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.


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.


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.


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.


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.


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.


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.


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. The results of CAMELOT can be taken only as hypothesis generating because the effect of achieved BP on ath- eroma volume was not a prespecified outcome. Because this was a post-hoc analysis, there is the potential for residual confound- ing effects, especially because the individuals in the higher BP cohort were older and were more likely to have been assigned to the placebo arm of the study and therefore not treated with either amlodipine or enalapril. 3.2.2. Observational Studies and Clinical Trials If coronary autoregulation were clinically important, it would be predicted that a U-shaped or J-shaped relationship should exist between DBP and CAD events. Furthermore, the pres- ence of structural CAD could be expected to affect the pres- sure-flow relationships in the coronary arteries, with a lower tolerance of diastolic pressures.


Furthermore, the pres- ence of structural CAD could be expected to affect the pres- sure-flow relationships in the coronary arteries, with a lower tolerance of diastolic pressures. There is evidence from clini- cal trials to both support and refute the existence of a J curve. The first retrospective study in 1979 reported a 5-fold increase in MI among treated patients with DBP (Korotkoff phase IV) values <90 mmHg,133 roughly equivalent to <80 to 85 mmHg using the more universal Korotkoff phase V. This observation was confirmed by a subsequent meta-analysis in and a reanalysis of the 1985 MRC trial of mild hyper- tension, which reported an increased MI prevalence in those with achieved DBP <80 mmHg.135 However, other investiga- tors using the same data have drawn opposite conclusions about whether a J curve really exists.136,137 A secondary analysis of data from INVEST138,139 of patients with known CAD and hypertension showed a J-shaped relationship between BP and the primary outcome (all-cause death, nonfatal stroke, and nonfatal MI), all-cause death, and total MI, with a nadir at 119/84 mmHg. This was not the case for stroke. These post hoc results were also cited in an analysis by Thune et al140 and an accompanying editorial141 as support for the existence of a J curve and a warning against exces- sive lowering of BP. However, what was not mentioned was that patients in that trial who had a BP <120/70 mmHg (the level below which the risk of adverse outcomes seemed to rise) were older and had a history of more MI, coronary artery bypass grafting or percutaneous coronary intervention, stroke or transient ischemic attack, diabetes mellitus, HF, and cancer, all confounding factors.


However, what was not mentioned was that patients in that trial who had a BP <120/70 mmHg (the level below which the risk of adverse outcomes seemed to rise) were older and had a history of more MI, coronary artery bypass grafting or percutaneous coronary intervention, stroke or transient ischemic attack, diabetes mellitus, HF, and cancer, all confounding factors. After adjustment for these and other comorbidities, there was no increased risk down to a DBP of A different nadir for a J-shaped relationship of BP with outcome, 146.3/81.4 mmHg, was identified in another sec- ondary analysis, this time of the Treating to New Targets Trial (TNT) in patients with clinically evident CAD.142 The Secondary Manifestations of Arterial Disease (SMART) study of patients with manifest arteriosclerotic disease had a nadir of The implication of these trials is that there is a higher risk of coronary events if the SBP is <146.3 or 143 mmHg, which is clearly at odds with the mass of data from clinical trials over many decades, which show that SBPs <140 mmHg are cardioprotective. There are much debate and disagreement about the meth- odological assumptions and pitfalls, and several reports have articulated how confounding variables, especially age and comorbidities, including late-stage HF, could have affected In none of the retrospective analyses was it possible to control adequately for the many interact- ing comorbid conditions that accompany and confound low DBP or for the complex relationships among age, DBP, and CVD risk. Age, DBP, and cardiovascular risk are positively associated until 50 years of age. For the remainder of life, DBP decreases and pulse pressure widens, whereas car- diovascular risk increases exponentially.


For the remainder of life, DBP decreases and pulse pressure widens, whereas car- diovascular risk increases exponentially. Age is by far the most important risk factor for CAD; the prevalence of fatal ischemic cardiac events increases by 64-fold as age doubles from 40 to 80 years. However, a high SBP, a low DBP, and a wide pulse pressure are each independent risk factors for CAD, but SBP was a better predictor of outcomes than pulse Thus, the effects of a low DBP or wide pulse pressure cannot be separated easily from those of aging in predicting the risk of a fatal MI. This important confounder may explain much of the confusion over the existence of a J curve in observational studies. These results suggest that wide pulse pressure is a signifi- cant determinant of whether the DBP is a major risk predictor. Therefore, in those studies that reported a J curve, possible explanations include diminished myocardial perfusion during diastole, an age-related increase in pulse pressure reflecting stiffer large arteries, or an epiphenomenon related to a known or undetected underlying illness (eg, cancer, HF), so-called reverse causality in which the pre-existing illness explains both the low BP and the high risk of death. There is also direct evidence against the concept of the J curve. For example, in the CAMELOT trial,150 had angiographically documented CAD, and the mean entry BP was 129/77 mmHg. Treatment with either an ACE inhibi- tor or a CCB lowered BP by an additional 5/2 mmHg, with no evidence of a J-curve in either treated group. 3.2.3. Clinical Trials to Specifically Evaluate Lower BP Goals Data from controlled trials designed primarily to evaluate lower BP goals in hypertensive subjects have not shown a J curve.


