Hypertension and ischemic heart disease (IHD) are strongly related and the two co-occur frequently, particularly in aging populations. Both conditions cause or contribute to substantial disability and mortality worldwide and both are responsible for substantial health care use and economic burden. IHD affects only around 6% of adults in the United States but is the leading proximal cause of death in the U.S. with an age-adjusted mortality rate of around 170 per 100,000 person-years among the general adult population. Moreover, hypertension with IHD is among the most prevalent dyads, and together with hyperlipidemia, the most prevalent triad in our Medicare population.
Numerous pathophysiologic mechanisms contribute to hypertension development (see Chapter 5 ) and associated organ damage, including IHD. Such mechanisms include sympathetic nervous system and renin angiotensin aldosterone system (RAAS) activation, increased conduit vessel stiffness, endothelial dysfunction, increased inflammatory mediators, hemodynamic changes, and reduced vasodilator reserve or activity. However, hypertension, per se, also directly promotes IHD development through mechanisms that affect the balance of myocardial oxygen supply and demand. For example, any increase in systolic blood pressure (BP) increases myocardial oxygen requirements, whereas more chronic BP elevations promote endothelial injury, resulting in impaired vasodilator (e.g., nitric oxide) release and increased release of inflammatory mediators that promote development of atherosclerosis and vascular occlusion. Oxygen demand can increase because of increased impedance to left ventricular (LV) ejection (e.g., “afterload”), development of LV hypertrophy (LVH) impairing coronary blood flow during diastole, or both, secondary to chronically elevated BP. This combination of limited oxygen supply and increased demand is particularly pernicious and explains, in part, why patients with elevated BP at any level, compared with those without elevated BP, are more likely to develop manifestations of IHD (angina, myocardial infarction [MI], or other major coronary event), and to be at higher mortality risk following an event.
Relationship Between Hypertension and Coronary Artery Disease
Hypertension is well documented as the most prevalent independent risk factor for the development of coronary artery disease (CAD), cardiac failure, stroke, and peripheral arterial disease (PAD). Younger subjects with hypertension (i.e., aged <50 years) often have an increased diastolic BP (DPB), whereas older subjects usually have increased systolic BP (SBP). Accordingly, in younger individuals, DBP is more closely associated with IHD development, whereas SBP is more predictive in those aged 60 years or older. Moreover, in this older age group, DBP is inversely related to CAD development, such that pulse pressure (PP) becomes a strong predictor of CAD risk. Importantly, the risk of CAD-attributable fatal events doubles for every 20-mm Hg increase in SBP or 10-mm Hg increase in DBP between a BP range of 115/75 to 185/115 mm Hg. Thus, patients need not be “hypertensive” by conventional BP thresholds (e.g., >140/90 mm Hg) to be at increased risk of major adverse cardiovascular events.
Arteriosclerotic disease is the consequence of a complex interaction of inflammation, cytokines, free radicals, growth factors, lipids, and endocrine and paracrine factors. Many of these latter substances adversely affect endothelial function and cause, through a common pathway, hypertrophy and reduced compliance of large- and medium-sized arteries and arterioles ( Fig. 31.1 ). Frequently, these changes are present in the vasculature of young individuals before they develop hypertension, especially in the children of hypertensive parents; a finding supporting the notion of a genetic component, but also that hypertension is a consequence of the vasculopathy. Hypertension causes fragmentation and fracture of elastin fibers as well as collagen deposition in arteries, changes that contribute to thickening and stiffening of those arteries. Hypertension also induces endothelial dysfunction, thus reducing many endothelium-dependent functions (e.g., vasodilator capacity, anticoagulation, thrombolysis).
