<35 35 \200\22344 45 \200\22349 50 \200\22354 >60 <0.90 0.91 \200\2231.16 1.17 \200\2231.29 1.30 \200\2231.55 >1.56 2 1 0 0 \200\2231 Systolic blood pressure, mmHg <120 120 \200\223129 130 \200\223139 140 \200\223159 (cid:116 )160 Coronary heart disease (CHD) risk Diastolic <80 mmHg 0 0 1 2 3 Diastolic 80 \200\22384 mmHg 0 0 1 2 3 Diastolic 85 \200\22389 mmHg 1 1 1 2 3 Diastolic 90 \200\22399 mmHg 2 2 2 2 3 Diastolic \211 100 mmHg 3 3 3 3 3 Total points 10-year CHD risk (%) Total points 10-year CHD risk (%) < \200\2233 \200\2232 \200\2231 0 1 2 3 4 5 1 2 2 3 4 5 6 7 9 6 7 8 9 10 11 12 13 14 11 14 18 22 27 33 40 47 56 Use to calculate the risk of developing clinical coronary heart disease (CHD) in men who do not have known CHD. To calculate the Framingham risk estimate, add points for age, presenc e of diabetes, smoking status, LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and blood pressure. Find the total point score on the bottom table to determine the 10-year risk of C HD. Reprinted with permission from Wilson PW, et al. (1998). Prediction of coronary heart d isease using risk factor categories. Circulation 97:1837 \200\2231847. CHAPTER 6 Preventive cardiology 254 Table 6.2 Framingham risk scoring system for women Age Diabetes Years Points Points 30 \200\22334 35 \200\22339 40 \200\22344 45 \200\22349 50 \200\22354 55 \200\22359 60 \200 \22364 65 \200\22369 70 \200\22374 \200\2239 \200\2234 0 3 6 7 8 8 8 No Yes 0 4 Smoker Points 0 2 No Yes LDL-C HDL-C mg/dL mmol/L Points mg/dL mmol/L Points <100 100 \200\223129 130 \200\223159 160 \200\223190 >190 <2.59 2.60 \200\2233.36 3.37 \200\2234.14 4.50 \200\2234.92 >4.92 \200\2232 0 0 2 2 <35 35 \200\22344 45 \200\22349 50 \200\22354 >60 <0.90 0.91 \200\2231.16 1.17 \200\2231.29 1.30 \200\2231.55 >1.56 5 2 1 0 \200\2232 Systolic blood pressure, mmHg Diastolic <80 mmHg Diastolic 80 \200\22384 mmHg Diastolic 85 \200\22389 mmHg Diastolic 90 \200\22399 mmHg Diastolic \211 100 mmHg \200\2233 <120 0 120 \200\223129 0 130 \200\223139 2 140 \200\223159 3 (cid:116)160 Corona ry heart disease (CHD) risk 0 0 0 2 3 0 0 0 2 3 2 2 2 2 3 3 3 3 3 3 Total points 10-year CHD risk (%) Total points 10-year CHD risk (%) < \200\2232 \200\2231 0 1 2 3 4 5 6 7 1 2 2 2 3 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 8 9 11 13 15 17 20 24 27 32 Use to calculate the risk of developing clinical coronary heart disease (CHD) in men who do not have known CHD. To calculate the Framingham risk estimate, add points for age, presenc e of diabetes, smoking status, LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and blood pressure. Find the total point score on the bottom table to determine the 10-year risk of C HD. Reprinted with permission from Wilson PW, et al. (1998). Prediction of coronary heart d isease using risk factor categories. Circulation 97:1837 \200\2231847. ASSESSMENT OF ATHEROSCLEROTIC RISK 255 CAD risk equivalents Patients with atherosclerotic disease in other vascular territories, i ncluding peripheral arterial disease, abdominal aortic aneurysms, and carotid dis- ease, ar e at high risk (10-year risk >20%) and should be managed aggres- sively in terms of seconda ry prevention. Diabetic patients have a similar risk for cardiac events as those with established coronary disease and are therefore high risk (10-year risk >20%) as well. CHAPTER 6 Preventive cardiology 256 Risk factors for coronary artery disease Age The U.S. population is aging. In the United St ates, the proportion of the population aged (cid:116)65 years is projected to increase from 12.4% in 2000 to 19.6% in 2030. The number of persons aged (cid:116)65 years is expected t o increase from approximately 35 million in 2000 to an estimated 71 million in 2030, and th e number of persons aged (cid:116)80 years is expected to increase from 9.3 million in 2000 to 19.5 million in 2030. Aging is a major risk factor for atherosclerotic disease because of the degenerative proces s associated with aging and the cumulative impact of the worsening risk factor pro \201 le that develops with increasing age. For men, the reported prevalence increases with age, from 7% at ages 40 \200\22349 years to 13% at 50 \200\22359 years, 16% at 60 \200\22369 years, and 22% at 70 \200\22379 years. Th e corresponding estimates for women are substantially lower than for men: 5%, 8%, 11%, and 14%, respectively. Although about 45% of myocardial infarctions occur in people under 65 years of age, this co ndition is more likely to be fatal in older individuals, with 80% of deaths due to MI seen in those over 65. Gender, menopausal status, and hormone replacement therapy (HRT) CAD is more common and ten ds to occur at an earlier age in men than in women. The incidence of CHD in women increases rapidly at menopause and is similar to that seen in men in the population over 65. Althoug h less common, the disease remains the leading cause of death in