Clinical Trials to Specifically Evaluate Lower BP Goals Data from controlled trials designed primarily to evaluate lower BP goals in hypertensive subjects have not shown a J curve. Population-based studies suggest that 45% of white adults with diabetes mellitus have coronary heart disease compared with 25% in nondiabetic individuals.151 This makes the ACCORD study relevant to the issue of BP targets in patients with CAD. ACCORD was a trial to evalu- ate the overall effects of intensified glycemic control, inten- sive BP lowering, and reduced triglyceride levels in patients with type 2 diabetes mellitus and other risk factors for CVD. The BP study20 randomized 4733 patients, of whom 34% had had a previous cardiovascular event, to an intensive therapy arm, with an SBP target of <120 mmHg, or to standard ther- apy, targeting an SBP of <140 mmHg. After 1 year, the mean SBP was 119.3 mmHg in the intensive therapy group, and 133.5 mmHg in the standard therapy group, a difference of 14 mmHg. During the mean follow-up of 4.7 years, there was no significant difference between the 2 groups with respect to the primary composite outcome (nonfatal MI, nonfatal stroke, or death resulting from cardiovascular causes), nonfa- tal MI, all-cause mortality, cardiovascular death, major coro- nary disease event, or fatal or nonfatal HF. However, the risk of the primary composite end point was numerically lower (by 12%) in those randomized to the lower goal. Similarly, the risk of MI was lower (by 13%) in the group randomized to the lower BP target, but this was not statistically significant. There was a putatively significantly lower incidence of stroke in the intensive therapy group (ie, uncorrected for multiple comparisons), but the number of strokes was small (at 98).


There was a putatively significantly lower incidence of stroke in the intensive therapy group (ie, uncorrected for multiple comparisons), but the number of strokes was small (at 98). The main conclusion drawn by the investigators from this study is that an SBP <120 mmHg in patients with type 2 dia- betes mellitus is not justified.20,152 In the context of the J-curve conundrum discussed above, it is worthwhile noting that the mean achieved DBP in the intensive therapy group at 4 to 8 years after randomization was in the range of 60 to 65 mmHg and that there was not only no significant increase in coronary events at these DBPs but in fact a numerical decrease in such events. This finding, together with the significant protection from stroke, seen in ACCORD and most other trials could suggest a different interpretation of the ACCORD results, namely that lower DBPs are safe, at least in the range of 60 to 65 mmHg, and may protect against stroke. The Systolic Blood Pressure Intervention Trial (SPRINT), now underway, has a trial design very similar to that of ACCORD but has enrolled only nondiabetic subjects, with a heavy representa- tion of the elderly and patients with CKD. 3.2.4. Lower BP Goals and Diabetes Mellitus Besides the ACCORD study, discussed above, there have been other studies relevant to secondary prevention of cardiovascu- lar events in patients with hypertension and CAD. In a diabetic cohort of subjects with hypertension and CAD in INVEST,116 tight control of SBP (<130 mmHg) was not associated with Rosendorff et al Treatment of Hypertension in Patients With CAD 1385 improved cardiovascular outcomes compared with usual con- trol (130 139 mmHg), although in an extended follow-up of 9 years, the risk of all-cause mortality was 22.8% versus 21.8%, respectively, which was just statistically significant.


In a diabetic cohort of subjects with hypertension and CAD in INVEST,116 tight control of SBP (<130 mmHg) was not associated with Rosendorff et al Treatment of Hypertension in Patients With CAD 1385 improved cardiovascular outcomes compared with usual con- trol (130 139 mmHg), although in an extended follow-up of 9 years, the risk of all-cause mortality was 22.8% versus 21.8%, respectively, which was just statistically significant. This is a small difference, and it is uncertain whether this can be regarded as a contribution to clinical decision making. In the earlierAppropriate Blood Pressure Control in Diabetes (ABCD) trial, the mean BP achieved was 132/78 mmHg in the intensive group and 138/86 mmHg in the moderate BP con- trol group. After 5 years, there was no difference between the groups in the progression of diabetic microvascular complica- tions or in the rate of MI, stroke or HF. However, unlike the result in INVEST, theABCD participants in the intensive group had a significant reduction in all-cause mortality.153 The latest standards of medical care in diabetes mellitus of the American Diabetes Association recommend a goal BP of <140/80 mmHg; lower values, <130/80 mmHg, may be appropriate for certain individuals, such as younger patients, if it can be achieved without undue treatment burden. 3.2.5. Lower BP Goals for the Prevention of Stroke Patients with atherosclerotic stroke should be included among those deemed to be at high risk ( 20% over 10 years) of fur- ther atherosclerotic cardiovascular events.154 Besides ACCORD, in which there was no excess MI from intensive BP lowering and some benefit in preventing stroke, there have been other studies in which the effects of BP lower- ing on stroke outcomes have been documented. With 1 excep- tion, the reports are consistent with supporting better stroke outcomes with BPs <130/80 mmHg.