One of the hallmarks of hypertension is stiff arteries. Compliance of an artery may be defined as the change of lumen diameter (ΔD), or of cross-sectional area (ΔA) during each cardiac cycle, as a function of the change of distending pressure over one cardiac cycle (ΔP). This change in the distending pressure over one cardiac cycle (ΔP) is the PP. Compliance is thus represented by the slope of ΔD/ΔP (or ΔA/ΔP). In arteriosclerotic disease, ΔD is diminished because of the structural rigidity of the conduit vessels. PP is a function both of the stroke volume, which is usually normal in patients with established or stable hypertension, and of the stiffness of conduit vessels, which is typically increased in hypertension. However, an additional mechanism for increasing PP has been recognized ( Fig. 31.2 ). Pressure and flow waves are generated with each ejection of blood from the LV. The stiffer the large arteries, the greater the pulse wave velocity (PWV). That wave is reflected back from points of discontinuity (branch points) or increased resistance in the arterial tree, particularly at the level of small arteries and arterioles, and the reflected wave returns to the proximal aorta. In younger persons, this reflected wave reaches the aortic valve after closure, leading to a higher DBP, thus enhancing coronary perfusion. In older individuals with stiffer conduit vessels, the reflected pressure wave has a greater velocity and may reach the aortic valve before closure, leading to a higher SBP and afterload and a lower DBP, thus decreasing coronary perfusion pressure. Importantly, although reflected pressure waves add to the incident pressure wave, reflected flow waves subtract from the incident blood flow wave, thus reducing end-organ blood flow, including coronary blood flow (and cardiac output), renal blood flow, and others. These mechanisms help to explain why older individuals exhibit isolated systolic hypertension, with a normal or low DBP, and elevated PP. Also, why ischemia, heart failure, renal failure, and other associated comorbidities are more prevalent among the elderly. Increased myocardial oxygen demand results both from the increased resistance to LV ejection and from LVH. The myocardial oxygen supply is diminished, not only because of the atherosclerotic CAD, but also because of the decreased coronary filling pressure associated with the lower-than-normal DBP. This combination of increased oxygen demand and reduced supply in the myocardium of patients with hypertension is particularly problematic because the myocardium, unlike the brain, has relatively fixed oxygen extraction from coronary blood circulation and is unable to adequately compensate for decreased blood flow and oxygen supply.
Primary Prevention of Coronary Artery Disease in Patients with Hypertension
Any increase in BP above 120 mm Hg systolic or 85 mm Hg diastolic is associated with increased risk of developing CAD and mitigating this risk factor is a major goal of primary prevention. Consequently, patients with prehypertension or hypertension should receive guidance on risk-reducing healthy lifestyles, including smoking cessation; management of lipids, diabetes, and weight, as necessary; and a suitable exercise regimen. Daily aspirin reduces the risk of cardiovascular events broadly in at-risk individuals, including those with hypertension, and should be considered in patients at increased risk of developing CAD.
Effective antihypertensive therapy substantially reduces all cardiovascular adverse outcomes. Safely lowering BP is the main goal, which can be accomplished with any number of currently available antihypertensive agents, and most patients will require combination therapy. Whether specific antihypertensive agents exhibit additional benefits, that is, beyond BP-lowering, remains a subject of debate. However, as discussed later, few trials have focused on primary prevention of CAD and existing data do not strongly support any particular agent in preventing CAD development. The optimal BP goal for reducing risk of CAD development is not known. Previous guidelines recommended a goal of less than 130/80 mm Hg for both management of CAD and prevention (in those at high risk), but data supporting this goal, particularly in primary prevention, remain scarce.
Evidence for Antihypertensive Drugs for Primary Prevention of Coronary Heart Disease
Diuretics and Beta-Blockers
Most early clinical trials of antihypertensive therapy used diuretics, beta-blockers, or both and generally found that these agents significantly reduced adverse outcomes, especially stroke morbidity and mortality, in all age groups. More recent meta-analyses have shown that, compared with placebo, thiazide diuretic–based therapy reduces relative rates of heart failure (HF) by 41% to 49%, stroke by 29% to 38%, IHD by 14% to 21%, and all-cause death by 10% to 11%.
