How to cite this article: Rosas-Peralta M, Borrayo-Sánchez G, Madrid-Miller A, Ramírez-Arias E, Pérez-Rodríguez G. [Treatment of hypertension in patients with coronary arterial disease]. Rev Med Inst Mex Seg Soc 2016;54(5):636-63.
Received: October 15th 2015
Accepted: November 23rd 2015
Martín Rosas-Peralta,a Gabriela Borrayo-Sánchez,b Alejandra Madrid-Miller,c Erick Ramírez-Arias,d Gilberto Pérez-Rodrígueze
aDivisión de Investigación en Salud
cServicio de Terapia Posquirúrgica
dServicio de Urgencias
Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
Communication with: Martín Rosas-Peralta
Reports of randomized controlled trials and prospective observational studies provide the most reliable data on the association between blood pressure and coronary heart disease (CHD). The totality of the evidence indicate a strong association between blood pressure and coronary heart disease, which is continuous at levels of less than 115 mm Hg of systolic. In general, 60 to 69 years of age, 10 lower mm Hg systolic blood pressure is associated with lower risk of one-fifth of a coronary heart disease event. The size and shape of this Association are consistent in all regions, for men and women and life-threatening events such as stroke and myocardial infarction. Trials that compared active treatment with placebo or no treatment have shown that the benefits of reducing blood pressure with different classes of drugs (e.g., diuretics, beta-blockers, ACE inhibitors, calcium antagonists) are quite similar, with about a fifth of reduction in coronary heart disease. The important points in this review are: First, that the relative benefit to the decline in blood pressure for the prevention of coronary heart disease appears to be constant in a range of different populations. Second, it is likely that considerable benefit with blood pressure low below thresholds of “traditional” blood pressure (140/90 mm Hg), especially in those with high absolute risk. Third, start, reduce with caution -especially in adult- and keep the maximum tolerance of blood pressure reduction is an issue more important than the choice of the initial agent.
Keywords: Hypertension; Myocardial Ischemia; Prevention
Epidemiological studies have established a strong association between hypertension (HT) and coronary artery disease (CAD). Hypertension is a major independent risk factor for the development of CAD, stroke, and kidney failure. The optimal choice of antihypertensive agents remains controversial, and there are only partial answers to the important questions in the treatment of hypertension to prevent and manage ischemic heart disease (IHD):1
All of the discussion and recommendations in this document refer to adults.2 This should make it easier for doctors to extract the relevant information for any particular patient without cross-references; we hope that this will increase the usefulness of this document.
A summary of antihypertensive drug therapy is presented in Table I.
|Table I Summary of pharmacological treatment of hypertension in the management of ischemic heart disease|
|Drug/condition||Stable angina||ACIS||Heart failure|
|HT = hypertension; ACIS = acute coronary ischemic syndrome; ACEI = angiotensin-converting-enzyme inhibitor; ARBs = Angiotensin II receptor blockers; ALD = Aldosterone; 1 = First choice; 2 = Second choice *or in conjunction with the first choice.
Chlorthalidone is the recommended drug; loop diuretics are better with heart failure with reduced ejection fraction; caution should be exercised in patients with preserved ejection fraction
The goals are based on meta-analyses and clinical trials establishing that in elderly patients (> 80 years), the goal should be < 150/90 mm Hg, since pressures lower than 120/80 mm Hg are poorly tolerated in up to 50%. In patients with acute or stable coronary artery disease, pressure < 140/90 mm Hg is recommended. There is no general consensus on target figures for those patients who have had myocardial infarction, stroke (S), or peripheral arterial disease; it is generally accepted that a value of < 130/80 mm Hg is the most widely accepted goal.3
Hypertension is a major independent risk factor of CAD for all age, race, and sex groups. If we take a value ≥ 140/90 mm Hg as a criterion, it is estimated that there are 65 million American adults, or nearly a quarter of the adult population of the United States with HT. Another quarter of the population has prehypertension, defined as SBP of 120 to 139 mm Hg, or DBP 80 to 89 mm Hg. In Mexico, the CONAPO population estimate for 2015 is 121 million, of whom 76.4 million will be 20 years or older, with an HT prevalence of 31%; the overall estimate of the hypertensive population for 2015 is 23.7 million, and there will be a similar number in the pre-hypertensive population.
The forms of elevated BP differ according to age, with diastolic elevation predominant in young hypertensive individuals, and often isolated systolic hypertension (isolated systolic hypertension) in the elderly. The prevalence of hypertension is therefore directly proportional to the age of the population, which accounts for more than half of Americans over age 65 having HT.4 In addition, with age there is a change in the relative importance of systolic blood pressure and diastolic blood pressure as risk indicators. Before age 50, DBP is the main predictor of CHD risk, whereas after age 60, SBP is more important.5 It is important to note that in the population ≥ age 60, DBP is inversely related to the risk of CAD, and pulse pressure becomes the strongest predictor of CAD. In a meta-analysis of 61 studies involving nearly one million adults,6 BP was associated with fatal CAD over the BP range of 115/75 to 185/115 BP mm Hg for all ages. In general, each increase in SBP of 20 mm Hg (or every 10 mm Hg increase in DBP) doubles the risk of a fatal coronary event.
Epidemiological studies have shown that a high BP is the most important determinant of the risk of stroke. The risk is almost linear, from relatively low levels of SBP and DBP,7 and reducing elevated BP is an important factor in the impressive reduction in rates of stroke death during the last half of the twentieth century and the first part of the 21st century.7,8
The absolute risk of these adverse outcomes also increases with age. For any SBP, the risk of fatal coronary heart disease was 16 times higher for people 80 to 89 years old than for those 40 to 49 years old.5 In the screening project for industrial workers in Chicago, males 18 to 39 years of age at baseline had a blood pressure of 130 to 139/85 to 89 mm Hg, or stage 1 hypertension (140-159/90-99 mm Hg), which represents almost 60% of the total excess of CVD in general, or all-cause mortality.9 Epidemiological data show that levels of BP are associated with lower risk of minor illnesses, suggesting that future coronary events can be prevented by BP reduction.10 Elevated BP represents a substantial risk that is attributable to the population and affects men and women of any ethnicity.11,12
It has been shown that the risk of cardiovascular disease in patients with hypertension can be reduced largely with effective antihypertensive therapy. The main reductions in morbidity and mortality from cardiovascular disease in the last 50 years have been attributed to increased availability and use of medication treatment for hypertension. Randomized trials have shown that lowering BP in patients with hypertension results in rapid reductions in cardiovascular risk,13 which is consistent with data from observational studies. For example, a reduction in everyday SBP of 10 mm Hg (or 5 mm Hg in everyday DBP) is associated with a reduced risk of death from stroke (50 to 60%) and a lower risk of death (40 to 50%) from CAD or other vascular causes in middle age; the benefits are only slightly lower in the elderly.6 However, in a study by van Bemmel et al., high blood pressure in the very elderly (those over 85 years) was not a risk factor for mortality, regardless of a history of hypertension. For this, one must take into account that in the same study blood pressure values below 140/70 mm Hg were associated with excess mortality.14 Similarly, there are inconsistencies between the final goals in the older population, with a significant association of low BP with lower deaths from stroke and heart failure (HF), but not with a lower rate of myocardial infarction (MI) in patients over 80 years old.15
Several studies (Heart Outcomes Prevention Evaluation [HOPE],16 Survival and Ventricular Enlargement [SAVE],17 and the European trial on reduction of cardiac events with perindopril in stable coronary artery disease [EUROPE]),18 have shown a beneficial effect of ACE inhibitors (ACEI) on the results of CVD in some hypertensive patients and not others, but in all those with established CVD or at high risk of developing it. However, we do not yet have the results of prehypertension treatment studies in individuals with BP in the range of 130 to 139/80 to 89 mm Hg. The only prospective clinical trial to reduce blood pressure in people with normal BP is the Trial Of Preventing Hypertension (TROPHY),19 in which subjects with SBP of 130-139 mm Hg or DBP 85 to 89 mm Hg were randomized to be treated, plus they were followed for two years with the angiotensin receptor blocker (ARB) candesartan or with placebo. Hypertension developed more significantly (p < 0.007) among participants in the placebo group (two-thirds of this cohort at four years) than in the candesartan group, with a relative risk reduction of 66.3% at two years and 15.6% at four years. In addition, prehypertension treatment with candesartan appeared to be well-tolerated, and serious adverse effects occurred at 3.5% and 5.9% in patients treated with candesartan vs placebo, respectively. However, the study was not designed or powered to evaluate the results of CVD.
In the study Action to Control Cardiovascular Risk in Diabetes (ACCORD), with a mean follow-up of 4.7 years, a BP goal of < 120 compared to < 140 mm Hg was not associated with a lower risk of a composite of cardiovascular events (heart attack, stroke, or cardiovascular death).20 However, the incidence of stroke was significantly lower in the intensively treated group.