With 1 excep- tion, the reports are consistent with supporting better stroke outcomes with BPs <130/80 mmHg. The exception is a post hoc observational analysis of the Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) data, involving 20 330 patients with recent ischemic stroke. Hypertension was not an inclusion criterion, although most of the patients had elevated BP. PROFESS was also not a clinical trial of antihypertensive therapy but primarily of antiplatelet agents. During the 2.5 years of follow-up, the adjusted hazard ratio for subjects with an SBP in the 120- to 129-mm Hg range, compared with those in the 130- to 139-mm Hg range, was 1.10 (95% confidence interval, 0.95 1.28) for stroke and 1.01 (95% confidence interval, 0.64 1.89) for fatal stroke, both not statistically significant, and 1.16 (95% confidence interval, 1.03 1.31) for a composite end point of stroke, MI, or vas- In a very large meta-analysis of 147 randomized trials of the percentage reductions in coro- nary heart disease events and stroke were similar in people with and without CVD and regardless of BP before treatment (down to 110 mmHg SBP and 70 mmHg DBP). A meta- regression analysis that included 31 intervention trials of BP lowering in 74000 patients with diabetes mellitus reported a decrease of 13% in the risk of stroke for each 5-mmHg reduc- tion in SBP and of 11.5% for each 2-mmHg reduction in DBP. In contrast, the decrease in the risk of MI approached but did not achieve statistical significance.157 In ONTARGET, the benefits from lowering SBP to <130 mmHg were driven mostly by a reduction in stroke.


In contrast, the decrease in the risk of MI approached but did not achieve statistical significance.157 In ONTARGET, the benefits from lowering SBP to <130 mmHg were driven mostly by a reduction in stroke. MI was unaffected and cardiovascular mortality was unchanged.90 There is consistency in these reports, namely that inten- sive BP lowering to <130/80 mmHg does not significantly decrease or increase coronary morbidity or mortality but may be protective against stroke. However, the PROFESS data are different, so the issue is still somewhat moot. 3.2.6. The Elderly It might be predicted that a J curve would have a more dev- astating effect on elderly individuals, with a nadir at higher pressures, because of the greater likelihood of their having CAD and a lower coronary reserve. Very few studies have addressed this question, but those that have addressed it have produced reasonably reassuring results. An INVEST sub- showed a J-shaped relationship between DBP and the primary outcome (all-cause death, nonfatal MI, or nonfa- tal stroke) but with a nadir of 75 mmHg, except for the very old, for whom it was even lower at 70 mmHg. In HYVET,15 patients >80 years of age with a mean BP of 173.0/90.8 mmHg were randomized to receive treatment with indap- amide, with perindopril added if necessary, versus placebo. In the active treatment group, the mean BP fell by almost 30/13 mmHg and produced a 30% reduction in stroke and a 64% reduction in HF but had no significant effect on MI.


In the active treatment group, the mean BP fell by almost 30/13 mmHg and produced a 30% reduction in stroke and a 64% reduction in HF but had no significant effect on MI. The HYVET authors stated, The results support a target BP of 150/80 mmHg in patients receiving treatment, since that target was reached in nearly 50% of such patients in HYVET With regard to the 65- to 79-year range, we take note of the recommendation of the ACC Foundation/AHA 2011 expert consensus document on hypertension in the elderly,159 which states: The general recommended goal BP in people with uncomplicated hypertension is <140/90 mmHg. However, this target for elderly patients with hypertension is based on expert opinion rather than on data from RCTs [randomized, controlled trials], and it is unclear whether the target SBP should be the same in 65 to 79 year old versus older patients. We have therefore retained a target of <140/90 mmHg for this age group. Lower SBP values may be associated with better stroke out- comes except in the case of PROFESS, and the evidence for CAD outcomes is equivocal. The evidence that excessive low- ering of DBP may compromise cardiac outcomes (the J curve) is inconsistent. Epidemiological and clinical trial evidence both support and refute the existence of a J curve for DBP but not SBP, which suggests the presence of major confounders of data interpretation, including selection bias, comorbidities, and nonlinear interactions among age, decreasing DBP, and increasing cardiovascular risk. The vast majority of hyperten- sive individuals, including those with overt cardiac disease, will not experience problems related to lowering of DBP when standard antihypertensive medications are used.


