, stroke rates

Minnesota Heart Health Program10

Effectiveness of community education in reducing CHD morbidity and mortality

Quasi-experimental design: 6 communities (3 pairs) with 1 intervention and 1 comparison community per pair 1 center

1980–1993

6 communities of 25,000 to 110,000 population

5–6-year program of mass media, community and professional education for hypertension control, healthful eating, nonsmoking, and physical activity

Intermediate: knowledge, CHD risk factor changes Primary: CVD morbidity and mortality

Pawtucket Heart Health Program11

Effectiveness of community education in reducing CHD risk

Quasi-experimental design: 1 intervention community and 1 comparison community 1 center

1980–1995

2 communities of 71,000 to 98,000 population

7-year community organization and educational intervention to reduce blood cholesterol, BP, smoking, obesity, and increase physical activity

Primary: changes in CVD risk factors

Physicians’ Health study6, a

Efficacy of aspirin in preventing CVD mortality

2 3 2 factorial randomized controlled trial: 3 intervention groups and 1 placebo control group 1 center

1981–1987 (for aspirin)

22,071 men apparently healthy, no previous MI

(1) aspirin (2) beta-carotene (3) combination

Primary (for aspirin): CVD mortality Secondary (for aspirin): total mortality, nonfatal MI, stroke

Table 1. Continued

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Study

Purpose

Design

Years

Participants

Interventions

Outcomes

SHEP13

Efficacy of antihypertensive drug treatment in reducing risk of stroke in isolated systolic hypertension (ISH)

Randomized controlled trial: 1 intervention group and 1 placebo control group 16 centers

1985–1990

4,736 men and women aged 60 years and older with isolated systolic hypertension

Stepped-care drug treatment of ISH

Primary: total stroke Secondary: CHD and CVD morbidity and mortality, total mortality, quality of life

TOMHS7

Efficacy of various antihypertensive medications for mild hypertension

Randomized controlled trial: 5 intervention groups and 1 placebo control group (all received nutrition-hygienic treatment) 4 centers

1985–1994

902 adults with diastolic BP 85–99 mm Hg

(1) (2) (3) (4) (5)

chlorthalidone acebutolol doxazosin amlodipine enalapril

BP, quality of life, side effects, incidence of CVD events, others

TOHP I14

Short-term feasibility and efficacy of 7 nonpharmacologic interventions in high normal DBP

3 randomized controlled trials: (1) lifestyle trial with 3 intervention and 1 usual care control group; (2) 2 supplement trials with 2 intervention and 1 placebo control group each 9 centers

1986–1990

2,182 men and women with DBP 80–89 mm Hg

3 lifestyle: (1) weight reduction (2) dietary sodium reduction (3) stress management 4 dietary supplement: (4) calcium (5) magnesium (6) potassium (7) fish oil

Primary: change in DBP Secondary: change in SBP, intervention compliance

CATCH2

Effectiveness of schoolbased interventions for preventing CVD risk factors in children

Randomized controlled school study; 2 intervention groups, 1 usual care control group 4 centers

1987–1994

96 elementary schools with cohort of 3,936 3rd-grade students

Two school-based interventions: (1) curriculum 1 food service 1 PE; (2) curriculum 1 food service 1 PE 1 parent involvement

Primary: blood cholesterol Secondary: BP, physical activity, dietary fat intake, school policies, and others

PATHS

Efficacy of reduction of alcohol intake in lowering elevated BP

Randomized controlled trial: 1 intervention group and 1 control group 7 centers

1988–1994

641 men with moderately heavy alcohol intake and elevated diastolic BP

Behavioral intervention to reduce alcohol intake

Primary: Systolic and diastolic BP at 6 months Secondary: Systolic and diastolic BP, and alcohol intake through 2 years; LV mass at 6 months

TOHP II15

Efficacy of weight loss and dietary sodium reduction, separately or in combination, in reducing BP for highnormal BP

