cy wwewne ut onal High Blood Pressure Education Program (NHBPEP) National Cholesterol Education Program (NCEP) WorKING GRouP REPORT ON MANAGEMENT OF PATIENTS WITH HYPERTENSION AND HIGH BLOOD CHOLESTEROL SERVIC g SS , 4, = », ° = 5 < s = % Cc % %, Me, "e109 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health ''wena He ALTA LIBRARY S€Rnx gig LIBRARY | , UNIVERSITY oP | \\ CALIFORDMIA en '' National High Blood Pressure Education Program (NHBPEP) and National Cholesterol Education Program (NCEP) WoRrRKING GROUP REPORT ON MANAGEMENT OF PATIENTS WITH HYPERTENSION AND HIGH BLOOD CHOLESTEROL U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health National Heart, Lung, and Blood Institute NIH Publication No. 90-2361 August 1990 '' The National High Blood Pressure Education Program Coordinating Committee Member Organizations American Academy of Family Physicians American Academy of Ophthalmology American Academy of Physician Assistants American Association of Occupational Health Nurses American College of Cardiology American College of Chest Physicians American College of Occupational Medicine American College of Physicians American College of Preventive Medicine American Dental Association American Diabetes Association, Inc. American Dietetic Association American Heart Association American Hospital Association American Medical Association American Nurses’ Association, Inc. American Optometric Association American Osteopathic Association American Pharmaceutical Association American Podiatric Medical Association American Public Health Association American Red Cross American Society of Hospital Pharmacists American Society of Hypertension Association of Life Insurance Medical Directors of America Citizens for the Treatment of High Blood Pressure, Inc. National Black Nurses’ Association, Inc. National Heart, Lung, and Blood Institute National Heart, Lung, and Blood Institute Ad Hoc Committee on Minority Populations National Hypertension Association, Inc. National Kidney Foundation National Medical Association National Optometric Association Society for Nutrition Education '' The National Cholesterol Education Program Coordinating Committee Member Organizations American Academy of Family Physicians American Academy of Pediatrics American Association of Occupational Health Nurses American College of Cardiology American College of Chest Physicians American College of Obstetricians and Gynecologists American College of Occupational Medicine American College of Physicians American College of Preventive Medicine American Diabetes Association, Inc. American Dietetic Association American Heart Association American Hospital Association American Medical Association American Nurses’ Association, Inc. American Osteopathic Association American Pharmaceutical Association American Public Health Association American Red Cross Association of Black Cardiologists Association of Life Insurance Medical Directors of America Association of State and Territorial Health Officials Citizens for Public Action on Cholesterol National Black Nurses’ Association, Inc. National Heart, Lung, and Blood Institute National Medical Association Society for Nutrition Education Liaison Representatives Centers for Disease Control Coordinating Committee for the Community Demonstration Studies Department of Agriculture Department of Defense Department of Veterans Affairs Food and Drug Administration Health Resources and Services Administration National Cancer Institute National Center for Health Statistics National Heart, Lung, and Blood Institute Ad Hoc Committee on Minority Populations Office of Disease Prevention and Health Promotion iit '' 10 Members of the Working Group on Management of Patients With Hypertension and High Blood Cholesterol Chairman Aram V. Chobanian, M.D. Dean Boston University School of Medicine Boston, Massachusetts Therese A. Dolecek, Ph.D., R.D. Assistant Professor of Public Health Sciences (Nutrition and Epidemiology) Department of Public Health Sciences Bowman Gray School of Medicine Winston-Salem, North Carolina Harriet P. Dustan, M.D. Veterans Administration Distinguished Physician Emeritus Professor of Medicine University of Alabama School of Medicine Birmingham, Alabama Ray W. Gifford, Jr., M.D. Vice Chairman, Division of Medicine Senior Physician, Department of Hypertension and Nephrology Cleveland Clinic Foundation Cleveland, Ohio DeWitt S. Goodman, M.D. Professor of Medicine Columbia University College of Physicians and Surgeons New York, New York Scott M. Grundy, M.D., Ph.D. Director, Center for Human Nutrition University of Texas Southwestern Medical Center at Dallas Dallas, Texas Donald B. Hunninghake, M.D. Professor of Medicine and Pharmacology Director, Heart Disease Prevention Clinic University of Minnesota Minneapolis, Minnesota Ex Officio Members James I. Cleeman, M.D. Coordinator, National Cholesterol Education Program Office of Prevention, Education, and Control National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland Nancy Ernst, M.S., R.D. Nutrition Coordinator National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland William Harlan, M.D. Associate Director, Division of Epidemiology and Clinical Applications National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland Michael J. Horan, M.D., Sc.M. Associate Director for Cardiology Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland Basil M. Rifkind, M.D., F.R.C.P. Chief, Lipid Metabolism - Atherogenesis Branch Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland Edward J. Roccella, Ph.D., M.P.H. Coordinator, National High Blood Pressure Education Program Office of Prevention, Education, and Control National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland '' Staff Mary McDonald, R.N., M.S. University Research Corporation Bethesda, Maryland The authors would like to thank John C. LaRosa, M.D., George Washington Univer- sity, Washington, DC, and Sherri Jackson, M.D., National Heart, Lung, and Blood Institute, for their assistance and advice in preparation of the manuscript. '''' Table of Contents EXECUTIVE SUMMAR Y swssesaseseoaston cnn nerecennmnnenerainnmmammumnnammnnamamee Vili INTRODUCTION on. ccccccccceseseseseesesesesesenesseseseseecsesesssseseseaesenesesssecsesesesessesesesesesessacasseasscscscesecescecasetsees 1 Purpose and Rationale of the Report ..........cccccccccessssesessesesseseseseesesenesuencseseneseeneaeeneasaneeneseeneaees al Current Guidelines for Individual Management of Hypertension and High Blood ‘Cholesterol ssssssesessvseswesasauesanesavsanesases tetacisaccecneaceeaneenneereaeanerencnpneorsennecorveatervessenevsnrenesacneenss 1 REVIEW OF EPIDEMIOLOGIC DATA. sssssssssssssccsescenssncrsssavaccsvscsseasaesssecesavissastosescensacesecsnennenssencensnnseeae 5 EXPERIMENTAL STUDIES ON THE EFFECTS OF HYPERTENSION AND HIGH BLOOD CHOLESTEROL ON ATHEROSCLEROSIS ..0..cecccecceceseseseseseseseseseseceescecseseseseseeeees a INTERVENTION TRIALS 200... cccccseeseecscseseseeesscseseseneneneseessesesesesenenecaeseaeneneenseseseaeseseaeseneeesseseseseeees 8 Cholesterol sssscvsszczeveneus sso sessessisasicossnsncncanesensenneuennonnnenentnoneneneneatsnenessavareneteanrearacsnensneneanaanansneseanciecennn 8 FLY PertenSiOn ecsecesscersseeneeeseeeesnseonsunemerzoenrmsanesvesivsasneeranevecananeerearerearea Ran aNaaRANT EAE RA eaeaesadicarcescennennenease 8 TREATMENT OF PATIENTS WITH HYPERTENSION AND HIGH BLOOD CHOLESTEROL .0...ceccccecceececseesesscseseneeseesscsesesesscscseseseneeassesescsesesesenenessessseseneseesesesesesesssensseescseseseseseeeeeeses 9 Nonpharmacologic Therapy .......:.sccccsscssesessssesesscsessessessesesesesssesesesneseseesucsnsusssensansecsesaseeeeneaseneass 9 Pharmacologic Intervention... ccc scssessssssssesesesessseseeseseseneseseseaeseneceseseseensneneaeseseseeeeeeneseseseseaes 11 SPECIAL, CONSIDERATIONS. ssssceseavsxsuznasaceasusevensaveanansnananssaneasaxziwiea cies sareaceeniaecvenarerenennneneacenarensnancees 15 Cigarette: SMOKING cscsscvsvosssa reas eeerereseornsersroproreanen exerci siareny austen omen ene NETS 15 Diabetes Mellitus oo... ccc ccccescessesseseseessseseseseseneseneeseessesesenesenesesaeseseneseeecseaeseaeseaeseseeeeecseeeaeaees 15 Patients with Renal, Cardiovascular, and Cerebrovascular Disease ...........ccccssscessceeeesseeeees 17 Hormone Treated Patients ........cccccscsessssessseseseeeeeeeesesescseseseseseecseaeseseenseseseseaenenenseenenseseseseaeneneees 19 Age 'CONSIGErAtIONS sess mmmnenammm emer aT ARE 20 COSt (CORSIGEPAUOHS ssecscscocrssesererremsenwneoree er mermsunecensemnen en unereneeuraremen 21 DEVELOPING EDUCATIONAL MESSAGES FOR PATIENTS .......ccccccssesssseseseeeeeeseseeeeseseeseseeess 23 Multiple Risk Factor Intervention Relationships .............ccccccessssesesessesessesesesseseseesesnsesseeesenees 23 REFERENCES seccssszssessvcecsuseaasassavessansspsimsesnscasdensnicesientercossnennenentnsnsentt edstancnnnensantnsneneatananeneranenenensneynadsiirsane 25 TABLES AND FIGURES Table I: Risk Status Based on Presence of Coronary Heart Disease Risk Factors Other Than LDL-Cholesterol ..........0ccccccccscssescecsesseescseesesssnsseseenesesesnssassneasanseseeseeacanense 3 Table II: Classification and Treatment Decisions Based on LDL-Cholesterol ............0.:.0ecee 4 Table III: Dietary Therapy for High Blood Cholesterol and Hypertension ..........0.cccccceeeees 10 Table IV: Lipid and Lipoprotein Effects of Antihypertensive Drugs ...........0cc eee 11 Figures la and 1b: Predicted CHD Incidence by Number of Risk Factors ...........cccccceseseseseseees 6 — aa — — vii '' Executive Summary Cardiovascular diseases caused nearly one of every two deaths in 1987 and cost the United States economy an estimated $127 billion an- nually in direct and indirect costs. Epidemiological data have demonstrated that individuals with fewer or lower levels of cardiovascular disease (CVD) risk factors are less likely to suffer a cardiovascular event. In addition, the greater the level of any single CVD risk factor, the greater the chance of incurring disease. Moreover, a combina- tion of risk factors creates a synergistic effect further increasing risk. Conversely, reduc- ing cardiovascular risk factors prevents death and disability from cardiovascular diseases. This report is designed to guide the clinician in managing patients with multiple cardio- vascular risk factors, placing a special emphasis on hypertension and high blood cholesterol.