Although an elevated BP increases myocardial oxygen demand, rapid and excessive lowering of the DBP has the potential to result in impairment of coronary blood flow and oxygen supply, as discussed in the BP Goals section. In addition, patients with ACS often have vasomotor instability with an increased ten- dency to exaggerated responses to antihypertensive therapy. Because specific trials of BP lowering have not been per- formed in patients with ACS, the selection of antihypertensive agents for use in the patient with ACS should be focused on selecting drugs that have an established evidence-base for risk reduction for patients with ACS independently of BP lower- ing. These drugs, which include -blockers, ACE inhibitors (or ARBs), and, in selected patients, aldosterone antagonists, should typically be titrated to full doses before other agents that do not have an established evidence base are initiated. Therapeutic targets for BP have not been established specifi- cally for patients withACS. Current guidelines recommend a BP target of <140/90 mmHg and <130/80 mmHg for patients with diabetes mellitus or CKD, 1,187 but this applies more to second- ary prevention than the management of hypertension in the acute phase of MI. The BP may fluctuate early after ACS; thus, efforts should focus on pain control and clinical stabilization before BP is specifically targeted. Second, the BP should be lowered slowly, and caution is advised to avoid decreases in DBP to <60 mmHg because this may reduce coronary perfusion and worsen ischemia. A BP target of <130/80 mmHg at the time of hospital discharge is a reasonable option. In older hypertensive individu- als with wide pulse pressures, lowering SBP may lead to very low DBP values, contributing to worsening myocardial ischemia. 5.3. Specific Antihypertensive Agents in ACS Nitroglycerin has been a cornerstone of therapy for decades, and in the hypertensive patient withACS, nitroglycerin is effective in relieving symptoms of ischemia and pulmonary congestion and is moderately effective in lowering arterial BP. However, clinical trial evidence does not support an effect of nitrates on outcomes in ACS. The Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto Miocardico (GISSI)-3 and International Study of Infarct Survival (ISIS)-4 trials included almost 80000 patients with STEMI and found no difference in mortality with the use of nitrates (7.0% for those treated versus 7.2% who received pla- Thus, the ACC/AHA guidelines for STEMI do not recommend nitroglycerin to reduce events but only to relieve ischemic pain or acute hypertension or to manage pulmonary congestion at a Level of Evidence C. Nitrates should be used with caution in patients with inferior STEMI and are contraindicated if right ventricular infarction is present because of their effects on low- ering preload. The guidelines caution that nitroglycerin should not be used at the expense of agents with proven benefits on outcomes such as -blockers orACE inhibitors (below), particu- larly in the convalescent stage.190 Experience with nitrates in non ST-segment elevationACS is largely extrapolated from STEMI because clinical trials in UA/ NSTEMI have been relatively small. Nitroglycerin should be first administered via the sublingual route in patients with ACS, which can be followed by intravenous or topical administration of nitroglycerin or oral administration of longer-acting nitrate preparations. Patients treated with nitrates need to be monitored for potential adverse effects, in particular profound hypotension, which can exacerbate ischemia. Patients at increased risk include the elderly, individuals who are volume depleted, or those have tolerance is a problem even within the first 24 hours, and attempts should be made to minimize this by reducing intravenous doses and implementing intermittent dosing by nonintravenous routes once the patient is stable from an ischemic standpoint. -Blockers are a cornerstone of ACS treatment because of their ability to reduce both heart rate and BP and thus myo- cardial oxygen demand. These agents were among the first therapies demonstrated to reduce infarct size. -Blockers reduce early sudden death after MI both via antiarrhythmic effects and by preventing myocardial rupture. In patients with STEMI, the long-term benefits of long-term postdischarge -blocker administration have been shown in multiple trials.191 Therefore, routine discharge use of -blockers is now a qual- ity performance measure for patients with ACS. Although -blockers should be initiated early and contin- ued for at least 3 years after ACS,176 there has been increased attention on the appropriate selection of patients for the use of early intravenous -blockers after ACS. Early intravenous -blockade was shown in a number of trials performed in the fibrinolytic era to reduce either mortality or recurrent MI192,193 and thus was used as routine therapy in ACS for many years. However, the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT)/Chinese Cardiac Study (CCC) 2 trial has led to a revision of the recommendations for intra- venous -blocker use in ACS.194 This study randomized 45852 AMI patients at presentation to intravenous and then oral -blockers versus placebo and assessed the coprimary outcomes of the composite of death, reinfarction, or cardiac arrest and death resulting from any cause. At discharge or up to 4 weeks, neither outcome was reduced with metoprolol. However, the COMMIT trial demonstrated a reduction in rein- farction (2.0% versus 2.5%) and ventricular fibrillation (2.5% versus 3.0%), but at the expense of an increase in cardiogenic shock (5.0% versus 3.9%) with intravenous -blocker use. The excess risk of shock was highest in the first 2 days of hospitalization, especially in patients with evidence of hemo- dynamic instability or borderline hemodynamics at presenta- tion. In a subset analysis of patients with hypertension (SBP >140 mmHg), there were no statistically significant differ- ences between the -blocker and placebo arms with respect to the composite primary end point, death or cardiogenic shock alone, although there was a trend in favor of the -blocker. This important study demonstrated that early intravenous -blocker therapy should be used selectively and restricted to patients with significant hypertension or tachycardia (ie, caused by atrial arrhythmias), those with ongoing ischemia, and those at low risk for hemodynamic compromise. CurrentACC/AHA guidelines for STEMI and UA/NSTEMI