Randomized controlled trial, 2 3 2 factorial design: 3 intervention groups and 1 usual care control group 9 centers

1990–1995

2,382 overweight adults with highnormal diastolic BP (83–89 mm Hg)

3-year behavioral interventions for (1) weight loss, (2) dietary sodium reduction, and (3) combination

Primary: DBP at 3 years Secondary: SBP and DBP at other time points, incidence of hypertension

Primary: DBP at 8 weeks Secondary: SBP Feeding study of diets: (1) high in fruits and vegetables, (2) high in fruits, vegetables, and low-fat dairy, lower in fat, saturated fat, cholesterol, and higher in protein 450 adults with high-normal BP

b

a

Also supported by the National Cancer Institute for cancer outcomes. Also supported by the National Institute of Aging.

1993–1997 Efficacy of different dietary patterns in reducing BP for adults with high-normal BP or Stage 1 hypertension DASH16

Randomized controlled trial: 2 intervention groups and 1 control group 4 centers

Primary: failure of drug withdrawal (1) weight loss (2) sodium reduction (3) combination 975 adults on singledrug antihypertensive medication 1991–1996 Efficacy of weight loss and/or reduction of dietary sodium in reducing the need for hypertension medication TONE8,b

Randomized controlled trial: 2 3 2 design in overweight; 1 intervention group and 1 usual care control group in normoweight 4 centers

Outcomes Interventions Participants Years Design Purpose Study

Table 1. Continued 322

even for “mild” diastolic hypertension (diastolic BP 90 –104 mm Hg), reduces subsequent morbidity and mortality outcomes. The SHEP provided evidence that lowering BP in elderly patients with isolated systolic hypertension (SBP .160 mm Hg) significantly reduces stroke and major cardiovascular events. Other studies have examined the efficacy of various medications or lifestyle factors in reducing elevated BP. The Treatment of Mild Hypertension Study (TOMHS) compared effects on BP, blood lipids, quality of life, and other outcomes of five antihypertensive medications added to lifestyle intervention for mild hypertension.7 The Trials of Hypertension Prevention I (TOHP I) tested seven different interventions as to their efficacy in lowering elevated blood pressure in normotensive adults, including lifestyle changes and dietary supplements.14 The Trials of Hypertension Prevention II (TOHP II) tested the efficacy of weight loss and dietary sodium reduction, alone and in combination, in reducing elevated BP and hypertension incidence in adults with high normal BP.15 The Dietary Approaches to Stop Hypertension (DASH) trial tested the efficacy of two dietary patterns in reducing elevated BP in adults.16 These studies have found that weight loss and reduction of dietary sodium lower BP in normotensive adults with high-normal BP, and that the addition of each medication to lifestyle changes reduces blood pressure levels similarly across medications in adults with mild hypertension. The DASH study found that a dietary pattern high in fruits, vegetables, and low-fat dairy products, as well as lower in total fat, saturated fat, and cholesterol, with a small increase in protein (termed the “combination” diet), quickly and significantly lowered BP in adults with high normal BP to stage 1 hypertension. The Trial of Nonpharmacologic Interventions in the Elderly (TONE) tested the efficacy of weight loss and/or reduction of dietary sodium in reducing the need for antihypertensive medication in older patients with hypertension,8 and the Prevention and Treatment of Hypertension Study (PATHS) tested the effects on elevated BP of reducing alcohol intake. The detailed results of TONE and PATHS are forthcoming. Use of medication for primary prevention has been the focus of a few major studies. Reducing blood lipids by medication in persons without CHD was the primary focus of the Lipid Research Clinics-Coronary Primary Prevention Project (LRC-CPPT), which tested the effects of cholesterol-lowering by cholestyramine on CHD morbidity and mortality.17 The Physician’s Health Study tested aspirin for CVD prevention (and betacarotene for cancer prevention).6 These studies have found that lowering blood cholesterol in asymptomatic men with hypercholesterolemia reduces incidence and mortality from CHD and that aspirin results in a significant reduction in risk of nonfatal MI in men.