Data from the Framingham Heart Study have provided evidence of a predictive role for hypertension, dyslipidemia, glucose intolerance, cigarette smoking, and left ventricular (LV) hypertrophy in cardiovascular disease.21 These five main factors risk are the most important modifiable determinants of CVD risk, and appear to operate independently of each other. This has led to the idea that the threshold at which a patient should be treated for hypertension must be determined by the burden of CVD risk factors, which, in turn, determine a patient’s level of CVD risk. In the guidelines developed by the National Kidney Foundation,22 this principle has been followed for patients with albuminuria and chronic kidney failure, even in a modest stage, for which the threshold BP for antihypertensive therapy is 130/80 mm Hg. The American Diabetes Association has based its recommendation on age. People with diabetes mellitus should be treated to a blood pressure < 140/80 mm Hg, except when lower systolic pressure goals, for example, < 130 mm Hg, may be appropriate for certain individuals, like younger patients, if this can be done without undue treatment burden.23 In addition, a correlation exists between blood pressure and body mass index (BMI), both strongly correlated with CAD. Hypertension and abdominal obesity are components of a major constellation of cardiovascular risk factors: metabolic syndrome, which also includes a characteristic form of dyslipidemia (high triglycerides and low high-density lipoprotein cholesterol), and high fasting blood glucose.24
Reducing risk factors
Hypertension, dyslipidemia, diabetes mellitus, smoking, obesity, and chronic kidney disease (CKD) are independent determinants of CVD risk. Moreover, the diagnosis of peripheral arterial disease (PAD) significantly increases the risk of acquiring prevalent diseases and incidents in other vascular beds, including coronary and cerebral circulation.25,26 As noted above, hypertension is an independent risk factor for cardiovascular disease, and evidence indicates that the concomitant presence of other cardiovascular risk factors is recognized in a multiplicative increase in the risk of cardiovascular events. Some current guidelines require a more aggressive approach to BP in the presence of other cardiovascular risk factors. Reducing BP heedless other risk factors is insufficient to reduce cardiovascular risk. Readers should be aware that several recently published documents give detailed guidance regarding strategies for evaluation and risk assessment. The recommendations in this document reflect the published consensus, but readers should consult other recent guidelines, such as those relating to cardiovascular risk assessment,27 lifestyle (especially with regard to diet and exercise),28 obesity management,29 and dyslipidemia.30
Cardiovascular risk factors can be described as non-modifiable or modifiable. Potentially modifiable risk factors include dyslipidemia, diabetes mellitus, smoking, obesity, DBP, and kidney failure.
The management of dyslipidemia was the subject of a recent guide (ACC/AHA).30 In essence, the new guideline supports using levels of specific low-density lipoprotein (LDL) or non-high-density cholesterol as treatment goals. Patients with CVD and those under age 75 with LDL cholesterol ≥ 190 mg/dL, or a CVD risk at 10 years ≥ 7.5%, should receive treatment with an intense dose of statins (e.g., atorvastatin 40-80 mg a day or rosuvastatin 20-40 mg a day to reduce LDL cholesterol by about 50%). People with cardiovascular disease, people over 75, or those with diabetes mellitus, but with a 10-year risk of over 7.5%, should receive moderate-intensity therapy with statins, such as simvastatin (20-40 mg daily), atorvastatin (10-20 mg daily), or rosuvastatin (5-10 mg daily) to lower LDL cholesterol by 30 to 50%.
According to the guideline, therapies without statins do not provide acceptable risk-reduction benefits for CVD compared to their potential adverse effects in the routine prevention of this disease.
Type 2 diabetes mellitus is defined as a level of fasting plasma glucose ≥ 126 mg/dL, or two-hour oral glucose tolerance test values ≥ 200 mg/dL, hemoglobin A1C ≥ 6.5%, or random plasma glucose ≥ 200 mg/dL in a patient with classic symptoms of hyperglycemia.23
This type of diabetes is a strong independent factor of risk for CAD. So strong is this association that diabetes mellitus can be considered a coronary heart disease risk equivalent,24 although this is controversial.31 Hypertensive patients with type 2 diabetes are also at higher risk of specific complications of this disease, including retinopathy and nephropathy.
The pharmacological management of diabetes mellitus is beyond the scope of this review. Care of diabetes mellitus is complex and requires addressing many issues beyond glycemic control.
There is general consensus that tobacco use increases the risk of cardiovascular events. Many studies have shown a correlation between smoking and death. Life expectancy is reduced by 13.2 years in male smokers compared with nonsmokers, and the trend is increasing in women smokers, reducing life expectancy 14.5 years.32 Cigarette use independently predicts an increased risk of cardiac arrest in patients with CAD,33 and even exposure to secondhand smoke increases the risk of developing CAD in a range between 25 and 30%.34 As with other risk factors, there is a synergistic increase in cardiovascular risk in smokers who have other concurrent cardiovascular risk factors. High cholesterol confers an increased risk of cardiovascular events in smokers than in nonsmokers, and in smokers the tendency to have unfavorable lipoprotein profiles increases disproportionately.35 In patients with hypertension, smokers are five times more likely to develop severe hypertension than non-smokers, and smokers with severe hypertension have higher mortality rates than nonsmokers.36
It is encouraging that studies of smokers who quit smoking show a significant long-term reduction (15% over 14 years) in the mortality of patients participating in smoking cessation activities.37
The prevalence of obesity, defined as a BMI ≥ 30 kg/m2, has increased in recent years. Approximately 30% of the adult population of the United States falls into this category.38 The positive relationship between obesity and BP is well documented.39-41 Obese adults are about three times more likely to be hypertensive compared to non-obese adults,40-42 and increased adiposity may account for over 60% of hypertension in adults.40 Moreover, obesity is considered a major risk factor for poor control of BP in hypertensive patients.3
Although the mechanisms of hypertension associated with obesity are numerous (including activation of the sympathetic nervous system, sodium retention, activation of the renin-angiotensin-aldosterone system [RAAS], insulin resistance, and impaired vascular function)43 there is no acceptable guide to the antihypertensive drug of choice for the management of hypertension in obese patients.43,44
Some researchers believe that ACE inhibitors are the drugs of choice for adequate BP control in hypertension associated with obesity, due to their ability to increase insulin sensitivity and, therefore, reduce the risk diabetes mellitus.45 This contrasts with thiazide diuretics, which are associated with an increased risk of diabetes mellitus.46 That said, the effectiveness of thiazide diuretics in reducing BP and improving cardiovascular outcomes in obese hypertensive patients is well established.47 Beta-blockers also have adverse effects on glucose metabolism, but have resulted in significant improvement of blood pressure in hypertensive obese patients, as they decrease renin activity and cardiac output, which are often elevated in obese patients.48 However, enthusiasm for the use of beta-blockers as initial treatment is dampened, largely because of its negative profile in outcomes of stroke (S), compared with placebo and other classes of antihypertensive drugs.49
There is abundant evidence supporting the effectiveness of lifestyle interventions to improve BP control among obese hypertensive patients. Recently, the American Heart Association (AHA), the American College of Cardiology (ACC), and the Obesity Society have published guidelines29 for the management of overweight and obesity in adults. These include the identification of patients who need to lose weight, weight loss diets, lifestyle intervention, and counseling, as well as the selection of patients for bariatric surgery.
Peripheral arterial disease
Treatment of hypertension in patients with peripheral arterial disease (PAD) was associated with a significant reduction in the risk of myocardial infarction, stroke, heart failure, and death. Similarly, the intensive management of LDL reduction is associated with a significant decrease in cardiovascular events in patients with PAD.50 Therefore, the management of hypertension in patients with PAD should be based on intensive surveillance and aggressive management of other concomitant cardiovascular risk factors, in addition to reducing BP.3 Particularly important in this regard is the management of dyslipidemia, smoking cessation, antiplatelet therapy, care of diabetes mellitus, diet, and exercise.
Currently, there is no recommended choice for the treatment of hypertension in patients with DBP, because clinical trials of antihypertensive agents such as ACE inhibitors, calcium channel blockers (CCB), alpha-adrenergic blockers, and direct vasodilators have not succeeded in improving the symptoms of claudication or walking distance in patients with DBP.51-53 Although beta-blockers constrict resistance vessels, a meta-analysis concluded that this class of drugs does not worsen intermittent claudication.54 Therefore, beta-blockers can be used in patients with DBP with weight indications for use in cases of CAD or HF.
The recommendations of the ACC/AHA practice guidelines on PAD55 are as follows:
Chronic kidney disease
There has been a steady increase in the prevalence of CKD, defined as kidney damage, documented by markers of renal biopsy or serum for more than three months, or a decrease in the glomerular filtration rate < 60 mL/min -1/1.73/m/-2 for more than three months.22 Renal failure, defined as a glomerular filtration rate < 15 mL/min -1/1.73 ms/-2; renal disease and end-stage renal disease, requiring the initiation of treatment with replacement therapy,22 affecting over 525,000 patients in the United States, 65% of whom are in long-term hemodialysis.56 Hypertension represents an important independent risk factor for kidney failure, with a prevalence of 28% in hypertensive patients.56 In patients with chronic renal disease, cardiovascular death is more likely than the progression to end-stage kidney disease, and in patients with end-stage kidney disease, cardiovascular disease is the leading cause of death, and is five to 30 times higher in dialysis patients than in the general population.57
Even in patients in lower stages of CKD, the risk of cardiovascular disease increases regardless of other risk factors, and even the smallest degree of albuminuria increases the risk of cardiovascular disease and all causes of death.57 In this population of patients, hypertension is itself a major cause of renal failure. The BP goals in patients with chronic renal disease and microalbuminuria are lower than in the general population;22,58 the goal is the same as in patients with established heart disease. Recent research has shown that standard treatments for cardiovascular risk factors, including statin therapy, ACE inhibitors, ARBs, and antiplatelet agents are equally effective in reducing the risk in both patients with chronic kidney disease (who are not on dialysis) and in those without CKD.59 In these patients, serum potassium levels should be monitored frequently. Questions remain about whether to directly address non-traditional risk factors in patients with early evidence of renal failure, and whether it has efficacy in terms of results.