recommend that oral -blockade should be started within the first 24 hours, once it is established that the patient is stable and there are no contraindications.190,195 The choice of a -blocker is based on pharmacokinetic and side-effect criteria and phy- sician familiarity, but in general, short-acting cardioselective -selective) -blockers without intrinsic sympathomimetic activity such as metoprolol or bisoprolol are preferable. Carvedilol, which also blocks 2 adrenergic receptors, has more potent BP-lowering effects than 1 -selective agents and therefore may be a good choice for patients with ACS and severe hypertension. However, it should be avoided in patients with obstructive airways disease because of the effects of 2 antagonism on airway resistance. Contraindications to the use of -blockers in ACS include marked first-degree heart block (ECG PR interval >0.24 second), second- or third-degree heart block, severe bronchospastic lung disease, decompen- sated HF, and hypotension. Several meta-analyses concluded that cardioselective -blockers do not produce clinically sig- nificant adverse respiratory effects in patients with chronic obstructive pulmonary disease, suggesting that -blockers should not be withheld from these patients.196,197 5.3.3. Calcium Channel Blockers In general, CCBs have not been found to be useful in the set- ting of acute STEMI. Clinical trials of the rapid-release form of nifedipine showed an increase in mortality in patients treated with this agent after MI,198 and there is currently no role for short-acting nifedipine in clinical practice. The non- dihydropyridine agents diltiazem and verapamil have also been disappointing in the early-MI setting and are not recom- mended for routine use in patients with STEMI.190,195 Although several randomized, clinical trials suggested somewhat greater efficacy for CCBs in non ST-segment some of these studies were performed 30 years ago and predate the era of routine -blocker use. Moreover, benefit in these trials was limited to nonfatal recur- rent ischemic events, and among patients with LV dysfunc- tion, a detrimental effect on mortality was seen.118,201 Thus, there is no indication for routine use of CCBs in patients with UA or NSTEMI. The AHA/ACC guidelines for the manage- ment of UA and NSTEMI suggest that, in patients with con- tinuing or frequently recurring ischemia when -blockers are contraindicated, a nondihydropyridine CCB (verapamil or dil- tiazem) may be used as an alternative in the absence of severe LV dysfunction or other contraindications.195 It is prudent to avoid the use of verapamil or diltiazem in patients who have LV dysfunction, and they should not be used together with -blockers in that situation. Evidence for the utility of dihydropyridine CCBs in ACS is limited. These agents effectively lower BP and may relieve ischemic symptoms. All CCBs have the potential to cause hypotension, and the nondihydropyridine CCBs may precipi- tate conduction disturbances, particularly when used in con- junction with -blockers. 5.3.4. ACE Inhibitors ACE inhibitors are indicated for most patients with ACS and are a preferred option for BP management in both STEMI and non-ST elevation ACS. The data are most robust for ACE inhibitors in the STEMI population, in whom most of the tri- als have been performed, with results extrapolated to UA/ NSTEMI. Rosendorff et al Treatment of Hypertension in Patients With CAD 1391 In STEMI, ACE inhibitors reduce infarct expansion, pre- venting LV remodeling and chamber dilatation,202 which help to prevent downstream sequelae such as ventricular arrhyth- mia, HF, or even myocardial rupture. The GISSI-3, ISIS-4, and CCS-1 trials demonstrated a benefit from early adminis- tration of ACE inhibitors, with absolute reductions in mortal- ity of 0.8%, 0.5%, and 0.5% seen as early as 4 weeks after A meta-analysis from the ACE Inhibitor Myocardial Infarction Collaborative Group, which included 100 000 patients treated within 36 hours of acute MI, found a 7% lower relative mortality rate at 30 days in patients treated with ACE inhibitors.204 The benefit was largest in high-risk groups such as those with HF at presentation (23 lives saved per 1000 patients) and those with an anterior MI (11 lives saved per 1000 patients). Rates of nonfatal HF were also reduced, but hypotension and renal dysfunction were more common. When ACE inhibitors are started later after MI among individuals with LV dysfunction and continued long term, their benefits are even more robust; mortality rates have been reduced by 20% to 25% in long-term trials evaluating ACE inhibitors in these high-risk subgroups.205,206 5.3.5. Angiotensin Receptor Blockers ARBs are a useful alternative to ACE inhibitors in patients with anACEinhibitorcontraindicationorintolerance.TheVALIANT randomized patients with LV dysfunction or HF within 10 days after acute MI to additional therapy with valsartan, capto- pril, or the combination of the two. Valsartan was as effective as captopril for reducing cardiovascular events in these high- risk patients through 2 years of follow-up. However, combin- ing valsartan with captopril increased the rate of adverse events without improving survival. On the other hand, OPTIMAAL showed a trend toward increased mortality in patients receiving losartan 50 mg once daily over patients receiving captopril 50 These negative results may have been attrib- utable to inadequate dosing of losartan. In summary, because of the larger and more consistent evidence base for ACE inhibi- tors, these agents are preferred over ARBs for patients who can tolerate them, but ARBs are a first-line alternative for ACE inhibitor intolerant patients. 