In the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), among high-risk hypertensive patients, chlorthalidone was superior to lisinopril in preventing stroke, and superior to lisinopril and amlodipine in preventing HF. Importantly, no significant differences were observed among chlorthalidone-treated, lisinopril-treated, or amlodipine-treated patients with regard to combined fatal CAD or nonfatal MI (the primary outcome of the study), combined CAD (fatal CAD, nonfatal MI, coronary revascularization, or hospitalization for angina), or all-cause mortality. However, the so-called “second step” drugs supplied (e.g., atenolol, clonidine, reserpine, hydralazine) were problematic with the possible exception of atenolol. That is, the lack of optimal pharmacologic combination therapy made the results difficult to translate to the clinic, particularly for patients with CAD. In addition, whether thiazide-type diuretics, used at contemporary doses, are equivalent with respect to outcome prevention remains a subject of debate. Recent data suggest that chlorthalidone may reduce cardiovascular events significantly more than hydrochlorothiazide, but at the expense of more hypokalemia and/or hyponatremia.
Spironolactone, a steroidal aldosterone antagonist, reduces morbidity and mortality in HF with reduced ejection fraction, with or without CAD and effectively lowers BP in patients with hypertension, including resistant hypertension. However, spironolactone has not been studied in prospective clinical trials, with objective outcomes, for the treatment of hypertension, with or without CAD. Eplerenone is a more selective steroidal aldosterone antagonist with lower affinity for androgen, progesterone, and glucocorticoid receptors accounting for its reduced side effect profile (i.e., less gynecomastia in men and dysmenorrhea in women) relative to spironolactone. Eplerenone reduces morbidity and mortality in patients with HF and reduced ejection fraction, and among CAD patients who are post-MI, regardless of the presence of hypertension. It is not known whether these agents are more or less effective at reducing coronary heart disease (CHD) compared with other antihypertensive agents. Several newer nonsteroidal aldosterone blockers are under investigation for patients with CAD, diabetes, and HF, that could yield improved outcomes among patients with CAD and hypertension.
Beta-blockers, long considered agents of choice among CAD patients with hypertension, have a more mixed outcome profile. Meta-analyses suggest that, compared with placebo, beta-blockers are associated with a 12% reduction in stroke, but no difference in mortality or CHD, and that beta-blockers are inferior to other major antihypertensive classes combined for major cardiovascular events (relative risk [RR] 1.17), stroke (RR 1.24), and all-cause mortality (RR 1.06), but not HF or CHD. In addition, beta-blockers may not be very effective for BP control among the elderly. However, most beta-blocker trials have used atenolol, often at suboptimal doses or only once daily. Accordingly, questions have been raised over whether these results apply broadly to all beta-blockers, only nonvasodilating beta-blockers, or to atenolol only. In part because of these and other data, beta-blockers have generally been downgraded to second-line therapy in the absence of compelling indications in most contemporary guidelines.
Calcium Channel Blockers
Since the mid-1990s, several trials of calcium channel blockers (CCBs) have been conducted for the primary prevention of cardiovascular complications of hypertension, particularly those related to IHD/CAD. The CCB trials tended to show a significant prevention of stroke, usually compared with placebo or with a diuretic, beta-blocker, or both. However, the absolute risk reduction in IHD deaths or nonfatal coronary events with CCBs has been less impressive, and in some cases absent. An extensive meta-analysis by the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) strongly supports the benefits of CCBs over placebo and for regimens that targeted lower BP goals; however, it found that CCBs, compared with diuretics and/or beta-blockers, significantly lowered stroke risk, but not CAD-related outcomes, and CCBs were associated with a 33% increase in HF. Moreover, CCBs were less effective in preventing CHD and HF than angiotensin converting enzyme (ACE) inhibitors.
Importantly, most of these trials were limited by the inability to determine, with certainty, which patients had preexisting CAD. To this end, the INternational VErapamil SR/trandolapril STudy (INVEST) enrolled only patients with hypertension and documented CAD to evaluate the effects of two different initial pharmacologic combination strategies (a beta-blocker plus hydrochlorothiazide strategy versus a nondihydropyridine CCB [verapamil] plus ACE inhibitor strategy). These INVEST combination strategies yielded excellent BP control (∼72% achieving <140/90 mm Hg) with equivalent reductions in all-cause mortality and other major cardiovascular outcomes. Similar risk reduction has also been observed between amlodipine and enalapril in patients with CAD and DBP less than 100 mm Hg. On the basis of the published trials, CCBs may be superior to hydrochlorothiazide in the prevention of coronary events, but not to other antihypertensive agents, particularly chlorthalidone and ACE inhibitors. CCBs also may be modestly superior to other major classes in reducing stroke, but inferior in reducing HF.