A variety of pathophysiological mechanisms contribute to the genesis of high BP and related target organ damage, including CAD. These mechanisms also include the sympathetic nervous system and increasing RAAS activity; there are deficiencies in the release or activity of vasodilators, for example, nitric oxide and prostacyclin, and changes in the concentration of natriuretic peptide; increased expression of growth factors and inflammatory cytokines in the arterial tree; hemodynamic effects; and structural and functional abnormalities in conductance and resistance arteries, particularly increased vascular stiffness and endothelial dysfunction.60 These neurohormonal pathways interact with genetic, demographic, and environmental factors (such as exposure or response to high psychosocial stress, excessive dietary sodium intake, and inadequate intake of potassium and calcium) to determine whether a person will develop hypertension and related heart disease. Concomitant metabolic disorders, for example: diabetes mellitus, insulin resistance, and obesity, also lead to the production of vasoactive adipocytokines that promote vasoconstriction, endothelial dysfunction, inflammation, and increased oxidative stress in the vasculature, making both BP and CVD risk increase.61,62 These shared pathophysiological mechanisms offer potential new therapeutic targets for the prevention and treatment of hypertension and coronary heart disease, with benefits that can go beyond the reduction of BP.
Genomic association studies have identified multiple genetic susceptibility variants, mostly single nucleotide polymorphisms, for atherosclerotic disease.63 It has been suggested that polymorphisms of the RAAS genes, particularly of ACE, the type 1 angiotensin II and angiotensinogen receiver, are involved in the development of CAD and AMI.64,65 The presence of hypertension increases the risk of further heart disease and may explain why some people are more likely than others to develop coronary events. Some polymorphisms have also been implicated in the response to antihypertensive treatment. For example, genetic polymorphisms encoding the metalloproteinases of the extracellular matrix appear to modify the results of CVD in hypertensive patients treated with chlorthalidone, amlodipine, or lisinopril.66 These data suggest that in the future the determination of genetic variants can be of some use for the selection of the appropriate antihypertensive to reduce both BP and the risk of CAD. However, because CAD is polygenic and its causes are multifactorial, genetic studies explain only a small proportion of the heritability of the disease.67
Physical forces (pressure and flow) are the main determinants of the structure and cardiac function and coronary artery remodeling that bring about atherosclerosis. When SBP is high, both the output impedance of LV and the increased tension of the intramyocardial wall result in an increase in myocardial oxygen demand. Wide pressure pulse and systolic hypertension in the elderly are generally attributable to high or inappropriate aortic impedance, resulting from decreased aortic diameter or increased effective stiffness caused by thickening of the aortic wall and changes in the wall composition. Aging is associated with thinning, fragmentation of vascular elastin, and increased collagen deposition, a degenerative process that causes an increase in arterial stiffness (reduced elasticity) with an associated elevation of SBP and increased pulse pressure.68-70
Increased arterial stiffness from SBP is raised through the increased pulse wave velocity and alteration of the wave reflection from the periphery.68,71-74 With blood ejection from the LV, a wave (pulse) is generated, and the pressure shifts from the heart to the periphery in a pulse wave velocity that depends on the elastic properties of the conduit arteries. Pulse wave is reflected at any point of discontinuity in the arterial tree and returns to the aorta and the LV. The elastic properties and length of the conduit arteries determine the time of wave reflection.73 In younger people, the pulse wave velocity is sufficiently slow (approximately 5 m per second) for the reflected wave to reach the aortic valve after closure, which causes a greater DBP and improves coronary perfusion, providing an additive effect. In older people, especially those who are hypertensive, the pulse wave velocity increases considerably (approximately 20 m per second) because of central arterial stiffness. Therefore, the reflective wave reaches the aortic valve before closing, leading to higher SBP, pulse pressure, and afterload, and a lower DBP. The increase in SBP increases cardiac metabolic requirements and predisposes to the development of LV hypertrophy and heart failure. Pulse pressure is closely related to SBP, and is linked to cardiovascular events, including myocardial infarction and stroke. Aortic stiffness is an independent predictor of all causes of cardiovascular mortality, fatal and nonfatal coronary events, and fatal stroke in patients with hypertension, type 2 diabetes mellitus, and end-stage renal disease.73
Endothelial dysfunction, characterized by an unfavorable balance between vasodilators (e.g., nitric oxide and prostaglandin E1), and vasoconstrictors (e.g. endothelin and angiotensin II), is a major contributor to increased blood pressure in people with vascular disease. Injured endothelium loses its vasodilatory capacity and contributes to thrombosis and vascular occlusion. The release of chemotactic cytokines and adhesion molecules on the luminal surface of the injured endothelium promotes the adhesion of circulating mononuclear leukocytes to the vessel wall. In low grade, vascular inflammation is self-perpetuating and underlies the atherosclerotic process. Inflammatory mediators activate medial smooth muscle cells, making them proliferate and migrate into the subintimal space. In the presence of dyslipidemia, monocytes in the vessel wall incorporate oxidized low-density lipoprotein cholesterol and become lipid-laden macrophages. In established lesions, resident macrophages secrete metalloproteinases and cathepsins, destabilizing the fibrous cap of the plaque, which can lead to plaque rupture and release of tissue factor to cause thrombosis, coronary occlusion, and AMI.
Endothelial dysfunction and decreased availability of nitric oxide related to mechanical and inflammatory injury of arteries are also associated with increased arterial stiffness and the development of isolated systolic hypertension.75 Decreased flow-mediated vasodilator capacity is attributable to decreased nitric oxide derived from the endothelium, which occurs in aging and subclinical vascular disease.76 Deteriorating endothelium-mediated vasodilation is responsible for the extreme BP increases induced by exercise seen in these population groups.77
Oxidative stress is a critical feature of hypertension and atherogenesis.60 In vascular tissue, the main effectors of oxidative injury are NAD(P)H oxidase, which is activated by mechanical forces (such as hypertension), hormones (in particular angiotensin II), oxidized cholesterol, and cytokines. Several isoforms of NAD(P)H oxidase are expressed in endothelial cells and vascular smooth muscle cells that are upregulated in remodeling atherosclerosis and arterial injury. Activation of the NAD(P)H oxidase-dependent angiotensin II receptor stimulates the formation of oxidant superoxide anion (O2-), which reacts with nitric oxide to form the powerful oxidant peroxynitrite (ONOO-). The resulting reduction in nitric oxide bioactivity contributes to the vasoconstrictor response to angiotensin II and raises BP. Activation of angiotensin II by NAD(P)H oxidase also stimulates the oxidation of low-density lipoprotein cholesterol and increases the expression of monocyte chemotactic protein-1 and vascular cell adhesion molecule-1, thereby linking RAAS activation for the atherosclerotic process.
Many of the mechanisms that initiate and maintain hypertension also damage the target organs, including the coronary arteries and myocardium. Angiotensin II raises BP and promotes target organ damage, including atherosclerosis, by mechanisms including direct effects on the constriction and remodeling of resistance vessels, stimulation of aldosterone synthesis and release; improved sympathetic outflow from the brain; and facilitating the release of catecholamines from the adrenal glands and the peripheral sympathetic nerve terminals.1 Aldosterone can mimic or enhance the vasotoxic properties of angiotensin II and noradrenaline. Angiotensin II promotes heart and vascular smooth muscle cell hypertrophy directly through the activation of angiotensin II receptor type 1 (AT1), and indirectly by stimulating the expression of a number of growth factors, cytokines, and adhesion molecules. AT1 receptor activation also contributes to atherogenesis and endothelial damage by inhibiting the mobilization of endothelial progenitor cells of the bone marrow; it therefore alters the endothelial regeneration and vascular repair processes.78 There is also a link between RAAS activation and fibrinolysis. Angiotensin II induces the formation of plasminogen activator inhibitor-1 through a dependent effect of AT1 receptor on endothelial cells, whereas CAD downregulates the production of tissue plasminogen activator by degrading bradykinin, a potent endothelial tissue stimulator for the expression of plasminogen activator.
ACE inhibitors and ARBs limit oxidative reactions in the vasculature by blocking the activation of NAD(P)H oxidase, supporting the concept that these RAAS blockers may have important vasoprotective effects beyond reducing BP.79 Furthermore, there is evidence of interaction between the RAAS and dyslipidemias: hypercholesterolemia upregulates RAAS, the density particularly of vascular AT1 receptors, the functional response capacity and synthesis of systemic angiotensin II peptides,80,81 while RAAS stimulates the accumulation of low-density lipoprotein cholesterol in the arterial wall. These findings suggest that these classes of antihypertensive drugs may have clinically important vasoprotective effects, beyond BP reduction. This hypothesis has not been supported by the results of randomized controlled trials.82
Recent evidence suggests that a second subtype of angiotensin II receptor (AT2), which is not expressed in normal vasculature, but which appears to be induced in the setting of vascular inflammation/hypertension/atherosclerosis, may oppose the vasoconstrictive, antinatriuretic, and proinflammatory effects of the AT1 receptor.83 Because of the apparent vasoprotective effects of AT2 receptor activation, agonists of this have been considered for the treatment of hypertension,84 but there is no evidence that they are effective in the treatment of hypertension in humans.