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Some studies have addressed multiple risk factors. A major study was the Multiple Risk Factor Intervention Trial (MRFIT), which tested an individual-based multifactorial intervention for control of hypertension, hypercholesterolemia, and smoking in high-risk men to reduce CHD mortality.3,4 Although short-term effects were not significant, results 16 years after intervention show a widening gap in CHD and total mortality between intervention and usual care participants.4 The Child and Adolescent Trial for Cardiovascular Health (CATCH) assessed the effectiveness of school-based interventions in preventing CVD risk factors in children.2 Three community studies examined the effects of community-wide educational interventions on cardiovascular disease risk factors and morbidity and mortality: The Stanford Five-City Project,9 the Minnesota Heart Health Program,10 and the Pawtucket Heart Health Program.11 The school- and community-based studies have shown that population-based interventions can improve behavioral factors, but effects on biological risk factors such as BP and blood cholesterol are equivocal, and effects on actual CHD risk are yet to be shown. These primordial and primary prevention studies, taken as a whole, have provided an invaluable contribution to the field of cardiovascular disease prevention and a firm foundation for national recommendations for lifestyle changes and medication to reduce blood pressure and blood cholesterol for prevention of cardiovascular disease.18,19 The focus on important questions, relevant clinical populations, and practical settings have made their results generalizable to a broad range of patients and population groups. Six selected major primordial and primary prevention studies currently being conducted at the NHLBI are summarized in Table 2. The Women’s Health Study is a single-center study that was investigator-initiated; DASH2 is an investigator-initiated multi-center study; the others are multi-center studies that were Instituteinitiated. Pathways is a randomized school trial, and the others are randomized trials of individuals. Two studies in children are being conducted: the Dietary Intervention Study in Children (DISC) and Pathways. DISC is testing the efficacy and safety of a dietary intervention to lower intake of fat and cholesterol in children with elevated blood cholesterol; 3-year results have been published, which showed that dietary intervention can significantly reduce LDL cholesterol levels through early puberty with no adverse effects on growth and development or serum iron stores.20 The DISC study is being continued until the children are in late adolescence. Pathways is assessing the effectiveness of school-based interventions for preventing obesity in Native American children; the full-scale study has just begun. The effect of various classes of antihypertensive med-

ications is being addressed in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which is examining the effects on incidence of nonfatal MI and CHD death in high-risk hypertensive patients of three major classes of antihypertensive drug treatment: an ACE inhibitor, a calcium antagonist, and an alpha-1-blocker, compared with a diuretic control group. ALLHAT also is testing LDLcholesterol lowering with an HMG CoA reductase inhibitor to reduce total mortality in this older population. Further research on the effects of aspirin in CVD is the topic of the Women’s Health Study, which is also testing antioxidant vitamins for CVD and cancer prevention. Behavioral approaches to improving risk factors are being examined in the Activity Counseling Trial (ACT), which is testing the effectiveness of interventions delivered in the primary health care setting to increase physical activity in sedentary patients. The DASH2 study is comparing the effects on BP of the successful “combination” diet from DASH coupled with three levels of dietary sodium. These current studies should help further refine approaches to preventing cardiovascular disease through diet, physical activity, blood pressure control, and other approaches. NHLBI also has funded demonstration research studies of CVD prevention where several related studies are conducted in response to an Institute initiative. The purpose of Assisting Primary-Care Providers with LipidLowering Intervention (APPLI) was to develop and evaluate methods to assist primary care practitioners and patients in implementing the Adult Treatment Panel Guidelines for Detection, Evaluation, and Treatment of High Blood Cholesterol.21 APPLI consisted of four randomized controlled trials with the medical practice or physician as the unit of assignment, with 15 to 22 medical practices in each study. The studies compared basic physician instruction with coordinated, tailored, multidisciplinary approaches to screening, evaluation, and treatment.21 Two other ongoing programs are Improving Hypertensive Care for Inner City Minorities and CVD Nutrition Education for LowLiteracy Skills. The former is a group of five studies to develop and evaluate for feasibility, acceptability, and effectiveness methods to maintain therapy and control of hypertension among inner-city minority populations. The latter consists of six studies to develop and validate nutrition education programs designed to reduce CVD risk factors related to nutrition in at-risk adults with low-literacy skills. These studies will provide information applicable to implementing prevention programs in practice settings, and in populations with special needs.

