First Edition

Primary Prevention

Nicholas B. Norgard, Pharm.D., BCPS

Primary Prevention

Section 1

Primary Prevention

Introduction
Vascular disease, including coronary disease, cerebrovascular disease, and peripheral arterial disease, is the leading cause of death in the United States, accounting for more than 900,000 deaths annually. In fact, approximately 30% of all deaths worldwide are to due to cardiovascular causes. This percentage will most likely go up because of worldwide lifestyle changes. CVD is the #1 killer in the U.S. accounting for ~40% of all deaths. CVD is responsible for 1 death every 33 seconds. 1 in every 5 deaths in the US is caused by coronary heart disease (CHD). At age 40, the lifetime risk of developing coronary disease is 49% for men and 32% for women. Although mortality rates have decreased by approximately 25% over the past 30 years, the rate of decline has slowed since 1990. Autopsy data have conrmed a decreased prevalence of coronary atherosclerosis in both men and women since the late 1970s. A substantial component of this reduction is the modication of risk factors, particularly decreased smoking and better hypertension treatment. A concerning trend in recent times is the rising prevalence of obesity and diabetes, particularly among younger people. This trend may explain the declining mortality rate reduction from cardiovascular disease.

Approximately 14 million people in the United States have symptomatic coronary disease. This number is likely an underestimation of the total population disease burden, as many patients are asymptomatic or have silent or clinically unrecognized manifestations of disease. Much of our understanding of cardiovascular disease risk factors is derived from large epidemiologic studies, including the Framingham Heart Study. As we will discuss, the important modiable risk factors for cardiovascular disease include smoking, diet, hypertension, dyslipidemias, physical inactivity, obesity, and diabetes. It is important to recognize that many patients with cardiovascular disease have multiple risk factors, each of which requires appropriate management for optimal risk reduction.
Vascular Disease includes four major areas: CAD manifested by myocardial infarction (MI), angina pectoris, heart failure (HF), and coronary death Cerebrovascular disease manifested by stroke and transient ischemic attack Peripheral arterial disease manifested by intermittent claudication Aortic atherosclerosis and thoracic or abdominal aortic aneurysm

the arterial wall. This may eventually result in a signicant narrowing of the vessel lumen, impairing blood ow. These plaques may also become unstable and thrombose leading to an acute coronary syndrome. Pathophysiology The atherogenic process is characterized by dysfunction of the endothelial lining of the vessel, associated with inammation of the vascular wall. This leads to the buildup of lipids, inammatory cells, and cellular debris within the intima and subintimal layers of the vessel, resulting in plaque formation and remodeling of the arterial wall. This process is complex, involving a series of interactions between endothelial and smooth muscle cells, leukocytes and platelets in the vascular wall. The vascular system regulates its health and tone through a chronic active balance between vasoconstrictors, inammatory/ autoimmune mediators, oxidative stress mediators, procoagulants, and growth promoters vs. vasodilators, antiinammatory/

Atherosclerosis
Atherosclerosis is a disease of the large and medium-sized arteries, characterized by a gradual buildup of fatty plaques within

autoimmune mediators, antioxidants, anticoagulants, and growth inhibitors. The key to vascular health is ensuring proper function of the endothelium. The endothelium is the thin layer
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of cells that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells line the entire circulatory system, from the heart to the smallest capillary. An imbalance within the circulatory system creates an environment that promotes the development of atherosclerosis. Therefore, poor vascular health is at the root of the development and progression of atherosclerosis.
Endothelial cells are involved in many aspects of vascular biology, including: Vasoconstriction and vasodilation, and hence the control of blood pressure Blood clotting (thrombosis & brinolysis) Atherosclerosis Formation of new blood vessels (angiogenesis) Inammation Barrier function - the endothelium acts as a selective barrier between the vessel lumen and surrounding tissue

Endothelial dysfunction The atherosclerotic process appears to be triggered by endothelial cell injury from exposure to stimuli such as tobacco toxins, oxidized low-density lipoprotein (LDL), advanced glycation end products, elevated homocysteine, or infectious agents. This initiates a cascade of events resulting in cellular dysfunction (see Figure 2).

Figure 2. Endothelial dysfunction is the underlying process in atherosclerosis, from lesion initiation, progression, through to acute cardiovascular events. Endothelial dysfunction is caused by a variety of genetic factors (and aging), as well as environmental factors that can be modied.

The hallmark of endothelial dysfunction is a change in the balance of production of endothelium-derived vasoactive molecules. There is a reduced bioavailability of endothelial nitric oxide (NO), which possesses important vasodilator, antithrombotic, and antiproliferative properties, in parallel with increased generation of the potent vasoconstrictor agents, endothelin-1 and angiotensin-II, which also promote cell migration and growth. Dysfunctional endothelial cells also express adhesion molecules and secrete chemokines promoting cell migration and adhesion. Levels of plasminogen activator inhibitor and tissue factor are increased, tissue plasminogen activator and thrombomodulin are reduced, and low NO release results in increased platelet activation and adhesion. Atherosclerosis is a systemic disease Atherosclerosis in one vascular territory is often associated with disease elsewhere, as the risk factors for coronary disease, stroke, and peripheral vascular disease are similar. It is important to recognize this association, as clinically evident disease in one vascular bed may be a harbinger of silent, and potentially modiable, disease in another, particularly the coronary arterial system. Cardiac events are the leading cause of mortality

in patients with peripheral vascular disease. For this reason, cerebrovascular disease and peripheral vascular disease are considered coronary disease equivalents. Appropriate preventive strategies and goals should be applied in these patients.

Development of atherosclerotic plaques

Endothelial dysfunction creates a local milieu that facilitates initiation and development of the atherosclerotic plaque. Circulating leukocytes, predominantly monocytes, are attracted and bind to dysfunctional endothelial cells and migrate into the subendothelial layer where they transform into macrophages. Here they act as local scavenger cells taking up modied LDL

cholesterol, ultimately becoming the characteristic foam cells

M OVIE 1.1 Biology of the Progression of Atherosclerosis

The earliest lesions are known as fatty streaks, which consist predominantly of lipids and foam cells. These lesions may develop into brous plaques, as a consequence of further lipid acof established atherosclerosis. cumulation accompanied by local migration, proliferation, and brous transformation of smooth muscle cells. These cells are responsible for the deposition of extracellular connective tissue
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matrix, leading to formation of a brous cap. This cap overlies a central core consisting of foam cells, extracellular lipid, necrotic cellular debris, and a mixture of other inammatory cells, including T lymphocytes. This process is facilitated by ongoing endothelial dysfunction. Further growth of the plaque initially causes outward remodeling of the vessel wall, thus minimizing the impact on the crosssectional area of the lumen. However, progressive plaque accumulation results in luminal narrowing and ultimately vessel obstruction. Erosion of the endothelial layer, or rupture of the overlying brous cap, may expose the highly thrombogenic, lipid-rich core of the plaque to circulating blood. Collagen, tissue factor, and other factors activate platelets and trigger the coagulation cascade, leading to acute thrombosis, which may rapidly occlude the vessel resulting in a myocardial infarction (MI). Atheromatous plaques that have a thin brous cap and a large necrotic lipid core and containing a high proportion of inammatory cells and mediators are particularly predisposed to destabilization or rupture, with consequent thrombosis. Certain dyslipi-

demia and hypertension drugs can thicken the brous cap and reduce the chance of myocardial infarction.

Assessment of atherosclerotic risk

Identication and treatment of risk factors is essential for the prevention of atherosclerotic disease in individuals and society. When multiple risk factors such as dyslipidemia, high blood pressure, and smoking coexist, as is commonly the case, the cardiovascular risk is greatly increased, suggesting a synergistic interaction among these factors (Figure 5). For example, the absolute risk of a cardiovascular event occurring in a patient with high blood pressure is greatly inuenced by their age, sex, lipid prole, presence of diabetes and other factors. Thus, modern approaches to risk management should involve careful consideration of the combined impact of all important factors operating in the individual that contribute to their risk of atherosclerotic disease.
Figure 5. Cumulative absolute risk of cardiovascular disease (CVD) at ve years according to systolic blood pressure and specied levels of other risk factors. The reference category is a nondiabetic, nonsmoking 50 year-old woman with a serum total cholesterol (TC) of 154 mg/dL and HDLcholesterol of 62 mg/dL . The CVD risks are given for systolic blood pressure levels of 110, 130, 150, and 170 mmHg. In the other categories, the additional risk factors are added consecutively. As an example, the diabetes category is a 50-year-old diabetic man who is a smoker and has a total cholesterol (TC) of 270 mg/dL and HDL-cholesterol of 39 mg/dL. Adapted from Jackson, R, Lawes, CM, Bennett, DA, et al, Lancet 2005; 365:434

Global risk assessment Several risk assessment systems are currently available, derived from large, prospective population cohorts, most commonly the Framingham study (Figure 6a and 6b). These systems allow the calculation of the absolute risk of having a car-

diovascular event (i.e., the probability of having a heart attack or stroke) within the next 10 years, which is derived from pa8

tients risk factor variables (age, sex, cholesterol, HDL, BP, smoking). Subjects with established coronary disease or stable angina have a 10-year event rate of approximately 20%. Therefore, subjects without clinical disease that have a predicted 10-year likelihood of suffering a cardiovascular event of 20% are considered to be at high risk and are candidates for aggressive risk factor management. Although these conventional scoring systems have the potential to identify most high-risk individuals in Western populations, a signicant proportion of events occur in subjects calculated to be at intermediate and low risk. For example, risk is typically underestimated when using conventional methods in young subjects with multiple risk factors, subjects with a family history of premature cardiovascular disease, and certain ethnic groups, including individuals of South Asian racial origin. Identication of subjects with intermediate (10%20%) conventional risk scores that are actually at high risk remains a major challenge, as these individuals are also likely to benet from aggressive preventive therapy.

It has been proposed that measurement of C-reactive protein (CRP) levels, ultrasound assessment of carotid artery intimamedial thickness, and coronary artery calcium scoring with CT scanning may improve risk assessment, especially in patients at intermediate risk based on traditional risk factor assessment. These techniques are highly promising and under intense investigation, but their clinical utility and cost have not yet been conrmed in large prospective clinical studies, and they are not currently used in routine clinical practice. However, in selected asymptomatic patients at intermediate risk based on traditional scoring systems, the use of these techniques may be appropriate if the results will alter the management strategy by reclassifying a patient as low or high risk. Likewise, routine use of stress testing for coronary artery disease (CAD) screening in asymptomatic subjects is also not currently recommended.