women. For example, the ag e-adjusted mortality rates from heart disease are four to six times higher than their morta lity rates from breast cancer. Although cardiovascular risk factors promote disease in both genders, the strength of the a ssociation differs. For example, diabetes and low high- density lipoprotein (HDL) cholester ol are stronger risk factors for women than for men. Female sex hormones probably contribute to the lower risk of athero- sclerotic disease in p remenopausal women. Additionally, observational studies showed that the risk of ischemic he art disease is reduced by up to 40% in women using HRT. However, HRT users are typically he althier than nonusers, suggesting that these results could be explained by selec- tion bias . Several large, randomized, controlled trials of HRT in postmenopausal women (WHI, HERS/HERS II, ESPRIT, ERA) with and without atheroscle- rosis have suggested that HRT does not reduc e the risk of cardiovascular events and, in fact, leads to a small but statistically signi \201 cant increase in morbidity and mortality from cardiovascular disease. The age at entr y into these trials has recently brought the broad implications of these data into question . However, HRT should not be recommended for primary or secondary prevention of atherosclerotic disease in postmenopausal women. RISK FACTORS FOR CORONARY ARTERY DISEASE 257 Family history of atherosclerotic disease CAD is a multifactorial, polygenic disorder, caus ed by interactions among lifestyle, the environment, and the effects of variations in the g enetic sequence of a number of genes (see Table 6.3 and Box 6.1). The family history is con sidered signi \201 cant when atherosclerotic disease presents in a \201 rst-degree male relative before the age of 55, or before age 65 in a female relative. A positive family history is associated with a 75% increase in risk in men, and an 84% incr ease in women. The risk is even greater if both parents are affected. In the Physician \200\231s Health Study, compared to no parental history of an MI, a matern al history, a paternal history, and both maternal and paternal history were associated with a relative risk of cardiovascular disease of 1.71, 1.40, and 1.85 in men and 1.46, 1.15, a nd 2.05 in women. In the Framingham Offspring Study, cardiovascular disease in a sibling was associated with a signi \201 cant increase in cardiovascular disease risk with an adjusted odds ratio of 1 .45. Table 6.3 Risk factors for coronary heart disease Nonmodi \201 able risk factors \200 \200 \200 \200 Modi \201 able risk factors \200 \200 \200 \200 \200 \200 \200 \200 Age Male gender Family history Ethnic origin Smoking High blood pressure Dyslipidemia Diabetes mellitus Obesity and the metabolic syndro me Psychological stress High-calorie high-fat diet Physical inactivity Box 6.1 Emerging risk factors and disease markers \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 In \202 ammation, elevated C-reactive protein Fibrinogen, and other factors involved in th romboregulation Elevated homocysteine Chronic kidney disease, microalbuminuria Estrogen de \201 ciency Oxidative stress Endothelial dysfunction, decreased endothelial progenitor cel ls Asymmetric dimethylarginine Hyperuricemia Carotid \200\223intimal media thickness Collag en vascular disease Coronary artery calcium CHAPTER 6 Preventive cardiology 258 Ethnic origin A difference in cardiovascular disease prevalence among various ethnic groups is likely explained by clustering of risk factors in these groups, although a genetic comp onent may be contributing as well. Between 1970 and 2000, the rate of coronary disease decreased in whites while the rates act ually increased for blacks and Hispanics. Differences in the delivery of health care, as we ll as risk factors, among these groups may explain this trend. Smoking Smoking increases the risk of coronary disease by approximately 50%, with mortality from any cardiovascular disease around 60% higher in smokers (and 85% higher in heavy smok ers) than in nonsmokers (see Fig. 6.3). In 2004, approximately 21% of U.S. adults (23% of men, 19% of women) were current smokers. Although the number of smokers has declined sub- stantially over the past 50 years, this tr end has slowed in the adolescent population, where smoking prevalence has not declined sinc e 2002. The incidence of an MI is increased sixfold in women and threefold in men who smoke at least 20 cigarettes per day compared to subjects who never smoked. Second-hand smoke (s moke that has been exhaled by a smoker) also increases the risk of coronary disease by arou nd 25%. Smoking cessation carries almost immediate bene \201 t and the long-term bene \201 ts are greatest in those who stop smoking before the age of 40, such that the survival curve over laps with nonsmokers. Stopping smoking in middle age is also bene \201 cial. For example, in those aged 