Note: Authors from the National Institutes of Health/National Heart, Lung, and Blood Institute represent themselves and not the opinions of the National Institutes of Health/National Heart, Lung, and Blood Institute. The American Heart Association, the American College of Cardiology, and American Society of Hypertension make every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This document was approved by the American Heart Association Science Advisory and Coordinating Committee on September 22, 2014, by the American College of Cardiology on October 10, 2014, and by the American Society of Hypertension on September 30, 2014. The American Heart Association requests that this document be cited as follows: Rosendorff C, Lackland DT, Allison M, Aronow WS, Black HR, Blumenthal RS, Cannon CP, de Lemos JA, Elliott WJ, Findeiss L, Gersh BJ, Gore JM, Levy D, Long JB, O Connor CM, O Gara PT, Ogedegbe G, Oparil S, White WB; on behalf of the American Heart Association, American College of Cardiology, and American Society of Hypertension. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. Hypertension. 2015;65:1372 1407. This article has been copublished in Circulation, the Journal of the American College of Cardiology, and the Journal of the American Society of Hypertension. Copies: This document is available on the World Wide Web sites of the American Heart Association (my.americanheart.org), the American College of Cardiology (www.cardiosource.org), and the American Society of Hypertension (http://www.ash-us.org/). A copy of the document is available at http:// my.americanheart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase additional reprints, call 843-216- 2533 or e-mail kelle.ramsay@wolterskluwer.com. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the Policies and Development link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page. 2015 by the American Heart Association, Inc., the American College of Cardiology Foundation, and American Society of Hypertension, Inc. Treatment of Hypertension in Patients With Coronary Artery Disease A Scientific Statement From the American Heart Association, American College of Cardiology, and American Society of Hypertension Clive Rosendorff, MD, PhD, DScMed, FAHA, FACC, FASH, Chair; Daniel T. Lackland, DrPH, FAHA, FASH, Co-Chair; Matthew Allison, MD, FAHA; Wilbert S. Aronow, MD, FAHA, FACC; Henry R. Black, MD, FAHA, FASH; Roger S. Blumenthal, MD, FAHA, FACC; Christopher P. Cannon, MD, FAHA, FACC; James A. de Lemos, MD, FAHA, FACC; William J. Elliott, MD, PhD, FASH; Laura Findeiss, MD, FAHA; Bernard J. Gersh, MB ChB, DPhil, FAHA, MACC; Joel M. Gore, MD, FAHA, FACC; Daniel Levy, MD, FACC; Janet B. Long, MSN, FAHA; Christopher M. O Connor, MD, FACC; Patrick T. O Gara, MD, FAHA, FACC; Gbenga Ogedegbe, MD, MPH, FASH; Suzanne Oparil, MD, FAHA, FACC, FASH; William B. White, MD, FAHA, FASH; on behalf of the American Heart Association, American College of Cardiology, and American Society of Hypertension AHA/ACC/ASH Scientific Statement Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYP.0000000000000018 Table of Contents 1. Relationship Between Hypertension and CAD 1374 1.1. Epidemiology of Hypertension and CAD 1374 1.1.1. Effects of Treatment 1374 1.1.2. Risk Factor Interactions 1376 1.1.3. Risk Factor Reduction 1376 1.1.4. Dyslipidemia 1376 1.1.5. Diabetes Mellitus 1377 1.1.6. Smoking 1377 1.1.7. Obesity 1377 1.1.8. Peripheral Artery Disease 1377 1.1.9. Chronic Kidney Disease 1378 1.2. Mechanisms of Hypertension and CAD 1378 1.2.1. Genetics 1378 1.2.2. Physical Forces and Hemodynamics 1378 1.2.3. Endothelial Dysfunction 1379 1.2.4. Oxidative Stress 1379 1.2.5. Humoral and Metabolic Factors 1379 1.2.6. Calcium 1380 Rosendorff et al Treatment of Hypertension in Patients With CAD 1373 This is an update of the American Heart Association (AHA) scientific statement Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: A Scientific Statement From the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention, published in 2007.1 A number of important studies have been published since that date that serve to modify or at least to further refine the recommendations of that statement, so an update was considered appropriate and timely. Because an AHA/American College of Cardiology (ACC)/American Society of Hypertension guideline on the treatment of hyper- tension in primary prevention is in process, this document is concerned with the epidemiology of hypertension and its treatment in secondary prevention, specifically in the setting of coronary artery disease (CAD). Epidemiological studies have established a strong asso- ciation between hypertension and CAD. Hypertension is a major independent risk factor for the development of CAD, stroke, and renal failure. The optimal choice of antihyperten- sive agents remains controversial, and there are only partial answers to important questions in the treatment of hyperten- sion for the prevention and management of ischemic heart disease (IHD): What are the appropriate systolic blood pressure (SBP) and diastolic blood pressure (DBP) targets in patients with established CAD? Are the beneficial effects of treatment simply a function of blood pressure (BP) lowering, or do particular classes of drugs have uniquely protective actions in addition to lowering BP? Are there antihypertensive drugs that have shown par- ticular efficacy in the secondary prevention of IHD? Which antihypertensive drugs should be used in patients who have established CAD with stable angina pectoris, in those with acute coronary syndrome (ACS), which in- cludes unstable angina pectoris (UA), non ST-segment elevation myocardial infarction (NSTEMI), and ST- elevation myocardial infarction (STEMI), and in those with heart failure (HF) caused by CAD? This scientific statement summarizes the published data relating to the treatment of hypertension in the context of Prevention of Cardiovascular Events in Patients With Hypertension and CAD 1380 Antihypertensive Drugs for the Secondary Prevention of Cardiovascular Events in Patients With CAD 1380 Thiazide and Thiazide-Type Diuretics 1380 -Blockers 1380 2.1.3. ACE Inhibitors 1380 Angiotensin Receptor Blockers 1381 2.1.5. Aldosterone Antagonists 1381 Calcium Channel Blockers 1382 Direct Renin Inhibitors 1382 3. BP Goals 1382 Epidemiology and Coronary Physiology 1382 3.1.1. Epidemiological Studies 1382 3.1.2. Coronary Perfusion, Autoregulation, and the J-curve 1382 3.2. Clinical Studies 1383 Lower BP With a Surrogate Outcome 1383 Observational Studies and Clinical Trials 1383 Clinical Trials to Specifically Evaluate Lower BP Goals 1384 Lower BP Goals and Diabetes Mellitus . 1384 Lower BP Goals for the Prevention of Stroke 1385 3.2.6. The Elderly 1385 3.2.7. Conclusions 1385 3.3. Recommendations 1386 Management of Hypertension in Patients With CAD and Stable Angina 1386 4.1. Pharmacological Therapy 1386 -Blockers 1386 Calcium Channel Blockers 1386 4.1.3. ACE Inhibitors 1387 Angiotensin Receptor Blockers 1387 4.1.5. Diuretics 1387 4.1.6. Nitrates 1388 4.2.  