The vast majority of hyperten- sive individuals, including those with overt cardiac disease, will not experience problems related to lowering of DBP when standard antihypertensive medications are used. Concerns that coronary perfusion is limited by an autoregulatory threshold have not yet been validated in humans with healthy or even diseased coronary arteries, and no consensus exists on the min- imum safe level of DBP in these individuals.Although an auto- regulatory threshold has not been defined in humans, with or without CAD, it is clear, mainly fromACCORD, that lower BP targets, down to levels <120/80 mmHg, protect against stroke and do not significantly increase CAD events. Most studies that have addressed lower BP targets have achieved DBP val- ues in the 70- to 79-mmHg range, which appears to be safe. Therefore, a reasonable recommendation would be a BP target of <140/90 mmHg for the secondary prevention of car- diovascular events in patients with CAD. However, there are some epidemiological data, several post hoc analyses of clini- cal trials, and a plethora of other data that support, but do not prove, that a lower target (<130/80 mmHg) may be appropri- ate in some individuals with CAD. We counsel that the BP should be lowered slowly in patients with occlusive CAD with evidence of myocardial ischemia, and caution is advised in inducing decreases in DBP to <60 mmHg, particularly if the patient is >60 years of age. In older hypertensive individu- als with wide pulse pressures, lowering SBP may cause very low DBP values (<60 mmHg). This should alert the clinician to assess carefully any untoward signs or symptoms, espe- cially those resulting from myocardial ischemia.


This should alert the clinician to assess carefully any untoward signs or symptoms, espe- cially those resulting from myocardial ischemia. In patients >80 years of age, a reasonable BP target is <150/80 mmHg, although there are no direct data to support this, or any other specific BP goal, in this age group. 1. The <140/90-mmHg BP target is reasonable for the secondary prevention of cardiovascular events in pa- tients with hypertension and CAD (Class IIa; Level of Evidence B). 2. A lower target BP (<130/80 mmHg) may be appropri- ate in some individuals with CAD, previous MI, stroke or transient ischemic attack, or CAD risk equivalents (carotid artery disease, PAD, abdominal aortic aneu- rysm) (Class IIb; Level of Evidence B). 3. In patients with an elevated DBP and CAD with evidence of myocardial ischemia, the BP should be lowered slowly, and caution is advised in induc- ing decreases in DBP to <60 mmHg in any patient with diabetes mellitus or who is >60 years of age. In older hypertensive individuals with wide pulse pres- sures, lowering SBP may cause very low DBP values (<60 mmHg). This should alert the clinician to assess carefully any untoward signs or symptoms, especially those resulting from myocardial ischemia (Class IIa; Level of Evidence C). 4. Management of Hypertension in Patients With CAD and Stable Angina The management of hypertension in patients with chronic CAD and chronic stable angina is directed toward the prevention of death, MI, and stroke; a reduction in the frequency and duration of myocardial ischemia; and the amelioration of symptoms. Lifestyle changes and the adoption of a heart healthy approach are critical, with the usual attention to diet, sodium intake, mod- eration of alcohol intake, regular exercise, weight loss, smoking cessation, glycemic control, lipid management, and antiplate- let therapy.


Lifestyle changes and the adoption of a heart healthy approach are critical, with the usual attention to diet, sodium intake, mod- eration of alcohol intake, regular exercise, weight loss, smoking cessation, glycemic control, lipid management, and antiplate- let therapy. Recognition and treatment of hypothyroidism and obstructive sleep apnea are important adjuncts in at-risk patients. Pharmacological management is inevitably required. A reasonable BP target for hypertensive patients with dem- onstrated CAD is <140/90 mmHg.20,155,159 167 A lower target BP (<130/80 mmHg) may be appropriate in some individuals with CAD or those with previous MI, stroke or transient isch- emic attack, or CAD risk equivalents (carotid artery disease, PAD, abdominal aortic aneurysm). 4.1. Pharmacological Therapy -Blockers are the drugs of first choice for the treatment of hypertension in patients with CAD that causes angina.168,169 They alleviate ischemia and angina primarily as a function of their negative inotropic and chronotropic actions. The decreased heart rate increases diastolic filling time for coro- nary perfusion. -Blockers also inhibit renin release from the juxtaglomerular apparatus. Cardioselective ( 1 ) agents without intrinsic sympathomimetic activity are used most fre- quently. Relative contraindications to their use include signifi- cant sinus or atrioventricular node dysfunction, hypotension, decompensated HF, and severe bronchospastic lung disease. PAD is rarely made symptomatically worse by the use of these agents, and mild bronchospastic disease is not an abso- lute contraindication. Caution is needed when brittle diabetic patients with a history of hypoglycemic events are treated because -blockers may mask the symptoms of hypoglycemia. Recently, there has been considerable controversy concern- ing the appropriateness of using -blockers as first-line therapy in hypertension in those patients who do not have a compel- ling indication; however, their use in patients with angina, prior MI, or HF has a solid basis of positive data.