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Table 2. Selected major current primordial and primary prevention studies funded by NHLBI

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Study

Purpose

Design

Years

Participants

Interventions

Outcomes

DISC

Efficacy and safety of dietary intervention to reduce elevated LDLC in children

Randomized controlled trial: 1 intervention group and 1 usual-care control group 6 centers

1986–1998

663 8–11-year-old children with elevated LDL-C

One-on-one and group education on DISC dietary guidelines for reduced fat diet to lower blood cholesterol

Efficacy: LDL-C Safety: height and serum ferritin

Pathways

Effectiveness of school-based interventions to prevent obesity in Native American children

Feasibility study: 1 intervention and 1 usualcare school per site Full-scale study; randomized school trial 4 centers

1993–2001

Native American children Feasibility study: 8 schools; Full-scale study; 40 schools

School-based intervention: curriculum 1 food service 1 PE 1 parent involvement

Percent body fat

ALLHAT

Effectiveness of various antihypertensive medications in reducing CHD morbidity and mortality; effectiveness of cholesterol-lowering in reducing total mortality

Large simple randomized controlled trial: 4 3 2 partial factorial, antihypertensive component double-blind 400 centers

1994–2002

40,000 high-risk hypertensive patients; 20,000 patients with moderately high LDL cholesterol

3 drug interventions for hypertension: (1) diuretic (2) ACE inhibitor (3) calcium antagonist, and (4) alpha-1-blocker HMG CoA reductase inhibitor for cholesterol lowering

Primary: combined incidence of nonfatal MI and CHD death for hypertensive component, total mortality for lipid component

Women’s Health Studya

Efficacy of low-dose aspirin and antioxidant vitamins in prevention of CVD and cancer

2 3 2 3 2 factorial randomized controlled trial: 7 intervention groups and 1 control group 1 center

1992–2001

41,600 female health professionals, aged 45 or older, postmenopausal or with no intent to become pregnant, without CVD

(1) aspirin (2) vitamin E (3–5) combinations of the above

Primary: CVD mortality, nonfatal MI, nonfatal stroke, decrease in selected cancers

ACT

Effectiveness of behavioral interventions in increasing physical activity in primary care patients

Randomized controlled trial: 2 intervention groups and 1 minimal intervention control group 3 centers

1994–1999

810 adult patients of primary care practices without clinical CHD

2-year behavioral interventions feasible for delivery in primary care settings: (1) staff counseling (2) staff assistance

Primary: caloric expenditure and aerobic capacity at 2 years Secondary: submaximal exercise performance, BP, lipids, others

DASH2

Efficacy of a “combination” dietary pattern across three levels of dietary sodium in reducing BP for adults with high-normal BP or Stage 1 hypertension

Randomized controlled parallel trial with nested cross-over: two parallel groups (1 dietary pattern intervention group and 1 control group) and 3 crossover levels of dietary sodium 4 centers

1997–2001

400 adults with high-normal BP to stage 1 hypertension

Feeding study of a diet high in fruits, vegetables, and low-fat dairy, lower in fat, saturated fat, cholesterol, and higher in protein at 3 levels of dietary sodium

Primary: SBP at 30 days Secondary: DBP

20

a

Also supported by National Cancer Institute.