Figure 6a and 6b Framingham Risk Scoring System

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Risk factors for coronary artery disease

mulative impact of the worsening risk factor prole that develops with increasing age. CAD tends to occur at an earlier age in men than in women. For men, the reported prevalence increases with age, from 7% at ages 4049 years to 13% at 5059 years, 16% at 6069 years, and 22% at 7079 years. The incidence of CHD in women increases rapidly at menopause and is similar to that seen in men in the population over 65. The corresponding estimates for women are substantially lower than for men: 5%, 8%, 11%, and 14%, respectively. Female sex hormones probably

Age The U.S. population is aging. In the United States, the proportion of the population aged 65 years is projected to increase from 12.4% in 2000 to 19.6% in 2030. The number of persons aged 65 years is expected to increase from approximately 35 million in 2000 to an estimated 71 million in 2030, and the number of persons aged 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 process associated with aging and the cu-

contribute to the lower risk of atherosclerotic disease in premenopausal women. Although about 45% of myocardial infarctions occur in people under 65 years of age, this condition is more likely to be fatal in older individuals, with 80% of deaths due to MI seen in those over 65. Family history of atherosclerotic disease CAD is a multifactorial, polygenic disorder, caused by interactions among lifestyle, the environment, and the effects of variations in the genetic sequence of a number of genes. The family history is considered signi cant when atherosclerotic disease
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presents in a 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% increase in women. The risk is even greater if both parents are affected. In the Physicians Health Study, compared to no parental history of an MI, a maternal 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, and 2.05 in women. In the Framingham Offspring Study, cardiovascular disease in a sibling was associated with a signicant increase in cardiovascular disease risk with an adjusted odds ratio of 1.45. 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 smokers) than in nonsmokers. In 2004, approximately 21% of U.S. adults (23% of men, 19% of women) were current smokers. Although the number of smokers has declined substantially over the past 50 years, this trend

has slowed in the adolescent population, where smoking prevalence has not declined since 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 (smoke that has been exhaled by a smoker) also increases the risk of coronary disease by around 25%. Smoking cessation carries almost immediate benet and the long-term benets are greatest in those who stop smoking before the age of 40, such that the survival curve overlaps with nonsmokers. Stopping smoking in middle age is also benecial. For example, in those aged 3059 who stop smoking after an
Figure 7. Survival from age 35 for continuing cigarette smokers and lifelong nonsmokers among UK male doctors born 19001930, with percentages alive at each decade of age. Adapted with permission from Doll R, et al. (2004). BMJ 328(7455):1519.

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MI, the 5-year mortality is 10% compared with 14% in those who continue to smoke. Individuals with established atherosclerosis, as well as those at risk, should be advised to stop smoking. Evidence shows that focused psychosocial support, nicotine replacement therapy, and bupropion are quite effective in smoking cessation, with higher quit rates than those for no intervention. Obesity Obesity signicantly increases the risk of CAD, with 25%49% of cases in developed countries attributable to increased body mass index (BMI). Obesity is also associated with a number of other risk factors for atherosclerosis, including hypertension, insulin resistance and glucose intolerance, hypertriglyceridemia, and reduced HDL cholesterol. Overweight is dened 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 identied by a high waistto-hip ratio and confers a particularly high relative risk if the waist circumference is >40 inches in men and >35 inches in women.

The prevalence of obesity is increasing rapidly worldwide. Compared to NHANES data from 1988 to 1994, data from NHANES 1999 to 2000 demonstrates an increase in the prevalence of overweight and obese adults, from 55.9% to 64.5% for overweight and from 22.9% to 30.5% for obese adults. Of particular concern is the dramatic increase in prevalence of obesity in children, a trend that is likely to exacerbate the problem in adulthood and undo many of the other recent improvements in cardiovascular health. Overweight and obese individuals also tend to be less physically active and consume unhealthy diets with excess calories, which further contributes to their atherogenic risk. Dietary modication and exercise are thus the rst-line interventions in these individuals, together with careful surveillance for and aggressive management of other risk factors and complications of obesity when present. Bariatric surgery may have a role in selected patients, especially if more conservative weight loss measures fail. Dietary measures Several dietary measures can reduce the risk of developing cardiovascular disease. Total fat intake should be reduced to be13

low <30% of total calories. Intake of saturated 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 Health Study, the risk of coronary heart disease would be reduced by 42% if 5% of energy from saturated fat were replaced by energy from unsaturated fats, and by 53% if 2% of energy from trans fat was replaced by energy from unhydrogenated, unsaturated fat. Recommended cholesterol intake is <200 mg/day. Dietary salt intake should be reduced and intake of fresh fruits and vegetables increased (5 portions per day). Fish consumption, especially oily sh, should be encouraged, as evidence suggests that at least one sh meal 23 times per week can reduce the incidence of heart attack and stroke. High ber intake is also associated with a reduced risk of cardiovascular disease. Physical activity Observational studies have shown a strong inverse relationship between exercise and risk of coronary disease and death. The effect appears to be graded such that the greater the degree of physical activity, the lower the risk of coronary events. This ef-

fect is mediated, at least in part by weight loss, a reduction in blood pressure, and improvements in lipid prole (particularly increased HDL). Regular, aerobic exercise of moderate intensity should be undertaken at least 3 times per week for at least 30 minutes. Greater frequency and duration of exercise is associated with increasing benets, both in primary and secondary prevention. Inammation Inammation is involved in the atherosclerotic process from plaque origination and progression to acute rupture and thrombosis. This inammatory process directly links known risk factors to the underlying mechanism of disease. Large studies have shown that low-grade elevation of inammatory markers, most notably CRP, predicts outcomes from cardiovascular disease and may add to the prognostic information provided by traditional risk factors. It has been suggested that a CRP level below 1 mg/L is associated with low risk, between 1 and 3 mg/L reects intermediate risk, and a level above 3 mg/L is associated with a high long-term risk of vascular events. Certain treatments that reduce atherosclerotic risk, particularly statins, have anti-inammatory effects that may contribute to
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their clinical benets. However, the incremental value of CRP as a marker of risk and target of therapy in global risk management remains a controversial topic that requires further investigation, such as the recently completed JUPITER trial, which demonstrated improved outcomes with rosuvastatin in patients with elevated CRP and normal lipids. 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 associated 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 benet of moderate alcohol consumption must be weighed against the potential risks.

Primary Prevention
Many factors are responsible for atherosclerotic progression, therefore a multidimensional prevention plan must be used to prevent or delay disease onset. A primary prevention plan includes a combination of risk factor modication (i.e. diet, exercise, smoking cessation) and pharmacotherapy with antihypertensives, lipid-lowering drugs, and aspirin (Figure 8).

Figure 8. Components of the primary prevention of cardiovascular disease.

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Section 2

Hypertension
Objectives 1. Identify hypertension related target-organ damage and major cardiovascular (CV) risk factors. 2. Dene the Blood Pressure classication. 3. State the overall purpose of treating hypertension and list specic BP goals. 4. Outline recommended management of patients with prehypertension and hypertension. 5. Compare and contrast the clinical characteristics (pharmacology/mechanism of action, benets, adverse effects, interactions, unique dosing considerations, contraindications, monitoring) of antihypertensive drugs. 6. Devise appropriate antihypertensive therapy and monitoring plans for patients with hypertension.

Hypertension is a major risk factor for premature vascular disease and is more common than the other risk factors. Hypertension affects 60 million Americans and 1 billion people worldwide and remains the most common risk factor for myocardial infarction, stroke, heart failure, atrial brillation, aortic dissection, and peripheral arterial disease. The prevalence of hypertension increases with advancing age to the point where more than half of people 6069 years of age and approximately three-fourths of those 70 years of age and older are affected. Because of escalating obesity and population aging in developed and developing countries, the global burden of hypertension is rising and projected to affect 1.5 billion persons, one third of the world's population, by the year 2025. Thus, hypertension remains the leading cause of death worldwide and one of the world's great public health problems. Current control rates for hypertension in the United States are clearly unacceptable. Approximately 30 percent of adults are still unaware of their hypertension, >40 percent of individuals with hypertension are not on treatment, and two-thirds of hypertensive patients are not being controlled to target BP levels.

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A continuous relationship exists between increasing blood pressure and cardiovascular risk (Figure 9). Systolic blood pressure (BP) is at least as powerful a coronary risk factor as the diastolic BP, and isolated systolic hypertension is now established as a major risk for coronary disease and stroke. Both the duration and degree of hypertension are risk factors.

sure should also ideally be measured in both arms. The levels of blood pressure above which the risk increases signicantly and treatment can provide signicant benet are used as a working denition of hypertension. The risk of disease increases beginning at 115/75 mmHg and doubles with each increment of 20/10 mmHg (Figure 10).

The average of two readings at each of a number of visits should be used to dene a patients blood pressure. Blood pres17

hypertensive medications, and vasodilatation from anaphylactic shock. Measurement of peripheral vascular resistance can help distinguish different types of shock. In anaphylactic shock and septic shock, peripheral vascular resistance is typically low in the early stages. In cardiogenic shock and hypovolemic shock, peripheral vascular resistance is elevated in the bodys attempt to maintain the blood pressure and hence perfusion, to vital organs.

Blood Pressure
Each time the heart beats, a volume of blood is ejected. This stroke volume (SV), times the number of beats per minute (heart rate, HR), equals the cardiac output (CO). CO = SV HR Ventricular stroke volume is the difference between the ventricular end-diastolic volume (EDV) and the end-systolic volume (ESV). SV = EDV - ESV The EDV is the filled volume of the ventricle prior to contraction. The ESV is the residual volume of blood remaining in the ventricle after ejection. Blood pressure is the pressure exerted against the arterial wall. It is hemodynamically generated by the interplay between blood BP = cardiac output (CO) X systemic vascular resistance (SVR) ow and resistance to blood ow. The SVR is determined by the vascular tone (i.e., state of constriction) of resistance vessels, whereas the CO is determined by heart rate and stroke volume.
Preload Heart Rate Cardiac Output

Blood Pressure

Peripheral Vascular resistance

Stroke Volume

Contractility

Afterload

Although cardiac output is pulsatile the calculation of vascular resistance uses a modification of Ohms law used for continuous flow. Resistance is the ratio between the

The two typical BP values are: 1) Systolic BP (SBP) is achieved during cardiac contraction11 and represents peak pressure 2) Diastolic BP (DBP) is the pressure after contraction when the ventricles are relaxed and lling and represents the nadir pressure

In patients <50 years DBP is a better predictor of risk, but over the age of 50 SBP is more important. Pulse pressure (PP) is the difference between SBP and DBP and is a measure of atrial wall tension.
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Mean atrial pressure (MAP) is the average pressure throughout the cardiac cycle ! MAP = (SBP X 1/3) + (DBP X 2/3)

Pathophysiology of Hypertension
Pathogenic mechanisms of hypertension involve increased CO, increased SVR, or both. In most patients, CO is normal or slightly increased, and SVR is increased. Chronic hypertension involves physiologic dysregulation and structural maladaptations that derive from inappropriate activation of: Sympathetic nervous system Renin-angiotensin-aldosterone system Renal salt and water retention Vascular dysfunction and remodeling A multitude of neurohormonal, renal, and vascular mechanisms interact to varying degrees in contributing to hypertension. The fundamental hemodynamic fault in hypertension is an elevated systemic vascular resistance coupled with an inappropriately high cardiac output from sympathetic overactivity. The increased sympathetic drive causes vasoconstriction of the affer19

ent arterioles of the kidney, reducing renal perfusion and promoting an inappropriately high release of renin stimulating the renin-angiotensin-aldosterone-system (RAAS). RAAS stimulation leads to renal sodium retention which expands the plasma volume, increases cardiac output and triggers angiotensin II production that increases systemic vascular resistance and stimulates more sympathetic discharge. The process continues to feed itself. However, a key defense mechanism against high blood pressure is vasodilation mediated by endothelium and vascular smooth muscle through the release of vasoactive substances such as nitric oxide, prostacyclin, and bradykinin.

These substances are important in regulating blood vessel tone and BP. Unfortunately, long-standing hypertension can result in endothelial dysfunction causing a deciency in vasoactive substance production and inadequate vasodilation. In addition, long-standing hypertension results in vascular remodeling which increases artery stiffness and reduces lumen diameter, increasing systemic vascular resistance. Sympathetic Nervous System (SNS) The sympathetic nervous system (SNS) regulates the constriction of peripheral veins and arterioles and contributes to control of heart rate, cardiac output, and BP. Overactivity of the SNS and enhanced beta-adrenergic responsiveness leads to vasoconstriction and an inappropriately high cardiac output. This is typically a result of obesity, sleep apnea, type 2 diabetes mellitus, metabolic syndrome, stress, chronic kidney disease or genetics. Sympathetic overactivity also causes vasoconstriction of the afferent arterioles of the kidney, reducing renal perfusion and promoting renin release. Renin-Angiotensin-Aldosterone System (RAAS) Activation of the renin-angiotensin-aldosterone system (RAAS) is one of the most important mechanisms contributing to endothelial cell dysfunction, vascular remodeling, and hypertension

(Figure 12).