* Unpublished data from the National Health and Nutrition Examination Survey II show that 40 percent of individuals who have blood pressures 2140/90 mm Hg or who are taking antihypertensive medica- tions have blood cholesterol levels 2240 mg/ dL. Likewise, 46 percent of those with blood cholesterol levels 2240 mg/dL have blood pressures 2140/90 mm Hg. Nonpharmacologic therapy is the foundation for management of both hypertension and high blood cholesterol. Diet to reduce calories, saturated fat, total fat, cholesterol, sodium, and alcohol consumption is an important first step. Exercise helps maintain energy balance and cardiovascular fitness. Smoking cessation also should be a key feature of any therapeutic program. The patient who smokes should be counseled not to smoke, past smokers should be praised for giving up the habit, and persons who never smoked should be congratulated. Clinicians should begin managing cardio- vascular risk factors with these nondrug measures which will serve either as defini- tive or adjunctive therapy. Pharmacologic agents can be very beneficial in managing cardiovascular risks imposed by elevated levels of blood pressure and/or blood cholesterol. In selecting medications, it is important to weigh their benefits, costs, and potential untoward effects. For ex- ample, some antihypertensive agents may adversely affect serum lipid and lipoprotein levels, but their adverse effects can be blunted by dietary modification, by a reduction in drug dosage, or by switching to other agents. Some cholesterol-lowering agents such as bile acid sequestrants and nicotinic acid may compromise an anti- hypertensive drug’s ability to lower blood pressure. Switching to other agents or cutting back on drug dosage may help in these cases. Clinicians must consider these issues in managing the patient with multiple risk factors but should not avoid managing any risk factor or quickly dismiss any particular mode of therapy simply because of the potential for adverse effects. The goal of controlling cardiovascular risk factors should be pursued aggressively to achieve major reductions in cardiovascular morbid- ity and mortality. * Guidelines for the management of hypertension, high blood cholesterol, hypertension and diabetes, and smoking are available from the National Heart, Lung, and Blood Institute (NHLBI) Information Center, 4733 Bethesda Avenue, Suite 530, Bethesda, MD 20814. '' Introduction Cardiovascular diseases are responsible for nearly one of every two deaths, and their economic costs have been estimated at more than $127 billion annually (1). Elevated blood pressure or blood cholesterol levels increase the risk for premature cardiovascular disease (CVD) morbidity and/or mortality (2). Other major CVD risk factors include cigarette smoking, diabetes mellitus, a low high density lipoprotein (HDL)-cholesterol level, severe obesity (230 percent overweight), male sex, and a family history of CVD. An estimated 58 million individuals have blood pressures 2140/90 mm Hg or take antihypertensive medication (3), and about 60 million Americans age 20 and older have blood cholesterol levels that require medical advice and intervention using dietary therapy as the primary mode of treatment (4). Hypertensive patients have a greater-than-expected prevalence of high blood cholesterol, and conversely, patients with high blood cholesterol have a higher- than-expected prevalence of high blood pressure. According to unpublished data from the National Health and Nutrition Examination Survey II (NHANES ID), 40 percent of individuals who have blood pressures 2140/90 mm Hg or who are taking antihypertensive medications have blood cholesterol levels 2240 mg/dL. Likewise, 46 percent of those with blood cholesterol levels 2240 mg/dL have blood pressures 2140/90 mm Hg.* Purpose and Rationale of the Report This report provides clinicians with an integrated approach to the identification and management of patients with multiple cardiovascular disease risk factors, particu- larly patients with both high blood pressure and high blood cholesterol. Smoking cessation and adoption of other healthy lifestyle behaviors are also emphasized. The overall goal of this report is to prevent morbidity and mortality from CVD. The information provided here can also be useful to programs designed to control these important public health problems. Current Guidelines for Individual Management of Hypertension and High Blood Cholesterol Hypertension Guidelines for the management of hyperten- sive patients have been provided in The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC IV) (5). Hypertension is defined as blood pressure 2140/90 mm Hg or current use of antihypertensive medica- tion. The majority of hypertensive patients have mild elevations of systolic or diastolic blood pressure. * Data calculated by National Heart, Lung, and Blood Institute (NHLBI) staff from NHANES II data tape. '' JNC IV advocates nonpharmacologic therapy (sodium and alcohol restriction, weight control, and control of other cardio- vascular risk factors) as the foundation for antihypertensive treatment, particularly in patients with mild hypertension. For those who have not responded adequately to nonpharmacologic therapy in 3 to 6 months and who require antihypertensive medica- tions, any one of four classes of drugs—diuretics, beta-blockers, calcium antagonists, and angiotensin converting enzyme (ACE) inhibitors—are recommended as a first choice. JNC IV recommends an individualized step-care algorithm; that is, starting out with one class of drug at less than full dose, then either a) increasing the drug dosage, b) adding another class of agent, or c) substituting one class of drug for another class. This approach permits the clinician to select therapy that best fits the patient’s needs and to keep doses and numbers of medications at a minimum. Several factors can help tailor drug therapy to the characteristics of the patient, including demographics, presence of other conditions, and use of other therapies. For example, black patients tend to respond better to diuretics and calcium antagonists than to beta-blockers or ACE inhibitors as mono- therapy. Beta-blockers should be avoided in the asthmatic hypertensive and in the hyper- tensive patient with heart failure but are the drugs of choice for hypertensive patients with previous myocardial infarction and angina pectoris. ACE inhibitors, on the other hand, may be selected for the diabetic patient with renal disease or for the hyper- tensive patient with heart failure. Satisfactory control of hypertension can be achieved in virtually all patients. The key clinical issue now is not whether elevated blood pressure can be reduced, but whether it can be reduced at reasonable cost with an absence or minimum of adverse effects, and whether reducing blood pressure in the mild hypertensive will reduce the incidence of coronary heart disease (CHD), other atherosclerotic complications, and overall mortality. High Blood Cholesterol The guidelines developed by the National Cholesterol Education Program’s Expert Panel on Detection, Evaluation, and Treat- ment of High Blood Cholesterol in Adults (Adult Treatment Panel or ATP report) (6) identified low density lipoprotein (LDL)- cholesterol as the major target for choles- terol-lowering therapy. The report empha- sized two important principles regarding CHD risk factors. First, all major CHD risk factors should be considered when assessing CHD risk, and intervention should be directed towards all modifiable risk factors. Second, when CHD or CHD risk factors other than high LDL-cholesterol are present, the guidelines recommend lower cutpoints for initiation of therapy and lower goals for LDL-cholesterol reduction. Every adult 20 years of age and older should have total cholesterol measured at least once every 5 years. Fasting is not required for sampling. If the initial level is 2200 mg/dL, a total cholesterol measurement should be repeated and the two results averaged. If the two tests average 200-239 mg/dL (i.e., borderline-high) and if the patient does not have two of the other CHD risk factors or clinically significant CHD (table I), he or she should be advised to follow a cholesterol- lowering diet and to have total cholesterol remeasured in 1 year. If the total cholesterol is 2240 mg/dL, or is in the range of 200 to 239 mg/dL and CHD or two other CHD risk factors are present, a lipoprotein analysis '' should be carried out. If lipoprotein analysis is needed, LDL-cholesterol should be determined, because clinical decisions about cholesterol-lowering therapy depend on levels of LDL-cholesterol. Table II shows the classification of LDL- cholesterol levels and recommended treat- ment based on these classifications. Patients should be advised to follow a blood choles- terol-lowering diet (see section on nonphar- macologic therapy) and should have choles- terol levels checked periodically, as de- scribed in the ATP report. At least 6 months of intensive dietary therapy should be carried out to provide a fair trial of this intervention. Drugs should be reserved for patients who, despite such dietary therapy, still have very high LDL- cholesterol levels (2190 mg/dL, or 2160 mg/ dL with CHD or two or more of the other CHD risk factors). The use and role of HDL-cholesterol levels in clinical practice have been reviewed in detail by the National Cholesterol Education Program (NCEP) (7), which recommended that HDL-cholesterol be used as an index of risk but not as a target of therapy. The patient is considered to have a high-risk status if he or she has either: A. Definite CHD: t The characteristic clinical picture and objective laboratory findings of either: 1. Definite prior myocardial infarction, or 2. Definite myocardial ischemia such as angina pectoris. OR B. (Two other CHD risk factors: 1. Male sex $ 2. Family history of premature CHD (definite MI or sudden death before age 55 in a parent or sibling) Cigarette smoking Hypertension Diabetes mellitus SN SD oF PE Severe obesity (230% overweight). * LDL indicates low density lipoprotein cholesterol. + CHD indicates coronary heart disease. Low HDL-cholesterol (<35 mg/dL) Definite history of cerebrovascular or occlusive peripheral vascular disease $£ Male sex is considered a risk factor in this scheme because the rates of CHD are three to four times higher in men than in women in the middle decades of life and roughly two times higher in the elderly. Source: The Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988;148:36-39. Table I Risk Status Based on Presence of Coronary Heart Disease Risk Factors Other Than LDL*-Cholesterol '' Table II Classification and Treatment Decisions Based on LDL*-Cholesterol Classification <130 mg/dL Dessivabile LDL-Cholesterol 130-159 mg/dL Borderline-High-Risk LDL-Cholesterol 2160 mg/dL High-Risk LDL-Cholesterol Dietary Therapy 7 Initiation Level Minimal Goal Without CHD and <2 2160 mg/dL <160 mg/dL other risk factors WithCHDor22 2130 mg/dL <130 mg/dL other risk factors Drug Treatment Initiation Level t Minimal Goal Without CHD or two 2190 mg/dL <160 mg/dL other risk factors WithCHDortwo 2160 mg/dL <130 mg/dL other risk factors * LDL indicates low density lipoprotein cholesterol. + After at least 6 months of intensive dietary therapy. Adapted from: The Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988;148:36-39. '' Review of Epidemiologic Data Both systolic and diastolic blood pressures are directly related to CHD. Data from the 356,222 persons screened for the Multiple Risk Factor Intervention Trial (MRFIT) with no history of hospitalization or myocardial infarction delineate the risk of CHD mortal- ity over the 6 years of followup. The higher the systolic or diastolic blood pressure, the greater the risk for CHD (8). The effects of serum cholesterol on CHD mortality (9) have a risk gradient similar to that for blood pressure: the higher the serum cholesterol, the greater the risk of CHD. HDL-choles- terol has an inverse relationship to CHD risk; increased risk is associated with lower levels of HDL-cholesterol. Cigarette smoking is a major influence on fatal and nonfatal CHD events and strokes, increasing risk in both men and women and for all racial groups in the