Recently, there has been considerable controversy concern- ing the appropriateness of using -blockers as first-line therapy in hypertension in those patients who do not have a compel- ling indication; however, their use in patients with angina, prior MI, or HF has a solid basis of positive data. -Blockers should be prescribed as initial therapy for the relief of symptoms in patients with stable angina. -Blockers may be considered as long-term therapy for all other patients with coronary or other vascular disease. Recent ACC Foundation/AHA guide- have recommended -blocker therapy in patients with normal LV function after MI or ACS (Class I; Level of Evidence B), specifically carvedilol, metoprolol succinate, or bisoprolol, in all patients with LV systolic dysfunction (ejec- tion fraction 40%) or with HF or prior MI unless contrain- dicated (Class I; Level of Evidence A). -Blockers should be started and continued for 3 years in all patients with normal LV function after MI or ACS (Class I; Level of Evidence B).168 170 4.1.2. Calcium Channel Blockers As a class, CCBs reduce myocardial oxygen demand by decreasing peripheral vascular resistance and lowering BP and increase myocardial oxygen supply by coronary vasodilation. The nondihydropyridine agents diltiazem and verapamil also decrease the sinus node discharge rate and slow atrioventricu- lar nodal conduction.


The nondihydropyridine agents diltiazem and verapamil also decrease the sinus node discharge rate and slow atrioventricu- lar nodal conduction. CCBs or long-acting nitrates should be prescribed for the relief of symptoms when -blockers are contraindicated or cause unacceptable side effects in patients with stable angina (Class IIa; Level of Evidence B).168 CCBs or long-acting nitrates in combination with -blockers should be prescribed for the relief of symptoms when initial therapy with -blockers is unsuccess- ful in patients with stable angina (Class IIa; Level of Evidence CCBs are added to, or substituted for, -blockers when BP remains elevated, when angina persists, or when drug side effects or contraindications mandate.171 Long-acting dihydropyr- idine agents are preferred over nondihydropyridines (diltiazem Rosendorff et al Treatment of Hypertension in Patients With CAD 1387 or verapamil) for use in combination with -blockers to avoid excessive bradycardia or heart block. Diltiazem or verapamil should not be used in patients with HF or LV systolic dysfunc- and short-acting nifedipine should be avoided because it causes reflex sympathetic activation and worsening myocardial Although CCBs are useful in the management of hyperten- sion in patients with stable angina, there is no consensus about their role in preventing cardiovascular events in patients with established CAD. The INVEST investigators randomized >22000 hypertensive patients with chronic CAD to the non- dihydropyridine CCB verapamil or the -blocker atenolol.116 By 24 months, the ACE inhibitor trandolapril had to be added in 63% of verapamil patients and 52% of atenolol patients, and hydrochlorothiazide was added in 44% of verapamil and 60% of atenolol patients. There was no difference between the groups in the composite end point of death, MI, or stroke over a mean follow-up of 2.7 years.


There was no difference between the groups in the composite end point of death, MI, or stroke over a mean follow-up of 2.7 years. More than 50% of patients in ALLHAT had a history or signs of atherosclerotic vascular disease, and there was no significant difference in the inci- dence of coronary end points among patients allocated a thiazide-type diuretic, a long-acting dihydropyridine CCB, or an ACE inhibitor.96 CAMELOT compared amlodipine or enalapril with placebo in normotensive patients with CAD, 60% of whom had a history of hypertension.150 Although the BP reduction was similar in the 2 active treatment groups, adverse cardiovascular events occurred less frequently in the amlodipine group than in the enalapril group. An intravascu- lar ultrasound substudy of CAMELOT showed progression of atherosclerosis in the placebo group (P<0.001), a trend toward progression in the enalapril group (P=0.08), and no progression in the amlodipine group (P=0.31). Amlodipine may have pleiotropic effects beyond BP lowering that favor atherosclerotic plaque stabilization.172,173 The VALUE trial randomized 15245 hypertensive patients at high risk of cardiac events to valsartan or amlodipine.107 Forty-six percent of patients in both groups had CAD. Mean follow-up was 4.2 years. No difference between groups was observed in the primary composite end point of cardiac mor- bidity and mortality. The risk of MI was lower in the amlodip- ine group, whereas the risk of new-onset diabetes mellitus was lower in the valsartan group. Of note, amlodipine was signifi- cantly more effective in reducing BP, especially over the first year of the trial. There was also a strong trend for an excess risk of stroke in the valsartan group, likely resulting from this same BP differential that favored amlodipine.