30 \200\22359 who stop smoking after an MI, the 5-year mortality is 10% compa red with 14% in those who continue to smoke. Doctors born 1900 \200\2231930 100 97 91 5 3 94 81 e g a m o r f 80 81 Non-smokers 58 59 60 l Cigarette smokers a v v r u s i 10 years 40 e g a t n e c r e P 24 26 20 2 4 90 100 Age (years) 0 70 80 40 50 60 Figure 6.3 Survival from age 35 for continuing cigarette smokers and lifelong nonsmokers am ong UK male doctors born 1900 \200\2231930, with percentages alive at each decade of age. A dapted with permission from Doll R, et al. (2004). BMJ 328(7455):1519. RISK FACTORS FOR CORONARY ARTERY DISEASE 259 Individuals with established atherosclerosis, as well as those at risk, should be advised t o stop smoking. Evidence shows that focused psycho- social support, nicotine replacement th erapy, and bupropion are quite effective in smoking cessation, with higher quit rates than those for no intervention. Obesity Obesity signi \201 cantly increases the risk of CAD, with 25% \200\22349% of cases in developed countries attributable to increased body mass index (BMI). Obesity is also as sociated with a number of other risk factors for athero- sclerosis, including hypertension, insulin resistance and glucose intoler- ance, hypertriglyceridemia, reduced HDL cholestero l, and low levels of adiponectin. Overweight is de \201 ned as a BMI between 25 and 30 kg/m2, and obesity as a BMI 30 kg/m2. Central obesity, in which excess fat is localized in the abdomen, can be identi \201 ed b y a high waist-to-hip ratio and confers a par- ticularly high relative risk if the waist ci rcumference is >40 inches in men and >35 inches in women. The prevalence of obesity is increasing rapidly worldwide. Compared to NHANES data from 198 8 to 1994, data from NHANES 1999 to 2000 dem- onstrates an increase in the prevalence of ov erweight and obese adults, from 55.9% to 64.5% for overweight and from 22.9% to 30.5% for o bese adults. Of particular concern is the dramatic increase in prevalence of obesity in children, a tren d that is likely to exacerbate the problem in adulthood and undo many of the other recent i mprovements in cardiovascular health. Overweight and obese individuals also tend to be less physically active and consume unhealt hy diets with excess calories, which further contrib- utes to their atherogenic risk. Dieta ry modi \201 cation and exercise are thus the \201 rst-line interventions in these indiv iduals, together with careful sur- veillance for and aggressive management of other risk fa ctors and compli- cations of obesity when present. Bariatric surgery may have a role in selected patients, especially if more conservative weight loss measures fail. Psychological stress The burden of risk attributable to psychological stress is dif \201 c ult to quan- tify. However, increased stress at work, lack of social support, hostile perso nality type, anxiety, and depression are consistently associated with increased risk of ath erosclerosis and acute coronary events. The link between psychological stress and atherosclerosis may be both direct, through endot helial damage, and indirect, via exacerbation of tradi- tional risk factors such as smoking and hypertension. In \202 ammation In \202 ammation is involved in the atherosclerotic process from plaque origi- nation and progression to acute rupture and thrombosis. This in \202 amma- tory pro cess directly links known risk factors to the underlying mechanism of disease. CHAPTER 6 Preventive cardiology 260 Large studies have shown that low-grade elevation of in \202 ammatory markers, most notabl y CRP, predicts outcomes from cardiovascular dis- ease and may add to the prognostic inform ation provided by traditional risk factors. It has been suggested that a CRP level below 1 mg/L is associ- ated with low risk, between 1 and 3 mg/L re \202 ects intermediate risk, a nd a level above 3 mg/L is associated with a high long-term risk of vascular events. Certain treatments that reduce atherosclerotic risk, particularly stat- ins, have anti-in \202 ammatory effects that may contribute to their clinical bene \201 ts. However, the inc remental value of CRP as a marker of risk and target of therapy in global risk management r emains a controversial topic that requires further investigation, such as the recently comp leted JUPITER trial, which demonstrated improved outcomes with rosuvastatin in patients wit h elevated CRP and normal lipids. Homocysteine The genetic disease homocystinuria is associated with aggressive, prema- ture atherosclerosis. Additionally, strong epidemiological and mechanis- tic evidence suggests t hat even modest increases in homocysteine levels promote atherosclerosis progression. Vascu lar in \202 ammation and oxidative stress appear to be the responsible mechanisms. Dietary supplementation with folic acid, alone or in combination with vitamins B6 and B12, can reduce