Under normal circumstances, the RAAS is a ma-

jor mechanism to counter hypotension. However, when blood pressure is high or normal the RAAS should be turned off. Inap-

Figure 12. Renin, produced solely by the renal juxtaglomerular cells, cleaves angiotensinogen (produced by the liver) to angiotensin I, which is converted by angiotensin-converting enzyme (ACE) to angiotensin II. ACE is most abundant in the lungs but is also present in the heart and systemic vasculature (tissue ACE). Chymase, a serine protease in the heart and systemic arteries, provides an alternative pathway for conversion of angiotensin I to angiotensin II. The interaction of angiotensin II with AT1 receptors activates numerous cellular processes that contribute to hypertension and accelerate hypertensive end-organ damage. These include vasoconstriction, generation of reactive oxygen species, vascular inammation, vascular and cardiac remodeling, and production of aldosterone. There is increasing evidence that aldosterone, angiotensin II, and even renin activate multiple signaling pathways that can damage vascular health and cause hypertension.

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propriate RAAS activity is an important contributor to hypertension. Renal salt and water retention The kidney is the culprit and victim in hypertension, producing a vicious cycle of progressive renal dysfunction and hypertension. In normotensive individuals, BP elevation invokes an immediate increase in renal sodium excretion to shrink plasma volume and return BP to normal. Any acquired or inherited defect in the kidneys' ability to excrete the excessive sodium load leads to renal sodium retention which expands the plasma volume, increases cardiac output and triggers autoregulatory responses that increase systemic vascular resistance. Salt retention also augments the smooth muscle contraction produced by endogenous vasoconstrictor substances. Vascular Mechanisms Deciency of vasodilators rather than excess of vasoconstrictors may cause hypertension. Alterations in the structure and function of small and large arteries play a pivotal role in the pathogenesis and progression of hypertension. The endothelial lining of blood vessels is critical to vascular health and constitutes a major defense against hypertension. The endothelium induces vasodilation by releasing vasoactive substances such

as nitric oxide, prostacyclin, and bradykinin. These substances are important in regulating blood vessel tone and BP. However, endothelial dysfunction is a culprit and victim in hypertension as hypertension both causes endothelial damage and is worsened by endothelial dysfunction. Long-standing hypertension causes endothelial dysfunction resulting in a deciency in vasoactive substance production and inadequate vasodilation.

Figure 13. Vessel remodeling from long-standing hypertension.

Over time, endothelial cell dysfunction, neurohormonal activation, and elevated BP cause remodeling of blood vessels, which
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further perpetuates the hypertension . There is an increase in artery stiffness and a reduction in lumen diameter which increases systemic vascular resistance (Figure 13). Thus, hypertension leads to more hypertension.

Clinical Management Blood pressure level is a continuous variable in which there is an increased incidence of poor outcomes as the blood pressure rises. Cardiovascular risk increases sharply as BP goes up. At any blood pressure, the cardiovascular risk is signicantly affected by the presence or absence of other risk factors that

Treatment of Hypertension
Antihypertensive therapy may not provide optimal vascular protection unless vascular remodeling is prevented or reversed by normalizing hemodynamic load, restoring normal endothelial cell function, and eliminating the underlying neurohormonal activation. Our goal is to create a sophisticated pharmacologic hypertension treatment plan based on pathophysiology and our knowledge of the complex interplay of the components of vascular biology. It is important to realize that by denition, all antihypertensive drugs lower BP, which is clearly the most important determinant for the reduction of CV risk. However, differences exist among the various antihypertensive drug classes, as well as within the same class, with respect to target organ disease and prevention of major CV events.

need to be considered when deciding when and how to treat. The excess vascular risk associated with hypertension is evident in subgroups with other vascular risk factors or underlying target organ damage. Individuals with vascular disease or at highest risk for vascular disease benet the most from antihypertensive therapy. Therefore, a thorough risk assessment is an integral part of hypertension therapy. Once it has been determined that the patient has persistent hypertension, an evaluation should be performed to ascertain the following information:
1. 2. 3. 4.

To measure and stage BP To rule out identiable and often curable causes of hypertension To determine the extent of target organ damage Set a BP goal

The hypertension workup requires a comprehensive clinical history that should include:
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 Current symptoms of coronary heart disease, heart failure, cerebrovascular disease, peripheral vascular disease, diabetes, and renal disease; Information on the use of drugs known to raise blood pressure (oral contraceptives, non-steroidal, anti-inammatory drugs, licorice, cocaine, amphetamine, erythropoietin, cyclosporines and steroids); The family history of high blood pressure, diabetes, dyslipidemia, coronary heart disease, stroke and renal disease; The personal history of coronary heart disease, heart failure, cerebrovascular disease, peripheral vascular disease, diabetes, gout, bronchospasm, sexual dysfunction, and renal disease; Symptoms suggestive of secondary hypertension, i.e. hypertension caused by an underlying condition; Information on behavior, including tobacco use, physical activity and dietary intake of fat, salt and alcohol; Personal, psychosocial, occupational and environmental factors that could inuence the course and outcome of longterm care.

Staging of BP (Table 2) Based upon the average of two or more properly measured readings at two or more visits. If there is a difference in category between the systolic and diastolic pressures, the higher value determines the severity of the hypertension.

Hypertension Follow-Up

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Target-Organ Damage Patients who already have target-organ damage are at very high risk of future vascular events and death (Box 1). Therefore, patients should be assessed for the evidence of targetorgan damage which can develop as a complication of hypertension. Most of these conditions have outcome studies that support the use of one or more specic antihypertensive drug classes as part of the antihypertensive therapy regimen. The primary organs affected are the eye, brain, heart, kidneys, and peripheral blood vessels.

Hypertension is the most common and most important risk factor for stroke and/or transient ischemic attacks (TIA). Hypertension is the most important risk factor for the development of intracranial hemorrhage Left ventricular hypertrophy (LVH) is a common problem in patients with hypertension. In hypertensive patients, left ventricular hypertrophy is a powerful independent predictor of morbidity and mortality, predisposing to heart failure, ventricular tachyarrhythmia, ischemic stroke, atrial brillation, and embolic stroke. Hypertension increases the risk of and harm from coronary artery disease (CAD). CAD is the most common cause of death from hypertension. Hypertension increases the risk of heart failure with the hazard increasing with the degree of blood pressure elevation. Hypertension is a risk factor for chronic renal insufciency and end-stage renal disease The peripheral vasculature is a target organ. The risk of atherosclerosis in the peripheral arteries and abdominal aortic aneurysm increases with hypertension.
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 Retinopathies can occur in hypertension and lead to various forms of ocular damage Marked elevations in blood pressure can cause an acute, life-threatening emergency (hypertensive emergency) Hypertension Treatment Goals Antihypertensive therapy seeks to prevent vascular morbidity and mortality. We use a target blood pressure as a surrogate goal of therapy. Based on data from many large studies, it is believed that the risk of vascular morbidity and mortality is highest when BP is above 140/90 mmHg. Using this a threshold, about half of people with hypertension develop related end-organ damage if BP is left untreated over 7 to 10 years. Treating hypertension to prevent target-organ damage is more effective than trying to reverse the changes once established. Getting patients to goal signicantly reduces the risk of vascular disease and target-organ damage. Antihypertensive therapy has been associated with reductions in (1) stroke incidence, 3540%; (2) myocardial infarction (MI), 2025%; and (3) HF, >50%. Achieving a sustained 12 mmHg reduction in systolic BP over 10 years will prevent 1 death for every 11 patients treated. However, reducing the BP to goal does not guarantee that vascular disease

and target-organ damage will not occur. Nevertheless, controlling BP after target-organ damage carries proven benet. For patients with uncomplicated (essential) hypertension, the goal systolic pressure is less than 140 mmHg and the goal diastolic pressure is less than 90 mmHg. However, the diastolic blood pressure should not be reduced to less than 65 mmHg in elderly patients to attain the target systolic pressure. There are certain circumstances in which the target BP is lower. A BP of < 130/80 mmHg is the goal for patients with: Diabetes Chronic kidney disease Coronary artery disease (CAD) - Stable angina - Unstable angina - Non-ST segment elevation myocardial infarction (NSTEMI) - ST segment elevation myocardial infarction (STEMI) CAD equivalent - Cerebrovascular disease (stroke/TIA) - Peripheral artery disease - Abdominal aortic aneurism - 10-year Framingham risk score 10% A BP of <120/80 mmHg is the goal for patients with left ventricular dysfunction and/or heart failure.

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Antihypertensive therapy
Nonpharmacologic therapy, including diet and lifestyle changes, remains essential for all patients. These measures are the primary therapy in patients with prehypertension and should be followed in all individuals with hypertension. However, nonpharmacologic therapy should not be the sole treatment of patients with stage 1 or 2 hypertension. Adopting and maintaining these lifestyle measures is often difcult. Implementation is most successful in a multidisciplinary professional setting when supported by clear written information including individualized strategies and goals. Antihypertensive pharmacotherapy After determining that a patient requires antihypertensive treatment, we must decide which antihypertensive regimen to use. All antihypertensive drugs are designed to have the same effectlower the blood pressure. Although considerable variation in individual response is observed in populations, most available drugs reduce diastolic BP by 4 to 8 mm Hg and systolic BP by 7 to 13 mm Hg when corrected for placebo effect. Differences exist among the various antihypertensive drug classes with respect to prevention of target-organ and vascular
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Figure 15. Nonpharmacologic therapy

disease. Recommendations for the choice of initial therapy have been increasingly based on the compelling indications of other conditions that frequently coexist with hypertension. A compelling indication is a high-risk condition associated with hypertension for which there is clinical trial evidence of a specic outcome benet of a given class of antihypertensive drugs.

The most comprehensive strategy for selecting antihypertensive therapy is the individualized approach.
The ideal antihypertensive: Maintains full 24-hour BP control Avoids compensatory neurohumoral reexes, such as reex tachycardia, RAAS stimulation, salt and water overload, and reex vasoconstriction Maintains BP control under all circumstances: rest, exercise, stress, mental function, and during the diurnal variation

(bradykinin) while decreasing the concentration of a vasoconstrictor hormone (angiotensin II), thereby decreasing peripheral vascular resistance. Reductions in BP are equal to other classes of antihypertensive agents. ACEIs lower blood pressure mainly by reducing peripheral resistance with little, if any, effect on heart rate, cardiac output, or body uid volumes, probably reecting preservation of baroreceptor reexes. They restore endothelium-dependent vasodilation plus arteries become less thickened and more re-

Antihypertensive Drugs
ACE Inhibitors The antihypertensive mechanism of ACE inhibitors can be tied to the inhibition of the conversion of angiotensin I to angiotensin II and inhibition of the breakdown of bradykinin. Thus, ACEIs increase the concentration of a vasodilating hormone
Drug Benazepril (Lotensin) Captopril (Capoten) Enalapril (Vasotec) Fosinopril (Monapril) Lisinopril (Zestril, Prinivil) Moexipril (Univasc) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik) Perindopril (Aceon) Usual Dose (mg) 5-40 mg/day 12.5-150 mg bid-tid 2.5-40 mg/day 10-80 mg/day 5-40 mg/day 7.5-60 mg/day 5-80 mg/day 1.25-20 mg/day 1-4 mg/day 4-16 mg/day

sponsive. There is evidence that they have benecial vascular effects that are due to both the antihypertensive effect and the nonantihypertensive effect. Hemodynamic Effects Reduce SVR, preserve CO, and improve arterial compliance and perfusion Clinical Use and Vascular Risk Reduction ACE inhibitors are a rst line antihypertensive. ACE inhibitors signicantly reduce morbidity and mortality from: - Cerebrovascular disease - CAD and MI
27

- Heart failure (Systolic and diastolic dysfunction) - Renal insufciency, ESRD, diabetic nephropathy, microalbuminuria, and proteinuria - Dementia and cognitive dysfunction ACE inhibitors improve endothelial function and arterial compliance

- Hypotension can occur in patients with volume and/or salt depletion. - Dry cough can occur due to the increase in bradykinin. Drug discontinuation is the only way to eliminate the cough. - Angioedema is a rare, but potentially life threatening adverse effect on ACE inhibitors. Increases in bradykinin is thought to also be the mechanism of this adverse effect.