Calcium ions (Ca2 +) are the main intracellular mediators of smooth muscle cell contraction. Ca2 + enters vascular smooth muscle cells, cardiomyocytes, and pacemaker cells via L-type and T-type voltage-gated calcium channels. In vascular smooth muscle, the L-type voltage channel (which is long-acting and slowly activated) allows sufficient Ca2 + entry to initiate intracellular Ca contraction induced by calcium 2+ released from the sarcoplasmic reticulum. Increased intracellular Ca 2+ also has effects promoting atherosclerosis.
Dihydropyridine calcium channel blockers (CCBs) bind to the L-channel 1-alpha subunit and are highly selective for arterial/arteriolar tissues, including the coronary arteries, where they are vasodilators. Nondihydropyridine CCBs, including phenylalkylamines (verapamil-like) and benzothiazepines (diltiazem-like), bind to different sites of the 1-alpha subunit and are less selective for vascular tissue; they have negative chronotropic effect and dromotropic effects on sinoatrial and atrioventricular nodal conduction tissue, and negative inotropic effects on cardiomyocytes. Nondihydropyridine CCBs have greater effects on the atrioventricular node than on the sinus node, and may predispose high-grade atrioventricular blockage in patients with preexisting atrioventricular nodal condition or when administered with other agents, such as beta-blockers, which suppress the atrioventricular node. Both CCB subclasses are indicated for the treatment of hypertension and angina. The antianginal effects of CCBs result from the reduction of afterload, i.e. their ability to decrease SBP and coronary vasodilation, and, in the case of nondihydropyridine CCBs, slowing the heart rate. CCBs are particularly effective in the treatment of angina caused by coronary spasm, for example, Prinzmetal angina or angina induced by cold.85
A meta-analysis of antihypertensive trials has shown that lowering BP is more important than the particular class. Combined antihypertensive drug therapy is typically necessary to achieve and sustain effective long-term BP control. Therefore, there is no evidence to support initial therapy with any class of antihypertensive drug over another for the primary prevention of IHD. On the other hand, for secondary protection in individuals with underlying comorbid diseases, such as IHD, CKD, or recurrent stroke, it has not been shown that all kinds of drugs confer the same level of benefit.
If there are class effects of antihypertensive medications and if each drug must be considered individually on the basis of the results of clinical trials, this is not clearly defined. It is reasonable to assume that there are no class effects for thiazides, ACE inhibitors, and ARBs, which have a high degree of homogeneity, both in their mechanisms of action and side effects.13,86,87 There are great pharmacological differences between drugs within more heterogeneous classes of agents such as beta-blockers and CCBs.88,89 Finally, recent evidence suggests that the combination of ACE inhibitors and ARBs is not beneficial for the secondary prevention of cardiovascular events,90,91 while combinations of RAAS-blocking agents with thiazide diuretics or CCBs show significant clinical benefits.92
Thiazides and thiazide-type diuretics
Thiazide diuretics and thiazide-type diuretics, such as chlorthalidone or indapamide, are very effective in reducing BP and in preventing cerebral vascular events, as demonstrated most convincingly in studies from the Veterans Administration93 and the Medical Research Council (MRC),94 as well as the Systolic Hypertension in the Elderly Program (SHEP),95 and Hypertension in the Very Elderly Trial (HYVET).15 The benefit of chlorthalidone-based therapy in the treatment of hypertension is evident thanks to the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).96 Since the publication of the results of ALLHAT, there have been concerns about whether thiazide-induced hyperglycemia and diabetes mellitus contribute to the long-term risk of IHD not measured during the study,97 but this does not seem to be the case.98-100
Beta-blockers and CAD
Beta-blockers are a heterogeneous class of antihypertensive drugs with different effects on resistance vessels and cardiac conduction and contractility. The administration of beta-blockers is still the gold standard in patients with angina pectoris, those who have had a heart attack, and those with left ventricular dysfunction with or without HF symptoms, unless it is contraindicated. Carvedilol, metoprolol, and bisoprolol beta-blockers have been shown to improve outcomes in patients with HF.1
ACE inhibitors are effective in reducing early events of IHD and are recommended for consideration in all patients after AMI. These inhibitors have been shown to prevent and improve HF,101,102 and progression of CKD.103 When combined with thiazide diuretics, ACE inhibitors reduce the incidence of recurrent stroke.104 Major trials have addressed the use of ACE inhibitors in patients with HF, but without heart failure or known significant impairment of LV systolic function.
In the HOPE study,16 9297 patients at high risk, 80% of whom had a history of coronary disease, were assigned to receive ramipril (10 mg once per night) or placebo and followed for a mean of 5.0 years. Treatment with ramipril was associated with a 22% reduction in the composite assessment criterion of cardiovascular death, myocardial infarction, and stroke (p < 0.001), and significant comparable reductions in each of the individual components.105 There were also significant reductions in rates of revascularization, cardiac arrest, heart failure, worsening angina, and all-cause mortality with ramipril therapy. The average reduction in clinical BP with active treatment was 2 to 3 mm Hg. In the EUROPA study, 12,218 patients were randomized to perindopril (ACE inhibitor) or placebo.18 Although only 27% of patients were classified as hypertensive, the definition of hypertension was based on a clinical BP > 160/95 mm Hg or antihypertensive treatment at baseline. The mean follow-up in the EUROPA study was 4.2 years. Treatment with perindopril (target dose, 8 mg daily) was associated with a relative risk reduction of 20% in the composite assessment criterion of cardiovascular death, myocardial infarction, or cardiac arrest (p < 0.003). The researchers defined that the benefit of active treatment with perindopril was similar in patients with or without hypertension. The average reduction in blood pressure in the clinic was 2 to 5 mm Hg. At the beginning of the EUROPA study, patients had a lower cardiovascular risk than patients in the HOPE study: one-third were over 55 years old; fewer had diabetes mellitus (12% versus 39%), and proportionally more patients in the EUROPA study took antiplatelet therapy (92% versus 76%) and lipid-lowering drugs (58% versus 29%).
Patients who sought to prevent events with the use of angiotensin-converting enzyme inhibitors (PACE),106 had stable ischemic heart disease and normal or slightly reduced left ventricular function, and were randomized to trandolapril (target dose, 4 mg) or placebo. Median follow-up was 4.8 years. No differences were found between groups in the incidence of the primary composite endpoint of cardiovascular death, myocardial infarction, or coronary artery revascularization. 46% of patients were hypertensive, and treatment with trandolapril was associated with an average reduction in blood pressure of 4.4/3.6 mm Hg.
The annualized rate of death from any cause in PACE was only 1.6%, a rate similar to that of an age- and sex-matched cohort without IHD. There was a relatively high use of revascularization before randomization in the PACE study, which may have contributed to the low event rate.
The researchers concluded that ACE inhibitors may not be necessary as routine therapy in patients with low-risk IHD with preserved LV function, especially those who have received intensive treatment with revascularization and lipid-lowering agents. Therefore, two large studies in patients at high cardiovascular risk (HOPE and EUROPA) showed cardiovascular protective effects of ACE inhibitors, and a study in patients with low cardiovascular risk (PACE) did not.
The use of telmisartan alone and in combination with ramipril is explained in the Global Endpoint Trial (ONTARGET),90 which randomized 25,620 patients, 74% of whom had a history of CAD. The ACEI was assigned ramipril (10 mg daily), and ARA II was assigned telmisartan (80 mg daily), or the combination of these two drugs. After a median follow up of 4.7 years, there was no difference in the primary outcome of cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for HF among the three groups. In the combination treatment group there was an increased risk of symptomatic hypotension, syncope, and renal dysfunction compared to those in the ramipril group. The researchers concluded that ramipril and telmisartan had similar benefits, but that the combination of ACE inhibitors and ARBs in this high cardiovascular risk group is associated with more side effects without increasing benefits.
Angiotensin II antagonist receptors
Several ARBs have been shown to reduce the incidence or severity of IHD events, progression of kidney disease in type 2 diabetes mellitus, and cerebrovascular events. ARBs are often considered as an alternative therapy in people with cardiovascular disease who cannot tolerate ACE inhibitors. The behavior of valsartan (a long-term antihypertensive in the VALUE study that was used to protect against a composite of cardiovascular events including AMI and HF) was similar to that observed in amlodipine (CCBs).107 However, there were significant differences in BP control in the early stages of the VALUE trial (a significant difference in favor of amlodipine), which may have confounded the results of AMI and especially stroke.108
The beneficial cardiovascular outcomes have not been shown in the study with losartan (OPTIMAAL).109 The lack of benefit may have been attributable to inadequate doses of this drug. In the study Valsartan in Acute Myocardial Infarction (VALIANT), ARBs (valsartan itself) had similar effects to the ACE inhibitor captopril in reducing cardiovascular event endpoints.91 The combination of ARBs with ACE inhibitors resulted in an increase in adverse events with no added benefit for cardiovascular events.