Recommendations 1388 Management of Hypertension in Patients With ACS 1388 5.1. Prevalence and Impact on Prognosis 1388 General Principles of BP Management in the Patient With ACS 1389 5.3. Specific Antihypertensive Agents in ACS 1389 5.3.1. Nitroglycerin 1389 -Blockers 1390 Calcium Channel Blockers 1390 5.3.4. ACE Inhibitors 1390 Angiotensin Receptor Blockers 1391 5.3.6. Aldosterone Antagonists 1391 5.3.7. Diuretics 1391 Safety of Anticoagulation in Patients With Uncontrolled Hypertension 1391 5.5. Conclusions 1391 5.6. Recommendations 1392 Management of Hypertension in HF of Ischemic Origin 1392 Hypertension and HF 1392 6.2. Demographics 1392 Hypertension and HF Pathophysiology 1393 CAD and Acute HF 1393 6.5. Therapeutic Strategies 1393 6.6. Nonpharmacological Therapies 1393 6.7. Pharmacological Therapies 1393 6.7.1. Diuretics 1393 6.7.2. ACE Inhibitors 1394 Angiotensin Receptor Blockers 1394 -Blockers 1394 Nitrates and Hydralazine 1395 6.7.6. Aldosterone Receptor Antagonists 1395 6.8. Renal Denervation 1395 6.9. Goal BP 1395 6.10. Drugs to Avoid 1395 6.11. Recommendations 1396 CAD prevention and management. It attempts, on the basis of the best available evidence, to develop recommendations that will be appropriate for both BP reduction and the man- agement of CAD in its various manifestations. When data are meager or lacking, the writing group has proposed consensus recommendations and has highlighted opportunities for well- designed prospective clinical trials to fill knowledge gaps. All of the discussion and recommendations refer to adults. The writing committee has not addressed hypertension or IHD in the pediatric age group. In addition, there is no discussion of the different modes of assessing BP, including 24-hour ambulatory BP monitoring. These were the subject of an AHA scientific statement in 2005.2 Recommendations, with levels of evidence, have been developed according to the AHA format shown in Table 1. The general design of the scientific statement is based on the concept that each of the clinical sections refers to a particular subset of patients, so each section should pro- vide a stand-alone description of the recommendations and their justification independently of the other sections. This should make it easier for practitioners to extract the infor- mation relevant to any particular patient without needing to cross-reference, and we hope it will thereby increase the utility of this document. With this organization, there may be some repetition of information from one section to the next, but we have tried to keep that to a minimum. A summary of the main recommendations is presented in Tables 2 and 3. 1. Relationship Between Hypertension and CAD 1.1. Epidemiology of Hypertension and CAD Hypertension is a major independent risk factor for CAD for all age/race/sex groups. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure3 uses the traditional definition of hypertension as an SBP of 140 mmHg or a DBP of 90 mmHg and/or the current use of antihyperten- sive medication. With this definition, an estimated 65 million adult Americans, or nearly one fourth of the adult population of the United States, have hypertension.Another quarter of the population have prehypertension, defined as an SBP of 120 to 139 mmHg or a DBP of 80 to 89 mmHg. The forms of BP elevation differ as a function of age, with DBP elevation predominating in young hypertensive indi- viduals and systolic hypertension, often in isolation (isolated systolic hypertension), emerging in older age. The prevalence of hypertension is thus directly proportional to the age of the population, with more than half of Americans >65 years of age having a high BP. The Framingham Heart Study has esti- mated the remaining lifetime risk of developing hypertension at 90% for men and women not yet hypertensive by middle In addition, there is a change with age in the relative importance of SBP and DBP as risk indicators. Before 50 years of age, DBP is the major predictor of IHD risk, whereas after 60 years of age, SBP is more important.5 It is important to note that, in this population 60 years of age, DBP becomes inversely related to CAD risk and pulse pressure becomes the strongest predictor for CAD. In a meta-analysis of 61 studies that included almost 1 million adults,6 BP was related to fatal CAD over the BP range of 115/75 to 185/115 mmHg for all ages. Overall, each increase in SBP of 20 mmHg (or each 10-mmHg increase in DBP) doubles the risk of a fatal coro- nary event. Epidemiological studies have also shown that an elevated BP is the most important determinant of the risk of stroke. The risk is almost linear, beginning at relatively low levels of SBP and DBP,7 and the lowering of high BP is a major factor in the impressive reduction in the stroke death rates during the last half of the 20th century and the early part of the 21st The absolute risk of these adverse outcomes also increases with age. For any given SBP, the risk of fatal CAD was 16- fold higher for people 80 to 89 years of age than for those In the Chicago Heart Association Detection Project in Industry, men 18 to 39 years of age at baseline with a BP of 130 to 139/85 to 89 mm Hg or with stage 1 hypertension (140 159/90 99 mm Hg) accounted for nearly 60% of all excess IHD, overall cardiovascular disease (CVD), or all-cause mortality.9 Epidemiological data show that lower BP levels are associated with lower disease risks, suggesting that future coronary events can be prevented by reducing BP.10 Elevated BP represents a sub- stantial population-attributable risk for men and women, both black and white.11,12 1.1.1. Effects of Treatment The risk of CVD in the patient with hypertension has been shown to be greatly reduced with effective antihypertensive therapy. Major reductions in CVD morbidity and mortality over the past 50 years have been attributed to the increased availability and use of drug treatment for hypertension. Randomized trials have shown that BP lowering in patients with hypertension produces rapid reductions in cardiovascu- that are highly consistent with data from observa- tional studies. For example, a 10-mmHg lower usual SBP (or a 5-mmHg lower usual DBP) is associated with a 50% to 60% lower risk of stroke death and an 40% to 50% lower risk of death resulting from CAD or other vascular causes at middle age, benefits that are only slightly smaller in older However, in one study, high blood pressure in the very elderly (>85 years) was not a risk factor for mortal- ity, irrespective of a history of hypertension. Whereas blood pressure values below 140/70 mm Hg were associated with Likewise, there are inconsistencies across end points in the older population, with a significant associa- tion of lower BP with lower stroke deaths and HF but not with a lower rate of myocardial infarction (MI) in patients Several studies (Heart Outcomes Prevention Evaluation Survival and Ventricular Enlargement [SAVE],17 and European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease [EUROPA])18 have shown a beneficial effect of angiotensin-converting enzyme (ACE) inhibitors on CVD outcomes in individuals, some hypertensive and some not, but all with established CVD or at high risk for its development. However, we do not yet have outcome studies of treatment of prehypertension Rosendorff et al Treatment of Hypertension in Patients With CAD 1375 in individuals with BPs in the range of 130 to 139/80 to 89 mmHg. The only prospective clinical trial of BP reduction in individuals with normal BPs is the Trial of Preventing Hypertension (TROPHY) study,19 in which subjects with an SBP of 130 to 139 mmHg or a DBP of 85 to 89 mmHg were randomized to be treated for 2 years with either the angio- tensin receptor blocker (ARB) candesartan or placebo and followed up for an additional 2 years. Hypertension devel- oped in significantly (P<0.007) more participants in the pla- cebo group (two thirds of this cohort at 4 years) than in the candesartan group, with a relative risk reduction of 66.3% at 2 years and 15.6% at 4 years. In addition, the treatment of prehypertension with candesartan appeared to be well toler- ated, and serious adverse events occurred in 3.5% and 5.9% in patients treated with candesartan and placebo, respectively. However, the study was not designed or powered to assess CVD outcomes. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, with a mean follow-up of 4.7 years, a tar- get BP of <120 compared with <140 mmHg was not associ- ated with a reduced risk of a composite of CVD events (heart attack, a stroke, or a cardiovascular death).20 However, the incidence of stroke was significantly less in the intensively treated group. Table 1. Applying Classification of Recommendations and Levels of Evidence. A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. 