5.3.6. Aldosterone Antagonists Aldosterone, which is incompletely suppressed even among individuals on high doses of ACE inhibitors, is thought to con- tribute to both adverse ventricular remodeling and myocar- dial fibrosis after MI. The EPHESUS trial112 patients with MI who had an LV ejection fraction 40% and either signs of HF or diabetes mellitus. Patients were random- ized to the selective aldosterone inhibitor eplerenone or pla- cebo, initiated 3 to 14 days after MI. Eplerenone reduced total mortality by 15% and cardiovascular mortality by 17%, with a reduction in sudden cardiac death of 21%. Of those enrolled, 87% were receiving ACE inhibitors and 75% were receiving -blockers, indicating that aldosterone antagonist therapy pro- vides incremental benefit to these agents. Although spirono- lactone has not been studied specifically in ACS, this agent demonstrated a significant mortality benefit for patients with NewYork Heart Association (NYHA) class III or IV HF in the and it is also reasonable to use spironolactone for patients after ACS who meet EPHESUS criteria. Aldosterone antagonists should be avoided in patients with significantly elevated serum creatinine levels ( 2.5 mg/dL in men, 2.0 mg/dL in women) or elevated potassium levels ( 5.0 mEq/L) because there is a serious risk of hyperkalemia with the use of these agents in patients with an estimated cre- atinine clearance of <50 mL/min.176 Close clinical and labo- ratory follow-up is needed for patients receiving long-term treatment with aldosterone antagonists to mitigate the occur- rence and complications of hyperkalemia.207 Mineralocorticoid antagonists are underused among evi- dence-based medications after MI. This likely reflects appro- priate concerns about the risk for hyperkalemia with these agents. However, many patients can safely receive these highly effective and inexpensive agents with careful follow-up. Although thiazide and thiazide-type diuretics play a major role in the long-term control of BP, inACS, diuretics are used primar- ily for patients with evidence of increased filling pressures, pul- monary venous congestion, or HF. Particular caution is needed with regard to hypokalemia, which may precipitate arrhythmias Loop diuretics are preferred over thiazide and thia- zide-type diuretics for patients with ACS who have HF (NYHA class III or IV) or for patients with CKD and an estimated glo- merular filtration rate of <45 mL/min. 5.4. Safety of Anticoagulation in Patients With Uncontrolled Hypertension ACS therapy includes several strategies that involve platelet inactivation and anticoagulation to reduce the risk of thrombosis and poor clinical outcomes. The relative efficacy and safety of anticoagulant and antiplatelet therapy do not differ substantially in patients with STEMI, NSTEMI, or UA. In the ACS popula- tion, these drugs are most effective when given early. These ther- apies can lead to major bleeding complications, most commonly in the gastrointestinal tract and at the site of femoral access for percutaneous coronary interventions. Most concerning is that, in the setting of uncontrolled hypertension, the risk of hemor- rhagic stroke is increased.208 This provides another rationale for the aggressive control of hypertension in patients with ACS. Rapidly stabilizing patients to facilitate prompt coronary reperfusion is challenging in ACS patients with severe hyper- tension. Inherent to the use of medications largely limiting or disrupting intraluminal thrombus formation is the potential for severe secondary bleeding. The decision to pursue an inva- sive as opposed to a conservative approach should be based on standard clinical, demographic, and angiographic criteria. Although hypertension per se should not influence revascu- larization decisions other than indirectly in relation to factors such as renal function, it should be remembered that bleeding risks are notably higher with uncontrolled hypertension. Hypertension will continue to be highly prevalent among patients with ACS, particularly as the ACS population ages. The majority will respond to standard methods of hypertension control. To control BP, specific agents should be selected that have an established evidence base for risk reduction in ACS. These agents include -blockers, ACE inhibitors or ARBs, and, in selected patients, aldosterone antagonists. Although nitrates do not change the natural history of ACS, they are very useful for hypertensive patients with ACS, particularly if there is ongoing ischemia or pulmonary congestion. Particular care should be taken to avoid hypotension, with the risk of worsening myocardial ischemia. The benefits of treating hypertension in the ACS setting are logical, but perhaps the major impact on long-term morbidity and mortality depends on the efficacy of continued outpatient BP control once effec- tive therapy has been initiated in hospital. 1. If there is no contraindication to the use of - blockers, in patients with ACS, the initial therapy of hypertension should include a short-acting 1 - selective -blocker without intrinsic sympathomi- metic activity (metoprolol tartrate or bisoprolol). -Blocker therapy should typically be initiated orally within 24 hours of presentation (Class I; Level of Evidence A). For patients with severe hy- pertension or ongoing ischemia, an intravenous -blocker (esmolol) can be considered (Class IIa; Level of Evidence B). For hemodynamically un- stable patients or when decompensated HF exists, the initiation of -blocker therapy should be de- layed until stabilization has been achieved (Class I; Level of Evidence A). 2. In patients with ACS and hypertension, nitrates should be considered to lower BP or to relieve on- going ischemia or pulmonary congestion (Class I; Level of Evidence C). Nitrates should be avoided in patients with suspected right ventricular infarc- tion and in those with hemodynamic instability. Sublingual or intravenous nitroglycerin is pre- ferred for initial therapy and can be transitioned later to a longer-acting preparation if indicated. 3. If there is a contraindication to the use of a -blocker or intolerable side effects, then a nondihydropyridine CCB such as verapamil or diltiazem may be substi- tuted for patients with ongoing ischemia, provided that LV dysfunction or HF is not present. If the an- gina or hypertension is not controlled on a -blocker alone, a longer-acting dihydropyridine CCB may be added after optimal use of an ACE inhibitor (Class IIa; Level of Evidence B). 4. An ACE inhibitor (Class I; Level of Evidence A) or an ARB (Class I; Level of Evidence B) should be added if the patient has an anterior MI, if hypertension per- sists, if the patient has evidence of LV dysfunction or HF, or if the patient has diabetes mellitus. For lower- risk ACS patients with preserved LV ejection frac- tion and no diabetes mellitus, ACE inhibitors can be considered a first-line agent for BP control (Class IIa; Level of Evidence A). 5. Aldosterone antagonists are indicated for patients who are already receiving -blockers and ACE inhibitors after MI and have LV dysfunction and either HF or diabetes mellitus. Serum potassium levels must be monitored. These agents should be avoided in patients with elevated serum creatinine levels ( 2.5 mg/dL in men, 2.0 mg/dL in women) or elevated potassium levels ( 5.0 mEq/L) (Class I; Level of Evidence A). 