In the Telmisartan Randomised Assessment Study in ACE-intolerant subjects with cardiovascular Disease (TRANSCEND),110 5296 high-risk patients, 75% of whom had CAD, were randomized to telmisartan (80 mg daily) or placebo for an average 4.7 years. The average BP in the telmisartan group was 4.0/2.2 mm Hg, which was lower than in patients randomized to placebo. The primary outcome of cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for HF occurred in 15.7% in the telmisartan arm, and 17.0% of the placebo group (p = 0.216). The combination of cardiovascular death, nonfatal AMI, and stroke occurred in 13% of patients treated with telmisartan compared with 14.8% in the placebo group (p = 0.048), and fewer patients in the telmisartan group had a cardiovascular hospitalization, with 30.3% compared to 33% in the placebo group (p = 0.025). The tolerability of telmisartan was similar to placebo. The researchers concluded that telmisartan had modest benefits in the composite endpoint outcome of cardiovascular death, myocardial infarction, and stroke, and was well tolerated.
Spironolactone and eplerenone are aldosterone antagonists that serve to lower BP alone or when added to other antihypertensive agents, and they have protective effects in patients with chronic and advanced HF (in the Randomized Aldactone Evaluation Study [RALES]),111 in patients with left ventricular dysfunction after AMI (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study [EPHESUS]),112 and in patients with chronic heart failure 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, most subjects had ischemic heart disease.
Calcium channel blockers (CCBs)
Calcium channel blockers (CCBs) are a heterogeneous class of agents that reduce BP, but have different effects on cardiac conduction and myocardial contractility. In the ALLHAT study, primary prevention of cardiovascular events with amlodipine (dihydropyridine CCBs) was equivalent to that produced by the diuretic chlorthalidone or the ACE inhibitor lisinopril,96 and their superiority over a beta-blocker was confirmed in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).114 It was shown that primary protection with verapamil-based therapy was similar to a diuretic (hydrochlorothiazide) or a beta-blocker (atenolol) in the study CONVENCER115 and the International Verapamil-Trandolapril Study (INVEST).116 In the Nordic Diltiazem Study (NORDIL),117 overall rates of cardiovascular events were similar for diltiazem and a combination of diuretics and a beta-blocker. Therefore, CCBs are alternatives to betablockers in treating angina, but are not recommended for secondary cardioprotection because of the relative lack of benefit of this class in preventing HF,118 especially compared with ACE inhibitors96 or ARBs.107
Direct renin inhibitors
The direct renin inhibitor aliskiren decreases BP alone or when added to other antihypertensive agents, but has not been shown to have protective effects in patients with cardiovascular disease, including HF.119 In 2011, the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) was stopped on the recommendation of its Data Monitoring Committee.119 This study was comparing placebo with aliskiren 300 mg once daily added to ACE inhibitor therapy or ARBs in patients with diabetes mellitus or increased urinary albumin excretion or reduced estimated glomerular filtration and established CVD. The primary outcome of ALTITUDE was a composite of cardiovascular death, survival of sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, end-stage renal disease, renal death, or doubling of the concentration of baseline serum creatinine, sustained for at least one month.
The basis for stopping the study was the insignificance of success and safety concerns, including renal dysfunction, hyperkalemia, hypotension, and an excess of strokes. The number of patients experiencing a non-fatal stroke in the placebo group was 85 (2.0%), and in the aliskiren group it was 112 (2.6%; unadjusted p = 0.04). Given the above data relating to the use of antihypertensive therapy to reduce the incidence of stroke in patients with diabetes mellitus, it is possible that the imbalance in data represents a chance finding. However, the general recommendation today is to avoid the use of aliskiren in combination with other renin-angiotensin system blockers in patients with hypertension for the primary prevention of cardiovascular disease.
The overall goal of therapy is to reduce excess morbidity and unnecessary deaths. In the case of hypertension, dyslipidemia, and diabetes mellitus, the surrogate endpoints (BP, cholesterol, and blood glucose) have been established as diagnostic markers, and the discrete values of these markers have been established as therapeutic targets. A commonly cited target for BP is < 140/90 mm Hg in general and < 130/80 mm Hg in some individuals with diabetes mellitus or CKD.3,22,23 In the first scientific statement from the AHA on the treatment of hypertension in the prevention and management of HF, the association also recommended a target of < 130/80 mm Hg in patients with established CAD, CAD equivalents, or a Framingham risk score ≥ 10%.1
Recent meta-analyses have suggested that lower BP targets for high-risk patients are not supported by high-quality evidence or randomized clinical trials.120-122 Yes, the lowest BP target is appropriate for preventing coronary disease, and due to the established treatment of this disease, it is the subject of intense debate. There is a historical tendency to achieve lower BP goals, especially in those with target organ damage. The controversy remains, however, about the specific goals of BP treatment for individuals with incipient or overt CAD. On the one hand, it can be argued based on pathophysiological principles that very low SBP values (i.e., < 120 mm Hg) may be appropriate to reduce the workload of the myocardium.123 At the same time, there is concern that the excessive decrease of DBP can affect coronary perfusion. At present, despite the ACCORD study,20 there is no consensus on the question of what should be the most appropriate blood pressure target in individuals with latent or overt CAD or prominent risk factors for CAD. We believe, however, that reasonable recommendations can be developed from a synthesis of the results of relevant epidemiological studies, consideration of the theoretical question of the J-curve, data from animal studies, human studies involving indirect and random criteria, and clinical trials aimed at different BP targets with cardiovascular events as endpoints.
Although epidemiological correlations cannot be used as proof of the value of treatment, they are useful in establishing reasonable expectations for treatment strategies. More specifically, epidemiological data do not necessarily predict cardiovascular outcomes when BP is reduced as a result of antihypertensive treatment. However, population studies, such as the Prospective Studies Collaboration,6 the Framingham Heart Study,124 the Women’s Health Initiative,125 and the Hisayama Study in Japan,126 provide some support for a "less is more" strategy for BP control. The debate on lower BP targets revolves around the question of the so-called J-curve and, more specifically, asks whether lower BP targets are appropriate or even if they are safe for patients with CAD.
Many studies show that the reduction in SBP, DBP, or both decreases overall cardiovascular risk. However, the concern remains that the excessive reduction of DBP may have adverse consequences for the heart. In almost all cases, SBP reduction improves heart function and outcomes, probably through a reduction in cardiac work and improved myocardial oxygen balance. On the other hand, it is theoretically possible that DBP reduction only improves cardiovascular outcomes 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, coronary circulation can autoregulate, so a decrease in perfusion pressure is accompanied by coronary vasodilation, which maintains a fairly constant coronary blood flow. The problem that this coronary capacity of the resistance vessels dilates in response to a drop in perfusion pressure is certainly limited, and at the point of maximum vasodilatation, an additional decrease in coronary perfusion pressure will result in decreased flow. In dogs, consciously applied, contractile function (transmural wall thickening and subendocardial segment shortening) is well maintained in average coronary filling pressures of 40 mm Hg, which corresponds to a DBP of ≈30 mm Hg.127-129 The lower limit of autoregulation in dogs with LV hypertrophy moves up from 15 to 20 mm Hg, but may be partially restored by ACE inhibition, with accompanying regression of LV hypertrophy.129 These studies were conducted in dogs with normal intramural coronary arteries. We do not have good equivalent data for human coronary circulation values.
In the presence of occlusive CAD, hemodynamics is much more complicated. Significant CAD will push the lower self-regulatory limit upwards. However, since myocardial blood flow is very heterogeneous,130 the consequences of coronary hypoperfusion are unpredictable and may depend on the tension of the intramyocardial wall (which in turn is increased by high blood pressure, but decreases in LV hypertrophy), the effects of antihypertensive drugs on these variables and, of course, the severity of occlusive coronary artery disease.
There is also a reduced coronary flow reserve (defined as the difference between resting flow and flow through a coronary circulation dilated maximally at any level of perfusion pressure) in patients with LV hypertrophy, coronary atherosclerosis, or microangiopathy, with reduced functional or structural capacity of the coronary resistance vessels to dilate.131 This potential damage to the myocardial oxygen supply can be exacerbated by increased myocardial oxygen demand resulting from exercise, LV hypertrophy, and increased LV outflow impedance caused by increased SBP. This combination of reduced oxygen supply and increased oxygen demand, especially during exercise, is particularly harmful to the heart, since it is an aerobic organ that can develop only a small oxygen debt, and oxygen extraction is almost maximum even at rest and may increase slightly with increasing demand.
It is therefore theoretically possible that, although BP reduction improves cardiovascular outcomes in hypertensive patients (provided coronary perfusion remains above the lower autoregulatory limit for coronary blood flow), any further DBP reduction to levels below the lower autoregulatory limit would reduce coronary blood flow. This could lead to an increase in the incidence of coronary events as DBP decreases beyond this point, especially when myocardial oxygen consumption increases, as during exercise.