There was also a strong trend for an excess risk of stroke in the valsartan group, likely resulting from this same BP differential that favored amlodipine. The investiga- tors highlighted the need for aggressive BP control in high-risk hypertensive patients, a goal that frequently requires combina- tion therapy at the outset, a concept supported by the Blood Pressure Lowering Treatment Trialists Collaboration.174 4.1.3. ACE Inhibitors ACE inhibitors should be prescribed to all CAD patients with stable angina who also have hypertension, diabetes mellitus, an LV ejection fraction 40%, or CKD unless contraindicated (Class I; Level of Evidence A).169 The clinical trials that sup- port the use of ACE inhibitors in the management of patients with stable CAD were described in the Antihypertensive Drugs for the Secondary Prevention of Cardiovascular Events in Patients With CAD section. They are the HOPE study,16 in which high-risk individuals, 80% of whom had CAD, were given an ACE inhibitor (ramipril 10 mg/d), with a reduction in CVD end points by 20% to 25%; EUROPA,18 which showed a 20% relative risk reduction in the primary end point, a com- posite of cardiovascular death, MI, or cardiac arrest in patients in subjects with established CAD treated with perindopril 8 mg/d versus placebo; and SAVE.17 On the other hand, there have been negative studies. These in which patients with stable CAD and normal or slightly reduced LV function were randomized to trandolapril (target dose, 4 mg) or placebo. No difference between the groups was found in the incidence of the primary composite end point of cardiovascular death, MI, or coronary revascularization. Patients in the PEACE trial were at lower risk and were receiving more aggressive secondary prevention therapy than those in the HOPE trial.


Patients in the PEACE trial were at lower risk and were receiving more aggressive secondary prevention therapy than those in the HOPE trial. In ALLHAT,96 in which 25% of participants had CAD, there were no significant differ- ences among patients taking chlorthalidone, amlodipine, and lisinopril in the combined outcomes of fatal CAD and nonfa- tal MI (the primary outcome of the study), in combined CAD (the primary outcome plus coronary revascularization or hos- pitalization for angina), or in all-cause mortality. Soon after the ALLHAT results were published, the Second Australian National Blood Pressure Study (ANBP-2) reported the results of a prospective, open-label study in patients 65 to 84 years of age with hypertension that showed, in men but not in women, better cardiovascular outcomes with ACE inhibitors than with diuretic agents despite similar reductions in BP.175 4.1.4. Angiotensin Receptor Blockers ARBs are recommended for all patients with stable angina who also have hypertension, diabetes mellitus, LV ejection fraction 40%, or CKD and have indications for, but are intol- erant of, ACE inhibitors (Class I; Level of Evidence A).169 ARBs are indicated during hospitalization and at discharge for STEMI patients who are intolerant of ACE inhibitors and have HF or an ejection fraction <0.40 (Class I; Level of The combination of ACE inhibitors and ARBs has been used for the treatment of advanced or persistent HF in the convalescent or chronic phase after STEMI,177 but the failed to show additive benefit but with a substantial increase in side effects, so this combination is not recommended.


Angiotensin Receptor Blockers ARBs are recommended for all patients with stable angina who also have hypertension, diabetes mellitus, LV ejection fraction 40%, or CKD and have indications for, but are intol- erant of, ACE inhibitors (Class I; Level of Evidence A).169 ARBs are indicated during hospitalization and at discharge for STEMI patients who are intolerant of ACE inhibitors and have HF or an ejection fraction <0.40 (Class I; Level of The combination of ACE inhibitors and ARBs has been used for the treatment of advanced or persistent HF in the convalescent or chronic phase after STEMI,177 but the failed to show additive benefit but with a substantial increase in side effects, so this combination is not recommended. In the VALUE trial,107 there was no difference in cardiac mortality and morbidity in patients with hyperten- sion and high risk of cardiovascular events who were treated with regimens based on valsartan versus amlodipine, even though the BP-lowering effect of amlodipine was greater than that of valsartan. In VALIANT,91 valsartan was as no more effective than captopril in patients who were at high risk for cardiovascular events after MI. Thiazide diuretics and thiazide-like diuretics reduce car- diovascular events, as demonstrated most convincingly in early studies such as the Veterans Administration studies,93 the MRC Trial,94 and in later studies such as These studies included subjects with CAD, and it is a reasonable assumption that diuretics are as effective in the secondary as in the primary prevention of cardiovascular events.