6. Loop diuretics are preferred over thiazide and thiazide-type diuretics for patients with ACS who have HF (NYHA class III or IV) or for patients with CKD and an estimated glomerular filtration rate <30 mL/min. For patients with persistent hypertension not controlled with a -blocker, an ACE inhibitor, and an aldosterone antagonist, a thiazide or thiazide-type diuretic may be added in selected patients for BP control (Class I; Level of Evidence B). 7. The target BP is <140/90 mmHg in patients with ACS who are hemodynamically stable (Class IIa; Level of Evidence C). A BP target of <130/80 mmHg at the time of hospital discharge is a reasonable op- tion (Class IIb; Level of Evidence C).The BP should be lowered slowly, and caution is advised to avoid decreases in DBP to <60 mmHg because this may reduce coronary perfusion and worsen ischemia. 6. Management of Hypertension in HF of Ischemic Origin Although guidelines from the ACC and the AHA exist for the treatment of chronic HF,177,209 evidence on which to base guidelines for the treatment of hypertension in patients with HF of ischemic origin is limited. On the basis of informa- tion from the Acute Decompensated Heart Failure National 75% of patients hospitalized with HF had hypertension, with most having SBPs >140 mmHg. In the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE-HF), >60% of patients seen in outpatient cardiology practices had a history of hypertension.211 Additional observational data from the Duke Databank for Cardiovascular Disease suggest a similar prevalence of hypertension in patients with ischemic 6.1. Hypertension and HF Most patients with HF have arterial hypertension.213 Not only is hypertension an important concomitant disorder, but it also contributes to the pathogenesis of both HF with reduced ejection fraction and HF with preserved ejection fraction. Hypertension is a major risk factor for IHD and can lead to the development of HF by causing LV hypertrophy, impaired cardiac myocyte contractility, ventricular chamber remodel- ing, and eventually ventricular dysfunction.214-216 Elevated levels of DBP and especially SBP are major risk fac- tors for the development of HF,217,218 and long-term treatment of both systolic and diastolic hypertension has been shown to reduce the risk of HF.93,123,219 The subsequent structural abnor- malities that occur in patients with hypertension, including LV hypertrophy or MI (eg, stage B HF), portend a higher number of Rosendorff et al Treatment of Hypertension in Patients With CAD 1393 adverse cardiovascular outcomes. Patients presenting with HF are more likely to be older and hypertensive, and more than half have a normal LV ejection fraction.210,220 Early investigations of patients with HF such as the Framingham Heart Study cited hypertension as the most frequent comorbidity; hypertension accounted for 39% of HF cases in men and 59% in women.217 In a population-based study in Olmstead County, Minnesota, 50% of patients presenting with new-onset HF had hyperten- However, recent randomized trials have probably under- estimated the contribution of hypertension to the development and progression of HF, possibly because elderly patients often are not included in clinical trials of HF. Of note, HF symptoms are rare in hypertensive individuals whose BP is well controlled at goal and who have not sustained an MI.222 6.3. Hypertension and HF Pathophysiology Initially, concentric hypertrophy of the LV compensates for pressure overload and normalizes systolic wall stress. This adaptive hypertrophy is accompanied by structural modifi- cations of the cardiac muscle, including alterations in gene expression, loss of cardiomyocytes, defective vascular development, and fibrosis. Thus, the compensatory response may transition to HF with progressive contractile dysfunc- In the second stage, CAD causes myocardial isch- emia or MI, which results in HF. BP falls as HF develops, so the contribution of hypertension to the HF syndrome may be underestimated. The mechanisms by which increased LV mass leads to depressed LV ejection fraction remain ill defined. Traditionally, an MI has been viewed as an obliga- tory event in the transition to depressed systolic function. Because MI occurs in 16% of those who develop depressed LV ejection fraction compared with 3% of those who do not, it is an important risk factor.224 However, there must be other mechanisms because increased LV mass remains associated with the development of depressed LV ejection fraction even in patients free of clinically manifest CAD, including MI. With antihypertensive treatment, the incidence of LV hyper- trophy is reduced by 35%, and the development of HF is reduced by 52%.222 The mechanisms for the progression from hypertension to clinical HF with preserved ejection fraction represent an area of ongoing investigation.225 Potential mechanisms include progressive changes in the myocardial extracellular matrix and elevation in LV filling pressures.226-231 6.4. CAD and Acute HF Ischemia may trigger acute pulmonary edema. The majority of patients with flash pulmonary edema have preserved systolic These patients are generally elderly and have severe CAD, typically with 1 occluded vessel and a severely stenosed coronary artery supplying collateral flow.234-236 Patients with preserved systolic function and LV hypertrophy are particularly susceptible to this type of episode because of their reduced ventricular distensibility, in which small changes in ventricular volume status can lead to large changes in filling pressures. This abnormal diastolic pressure volume relationship may also explain why these patients frequently improve quickly with diuresis and lowering of BP.237 In terms of management, the same principles apply when this occurs in the setting of ischemic cardiomyopathy as in ACS. Refer to the Management of Hypertension in Patients With ACS section above. 6.5. Therapeutic Strategies The therapeutic goals in patients presenting with HF are to reverse hemodynamic abnormalities, to relieve symptoms, and to initiate treatments that will decrease disease progres- sion and improve survival. 