1.1.2. Risk Factor Interactions Data from the Framingham Heart Study have provided evi- dence of a predictive role of hypertension, dyslipidemia, glucose intolerance, cigarette smoking, and left ventricular (LV) hypertrophy in CVD.21 These 5 primary risk factors are the most important modifiable determinants of CVD risk and appear to operate independently of one another. This has led to the idea that the threshold at which a patient should be treated for hypertension should be determined by a patient s burden of CVD risk factors, which in turn deter- mine the level of CVD risk. In the guidelines developed by the National Kidney Foundation,22 this principle has been followed for patients with albuminuria and even modest chronic renal insufficiency, for which the BP threshold for the initiation of antihypertensive therapy is 130/80 mm Hg. The American Diabetes Association has based its recom- mendation on age: People with diabetes mellitus should be treated to a BP of <140/80 mm Hg, except that lower systolic targets, such as <130 mm Hg, may be appropri- ate for certain individuals, such as younger patients, if it can be achieved without undue treatment burden. 23 Furthermore, there is a correlation between hypertension and body mass index, with both strongly correlated with CAD. Hypertension and abdominal obesity are components of a larger risk factor constellation of cardiovascular risk factors, the metabolic syndrome, which also includes a characteristic form of dyslipidemia (high triglycerides and low high-density lipoprotein cholesterol) and an elevated fasting blood glucose level.24 1.1.3. Risk Factor Reduction Hypertension, dyslipidemia, diabetes mellitus, cigarette smoking, obesity, and chronic kidney disease (CKD) are independent determinants of CVD risk. Moreover, a diagno- sis of peripheral artery disease (PAD) significantly increases the risk for both prevalent and incident disease in other vascular beds including the coronary and cerebral circula- As indicated previously, hypertension represents an independent risk factor for CVD, and evidence indicates that the concomitant presence of other recognized cardiovascu- lar risk factors results in a multiplicative increase in risk for cardiovascular events. Some current guidelines call for more aggressive BP management in the presence of other cardio- vascular risk factors, and BP reduction without attention to other risk factors is inadequate to reduce cardiovascular risk. Readers should be aware that several recently published guideline documents detail the strategies for risk assessment and management. The recommendations in this document reflect the published guidelines, but readers are advised to consult other recent guidelines such as those on the assess- ment of cardiovascular risk,27 lifestyle management, particu- larly as it relates to diet and exercise,28 and the management Cardiovascular risk factors may be described as nonmodifi- able or modifiable. The nonmodifiable risk factors of age, sex, race/ethnicity, and genetic predisposition/family history are not addressed in this report. The potentially modifiable risk factors include dyslipidemia, diabetes mellitus, smoking, obe- sity, PAD, and renal insufficiency. The management of dyslipidemia was the subject of a recent In essence, the new guideline does not support continued use of specific low-density lipoprotein (LDL) cholesterol or non high-density lipoprotein cholesterol treatment targets. The guideline advocates the use of a 10-year risk calculator to Table 2. Summary of Pharmacological Treatment of Hypertension in the Management of Ischemic Heart Disease. ACEI or ARB Diuretic -Blocker Non-DHP CCB DHP CCB Nitrates Aldosterone Antagonist Hydralazine/ Isosorbide Dinitrate ACEI indicates angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; DHP, dihydropyridine; HF, heart failure; 1, drug of choice; and 2, add-on, alternative drug, or special indications. *Especially if prior myocardial infarction, left ventricular systolic dysfunction, diabetes mellitus, or proteinuric chronic kidney disease is present. Chlorthalidone is preferred. Loop diuretic should be used in the presence of HF (New York Heart Association class III or IV) or chronic kidney disease with glomerular . Caution should be exercised in HF with preserved ejection fraction. If -blocker is contraindicated, a non-DHP CCB can be substituted, but not if left ventricular dysfunction or HF is present. Caution should be exercised if combining a non-DHP CCB with a -blocker. Esmolol (intravenous) or metoprolol or bisoprolol (oral). Spironolactone or eplerenone if left ventricular dysfunction, HF, or diabetes mellitus is present. Carvedilol, metoprolol succinate, or bisoprolol. Table 3. Summary of BP Goals BP Goal, mmHg Condition Class/Level of Evidence <140/90 CAD IIa/B ACS IIa/C HF IIa/B <130/80 CAD IIb/B Post myocardial infarction, stroke or TIA, carotid artery disease, PAD, AAA IIb/B AAA indicates abdominal aortic aneurysm; ACS, acute coronary syndrome; BP, blood pressure; CAD, coronary artery disease; HF, heart failure; PAD, peripheral arterial disease; and TIA, transient ischemic attack. Rosendorff et al Treatment of Hypertension in Patients With CAD 1377 determine the appropriate intensity of statin therapy to reduce CVD risk in those most likely to benefit. Those patients with CVD and age 75 years, with LDL cholesterol 190 mg/dL, or with a 10-year CVD risk 7.5% should receive high- intensity statin therapy (eg, atorvastatin 40 80 mg/d or rosuvastatin 20 40 mg/d to reduce LDL cholesterol by approximately 50%). Those with CVD who are >75 years of age or those with diabetes mellitus but with a 10-year risk of <7.5% should receive moderate-intensity statin therapy such as simvastatin 20 to 40 mg/d, atorvastatin 10 to 20 mg/d, or rosuvastatin 5 to 10 mg/d to decrease LDL cholesterol by 30% to 50%. According to the guideline, nonstatin therapies do not provide acceptable CVD risk reduction benefits compared with their potential for adverse effects in the routine prevention of CVD. 1.1.5. Diabetes Mellitus Type 2 diabetes mellitus is defined as a fasting plasma glucose 126 mg/dL, a 2-hour oral glucose tolerance test value 200 mg/dL, hemoglobin A1C 6.5%, or random plasma glucose 200 mg/dL in a patient with classic symptoms of hypergly- Type 2 diabetes mellitus is a strong and independent risk factor for coronary heart disease. So strong is this associa- tion that a diagnosis of diabetes mellitus could be considered a coronary heart disease risk equivalent,24 although this is con- Hypertensive patients with type 2 diabetes mel- litus are also at increased risk for diabetes mellitus specific complications, including retinopathy and nephropathy. The pharmacological management of diabetes mellitus is beyond the scope of this review. Diabetes mellitus care is complex and requires that many issues, beyond glycemic con- trol, be addressed. There is general consensus that smoking increases the risk of cardiovascular events. Many studies have shown a correlation between smoking and death. Life expectancy is reduced by 13.2 years in male smokers compared with nonsmokers, and this trend is stronger in female smokers, with a 14.5-year decrease in life expectancy.32 Cigarette smoking independently predicts increased risk of cardiac arrest in patients with CAD,33 and even exposure to secondhand smoke increases the risk of develop- ing CAD by 25% to 30%.34 As with other risk factors, there is a synergistic increase in cardiovascular risk in smokers who have other, concurrent, cardiovascular risk factors. Elevated cholesterol confers a higher risk of cardiovascular events in smokers than in nonsmokers, and smokers disproportionately tend toward unfavorable lipoprotein profiles.35 In patients with hypertension, smokers are 5 times more likely to develop severe hypertension than nonsmokers, and smokers with severe hyper- tension have higher mortality rates than nonsmokers.36 It is encouraging that studies of smoking cessation dem- onstrate significant long-term reduction (15% over 14 years) in mortality in patients who participate in smoking cessation The prevalence of obesity, defined as a body mass index 30 , has increased in recent years, with 30% of the adult US population falling into this category.38 The positive rela- tionship between obesity