Angiotensin-Converting Enzyme Inhibitors
In the Heart Outcomes Prevention Evaluation (HOPE) study, after 4.5 years, ramipril, compared with placebo, was associated with relative risks of 0.74 for death from cardiovascular causes, 0.80 for MI, 0.85 for revascularization procedures, 0.63 for cardiac arrest, and 0.77 for HF. The results were applicable to patients with and without hypertension as well as to those with known IHD and those without CAD at baseline. Broadly similar results were observed in the smaller Prevention of Atherosclerosis with Ramipril Trial (PART-2), where ramipril, compared with placebo, reduced the risk for fatal CAD by 57%, but not the occurrence of MI or unstable angina.
Interestingly, active-comparator trials have suggested that ACE inhibitors lower overall cardiovascular morbidity and mortality, especially stroke, but are not demonstrably better than diuretics and/or beta-blockers for prevention of acute coronary events. Likewise, in the hypertensive subset of Appropriate Blood Pressure Control in Diabetes (ABCD-Hypertension), in comparison with nisoldipine, perindopril was associated with significantly fewer MIs, but no difference in stroke, HF, or death, although events were few. The BPLTTC meta-analysis found that for the outcome of CAD, ACE inhibitors were better than placebo (RR 0.80), but no better than diuretics, beta-blockers, or CCBs.
Angiotensin Receptor Blockers
The use of ARBs for the treatment of hypertension in patients with CAD has a solid foundation in animal studies and surrogate endpoint studies in humans. The Losartan Intervention For Endpoint reduction (LIFE) study found that losartan was significantly better than atenolol in reducing stroke, but not cardiovascular mortality or MI. In the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial, no significant difference was seen in the primary endpoint (a composite of nine cardiovascular events) between a valsartan-based and an amlodipine-based treatment regimen in high-risk patients. However, this finding is complicated by the fact that nearly all subjects were taking other therapy, mainly diuretics (∼25%), other combinations of study drugs (∼20%), or no study drug (∼25%) by study end, and because amlodipine lowered BP more than valsartan, especially during the early months of treatment.
Somewhat unexpected were the results of Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) in which telmisartan was no better than placebo, when added to concomitant therapies, in preventing cardiovascular events in ACE-intolerant patients with cardiovascular disease or diabetes, of whom 76% had hypertension. This finding seems to be at odds with the results of HOPE, in which ramipril improved outcomes compared with placebo, given that ACE inhibitors and ARBs have generally been considered equivalent in terms of cardiovascular outcomes. Among the possible reasons for this discrepancy were that in TRANSCEND, compared with HOPE: the incidence of prior CAD and MI was lower; baseline use of other cardiovascular risk–reducing medications was higher; the study may have been underpowered to identify an expected 19% risk reduction; and, hospitalization for HF was included in the composite endpoint. Interestingly, when the primary HOPE composite endpoint, which did not include hospitalization for HF, was assessed in TRANSCEND as a prespecified secondary endpoint, there was a 13% relative risk reduction ( p = 0.068).
Blood Pressure Targets
The coronary vascular bed, like most others, is capable of autoregulating flow in the face of large changes in perfusion pressure ( Fig. 31.3 ). The relationship of coronary blood flow (F), perfusion pressure (P), and coronary vascular resistance (R) is F∝P/R. In a rigid tube with a fixed resistance, F∝P. The coronary circulation, however, can alter its resistance, such that an increase in P causes coronary vasoconstriction (increased R), so that, if ventricular work is kept constant, flow remains relatively constant, up to a level at which the vasoconstriction is maximal (the upper limit of coronary vascular autoregulation). Conversely, a fall in P will stimulate vasodilation so that flow remains relatively constant, down to a level of P at which vessels are maximally dilated (the lower limit of coronary vascular autoregulation). Below that limit, any further decline in P will result in decreased flow. Most coronary blood flow occurs in diastole; thus the P referred to here is the mean DBP. The instantaneous coronary flow is a function of DBP, and the total flow per cardiac cycle is proportional to both DBP and the duration of diastole, assessed by the integrated area under the pressure curve during diastole.