levels of homocysteine and improve aspects of vascular biology in vivo as well a s in vitro. However, large randomized trials (VISP, WENBIT, NORVIT, HOPE-2) of vitamin supp lementation to lower homocysteine levels in patients with established cardiovascular dis- e ase have found no decrease in cardiovascular events or death. Therefore, folate B6/B12 s upplementation is not currently recommended for sec- ondary prevention in patients with car diovascular disease. Folate supplementation as primary prevention has yet to be examined in a large randomized trial so this use is also not currently recommended. Antioxidant vitamins Despite excellent epidemiological and mechanistic evidence that increa sed oxidative stress is associated with vascular injury, in \202 ammation and increased ri sk of cardiovascular morbidity and mortality, large randomized controlled trials (HOPE, HPS and GISSI-P) of vitamin A, C, and E supple- mentation have shown no effect on cardiovascul ar outcomes in primary or secondary prevention. Currently, antioxidant vitamin supplementation should not be routinely recommended for prevention of atherosclerotic disease. Dietary measures Several dietary measures can reduce the risk of developing cardiovascu- la r disease. Total fat intake should be reduced to below <30% of total calories. Intake of sa turated fat and foods high in trans fatty acids should be limited to <7% total calories and replaced with monounsaturated fat (canola and olive oil). Based on data from the Nurses \200\231 Health Study, the risk of coronary heart disease wou ld be reduced by 42% if 5% of energy from saturated fat were RISK FACTORS FOR CORONARY ARTERY DISEASE 261 replaced by energy from unsaturated fats, and by 53% if 2% of energy from trans fat was rep laced by energy from unhydrogenated, unsaturated fat. Recommended cholesterol intake is <200 mg/day. Dietary salt intake should be reduced and in take of fresh fruits and vegetables increased (5 portions per day). Fish consumption, espec ially oily \201 sh, should be encouraged, as evidence suggests that at least one \201 s h meal 2 \200\2233 times per week can reduce the incidence of heart attack and stroke. High \201 ber intake is also associated with a reduced risk of cardiovascular disease. Physical activity Observational studies have shown a strong inverse relationship between ex ercise and risk of coronary disease and death. The effect appears to be graded such that th e greater the degree of physical activity, the lower the risk of coronary events. This effe ct is mediated, at least in part by weight loss, a reduction in blood pressure, and improve ments in lipid pro \201 le (par- ticularly increased HDL). Regular, aerobic exercise of moderate intensity should be undertaken (cid:116)3 times per w eek for at least 30 minutes. Greater frequency and dura- tion of exercise is associated wit h increasing bene \201 ts, both in primary and secondary prevention. Alcohol Consumption of small to moderate amounts of alcohol (one or two drinks per day) is associated with a reduced risk of cardiovascular disease, whereas higher levels of alcohol intake, particularly in binges, are associ- ated with an increased risk of disease. The United States Dietary Guidelines recommend alcohol intake in moderation, if at all (one drink per day for women and up to two drinks per day for men). Any bene \201 t of moderat e alcohol consumption must be weighed against the potential risks. CHAPTER 6 Preventive cardiology 262 Hypertension De \201 nition and etiology There are approximately 60 million adults in the United States with high blood pressure. A continuous relationship exists between increasing blood pressure and cardiovascular risk; therefore it is impossible to de \201 ne hyperten sion precisely. Systolic blood pressure (BP) is at least as powerful a coronary risk factor as the diastoli c BP, and isolated systolic hypertension is now established as a major risk for coronary di sease and stroke. Both the duration and degree of hypertension are risk factors. For practical purposes, levels of blood pressure above which the risk increases signi \201 cantly and treatment can provide signi \201 cant bene \201 t are used as a working de \201 nition of hypertension (see Table 6.4). According to the Seventh Report of the Joint National Committee on Prevention, Detection, E valuation, and Treatment of High Blood Pressure (JNC-7), in persons older than 50 years, sy stolic BP >140 mmHg is a much more important cardiovascular disease risk factor than diasto lic BP. Also, the risk of disease increases beginning at 115/75 mmHg and doubles with each increment of 20/10 mmHg. The average of two readings at each of a number of visits should be used to de \201 ne a p atient \200\231s blood pressure. Blood pressure should also ideally be measured in both arm s. The majority of patients (>95%) have essential (primary) hypertension, in which an underlyi ng cause for the hypertension is not found. Others have secondary hypertension, in which a recognizable etiology is identi \201 ed (see Box 6.2). Symptoms and signs Hypertension is usually asymptomatic, although a patient will occasion- ally complain of headache. A history of cardiac or neurological symptoms should always be s ought. The cardiovascular system should be examined in detail and fundoscopy should be perf ormed to look for retinopathy (see Box 6.3). Clinical signs of an underlying cause (radiofemoral delay or weak femoral pulses, renal enl argement or bruit, or cushingoid features) and evidence of end-organ damage (heart failure, retinopathy, aortic aneurysm, carotid or femoral bruit) should be sought. Malignant hypertension is diagnosed when severe hypertension (SBP >200 DBP >130 mmHg) is identi \201 ed together with grade III \200\223IV retino- pathy. The patient may have a h eadache and occasionally visual distur- bance. Proteinuria and hematuria are often present. This is a medical emergency requiring immediate treatment to prevent rapid progression to renal failure, heart failure, and/or stroke. Investigation All patients presenting with hypertension should have an ECG, fasting glucose , lipid pro \201 le, blood urea nitrogen (BUN)/creatinine, and urinalysis for blood and pr otein. HYPERTENSION 263 If secondary hypertension is suspected, further investigation should focus on the possible underlying cause (e.g., urine cortisol, plasma renin- aldosterone levels, renal ultrasound, MRA of renal arteries, and 24-hour urinary catecholamines). Table 6.4 JNC-7 Blood pressure classi \201 cation Category SBP (mmHg) DBP (mmHg) Normal BP <120 AND <80 Pre-hypertension 120 \200\223139 OR 80 \200\22389 Stage 1 hypertension 140 \200\223159 OR 90 \200\22399 Stage 2 hypertension (cid:116)160 OR (cid:116)100 Box 6.2 Secondary hypertension (<5%) Renal disease \200 Diabetic nephropathy, renovascular disease, glomerulonephritis, vasculitis, chronic pyelone phritis, polycystic kidney disease Endocrine disease \200 Conn \200\231s and Cushing \200\231s syndromes, pheochromocytoma, acromegaly, hyperthyroidi sm, hyperparathyroidism Other \200 \200 \200 \200 \200 Aortic coarctation Pregnancy-induced hypertension and pre-eclampsia Obesity Excessive dieta ry salt or licorice intake Drugs (NSAIDs, sympathomimetics, illicit stimulants, oral contra ceptives) Obstructive sleep apnea Box 6.3 Grading of hypertensive retinopathy I. Tortuous arteries, with thickened bright walls ( \200\234silver wiring \200\235) II. Art eriovenous nicking (narrowing in a vein where crossed by an artery) III. Flame hemorrhages and cotton wool spots (small retinal bleeds and exudates) IV. Papilledema CHAPTER 6 Preventive cardiology 264 Treatment of high blood pressure When to treat The predicted decrease in mortality from the 5 to 6 mmHg average fall in diastolic blood pressure achieved in the multiple clinical tri als performed over the past 30 years is a 40% reduction in stroke mortality and a 25% reduc tion in coronary mortality. At any blood pressure, the cardiovascular risk is signi \201 c antly affected by the presence or absence of other risk fac- tors that need to be considere d when deciding when and how to treat. Patients with malignant hypertension or with persistent BP >140/90 mmHg after lifestyle mea sures should receive drug treatment. Subjects with BP >140/90 mmHg after lifestyle measures who have evidence of end-organ damage (LVH on ECG, proteinuria, or retinopathy) or a cal- culated 10-year risk of a cardiovascular event (cid:116)20% should also receive drug treatm ent. In patients with diabetes, chronic kidney disease, or known cardiovas- cular disease, antih ypertensive therapy is indicated when the systolic pres- sure is persistently above 130 mmH g and/or the diastolic pressure is above 80 mmHg. Blood pressure targets Most patients should have their blood pressure lowered to a target o f <140/85 mmHg. Patients with diabetes and chronic kidney disease have been shown to bene \201 t from more aggressive BP reduction (UKPDS and HOT studies) and a target of <130/80 mm Hg is more appropriate in this group. Lifestyle measures \200 \200 Minimize dietary salt intake (<2.4 g sodium/day). Limit alcohol consumption to 2 drinks/day for men and 1 drink/day for women. Regular aerobic exercise (at least 30 minutes, Achieve and maintain healthy BMI (20 \200\22325 kg/m Adopt DASH diet. Consume at least \201 ve po rtions/day of fresh fruit and Reduce dietary fat content, especially saturated and trans-fa tty acids. Stop smoking. \200 \200 \200 \200 \200 (cid:116)3 times/week). 