United States. Diabetes mellitus is a risk factor for the development of CHD. On average, the acute and late manifestations and outcomes of coronary events are more severe and more lethal in diabetics than in nondiabetic persons of the same age. Complications of myocardial infarction are more severe and heart failure is more common in diabetics. Diabetic women have approximately twice the risk of myocardial infarction as nondia- betic men and twice the risk of recurrent infarction. The typical 10- to 15-year delay in cardiovascular complications in women compared with men is not seen in diabetic women (10). Obesity is associated with CHD and is an important factor in the development of hypertension and diabetes mellitus. It also contributes to elevation of blood lipid levels (11,12), especially in raising triglyceride and lowering HDL-cholesterol. There is a tendency for more than one risk factor to be found in an individual (13). The clustering of risk factors is the result, in part, of a genetic propensity for these conditions. The presence of more than one risk factor in general increases, in both men and women, the likelihood of developing CHD. Figures la and 1b use data from the Framingham study to illustrate this effect for three risk factors: systolic blood pressure >140 mm Hg, serum cholesterol 200-239 mg/dL or 2240 mg/dL, and cigarette smoking. When no risk factors are present, the risk of a CHD event in the succeeding 8 years is relatively low for both men and women. As the number of risk factors increases, the risk for CHD increases. Note that the illustrations for 50-year-old men and 60-year-old women are similar; that is, the risk for CHD in 60- year-old women rises in the same way as it does for 50-year-old men. This is true even in the range of 200-239 mg/dL cholesterol levels (2). '' Figure la 8 Year Risk of CHD Per 1000 Predicted CHD Incidence By Number of Risk Factors 20 15 10 Jf. / 50-YrOld Men 5 2 i 60-Yr-Old Women 0 None One Two Three Number of Risk Factors Risk factor defined as: Cholesterol 200-239 mg/dL; Systolic Blood Pressure 2 140 mm Hg; Cigarette Smoking Source: | Harlan WR, Garrison RF. Framingham Data. National Heart, Lung, and Blood Institute, Bethesda, MD. 1990. Figure Ib 8 Year Risk of CHD Per 1000 Predicted CHD Incidence By Number of Risk Factors 20 15 _/ 50-Yr-Old Men / ra Y 60-Yr-Old Women None One Two Three Number of Risk Factors Risk factor defined as: Cholesterol 2 240 mg/dL; Systolic Blood Pressure 2 140 mm Hg; Cigarette Smoking Source: Harlan WR, Garrison RF. Framingham Data. National Heart, Lung, and Blood Institute, Bethesda, MD. 1990. 6 _ '' Experimental Studies on the Effects of Hypertension and High Blood Cholesterol on Atherosclerosis Elevations in serum total and LDL-choles- terol accelerate atherogenesis. These relationships are well documented by both clinical and postmortem studies in humans and by extensive studies in a variety of animal species including monkeys and baboons (14). Hypertension likewise in- creases the extent and severity of athero- sclerosis in humans (15). When combined with elevated serum cholesterol, hyperten- sion appears to be particularly injurious to the arterial wall. Studies in experimental animals indicate that hypertension alone does not contribute to atherogenesis, but when combined with hypercholesterolemia, it markedly accelerates atherosclerosis (16,17). '' Intervention Trials Cholesterol Results from 22 randomized clinical trials of cholesterol-lowering to prevent CHD, which involved about 40,000 individuals, indicate an average 23 percent reduction in risk of nonfatal myocardial infarction plus cardiac deaths in treated groups compared with controls. Reduction in coronary disease was directly related to both the degree and duration of cholesterol reductions. A 10 percent reduction in cholesterol levels led to about a 10 percent reduction in CHD in trials with less than 4 years of treatment, while studies of more prolonged therapy showed that a 10 percent decrease in cholesterol was associated with an approximate 20 percent reduction in CHD (18). The benefits of cholesterol lowering appeared to be equal regardless of whether drug or diet was used and whether fatal or nonfatal coronary events were considered. Although lowering total blood cholesterol and LDL-cholesterol definitely reduced the risk of fatal and nonfatal CHD, total mortal- ity was not affected in these intervention trials. The size and length of these studies may not have been adequate to evaluate the effect on total mortality. Post-trial observa- tions of participants in the Coronary Drug Project did show a reduction in total mortal- ity in the nicotinic-acid-treated group (19). Concern has also been expressed that lowering cholesterol may increase non- coronary mortality. But, with the exception of the World Health Organization (WHO) Clofibrate Trial which showed a significant excess of deaths due to gallstones or acute pancreatitis, no study has demonstrated systematic excesses in mortality from other causes (18). Hypertension Antihypertensive drug therapy is associated with an impressive reduction in many major cardiovascular complications (20). In both mild and severe hypertension, trials of drug therapy have shown that it protects against stroke, congestive heart failure, and progres- sion to more severe levels of hypertension. A 30-50 percent reduction in both fatal and nonfatal strokes with drug therapy has been demonstrated. However, protection against the complications of CHD as a result of antihypertensive therapy has not been convincingly shown. A summary analysis of nine clinical trials shows a trend toward reduced mortality from CHD in intervention groups, but the difference does not reach statistical significance (20). However, one post-trial followup has shown a statistically significant reduction in CHD (21). These clinical trials have generally used diuretics as initial therapy, although the Medical Research Council (MRC) trial included a propranolol-treated group (22). Long-term followup of clinical trials has not yet been conducted on the effects of alpha- blockers, ACE inhibitors, or calcium antago- nists on cardiovascular complications and mortality in hypertensive patients. '' Treatment of Patients With Hypertension and High Blood Cholesterol Nonpharmacologic Therapy Nonpharmacologic interventions for man- agement of both hypertension and high blood cholesterol are recognized as the essential first step of therapy. Both the JNC IV and the ATP report identified dietary therapy as the foundation of medical management. Dietary therapy for hypertension and high blood cholesterol is based on common prin- ciples. Of greatest importance is weight control, which is essential to management of both blood pressure and blood lipids. Weight loss of even a few pounds among obese patients can serve as a powerful catalyst to reduce blood pressure and blood cholesterol, very low density lipoprotein (VLDL)-cholesterol, and LDL-cholesterol. It may also raise HDL-cholesterol. In turn, excessive weight exacerbates several risk factors. It raises blood pressure, serum total cholesterol, LDL-cholesterol, and increases the risk for diabetes mellitus (11). In addition, obesity is associated with reduced HDL-cholesterol levels, and may increase the risk for CHD independent of its influence on other risk factors. The distribu- tion of weight may influence risk, according to accumulating evidence that upper body rather than lower body obesity is associated with increased CHD risk (23). Weight gain in early adult life contributes substantially to the development of hypertension later in life (24). Recent data suggest that resistance to the peripheral action of insulin and hyperin- sulinemia secondary to obesity may partly explain the hypertensive response to excess body weight, although the mechanism is not fully understood (12). Elevated serum insulin levels may cause sodium retention. Weight reduction largely reverses these abnormalities. Many patients with mild hypertension experience a fall in blood pressure with caloric restriction even before desirable weight is reached. This benefit can be achieved by restricting calories alone, without necessarily restricting sodium intake (25). Clinical studies have demonstrated that weight reduction also improves glycemic control (26). It improves carbohydrate tolerance in patients not frankly diabetic and lessens hyperglycemia in obese diabetic patients. Because of the adverse effects of obesity on risk factors for CHD, weight reduction is strongly recommended for all obese patients. In addition, children of parents with hyper- tension, high blood cholesterol, or diabetes should be counseled about the cardiovas- cular risks of obesity. The necessity for weight control should be viewed as chronic rather than acute treat- ment. The goal is successful long-term weight management through lifestyle modification, emphasizing nutritional balance and physical activity and accom- plished gradually over time. Patients’ interest in rapid weight loss through very low calorie or starvation diets should be redirected towards sustained maintenance of lower body weight and away from an emphasis on total pounds lost. Exercise facilitates weight reduction and should be a component of all weight loss / weight control programs. A recent study showed that weight loss achieved by a regular exercise program without caloric restriction decreased plasma triglycerides, '' increased HDL-cholesterol, and reduced body weight as much as dietary restriction alone (27). Table III presents the step-one and step-two diets for treatment of high blood cholesterol developed by the ATP with additional recommendations from JNC IV for alcohol and sodium restriction. These combined recommendations should guide food selection in the treatment of patients with high levels of blood cholesterol and blood pressure. In addition to eliminating excess calories, the therapeutic diet is designed to reduce intakes of total fat, saturated fatty acids, and cholesterol. The goal of these diets is to reduce elevated blood cholesterol levels while maintaining a nutritionally adequate eating pattern. A minimum of 6 months of intensive dietary therapy and counseling should usually be carried out in most patients before considering drug therapy. An exception to this rule is made for some patients with severe forms of hyper- cholesterolemia. The first level of dietary modification is the step-one diet. If the blood cholesterol response to this diet is inadequate (after a minimum of 3 months), patients should move to the step-two diet. Table III includes JNC IV goals for sodium and alcohol intake: 70-100 mEq per day for sodium (equivalent to 4 to 6 grams of table salt) and 30 grams (1 ounce”) or less per day for alcohol. The moderation or elimination * One ounce of alcohol or ethanol is contained in 2 ounces of 100 proof whiskey, approximately 8 ounces of wine, or 24 ounces of beer. Table III Dietary Therapy for High Blood Cholesterol and Hypertension 10 NUTRIENT Step-One Diet Total Calories Total Fat Saturated Fatty Acids Polyunsaturated Fatty Acids Monounsaturated Fatty Acids Carbohydrates Protein Cholesterol Sodium Alcohol Less than 10% of Total Calories Less than 300 mg RECOMMENDED DAILY INTAKE Step-Two Diet To achieve and maintain desirable weight