and BP is well documented.39 41 Obese adults are 3 times more likely to be hypertensive compared with nonobese adults,40 42 and increased adiposity may explain >60% of hypertension in adults.40 Furthermore, obesity is considered a major risk factor for poor BP control in hypertensive patients.3 Although the mechanisms of obesity-related hypertension are numerous, including activation of the sympathetic nervous system, sodium retention, activation of the renin-angiotensin- aldosterone system (RAAS), insulin resistance, and altered there is no acceptable guideline on the antihypertensive drug of choice for the management of hyper- tension among obese patients.3,44 Some investigators consider ACE inhibitors the drugs of choice for adequate BP control in obesity-related hyperten- sion because of their capacity to increase insulin sensitivity and thus reduce the risk of diabetes mellitus.45 This is in con- trast to thiazide diuretics, which are associated with increased risk of diabetes mellitus.46 That said, the efficacy of thiazide diuretics in lowering BP and improving cardiovascular out- comes in obese hypertensive patients is well established.47 -Blockers also have adverse effects on glucose metabo- lism but have led to significant improvement in BP in obese hypertensive patients because they decrease renin activity and cardiac output, which are often elevated in obese patients.48 However, enthusiasm for the use of -blockers as initial ther- apy is largely dampened by their negative profile on stroke outcomes compared with placebo and other antihypertensive There is abundant evidence in support of the effectiveness of lifestyle interventions in improving BP control among obese hypertensive patients. Recently, the AHA, ACC, and Obesity Society have published guidelines29 for the manage- ment of overweight and obesity in adults, including identi- fying patients who need to lose weight, matching treatment benefits with risk profiles, diets for weight loss, lifestyle inter- vention and counseling, and the selection of patients for bar- iatric surgery. There is also much useful information, particularly on diet and physical activity, in another AHA/ACC guidelines docu- ment on lifestyle management.28 1.1.8. Peripheral Artery Disease Treatment of hypertension in patients with PAD is associated with a significant reduction in the risk of MI, stroke, HF, and death. Similarly, intensive management of LDL is associated with significant reduction of cardiovascular events in patients Thus, management of hypertension in patients with PAD should be based on intensive screening for and aggressive management of other concomitant cardiovascular risk factors in addition to BP reduction.3 Particularly impor- tant in this regard is the management of dyslipidemia, smoking cessation, antiplatelet therapy, diabetes mellitus management, diet, and exercise. Currently, there is no recommended drug of choice for the treatment of hypertension in patients with PAD because clinical trials of antihypertensive drug agents such as ACE inhibitors, calcium channel blockers (CCBs), -adrenergic blockers, and direct vasodilators have been largely unsuccess- ful in improving symptoms of claudication or walking dis- tance in patients with PAD.51 53 Although -blockers constrict resistance vessels, a meta-analysis concluded that this drug class does not worsen intermittent claudication in patients with intermittent claudication.54 Thus, -blockers can be used in PAD patients with compelling indications for their use such as CAD or HF. The recommendations of the ACC/AHA 2005 prac- tice guidelines on PAD55 include the following: (1) Antihypertensive therapy should be administered to hyperten- sive patients with lower-extremity PAD to achieve a goal of <140/90 mmHg (nondiabetics) or <130/80 mmHg (diabetics and individuals with chronic renal disease) to reduce the risk of MI, stroke, congestive HF, and cardiovascular death (Level of Evidence A); (2) -adrenergic blocking drugs are effective antihypertensive agents and are not contraindicated in patients with PAD (Level of EvidenceA); (3) the use ofACE inhibitors orARBs is reasonable for patients with symptomatic (Level of Evidence B) or asymptomatic (Level of Evidence C) leg PAD. 1.1.9. Chronic Kidney Disease There has been a steady increase in the prevalence of CKD, defined as kidney damage, documented by kidney biopsy or serum markers for 3 months, or a decrease in glomerular filtration rate to <60 mL min 1 Kidney failure, defined as a glomerular filtration rate of <15 , and end-stage renal disease, which neces- sitates the initiation of treatment by replacement therapy,22 afflicts >525000 patients in the United States, 65% of whom are on long-term hemodialysis.56 Hypertension represents a major independent risk factor for renal failure, with a preva- lence of 28% in hypertensive patients.56 In patients with CKD, cardiovascular death is more likely than progression to end- stage renal disease, and in patients with end-stage renal dis- ease, CVD is the leading cause of death, being 5 to 30 times higher in patients on dialysis than in the general population.57 Even in patients with lower stages of CKD, the risk of CVD is increased independently of other risk factors, and even the smallest degree of albuminuria increases risk for CVD and all- In this patient population, hypertension itself is a leading cause of renal failure. BP goals in patients with CKD and microalbuminuria are lower than in the general popula- with a target the same as that in patients with estab- lished CAD. Recent investigations have demonstrated that standard treatments for cardiovascular risk factors, including statin therapy, ACE inhibitors, ARBs, and antiplatelet agents, are equally effective at risk reduction in patients with CKD (who are not on dialysis) as in those without CKD and should be offered to this patient population.59 In these patients, the serum potassium concentration should be monitored fre- quently. Questions remain as to whether directly addressing nontraditional risk factors in patients with early evidence of renal impairment has efficacy in terms of outcomes. 1.2. Mechanisms of Hypertension and CAD A variety of pathophysiological mechanisms contribute to the genesis of BP elevation and related target-organ dam- age, including CAD. These mechanisms include increased sympathetic nervous system and RAAS activity; deficiencies in the release or activity of vasodilators, for example, nitric oxide and prostacyclin, and changes in the natriuretic peptide concentration; increased expression of growth factors and inflammatory cytokines in the arterial tree; hemodynamic effects; and structural and functional abnormalities in conduc- tance and resistance arteries, particularly increased vascular stiffness and endothelial dysfunction.60 These neurohumoral pathways interact with genetic, demographic, and environ- mental factors (such as heightened exposure or response to psychosocial stress, excessive dietary intake of sodium, and inadequate dietary intake of potassium and calcium) to deter- mine whether a person will develop hypertension and related CAD. Concomitant metabolic disorders, for example, diabe- tes mellitus, insulin resistance, and obesity, also lead to the production of vasoactive adipocytokines that promote vaso- constriction, endothelial dysfunction, inflammation, and increased oxidative stress in the vasculature, thus increasing both BP and CVD risk.61,62 These shared pathophysiological mechanisms offer potential novel therapeutic targets for the prevention and treatment of both hypertension and CAD, with benefits that may go beyond BP lowering. Genome-wide association studies have identified multiple genetic susceptibility variants, mostly single-nucleotide poly- morphisms, for atherosclerotic disease.63 It has been suggested the polymorphisms of genes of the RAAS, particularly ACE, angiotensin II receptor type 1, and angiotensinogen, are impli- cated in the development of CAD and MI.64,65 The presence of hypertension further increases the risk