Secondary Prevention Studies Table 3 summarizes 13 selected major secondary prevention trials that are completed. The Coronary Drug Project22 was a collaborative initiative between investigators and Institute; the POSCH23 study was investigator-initiated; the other studies were Institute-initiated. Several major studies have focused on blood cholesterol as a risk factor for subsequent morbidity or mortality in individuals with CVD. The Coronary Drug Project examined the efficacy and safety of five treatments for serum cholesterol in men with previous MI.22 The Program on Surgical Control of the Hyperlipidemias (POSCH) assessed whether reductions in total and LDL-cholesterol by partial ileal bypass surgery would reduce overall and CHD mortality in patients after first MI.23 Post-CABG tested the effects of cholesterol-lowering and minidose warfarin in preventing graft occlusion after coronary artery bypass graft (CABG) surgery. Results of the Coronary Drug Project and POSCH provided further evidence of the importance of lowering blood cholesterol in reducing subsequent CHD mortality. Publication of Post-CABG results is in progress. Four of the trials examined the efficacy of various treatments in reducing mortality in patients with coronary heart disease (CHD), i.e., patients following myocardial infarction or with chronic angina. The Aspirin Myocardial Infarction Study (AMIS) studied the effects of aspirin,24 the Coronary Artery Surgery Study (CASS) evaluated the effects of CABG surgery,25 the BetaBlocker Heart Attack Trial (BHAT) tested the effects of the beta-blocker propranolol,5 and the Cardiac Arrhythmia Suppression Trials I and II (CAST I and CAST II) studied the effects of drug treatment of ventricular arrhythmias.26,27 The Thrombolysis in Myocardial Infarction trials (TIMI I and TIMI II) examined the effects on coronary artery patency (TIMI I) and mortality or reinfarction (TIMI II) of various revascularization strategies in patients experiencing acute MI.28,29 These studies have provided evidence that has helped define the beneficial effects of aspirin, CABG, betablockers, and thrombolysis on clinical outcomes in certain CHD patients. Further, CAST discovered that excess mortality resulted from arrhythmia treatment by encainide or flecainide, which had important implications for clinical practice. Several studies have tested approaches to reducing subsequent morbidity and mortality in congestive heart failure (CHF). The Studies of Left Ventricular Dysfunction (SOLVD) examined the effects on mortality of ACE inhibitors in CHF patients.30 Recently, the Digitalis (DIG) trial examined the effects of digitalis on CHF survival and morbidity.31 SOLVD found a significant reduction in mortality with the addition of enalapril to standard therapy in CHF, and DIG found that

digitalis did not reduce overall mortality but did reduce hospitalization rate. Finally, the Arterial Disease Multifactorial Intervention Trial (ADMIT) evaluated the effects of niacin, mini-dose warfarin, and antioxidant vitamins on intermediate outcomes, and assessed the feasibility of conducting a full-scale trial among peripheral artery disease patients. Results have not yet been published. These secondary prevention studies have contributed to the evolution of current treatments for acute and chronic heart disease and to recommendations for aspirin, beta-blockers, thrombolytic therapy, cholesterol lowering, CABG surgery, and ACE inhibitor therapy in patients with CVD.32–34 Table 4 summarizes eight selected major current NHLBI secondary prevention and CVD treatment trials. The CABG-Patch trial and the Multicenter Unsustained Tachycardia Trial (MUSTT) were investigatorinitiated; the others were Institute-initiated. CABGPatch is testing the efficacy of implantable defibrillators for reducing morbidity and mortality following CABG surgery.35 MUSTT is testing the effectiveness of aggressive electrophysiologic pacing in the prevention of sudden cardiac death in patients with CHD who have ventricular tachycardia. The Beta-Blocker Evaluation of Survival Trial (BEST) is examining the effects of betablockers on CHF survival.36 Treatment of cardiac arrhythmias is being studied in the Antiarrhythmic Versus Implantable Cardiac Defibrillators (AVID) trial,37 which is testing implantable cardiac defibrillators compared with medication for ventricular arrhythmias, and the AFFIRM trial, which is testing two contrasting drug approaches to treatment of atrial fibrillation in the elderly.38 Rapid Early Action for Coronary Treatment (REACT) is a community trial testing a communitybased intervention to reduce time from onset of MI symptoms to arrival at the hospital Emergency Department in order to enable early detection and treatment of acute MI. Prevention of Events with Angiotensin Converting Enzyme (PEACE) is testing the morbidity and mortality effect of ACE inhibitors added to standard care in CHD patients with good ventricular function. Finally, Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) is studying the effect of psychosocial supportive interventions on morbidity and mortality following acute MI. Results from these studies will contribute to approaches for early detection and effective treatment for patients with cardiovascular disease to prevent subsequent morbidity and mortality.