Less than 30% of Total Calories Less than 7% of Total Calories Up to 10% of Total Calories 10 to 15% of Total Calories 50 to 60% of Total Calories 10 to 20% of Total Calories Less than 200 mg 70 to 100 mEq Less than 30 grams* * 30 grams (1 ounce) of alcohol or ethanol are contained in 2 ounces of 100 proof whiskey, approximately 8 ounces of wine, or 24 ounces of beer. Adapted from: The Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988;148:36-39 and The 1988 Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1988;148:1023-38. '' of alcohol use by persons with high blood pressure is recommended because excess alcohol often raises blood pressure (28). Alcohol also can raise blood triglyceride levels. Reducing alcohol consumption contributes to weight loss and has favorable effects on blood pressure and serum lipids. Perhaps the only nutritional principle not common to management of both risk factors is limiting salt intake. This dietary practice is recommended for all hypertensives, par- ticularly those individuals who are consid- ered salt-sensitive such as blacks and older Pharmacologic Intervention Effect of Antihypertensive Medications on Serum Lipids The effect of antihypertensive drugs on serum lipids must be considered when prescribing for hypertensives with dyslipid- emia (29). In general, beta-blockers lacking appreciable intrinsic sympathomimetic activity (ISA) or alpha-blocking properties tend to reduce HDL-cholesterol and increase serum triglycerides. They have varying effects on total serum cholesterol (table IV). patients. Drug Total LDL HDL Table IV Class Cholesterol Cholesterol Triglycerides Cholesterol / a 7 So - - - a Lipid and Lipoprotein Thiazides and loop T T T 0 Effects of diuretics Antihypertensive + Beta-blockers 0 0 T 1, Drugs Beta-blockers 0 0 0 0 (ISA) Alpha-/beta-blockers 0 0 0 0 Alpha,-antagonist L L 0 0 Central adrenergic L d, 0 0 inhibitors ACE inhibitors 0 0 0 0 Calcium antagonists 0 0 0 0 KEY: LDL = low density lipoprotein HDL = high density lipoprotein ISA = intrinsic sympathomimetic activity T = raises L = lowers 0 = neutral effect * These are composite data showing trends which may not be applicable to individual situations. Adapted from: Weidmann P, Uehlinger DE, Gerber A. Editorial review. Antihypertensive treatment and serum lipoproteins. Journal of Hypertension 1985; 3:297-306. '' 12 Thiazide-type diuretics tend to produce modest increases (averaging 5-10 mg/dL) in serum total cholesterol and LDL-cholesterol and serum triglycerides with little or no adverse effect on HDL-cholesterol. Some reports have suggested that indapamide does not affect serum lipids, but data regarding indapamide are inconclusive. The alpha-1-adrenergic blockers and cen- trally acting alpha-2-receptor agonists have a slight beneficial effect on blood lipids by decreasing total blood cholesterol and LDL- cholesterol. Drugs having minimal if any effects on serum lipids are calcium antagonists, ACE inhibitors, reserpine, hydralazine, minoxidil, the potassium-sparing diuretics, the ISA beta-blockers, and the beta-blocker labetalol, which has alpha-1-adrenergic blocking properties. The effect of antihypertensive drugs on the efficacy of lipid-lowering agents has not been carefully evaluated. However, among participants in the Coronary Primary Prevention Trial (CPPT), those who were taking thiazide diuretics did not reduce LDL-cholesterol as much as those who were not using thiazide diuretics (30,31). Development of a Pharmacologic Treatment Protocol Hypertension Hypertensive patients with elevated blood cholesterol levels should have the hyperten- sion treated aggressively even if it is in the mild range (diastolic blood pressure 90-104 mm Hg). In the absence of target organ disease and when diastolic blood pressure is less than 100 mm Hg, it is reasonable to prescribe nonpharmacologic treatment (see section on nonpharmacologic therapy) for a period of 3-6 months. If diastolic blood pressure remains at or above 90 mm Hg, antihypertensive drug therapy is generally indicated. The selection of antihypertensive drugs for patients who also have elevated LDL-choles- terol should follow the guidelines outlined in the JNC IV report. Pharmacotherapy usually is started with either a diuretic, beta- blocker, calcium antagonist, or ACE inhib- itor. Alpha-1-adrenergic blocking agents also are a reasonable choice for initial therapy in these patients because of their mild cholesterol-lowering effect. The desire to avoid diuretics and beta- blockers because of their adverse effect on blood lipids (table IV) should be balanced by considerations of efficacy, tolerability, cost, and adherence. Avoiding their use does not justify less-than-optimal blood pressure control. These agents should be prescribed when there are strong indications for their use such as the post-myocardial infarction state for non-ISA beta-blockers or salt- dependent hypertension for diuretics. In such cases, serum lipids should be monitored on a regular basis. Many patients are not sensitive to the lipid altering effects of diuretics (32). A low-saturated-fat, low- cholesterol diet, which should be prescribed for all patients with high LDL-cholesterol, will often blunt or negate the adverse effect of diuretics on serum lipids (33). Further- more, many trials of more than 1 year in duration have not shown that diuretics have a persistent hyperlipidemic effect (34,35). Some, but not all, studies have shown that the adverse effect of diuretics on serum cholesterol is dose-related, suggesting that low-dose diuretic therapy may minimize the problem. This hyperlipidemic effect of diuretics may be less in patients with high serum cholesterol, for whom diet and drug therapy to control cholesterol will be neces- sary regardless of what antihypertensive agent is prescribed (13,36). On the other hand, a diuretic-induced rise in serum cholesterol in patients with borderline-high serum levels (200-239 mg/dL) could make anticholesterolemic drug therapy necessary. In this case, it would be prudent to substitute an antihypertensive agent that would not raise serum cholesterol. '' Unless contraindicated, when the hyper- tensive patient receiving diuretics and/or certain beta-blockers presents with elevated LDL-cholesterol levels, it may be appropriate to discontinue temporarily the antihyperten- sive medications, using caution and closely observing the effects of withdrawal on blood cholesterol and blood pressure levels. High Blood Cholesterol Cholesterol-lowering drugs may be consid- ered when the LDL-cholesterol level remains significantly elevated after 6 months of appropriate dietary therapy. LDL-choles- terol levels that warrant drug therapy are listed in table II. For patients with two CHD risk factors, one of which can be hyperten- sion, drug therapy may be indicated if LDL- cholesterol is 2160 mg/dL. Since male gender is a CHD risk factor, all hypertensive men are candidates for cholesterol-lowering drugs if their LDL-cholesterol levels are persistently 2160 mg/dL after maximal dietary therapy. In hypertensive women who have no other risk factors, LDL- cholesterol levels 2190 mg/dL are an indication to consider drug therapy. A variety of factors may affect the choice of drugs in patients with elevations of both blood pressure and LDL-cholesterol. These are discussed below. Bile acid sequestrants. These drugs include cholestyramine and colestipol. In the Lipid Research Clinics (LRC) CPPT, they were proven both safe and effective for reducing CHD risk (37). For this reason, they are considered first-line therapy for reducing CHD risk. These drugs produce dose- dependent gastrointestinal side effects, particularly constipation, which can be minimized by using the lowest effective dose and by increasing intake of fluid and fiber. Calcium channel blockers also increase constipation. Bile acid sequestrants can decrease absorption of some antihyperten- sive agents, including thiazide diuretics and propranolol. As a general recommendation, all other drugs should be administered either 1 hour before or 4 hours after the bile acid sequestrant. Nicotinic acid. This drug has multiple beneficial effects on lipoprotein metabolism. It reduces levels of LDL-cholesterol and triglycerides and raises HDL-cholesterol. Nicotinic acid was shown to reduce recur- rence rates of myocardial infarction and long-term total mortality in the Coronary Drug Project (38). Nicotinic acid generally does not cause serious toxicity, and any side effects that do occur usually disappear when the drug is withdrawn. Aspirin and other nonsteroidal anti-inflammatory drugs, which are frequently used along with nicotinic acid to diminish flushing, could interfere with the hypotensive action of several antihypertensive agents. Common side effects of nicotinic acid are flushing and itching of the skin, gastrointes- tinal distress, and abnormalities of liver function. It can cause hyperuricemia and hyperglycemia, the latter being particularly undesirable in patients with noninsulin- dependent diabetes mellitus (NIDDM). Con- current thiazide diuretic therapy may exac- erbate the hyperglycemia. Because nicotinic acid can adversely affect liver function, it should be used with caution in combination with methyldopa. In patients receiving other antihypertensive agents, nicotinic acid can produce hypotension, vascular head- aches, and tachycardia. Lovastatin. This cholesterol-lowering drug appears to date to be safe for most patients. A low incidence of hepatic dysfunction and myopathy, however, has been reported. No large, long-term clinical trials have been carried out with lovastatin that prove safety or efficacy for reducing risk for CHD. No specific drug interactions between lovastatin and antihypertensive agents have been reported. However, lovastatin must be used with caution in patients receiving cyclo- sporine (see section on Special Considera- tions); the combination of lovastatin and cyclosporine greatly increases the risk of severe myopathy (39). 