Adverse Effects ACE inhibitors are well-tolerated and adherence rates are high for this group of drugs. - Renal insufciency Initial rise in serum creatinine up to 20% above baseline is normal and expected in patients with any renal impairment and does not require treatment cessation. Can lead to hyperkalemia Patients given ACE inhibitors can usually tolerate up to a 30 to 35% increase in serum creatinine above baseline. ACE inhibitors can cause acute renal failure in patients who are hypovolemic or who have severe HF, severe bilateral renal artery stenosis, or severe stenosis in the artery to a solitary kidney.

- ACE inhibitors are pregnancy category X. Angiotensin Receptor Blockers Angiotensin receptor blockers (ARB) interfere with the reninangiotensin system by displacing angiotensin II from its specic AT1 receptor, antagonizing all of its known effects and resulting in a dose-dependent fall in peripheral resistance and little change in heart rate or cardiac output. Angiotensin II receptor blockers and ACE inhibitors are equally effective as antihypertensives.
Drug Usual Dose (mg)

Candesartan (Atacand) Irbesartan (Avapro) Losartan (Cozaar) Olmesartan (Benicar) Telmisartan (Micardis) Valsartan (Diovan) Eprosartan (Teveten)

8-32 mg/day 75-300 mg/day 25-100 mg/day 20-40 mg/day 20-80 mg/day 80-320 mg/day 400-1200 mg/day

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Hemodynamic Effects Reduce SVR, preserve CO, and improve arterial compliance and perfusion Clinical Use and Vascular Risk Reduction ARBs are a rst-line antihypertensive with vascular protection similar to ACE inhibitors. Usually saved for patients intolerant to ACE inhibitors because of cost. Adverse Effects The ARB have the highest adherence rates of all the antihypertensives. Same as ACE inhibitors except since these drugs do not cause an increase in bradykinin they do not cause dry cough and cause signicantly less angioedema compared to ACE inhibitors. Patients who develop a cough or suffer angioedema while on ACE inhibitors can be switched to ARB. Aliskerin (Direct Renin Inhibitors) Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Angiotensin I. Angiotensin I suppression decreases the formation of angiotensin II. Clinical Use and Vascular Risk Reduction

Aliskerin is a newly approved drug with limited number of clinical research. Its long half-life makes it a good choice in patients that have compliance problems. Hemodynamic Effects Reduce SVR, preserve CO, and improve arterial compliance and perfusion. Adverse Effects Same as ARB. Aldosterone Antagonists Aldosterone, a mineralocorticoid, increases blood pressure primarily by inducing sodium and water retention. In addition, aldosterone also has adverse vascular effects including inhibition of release of nitric oxide. Aldosterone production increases in response to increased stimulation by angiotensin-II. Spironolactone and eplerenone selectively block mineralocorticoid receptors reducing blood pressure in a dosedependent manner and appears to prevent myocardial and vascular brosis. Clinical Use and Vascular Risk Reduction
Drug Spironolactone (Aldactone) Eplerenone (Inspra) Usual Dose (mg)
25-50 mg/day

50-100 mg/day

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Clinically used as a secondary antihypertensive in patients with resistant hypertension. They have shown the most benet in patients with HF and hyperaldosteronism Adverse Effects - Renal dysfunction - Hyperkalemia - Endocrine (more with spironolactone) gynecomastia, breast pain, menstrual irregularities, impotence, and decreased libido Alpha-Adrenergic Blockers Competitively inhibits postsynaptic alpha-adrenergic receptors which results in vasodilation of Drug Usual Dose (mg) veins and arteriprazosin (Minipress) 1-20 mg/day in divided doses oles and a deterazosin (Hytrin) 1-20 mg/day crease in total peripheral resisdoxazosin (Cardura) 1-4 mg/day tance and blood pressure Hemodynamic Effects Reduce SVR, preserve CO Clinical Use and Vascular Risk Reduction Alpha blockers have been shown to signicantly increase the risk of heart failure compared to other antihypertensives. Thus, an alpha blocker is not recommended for initial monotherapy, with the possible exception of older men with symptoms of

prostatism, particularly if they are not at high cardiovascular risk. They are also clinically used in patients with benign prostatic hypertrophy and as a secondary antihypertensive in patients with resistant hypertension. Adverse Effects - Drowsiness - Diarrhea - Postural hypotension - Syncope - Tachycardia - Fluid retention & heart failure Beta-Blockers Beta-blockers block the binding of norepinephrine and epinephrine to adrenergic receptors within the myocardium (1receptors) and within the vascular smooth muscle (2-receptors and 1-receptors). This inhibits normal sympathetic effects that act through these receptors. All beta-blockers decrease arterial blood pressure by reducing cardiac output and a central nervous system effect to reduce sympathetic activity. The rst generation of beta-blockers were non-selective, meaning that they blocked both 1 and 2 receptors. Second generation beta-blockers are more cardioselective in that they are relatively selective for 1 receptors. Note that this relative selectivity can be lost at higher drug doses. The
30

third generation beta-blockers are drugs that also possess vasodilator actions through blockade of vascular alpha1-receptors. The new fourth generation beta-blocker, nebivolol, is a selective for 1 receptors but also possesses vasodilator actions through a nitric oxide-potentiating effect. All beta-blockers are also associated
Carvedilol Atenolol Betaxolol Bisoprolol Nadolol

Drug Non-Selective

Usual dose

Hemodynamic Effects Increase SVR and reduce CO, perfusion, and arterial compliance Central arterial pressure is not reduced as much as the brachial arterial pressure, and the reduction is inferior compared to other antihypertensive drugs. Clinical Use and Vascular Risk Reduction Beta blockers are not commonly used for initial monotherapy in the absence of a compelling indication, since they do not offer vascular protection in some cardiovascular outcomes BB monotherapy in the treatment of hypertension CAD and MI are not signicantly reduced. However, beta blockers do reduce MI in patients with a history of CAD. HF is reduced and prevented Renal protection and reduction in proteinuria is inferior to ACEI, ARB, and CCB, but better than thiazide diuretics
31

40-320 mg/day 20-160 mg twice/day 10-30 mg twice/day 60-320 mg/day

Propranolol Timolol Propranolol extendedrelease

Cardioselective 25-100 mg/day 5-20 mg/day 2.5-20 mg/day 25-200 mg twice/day 50-400 mg/day Vasodilating 3.125-25 mg twice/day 20-80 mg/day 100-900 mg twice/day 5-40 mg/day

Figure 16. Beta Blocker mechanism of action.

Metoprolol tartrate metoprolol succinate

Carvedilol controlledrelease Labetalol Nebivolol

with a fall in plasma renin concentrations leading to a decrease in angiotensin II and aldosterone, possibly due to acute peripheral 1-adrenergic blockade.

Most of the -blockers benet is due to secondary cardiovascular protection in patient with established cardiovascular disease. They are best reserved for treatment of hypertensive patients with ischemic heart disease, particularly after a myocardial infarction, heart failure, or tachyarrhythmias. Not all beta blockers are considered equal Atenolol is one of the most widely used -blockers, is commonly used as a rst-line drug in treatment of hypertension. Although atenolol is superior to placebo in decreasing BP, it is not different in overall mortality or MI. One meta-analysis revealed signicantly higher overall mortality with atenolol than with other anti-hypertensive therapies. -blockers have been shown to have a lack of effectiveness in primary prevention. However, when atenolol is removed from these meta-analysis, -blockers appear to provide vascular protection similar to other rst-line drugs. Adverse Effects The adverse effects are high and the compliance rates are low. - Bradycardia - Heart block - Fatigue - Reduced exercise capacity - Bronchospasm Avoid in severe reactive airway disease

- Depression - Masks hypoglycemia - Metabolic abnormalities Dyslipidemia (reduction in HDL and elevation of triglycerides) Hyperglycemia Insulin resistance Central 2-Agonists These agents stimulate 2-adrenergic receptors in the brain stem and leading to a reduction in central sympathetic outow, lowering BP.
Drug Clonidine Methyldopa Guanfacine Guanabenz Usual Dose 0.05-0.3 mg twice/day 250-1000 mg twice/day 0.5-3 mg/day 2-16 mg twice/day

Clinical Use and Vascular Risk Reduction Current use of these drugs is limited as a rst-line therapy, due to a lack of evidence of vascular protection and a high incidence of side effects. Clonidine is used in resistant hypertension and pheochromocytoma. Methyldopa can be used to treat hypertension during pregnancy. Adverse Effects
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-Dry mouth -Dizziness -Lethargy -Drowsiness and sedation -Constipation -Sexual dysfunction -Rebound hypertension with abrupt withdrawal These drugs can be dangerous in patients with adherence problems. Abrupt withdrawal can lead to hypertensive emergencies. Calcium Channel Blockers (CCBs) There are two basic categories of CCBs: dihydropyridine and non-dihydropyridine. All CCBs reduce vascular resistance

through L-type calcium channel blockade, which directly reduces intracellular Ca2+ causing vasodilation due to vascular smooth muscle relaxation. The non-dihydropyridine CCBs (verapamil, diltiazem) also block L-type calcium channels in cardiac myocytes and cardiac nodal tissue (sinoatrial and atrioventricular nodes). This causes a decrease in heart rate, decrease in atrioventricular conduction, and a decrease in myocardial contractility. The dihydropyridine CCBs have high vascular selectivity, meaning these drugs are potent peripheral vasodilators and reduce BP by decreasing SVR without out a signicant on heart rate. In fact, they sometimes cause reexive tachycardia. Hemodynamic Effects Reduce SVR, preserve CO, and improve arterial compliance and perfusion Clinical Use and Vascular Risk Reduction Calcium channel blockers are a rst line antihypertensive. - Shown to reduce cardiovascular events and deaths

Figure 17. Calcium Channel Blocker: Cardiac vs Vascular Selectivity

- Effective in prevention of stroke in older adult hypertensives

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 CCBs reduce strokes more but myocardial infarctions less than other therapies while having similar effects on overall mortality - CCBs are renoprotective but not as renoprotective as an ACEI or ARB when used as the initial drug but are benecial as an add-on They also appear to lower blood pressure in blacks better than in other racial groups Adverse Effects Dihydropyridine CCBs can cause ushing, headache, excessive hypotension, reex tachycardia and peripheral edema. The peripheral edema seen with CCBs is caused by greater arteriolar than venous dilation and an increase in lower extremity transcapillary pressure gradients. Non-dihydropyridine CCBs can cause constipation, excessive bradycardia and hypotension, atrioventricular nodal block, and can cause or worsen heart failure. Thiazide Diuretics Acutely, thiazides inhibit Na/Cl reabsorption pump in distal convoluted tubule increasing urinary excretion. This reduces extracellular uid volume, cardiac preload, and cardiac output. This

also causes increased excretion of sodium, potassium, and magnesium and decreased calcium excretion. After chronic thiazide use the extracellular uid volume, cardiac preload, and cardiac output return to normal. BP lowering occurs due to dilation of peripheral arterioles, which causes a reduction in systemic vascular resistance.