Further considerations are the effects of myocardial hypertrophy and exercise. At any given P, coronary reserve is the difference between autoregulated and maximally dilated coronary flow. In Fig. 31.3 , curve A 1 represents coronary blood flow over a wide range of perfusion pressures, and the perfusion pressure P 1 is at the lower limit of autoregulation. If the coronary vessels are maximally dilated, a steep, linear pressure-flow relationship exists between pressure and flow (line D 1 ). The difference between autoregulated and maximally vasodilated flow at any given P represents the coronary flow reserve (R 1 ). If myocardial hypertrophy is present, total coronary flow is greater, with a higher autoregulatory line (curve A 2 ) and a rightward shift of the lower limit of autoregulation (point P 2 ). However, the pressure-flow relation at maximal vasodilation is less steep (line D 2 ), so that the coronary flow reserve (R 2 ) at any given P is less. Moreover, the point at which coronary flow reserve is exhausted (point P 2 ) in the hypertrophied heart will coincide with a higher P than normal (point P 1 ). Thus, in patients with hypertension and LVH, the lower limit of autoregulation is set at a higher level of P (and therefore DBP), and at any level of P, or DBP, the coronary flow reserve is less than it would be in the normal ventricle.
Given these physiologic considerations, there exists some BP value at the lower limit of coronary vascular autoregulation, below which coronary blood flow is reduced. BP-lowering beyond this point reduces target perfusion and increases risk of adverse cardiovascular outcomes and death. This so-called “J-curve” in the relationship between BP and risk of outcomes continues to be a subject of debate, in part because we do not have very good data about the exact DBP level at which coronary blood flow begins to be reduced in the intact human coronary circulation. In addition, the presence of any significant occlusive coronary atherosclerotic disease will shift the lower limit of autoregulation upward, making patients less tolerant of low DBPs, especially if there is additional myocardial oxygen demand from LVH.
Data from the Framingham study clearly show a demonstrable increase in cardiovascular risk in the general population at DBP less than 80 mm Hg, but only when SBP is higher than 140 mm Hg. This finding makes sense, given that low DBP may reduce coronary perfusion pressure, and higher SBP increases myocardial oxygen demand and may increase intramyocardial wall tension, further limiting perfusion. In patients with occlusive CAD, the perfusion pressure downstream of the stenosis would be even further reduced, and the elevated LV SBP and the presence of LVH would further increase myocardial oxygen demand. These considerations are consistent with epidemiologic data that both PP and presence of LVH are strongly predictive of coronary events.
The Hypertension Optimal Treatment (HOT) trial was designed to prospectively answer the question of whether intensive lowering of DBP would increase cardiovascular events, and it remains one of only large trials to randomly assign patients to more than two BP targets. Only among diabetic patients with the lowest DBP target was the cardiovascular risk the lowest; overall, there was a small increase in major cardiovascular events, MI, and cardiovascular mortality (but not for stroke or renal failure) with DBP 80 or less mm Hg. This finding suggests a unique myocardial susceptibility to low diastolic perfusion pressures because, in contrast to the cerebral circulation, there is maximal oxygen extraction by the myocardium, which therefore cannot compensate for a reduced flow by increasing oxygen extraction. This concept would seem to be supported by the notion that whereas stroke morbidity and mortality is best correlated with the level of mean BP, the best predictor of coronary events seems to be PP. PP is usually greatest in isolated systolic hypertension, in which the DBP is “normal” and often below 80 mm Hg, even before treatment. However, in the elderly with isolated systolic hypertension and low DBP, no J-shaped curve has been described with antihypertensive therapy, even when DBP is reduced from baseline. In addition, a previous meta-analysis suggests that the increased mortality of patients with very low DBP (<65 mm Hg) may be unrelated to antihypertensive treatment and not specific to BP-related events. This evidence highlights the primary argument against the evidence supporting a J-curve at BPs achieved in clinical trial or epidemiologic data; that is, that reverse causality explains the apparent relationship observed in some studies between lower DBP and greater risk of adverse outcomes. In other words, poor health, including poor LV function, leading to a low BP and increased risk of death provide alternative explanations for the J-shaped curve.