13 ——_____—__— '' 14 Fibric acids. Drugs available in the United States in this category are gemfibrozil and clofibrate. These drugs are effective triglyc- eride-lowering agents, and they cause moderate reductions in LDL-cholesterol and increases in HDL-cholesterol. Gemfibrozil was found to be safe and effective for reducing risk of CHD in the Helsinki Heart Study (40). Clofibrate is used much less frequently than gemfibrozil, because of reports of toxicity in two long-term clinical trials, the Coronary Drug Project (38) and the WHO Clofibrate Trial (41). There was an increased incidence of gallstones in both studies. The fibric acids are excreted primarily by the kidney. An increased incidence of myopathy has been observed in patients with renal failure who are taking fibric acid derivatives; therefore, a reduced dose and careful monitoring is required for such patients. Gemfibrozil should be avoided in patients on chronic dialysis, since it is not removed in the dialysis and may accumulate in the body. '' Special Considerations Cigarette Smoking Cigarette smoking is a powerful independ- ent risk factor for CHD, stroke, and periph- eral vascular disease. Smoking also has been strongly implicated in the development of a variety of cancers and respiratory diseases. Cigarette smoking is especially detrimental in patients with hypertension, high blood cholesterol, and diabetes mellitus; and approximately one pack per day doubles the CHD risk. Therefore physicians are strongly urged to counsel patients not to smoke. The potential for weight gain that occurs in some patients with smoking cessation should not be a deterrent. (See the section on develop- ing educational messages for patients which discusses simultaneous intervention for multiple risk factors.) Diabetes Mellitus Diabetes is another major risk factor for CHD, both as insulin-dependent diabetes mellitus (IDDM) and NIDDM, but the mechanisms involved are complex and in- completely understood. Longstanding diabetes is usually accompanied by renal disease that can cause hypertension, and when this occurs, risk for CHD increases sharply. Diabetic patients, particularly those with NIDDM, may have various forms of dyslipidemia that probably contribute to coronary atherosclerosis. Several other atherogenic factors have been implicated, including abnormal platelet function and glycosylation of cell wall proteins and lipoproteins. Longstanding diabetes may affect myocardial function and predispose to congestive heart failure particularly in patients with established CHD. Diabetic patients are more prone to silent myocardial infarction than are nondiabetics, and more than 50 percent of NIDDM patients already have evidence of underlying CHD at time of first diagnosis of NIDDM (42). The usual female protection against premature CHD essentially disappears in the presence of diabetes (10). There is increasing evidence for a link between diabetes and hypertension, both in their pathogenesis and in their effects. Obe- sity predisposes both to NIDDM and to hypertension. Recent data suggest a strong interaction among obesity, insulin resistance and hyperinsulinemia, NIDDM, and hyper- tension (43). Coexistence of hypertension and diabetes greatly enhances risk for CHD, deterioration of renal function, development of retinopathy, and occurrence of stroke and peripheral vascular disease. The association of diabetes and dyslipidemia likewise is strong. Patients with NIDDM characteristically have increased serum VLDL-cholesterol and triglycerides and low levels of HDL-cholesterol. Their LDL- cholesterol levels may or may not be ele- vated, but in either case, these patients may have abnormalities in the metabolism and composition of LDL-cholesterol particles. The severity of diabetic dyslipidemia varies among different populations, but in several studies, diabetics had significant alterations in lipoprotein metabolism two or three times more often than nondiabetic individuals. Patients with IDDM and poorly controlled blood glucose may have marked hyper- triglyceridemia with chylomicronemia and elevated VLDL-cholesterol levels. With good glycemic control, these abnormalities 15 '' are markedly reduced. IDDM patients tend to have somewhat higher levels of LDL- cholesterol than matched nondiabetic individuals (44). Certain antihypertensive drugs may impair glucose tolerance as well as induce serum lipid abnormalities. For example, beta- blockers may worsen hyperglycemia, and in insulin-treated diabetic patients, nonselec- tive beta-blockers may blunt symptoms of hypoglycemia and delay recovery from hypoglycemia. Further, diuretics can induce insulin resistance (45), and potassium depletion induced by diuretics may impair release of insulin by pancreatic beta cells. Thus, in diabetic patients with hypertension and/or high blood cholesterol (or other dyslipidemias), it is most important to control all risk factor abnormalities as much as possible. Because most diabetic patients with hypertension and dyslipidemia are obese, weight reduction usually is the most important first step. Other nonpharmaco- logic recommendations are to restrict alcohol to less than 30 grams (1 ounce) of alcohol per day, to engage in regular aerobic exercise, and to stop smoking. The report of the Working Group on Hyper- tension in Diabetes (46) and JNC IV (5) provide guidance for pharmacologic man- agement. Among the beta-blockers, the beta-1 selective (cardioselective) agents are preferable to nonselective drugs, because the delay in recovery from insulin-induced hypoglycemia is less with the cardioselective agents. But because beta-blockers and thiazide diuretics can adversely affect lipid metabolism, other antihypertensive agents—ACE inhibitors, calcium antagonists, and alpha-adrenergic inhibitors—-may be preferable. Common side effects of antihypertensive drugs often are magnified in diabetic patients. For example, orthostatic hypoten- sion secondary to diabetic autonomic neuropathy can be intensified by many antihypertensive drugs. Impotence is frequent in diabetic patients and may be made worse by many antihypertensive drugs. Hyporeninemic hypoaldosteronism, although rare, occurs in patients with diabetic nephropathy, and the accompany- ing hyperkalemia can be intensified by potassium-sparing diuretics and ACE inhibitors. Glycemic regulation will also often improve altered lipid levels in NIDDM patients; thus glycemic regulation is the first approach to lipid abnormalities in diabetics. In IDDM patients, good control of blood glucose with insulin therapy is the most effective means of bringing serum lipids into the desirable range. Drug therapy may be required for control of dyslipidemia, but the choice of drugs in the diabetic may not be the same as for nondiabetic patients because of their particular metabolic abnormalities. For example, nicotinic acid effectively lowers lipid levels but may worsen hyperglycemia and raise serum uric acid. Bile acid seques- trants may cause severe constipation in diabetics with autonomic neuropathy and can accentuate hypertriglyceridemia. Lovastatin may be preferred to bile acid sequestrants or nicotinic acid for diabetic patients with elevated LDL-cholesterol and borderline hypertriglyceridemia. Gem- fibrozil is particularly useful for patients who have more severe forms of hyper- triglyceridemia, especially if the patient has chylomicronemia and is at increased risk for acute pancreatitis. '' Patients With Renal, Cardiovascular, and Cerebrovascular Disease Renal Disease Nephrotic Syndrome The nephrotic syndrome is characterized by proteinuria, edema, and severe hyperlipo- proteinemia. There is evidence that the dyslipidemia of the nephrotic syndrome increases the risk for CHD (47,48,49). However, if severe hyperlipidemia persists in spite of therapy, special consideration should be given to use of lipid-lowering drugs. The reader is referred to an excellent recent review on the subject (50). Chronic Renal Failure To retard the progression of renal disease, blood pressure should be reduced in hyper- tensive patients with renal failure. Hyper- triglyceridemia and low HDL-cholesterol levels are the most frequently described lipid abnormalities in these patients, with hyper- triglyceridemia occurring in about 30 percent of patients with chronic renal failure (51). Dyslipidemia should be treated, because CHD is a frequent cause of death of patients on dialysis (52) or following transplantation (53,54). In these patients treatment of dyslipidemias is frequently very complex, and referral to a specialist in lipid disorders should be considered. Dietary treatment of hyperlipidemia is complicated by the requirement that dietary protein must also be limited greatly in the presence of azotemia. Hypertension accompanying renal failure is usually sodium- or volume-dependent and often requires a loop diuretic such as furosemide or bumetanide. The ACE inhibitors reduce intraglomerular pressure and retard the progression of renal failure in experimental animals, but similar effects in man remain to be proved. However, progression of azotemia may be retarded in hypertensive patients with diabetic glomeru- losclerosis using other agents such as diuretics, methyldopa, metoprolol, reser- pine, and hydralazine (55). Serum potas- sium and creatinine should be monitored closely in azotemic patients taking an ACE inhibitor because hyperkalemia and sudden increases in serum creatinine may occur. In treating azotemic patients, doses of drugs that are excreted primarily by the kidney must be reduced appropriately. These include acebutolol, atenolol, nadolol, prazosin, terazosin, methyldopa, clonidine, guanabenz, ACE inhibitors, hydralazine, and fibric acid derivatives. Patients on chronic hemodialysis or perito- neal dialysis frequently have lipid abnor- malities as well as hypertension (56). While dialysis may not reverse the lipid abnormali- ties associated with chronic renal failure (e.g., hypertriglyceridemia, elevated VLDL- cholesterol, and decreased HDL-cholesterol), it usually controls the hypertension. Pre- ferred antihypertensive drugs, if needed, include calcium antagonists and beta- blockers. ACE inhibitors are effective but must be used cautiously because of their hyperkalemic effect and also because their hypotensive potency is greatly enhanced by volume depletion, which may occur with each hemodialysis. Lipid-lowering drug treatment in patients with chronic renal failure is difficult and may be hazardous. Gemfibrozil and lova- statin may cause myopathy; nicotinic acid may raise uric acid; and bile acid seques- trants may aggravate hypertriglyceridemia. These drugs should be used in low doses and their effects carefully monitored. 17 '' - 18 Renal and Cardiac Transplantation Complications of atherosclerosis are several times higher in renal and cardiac transplant recipients than in the normal population, and cardiovascular disease is second only to infection as the leading cause of death in these patients (57). Both hypertension and hyperlipidemia are more prevalent in renal transplant recipients than in the normal population (57). In addition, a high propor- tion of renal transplant recipients are diabetic. Steroid therapy used to combat rejection also has been implicated as a risk factor for atherosclerosis, diabetes, and hypertension. Cyclosporine A can produce large increases in blood cholesterol levels (58) and appears to be a major contributor to the hyper- cholesterolemia frequently seen in post- transplant patients. Cyclosporine A also is often associated with hypertension. The incidence of hypertension is higher for recipients of cardiac transplants than for recipients of renal transplants (59). In the former group, the frequency of cyclosporine- associated hypertension approaches 100 percent (60). In the management of cyclosporine-associ- ated hypertension, multidrug regimens are often necessary. Cyclosporine can induce hyperkalemia and hypomagnesemia, and the possibility that these electrolyte abnormali- ties could be aggravated by ACE inhibitors, potassium-sparing diuretics (hyperkalemia), or thiazide diuretics (hypomagnesemia) should be a concern. The pharmacologic treatment of hyperlipid- emia in patients receiving cyclosporine following either renal or cardiac transplan- tation is complicated by the interaction between cyclosporine and lovastatin. Approximately 30 percent of patients receiv- ing lovastatin plus cyclosporine have developed myositis, with several patients having severe rhabdomyolysis and acute renal failure (61). The Patient With Coronary Heart Disease There is now clear evidence that aggressive cholesterol-lowering