Drug Chlorothiazide (DIURIL) Chlorthalidone (HYGROTON) Hydrochlorothiazide (HYDRODIURIL) Indapamide (LOZOL) Methyclothiazide (ENDURON ) Metolazone (ZAROXOLYN)

Usual Dose (mg) 62.5500 mg twice/day 12.550 mg/day 12.550 mg/day 1.255 mg/day 2.55 mg/day 2.55 mg/day

Hemodynamic Effects Reduce SVR, CO, and perfusion, and worsen arterial compliance. Clinical Use and Vascular Risk Reduction Thiazides are considered a rst-line antihypertensive and are very inexpensive. They are thought to work synergistically in combination with other antihypertensives.
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They are better at reducing coronary artery disease, heart failure, stroke, and cardiovascular and total mortality than placebo Stroke risk is reduced about 3851%, which is similar to other antihypertensive drug classes but superior to BBs. CAD and MI are reduced by about 28% No improvement in renal disease and may be nephrotoxic with chronic use HF is reduced about 52%. LVH is not reduced as much as with ACEI, ARB, and CCB drugs. Thiazides do not improve endothelial function or arterial compliance despite BP lowering. Not all thiazides are the same Most antihypertensive trials incorporating a diuretic arm in the study design were designed to use chlorthalidone, however hydrochlorothiazide (HCTZ) remains the most commonly prescribed diuretic for BP control in North America. We make a generality by saying thiazide diuretics reduce vascular disease and should be a rst-line therapy. This may be an inappropriate generalization. There is no strong evidence for using HCTZ as

rst-line monotherapy. HCTZ has no published evidence that it reduces coronary artery disease or stroke. Chlorthalidone is 1.5 to 2 times more potent than hydrochlorothiazide. A possibly more important difference than potency is the longer duration of action of chlorthalidone (24 to 72 hours versus 6 to 12 hours with hydrochlorothiazide). Thus, HCTZ lowers the BP fairly well during the day, when the patient is in the ofce, but at night and early-morning hours, it loses its antihypertensive efcacy, so it creates a false sense of security. Compared to other antihypertensives HCTZ as 50% less BP lowering efcacy (Figure 18). Based on the above observations, chlorthalidone (12.5 to 25 mg/day) is the low-dose thiazide diuretic of choice.

Figure 18. Antihypertensive Efcacy as assessed by 24-hr ambulatory BP monitoring. Adapted from Messerli F, et al. J Am Coll Cardiol 2011;57: 590-600.

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Adverse Effects (Figure 19) Thiazides have low adherence rates.

Hyponatremia Occurs more commonly in thiazides than loop diuretics If Na <110 mEq/L discontinue thiazide and increase salt intake Hypokalemia If a patient becomes hypokalemic, potassium supplements can be used or a potassium-sparing diuretic, such as amiloride or triamterene, can be added.

Hypomagnesemia Low magnesium levels are known to increase the risk of cardiac arrhythmias Hyperuricemia& Thiazides can precipitate an acute gout attack and are therefore contraindicated in patients with a history of gout. Metabolic Acidosis The loss of uid from sodium excretion causes a contraction alkalosis Renal dysfunction Prerenal azotemia can develop due to intravascular volume depletion Thiazides are know to accelerate glomerular injury Thiazides lose efcacy as creatinine clearance drops below 50 ml/min and should not be used when creatinine clearance is less than 30 ml/min. Hypercholesterolemia Thiazides have been shown to lower HDL and raise triglycerides and LDL. This is most commonly seen in high doses of thiazides. Diabetes Compered to other antihypertensives, new onset type 2 diabetes and hyperglycemia are more common with thiazide diuretics.

36

Adverse Effects Direct Vasodilators Hydralazine and minoxidil reduce peripheral resistance and blood pressure as a result of a direct vasodilatory effect on vascular smooth muscle; the effect on the arteries is greater than on the veins. These drugs have no direct effect on the heart. Hemodynamic Effects Reduce SVR, preserve CO, and perfusion, but worsen arterial compliance In hypertensive patients, the decrease in blood pressure is accompanied by increased heart rate, cardiac output, and stroke volume, probably because of a reex response to decreased peripheral resistance. Clinical Use and Vascular Risk Reduction They are not rst-line therapy for hypertension and should be reserved for severe, refractory hypertension as well as treating acute hypertensive emergencies. Hydralazine is used for hypertension during pregnancy and in heart failure in combination with isosorbide dinitrate. Minoxidil is more potent than hydralazine but has more adverse effects
37

Both drugs may cause headache, tachycardia, and uid retention and may precipitate angina in patients with coronary artery disease. Long-term hydralazine has been associated with a druginduced lupus syndrome, which resolves when the drug is stopped. Minoxidil is associated with sodiumand water retention and hypertrichosis, which is poorly tolerated by women. It also can cause new or worsening pleural and pericardial effusions

Hypertension Guidelines
The JNC 7: Complete Report--Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure was published in 2003 (Figure 20). A new set of guidelines, JNC 8, are being developed and should be available in 2012. The American Heart Association Council for High Blood Pressure Research came out with two sets of guidelines the rst published in 2007: Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: A Scientic Statement From the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention, Rosendorff C, et al. Circulation. 2007 May 29;115(21): 2761-88. This was followed shortly in 2008 by Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management, 4th Edition, Editors: Izzo, Joseph L.; Sica, Domenic A.; Black, Henry R (Table 2).

Uncomplicated Hypertension
Stage 1 Hypertension Patients with uncomplicated Stage 1 hypertension can be initially started on a thiazide, CCB, ACEI, or ARB. Current JNC-7 guidelines recommend that thiazide-type diuretics should be used either alone for most patients with uncomplicated hypertension. (Note: Most authorities and worldwide hypertension guidelines do not agree with this recommendation or its validity).

38

This recommendation is based on the Antihypertensive LipidLowering Treatment to Prevent Heart Attack (ALLHAT) trial (Figure 21). The ALLHAT trial compared the effects of chlorthalidone, lisinopril, or amlodipine as initial treatment on the incidence of coronary heart disease and other cardiovascular disease events. A total of 33,357 participants aged 55 years or older with raised blood pressure and at least one other CHD risk factor were randomly assigned to receive chlorthalidone (12.525 mg/day), amlodipine (2.510 mg/day), or lisinopril (1040 mg/day), and followed up for an average of 4.9 years. The rates of primary outcomes death from CHD and non-fatal myocardial infarction were not different between treatment groups. Likewise, all-cause mortality was not different in the three groups. At the beginning of the study, there was a fourth group treated with an alpha-blocker; this treatment was stopped prematurely because of an increased risk of combined cardiovascular disease, to which heart failure was a major contributor. The ALLHAT may have shown an equality between a diuretic (chlorthalidone), an angiotensin-converting enzyme (ACE) inhibitor (lisinopril), and a CCB (amlodipine), but the extensive campaign to insist that a thiazide diuretic has thereby been

proven to be the best initial choice for therapy may be better justied as a cost-saving maneuver rather than as a rationale based on evidence. The cost savings are no longer present now that most ACE inhibitors and CCBs are generic. Thus, this recommendation is not present in the AHA guidelines and we likely be changed in future JNC guidelines.

Intensifying therapy If the initial antihypertensive fails to get a patient to their goal BP then therapy can be intensied by either increasing the dose on the initial agent, switching antihypertensives, or adding a second antihypertensive (Figure 22). Using a combination of
39

drugs often results in better blood pressure control with fewer side effects than maximizing the dose of an individual agent. Over time, most hypertensive patients will require two or more antihypertensive medications to achieve their BP goals. The addition of a second drug from a different class should be initiated when use of a single agent in adequate doses fails to achieve the goal (Table 3).

type diuretic. Most authorities and worldwide hypertension guidelines do not agree with this recommendation to use thiazide diuretics as initial or second drug therapy in most patients.

When 2 drugs are needed what combination is best? The ACCOMPLISH trial included 11,506 patients with hypertenStage 2 Hypertension When BP is >20 mmHg above systolic goal or 10 mmHg above diastolic goal, initial therapy should include two drugs, either as separate prescriptions or in xed-dose combinations (Table 3). Current guidelines say one of the drugs should be a thiazidesion who were at high risk for a cardiovascular event and, despite prior antihypertensive therapy in 97 percent (most requiring two or more drugs), had a mean baseline blood pressure of 145/80 mmHg (Figure 23). The patients were randomly assigned to initial combination therapy with benazepril (20 mg/
40

day) plus either amlodipine (5 mg/day) or hydrochlorothiazide (12.5 mg/day). Benazepril was increased to 40 mg/day in both groups at one month. If goal blood pressure was not attained, the amlodipine dose was increased to 10 mg/day and the hydrochlorothiazide dose to 25 mg/day. The primary end point was measured as the time to the rst event, which was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac death and coronary revascularization. The primary end point was achieved signicantly less often in the benazepril-amlodipine group (9.6 versus 11.8 percent, hazard ratio 0.80, 95% CI 0.72-0.90). There was a similar reduction in the secondary end point of cardiovascular death or nonfatal myocardial infarction or stroke (5.0 versus 6.3 percent, hazard ratio 0.79). These benets increased progressively over the duration of the trial. The JNC 7 recommends that one of the drugs should be a thiazide-type diuretic. The ACCOMPLISH study refutes this recommendation. It is likely that the new JNC guidelines will reect these results. Hypertension with compelling indications Hypertension may exist in association with other conditions for which there are compelling indications to use a particular treatment based on clinical trial data demonstrating benets of such therapy on the natural history of the associated condition. Compelling indications for specic therapies involve high-risk conditions that can be direct sequelae of hypertension (HF, IHD, chronic kidney disease, recurrent stroke) or commonly associated with hypertension (diabetes, high coronary disease risk) (Table 2). Therapeutic decisions in such individuals should be directed at both the compelling indication and BP lowering.
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There are also antihypertensives that may have benecial effect on comorbid conditions (Figure 24). These should not supersede the treatment for compelling indications.

Table 2. Subclassication Of Antihypertensive Drugs. From Izzo et al. Hypertension Primer: The Essentials of High Blood Pressure: Basic Science, Population Science, and Clinical Management, 4th Edition. 2008. Initial Treatment BP pattern Condition First-Line Approach Agents with potential problems _ Additional Therapy

SBP 120-139 DBP 80- 89 (No compelling indications) SBP 140-159 DBP 90-99

Pre-hypertension

Aggressive lifestyle modication

Stage 1 HTN

rst-line monotherapy Thiazide CCB ACE-I/ARB Primary 2-drug combination ACE-I/ARB + CCB ACE-I/ARB + Thiazide

2-drug combination of rst-line agents Add second-line therapy

SBP >160 DBP > 100

Stage 2 HTN

Intensify current agents 3-drug combination of rst-line agents Add second-line therapy

Figure 24. Favorable effects on comorbid conditions.