The relationship between DBP and coronary events, if this were true, would be a J-shaped curve. A major difficulty is that we do not have data on the level of the DBP corresponding to the lower limit of autoregulation in human coronary circulation, either 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 can be more dangerous in patients with hypertension combined with CAD, although we have no experimental evidence or clinical trials to support this idea. Therefore, we must rely on clinical studies with surrogate criteria and the few relevant clinical trials with outcome data to try to solve this problem.
An analysis of 274 patients with CAD who completed the intravascular ultrasound substudy of Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT)132 showed that subjects with 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 mm Hg) had a mean decrease in the volume of coronary atheroma of 4.6 mm3. Prehypertension subjects (120-139/80-89 mm Hg) had no significant change, and hypertensive subjects (≥ 140/90 mm Hg) had a mean increase in atheroma volume of 12.0 mm3. The authors concluded that the study suggests that in patients with CAD, the optimal target BP may be substantially lower than the level < 140/90 mm Hg.
CAMELOT results can be taken only as hypothesis-generating, because the effect of BP in atheroma volume was not a pre-specified outcome. Because this was a post hoc analysis, there is the possibility of residual confounding effects, especially because individuals in the cohort with higher BP were older and were more likely to have been assigned to the placebo group of the study and, therefore, were not treated with either amlodipine or enalapril.
If coronary autoregulation was clinically important, it was predicted that there must be a U-shaped or J-shaped relationship between DBP and CAD events. In addition, one can expect the presence of structural CAD to affect the pressure-flow relationship in the coronary arteries, with a lower tolerance of diastolic pressure.
The first retrospective study in 1979 reported a five-fold increase of AMI among patients treated with DBP values (Korotkoff phase IV) < 90 mm Hg,133 or < 80-85 mm Hg using the most universal Korotkoff phase, V. This observation was later confirmed by a meta-analysis in 1987,134 and a new analysis in 1985 of the MRC trial of mild hypertension, which reported an increased prevalence of AMI in those who achieved DBP < 80 mm Hg.135 However, other researchers using the same data have drawn opposite conclusions about whether there really is a J-curve.136,137
A secondary analysis of the data of 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 AMI, with a nadir at 119/84 mm Hg. This was not the case for stroke. These post hoc results were also cited in an analysis by Thune et al.140 and an accompanying editorial141 as supporting the existence of a J-curve and a warning against excessive BP reduction. However, what was not mentioned was that patients in the trial who had a BP < 120/70 mm Hg (the level below which the risk of adverse outcomes seemed to rise) were older and had a history of AMI, coronary artery bypass surgery, or percutaneous coronary intervention, stroke, or transient ischemic attack, diabetes mellitus, heart failure, and cancer, all confounding factors. After adjusting for these and other comorbidities, there was no increased risk at 50 mm Hg DBP.139
There is much debate and disagreement about the methodological assumptions and pitfalls, and several reports have articulated confounding variables, especially age and comorbidities, including late-stage HF, which could have affected the conclusions.142-147 None of the retrospective analysis was able to adequately control the many interacting comorbid conditions that make low DBP confusing, or the complex relationships between age, DBP, and CVD risk. These three factors are positively associated until approximately age 50. For the rest of life, DBP decreases and pulse pressure widens, while cardiovascular risk increases exponentially. Age is by far the most important risk factor for CAD; the prevalence of fatal cardiac ischemic events increases 64 times as age doubles from 40 to 80 years. However, SBP was a better predictor of the outcome of pulse pressure.5,148,149 Therefore, the effects of low DBP or widening pulse pressure cannot be easily separated from aging in predicting the risk of fatal AMI. This important factor may explain much of the confusion about the existence of a J-curve in observational studies.
These results suggest that wide pulse pressure is a significant determinant of whether DBP is an important predictor of risk. Therefore, in those studies reporting a J-curve, possible explanations include decreased myocardial perfusion during diastole, an increase in pulse pressure related to age (reflecting stiffer large arteries), or an epiphenomenon related to a known or undetected underlying disease (e.g. cancer, HF), called reverse causality, in which the pre-existing condition explains both low blood pressure 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 1991 patients had angiographically-documented CAD, and mean input BP was 129/77 mm Hg. Treatment with ACE inhibitors or CCBs lowered BP by an additional 5/2 mm Hg, without evidence of a J-curve in any of the treated groups.
Data from controlled trials primarily designed to assess minimum BP targets in hypertensive subjects have not shown a J-curve.
Population studies suggest that ≈ 45% of white adults with diabetes mellitus have coronary heart disease compared with 25% of non-diabetic individuals.151
This makes the ACCORD study relevant to the issue of BP targets in patients with CAD. ACCORD was a trial to assess the overall effects of intensified glycemic control, intensive BP lowering, and triglyceride level reduction in patients with type 2 diabetes mellitus and other CVD risk factors. The study20 randomized 4733 patients, of whom 34% had had a previous cardiovascular event, into an intensive care group, with a target SBP < 120 mm Hg, or standard treatment, with a target SBP < 140 mm Hg. After one year, the mean SBP was 119.3 mm Hg in the intensive therapy group and 133.5 mm Hg in the standard treatment group, with a difference of 14 mm Hg. During the mean follow-up of 4.7 years there were no significant differences between the two groups with respect to the composite primary outcome (nonfatal MI, nonfatal stroke, or death from cardiovascular causes), nonfatal MI, all-cause mortality, death from CVD, significant coronary disease event, or fatal or nonfatal HF. However, the risk was that the composite primary endpoint was numerically lower (12%) than those randomized to the lower target. Similarly, the risk of myocardial infarction was lower (13%) in the group randomized to the lower BP target group, but this was not statistically significant. There was an alleged significantly lower incidence of stroke in the intensive therapy group (i.e., uncorrected for multiple comparisons), but the number of strokes was small. The main conclusion drawn by the researchers of this study is that SBP < 120 mm Hg in patients with diabetes mellitus type 2 is not justified.20,152 Regarding the enigma of the J-curve discussed above, it is worth noting that the average DBP achieved in the intensive therapy group from 4 to 8 years after randomization was in the range of 60 to 65 mm Hg, and that there was no significant increase in coronary events in these patients, but actually a numerical decrease in such events was observed. This finding, together with the significant stroke protection seen in ACCORD and most other trials, may suggest a different interpretation of the results of ACCORD, namely that lower DBP values are safe, at least in the range of 60 to 65 mm Hg, and can protect against stroke. The Systolic Blood Pressure Intervention Trial (SPRINT), currently underway, has a very similar design to the ACCORD trial, but has registered only nondiabetic subjects with a strong representation of the elderly and patients with CKD.
In addition to the ACCORD study, discussed above, there have been other studies relevant to the secondary prevention of cardiovascular events in patients with diabetes/hypertension and coronary heart disease. In a cohort of diabetic subjects with hypertension and CAD in INVEST,116 strict control of SBP (< 130 mm Hg) was not associated with improved cardiovascular outcomes compared with normal controls (130-139 mm Hg), although in a prolonged tracking ≈ 9 years, the risk of all-cause mortality was 22.8% compared to 21.8%, respectively, which was only statistically significant. This is a small difference and it is not known whether it can be considered a contribution to clinical decision-making.
In the study Appropriate Blood Pressure Control in Diabetes (ABCD), mean BP achieved was 132/78 mm Hg in the intensive group and 138/86 mm Hg in the control group of moderate BP. After five years, there was no difference between groups in the progression of diabetic microvascular complications or the rate of myocardial infarction, stroke, or heart failure. However, unlike the results in INVEST, ABCD participants in the intensive group had a significant reduction in all-cause mortality.153
The latest standards of medical care in diabetes mellitus (2013)23 of the American Diabetes Association recommends a target blood pressure < 140/80 mm Hg; also lower values (< 130/80 mm Hg) may be appropriate for certain individuals, like younger patients, if they can be achieved without an undue burden of treatment.
Patients with atherosclerotic stroke should be included among those considered at high risk (≥ 20% in 10 years) for new atherosclerotic cardiovascular events.154
In addition to ACCORD, in which there was no excess of AMI, there was intensive BP reduction, plus some benefit in stroke prevention, there have been other studies that have documented the effects of BP reduction on stroke results. With some exceptions, the reports are consistent supporting better stroke results with BP < 130/80 mm Hg.
The exception was an observational post hoc analysis of the study Prevention Regimen For Effectively avoiding Second Strokes (PROFESS), involving 20,330 patients with recent ischemic stroke. Hypertension was not an inclusion criterion, although most patients had elevated BP. Nor was PROFESS a clinical trial of antihypertensive therapy, but mainly of antiplatelet agents. During the 2.5 years follow-up, the adjusted risk ratio for subjects with SBP in the range of 120 to 129 mm Hg, compared to the range of 130 to 139 mm Hg, was 1.10 (95% CI: 0.95 to 1.28) for stroke, and a confidence interval of 1.01 (95% CI: 0.64 to 1.89) for fatal stroke; neither was statistically significant, with 1.16 (95% CI: 01.03-01.31) for a composite endpoint of stroke, MI, or vascular death.155
In a large meta-analysis of 147 randomized trials of antihypertensive therapy,156 the percentages of reduction in coronary heart disease events and stroke were similar in people with and without cardiovascular disease, and regardless of blood pressure before treatment (up to 110 mm Hg SBP and 70 mm Hg DBP). A meta-analysis of regression that included 31 intervention trials of BP reduction in ≈ 74,000 patients with diabetes mellitus, reported a 13% decrease in the risk of stroke per 5 mm Hg in SBP reduction, and 11.5% for every 2 mm Hg reduction in DBP. In contrast, the decrease in the risk of AMI approached but did not reach statistical significance.157
In ONTARGET, the benefits of lowering SBP below 130 mm Hg were driven mainly by a reduction in stroke. AMI was unaffected and cardiovascular mortality remained unchanged.90
There is no consistency in these reports, namely an intense drop in BP down to 130/80 mm Hg neither decreases nor significantly increases coronary morbidity or mortality, but may have a protective effect against stroke. However, PROFESS data differ, so the issue is still debatable.