Challenges, Opportunities, and Future Directions There are many opportunities, as well as many challenges, for the future of cardiovascular disease prevention research at NHLBI. One of the Institute’s recent directions has been

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Table 3. Selected major completed secondary prevention studies funded by NHLBI Study

Purpose

Design

Years

Participants

Interventions

Outcomes

Coronary Drug Project22

Efficacy and safety of drug treatment of elevated serum cholesterol in preventing CHD events and death in men with previous MI

Randomized controlled trial: 5 intervention groups and 1 placebo control group 53 centers

1965–1975

8,341 men with elevated serum cholesterol

Five treatments: (1–2) conjugated estrogens, 2 dosages (3) clofibrate (4) dextrothyroxine (5) niacin

Primary: total mortality Secondary: CHD mortality, nonfatal cardiac events

POSCH23

Efficacy of plasma lipid lowering (total and LDL cholesterol) by partial ileal bypass surgery in reducing mortality after first MI

Randomized controlled trial: 1 intervention group and 1 control group. Both groups received AHA Phase 2 diet 4 clinical sites

1974–1990

838 patients after first MI, with elevated total or LDL cholesterol

Partial ileal bypass surgery

Primary: mortality due to CHD or confirmed MI Secondary: total mortality, MI incidence

AMIS24

Efficacy of aspirin in reducing mortality post-MI

Randomized controlled trial: 1 intervention group and 1 placebo control group 30 clinical centers

1975–1980

4,524 adults with previous MI

Aspirin

Primary: total mortality Secondary: CHD mortality, nonfatal CVD events, side effects

CASS25

Efficacy of CABG surgery in reducing mortality in chronic stable angina without left main CAD

Randomized controlled trial: 1 intervention group and 1 control group which received CABG only with progressive disease 15 clinical centers

1975–1983

780 adults with chronic stable angina

Coronary artery bypass surgery

Primary: total mortality Secondary: CHD mortality, nonfatal myocardial infarction

BHAT5

Efficacy of betablocker (propranolol) in reducing mortality post-MI

Randomized controlled trial: 1 intervention group and 1 placebo control group 32 clinical centers

1978–1981

3,837 adult patients post-MI

Propranolol

Primary: total mortality Secondary: CVD mortality

TIMI I28 TIMI II29

Efficacy of thrombolytic therapy in revascularization in acute MI

2 randomized controlled trials: TIMI I: streptokinase group and tissue plasminogen activator group 13 clinical centers TIMI II: invasive treatment and conservative treatment control group 24 clinical centers

TIMI I: 1984–1985 TIMI II: 1985–1991

TIMI I: 316 patients with 30 minutes of chest pain and ST-segment elevation on ECG TIMI II: 3,339 patients with 30 minutes of chest pain and ST-segment elevation on ECG

TIMI I: (1) streptokinase (2) tissue-type plasminogen activator TIMI II: (1) invasive (PTCA or CABG) (2) conservative

TIMI I Primary: recanalization of coronary artery TIMI II: Death and nonfatal reinfarction

Table 3. Continued

Am J Prev Med 1998;14(4)

Study

Purpose

Design

Years

Participants

Interventions

Outcomes

SOLVD30

Efficacy of ACE inhibitor in reducing mortality from CHF

2 randomized controlled trials: each with 1 intervention group and 1 placebo control group, in 2 strata (Treatment and Prevention trials) 23 clinical centers