BP >130/80 & Diseasespecic indication

Chronic CAD

1-2 drugs initially BB or CCB ACE-I/ARB

Minoxidil, hydralazine

2 or 3-drug combination of rst-line agents Add nitrate Add diuretic Add second-line agent

Post-ACS/ myocardial infarction

BB ACE-I/ARB

Minoxidil, hydralazine

Add nitrate Add CCB Add aldosterone antagonist Add second-line agent

LV dysfunction and/or heart failure

1-3 drugs initially ACE-I/ARB BB loop diuretic

Non-DHP CCB, -blocker

Add aldosterone antagonist Use ACE-I & ARB in combination 2-drug combination of rst-line agents Add second-line agent

Stroke/TIA

First-line monotherapy Thiazide or CCB or ARB 1-2 drugs initially ACE-I/ARB CCB Diuretic (thiazide or loop) use loop when CrCl <50 ml/min

BB

Chronic kidney disease

BB

Add CCB Add -blocker Add second-line agent

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There are several reasons why a patient remains hypertensive despite antihypertensive therapy. Because of this, patients should receive follow-up every 3 to 6 months to monitor treatment effectiveness and safety. Causes of Inadequate Responsiveness to Therapy
Pseudoresistance White coat or office elevations Pseudohypertension in the elderly Nonadherence to Therapy Side effects of medication Cost of medication Lack of consistent and continuous primary care Inconvenient and chaotic dosing schedules Instructions not understood Inadequate education of patients Dementia (e.g., memory deficit) Drug-Related Causes Doses too low Inappropriate combinations (e.g., two centrally acting adrenergic inhibitors) Rapid inactivation (e.g., hydralazine) Drug interactions Rebound after clonidine withdrawal Associated Conditions Smoking Increasing obesity Sleep apnea Insulin resistance or hyperinsulinemia Ethanol intake more than 1 oz/d (more than three portions) Anxiety-induced hyperventilation or panic attacks Chronic pain Intense vasoconstriction (Raynaud, arteritis)

Volume Overload Excess sodium intake Progressive renal damage (nephrosclerosis) Fluid retention related to reduction of blood pressure Inadequate diuretic therapy

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44

Section 3

Dyslipidemia
Objectives 1. Outline the pathogenesis of atherosclerotic plaque formation focusing on the roles of adhesion molecules, cytokines, LDL, oxidized LDL, HDL and the triglyceride-rich particles, very-low-density lipoprotein (VLDL). 2. List the major lipoprotein disorders associated with abnormalities of chylomicrons, VLDL, LDL, and HDL and relate them to the risk of cardiovascular disease. 3. Describe the role of lipoprotein analysis in the initial evaluation and long-term management of patients with lipid disorders, and list the major modiable and nonmodiable risk factors for coronary heart disease (CAD). 4. Describe the mechanism of action, effects on lipids and lipoproteins, starting and maintenance doses, adverse effects, drug interactions, and relative costs of bile acid resins, bric acid derivatives, niacin, ezetimibe, and statins. 5. 5. List the major primary prevention and secondary intervention clinical trials and describe the outcome for the major endpoint in each. 6. 6. Develop a plan for evaluating therapeutic outcomes and monitoring drug therapy in the management of hyperlipidemia.

Dyslipidemia is an important correctable risk factor for CHD. Numerous epidemiological studies have conrmed that a direct continuous relationship exists between plasma cholesterol level and risk of coronary artery disease. It is estimated that 50% of CHD is attributable to lipid disorders. This makes the treatment of dyslipidemia critical in the prevention of CAD. Cholesterol assessment forms an essential step in the assessment of almost every cardiac patient, whether middle-aged or elderly. Physiology Cholesterol is an essential component of cell membranes and a substrate for steroid hormones and bile acids. Many cell functions critically depend on membrane cholesterol; therefore cells tightly regulate cholesterol content. Cholesterol Synthesis Cholesterol is synthesized in the liver. Acetyl CoA is a product of the metabolism of any source of energy-- be it protein, fat, or carbohydrate. Acetyl CoA is then changed into
45

Cholesterol Synthesis

various other products by numerous enzymes, until it is converted into cholesterol or a ubiquinone (coenzyme 10). The HMG-CoA Reductase reaction is the rate-limiting step for cholesterol synthesis. This enzyme is highly regulated and the target of pharmaceutical intervention. Triglyceride Synthesis Triglycerides are the chemical form in which most fat exists. Triglycerides in plasma are derived from fats eaten in foods or made in the body from other energy sources like carbohydrates. Calories ingested in a meal and not used immediately by tissues are converted to triglycerides and transported to fat cells to be stored. Hormones regulate the release of triglycerides from fat tissue so they meet the body's needs for energy between meals.

Fat and liver cells can synthesize triglycerides. Like cholesterol, the process begins with acetyl CoA. Acetyl CoA goes through a number of reactions becoming fatty acids. Then 3 fatty acids are attached to a glyceride making a triglyceride. Lipoproteins Cholesterol and triglycerides are hydrophobic; consequently to circulate in the plasma they must be packed inside large complexes called lipoproteins. Lipoproteins have hydrophobic cores allowing for the storage and transport of cholesterol and triglycerides within the blood. Lipoproteins undergo a great amount of modication in the circulation that can alter the amount of triglycerides and cholesterol inside the core. This changes the density and size of the lipoproteins. The primary way lipoproteins are categorized is by the density. There 4 major families of lipoproteins: Chylomicrons Very-low density lipoproteins (VLDL) Low-density lipoproteins (LDL) High-density lipoproteins (HDL)

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Lipoprotein Transport Cholesterol and triglycerides are metabolized and transported by a complex lipoprotein transport system. The lipoprotein transport system has two major roles: 1. The efcient transport of triglycerides from the intestine and the liver to sites of utilization (fat tissue or muscle) 2. The transport of cholesterol to peripheral tissues, for membrane synthesis and steroid hormone production, or to the liver for bile acid synthesis. The lipoprotein transport system has 2 pathways: 1. Exogenous 2. Endogenous

While the lipoprotein core is hydrophobic, their surface is hydrophilic consisting of phospholipids and specialized proteins known as apolipoproteins. Apolipoproteins are necessary for the structure and enzymatic processes of lipids. Apolipoprotein A1 (apo A1) is the major component of HDL and apolipoprotein B (apo B) is the main apolipoprotein for the remaining non-HDL lipoproteins.
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Exogenous pathway Life requires fats. The human body derives essential fatty acids that it cannot make from the diet. Fat typically furnishes 20 to 40 percent of daily calories. Triglycerides comprise the major portion of ingested fats. Dietary fat is absorbed and the intestinal cells package them into the lipoprotein transport vehicles called chylomicrons, which are then released into the circulation. Chylomicrons bind to lipoprotein lipase (LPL) located on the surface of capillaries in muscle and adipose tissue. The LPL enzyme removes the triglycerides and breaks them down into free fatty acids. The free fatty acids are used as energy (muscle) or stored (adipose). The leftover material or chylomicron remnants are taken up by the liver by binding to the LDL receptor or the LDL receptor-related protein (LRP). Endogenous Pathway Food is not always available. The body must ensure that triglycerides are available to meet energy demands. The liver synthesizes triglycerides and cholesterol and packages them into VLDL. The major function of VLDL is energy transfer (in the form of triglycerides) from the liver to the peripheral cells. After its made VLDL is released in to the circulation. Lipoprotein lipase (LPL) extracts triglycerides from VLDL and breaks them down into FFA to be used by the muscle or adipose tissue. Two things can happen to the VLDL remnants. They are either taken
48

up by the liver by binding the LDL-receptor or broken down by hepatic lipase (HL) to form LDL. LDL can be taken up by peripheral cells or by the liver by binding to the LDL-receptor.

M OVIE 1.2 Lorem Ipsum dolor amet, consectetur

heart disease (CHD). Likewise, people with lower LDL levels have a lower risk of developLow-density lipoproteins (LDL) LDL is a by-product of VLDL. Approximately 70% of total circulating cholesterol resides within LDL making it the major carrier of cholesterol in the plasma. Studies have shown that LDL is the most atherogenic lipoprotein. Elevated LDL levels have been linked to an increased risk of atherosclerotic diseases, most important of which is coronary ing CHD. In addition, there have been several large-scale studies that shown reducing
49

LDL lowers a persons risk for CHD. In fact, every 1% reduction in LDL leads to a 1% risk reduction for CHD (Figure). Based on this, LDL is the primary therapeutic target of cholesterol therapy. Atherogenic LDL (Figure 31) LDL cannot passively diffuse through membranes into and out of cells. The LDL receptor is in charge of removing LDL from the circulation. LDL receptors are located in the liver and on the surface of various peripheral cells. In the blood vessels the

M OVIE 1.3 LDL in Atherogenesis

LDL-receptors reside on the endothelium. These receptors recognize LDL and allows it to cross the endothelium into the vascular intima. To prevent too much cholesterol from entering the vascular cells, the endothelium makes changes to its LDL receptors. For instance, when the amount of LDL in a cell goes up, the number of LDL receptors on its surface will be reduced (downregulated). With fewer receptors, the cell can take up less LDL. This prevents LDL from accumulating in the blood vessels. However, LDL can be modied, particularly oxidized, in a way that throws this system out of whack. Oxidized LDL provokes an inammatory response. This causes monocytes to migrate to the endothelium, enter then vessel wall, and transform into

Lorem ipsum dolor sit amet, consectetur adipisicing elit, sed do tempor incididunt ut labore et dolore magna aliqua.

macrophages. Macrophages engulf the oxidized LDL (becoming foam cells). This essentially lets the LDL hide in macrophages. Therefore, the elevation in intracellular LDL is NOT rec50

ognized and the number of LDL receptors stays the same or increases. This means LDL will continue to come into the cell even though it already has an LDL excess. LDL continues to enter the cells and more macrophages enter the vessel wall to eat it up. These LDL-lled macrophages are called foam cells. Foam cells continue to accumulate in the vessel wall becoming a fatty streak, the earliest form of atherosclerosis. Fatty streaks are prevalent in young people but dont cause symptoms. If serum LDL levels are controlled the fatty streak may eventually disappear. If a dyslipidemia develops or if cardiac risk factors (hypertension, diabetes, smoking, etc.) are uncontrolled the fatty streak may progress into an atheroma/atherosclerotic plaque. High-Density Lipoprotein (HDL) If LDL is the enemy, then HDL is the hero. HDL cholesterol transports excess cholesterol from peripheral tissues to the liver for excretion as bile and feces,
CHD risk ratio

4.0 3.0 2.0 1.0 0

4.0

a process known as reverse cholesterol transport. In addition, HDL inhibits the oxidation of LDL. Therefore, HDL is an antiatherosclerotic lipoprotein. A low level of HDL (less than

2.0

1.0

65 25 45 HDL-C (mg/dL)

51

40 mg/dL) is an independent risk factor for future cardiovascular events. In fact, for every 1% decrease in HDL, CHD risk goes up 2-3%. Causes of low HDL High triglycerides levels Obesity Physical inactivity Smoking Very high carbohydrate diet (>60% of diet) Type II diabetes Genetic factors HDL metabolism and reverse cholesterol transport HDL is synthesized in the intestine and the liver. From there HDL removes excess cholesterol from peripheral cells. The lecithin-cholesterol acyltransferase (LCAT) enzyme adds specic recognition markers to HDL and packages the cholesterol for transport back to the liver. When HDL gets to a certain size it transfers the excess cholesterol to the liver. Alternatively, the cholesteryl ester transfer protein (CETP) can convert HDL into VLDL or LDL and then return it to the lever by hepatic uptake of LDL. The transported cholesterol is kept in a hepatic cholesterol pool where it is used for bile acid synthesis and is eventually excreted in the bile and feces.
52

M OVIE 1.4 HDL in Reverse Cholesterol Transport

Treatment of Dyslipidemia
Most patients with dyslipidemia will not have any symptoms and are probably not aware of there disease. In fact, some people rst nd out that their LDL is high when they are admitted to the hospital for their rst myocardial infarction. The key is detecting dyslipidemia early to prevent the development of atherosclerosis and/or CHD. It is easiest when done in a stepwise process. Step 1: Determine lipoprotein levels - obtain complete lipoprotein prole Blood should ideally be sampled after a 12-hour fast, as triglycerides and calculated LDL cholesterol levels are affected by food intake (Friedewald equation: LDL = Total - HDL - [TG/5]). In general, a fasting lipid prole should be in all adults older than 20 years at least once every 5 years. It is essential to consider the lipid prole together in the context of the other risk factors present by estimating the cardiovascular risk. Step 2: Assess cardiovascular risk The rst step in planning therapy is to ascertain the patients cardiovascular risk based on presence coronary artery disease

or its equivalent (Table 4), presence of CAD risk factors (Table 5), determine the 10-year risk of cardiovascular events (Framingham score), and categorize the patient as low, moderate, moderately high, or high risk (Figure 34). Each category has recommended LDL goals and guidelines for when to initiate therapy (Table 6).