Thiazide diuretics and thiazide-like diuretics reduce car- diovascular events, as demonstrated most convincingly in early studies such as the Veterans Administration studies,93 the MRC Trial,94 and in later studies such as These studies included subjects with CAD, and it is a reasonable assumption that diuretics are as effective in the secondary as in the primary prevention of cardiovascular events. Long-acting nitrates or CCBs can be prescribed for the relief of symptoms when -blockers are contraindicated or cause unac- ceptable side effects in patients with stable angina (Class I; Level of Evidence B).169 Long-acting nitrates or CCBs in combination with -blockers should be prescribed for relief of symptoms when initial therapy with -blockers is unsuccessful in patients with stable angina (Class I; Level of Evidence B). Nitrates should not be used with phosphodiesterase inhibitors of the sildenafil type. Hypertension does not affect the use of long-acting nitrates for the prevention of angina or of sublingual nitrate preparations for relief of an anginal attack. Conversely, nitrates have generally not been shown to be of use in the management of hypertension. The management of symptomatic CAD, particularly angina pectoris, is directed to the relief of the angina and the pre- vention of both the progression of CAD and coronary events. The mainstays of angina treatment are -blockers, CCBs, and nitrates. Pharmacological strategies for the prevention of car- diovascular events in these patients include ACE inhibitors, ARBs, thiazide and thiazide-like diuretics, -blockers (par- ticularly after MI), CCBs, antiplatelet drugs, and drugs for the treatment of dyslipidemia.


Pharmacological strategies for the prevention of car- diovascular events in these patients include ACE inhibitors, ARBs, thiazide and thiazide-like diuretics, -blockers (par- ticularly after MI), CCBs, antiplatelet drugs, and drugs for the treatment of dyslipidemia. The recent ACC Foundation/AHA guidelines recommend ACE inhibitors and/or -blockers, with the addition of drugs such as thiazide diuretics or CCBs for the management of high BP in patients with stable IHD.169 There are no special contraindications in hypertensive patients for the use of nitrates, antiplatelet or anticoagulant drugs, or lipid-lowering agents for the management of angina and the prevention of coronary events, except that in patients with uncontrolled severe hypertension who are taking anti- platelet or anticoagulant drugs, BP should be lowered without delay to reduce the risk of hemorrhagic stroke. 1. Patients with hypertension and chronic stable angina should be treated with a regimen that includes: (a) -blocker in patients with a history of prior MI (b) An ACE inhibitor or ARB if there is prior MI, LV systolicdysfunction,diabetesmellitus,orCKD;and (c) A thiazide or thiazide-like diuretic (Class I; Level of Evidence A). 2. The combination of a -blocker, an ACE inhibitor or ARB, and a thiazide or thiazide-like diuretic should also be considered in the absence of a prior MI, LV systolic dysfunction, diabetes mellitus, or proteinuric CKD (Class IIa; Level of Evidence B). 3. If -blockers are contraindicated or produce intolerable side effects, a nondihydropyridine CCB (such as diltia- zem or verapamil) may be substituted, but not if there is LV dysfunction (Class IIa; Level of Evidence B). 4. If either the angina or the hypertension remains un- controlled, a long-acting dihydropyridine CCB can be added to the basic regimen of -blocker, ACE inhibitor, and thiazide or thiazide-like diuretic.


If either the angina or the hypertension remains un- controlled, a long-acting dihydropyridine CCB can be added to the basic regimen of -blocker, ACE inhibitor, and thiazide or thiazide-like diuretic. The combination of a -blocker and either of the nondihydropyridine CCBs (diltiazem or verapamil) should be used with cau- tion in patients with symptomatic CAD and hyperten- sion because of the increased risk of significant brady- arrhythmias and HF (Class IIa; Level of Evidence B). 5. For patients with stable angina, the BP target is <140/90 mmHg. (Class I; Level of Evidence A). See also the previous section BP and Treatment Goals. However, a lower target BP (<130/80 mmHg) may be considered in some individuals with CAD, with previ- ous stroke or transient ischemic attack, or with CAD risk equivalents (carotid artery disease, PAD, abdomi- nal aortic aneurysm) (Class IIb; Level of Evidence B). 6. There are no special contraindications in hyperten- sive patients for the use of antiplatelet or anticoagu- lant drugs, except that in patients with uncontrolled severe hypertension who are taking antiplatelet or anticoagulant drugs, the BP should be lowered with- out delay to reduce the risk of hemorrhagic stroke (Class IIa; Level of Evidence C). 5. Management of Hypertension in Patients With ACS Although a major risk factor for CVD, the impact of hyper- tension on ACS outcomes has not been well described. Few data are available on specific treatments for hypertension in patients with either STEMI or non ST-segment elevation ACS, including both UA and NSTEMI. 5.1.