6.6. Nonpharmacological Therapies Sodium restriction is important in the management of both hypertension and LV dysfunction. Exercise training238,239 has been shown to reduce recurrent cardiac events in patients with LV dysfunction resulting from ischemic causes. In the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study, exercise training was associated with modest reductions in both all-cause mortal- ity or hospitalization and cardiovascular mortality or HF hos- pitalization after adjustment for highly prognostic baseline Exercise training also conferred significant improvements in self-reported health status compared with For patients with HF, close medical supervision and careful monitoring of the BP response to exercise and of the ECG for ventricular arrhythmias are appropriate.242,243 Other nonpharmacological therapies, as discussed in the Risk Factor Reduction section, are also appropriate. These include management of dyslipidemia, diabetes mellitus, and obesity, as well as smoking cessation. 6.7. Pharmacological Therapies When an antihypertensive regimen is devised, optimal con- trol of BP should remain the primary goal, with the choice of drugs determined by the concomitant medical problems (eg, CAD, diabetes mellitus, or renal disease). Ultimately, an appropriate antihypertensive regimen frequently consists of several drugs used in combination. Diuretic-based antihypertensive therapy has repeatedly been shown to prevent HF in a wide range of target populations.244 Thiazide or thiazide-type diuretics are effective in prevent- ing HF in hypertensive patients.222 Thiazide or thiazide-type diuretics are the drugs of choice in patients with mild HF because of a more sustained natriuretic and diuretic action than loop diuretics, particularly in those individuals in whom BP control may be more important than correction of volume overload. In more severe HF, diuretics are used to reverse vol- ume overload and associated symptoms. Loop diuretics such as furosemide and torsemide usually are used because they produce a greater diuresis for the same degree of natriuresis; they work even in the presence of renal impairment, a fre- quent accompaniment of severe HF; and their dose-response characteristics are linear and steep, which allows escalation to high doses. By inducing sodium and water loss, diuretics also activate several adverse mechanisms. There may be a decrease in right ventricular filling pressure, with a decrease in stroke volume and activation of the RAAS and the sympa- thetic nervous system,245 effects that would be expected to be This problem is avoided by combining diuretic therapy with an ACE inhibitor or ARB, a -blocker, and/or an aldosterone antagonist, all of which have been shown to provide effective therapy in HF. The Diuretic Optimization Strategies Evaluation (DOSE) trial in patients with acute HF demonstrated that a high-dose furosemide strategy was asso- ciated with a nonstatistically significant trend toward greater improvement in patients global assessment of symptoms but no significant difference in creatinine levels. Although there were greater diuresis with the high-dose strategy and more favorable outcomes in a few secondary measures, there was also transient worsening of renal function.248 6.7.2. ACE Inhibitors ACE inhibitors are thought to reduce the remodeling that occurs after MI,249 to improve ischemic preconditioning,250 to reverse angiotensin II induced vasoconstriction and inotropy, to prevent the depletion of high-energy phosphate stores, to enhance nitric oxide release through prevention of bradyki- and to reduce blood coagulability through the endothelial release of tissue plasminogen ACE inhibitors have been shown in many trials to be ben- eficial in patients with LV dysfunction of ischemic origin. The Trandolapril Cardiac Evaluation (TRACE) trial showed a 7% absolute reduction in mortality rate.206.253 In the Acute Infarction Ramipril Efficacy (AIRE) trial,205 ramipril adminis- tered 3 to 7 days after MI reduced the relative mortality risk by 27% in the total cohort, by 15% in normotensive subjects, and by 41% in hypertensive subjects, which supports the particu- lar importance of ACE inhibition in hypertensive patients with LV dysfunction in the post-MI period. In the Assessment of Treatment With Lisinopril and Survival (ATLAS) trial, mor- tality was significantly lower in patients with HF who received a high dose of lisinopril (32.5 35 mg/d) than in those treated with a low dose of lisinopril (2.5 5 mg/d).254 Among patients with diabetes mellitus or other cardiovascular complica- ACE inhibitors have been most notable with respect to a reduction in the onset of HF and new-onset diabetes mel- litus. However, the message has not impacted clinicians as well as it should; in the IMPROVE-HF registry, only 80% of eligible patients with LV dysfunction were prescribed an ACE inhibitor/ARB at baseline.211 6.7.3. Angiotensin Receptor Blockers Compared with placebo, the ARBs losartan255 and irbesar- significantly reduced the incidence of HF in patients with type 2 diabetes mellitus and nephropathy. The VALIANT trial found valsartan to be noninferior to captopril, although it did not show superiority.61 The Evaluation of Losartan in the Elderly (ELITE) II trial compared the efficacy of losartan 50 mg/d with captopril 150 mg/d and found that the rates of all- cause mortality and sudden death or resuscitated arrests for the losartan group were not significantly different from those for the captopril group.257 The Valsartan Heart Failure Trial (Val-HeFT) assessed the efficacy of valsartan at doses up to 320 mg/d added to standard therapy for reducing morbidity and mortality in patients with HF.258 Patients receiving val- sartan demonstrated a 13.2% reduction in the combined end point of cardiovascular mortality and morbidity compared with patients receiving placebo. Additional insights into the value of ARBs are provided by the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity In patients not receiving ACE inhib- itors because of previous intolerance, the use of candesartan was associated with a significant reduction in the primary composite end point of cardiovascular death and hospital read- mission for HF compared with placebo.259 In the combination arm of VALIANT, valsartan and captopril together showed no increased effect over captopril alone and had a higher inci- dence of discontinuation because of adverse effects.91 These results differed from those of the CHARM-Added trial, in which patients with stable LV dysfunction benefited from the combination of an ACE inhibitor and the ARB candesartan.263 The lack of superiority of the combination treatment in the VALIANT trial was likely attributable to the fact that the ACE inhibitors and ARBs were titrated aggressively at the same time in the early post-MI