53

Risk Categories High-risk High-risk patients are those with CHD or CHD equivalent. The primary goal for patients in the high-risk category is an LDL <100 mg/dL. There is also an optional LDL goal of <70 mg/dL for patients considered very-high risk. Patients that should be considered for the LDL goal of <70 mg/dL include those with a known history of CHD in addition to one of the following: Acute coronary syndrome Diabetes Metabolic syndrome Severe, uncorrected risk factors Therapeutic lifestyle changes should be initiated when the LDL is > 100 mg/dL. Drug therapy should also be when LDL is > 100 mg/dL, however the very high-risk patients should have drug therapy started even when LDL is < 100 mg/dL. Moderately High-risk Patients with two or more risk factors are placed in moderate risk category. This group is further subdivided according to Framingham risk score. If the 10-year CHD risk is 10-20% the
54

patient is placed in the moderately high-risk group. The primary goal for this group is LDL <130 mg/dL. A lower goal of LDL <100 mg/dL should be considered if: Continued cigarette smoking Strong positive family history of premature CHD High TG (>200) or low HDL (<40) Metabolic syndrome High C-reactive protein (CRP)

Patients with < 1 CHD risk factors they are categorized as low risk. These patients have an LDL of < 160 and therapeutic lifestyle changes should be initiated when the LDL is > 160 mg/dL. Drug therapy should be considered for patients with an LDL >190 mg/dL after secondary causes of high LDL have been ruled out. Some experts believe that any LDL > 160 should qualify for drug therapy. Step 3: Non-pharmacologic treatments Therapeutic lifestyle changes (TLC), including exercise, weight loss, and dietary modications, are the rst step in treatment of all patients with dyslipidemia. The composition of the optimal diet is controversial, though general recommendations are listed in Table 7.

Therapeutic lifestyle changes should be initiated when the LDL is > 130 mg/dL. Drug therapy should also be when LDL is > 130 mg/dL, however patients with any of the above risk factors should have drug therapy started even if LDL is between 100129 mg/dL. Moderate risk If the 10-year CHD risk score is <10% the patient is categorized as moderate risk. The LDL goal is < 130 mg/dL and therapeutic lifestyle changes should be initiated when the LDL is > 130 mg/ dL. Drug therapy can be reserved for patients with an LDL >160 mg/dL. Low risk

55

Physical inactivity is a major risk factor for CHD. Exercise should also be done on a regular basis, although the resulting changes in LDL and HDL cholesterol are modest. Regular physical activity lowers blood pressure and reduces insulin resistance. It also has been reported to reduce risk for CHD independently of standard risk factors. An ideal program includes regular moderate intensity exercise daily if possible, or no less often than 3 times per week, for 30 to 45 minutes each day. Examples of moderate intensity exercise that may be useful to individuals are listed in Table 8. Suggestions to incorporate more exercise into daily life are shown in Table 9.

56

Weight reduction is a major focus of TLC. Moderate weight reduction can signicantly improve the lipid prole and lower CAD risk. Two measures important for assessing overweight and total body fat content are determining body mass index (BMI) and measuring waist circumference. The BMI, which describes relative weight for height, is signicantly correlated with total body fat content. Overweight is dened as a BMI of 25 or more and obesity as dened by a BMI of 30 or more. The presence of & Some persons do not qualify for immediate pharmacologic management to lower LDL because their LDL level is not above the threshold for drug therapy. The treatment model for such people includes the intensication of TLC in a stepwise manner (Figure 35). Approximately 6 weeks after starting the TLC diet, lipoprotein analysis is repeated and assessed. If the LDL cholesterol goal is achieved by 6 weeks, the patient should be commended for his/her adherence and encouraged to continue lifestyle changes. If the LDL goal has not been achieved, the LDLlowering TLC should be intensied. More vigorous reduction in saturated fats and cholesterol, adding plant stanols (2 g/day), increasing viscous ber, and referral to a nutrition professional can all enhance LDL lowering. If the LDL cholesterol goal has not been achieved after 3 months of TLC, a decision must be made whether to consider adding drug therapy. If drugs are
57

excess fat in the abdomen out of proportion to total body fat is an independent predictor of risk factors and morbidity. Waist circumference is positively correlated with abdominal fat content. It provides a clinically acceptable measurement for assessing a patient's abdominal fat content before and during weight loss treatment.A high waist circumference (Men: >102 cm ( >40 in.) or Women: >88 cm ( >35 in.)) is associated with an increased risk for type 2 diabetes, dyslipidemia, hypertension, and CHD in patients with a BMI in a range between 25 and 35. Furthermore, in obese patients with metabolic complications, changes in waist circumference are useful predictors of changes in CHD risk factors.

started, TLC should be continued indenitely in parallel with drug treatment.

Statins reduce cholesterol levels by inhibiting HMG CoAreductase, the rate-limiting enzyme in cholesterol biosynthesis. They also increase clearance of circulating LDL by upregulating LDL-receptor expression, further lowering cholesterol levels.

These agents are extremely effective at lowering cholesterol levels (Table 10). Statin therapy typically results in a small increase in HDL and decrease in triglycerides as well. They also have benecial effects beyond lipid reductions such as atheroFigure 35.

sclerotic plaque stabilization, reducing the inammatory component of plaques, and restoring endothelial function.

Step 4: Pharmacotherapy of Dyslipidemia Lipid-Lowering Medications Hydroxymethyl glutaryl coenzyme-A (HMG Co-A) reductase inhibitors (Statins)

58

More importantly, a large evidence base has emerged over the past decade that strongly supports the use of statins in primary and secondary prevention of cardiovascular disease. Numerous large-scale, randomized clinical studies (Figure 36) have shown that statins reduce major coronary events, reduce CHD mortality, reduce the need for coronary procedures (PCI/ CABG), reduce stroke, and reduce total mortality.

59

of transaminase elevation of greater than 3X ULN on at least 2 consecutive occasions occurs rarely (0.1%-2.3%). If the transaminase elevation persists the decision should be made whether to decrease dose, change statins, or discontinue therapy. The statin should be immediately discontinued if a patient has symptoms of liver toxicity such as pruritus and jaundice.

Statins are generally well tolerated. They can produce some mild GI complaints, myalgias, u-like symptoms, and headache. Hepatotoxicity and myopathy are the most clinically important adverse effects associate with statins. Hepatotoxicity occurs most frequently at high doses and/or in the presence of drugs that impair statin elimination. Liver transaminases (AST, ALT) should be measured at baseline and then 12 weeks following drug initiation and after any increase in dose. If the transaminases are less than 3X the upper limit of normal (ULN) the statin should be continued and transaminases rechecked in 3 months. Approximately 50% of elevations will resolve on its own. If the transaminases are greater than 3X the ULN the statin should again be continued, but the transaminases should be rechecked in a week. The incidence
60

Risk Factors for Myopathy: Advanced age (> 80 years) Small body frame and frailty Multisystem disease (e.g., chronic renal insufciency) Perioperative periods Large quantities of grapefruit juice (usually more than 1 quart per day) Alcohol abuse (independently predisposes to myopathy) Concomitant use of a CYP 3A4 inhibiting drug

Myopathy is dened by muscle pain or soreness plus an elevation in creatine kinase (CK), an enzyme found mainly in the heart, brain, and skeletal muscle. Patients should be encouraged to report any unusual muscle weakness or pain at any time during therapy with statins. A CK level should be obtained at baseline, however routine follow-up measurements are not indicated. A CK should be obtained if a patient reports muscle symptoms. If the CK is between 3X and 10X ULN the statin should be continued and symptoms and CK should be monitored weekly. The statin should be discontinued if the muscle symptoms worsen or CK rises to greater than 10X ULN. If the CK is greater than 10X ULN the statin should be stopped immediately. Bile acid sequestrants (BAS) These agents bind bile salts in the small bowel, which inhibits their reabsorption, resulting in upregulation of the LDL receptor on hepatocytes and increased plasma cholesterol clearance. Although these drugs effectively lower cholesterol levels, many patients experience intolerable GI side effects (abdominal bloating or pain, belching, atulence, heartburn, nausea, vomiting, aggravation of hemorrhoids, and constipation) that limit their widespread use. Hypertriglyceridemia can result from the use of these drugs. Decreased drug absorption dictates careful sched61

uling of medications 1 hour before or 3 hours after the patient takes bile acidbinding resins. These drugs are generally recommended as second- or third-line therapy in subjects with hypercholesterolemia and can be used in combination with statins in cases of severe hypercholesterolemia.

Ezetimibe This medication binds to an intestinal transport protein and inhibits cholesterol absorption. LDL cholesterol is reduced by 15%20%. Ezetimibe is most often used in combination with a statin in those patients who do not achieve their LDL cholesterol target at higher statin doses. However, the ENHANCE

Drug

Lipid Effects

Lipid Effects in Combination with Statin Further LDL 10-20% Further HDL 0-9%

Outcomes Data Primary Prevention: reduces cardiac events and procedures Secondary Prevention: reduce cardiac events

Approx. Comments Cost for 30day supply Can be tolerate due to GI side effects generic $254

trial did not support the efcacy of ezetimibe when added to a statin by failing to reduce the progression of atherosclerosis, despite ezetimibe signicantly lowering the LDL. Although it is effective in lowering LDL levels and has been used as monotherapy in statin-intolerant patients, clinical outcome data are currently lacking, so it should not be used as a rst-line substitute for statins.