Two recent trials are especially noteworthy in the discussion of BP targets. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, 4733 patients with type 2 diabetes were randomly assigned to intensive therapy, targeting an SBP less than 120 mm Hg, or standard therapy, targeting an SBP less than 140 mm Hg, for a mean period of 4.7 years. No significant difference was observed between the two BP target groups in the primary outcome (first occurrence of nonfatal MI, nonfatal stroke, and cardiovascular death), although stroke was modestly reduced (absolute risk reduction, 0.2% per year) at the expense of an increase in treatment-related adverse experiences. The latter led the investigators to conclude that there was no overall advantage to targeting an SBP of less than 120 mm Hg. A recent reanalysis of ACCORD suggests, however, that intensive SBP reduction, with or without intensive glycemic control, was associated with a reduction in the primary outcome, when compared with standard BP and standard glycemic control.
In the Systolic blood PRessure INtervention Trial (SPRINT), more than 9300 patients with hypertension and one or more other cardiovascular risk factor, but without diabetes, were randomly assigned to an intensive SBP goal (<120 mm Hg) or standard SBP goal (<140 mm Hg) for a median of 3.3 years. The trial was ended prematurely on the basis of a 25% lower risk of the primary outcome (first occurrence of MI, other acute coronary syndromes, stroke, HF, or death from cardiovascular causes) and a 27% lower risk of all-cause death in patients treated to an intensive versus standard SBP goal. The risk of HF and death attributed to cardiovascular causes were also lower, the latter being primarily attributable to fewer CHD and sudden cardiac deaths. Serious adverse events, overall, were similar between the treatment arms. Unfortunately, data on the subgroup of patients with prior CAD, MI, or other IHD findings like angina were not provided so it not possible to reach conclusions about lower BP targets in this important subgroup of hypertensive patients. Furthermore, because enrollment targets for women were not met, and the primary outcome was not significantly reduced with the lower BP target among women, it is not possible to reach a conclusion regarding women.
Previous recommendations have specified a goal BP less than 140/90 mm Hg in patients who have no evidence of CAD and proposed that less than 130/80 mm Hg be targeted for those patients without documented CAD, but with high risk for the development of CAD. Given the recent SPRINT trial results, lower systolic BP goals (i.e., <120 mm Hg) may be considered in patients without CAD, but who are at high risk for developing CAD. However, caution is warranted because such an aggressive goal will require multidrug regimens. Because many of the patients at high risk for developing CAD have isolated systolic hypertension, and thus lower baseline DBP, it seems prudent to lower the DBP slowly and caution is advised in inducing large DBP falls, particularly in patients aged over 60 years.
Management of Hypertension in Patients with Established Coronary Artery Disease
The following sections discuss management of hypertension in various forms of CAD, with a focus on pharmacologic therapy. Pharmacologic recommendations from the 2015 American Heart Association (AHA)/American College of Cardiology (ACC)/American Society of Hypertension (ASH) Scientific Statement are summarized in Table 31.1 .
| Drug/Class | Stable Angina | Acute Coronary Syndrome | Heart Failure |
|---|---|---|---|
| ACE inhibitor or ARB | 1 a | 1 a | 1 |
| Diuretic b | 1 | 1 | 1 |
| Beta-blocker | 1 | 1 c | 1 d |
| Non-DHP CCB | 2 | 2 | |
| DHP CCB | 2 | 2 | |
| Nitrates | 1 | 2 | 2 |
| Aldosterone antagonist | 2 | 2 | 1 |
| Hydralazine/isosorbide dinitrate | 2 e |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