Few data are available on specific treatments for hypertension in patients with either STEMI or non ST-segment elevation ACS, including both UA and NSTEMI. 5.1. Prevalence and Impact on Prognosis Contemporary data from the National Cardiovascular Data Registry (NCDR) Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry Get With The Guidelines (GWTG) demonstrate a prevalence of hyperten- sion of 65.2% among patients with STEMI and 79.2% among those with NSTEMI (ACTION Registry GWTG 2012 first- quarter report). The prevalence of hypertension increases notably with age among ACS patients, with hypertension prevalence rates approximately double among individuals >75 versus those <45 years of age.178 The impact of hypertension on outcomes in ACS is com- plex. In patients with stabilized ACS enrolled in the Sibrafiban Versus Aspirin to Yield Maximum Protection From Ischemic Heart Events Post-Acute Coronary Syndromes (SYMPHONY) trials, hypertension was an independent predictor of death and Moreover, hypertension is integrated into the Thrombolysis in Myocardial Infarction risk score for UA/ NSTEMI as one of several classic risk factors for CAD, and the variable of 3 risk factors for CAD was independently associ- ated with the composite end point of mortality and recurrent However, other multivariable risk models have not found hypertension, defined as a yes/no categorical variable, to be independently associated with in-hospital mor- tality. Indeed, lower BP more typically emerges as predictive of poor outcomes in contemporary evaluations. In both the Global Registry of Acute Coronary Events (GRACE)180 and ACTION- registries, for example, in-hospital mortality Rosendorff et al Treatment of Hypertension in Patients With CAD 1389 increased by 20% for every 10-mmHg decrease in BP at presentation.


In both the Global Registry of Acute Coronary Events (GRACE)180 and ACTION- registries, for example, in-hospital mortality Rosendorff et al Treatment of Hypertension in Patients With CAD 1389 increased by 20% for every 10-mmHg decrease in BP at presentation. In contrast to the Thrombolysis in Myocardial Infarction risk score for UA/NSTEMI, in the Thrombolysis in Myocardial Infarction risk score for STEMI, SBP <100 mmHg emerged as a powerful contributor to the model, but hyperten- IntheGlobalUseofStrategiestoOpenOccluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) and Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) a very low SBP ( 90 mmHg) was strongly associated with 48-hour and 30-day mortality, but there was little differ- ence in mortality between patients who had a high SBP (>140 mmHg) and those with an SBP in the normal or prehyperten- sive range (121 140 mmHg). Even severe hypertension (up to an SBP of 200 mmHg) appeared to be protective in the NCDR ACTION analysis of 80000 patients with MI.181 Although uncontrolled hypertension does not appear to significantly increase in-hospital mortality in patients with ACS, it is a major risk factor for intracranial hemorrhage and thus remains a relative contraindication to fibrinolysis.176 When broader bleeding outcomes are evaluated across the ACS spectrum, a U-shaped association between BP and in- hospital bleeding is observed, with excess bleeding for both patients with hypertension and those with hypotension. In an analysis from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) bleeding rates were lowest in patients with admis- sion SBP between 120 and 180 mmHg and increased progres- sively with BPs above and below these ranges.


In an analysis from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) bleeding rates were lowest in patients with admis- sion SBP between 120 and 180 mmHg and increased progres- sively with BPs above and below these ranges. Similarly, in the NCDR ACTION Registry Bleeding Risk Score, zero points are awarded for an SBP of 141 to 170 mmHg on arrival, with 2 points given for SBP >200 mmHg and 4 points for SPB 90 In contrast, BP variables did not emerge as indepen- dently associated with bleeding in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) and Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trials.186 These studies have important limitations that make it difficult to determine the impact of treating hypertension during an acute ACS episode. All of the data are observational, and it is likely that residual confounding explains some, if not most, of the observed adverse association between lower BP and mortality after ACS, particularly for BP values within or near the normal range. In addition, very limited information is available from these studies on the duration of and long-term disease burden of hypertension. Despite these limitations, the consistent asso- ciations observed between hypotension and both mortality and bleeding suggest that avoidance of hypotension should be an important treatment principle in ACS patients. 5.2. General Principles of BP Management in the Patient With ACS The cornerstone of the management of hypertension in patients with ACS is the modification of the balance between myocar- dial oxygen supply and demand.


General Principles of BP Management in the Patient With ACS The cornerstone of the management of hypertension in patients with ACS is the modification of the balance between myocar- dial oxygen supply and demand. Patients with ACS are espe- cially vulnerable to perturbations in this relationship because the development of an ACS is a clinical manifestation of an alteration in the supply-demand equation such that ischemia occurs at rest or at relatively low levels of demand. 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.


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 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.


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.


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.


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.


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.


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%.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.