Cholestyramine LDL (Questran) 9-28% Dosing: 416 g HDL 4-8% TG 11-28 %

Colesevelam (WelChol) Dosing: 5-20 g

LDL 15-19 % HDL 3-8% TG None

Further LDL 10-16% Further HDL 3-7%

None

Lower risk of GI side effects

$214

Drug

Lipid Effects in Lipid Effects Combination with Statin LDL 19% HDL 3.5% TG 8% Further HDL 0-6% Further TG 7-15% Further LDL 7-19%

Outcomes Data None

Comments

Approx. Cost for 30day supply

Ezetimibe (Zetia) Dosing: 10mg/day

Available in Zetia $106 combination with Vytorin $108 simvastatin as Vytorin

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Fibric Acid Derivatives (Fibrates) Fibrates improve the lipid prole by activating peroxisome proliferator activated receptor (PPAR-), resulting in a mild lowering of total and LDL cholesterol, a more signicant reduction in triglycerides (by 35%50%), and increases in HDL (by 15% 25%). Gembrozil and fenobrate are indicated for treatment of very high triglyceride levels in patients who are at risk for pancreatitis. Patients with a low HDL and/or high triglycerides respond well to brates. The Helsinki Heart Study, a primary prevention trial employing gembrozil, demonstrated a 37 percent reduction in fatal and non-fatal myocardial infarctions and no change in total mortality during the course of the study. The VA-HIT trial, a secondary prevention study, showed that gembrozil reduced major cardiovascular events in patients with average cholesterol and low HDL levels. Fenobrate, as monotherapy and added to a statin, has failed to reduce cardiovascular events in 2 large clinical trials. For most patients with and at risk of cardiovascular events, brates are typically recommended as second-line agents in patients intolerant of statins, particularly if they have low HDL or

high triglycerides. The likelihood of myopathy is increased if brates and statins are used in combination. Thus careful monitoring is recommended when using this combination. The risk is lower with fenobrate than that with other brates.
Lipid Effects Lipid in Outcomes Comments Effects Combination Data with Statin LDL 20% HDL 11% TG 29% Further LDL Prevention Good of CHD choice 0-6% in type 2 when TG high and/ Further HDL diabetes: Reduced or HDL low 13-17% non-fatal Less risk MI Further TG of and the 20-32 myopathy need for compared coronary to revasculari gembrozil zation when combined with statin Approx. Cost for 30-day supply generic $54 Tricor $109

Drug

Fenobrate Dosing generic: 40-120mg/d Antara: 43-130mg/d Tricor: 48-145mg/d Triglide: 50-160mg/d

63

(by 30%35%), and reduced hepatic synthesis results in a small reduction in LDL.

Although particularly benecial in mixed dyslipidemias, use of the short-acting formulation is limited by a high incidence of intolerable GI side effects and facial ushing. Flushing is the most Niacin Niacin reduces hepatic VLDL synthesis and inhibits fatty acid release from adipocytes. HDL levels are signicantly increased common reason for discontinuation of therapy. Pretreatment with aspirin can minimize ushing, and taking it with food or water can reduce the incidence of GI side effects. The modied-release formulation is more tolerable.
64

Niacin is particularly useful in patients with low HDL and is often used in combination with statins. Whether this reduces cardiovascular events is unknown at this time. The recent AIM-HIGH study found that niacin did not lower vascular events when added to statin therapy in patients with a low HDL.
Drug Niacor immediate release Dosing: 1.5-3 g/d Niaspan extended release Dosing: 1-2 g/d Lipid Effects LDL 12-14% HDL 17-24% TG 16-31% Lipid Effects in Combination with Statin Outcomes Data Comments Approx. Cost for 30day supply

Further LDL Secondary MI 7-14% prevention: Further HDL reduces mortality 24% Further TG 24%

Raises HDL Niacor $17 more than any other Niaspan agent $126 Available as Advicor Niaspan/ $114 lovastatin combination (Advicor)

Omega-3 fatty acids (Lovaza): Omega-3 fatty acids, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), are indicated for the treatment of severe hypertriglyceridemia. They are the most potent triglyceride lowering therapy. Like statin, omega-3 fatty acids are thought to have effects beyond lipid lowering. In contrast to the statins, omega-3 fatty acids do not have large clinical trials showing a reduction in cardiovascular events.
65

One prescription omega-3 fatty acid formulation and many dietary over-the-counter supplements are available. The supplements are appealing because they are cheaper than the prescription Lovaza. The sh oil supplements are not concentrated, containing very low amounts of EPA and DHA. Depending on the brand, the combined content of EPA plus DHA per 1 g capsule varies from approximately 300 to 850 mg. It can often require high number of capsules to achieve the amounts of EPA+DHA (>3 g/day) needed for signicant triglyceridelowering. Fish oil supplements can be a potentially unrecognized source of dietary calories, containing between 30 and 50 calories per capsule.

Drug Omega-3 fatty acids (Lovaza) Dosing: 4 g/ d

Lipid Effects LDL 45% HDL 9% TG 48%

Lipid Effects in Combination with Statin

Outcomes Data

Approx. Comments Cost for 30day supply Role in therapy: TG reduction Most effective at reducing TG $164

Further LDL Secondary No effect prevention: Further HDL reduce CV No effect death, MI, Further TG stroke 29%

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Step 5:Choosing pharmacologic agent Reduction in serum concentrations of LDL cholesterol is the primary approach to lowering the risk of CAD. Statins are the most effective class of drugs for reducing LDL-cholesterol and have the strongest clinical outcomes data. Thus, statins are considered the rst-line pharmacologic lipid lowering therapy and should be initiated at doses that will achieve at least a moderate risk reduction. Using stains doses to produce a small LDL reduction that will barely attain the LDL goal is not prudent use of LDL-lowering drugs. Every 1% reduction in LDL that is achieved with statins is estimated to reduce CAD risk by 1%. Therefore, statins should be initiated at doses that will lower the LDL by 30 to 40% (Table 17).

67

Cholesterol should be re-assessed after 6 weeks of therapy (Figure 42). If the LDL goal is not met after 6 weeks, statin therapy should be intensied by increasing the dose or switching to a more potent statin. The addition of secondary lipid-lowering medications have not been shown to lower cardiovascular

events, however high doses of statins have been found to be superior to lower doses. Therefore, statin therapy should be intensied until the LDL goal is met or until maximum doses are being used.

Figure 42. Titration of Dyslipidemia Pharmacotherapy

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Section 4

Metabolic Syndrome

Metabolic Syndrome Metabolic syndrome describes a frequently observed cluster of adverse risk factors within an individual. It has also been referred to as insulin resistance syndrome. Metabolic syndrome places patients at such a high CHD risk because of its link to prothrombotic and proinammatory states and the increase in highly atherogenic lipid particles. The syndrome is characterized by visceral obesity, insulin resistance, moderate hypertension, dyslipidemia (low HDL and high triglycerides with average cholesterol levels), and low-grade inammation.

69

Several denitions of this syndrome have been proposed, but the NCEP ATP-III diagnostic criteria (Table 18) are the most practical and widely used, as well as being a robust predictor of vascular risk.

Unless effective interventions to slow, and hopefully reverse, The prevalence of this syndrome is increasing in parallel with the increase in numbers of obese and overweight individuals. It has been described in a high proportion of American children and adolescents. Thus, the metabolic syndrome is projected to contribute substantially to the societal burden of atherosclerotic disease in the next few decades. this trend are delivered at a population level, much of the progress that has been made in the ght against coronary disease is likely to be overturned.

70

Mechanisms of increased risk Visceral obesity causes insulin resistance, which is associated with increase in blood glucose and abnormalities in the lipid prole. Increased levels of inammatory cytokines such as TNF-A, some of which are produced by adipocytes, cause endothelial dysfunction that increases vascular tone and blood pressure, as well as promoting local pro-atherosclerotic changes in the vascular wall (see Figure 43). Increased leptin and reduced adiponectin levels inuence insulin sensitivity, as well as some of the adverse metabolic consequences of obesity, but their incremental clinical value remains a subject of investigation. It has been proposed that the degree of insulin resistance is less important than the impact of other risk factors, including lipids, blood pressure, inammation and pro-thrombotic factors, but these factors also remain under investigation.

71

Metabolic syndrome: management The treatment of patients with the metabolic syndrome is essentially the same as treatment of the individual variables. Weight loss and exercise are the cornerstones of management, and cardiovascular risk factors should be further treated if they persist despite lifestyle modications. Management of insulin resistance with insulin-sensitizing drugs (e.g. metformin) has theoretical benets but is currently under investigation, as the ability of such an approach to improve outcomes compared to weight reduction and exercise alone is not yet well supported by clinical trials. The dyslipidemia should be treated with statins. Fibrates and niacin also have theoretical benets and are under investigation. The nature of the risk factor prole in the metabolic syndrome frequently results in the underestimation of 10-year risk, but at present no studies are currently available to support use of specic evidence-based drug therapy in this syndrome. Most, if not all, of these patients should also take a daily aspirin for primary prevention.

72

Section 5

Aspirin for primary prevention

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The Physicians Health Study (PHS) was the rst reported trial of aspirin in the primary prevention of cardiovascular disease. The study was stopped early because of a statistically signicant 44% reduction in rst MI. Aspirin provides differential benets for men as compared to women. Primary prevention studies of aspirin have found the following:

Source: U.S. Preventive Services Task Force. Aspirin for the Prevention of Cardiovascular Disease: Recommendation Statement. AHRQ Publication No. 09-05129-EF-2, March 2009. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf09/aspirincvd/aspcvdrs.htm.

The decision to prescribe aspirin for primary prevention should be an individual clinical judgment that weighs the benet of reducing risk of a rst MI, the risk factor prole of the patient, and the adverse effects of long-term administration, specically gastrointestinal bleeding. An important consideration is that, when aspirin is used for primary prevention, the absolute benet is much smaller than that for secondary prevention, while the risk of major gastrointestinal bleeding is the same. Harms from aspi73

rin include the risks of serious upper GI bleeding and hemorrhagic stroke. An individual's risk for GI bleeding from aspirin increases with age:

The following table provides the 10-year risk level at which the net benet from aspirin becomes favorable.

The concomitant use of nonsteroidal antiinammatory drugs (NSAIDs) with aspirin increases the risk of serious GI complications by a factor of 3-4. Prior GI ulcer, GI bleeding, or GI pain also increases risk by a factor of 2-3. Aspirin increases the risk of hemorrhagic stroke in men by a factor of 1.7 but does not appear to increase this risk in women. This risk does not increase with age.

Shared decision making about the use of aspirin should be used with individuals close to (either above or below) these 10year risk levels. For these individuals, the benets and risks of using aspirin are closely balanced. The recommendation to take aspirin becomes stronger as the patient's 10-year risk increases above these thresholds. Risk assessment and discussion should probably be held at least every 5 years with middle-aged and older people or when

Net benet is assessed by weighing the potential clinical benet against the potential harms. The baseline 10-year MI or stroke risk at which an individual would receive a favorable net benet from taking aspirin varies by age because of increased harms in older age groups.

CVD risk factors are detected. Focus on the individual's risk of MI or stroke, the potential benets and harms of aspirin therapy, and patient preferences.

74

U.S. Preventive Services Task Force recommends aspirin 81 mg daily for: Men Age 45 to 59 years with 10-year CVD risk of at least 4% Age 60 to 69 years with 10-year CVD risk of at least 9% Age 70 to 79 years with 10-year CVD risk of at least 12% Women Age 50 to 59 years with 10-year stroke risk of at least 3% Age 60 to 69 years with 10-year stroke risk of at least 8 % Age 70 to 79 with 10-year stroke risk of at least 11%

factors; 10-year CVD risk under 5%) as the potential adverse effects from bleeding offset the potential benets Low-dose aspirin use for prevention might be considered for those with diabetes at intermediate CVD risk (younger patients with 1 or more risk factors, or older patients with no risk factors, or patients with 10-year CVD risk of 5% to 10%) until further research is available

American Diabetes Association and American Heart Association jointly recommend: Low-dose (75162 mg/d) aspirin use for prevention for adults with diabetes and no previous history of vascular disease with 10-year CVD risk>10% This includes adults with diabetes at increased CVD risk: most men >50 years and women >60 years who have 1 or more additional major risk factors such as smoking, hypertension, dyslipidemia, family history of premature CVD, and albuminuria

Current data suggest that aspirin is underutilized, both for primary and secondary prevention. Approximately 40% of adults over age 40 in the United States have the metabolic syndrome and a 10-year risk of a rst cardiac event of 16% to 18%. Thus, wider use of aspirin in such patients seems warranted. A single daily dose of 81 mg aspirin is appropriate for primary prevention.

Aspirin should not be recommended for CVD prevention for adults with diabetes at low CVD risk (men under age 50 years and women under 60 years with no major additional CVD risk

75