2). vegetables. These measures should be followed in all individuals with hypertension, regardless of wheth er the decision has been made to implement drug therapy. Adopting and maintaining these lif estyle measures is often dif- \201 cult. Implementation is most successful in a multidisc iplinary professional setting when supported by clear written information including individ ual- ized strategies and goals. TREATMENT OF HIGH BLOOD PRESSURE 265 Choice of drug therapy Although recommendations for initiating medical therapy in essential hypertension have been proposed, there is no uniform agreement on which antihypertensive a gent should be used for initial treatment. A variety of different classes of drugs can be u sed in this setting, including thiazide diuretics, B-blockers (BB), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), and calcium channel blocke rs (CCB). Large meta-analyzes of blood pressure \200\223lowering trials have clearly shown that the d egree of blood pressure lowering is the best determinant of risk reduction. Comparative stu dies, such as ALL-HAT, have typically shown that there is little evidence favoring one clas s of drug over another with respect to overall cardiovascular outcome. Thiazide diuretics are effective and cheap and widely recommended as \201 rst-line antihy pertensive therapy. Although calcium channel blockers may be less protective than other age nts against the development of heart failure, their safety and effectiveness in preventing atherosclerotic events are now con \201 rmed. Treatment with the angiotensin receptor blocker losartan demon- strated a small advantage, particularly in reducing stroke, compared to B-blocker therapy in high-risk hypertensive pa tients with left ventricular hypertrophy (LIFE study). It is useful to review a patient \200\231s complete medical history, as other com- pelling indications for various antihypertensive medications may exist and guide therapeutic decisi on-making (see Table 6.5). CHAPTER 6 Preventive cardiology 266 Table 6.5 Considerations for individualizing antihypertensive therapy Indication Antihypertensive drugs Compelling indications ACE inhibitor or ARB, B-blocker, diuretic, aldosterone antagonist ACE inhibitor, B-blocker, aldosterone antagonist Systolic heart failure Post-myocardial infarction Proteinuric chronic renal failure ACE inhibitor and/or ARB High coronary disease risk Diuretic, ACE inhibitor Diabetes mellitus ACE inhibitor B-Blocker, calcium channel blocker B-Blocker, nondihydropyridine calcium chan nel blocker Angina pectoris Atrial \201 brillation rate control Favorable effect on comorbid conditions Benign prostatic hypertrophy A-Blocker B-Blocker (noncardioselective) B-Blocker B-Blocker, calcium channel blocker Thiaz ide diuretic B-Blocker Dihydropyridine calcium channel blocker Essential tremor Hyperthyroidism Migraine Osteoporosis Perioperative hypertension Raynaud \200\231s syndrome Indication Antihypertensive drugs Contraindications Angioedema ACE inhibitor B-Blocker Reserpine Bronchospastic disease Depression Liver disease Methyldopa Pregnancy ACE inhibitor, ARB B-blocker, nondihydropyridine calcium channel blocker Second- or third-degree heart block Adverse effect on comorbid conditions Depression B-Blocker Diuretic Gout Hyperkalemia Aldosterone antagonist, ACE inhibitor, ARB Hyponatremia Thiazide diuretic Renovascular disease ACE inhibitor or ARB Adapted from Chobanian AV, et al. (2003). JAMA 289(19):2560 \200\2232571. Copyright 2003 Am erican Medical Association. All rights reserved. COMBINING ANTIHYPERTENSIVE DRUGS 267 Combining antihypertensive drugs Many hypertensive patients require more than one drug for optimal blood pressure control. Using a combination of drugs often results in better blood pressure control with fewer side effects than maximizing the dose of an individual agent. T his is because most drug combinations use agents that act by different mechanisms and thus tend to have an additive effect. A low dose of a thiazide diuretic, e.g., increases the ant ihypertensive effect of all other antihypertensive drugs by minimizing volume expan- sion. It is also reasonable to administer two drugs as initial therapy in patients with blood pre ssures more than 20/10 mmHg above their goal. This approach may allow target blood pressure s to be reached more ef \201 - ciently. Fixed-dose combination pills are also available th at may improve patient compliance and lower costs. The JNC-7 report recommends the use of a thiazide diuretic when com- bination therapy is in dicated unless compelling indications exist for the use of other agents (see Fig. 6.4). The recent ACCOMPLISH trial, however, demonstrated the superior effectiveness of ACE inhibi tor + dihydropyridine calcium channel blocker (benazepril + amlodipine) to that of an ACE i nhibitor + thiazide combina- tion in reducing cardiovascular events. Other therapy The lipid-lowering arm of the ASCOT study was terminated early because of a s izeable reduction in major vascular events seen in patients with hypertension and \200\234 average \200\235 cholesterol levels treated with atorvastatin 10 mg daily for <4 