therapy can slow the progression of coronary atherosclerosis and induce atherosclerotic plaque regression. Reduced progression and/or regression of coronary atherosclerotic lesions have been demonstrated by repeat coronary angio- graphy studies in patients treated with a combination of diet plus resin and nicotinic acid (62,63) or lovastatin (63). There is also evidence that cholesterol-lowering therapy is effective for the secondary prevention of clinical CHD (19), as well as for primary prevention in persons without previously demonstrated CHD (31,40). In the Coronary Drug Project, the nicotinic-acid-treated group of heart attack survivors experienced fewer recurrent heart attacks than did the placebo group (19). In summary, both hypertension and elevated LDL-cholesterol levels should be treated aggressively in patients with CHD. Beta- blockers, despite their adverse effects on serum triglycerides and HDL-cholesterol, remain particularly useful for treatment of the hypertension because of their antianginal effect and their demonstrated action in the secondary prevention of myocardial infarc- tion. Calcium antagonists are also of value in such patients because of their antianginal action. Thiazide diuretics as initial therapy require caution in some patients in view of their adverse effects and their tendency to induce hypokalemia and secondary arrhythmias. '' Peripheral Arterial and/or Cerebrovascular Disease Peripheral or carotid arterial occlusive disease requires particular attention. With- out treatment, about one-third of patients presenting with intermittent claudication would be expected to die within the succeed- ing 5 years, primarily from associated CHD or stroke (64). Such patients usually have generalized arterial occlusive disease affecting blood supply to many organ systems. Therefore, the patient with symp- tomatic or asymptomatic disease of the peripheral arteries urgently needs treatment to reduce risk factors. Over 90 percent are current or former smokers; about 20 percent have NIDDM; about 30 percent have plasma lipid elevations; and about 40 percent are hypertensive (65). Each of these disorders requires attention, especially smoking, to prevent further progression of atherosclero- sis and fatal ischemic events. In management of these patients, several important side effects of drug treatment are pertinent. The use of beta-blockers to treat hypertension or arrhythmias may precipitate or aggravate intermittent claudication. In patients on warfarin anticoagulation ther- apy, the addition of lipid-lowering agents such as fibric acid derivatives or lovastatin necessitates more careful monitoring, rescheduling the time the drug is given, as well as occasional downward adjustment of the warfarin dosage. Hypertension is the major risk factor for both thrombotic and hemorrhagic stroke. The risk of stroke is related to the blood pressure level with a higher correlation for systolic than diastolic pressure. The risk is further escalated when hypertension is accompanied by hyperlipidemia, smoking, heavy alcohol intake, CHD, congestive heart failure, or diabetes mellitus. A history of prior cerebrovascular disease does not contraindicate treatment of hyper- tension except perhaps in the early period following an acute ischemic cerebral infarc- tion. In such cases, antihypertensive drug therapy may have to be withheld temporar- ily to avoid critical reduction in cerebral perfusion, unless the diastolic blood pres- sure is very high (i.e., greater than 105 mm Hg). Thereafter, the goal of therapy is to normalize blood pressure gradually and to avoid orthostatic hypotension. Elevated LDL-cholesterol also should be treated intensively in the patient with prior stroke, according to the ATP report. Carotid arterial disease is associated with an in- creased risk of CHD as well as of stroke (66). The presence of an asymptomatic carotid bruit doubles the risk of stroke or transient ischemic attacks, myocardial infarction, and all-cause mortality. The development of a carotid bruit is more likely in diabetic and hypertensive persons. It is a general marker for advanced atherosclerotic disease involv- ing all systemic arteries and affects the goal for LDL-cholesterol lowering to help reduce progression of vascular disease. Hormone-Treated Patients Exogenous hormones are currently being prescribed in the United States for more than 16 million women, either as oral contracep- tives or as postmenopausal replacement therapy. There is a growing body of evi- dence that these therapies affect coronary risk factors, including plasma lipids and blood pressure. Estrogens generally have a favorable effect on the lipoprotein profile, and progestins an adverse effect (67). Although neither type may significantly change total blood cholesterol, they may cause reciprocal changes in plasma lipopro- tein levels. Estrogen can increase HDL- cholesterol and decrease LDL-cholesterol levels. The opposite generally is true for certain progestins. The adverse effect of progestins on lipoprotein levels, however, — 19 - '' 20 appears to depend on both the dose and androgenic activity of a particular compound; those progestins with the greatest degree of androgenicity such as the 19-nortestosterone derivatives are most likely to adversely alter lipids (68,69). Progestins derived from newer 19-nortestosterone derivatives now being developed may not have such adverse effects (70). Although substantial elevations of both systolic and diastolic blood pressure can occur in certain oral contraceptives users, the incidence of such changes is usually rela- tively low (71,72). The lower doses of hormones in the newer oral contraceptives and in postmenopausal hormone replace- ment regimens appear to cause less hyper- tension. Smokers who use oral contracep- tives have a marked increase in incidence of coronary heart disease compared with nonsmokers on these drugs (73). On the other hand, postmenopausal hormone replacement therapy with unop- posed estrogen offers protection against ischemic heart disease (74). However, data on estrogen type, dose, and duration of use in relation to CHD are scarce. Moreover, the effect on CHD of adding a progestin to the replacement regimen, which is current practice in women with intact uteri, is unknown. In evaluating the value of exogenous hormones, the risk of reproductive cancers must be considered. Unopposed estrogen treatment of postmenopausal women promotes endometrial cancer, and the risk increases with cumulative dose and duration of use. Addition of a cyclic progestin reduces the risk of endometrial neoplasia (75). The association between estrogens, progestins, and breast cancer is less certain. While some studies have shown an associa- tion (either positive or negative) between estrogen use and breast cancer, others have not (76). On balance, the cardiovascular and other benefits of estrogen such as improving quality of life and reducing osteoporosis generally appear to outweigh the risks. Nevertheless, since progestins are commonly added to reduce endometrial cancer risk, further investigation of the estrogen/ progestin combination regimen in the postmenopausal state is important. Age Considerations Hypertension Ample evidence supports the concept that the roots of essential hypertension extend back to childhood. Prospective cohort data that could yield precise information about the relationship between childhood blood pressure and cardiovascular risk are not yet available. Nonetheless, high blood pressure in children represents a significant clinical problem even though its estimated preva- lence is under 3 percent (77). Isolated systolic hypertension, as well as diastolic hypertension, are associated with increased morbidity and mortality in people over age 65. According to data from the 1976-1980 NHANES II, the combined prevalence of these types of hypertension (2140 systolic and/or 90 mm Hg diastolic blood pressure) is estimated to be 64 percent in persons ages 65-74 years, with a higher prevalence in blacks (76 percent) than in whites (63 percent). The benefits of treating diastolic hyperten- sion in the elderly are unequivocal, and the goal of treatment is similar to the goal for younger patients: to reduce diastolic pressure to below 90 mm Hg (78). Nonphar- macologic therapy should be tried first in the elderly as well as in the young. An appro- priate health professional should provide education and counseling to ensure that any restricted diet is nutritionally adequate for '' elderly patients, who may already have marginal diets. Drug treatment in this group should follow the guidelines summarized previously (78). Proof of the benefit of drug treatment of isolated systolic hypertension (systolic blood pressure 2160 mm Hg, diastolic blood pressure <90 mm Hg) on cardiovascular and total mortality in the elderly must await completion of the Systolic Hypertension in the Elderly Program, a double-blind, placebo-controlled trial sponsored by the National Heart, Lung, and Blood Institute, and the National Institute on Aging, Bethesda, Maryland. High Blood Cholesterol Evidence exists that atherosclerosis often begins in childhood (79,80), and that, in general, children with relatively high cholesterol levels are likely to have elevated levels as adults (14). Sempos et al. (4) estimate that almost 60 percent of adults ages 60-74 have serum LDL-cholesterol levels high enough to warrant medical attention. Total serum cholesterol as well as LDL- and HDL- cholesterol levels have predictive power for CHD in the elderly. The strength of the association between serum cholesterol level and the risk of CHD (i.e., the relative risk of CHD related to cholesterol) declines with age (81); nevertheless, because of the high absolute rates of CHD in the elderly, the total attributable risk associated with cholesterol does not decline with age (82,83). Clinical trial data are not yet available regarding the effects of cholesterol lowering on CHD risk reduction in the elderly. Dietary therapy using the step-one diet should be the primary approach for treating most elderly patients with elevated LDL- cholesterol. Overly restrictive diets should be avoided because inadequate intakes of calories and protein can be a major problem in this age group. Cost Considerations Clinical manifestations and death from cardiovascular diseases constitute a huge economic burden on society, costing the United States an estimated $127 billion in 1986 (1). This includes $62 billion in direct costs and $65 billion in lost productivity and other indirect costs. A large proportion of these costs is for hospitalization and man- agement of coronary heart disease and stroke. Ambulatory management of risk factors costs considerably less. Controlling or reducing CVD risk factors to prevent cardiovascular diseases reduces hospitaliza- tions as well as morbidity and mortality. The management of hypertension costs one- fourth as much or less per year as the management of the complications of CHD and stroke (84). Therefore, there is an economic as well as a medical rationale for the treatment of risk factors. Within the last decade, it has become increasingly clear that for some patients, cost may be a barrier to effective treatment (85). In an effort to reduce barriers to effective care, clinicians should be aware of