of CAD and may explain why some individuals are more predisposed than oth- ers to developing coronary events. Some polymorphisms have also been implicated in the BP response to antihypertensive treatment. For example, genetic polymorphisms coding for the matrix metalloproteinases appear to modify CVD outcomes in hypertensive patients treated with chlorthalidone, amlodipine, These data suggest that, in the future, determi- nation of genetic variants may be of some use for selecting appropriate antihypertensive agents to reduce both BP and the risk for CAD. However, because CAD is polygenic and its causes are multifactorial, genetic studies explain only a small proportion of the heritability of the disease.67 1.2.2. Physical Forces and Hemodynamics Physical forces (pressure and flow) are the primary determi- nants of cardiac structure and function and influence coro- nary arterial remodeling and atherosclerosis. When SBP is elevated, both LV output impedance and intramyocardial wall tension increase, resulting in increased myocardial oxygen demand. The wide pulse pressure and systolic hypertension in older individuals are usually attributable to inappropriately high aortic impedance, which results from decreased aortic diameter or increased effective stiffness caused by aortic wall thickening and changes in wall composition. Aging is associ- ated with thinning and fragmentation of vascular elastin and increased collagen deposition, a degenerative process that causes increased arterial stiffness (reduction of elasticity) with an associated elevation in SBP and widening of the pulse Rosendorff et al Treatment of Hypertension in Patients With CAD 1379 Increased arterial stiffness elevates SBP by increasing pulse-wave velocity and altering wave reflection from the With each ejection of blood from the LV, a pressure (pulse) wave is generated and travels from the heart to the periphery at a pulse-wave velocity that depends on the elastic properties of the conduit arteries. The pulse wave is reflected at any point of discontinuity in the arterial tree and returns to the aorta and LV. The elastic properties and length of the conduit arteries determine the timing of the In younger people, the pulse-wave velocity is sufficiently slow ( 5 m/s) that the reflected wave reaches the aortic valve after closure, leading to a higher DBP and enhancing coronary perfusion by providing a boosting effect. In older people, particularly those who are hyper- tensive, pulse-wave velocity is greatly increased ( 20 m/s) because of central arterial stiffening. Thus, the reflective wave reaches the aortic valve before closure, leading to the higher SBP, pulse pressure, and afterload and a lower DBP. The increase in SBP increases cardiac metabolic require- ments and predisposes to the development of LV hypertro- phy and HF. Pulse pressure is closely related to SBP and is linked to CVD events, including MI and stroke. Aortic stiff- ness is an independent predictor of all-cause and cardiovas- cular mortality, fatal and nonfatal coronary events, and fatal stroke in patients with hypertension, type 2 diabetes mel- litus, and end-stage renal disease.73 1.2.3. Endothelial Dysfunction Endothelial dysfunction, characterized by an unfavorable balance between vasodilators, for example, nitric oxide and , and vasoconstrictors, for example, endo- thelin and angiotensin II, is an important contributor to BP elevation in people with vascular disease. The injured endothelium loses its vasodilator capacity and contributes to thrombosis and vascular occlusion. Release of chemotac- tic cytokines and adhesion molecules at the luminal surface of the injured endothelium promotes adhesion of circulat- ing mononuclear leukocytes to the vessel wall. This low- grade, self-perpetuating vascular inflammation underlies the atherosclerotic process. Inflammatory mediators activate medial smooth muscle cells, causing them to proliferate and migrate into the subintimal space. In the presence of dyslip- idemia, monocytes in the vessel wall incorporate oxidized low-density lipoprotein cholesterol and become lipid-laden macrophages, the core of the atherosclerotic plaque. In established lesions, resident macrophages secrete metal- loproteinases and cathepsins, destabilizing the fibrous cap of the plaque, which may result in plaque rupture and the release of tissue factor to cause thrombosis, coronary occlu- sion, and acute MI. Endothelial dysfunction and decreased nitric oxide avail- ability related to mechanical and inflammatory injury of arter- ies are also associated with increased arterial stiffness and the development of isolated systolic hypertension.75 A decline in flow-mediated vasodilator capacity attributable to decreased endothelium-derived nitric oxide occurs in aging and subclini- cal vascular disease.76 Impaired endothelium-mediated vaso- dilation is responsible for the exaggerated exercise-induced increases in BP seen in these population groups.77 1.2.4. Oxidative Stress Oxidative stress is a critical feature of both hypertension and In vascular tissue, the principal effectors of oxidative injury are the NAD(P)H oxidases, which are acti- vated by mechanical forces (eg, hypertension), hormones (particularly angiotensin II), oxidized cholesterol, and cyto- kines. Several NAD(P)H oxidase isoforms expressed in endo- thelial and vascular smooth muscle cells are upregulated in the setting of atherosclerosis and arterial injury. Angiotensin II receptor dependent activation of NAD(P)H oxidase stim- ulates formation of oxidant superoxide anion (O2 ), which reacts with nitric oxide to form the powerful oxidant per- oxynitrite (ONOO ). The resultant reduction in nitric oxide bioactivity contributes to the vasoconstrictor response to angiotensin II and elevates BP. Angiotensin II induced activa- tion of NAD(P)H oxidase also stimulates oxidation of low- density lipoprotein cholesterol and increases the expression of monocyte chemoattractant protein-1 and vascular cell adhe- sion molecule-1, thus linking activation of the RAAS to the atherosclerotic process. 1.2.5. Humoral and Metabolic Factors Many of the mechanisms that initiate and maintain hyper- tension also damage target organs, including the coronary arteries and the myocardium. Angiotensin II elevates BP and promotes target-organ damage, including atherosclerosis, by mechanisms that include direct effects on constriction and remodeling of resistance vessels, stimulation of aldosterone synthesis and release, enhancement of sympathetic outflow from the brain, and facilitation of catecholamine release from the adrenals and peripheral sympathetic nerve terminals.1 Aldosterone can mimic or potentiate the vasotoxic properties of angiotensin II and norepinephrine. Angiotensin II promotes cardiac and vascular smooth muscle cell hypertrophy directly via activation of the angiotensin II type 1 (AT1) receptor and indirectly by stimulating expression of a number of growth factors, cytokines, and adhesion molecules. AT1 receptor activation also contributes to endothelial damage and athero- genesis by inhibiting the mobilization of endothelial progeni- tor cells from the bone marrow, thus impairing endothelial regeneration and vascular repair processes.78 There is also a link between RAAS activation and fibrinolysis. Angiotensin II induces the formation of plasminogen activator inhibitor-1 via an AT1 receptor dependent effect on endothelial cells, whereas ACE downregulates tissue plasminogen activator production by degrading bradykinin, a potent stimulator of endothelial tissue plasminogen activator expression. ACE inhibitors and ARBs limit oxidative reactions in the vasculature by blocking the activation of NAD(P)H oxi- dase, supporting the concept that these RAAS blockers may have important vasoprotective effects beyond BP lowering.79 Furthermore, there is evidence of interaction between the RAAS and dyslipidemia: Hypercholesterolemia upregulates the RAAS, particularly vascularAT1 receptor density and func- tional responsiveness, and systemic angiotensin II peptide