1986–1992

4,228 patients with CHF, and 2,659 patients with LV dysfunction but few symptoms of CHF

Enalapril

Primary: total mortality Secondary: hospitalization for heart failure, CVD mortality, CHD death, or nonfatal infarction

CAST I26 CAST II27

Efficacy of drug treatment of ventricular arrhythmias after MI in reducing incidence of sudden cardiac death

2 randomized controlled trials: CAST I: 3 intervention groups and 1 placebo control group CAST II: 1 intervention group and 1 placebo control group 27 sites

1986–1991

CAST I: 2,309 post-MI patients with ventricular arrhythmia CAST II: 1,374 post-MI patients with ventricular arrhythmia

CAST I: (1) encainide (2) flecainide (3) moricizine CAST II: (1) moricizine

Primary: mortality from arrhythmia

PostCABG

Efficacy of cholesterol lowering by drug therapy and/or minidose warfarin in preventing CABG graft occlusion

2 3 2 factorial randomized controlled trial: 3 intervention groups and 1 control group 5 clinical centers

1987–1996

1,351 post-CABG patients

(1) Lovastatin (2) Minidose warfarin (3) Both

Primary: graft occlusion Secondary: clinical events

DIG31

Effects of digitalis on survival in CHF

Randomized controlled trial: 1 intervention group and 1 placebo control group 301 centers

1990–1996

900 patients with CHD and ventricular tachycardia

Aggressive electrophysiologic pacing by drug therapy or implantable defibrillator

Primary: sudden cardiac death

ADMIT

Efficacy of various drugs and drug combinations in affecting biochemical and hematologic factors in atherosclerotic disease (pilot study)

Randomized controlled trial with 2 3 2 3 2 factorial design 6 centers

1992–1996

469 patients with peripheral arterial disease

Three drug interventions: (1) to increase plasma HDL-C (2) antithrombotic (3) antioxidant

Primary: biochemical and hematologic factors Secondary: adherence

327

328

Table 4. Selected major current secondary prevention studies funded by NHLBI

American Journal of Preventive Medicine, Volume 14, Number 4

Study

Purpose

Design

Years

Participants

Interventions

Outcomes

MUSTT

Effectiveness of aggressive electrophysiologic pacing in preventing sudden death for patients with ventricular tachycardia and CHD

Randomized controlled trial: 1 intervention group and 1 conventional treatment control group 2 centers

1991–1996

900 patients with CHD and ventricular tachycardia

Aggressive electrophysiologic pacing by drug therapy or implantable defibrillator

Primary: sudden cardiac death

AVID37

Efficacy of implantable cardiac defibrillator versus antiarrhythmic drug in preventing mortality in post-arrest and high-risk arrhythmia patients

Randomized controlled trial: 1 group w/defibrillator and 1 group with antiarrhythmic drug treatment 50 clinical sites

1992–2000

1,200 patients with ventricular fibrillation or ventricular tachycardia

(1) Implantable cardiac defibrillator (2) amiodarone and sotalol therapy

Primary: total mortality Secondary: quality of life and cost of health care

CABG Patch35

Efficacy of implantable cardioverter defibrillator in post-CABG patients with low ejection fraction

Randomized controlled trial: 1 intervention group and 1 usual-care control group 33 sites

1993–1997

900 post-CABG patients with low ventricular ejection fraction and abnormal signalaveraged ECG

Implantable cardioverter defibrillator

Primary: total mortality Secondary: clinical events

REACT

Effectiveness of community education on delay time from onset of MI symptoms to ED arrival

Randomized community trial within matched community pairs 5 field centers

1994–1998

20 U.S. communities

Multi component community intervention: community organization, and public, provider, and patient education

Primary: time from MI symptom onset to ED arrival Secondary: severity of MI, receipt of thrombolytic therapy, MI case fatality

BEST36

Efficacy of addition of beta-blockers to standard therapy in reducing mortality in CHF

Randomized controlled trial: 1 intervention group and 1 usual-care control group 90 sites