the total cost to patients and should try to minimize expenses. The components of cost to patients include: 21 '' 22 e Indirect costs. These include such considerations as the patient’s transporta- tion costs to and from the office, and lost time from work. Initial workup costs. The cost of followup. Frequent visits generate greater costs but may enhance adherence to therapy and risk factor control, thereby reducing cardiovascular sequelae. Tactics that may reduce this component of cost include monitoring blood pressure at home or relying on other community resources and non- physician staff for monitoring. The selection and complexity of the medical regimen. These factors affect cost by influencing the impact on adher- ence rates, the burden of side effects, the laboratory tests required to monitor biochemical changes, the amount of time needed to adjust medication due to side effects, and additional treatment needed to counter side effects that are not avoided. ¢ Cost of treatment. Physicians should recognize that some drugs may be priced too high for certain patients, thus dimin- ishing their benefits by reducing adher- ence. In addition, some drugs that reduce the quality of life, regardless of cost, may reduce the overall benefit of treatment. And while nonpharmacologic therapies can be effective, the cost of lifestyle changes and the effectiveness of such approaches should also be considered fully. '' Developing Educational Messages for Patients The components of educational messages depend on individual patient characteristics, risk factor status, response and adherence to recommended treatment steps, and patient progress over time. Chances for successful management of both hypertension and high blood cholesterol are increased by: e Providing the patient with complete and relevant information. It may be helpful to establish the treatment plan by discuss- ing with the patient the desired changes and goals and developing the necessary steps required to reach the goal. The clinician and the patient should agree on the treatment plan, taking into considera- tion what is feasible for the patient. The written plan should be given to the patient and placed in the medical record. The patient may be given educational material to supplement the plan or be counseled by someone else on the health team. The treatment plan should serve as the basis for all educational counseling regardless of who provides it. e Simplifying the regimen when possible. e¢ Adopting office procedures that rein- force desired behaviors. Smoking should not be allowed in office waiting rooms. It is helpful to reinforce the education goals at each visit so that the patient realizes these are important. e Including a family member in the treat- ment plan. In some situations, meals are prepared by another family member who may not be aware of the need for, or understand how to cook, low-salt and/or low-fat meals. Also, it is more difficult to quit smoking if a spouse continues to smoke. ¢ Recognizing failures in changing behav- iors but giving them minimal emphasis while praising successes. Most patients greatly respect physicians’ opinions and will respond positively to the guidance provided to them. Each behavior represents a multitude of small, simple actions and choices, made by the individual in daily living situations, over and over again. Since lifestyle patterns are complex, behavioral changes made gradu- ally over time are more likely to be main- tained. Thus, treatment plans should be individualized, prioritized, and introduced gradually. Although it may be tempting to encourage behavioral change in every area, few individuals can immediately make and sustain many complex and simultaneous changes. The Physicians Guide: Improving Adherence Among Hypertensive Patients (86) and the ATP report (6) provide valuable guidance in this area.* Multiple Risk Factor Intervention Relationships Although there are many benefits to treating both hypertension and high blood choles- terol, some aspects of dual treatment may hinder progress or result in adverse out- comes if not anticipated and dealt with appropriately. For example, a patient may be adhering well to recommended dietary principles and reducing blood cholesterol but not reducing blood pressure. If placed on an antihyper- tensive drug that adversely influences blood * Available from the NHLBI Information Center. '' lipid levels, treatment of hypertension could interfere with dietary treatment for elevated blood cholesterol. The selection of drug therapy would be an important issue in this situation. All patients who smoke should be encour- aged to quit. Continuing smokers do not adhere as well to lifestyle intervention recommendations as individuals who have successfully quit smoking or those who have never smoked. Yet smoking cessation is associated with weight gain; this is thought to be due to metabolic as well as behavioral consequences of cessation (87). Such weight gain can aggravate elevations in blood pressure and blood lipid levels, thereby disrupting treatment efforts. Weight gain associated with smoking cessation is a serious barrier to the long-term elimination of smoking. Therefore, physi- cians must provide information on weight control and smoking cessation at the same time. Information on calorie content of foods and caloric expenditure associated with various forms of low-level physical activity (e.g., walking) may be helpful. Monitoring the patient’s weight during followup appointments is critical to initiate strategies directed at preventing serious weight gain. Physicians should not accept fear of weight gain as an excuse to continue smoking. For the majority of patients, smoking cessation reduces risk even if it is followed by weight gain. Generally, weight gains are less than patients anticipate, and some individuals do not gain weight after they stop smoking. Guidelines are available to assist physicians in developing approaches to effective smoking cessation. These include The Physician's Guide: How to Help Your Hyper- tensive Patient Stop Smoking (88) and Clinical Opportunities for Smoking Intervention: A Guide for the Busy Physician (89).* The dietary specifications discussed in table III under nonpharmacologic therapies are also appropriate for patients with abnormal glucose tolerance or frank diabetes mellitus (46). The treatment of multiple risk factors requires an integrated and comprehensive treatment plan. Physicians must carefully consider such plans, taking into account potentially adverse treatment interactions. Effective treatment of all risk factors in patients with multiple risks has great potential for the prevention and reduction of cardiovascular disease. * Available from the NHLBI Information Center. '' References 1. National Heart, Lung, and Blood Insti- Ts tute. National Heart, Lung, and Blood Institute Fact Book Fiscal Year 1988. Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, October 1988. 8. 2. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26-year follow-up of the Framingham popula- 9. tion. Am Heart J 1986;111:383-90. 3. Subcommittee on Definition and Prevalence of the 1984 Joint National Committee. Hypertension prevalence and the status of awareness, treatment, and control in the United States: final report of the Subcommittee on Defini- tion and Prevalence of the 1984 Joint 10. National Committee. Hypertension 1985;7:457-68. 4. Sempos C, Fulwood R, Haines C, et al. The prevalence of high blood choles- terol levels among adults in the United 11. States. JAMA 1989;262:45-52. 5. 1988 Joint National Committee. The 1988 Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1988;148:1023-38. 12. 6. The Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High 13. Blood Cholesterol in Adults. Arch Intern Med 1988;148:36-69. Grundy SM, Goodman DS, Rifkind BM, Cleeman JI. The place of HDL in cholesterol management. A perspec- tive from the National Cholesterol Education Program. Arch Intern Med 1989;149:505-10. Stamler J, Neaton JD, Wentworth DN. Blood pressure (systolic and diastolic) and risk of fatal coronary heart disease. Hypertension 1989;13(Suppl 1):12-112. Stamler J, Wentworth D, Neaton JD. Is the relationship between serum choles- terol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986;256:2823-8. Abbott RD, Donahue RP, Kannel WB, Wilson PWF. The impact of diabetes on survival following myocardial infarction in men vs women. JAMA 1988;260:3456-60. Kannel WB, Neaton JD, Wentworth D, et al. Overall and coronary heart disease mortality rates in relation to major risk factors in 325,348 men screened for the MRFIT. Am Heart J 1986;112:825-36. Ferrannini E, Buzzigoli G, Bonadonna R, et al. Insulin resistance in essential hypertension. N Engl J Med 1987; 317:350-7. Williams RR, Hunt SC, Hopkins PN, et al. Familial dyslipidemic hyperten- sion. Evidence from 58 Utah families for a syndrome present in approxi- mately 12% of patients with essential hypertension. JAMA 1988;259:3579-86. '' 26 14. 15. 16. 17. 18. 19. 20. 21. 22. National Research Council. Diet and Health: Implications for Reducing Chronic Disease Risk. Washington, DC: Na- tional Academy Press, 1989. Robertson WB, Strong JP. Athero- sclerosis in persons with hypertension and diabetes mellitus. Lab Invest 1968;18:538-51. Chobanian AV. The influence of hypertension and other hemodynamic factors in atherogenesis. Prog Cardio- vasc Dis 1983;26:177-96. Chobanian AV, Lichtenstein AH, Nilakhe V, Haudenschild CC, Drago R, Nickerson C. Influence of hypertension on aortic atherosclerosis in the Watanabe rabbit. Hypertension 1989;14:203-9. Yusuf S, Wittes J, Friedman L. Over- view of results of randomized clinical trials in heart disease. II. Unstable angina, heart failure, primary preven- tion with aspirin, and risk factor modification. JAMA 1988;260:2259-63. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245-55. MacMahon SW, Cutler JA, Furberg CD, Payne GH. The effects of drug treat- ment for hypertension on morbidity and mortality from cardiovascular disease: a review of randomized controlled trials. Prog Cardiovasc Dis 1986;XXIX(Suppl 1):99-118. Hypertension Detection and Follow-up Program Cooperative Group. Persis- tence of reduction in blood pressure and mortality of participants in the Hypertension Detection and Follow-up Program. JAMA 1988;259:2113-22. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J 1985;291:97-104. 23. 24. 25. 26. 273 28. 29. 30. Gillum RF. The association of body fat distribution with hypertension, hypertensive heart disease, coronary heart disease, diabetes and cardiovas- cular risk factors in men and women aged 18-79 years. J Chron Dis 1987;40:421-8. Kannel WB, Brand N, Skinner JJ Jr, Dawber TR, McNamara PM. The relation of adiposity to blood pressure and development of hypertension. The Framingham Study. Ann Intern Med 1967 ;67:48-59. Reisin E, Frohlich ED, Messerli FH, et al. Cardiovascular changes after weight reduction in obesity hyperten- sion. Ann Intern Med 1983;98:315-9. Nonpharmacological approaches to the control of high blood pressure: final report of the Subcommittee on Non- pharmacological Therapy of the 1984 Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 1986;8:444-67. Wood PD, Stefanick ML, Dreon DM, et al. Changes in plasma lipids and lipo- proteins in overweight men during weight loss through dieting as com- pared with exercise. N Engl J Med 1988;319:1173-9. Klatsky AL. The relations of alcohol and the cardiovascular system. Ann Rev Nutr 1982;2:51-71. Lardinois CK, Neuman SL. The effects of antihypertensive agents on serum lipids and lipoproteins. Arch Intern Med 1988;148:1280-8. Glueck CJ, Gordon DJ, Nelson JJ, Davis CE, and Tyroler HA. Dietary and other correlates of changes in total and low density lipoprotein cholesterol in hypercholesterolemic men: the Lipid Research Clinics Coronary Primary Prevention Trial. Am J Clin Nutr 1986;44:489-500. '' 31. 