syn- whereas the RAAS stimulates the accumulation of low-density lipoprotein cholesterol in the arterial wall. These findings suggest that these antihypertensive drug classes may have clinically important vasoprotective effects beyond BP lowering. This hypothesis has yet to be supported by the results of randomized, controlled trials.82 Recent evidence suggests that a second angiotensin II receptor subtype (AT2), which is not expressed in the normal vasculature but appears to be induced in the setting of vascular inflammation/hypertension/atherosclerosis, may oppose the vasoconstrictor, antinatriuretic, and proinflammatory effects Because of the apparent vasoprotective effects of AT2 receptor activation, AT2 receptor agonists have been considered for the treatment of hypertension,84 but there is no evidence that they are effective in treating hypertension in humans. Calcium ions (Ca2+ ) are major intracellular mediators of vas- cular smooth muscle cell contraction and inotropic and chro- notropic functions of the heart. Ca2+ enters vascular smooth muscle cells, cardiomyocytes, and pacemaker cells via volt- age-dependent L- and T-type calcium channels. In vascular smooth muscle, the voltage-gated L-type (long-acting, slowly activating) channel allows entry of sufficient Ca2+ for the ini- tiation of contraction by calcium-induced intracellular Ca2+ release from the sarcoplasmic reticulum. Increased intracel- also has atherosclerosis-promoting effects. The dihydropyridine CCBs bind to the 1 subunit of the L-type channel and are highly selective for arterial/arterio- lar tissues, including the coronary arteries, where they are vasodilators. The nondihydropyridine CCBs, including the phenylalkylamines (verapamil-like) and benzothiazepines (diltiazem-like), bind to different sites on the 1 subunit and are less selective for vascular tissue; they have nega- tive chronotropic and dromotropic effects on sinoatrial and atrioventricular nodal conducting tissue and negative ino- tropic effects on cardiomyocytes. The nondihydropyridine CCBs have greater effects on the atrioventricular node than on the sinoatrial node and may predispose to high-degree atrioventricular block in patients with preexisting atrioven- tricular nodal disease or when given with other agents, for example, -blockers, that depress the atrioventricular node. Both CCB subclasses are indicated for the treatment of hypertension and angina pectoris. The antianginal effects of CCBs result from afterload reduction, that is, their ability to decrease SBP, as well as coronary vasodilation and, in the case of nondihydropyridine CCBs, heart rate slowing. CCBs are particularly effective in treating angina caused by coronary spasm, for example, the Prinzmetal variant or 2. Prevention of Cardiovascular Events in Patients With Hypertension and CAD 2.1. Antihypertensive Drugs for the Secondary Prevention of Cardiovascular Events in Patients With CAD Meta-analyses of antihypertensive trials have demonstrated that BP lowering is more important than the particular drug class used in the primary prevention of the complications of hypertension, including IHD. Combination antihypertensive drug therapy is typically needed to achieve and to sustain effective long-term BP control. Thus, there is no evidence to support initiating therapy with any one antihypertensive drug class over another for the primary prevention of IHD. In con- trast, for secondary protection in individuals with underlying comorbid illnesses such as IHD, CKD, or recurrent stroke, not all drug classes have been proven to confer optimal or even the same level of benefit. Whether there are class effects for antihypertensive drugs and whether each drug should be considered individually on the basis of trial results are not clearly known. It is reasonable to assume that there are class effects for thiazide and thiazide- type diuretics, ACE inhibitors, and ARBs, which have a high degree of homogeneity in both their mechanisms of action and side effects.13,86,87 There are major pharmacological dif- ferences between drugs within more heterogeneous classes of agents such as the -blockers and CCBs.88,89 Finally, the most recent trials suggest that combining ACE inhibitors and ARBs is not beneficial for the secondary prevention of cardiovas- whereas combinations of renin-angiotensin blocking agents with thiazide diuretics or with CCBs show important clinical benefits.92 2.1.1. Thiazide and Thiazide-Type Diuretics Thiazide diuretics and the thiazide-type diuretics chlorthali- done and indapamide are highly effective in reducing BP and preventing cerebrovascular events, as demonstrated most con- vincingly in early studies such as the Veterans Administration the Medical Research Council (MRC) Trial,94 the Systolic Hypertension in the Elderly Program (SHEP),95 and the Hypertension in the Very Elderly Trial (HYVET).15 The benefit of chlorthalidone-based therapy in hypertension treatment is evident from the Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Since the publication of the results of ALLHAT, there have been concerns about whether thiazide-induced hyper- glycemia and diabetes mellitus contribute to long-term IHD risk not measured during the study interval,97 but this does not seem to be the case.98-100 -Blockers make up a heterogeneous class of antihyperten- sive drugs with differing effects on resistance vessels and on cardiac conduction and contractility. -Blocker administration remains the standard of care in patients with angina pectoris, those who have had an MI, and those who have LV dysfunc- tion with or without symptoms of HF unless contraindicated. The -blockers carvedilol, metoprolol, and bisoprolol have been shown to improve outcomes in patients with HF.1 2.1.3. ACE Inhibitors TheACE inhibitors are effective in reducing initial IHD events and are recommended for consideration in all patients after MI. They are proven to prevent and improve both HF101,102 and the progression of CKD.103 When combined with thiazide diuretics, ACE inhibitors reduce the incidence of recurrent Major trials have addressed the use of ACE inhibi- tors in patients with IHD but without HF or known significant LV systolic impairment. In the HOPE study,16 9297 high-risk patients, of whom 80% had a history of CAD, were assigned to receive either Rosendorff et al Treatment of Hypertension in Patients With CAD 1381 ramipril (10 mg once nightly) or placebo and followed up for a mean of 5.0 years. Treatment with ramipril was associ- ated with a 22% reduction in the composite end point of car- diovascular death, MI, and stroke (P<0.001) and comparably significant reductions in each of the individual components. There were also significant reductions in the rates of revascu- larization, cardiac arrest, HF, worsening angina, and all-cause mortality with ramipril therapy. The mean reduction in the clinic BP with active treatment was 3/2 mmHg. These car- diovascular benefits were initially thought to be independent of BP, but an interesting but very small HOPE substudy105 revealed a more marked reduction in 24-hour ambulatory BP with ramipril not observed in the main trial, which reported only the clinic BPs. In EUROPA, 12218 patients were randomized to the ACE inhibitor perindopril or placebo.18 Although just 27% of patients were classified as hypertensive, the definition of hypertension was based on a clinic BP >160/95 mmHg or antihypertensive therapy at baseline. The mean follow-up in EUROPA was 4.2 years. Treatment with perindopril (target dose, 8 mg daily) was associated with a 20% relative risk reduction in the composite end point of cardiovascular death, MI, or cardiac arrest (P<0.003). The benefit of active treat- ment with perindopril was similar for patients with or without hypertension as the investigators defined it. The mean reduc- tion in BP in the clinic setting was 5/2 mmHg. At baseline, EUROPA patients were at lower cardiovascular risk than HOPE patients: One third were <55 years of age; fewer had diabetes mellitus (12% versus 39%); and proportionately more EUROPA