years. Statin therapy should be initiated in these high-risk individuals regardless of baseline ch olesterol levels. It is also recommended that aspirin 75 \200\223162 mg daily be prescribed to hypertensive patients who have evidence of clinical atherosclerotic disease or (cid:116 )10% 10-year cardiovascular event risk. CHAPTER 6 Preventive cardiology 268 Hypertension Treatment Algorithm STEP 1: Initiate lifestyle modifications (exercise, low salt diet, weight loss, smoking ces sation) STEP 2: Initiate pharmacotherapy if not at goal BP with consideration of compelling indicat ions (see Table 6.5). Use agents for compelling indications if present STEP 3: Determine hypertension stage to guide pharmacotherapy \200 Stage 1 HTN: Use Thiaz ide-diuretic or may consider ACEI/ARB, or CCB \200 Stage 2 HTN: 2-drug combination for mo st: \200\223 Thiazide diuretic and an ACEI/ARB or CCB or BB OR \200\223 CCB + ACEI/ARB STEP 4: Add additional medications if needed, preferably a thiazide diurentic, ACEI/ARB, BB , OR CCB STEP 5: If not at goal BP: \200 Optimize doses \200 Add additional agents Consider furt her work-up for secondary causes of hypertension \200 Consider referral to hypertension s pecialist Figure 6.4 Hypertension treatment algorithm. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BB, B-blocker; BP, blood pressure; CCB, calcium chan nel blocker. Adapted in part from Chobanian AV, et al. (2003). JAMA 289(19):2560 \200\22325 71; Jamerson K, et al. (2008). N Engl J Med 359(23):2417 \200\2232428. LIPID MANAGEMENT IN ATHEROSCLEROSIS 269 Lipid management in atherosclerosis Dyslipidemia and risk of atherosclerosis Numerous epide miological studies have con \201 rmed that a direct continu- ous relationship exists betwe en plasma cholesterol level and risk of coro- nary artery disease, even within the normal r ange of cholesterol. Elevated LDL cholesterol levels appear to be the primary determinant o f this rela- tionship, but other atherogenic lipoprotein particles, including very low dens ity lipoprotein (VLDL), chylomicron remnants, and Lp(a) also appear to play an important ro le as well. LDL, particularly modi \201 ed LDL, is recognized by the scavenger receptor on the surface of macrophages in the arterial wall, which take up these cholesterol-rich particles and ev entually become the foam cells that form the lipid-rich core of atherosclerotic plaques. Increasing levels of HDL, involved in reverse cholesterol transportation from the peripheri es to the liver, protect against the development of athero- sclerosis. An increased triglyc eride level is also now recognized as an inde- pendent risk factor for coronary disease. Emerging data suggest that the nature of the lipoprotein particles plays an important part in their atherogenicity. For example, small, dense LDL particles, as seen in subjects with diabetes, are more readily taken up by macrophages and appear to be more atherogenic than l arger, less dense LDL. Lipids and risk assessment It is essential to consider the lipid pro \201 le together in t he context of the other risk factors present by estimating the 10-year cardiovascular risk. Although only total and HDL cholesterol are considered in most risk models, LDL cholestero l and triglyceride levels should also be considered in the assessment of risk (see Table 6. 6). Blood should ideally be sampled after a 12-hour fast, as triglycerides and calculated LDL c holesterol levels are affected by food intake. In general, a fasting lipid pro \201 le sho uld be obtained in individuals with known cardio- vascular disease and those at increased r isk (Box 6.4). Classi \201 cation of primary dyslipidemias is provided in Table 6.7. Secondary causes of dyslipidemia are listed in Box 6.5. Box 6.4 U.S. Preventive Services Task Force (USPSTF) recommendations \200 Strongly recommend screening men aged 35 and older for lipid disorders Recommend screening men aged 20 \200\22335 for lipid disorders if they are at increased risk for coronary heart disease No recommendation for or against routine screening for lipid disorders in men aged 20 \200\22335, or in women aged 20 and older who are not at increased risk for coronary he art disease CHAPTER 6 Preventive cardiology 270 Table 6.6 Adult Treatment Panel III classi \201 cation of LDL, total, and HDL cholesterol LDL cholesterol, mg/dL (mmol/L) Optimal Near or above optimal Borderline high High Very high <100 (2.58) 100 \200\223129 (2.58 \200\2233.33) 130 \200\223159 (3.36 \200\2234.11) 160 \200\223189 (4.13 \200\2234.88) (cid:116)190 (4.91) Total cholesterol, mg/dL (mmol/L) Desirable Borderline high High <200 (5.17) 200 \200\223239 (5.17 \200\2236.18) (cid:116)240 (6.20) HDL cholesterol, mg/dL (mmol/L) <40 (1.03) (cid:116)60 (1.55) Low High Adapted from Adult Treatment Panel III at http://www.nhlbi.nih.gov/ Table 6.7 WHO/Fredrickson classi \201 cation of primary dyslipidemias Phenotype