One could predict that a J-curve would have a devastating effect on older individuals, with a nadir at higher pressures due to the greater likelihood of CAD and a lower coronary reserve. Very few studies have addressed this issue, but those who have dealt with it have had quite reassuring results. A substudy of INVEST158 showed a J-shaped relationship between DBP and the primary outcome (all-cause death, nonfatal MI, or nonfatal stroke), but with a nadir of 75 mm Hg, except for the very old, for whom it was even lower (70 mm Hg). In HYVET,15 patients older than 80 years old with a mean BP of 173.0/90.8 mm Hg were randomized to receive treatment with indapamide and perindopril, if necessary, compared to placebo. In the active treatment group, the mean BP fell by nearly 30/13 mm Hg and produced a 30% reduction in stroke and a 64% reduction in HF, but had no significant effect on AMI. The HYVET authors stated that "The results support a target BP of 150/80 mm Hg in patients receiving treatment, since this target was reached in almost 50% of these patients after two years."15
As for the range of adults 65 to 79 years, we note the recommendation of the 2011 ACC/AHA Foundation expert consensus document on hypertension in the elderly,159 which states: "The general recommended target BP in people with uncomplicated hypertension is < 140/90 mm Hg. However, this target for elderly patients with hypertension is based on expert opinion, rather than data from controlled clinical trials, and it is unclear whether the SBP target should be the same in patients 65 to 79 years of age, compared to older patients." Therefore, we have maintained the target of < 140/90 mm Hg for this age group.
Lower SBP values may be associated with better stroke outcomes, except in the case of the PROFESS study, and evidence of CAD outcomes is unmistakable. The evidence that excessive DBP reduction may compromise cardiac outcomes (J-curve) is inconsistent. Epidemiological data and clinical trial evidence speak both for and against the existence of a J-curve for DBP, but not for SBP, suggesting the presence of major confounders of data interpretation, including selection bias, comorbidities, and nonlinear interactions between age, decreased DBP, and increased cardiovascular risk. The vast majority of hypertensive patients, including those with manifest heart disease, do not experience problems related to DBP reduction when standard antihypertensive medications are used. Concerns that coronary perfusion is limited by a self-regulatory threshold have not yet been validated in humans with healthy or even sick coronary arteries, and there is no consensus on the minimum safe level of DBP in these individuals. Although the autoregulation threshold has not been defined in humans, with or without CAD, it is evident, especially according to ACCORD, that lower target BP, below 120/80 mm Hg, protects against stroke and does not significantly increase CAD events. Most studies that have addressed lower BP targets have reached DBP values in the range of 70-79 mm Hg, which appear to be safe.
Therefore, a reasonable recommendation could be a target BP < 140/90 mm Hg for secondary prevention of cardiovascular events in patients with CAD. However, there are some epidemiological data, several post hoc analyses of clinical trials, and a plethora of other data that support, but do not prove, that a lower target (< 130/80 mm Hg) may be appropriate in some individuals with CAD. We suggest that BP should be slowly lowered in patients with occlusive CAD with evidence of myocardial ischemia, and caution is advised in induction that decreases DBP to less than 60 mm Hg, particularly if the patient is over 60 years old. In older hypertensive individuals with wide pulse pressures, making SBP decrease can cause very low values (DBP < 60 mm Hg). This should alert the clinician to carefully evaluate any adverse signs or symptoms, especially those resulting from myocardial ischemia. In patients older than 80, a reasonable target BP is < 150/80 mm Hg, although there is no direct evidence to support this or any other specific target BP in this age group.
The target BP < 140/90 mm Hg is reasonable for the secondary prevention of cardiovascular events in patients with hypertension and coronary heart disease (class IIb, level of evidence B).
A lower target BP (< 130/80 mm Hg) may be appropriate in some individuals with CAD, prior AMI, stroke, or transient ischemic attack, or CAD risk equivalents (carotid artery disease, PAD, or abdominal aortic aneurysm) (class IIb, level of evidence B).
In patients with high DBP and CAD with evidence of myocardial ischemia, BP should be lowered slowly, and caution is advised in the induction of DBP reduction below 60 mm Hg in any patient with diabetes mellitus or who is older than 60. In hypertensive individuals with wide pulse pressures, reducing SBP can cause very low values (DBP < 60 mm Hg). This should alert the clinician to carefully evaluate any adverse signs or symptoms, especially those resulting from myocardial ischemia. (class IIa, level of evidence C).
The management of hypertension in patients with chronic CAD and chronic stable angina is directed towards the prevention of death, myocardial infarction, and stroke; a reduction in the frequency and duration of myocardial ischemia; and improving symptoms. Changes in diet and adopting a healthy approach to the heart are critical, with the usual attention to diet, sodium intake, moderation of alcohol intake, regular exercise, weight loss, quitting smoking, glycemic control, management of lipids, and antiplatelet therapy. The recognition and treatment of hypothyroidism and obstructive sleep apnea are important complements for patients at risk. Inevitably drug treatment is required.
A reasonable target BP for hypertensive patients with demonstrated CAD is < 140/90 mm Hg.20,155,159-167 A lower target BP (< 130/80 mm Hg) may be appropriate in some individuals with CAD or those with AMI , prior stroke or transient ischemic attack, or CAD risk equivalents (carotid artery disease, PAD, abdominal aorta aneurysm).
Beta-blockers are the drugs of first choice for hypertension treatment in patients with coronary artery disease that causes angina.168,169 They relieve ischemia and angina mainly based on their negative inotropic and chronotropic actions. Decreased heart rate increases the diastolic filling time for coronary perfusion. Beta-blockers also inhibit renin release from the juxtaglomerular apparatus. Cardioselective agents (beta-1) without intrinsic sympathomimetic activity are used most frequently. Contraindications to their use include significant sinus bradycardia or atrioventricular node dysfunction, hypotension, decompensated HF, and severe spastic bronchopulmonary disease.
PAD rarely worsens symptomatically from the use of these agents, and mild bronchospastic disease is not an absolute contraindication. Caution should be exercised when treating diabetic patients with a history of episodes of hypoglycemia, since beta-blockers may mask the symptoms of hypoglycemia.
Recently, there has been considerable controversy over the appropriateness of using beta-blockers as first-line treatment for hypertension in patients who do not have a convincing indication; however, their use in patients with angina, previous myocardial infarction, or HF has a solid foundation of positive data. Beta-blockers should be prescribed as initial treatment for the relief of symptoms in patients with stable angina. In addition, beta-blockers may be considered as long-term therapy for all other patients with coronary vascular disease. Recent guidelines (ACC/AHA Foundation)169,170 have recommended beta-blocker therapy in patients with normal LV function after MI or acute coronary syndrome (ACS) (class I, level of evidence B), specifically carvedilol, metoprolol succinate, or bisoprolol, in all patients with LV systolic dysfunction (ejection fraction ≤ 40%) or HF or previous AMI, unless contraindicated (class I, level of evidence a). The use of beta-blockers should be initiated and continued for three years in all patients with normal left ventricular function after AMI or ACIS (class I, level of evidence B).168-170
Calcium channel blockers
As a class, CCBs reduce myocardial oxygen demand by decreasing peripheral vascular resistance and BP reduction and increasing myocardial oxygen supply due to coronary vasodilation. Nondihydropyridine agents, diltiazem and verapamil, also decrease the sinoatrial discharge rate and atrioventricular nodal conduction.