period, which resulted in more side effects. In stable HF patients undergoing an established ACE inhibitor therapy, the CHARM trial showed that the addition of an ARB was well tolerated and beneficial. This is a strategy that could be used to control BP if needed. -Blockers lower BP and are negatively inotropic and chro- notropic. They therefore alleviate ischemia and angina, in addition to lowering BP. The role of -blockers in the management of patients with HF is well established. The Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF) randomized patients with NYHA class II to IV HF symptoms to receive metoprolol succinate ver- This trial was stopped prematurely because of a 34% reduction in mortality in the metoprolol arm. Four clinical trials of carvedilol in HF were stopped prematurely because of a highly significant 65% reduction in mortality in patients treated with carvedilol compared with placebo.265 The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial assessed patients with severe HF symp- toms who were clinically not volume overloaded and who had an LV ejection fraction <25%. Compared with placebo, carvedilol reduced the mortality risk at 12 months by 38% and the risk of death or hospitalization for HF by 31%.266 The Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA) trial demonstrated that this effect of carvedilol is dose related, with higher doses of 25 mg twice daily showing greater LV functional and clinical superiority than 6.25 mg twice daily, a dose that was superior to placebo.267 Another longer-acting -blocker, bisoprolol, showed similar long-term benefit on survival in patients with HF. The Cardiac Insufficiency Bisoprolol Study (CIBIS-II) showed a 32% reduc- tion in all-cause mortality in bisoprolol-treated patients with NYHA class III or IV HF caused by ischemic and nonischemic cardiomyopathy at a median follow-up of 1.3 years. In that trial, sudden deaths were reduced by 44% in the bisoprolol-treated group, whereas pump failure deaths were reduced by 26%.170 Nebivolol is a 1 -selective -blocker with vasodilating properties related to nitric oxide modulation. In the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with heart failure (SENIORS) of 2128 patients 70 years of age with a history of HF, nebivolol Rosendorff et al Treatment of Hypertension in Patients With CAD 1395 significantly decreased all-cause mortality or cardiovascular hospital admissions over a 21-month follow-up.268 Although all 4 of these agents (metoprolol succinate, carvedilol, bisoprolol, and nebivolol) are beneficial in patients with HF, the Carvedilol or Metoprolol European Trial (COMET) demonstrated a 17% greater mortality reduction in favor of carvedilol compared with metoprolol tartrate (not the formulation used in MERIT-HF, which was metoprolol suc- with mean daily doses of 42 and 85 mg/d, respec- Carvedilol may be particularly appealing because of its additional -blocking properties. There also may be a more favorable effect on glycemic control. As a result of these studies, -blockers are recommended for the long-term management of patients with hypertension- related LV systolic dysfunction. Patients should preferably receive 1 of the 4 -blockers proven to reduce mortality (carvedilol, metoprolol succinate, bisoprolol, or nebivolol). 6.7.5. Nitrates and Hydralazine Nitrate tolerance has limited the ability of long-term nitrates alone to be effective as antihypertensive agents. The addition of hydralazine to a nitrate reduces this tolerance. The African- American Heart Failure Trial (A-heFT)270 showed that a com- bination of a fixed dose of isosorbide dinitrate and hydralazine provides additional benefit in African American patients with advanced HF. The trial was stopped early because of a signifi- cantly higher mortality rate in the placebo group than in the group receiving isosorbide dinitrate plus hydralazine (10.2% Therefore, for African Americans who require further BP control and relief of symptoms of HF (NYHA class III or IV), the combination of hydralazine and isosorbide is recommended together with ACE inhibitors, -blockers, and aldosterone antagonists.271 Given the lack of randomized trial evidence to support the prevention of car- diovascular events by the use of hydralazine in the treatment of primary hypertension272 and concerns that hydralazine may provoke angina, monotherapy with hydralazine in IHD is not recommended. 6.7.6. Aldosterone Receptor Antagonists Aldosterone has been shown to promote myocardial fibrosis. RALES reported the effect of adding the competitive aldoste- rone antagonist spironolactone versus placebo to standard HF therapy in patients with stage 3 (NYHA class III or IV) HF.There was a 30% reduction in total mortality with spironolactone.111 Eplerenone, a selective aldosterone inhibitor, showed similar survival benefit in the EPHESUS trial. Patients with an LV ejec- tion fraction of <40% were randomly assigned at 3 to 14 days after MI to therapy with eplerenone or placebo. During a mean follow-up of 16 months, eplerenone significantly improved mor- tality by 15%.112 The EMPHASIS trial supported the benefits of eplerenone in chronic HF (LV ejection fraction 35%) with mild symptoms (NYHA class II), in which there was a 37% reduction in the primary end point of cardiovascular death or HF hospi- Although these trials did not specifically evaluate patients with hypertension and HF, the improvement in relative risk with eplerenone was greater in the subgroup with a history of hypertension than in normotensive subjects,112 which suggests that these agents may be particularly beneficial in patients with hypertension and HF. This class of drug is especially beneficial in patients with hypokalemia.273 Electrolytes and renal function should be monitored to prevent hyperkalemia. 6.8. Renal Denervation The radiofrequency ablation of renal sympathetic nerves has recently gained attention for its ability to reduce BP in those with resistant hypertension.274,275 A small study has demonstrated the ability of renal denervation to induce LV hypertrophy regression and to improve LV systolic and dia- However, in the first large-scale clinical trial of renal denervation in patents with resistant hyper- tension, with an appropriate control group, namely a sham procedure (Renal Denervation in Patients With Uncontrolled Hypertension [SYMPLICITY HTN-3]),277 there was no sig- nificant difference between the 2 groups in the reduction of SBP, which leaves the future of renal denervation in the management of hypertension uncertain. The impact of renal denervation in HF patients is also unclear, and future ran- domized trials are needed to clarify its role in this patient population. 