Elevated particles Lipid levels Chylomicrons Triglycerides (TG) >99th percentile Type I (lipoprotein lipase de \201 ciency or apoCII de \201 ciency) Type IIa (familial hypercholesterolemia/ LDL receptor defects) Most common primary dyslipid emia LDL Total cholesterol (TC) >90th percentile; depending on type, may also see TG and/ or apolipo protein B (cid:116)90th percentile Type IIb (familial combined hyperlipidemia, defective apoprotein B-100) LDL and VLDL TC and/or TG (cid:116)90th percentile and apolipoprotein B (cid:116)90th percentile Type III (dysbetalipoproteinemia) IDL TC and TG >90th percentile Type IV (familial hypertriglyceridemia, familial combined hyperlipidemia) VLDL TC >90th percentile, TG >90th percentile, low HDL Type V Chylomicrons, VLDL TG >99th percentile LIPID MANAGEMENT IN ATHEROSCLEROSIS 271 Box 6.5 Secondary causes of dyslipidemia R \200 enal failure* \200 \200 \200 \200 \200 \200 Nephrotic syndrome* Hypothyroidism* Type 2 diabetes and obesity** Cholestasis Alcohol abuse Drugs \200 \200 \200 \200 \200 Antiretroviral protease inhibitors Thiazides Oral contraceptive pill Isotretinoin Steroids * Cholesterol elevation. ** Minor elevation in cholesterol, but greater increase in atherog enic VLDL, chylomicron remnants, and triglycerides, as well as a fall in HDL. CHAPTER 6 Preventive cardiology 272 Lipid-lowering medications Statins Atorvastatin, \202 uvastatin, pravastatin, rosuvastati n, simvastatin Statins reduce cholesterol levels by inhibiting HMG CoA-reductase, the rate- limiting enzyme in cholesterol biosynthesis. They also increase clear- ance of circulating LDL by up-regulating LDL-receptor expression, further lowering cholesterol levels. These agents are extremely effective at lowering cholesterol levels; e.g., the most potent statins, atorvastatin and rosuvastatin, can lower LDL cholesterol levels by >50%. Statin th erapy typically results in a small increase in HDL and decrease in triglycerides as well. A large evidence base has emerged over the past decade that strongly supports the use of st atins in primary and secondary prevention of cardio- vascular disease. Data from large rand omized clinical trials have shown a consistent reduction (25% \200\22330%) in the relative risk of major cardiovascular events with the use of atorvastatin, pravastatin, and simvasta tin in both the primary (ASCOT, WOSCOPS, HPS, CARDS) and secondary prevention settings (MIR ACL, CARE, LIPID, 4S, HPS). In the \201 rst outcome study comparing two statins, the PROVE-IT study showed that high- dose atorvastatin (80 mg) was more effective than prav- astatin (40 mg) at preventing furth er major cardiovascular events during the \201 rst 2 \200\2233 years after presentation w ith an acute coronary syndrome. Typically recommended evidence-based doses are simvastatin 40 mg, pravastatin 40 mg, and at orvastatin 10 \200\22380 mg. Statins should not be pre- scribed to individuals with porphyr ia or severe liver or muscle disease. Caution is advised with their use in milder liver dys function and in combi- nation with \201 brates. Fibrates Feno \201 brate, gem \201 brozil Fibrates improve the lipid pro \201 le by acti vating peroxisome proliferator- activated receptor A (PPAR-A), resulting in a mild lowering of total and LDL cholesterol, a more signi \201 cant reduction in triglycerides (by 35% \200\22350%), and increases in HDL (by 15% \200\22325%). Patients with combined hyperlipidemia or other reasons for a low HDL and/or high triglyceri des respond well to \201 brates. Although the VA-HIT study showed that gem \201 brozil r educed major cardiovascular events in patients with average cholesterol and low HDL levels, subgroup analysis of the Heart Protection Study (HPS) suggested that similar bene \201 ts were observed with simvastatin (40 mg) in such individuals. For most patients with and at risk of cardiovascular events, \201 brates are typically re commended as second-line agents in patients intolerant of statins, particularly if they hav e low HDL or high triglycerides. The likeli- hood of transaminitis or myopathy is increased if \201 brates and statins are used in combination. Thus careful monitoring is recommend ed when using this combination. The risk is lower with feno \201 brate than that with othe r \201 brates. LIPID-LOWERING MEDICATIONS 273 Anion-exchange resins Cholestyramine, cholestipol These agents bind bile salts in the small bowel, which inhibits their reabsorption, resulting in upregulation of the LDL receptor on hepato- cytes and increased plasma cholesterol clearance. Although these drugs effectively lower cholesterol levels, many patients experience intolerable GI side effects that limit their widespread use. These drugs are generally recommended as second- or third-line ther- apy in subjects with hypercholesterolemia. Inhibitors of intestinal cholesterol absorption Ezetimibe This medication binds to an intes