CCBs, or long-acting nitrates, should be prescribed for the relief of symptoms when beta-blockers are contraindicated or when they cause unacceptable side effects in patients with stable angina (class IIa, level of evidence B).168 CCBs in combination with beta-blockers should be prescribed for the relief of symptoms when initial therapy with beta-blockers is not successful in patients with stable angina (class IIa, level of evidence B).168 In addition, CCBs are added to, or are replaced by, beta-blockers when BP is still high, when angina persists, or if the drug’s side effects contraindicate its prescription.171 Long-acting dihydropyridine on nondihydropyridine agents (diltiazem or verapamil) are preferred for use in combination with beta-blockers to avoid excessive bradycardia or heart block. Diltiazem or verapamil should not be used in patients with heart failure or LV systolic dysfunction,171 and short-acting nifedipine should be avoided because it causes sympathetic reflex activation and worsening of myocardial ischemia.169
Amlodipine can have pleiotropic effects beyond BP reduction for stabilizing atherosclerotic plaque.172,173
The management of symptomatic CAD, especially angina, is aimed at angina relief and the prevention of progression of CAD and coronary events. The mainstays of angina pectoris treatment are beta-blockers, calcium channel blockers, and nitrates. Pharmacological strategies for the prevention of cardiovascular events in these patients include ACE inhibitors, ARBs, thiazide or thiazide-type diuretics, beta-blockers (especially after AMI), CCBs, antiplatelet drugs, and drugs to treat dyslipidemia. Recent guidelines from the ACC/AHA Foundation recommend ACE inhibitors or beta-blockers, with the addition of drugs such as thiazide diuretics or CCBs for the management of hypertension in patients with stable ischemic heart disease.169
There are no special contraindications in hypertensive patients for the use of nitrates, antiplatelet drugs, or anticoagulant or lipid-lowering agents for the treatment of angina and the prevention of coronary events, except that in patients with severe uncontrolled hypertension who are taking antiplatelet or anticoagulant drugs, BP must be reduced without delay so that there is a lower risk of hemorrhagic stroke.
Patients with hypertension and stable chronic angina should be treated with a regimen that includes:
If beta-blockers are contraindicated or produce intolerable side effects, a nondihydropyridine CCB (such as diltiazem or verapamil) can be replaced, but not if there is left ventricular dysfunction (class IIa, level of evidence B).
While angina or hypertension are still not controlled, a long-acting dihydropyridine CCB can be added to the basic regimen of beta-blockers, ACE inhibitors, and thiazide and thiazide-type diuretics or similar. The combination of a beta-blocker and any nondihydropyridine CCB (diltiazem or verapamil) should be used with caution in patients with symptomatic coronary artery disease and hypertension due to increased risk of significant bradyarrhythmias and HF (class IIa, level of evidence B).
For patients with stable angina, the BP goal is < 140/90 mm Hg (class I, level of evidence A). However, a lower target BP (< 130/80 mm Hg) may be considered in some individuals with CAD, with stroke or transient ischemic attack, or CHD risk equivalents (carotid artery disease, DBP, abdominal aortic aneurysm) (class IIb, level of evidence B).
There are no special contraindications in hypertensive patients for the use of antiplatelets or anticoagulants, except that in patients with severe uncontrolled hypertension who are taking antiplatelet or anticoagulant drugs, BP must be reduced without delay to reduce the risk of hemorrhagic stroke (class IIa; level of evidence C).
If there is no contraindication to the use of beta-blockers in patients with ACS, initial treatment of hypertension should include a short-acting beta-blocker, selective and without intrinsic sympathomimetic activity (metoprolol tartrate or bisoprolol). Normally beta-blocker therapy should be initiated orally within 24 hours of presentation (class I, level of evidence A). For patients with severe hypertension or ischemia in progress, an intravenous beta-blocker (esmolol) can be considered (class IIa, level of evidence B). For hemodynamically unstable patients, or when there is decompensated HF, initiation of beta-blocker therapy should be delayed until stabilization is achieved (class I, level of evidence A).
In patients with ACS and hypertension, nitrates should be considered to lower BP or to relieve ongoing ischemia or pulmonary congestion (class I, level of evidence C). Nitrates should be avoided in patients with suspected right ventricular infarction and in those with hemodynamic instability. Sublingual or intravenous nitroglycerin is preferred for initial treatment, and a transition can be made later to a longer-acting preparation if indicated.
If there is a contraindication to the use of a beta-blocker or intolerable side effects, a nondihydropyridine CCB such as verapamil or diltiazem can be used for patients with ongoing ischemia, provided that LV dysfunction or HF is not present. If angina or hypertension is not controlled with only a beta-blocker, a CCB like long-acting dihydropyridine can be added after the optimal use of an ACE inhibitor (class IIa, level of evidence B).
An ACE inhibitor (class I, level of evidence A) or an ARB (class I, level of evidence B) should be added if the patient had an AMI before, if hypertension persists, if the patient has evidence of LV dysfunction or HF, or if the patient has diabetes mellitus. For patients with low-risk ACS with preserved LV ejection fraction without diabetes mellitus, ACE inhibitors can be considered as a first-line agent for BP control (class IIa, level of evidence A).
Aldosterone antagonists are indicated for patients who are already receiving beta-blockers, and ACE inhibitors after AMI and with LV dysfunction, or HF or diabetes mellitus. Serum potassium levels should be monitored. These agents should be avoided in patients with elevated serum creatinine levels (over 2.5 mg/dL in men, over 2.0 mg/dL in women) or high potassium levels (≥ 5.0 mEq/L) (class I, level of evidence A).
Loop diuretics are preferred to thiazides and thiazide-type diuretics for patients with ACS with HF (NYHA class III or IV), or for patients with CKD and estimated glomerular filtration rate < 30 mL per minute. For patients with persistent uncontrolled hypertension with a beta-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).
The target BP is < 140/90 mm Hg in patients with ACS who are hemodynamically stable (class IIa, level of evidence C). The target BP < 130/80 mm Hg at the time of discharge is a reasonable option (class IIb, level of evidence C). BP should go down slowly, and caution is recommended to avoid DBP reduction below 60 mm Hg, as it can reduce coronary perfusion and worsen ischemia.
Treatment of hypertension in patients with HF should include managing risk factors, for example, dyslipidemia, obesity, diabetes mellitus, smoking, dietary sodium, and a closely-monitored exercise program (class I, level of evidence C).
Drugs that have been shown to improve outcomes for patients with heart failure with reduced ejection fraction may also reduce BP. Patients should be treated with ACE inhibitors (or ARBs), beta-blockers (carvedilol, metoprolol succinate, bisoprolol or nebivolol), and aldosterone receptor antagonists (class I, level of evidence A).
Thiazide or thiazide-type diuretics should be used to control BP and to reverse volume overload and associated symptoms. In patients with severe heart failure (NYHA class III and IV) or those with severe renal impairment (estimated glomerular filtration rate < 30 mL per minute), loop diuretics should be used for volume control, but they are less effective than thiazide-type or BP-reducing diuretics. Diuretics should be used in conjunction with an ACE inhibitor or an ARB and a beta-blocker (class I, level of evidence C).
Studies have shown the equivalence of the benefits of ACE inhibitors and ARBs, candesartan or valsartan, in heart failure with reduced ejection fraction. These are effective in reducing BP (class I, level of evidence A).
The aldosterone antagonists spironolactone and eplerenone have proven beneficial in HF and should be included in the regimen in case of heart failure (NYHA class II-IV) with reduced ejection fraction (less than 40%). They may be replaced by a thiazide diuretic in patients needing a potassium-sparing agent. If an aldosterone receptor antagonist is administered with an ACE inhibitor or an ARB, or in the presence of renal failure, serum potassium should be monitored frequently. These drugs should not be used, however, if the serum creatinine level is ≥ 2.5 mg/dL in men or ≥ 2.0 mg/dL in women, or if the level of serum potassium is ≥ 5.0 mEq/L. Spironolactone or eplerenone can be used with a thiazide or thiazide-type diuretic, especially in patients with resistant hypertension (class I, level of evidence A).
Hydralazine plus isosorbide dinitrate should be added to the regimen of diuretics, ACE inhibitors or ARBs, and beta-blockers in patients with NYHA class III or LV HF with reduced ejection fraction (class I, level of evidence A). Others may benefit similarly, but this has not yet been tested.
In patients with hypertension and heart failure with preserved ejection fraction, the recommendations are to control systolic and diastolic hypertension (class I, level of evidence A), the ventricular rate in the presence of atrial fibrillation (class I, level of evidence C), and pulmonary congestion and peripheral edema (class I, level of evidence C).
The use of beta-adrenergic-blocking agents, ACE inhibitors, ARBs, or CCBs in patients with heart failure with preserved ejection fraction and hypertension can be effective to minimize symptoms of HF (class IIb, level of evidence C).
In HF, the principles of therapy for hypertension with acute pulmonary edema are similar to those of STEMI and NSTEMI, as described above (class I, level of evidence A). If the patient is hemodynamically unstable, the onset of these therapies should be delayed until HF stabilization has been achieved.
Drugs to prevent hypertension in patients with HF with reduced ejection fraction are nondihydropyridine CCBs (such as verapamil and diltiazem), clonidine, moxonidine, and hydralazine without nitrate (class III harm; level of evidence B). Alpha-adrenergic blockers, such as doxazosin, should only be used when other medications for hypertension and HF treatment are insufficient to achieve BP control at the maximum tolerated dose. Nonsteroidal anti-inflammatory drugs should also be used with caution in this group (class IIa, level of evidence B).
The target BP is < 140/90 mm Hg, but one may consider reducing blood pressure further to < 130/80 mm Hg. In patients with high DBP who have CAD and HF with evidence of myocardial ischemia, BP should go down slowly. In hypertensive individuals with wide pulse pressures, reducing SBP can cause very low values (DBP < 60 mm Hg). This should alert the clinician to carefully evaluate any signs or adverse symptoms, especially those caused by myocardial ischemia and worsening HF (class IIa, level of evidence B). Octogenarians should be checked for the presence of orthostatic changes, and SBP < 130 mm Hg and DBP < 65 mm Hg should be avoided.
Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.