6.9. Goal BP Healthcare providers should lower both SBP and DBP in accordance with the recommendations provided in pub- lished guidelines, including the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.3 BP targets in HF have not been firmly established, but in most successful tri- als, SBP was lowered to the range of 110 to 130 mmHg. One demonstrated benefits of carvedilol in patients with entry criteria that included SBPs down to 85 mmHg and who had a mean pretreatment BP of 123/76 mmHg, which suggests that lower BPs (SBP <120 mmHg) may be desirable in some patients. Therefore, we make the rec- ommendation that the target BP in patients with HF should be <140/90 mmHg, but we also suggest that consideration should be given to lowering the BP even further, to <130/80 mmHg. Octogenarians should be checked for orthostatic changes with standing, and an SBP <130 mmHg and a DBP <65 mmHg should be avoided. 6.10. Drugs to Avoid Several classes of drugs should be avoided in patients with isch- emic systolic HF with hypertension. Because of their negative inotropic properties and the increased likelihood of worsening HF symptoms, nondihydropyridine CCBs such as diltiazem and verapamil should be avoided.278 The dihydropyridine CCB amlo- dipine appeared to be safe in patients with severe systolic HF in the Prospective Randomized Amlodipine Survival Evaluation as was felodipine as supplementary vasodila- tor therapy in the Vasodilator-Heart Failure Trial (V-HeFT) III.280 Although clonidine is an effective antihypertensive agent, another druginthesameclass,moxonidine,wasassociatedwithincreased mortality in patients with HF281 ; therefore, clonidine also should probably be avoided. In the ALLHAT trial, the doxazosin arm of the trial was discontinued because of a 2.04-fold increase in rela- tive risk of developing HF compared with chlorthalidone treat- Although there are several caveats about extrapolating these data to the management of hypertension in patients with HF, -blockers should be used only if other agents used for the management of hypertension and HF are inadequate to achieve good BP control, and even then, they should be used with cau- tion. Nonsteroidal anti-inflammatory drugs have been associated with increased BP accompanied by peripheral edema, weight gain, and worsening renal function, so they should be used with caution in HF patients.283,284 Studies of the direct renin inhibitor aliskiren added to ACE inhibitors or ARBs were stopped early because of concerns about increased adverse events, particularly in the setting of renal insufficiency or diabetes mellitus. Ongoing trials of aliskiren in HF with heightened safety monitoring should help define the role, if any, for this agent. Given the lack of ran- domized trial evidence to support the use of hydralazine without a nitrate in the treatment of primary hypertension and concerns that hydralazine may provoke angina, monotherapy with hydrala- zine in IHD is not recommended. 1. The treatment of hypertension in patients with HF should include management of risk factors such as dyslipidemia, obesity, diabetes mellitus, smoking, and dietary sodium and a closely monitored exercise program (Class I; Level of Evidence C). 2. Drugs that have been shown to improve outcomes for patients with HF with reduced ejection fraction gen- erally also lower BP. Patients should be treated with ACE inhibitors (or ARBs), -blockers (carvedilol, metoprolol succinate, bisoprolol, or nebivolol), and aldosterone receptor antagonists (Class I; Level of Evidence A). 3. Thiazide or thiazide-type diuretics should be used for BP control and to reverse volume overload and asso- ciated symptoms. In patients with severe HF (NYHA class III and IV) or those with severe renal impair- ment (estimated glomerular filtration rate <30 mL/ min), loop diuretics should be used for volume con- trol, but they are less effective than thiazide or thia- zide-type diuretics in lowering BP. Diuretics should be used together with an ACE inhibitor or ARB and a -blocker (Class I; Level of Evidence C). 4. Studies have shown equivalence of benefit of ACE inhibitors and the ARBs candesartan or valsartan in HF with reduced ejection fraction. Either class of agents is effective in lowering BP (Class I; Level of Evidence A). 5. The aldosterone receptor antagonists spironolactone and eplerenone have been shown to be beneficial in HF and should be included in the regimen if there is HF (NYHA class II IV) with reduced ejection frac- tion (<40%). One or the other may be substituted for a thiazide diuretic in patients requiring a potassium- sparing agent. If an aldosterone receptor antagonist is administered with an ACE inhibitor or an ARB or in the presence of renal insufficiency, serum potas- sium should be monitored frequently. These drugs should not be used, however, if the serum creatinine level is 2.5 mg/dL in men or 2.0 mg/dL in wom- en or if the serum potassium level is 5.0 mEq/L. Spironolactone or eplerenone may be used with a thiazide or thiazide-like diuretic, particularly in pa- tients with resistant hypertension (Class I; Level of Evidence A). 6. Hydralazine plus isosorbide dinitrate should be add- ed to the regimen of diuretic, ACE inhibitor or ARB, and -blocker in African American patients with NYHA class III or IV HF with reduced ejection frac- tion (Class I; Level of Evidence A). Others may benefit similarly, but this has not yet been tested. 7. In patients who have hypertension and HF with pre- served ejection fraction, the recommendations are to control systolic and diastolic hypertension (Class I; Level of Evidence A), ventricular rate in the pres- ence of atrial fibrillation (Class I; Level of Evidence C), and pulmonary congestion and peripheral edema (Class I; Level of Evidence C). 8. Use of -adrenergic blocking agents, ACE inhibitors, ARBs, or CCBs in patients with HF with preserved ejection fraction and hypertension may be effective to minimize symptoms of HF (Class IIb; Level of Evidence C). 