patients took antiplatelet (92% versus 76%) and lipid-lowering (58% versus 29%) drugs. Patients in the Prevention of Events With Angiotensin Converting Enzyme Inhibition (PEACE) trial106 had stable CAD and normal or slightly reduced LV function and were randomized to trandolapril (target dose, 4 mg) or placebo. Median follow-up was 4.8 years. No difference between the groups was found in the incidence of the primary compos- ite end point of cardiovascular death, MI, or coronary artery revascularization. Forty-six percent of patients were hyper- tensive, and treatment with trandolapril was associated with a mean reduction in BP of 4.4/3.6 mmHg. The annualized rate of all-cause mortality in PEACE was only 1.6%, a rate similar to that of an age- and sex-matched cohort without IHD. There was a relatively high use of revascularization before random- ization in the PEACE trial, which may have contributed to the low event rate. The investigators concluded that ACE inhibitors might not be necessary as routine therapy in low-risk IHD patients with preserved LV function, especially those who have received intensive treatment with revascularization and lipid-lower- ing agents. Thus, 2 large studies in high-cardiovascular-risk patients (HOPE and EUROPA) showed cardiovascular protec- tive effects by ACE inhibitors, and 1 study in low-cardiovas- cular-risk patients (PEACE) did not. The Ongoing Telmisartan Alone and In Combination with Ramipril Global Endpoint Trial (ONTARGET)90 trial random- ized 25620 patients, of whom 74% had a history of CAD, to the ACE inhibitor ramipril (10 mg/d), the ARB telmisar- tan (80 mg/d), or the combination of these 2 drugs. After a median follow-up of 4.7 years, there was no difference in the primary outcome of cardiovascular death, nonfatal MI, non- fatal stroke, and hospitalization for HF among the 3 groups. In the combination treatment group, there was an increased risk of hypotensive symptoms, syncope, and renal dysfunction compared with those in the ramipril group. The investigators concluded that ramipril and telmisartan had similar benefits but that the combination of the ACE inhibitor and ARB in this high-cardiovascular-risk group was associated with more side effects and no increase in benefit. 2.1.4. Angiotensin Receptor Blockers Several ARBs have been shown to reduce the incidence or severity of IHD events, the progression of renal disease in type 2 diabetes mellitus, and cerebrovascular events. ARBs are often considered to be an alternative therapy in individu- als with cardiovascular disease who are intolerant of ACE inhibitors. In the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study, protection against a composite of cardiovascular events that included MI and HF was similar to that observed for the CCB amlodipine.107 However, there were important differences in BP control in the early stages of the VALUE trial (a significant BP difference in favor of amlodipine) that may have confounded outcomes for MI and Beneficial cardiovascular outcomes were not shown in the Optimal Trial in Myocardial Infarction With the Angiotensin II Antagonist Losartan (OPTIMAAL).109 The lack of ben- efit may have been attributable to inadequate doses of losar- tan. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), the ARB valsartan had effects similar to those of the ACE inhibitor captopril in reducing cardiovascular event The combination of theARB with theACE inhib- itor yielded an increase in adverse events with no incremental benefit for cardiovascular events. In the Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease 5296 high-risk patients, of whom 75% had CAD, were randomized to telmisartan (80 mg daily) or placebo for a median duration of 4.7 years. The mean BP in the telmisartan group was 4.0/2.2 mmHg lower than that in patients randomized to placebo. The primary outcome of cardiovascular death, nonfatal MI, nonfatal stroke, and hospi- talization for HF occurred in 15.7% of the telmisartan group and 17.0% of the placebo group (P=0.216). The composite of cardiovascular death, nonfatal MI, and stroke occurred in 13% of patients on telmisartan versus 14.8% of the placebo group (P=0.048), and fewer patients in the telmisartan group had a cardiovascular hospitalization (30.3% versus 33%; P=0.025). The tolerability of telmisartan was similar to that of placebo. The investigators concluded that telmisartan had modest ben- efits on the composite outcome end point of cardiovascular death, MI, and stroke and was well tolerated. 2.1.5. Aldosterone Antagonists The aldosterone antagonists spironolactone and eplerenone lower BP alone or when added to other antihypertensive agents and have a protective effects in patients with chronic and advanced HF (in the Randomized Aldactone Evaluation in patients with LV dysfunction after MI (in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study [EPHESUS]),112 and in patients with chronic HF and mild symptoms (in the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure [EMPHASIS-HF]).113 In both RALES and EMPHASIS-HF, the majority of the subjects had IHD. 2.1.6. Calcium Channel Blockers CCBs form a heterogeneous class of agents that lower BP but have differing effects on cardiac conduction and myocardial contractility. In ALLHAT, the primary prevention of cardio- vascular events with the dihydropyridine CCB amlodipine was equivalent to that produced by the diuretic chlorthalidone or the ACE inhibitor lisinopril,96 and superiority over a -blocker was claimed in Anglo-Scandinavian Cardiac Outcomes Primary protection with verapamil-based therapy was shown to be similar to that of a diuretic (hydro- chlorothiazide) or a -blocker (atenolol) in the Controlled Onset Verapamil Investigation of Cardiovascular End Points and International Verapamil-Trandolapril In the Nordic Diltiazem (NORDIL) overall cardiovascular event rates were similar for diltiazem and a combination of diuretic and -blocker. Thus, CCBs are alternatives to -blockers in the treatment of angina pectoris but are not recommended for secondary cardiac pro- tection because of the relative lack of benefit of this class in particularly compared with ACE inhibitors96 2.1.7. Direct Renin Inhibitors The direct renin inhibitor aliskiren lowers BP alone or when added to other antihypertensive agents but has not been shown to have protective effects in patients with CVD, including In 2011, the Aliskiren Trial In Type 2 Diabetes Using Cardio-Renal Disease Endpoints (ALTITUDE) was stopped on the recommendation of its Data Monitoring Committee.119 ALTITUDE was comparing placebo with aliskiren 300 mg once daily added to background ACE inhibitor or ARB ther- apy in patients with diabetes mellitus and either increased urinary albumin excretion or both a reduced estimated glo- merular filtration rate and established CVD. The primary out- come in ALTITUDE was a composite of cardiovascular death, resuscitated sudden death, nonfatal MI, nonfatal stroke, hospi- talization for HF, end-stage renal disease, renal death, or dou- bling of baseline serum creatinine concentration, sustained for at least a month. The basis for stopping the trial was futility for success and safety concerns, including renal dysfunction, hyperka- lemia, hypotension, and an excess of strokes. The number of patients experiencing a nonfatal stroke in the placebo group was 85 (2.0%) and in the aliskiren group was 112 (2.6%; unadjusted P=0.04). Given prior data relating the use of antihypertensive therapy to a reduced incidence of stroke in patients with diabetes mellitus, it is possible that the imbal- ance in strokes represents a chance finding. Nevertheless, the general recommendation at present is to avoid the use of aliskiren in combination with another renin-angiotensin blocking agents in patients with hypertension for the pri- mary prevention of CVD. 3. BP Goals 3.1. Epidemiology and Coronary Physiology The overall goal of therapy is to reduce excess morbidity and unnecessary deaths. In the case of hypertension, dys- lipidemia, and diabetes mellitus, surrogate end points (BP, cholesterol, and blood glucose) have been established as diagnostic markers, and discrete values of these mark- ers have been established as therapeutic targets. A com- monly cited target for BP is <140/90 mmHg in general and <130/80 mmHg in some individuals with diabetes mellitus The first AHA scientific statement on the treat- ment of hypertension in the prevention and management of IHD also recommended a goal of <130/80 mmHg in individ- uals with established CAD, with CAD equivalents, or with a Framingham Risk Score of 10%.1 Some recent meta-analyses have suggested that the lower BP target for higher-risk patients is not supported by evi- dence from high-quality, randomized, clinical trials.120-122 Whether the lower BP goal is appropriate for the preven- tion of coronary disease and for the treatment of established coronary disease is the subject of intense debate. There is a historical trend for lower BP goals, especially in those with target-organ damage. Controversy remains, however, about specific BP treatment goals for individuals with nascent or overt CAD. On the one hand, it can be argued from patho- physiological principles that very low SBP values (ie, <120 mmHg) may be appropriate to reduce myocardial work- At the same time, there is a concern that excessive lowering of DBP may impair coronary perfusion. At present and despite the ACCORD study,20 discussed below, there is no consensus on the question of what the most appropriate BP target(s) should be in individuals with latent or overt CAD or prominent CAD risk factors. We believe, however, that reasonable recommendations can be developed from a synthesis of the results from relevant epidemiological stud- ies, consideration of the theoretical issue of the J curve, data from animal studies, human studies involving surrogate end points, and randomized, clinical trials targeting different BP goals with cardiovascular events as end points. 3.1.1. Epidemiological Studies Although epidemiological correlations cannot be used as proof of the value of treatment, they are useful in establish- ing expectations for reasonable treatment strategies. More specifically, epidemiological data do not necessarily predict cardiovascular outcomes when BP is lowered as a result of antihypertensive treatment. Nevertheless, population studies such as the Prospective Studies Collaboration,6 the Framingham Heart Study,124 the Women s Health Initiative,125 and the Hisayama Study126 in Japan provide some support for a lower is better strategy for BP control. The debate about lower BP targets revolves around the issue of the so-called J curve and, more specifically, whether lower BP targets are appropriate or even safe for patients with CAD. 3.1.2. Coronary Perfusion, Autoregulation, and the J Curve Many studies demonstrate that lowering SBP, DBP, or both decreases overall cardiovascular risk. Yet, concern has persisted that excessive DBP lowering may have adverse Rosendorff et al Treatment of Hypertension in Patients With CAD 1383 consequences for the heart. In virtually all instances, lower- ing SBP improves cardiac function and outcomes, probably through a reduction in cardiac work and an improved myocar- dial oxygen balance. On the other hand, it is theoretically pos- sible that lowering of DBP improves cardiovascular outcomes only when coronary perfusion is maintained above the lower limit of coronary autoregulation. Myocardial perfusion occurs almost exclusively during diastole; therefore, DBP is the coronary perfusion pressure. Like most vascular beds, the coronary circulation is capable of autoregulation, so that a decrease in perfusion pressure is accompanied by coronary vasodilation, which maintains a fairly constant coronary blood flow. The problem is that this ability of coronary resistance vessels to dilate in response to a falling perfusion pressure is limited, and at the point of maxi- mal vasodilation, a further decrease in coronary perfusion pressure will result in a decrease in flow. In conscious, instru- mented dogs, contractile function (transmural wall thickening and subendocardial segment shortening) is well maintained at mean coronary filling pressures down to 40 mmHg, which corresponds to a DBP of 30 mmHg.127-129 The lower limit of autoregulation in dogs with LV hypertrophy is shifted upward by 15 to 20 mmHg but can be partially restored byACE inhi- bition, with accompanying regression of LV hypertrophy.129 These studies were in dogs with normal intramural coronary arteries. We do not have good data on equivalent values for the human coronary circulation. In the presence of occlusive CAD, the hemodynamics are much more complicated. Significant CAD will shift the lower autoregulatory limit upward. However, because myocardial blood flow is very heterogeneous,130 the consequences of cor- onary underperfusion are unpredictable and may depend on intramyocardial wall stress (which in turn is increased by a high arterial pressure but decreased by LV hypertrophy), the effects of antihypertensive medications on these variables, and, of course, the severity of the occlusive coronary disease. There is also a reduced coronary flow reserve (defined as the difference between resting flow and flow through a maxi- mally dilated coronary circulation at any level of perfusion pressure) in patients with LV hypertrophy, coronary athero- sclerosis, or microangiopathy, with a reduced functional or structural capacity of coronary resistance vessels to dilate.131 This potential for impairment of myocardial oxygen supply may be compounded by an increased myocardial oxygen demand resulting from exercise, LV hypertrophy, and the increase in the output impedance of the LV caused by the increased SBP. This combination of a decreased oxygen sup- ply and an increased oxygen demand, especially during exer- cise, is particularly pernicious in the heart because the heart is an aerobic organ that can develop only a small oxygen debt, and oxygen extraction is almost maximal even at rest and can increase little with increased demand. It is theoretically possible, therefore, that although lower- ing BP improves cardiovascular outcomes in hypertensive patients (as long as coronary perfusion is maintained above the lower autoregulatory limit for coronary blood flow), any further reduction of DBP to levels below the lower autoregu- latory limit could reduce coronary blood flow. This could be translated to an upturn in the incidence of coronary events as DBP is lowered beyond this point, especially when myocar- dial oxygen consumption is increased such as during exercise. The relationship between DBP and coronary events would, if this were true, show a J-shaped curve. A major difficulty is that we do not have data on the DBP level that corresponds to the lower limit of autoregulation in the human coronary circu- lation, in healthy individuals, or in patients with hypertension and CAD. It would also be reasonable to assume that a rapid reduction in DBP to very low levels may be more hazardous in patients with combined hypertension and CAD, although we have no experimental or clinical trial evidence to support this idea. We therefore must rely on clinical studies with surrogate end points and the few relevant clinical trials with outcomes data to attempt to resolve this issue. 3.2. Clinical Studies 3.2.1. Lower BP With a Surrogate Outcome An analysis of the 274 patients with CAD who completed the intravascular ultrasound substudy of the Comparison of AmlodipineVersusEnalapriltoLimitOccurrencesofThrombosis showed that those subjects with a normal BP according to the definition given in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure3 (<120/80 mmHg) had a mean decrease in coronary atheroma volume of 4.6 mm3 , pre- hypertensive (120 139/80 89 mmHg) subjects had no signifi- cant change, and hypertensive ( 140/90 mmHg) subjects had a mean increase in atheroma volume of 12.0 mm3 . The authors concluded, This study suggests that in patients with CAD, the optimal BP goal may be substantially lower than the <140/90 mmHg level. 