32. 33. 34. 35. 36. 37. 38. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251:365-74. Ames RP, Hill P. Elevation of serum lipid levels during diuretic therapy of hypertension. Am J] Med 1976;61:748- 56. Grimm RH Jr, Leon AS, Hunninghake DB, Lenz K, Hannan P, Blackburn H. Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive patients. A double-blind controlled trial. Ann Intern Med 1981;94:7-11. Veterans Administration Cooperative Study Group on Antihypertensive Agents. Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. II. Results of long-term therapy. JAMA 1982;248:2004-11. Berglund G, Andersson O. Beta- blockers or diuretics in hypertension? A six-year follow-up of blood pressure and metabolic side effects. Lancet 1981;1:744-7. Goldman AI, Steele BW, Schnaper HW, Fitz AE, Frohlich ED, Perry HM Jr. Serum lipoprotein levels during chlorthalidone therapy. A Veterans Administration—National Heart, Lung, and Blood Institute cooperative study on antihypertensive therapy: mild hypertension. JAMA 1980;244:1691-5. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-64. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360-81. 39. 40. 41. 42. 43. 44. 45. 46. 47. Tobert JA. Efficacy and long-term adverse effect pattern of lovastatin. Am J Cardiol 1988;62:28]-34J. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: Primary- Prevention Trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237-45. Committee of Principal Investigators. A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Br Heart J 1978;40:1069-1118. Margolis JR, Kannel WB, Feinleib M, Dawber TR, McNamara PM. Clinical features of unrecognized myocardial infarction—silent and symptomatic. Eighteen year follow-up: the Framing- ham study. Am J Cardiol 1973;32:1-7. Reaven GM, Hoffman BB. A role for insulin in the aetiology and course of hypertension? Lancet 1987;2:435-6. Schonfeld G, Birge C, Miller JP, Kessler G, Santiago J. Apolipoprotein B levels and altered lipoprotein composition in diabetes. Diabetes 1974;23:827-34. Pollare T, Lithell H, Berne C. A com- parison of the effects of hydrochlo- rothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl ] Med 1989;321:868-73. Working Group on Hypertension in Diabetes, National High Blood Pres- sure Education Program. Statement on hypertension in diabetes mellitus: final report. Arch Int Med 1987;147:830-42. Mallick NP, Short CD. The nephrotic syndrome and ischaemic heart disease. Nephron 1981;27:54-7. 27 '' = 28 48. 49. 50. 51. 52. O35 54. 95. 56. 57. Alexander JH, Schapel GJ, Edwards 58. KD. Increased incidence of coronary heart disease associated with combined elevation of serum triglyceride and cholesterol concentrations in the 59 nephrotic syndrome in man. Med J Aust 1974;2:119-22. Berlyne GM, Mallick NP. Ischaemic 60. heart disease as a complication of nephrotic syndrome. Lancet 1969;2:399- 400. Grundy SM. Management of hyper- 61. lipidemia of kidney disease. Kidney Int 1990;37:847-53. Nestel PJ, Fidge NH, Tan MH. In- 62. creased lipoprotein-remnant formation in chronic renal failure. N Engl J] Med 1982;307:329-33. Lazarus JM, Lowrie EG, Hampers CL, Merrill JP. Cardiovascular disease in uremic patients on hemodialysis. Kidney Int Suppl 1975;(2):167-175. 63. Wing AJ, Brunner FP, Brynger H, et al. Combined report on regular dialysis and transplantation in Europe, VIII, 1977. Proc Eur Dial Transplant Assoc 1978;15:2-76. Ibels LS, Stewart JH, Mahony JF, Sheil AG. Deaths from occlusive arterial 64. disease in renal allograft recipients. Br Med J 1974;3:552-4. Parving HH, Andersen AR, Smidt UM, Svendsen PA. Early aggressive anti- hypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet 1983;1:1175-9. Cressman MD, Hoff HF, O’Neil J, Heyka RJ, Paganini EP, Koch JM. Incidence of dyslipoproteinemias during chronic hemodialysis [Ab- stract]. Clinical Res 1988;36:540A. Kasiske BL. Risk factors for accelerated atherosclerosis in renal transplant recipients. Am J Med 1988;84:985-92. 65. Ballantyne CM, Podet EJ, Patsch WP, et al. Effects of cyclosporine therapy on plasma lipoprotein levels. JAMA 1989;262:53-6. Porter GA, Bennett WM, Sheps SG. Cyclosporine-associated hypertension. Arch Intern Med 1990;150:280-3. Weidle PJ, Vlasses PH. Systemic hypertension associated with cyclo- sporine: a review. Drug Intell Clin Pharm 1988;22:443-51. Corpier CL, Jones PH, Suki WN, et al. Rhabdomyolysis and renal injury with lovastatin use. JAMA 1988;260:239-41. Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, Cashin- Hemphill L. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA 1987;257:3233-40. Brown BG, Lin JT, Schaefer SM, Kaplan CA, Dodge HT, Albers JJ. Niacin or lovastatin, combined with colestipol, regress coronary atherosclerosis and prevent clinical events in men with elevated apolipoprotein B [Abstract]. Circulation 1989;80(SuppIl II):II-266. Kannel WB, Wolf PA, Garrison RJ, eds. The Framingham Study: An Epidemio- logical Investigation of Cardiovascular Disease. Section 35. Survival Following Initial Cardiovascular Events: 30-Year Follow-up. Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, May 1988. Criqui MH, Browner D, Fronek A, et al. Peripheral arterial disease in large vessels is epidemiologically distinct from small vessel disease: an analysis of risk factors. Am J Epidemiol 1989;129:1110-9. '' 66. 67. 68. 69. 70. 71. 72. 73. 74. Wolf PA, Kannel WB, Sorlie P, Mc- Namara P. Asymptomatic carotid bruit and risk of stroke: The Framing- ham Study. JAMA 1981;245:1442-5. Lobo RA. Absorption and metabolic effects of different types of estrogens and progestogens. Obstet Gynecol Clin North Am 1987;14:143-67. Lipson A, Stoy DB, LaRosa JC, et al. Progestins and oral contraceptive- induced lipoprotein changes: a prospective study. Contraception 1986;34:121-34. Burkman RT, Robinson JC, Kruszon- Moran D, Kimball AW, Kwiterovich P, Burford, RG. Lipid and lipoprotein changes associated with oral contra- ceptive use: a randomized clinical trial. Obstet Gynecol 1988;71:33-8. Gaspard UJ, Buret J, Gillain D, Romus MA, Lambotte R. Serum lipid and lipoprotein changes induced by new oral contraceptives containing ethinyl estradiol plus levonorgestrel or desogestrel. Contraception 1985;31:395- 408. Stadel BV. Oral contraceptives and cardiovascular disease. N Engl ] Med 1981;30-5:612-8. Mandel FP, Geola FL, Lu JK, et al. Biologic effects of various doses of ethinyl estradiol in postmenopausal women. Obstet Gynecol 1982;59:673-9. Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N Engl J Med 1981;305:420-4. Bush TL, Barrett-Connor E, Cowan LD, et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Re- search Clinics Program Follow-up Study. Circulation 1987;75:1102-9. 75. 76. 77. 78. 79. 80. 81. 82. 83. Whitehead MI, Townsend PT, Pryse- Davies J, et al. Effects of various types and dosages of progestogens on the postmenopausal endometrium. J Reprod Med 1982;27(Suppl 8):539-48. Bergkvist L, Hans-Olov A, Persson I, Hoover R, Schairer C. The risk of breast cancer after estrogen and estrogen-progestin replacement. N Engl J Med 1989;321:293-7. Task Force on Blood Pressure Control in Children. Report of the Second Task Force on Blood Pressure Control in Children—1987. Pediatrics 1987;79:1-25. Working Group on Hypertension in the Elderly, National High Blood Pressure Education Program. State- ment on hypertension in the elderly. JAMA 1986;256:70-4. Newman WP III, Freedman DS, Voors AW, et al. Relation of serum lipopro- tein levels and systolic blood pressure to early atherosclerosis. N Engl J] Med 1986;314:138-44. Freedman DS, Newman WP III, Tracy RE, et al. Black-white differences in aortic fatty streaks in adolescence and early adulthood: the Bogalusa Heart Study. Circulation 1988;77:856-64. Pooling Project Research Group. Rela- tionship of blood pressure, serum cho- lesterol, smoking habit, relative weight, and ECG abnormalities to incidence of major coronary events: final report of the Pooling Project. J Chronic Dis 1978;31:201-306. Benfante R, Reed D. Is elevated serum cholesterol level a risk factor for coronary heart disease in the elderly? JAMA 1990;263:393-6. Harris T, Cook EF, Kannel WB, Goldman L. Proportional hazards analysis of risk factors for coronary heart disease in individuals aged 65 or older. The Framingham Heart Study. J Am Geriatr Soc 1988;36:1023-8. — 29 '' 84. 85. 86. Harlan WR, Parsons PE, Thomas JW, 87. etal. Health care utilization and costs of adult cardiovascular conditions, United States, 1980. National Medical 88. Care Utilization and Expenditure Survey. Series C, Analytical Report No. 7. Hyattsville, MD: U.S. Depart- ment of Health and Human Services, Public Health Service, National Center for Health Statistics, 1989. National Heart, Lung, and Blood Institute. Diagnosis and Management of Hypertension-1987: A Nationwide Survey of Physicians’ Knowledge, Atti- tudes, and Reported Behavior. Bethesda, 89. MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Septem- ber 1989. Working Group on Health Education and High Blood Pressure Control. The Physician's Guide: Improving Adherence Among Hypertensive Patients. Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, National High Blood Pressure Educa- tion Program, 1987. Rigotti NA. Cigarette smoking and body weight. N Engl J Med 1989;320:931-3. Working Group on Physician Behav- iors to Reduce Smoking Among Hypertensive Patients. The Physician's Guide: How to Help Your Hypertensive Patients Stop Smoking. Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, National High Blood Pressure Educa- tion Program, 1984. National Heart, Lung, and Blood Institute. Clinical Opportunities for Smoking Intervention: A Guide for the Busy Physician. Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health. August 1986. *U.S. GOVERNMENT PRINTING OFFICE : 1990 814-20840/275-780 ''''1S ''FE 18 19 ©0307 4yyq5 Discrimination Prohibited: Under provisions of applicable public laws enacted by Congress since 1964, no person in the United States shall, on the grounds of race, color, national origin, handicap, or age, be excluded from participation in, be denied the benefits of, or be subjected to discrimination under any program or activity (or, on the basis of sex, with respect to any education program or activity) receiving Federal financial assistance. In addition, Executive Order 11141 prohibits discrimination on the basis of age by contractors and subcontractors in the performance of Federal contracts, and Executive Order 11246 states that no federally funded contractor may discriminate against any employee or applicant for employment because of race, color, religion, sex, or national origin. Therefore, the NATIONAL HEART, LUNG, AND BLOOD INSTITUTE must be operated in compliance with these laws and Executive Orders. ''NIH Publication No. 90-2361 August 1990 ''