1994–1999

2,800 patients with moderate to severe CHF

Bucindolol

Primary: total mortality Secondary: clinical events

AFFIRM38

Efficacy of antiarrhythmic drugs in atrial fibrillation

Randomized controlled trial: 1 intervention group and 1 control group 200 sites

1995–2002

5,300 patients with atrial fibrillation over age 75 or with medical risk factors for stroke

(1) antiarrhythmic drugs to control heart rate and maintain sinus rhythm (2) antiarrhythmic drugs to control heart rate

Primary: total mortality Secondary: clinical events

ENRICHD

Effectiveness of psychosocially supportive interventions on morbidity/mortality in acute CHD

Randomized controlled trial: 2 intervention groups and 1 usual-care control group 8 clinical centers

1995–2001

3,000 acute MI patients

(1) health education (2) psychosocial intervention

Primary: reinfarction and CHD death Secondary: Health quality of life, ischemic events

PEACE

Efficacy of ACE inhibitor added to standard therapy on morbidity/ mortality in CAD

Randomized controlled trial: 1 intervention and 1 standard care group 150 clinical centers

1995–2003

14,000 CAD patients

ACE inhibitor plus standard care

Primary: CVD mortality or acute MI

toward large simple trials, such as the ALLHAT study, mentioned earlier. Large simple trials are conducted when there is a need to study ever larger sample sizes at affordable costs. The large sample sizes are driven by the goal of comparing alternative treatments, not just treatment versus no treatment, as well as by the ever lower rates of clinical events, which are a consequence, at least in part, of earlier advances. Thus, there is a need to have a large enough sample size to provide sufficient power to detect small differences between groups. The simplification of measurement is one of the hallmarks of large simple trials, which focus on measuring the primary outcome of interest. Primarily for reasons of efficiency, these types of studies use community practice settings, an approach that might also increase the generalizability of the results. Another Institute direction is the study of interventions for primordial prevention. As described earlier, there are several recently completed or current studies in children aimed at preventing the development of risk factors, including DISC, CATCH, and Pathways. One approach to primordial prevention involves the challenge of modifying the distribution of risk factors in whole communities. The community intervention studies at Stanford, Minnesota, and Pawtucket have had modest success in modifying risk factors. These studies have been implemented over a background of trends in the United States toward lower fat eating, improved BP control, and lower smoking prevalence. The challenge is to implement community interventions that show a significant effect beyond these secular trends. The REACT study is attempting to learn from these previous community studies in the development and implementation of a community intervention to reduce delay time from onset of MI symptoms to hospital arrival. In addition to including multiple components in the intervention program, REACT has selected a behavior as the primary outcome of the study, specifically the time from onset of acute MI symptoms to arrival at the hospital Emergency Department, which is a measure of the patient’s decision and action time. Although behavioral outcomes are more difficult to measure, they may be appropriate primary outcomes for interventions that specifically target behavior change. The challenge is to measure behaviors accurately. Another challenge is to investigate the effects of interventions in individuals with different genetic polymorphisms. Advances in human genetics are identifying the genetic polymorphisms involved in chronic diseases. In order to make use of this new knowledge, we must understand interactions between genotypes and the solidly established environmental and behavioral risk factors for cardiovascular diseases, and we must understand whether interventions have differential effects depending on genetic composition. Identi-

fication of high-risk individuals by genetic testing can be useful in targeting preventive intervention efforts, although it currently still leaves behavior change as a main avenue of reducing disease risk in these individuals. Thus, research in cardiovascular disease prevention has many challenges, as well as many opportunities. We need to find ways to detect smaller benefits through larger trials, conducted more cost-effectively, and make more use of properly validated surrogate endpoints, i.e., those other than morbidity and mortality. While health-related behaviors are undergoing dramatic changes in the population, we have much to learn about how to accelerate this process and ensure that we are reaching all segments of the population. Lastly, because intervention on established disease and established risk factors is far from completely effective, we need a continued emphasis on primordial prevention.

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