9. In IHD, the principles of therapy for acute hyperten- sion with pulmonary edema are similar to those for STEMI and NSTEMI, as described above (Class I; Level of Evidence A). If the patient is hemodynamical- ly unstable, the initiation of these therapies should be delayed until stabilization of HF has been achieved. Drugs to avoid in patients with hypertension and HF with reduced ejection fraction are nondihydro- pyridine CCBs (such as verapamil and diltiazem), clonidine, moxonidine, and hydralazine without a nitrate (Class III Harm; Level of Evidence B). - Adrenergic blockers such as doxazosin should be used only if other drugs for the management of hy- pertension and HF are inadequate to achieve BP control at maximum tolerated doses. Nonsteroidal anti-inflammatory drugs should also be used with caution in this group, given their effects on BP, vol- ume status, and renal function (Class IIa; Level of Evidence B). The target BP is <140/90 mmHg, but consideration can be given to lowering the BP even further, to <130/80 mmHg. In patients with an elevated DBP who have CAD and HF with evidence of myocardial ischemia, the BP should be lowered slowly. In older hypertensive individuals with wide pulse pressures, lowering SBP may cause very low DBP values (<60 mmHg). This should alert the clinician to assess care- fully any untoward signs or symptoms, especially those caused by myocardial ischemia and worsening HF (Class IIa; Level of Evidence B). Octogenarians should be checked for orthostatic changes with stand- ing, and an SBP <130 mmHg and a DBP <65 mmHg should be avoided. Rosendorff et al Treatment of Hypertension in Patients With CAD 1397 Disclosures Writing Group Disclosures Writing Group Member Employment Research Grant Other Research Support Speakers Bureau/Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other Clive Rosendorff VA Medical Center None None None None None None None Daniel T. Lackland Medical University of South Carolina None None None None None None None Matthew Allison UCSD None None None None None None None Wilbert S. Aronow New York Medical College None None None None None None None Henry R. Black NYU School of Medicine None None None None None None None Roger S. Blumenthal Johns Hopkins University School of Medicine None None None None None None None Christopher P. Cannon Brigham and Women s Hospital Accumetrics*; Arisaph ; AstraZeneca ; Boehringer- Ingelheim ; Janssen ; GlaxoSmithKline ; Merck ; Takeda None None None None BMS*; CSL Behring*; Essentialis*; GlaxoSmithKline*; Merck*; Takeda*; Lipimedix ; Pfizer ; Regeneron ; Sanofi None James A. de Lemos UT Southwestern None None None None None None None William J. Elliott Pacific Northwest University of Health Sciences Forest Research Institute None Forest Laboratories* None None Novartis Pharmaceuticals Corporation*; Takeda Pharmaceuticals North America* None Laura Findeiss University of California at Irvine None None None None None None None Bernard J. Gersh Mayo Clinic None None None None None Medtronic, Inc.*; Baxter Healthcare Corporation*; Cardiovascular Research Foundation*; TEVA Pharmaceuticals*; St. Jude Medical, Inc.*; Ortho-McNeil Janssen Scientific*; Cipla Limited*; Boston Scientific* None Joel M. Gore University of Massachusetts None None None None None None None Daniel Levy NIH None None None None None None None Janet B. Long Rhode Island Cardiology Center None None None None None None None Christopher M. O Connor Duke Clinical Research Institute, Duke University Medical Center None None None None None None None Patrick T. O Gara Brigham & Women s Hospital None None None None None None None Gbenga Ogedegbe NYU School of Medicine NIH None None None None None None (Continued) Suzanne Oparil University of Alabama at Birmingham Medtronic*; Merck & Co ; Novartis ; Takeda None None None None Bayer*; Daiichi Sankyo*; Pfizer* None William B. White University of Connecticut School of Medicine NIH (study of ambulatory blood pressure monitoring guided therapy to reduce functional decline in older persons) ; NIH (Impact of smoking cessation on blood pressure, SNS activity) None None None None None None This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be significant if (a) the person receives $10000 or more during any 12-month period, or 5% or more of the person s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10000 or more of the fair market value of the entity. A relationship is considered to be modest if it is less than significant under the preceding definition. *Modest. Significant. Writing Group Disclosures, Continued Writing Group Member Employment Research Grant Other Research Support Speakers Bureau/Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other Reviewer Disclosures Reviewer Employment Research Grant Other Research Support Speakers Bureau/Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other Jafna L. Cox Queen Elizabeth II Health Sciences Center, Capital District Health Authority, Halifax, NS, and Dalhousie University None None None None None None None Charles B. Eaton Memorial Hospital of Rhode Island Center for Primary Care and Prevention AHRQ (control hypertension grant)* None None None None None None Victor A. Ferrari Hospital of the University of Pennsylvania None None None None None Executive Committee, Society for Cardiovascular Magnetic Resonance* (unpaid) None Federico Gentile Studio Gentile, Naples Italy None None None None None None None Hani Jneid Baylor College of Medicine MEDVAMC None None None None None None None Cora E. Lewis University of Alabama at Birmingham NIH None None None None None None G.B. John Mancini University of British Columbia Merck Canada* None Merck* None None Amgen* None Peter A. McCullough St. John Providence Health System None None None None None None None Carl J. Pepine Department of Medicine, University of Florida None None None None None None None (Continued) Rosendorff et al Treatment of Hypertension in Patients With CAD 1399 References 1. Rosendorff C, Black HR, Cannon CP, Gersh BJ, Gore J, Izzo JL Jr, Kaplan NM, O Connor CM, O Gara PT, Oparil S. 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Waites Hattiesburg Clinic, Hattiesburg, MS None None None None None None None Howard S. Weintraub New York University Medical Center None None AstraZeneca ; Daiichi Sankyo*; Takeda ; Abbott ; Kowa*; Novartis None None None None This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be significant if (a) the person receives $10000 or more during any 12-month period, or 5% or more of the person s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10000 or more of the fair market value of the entity. A relationship is considered to be modest if it is less than significant under the preceding definition. *Modest. Significant. 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