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128
CHAPTER 8 Antithrombotic Therapy
56. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated
heparin with fi brinolysis for ST-elevation myocardial infarction. N Engl J Med
2006; 354: 1477–1488 .
57. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute
coronary syndromes. N Engl J Med 2006; 355: 2203–2216 .
58. Lincoff AM, Bittl JA, Harrington RA, et al . Bivalirudin and provisional glycopro-
tein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa
blockade during percutaneous coronary intervention: REPLACE-2 randomized
trial. JAMA 2003; 289: 853–863 .
59. Kastrati A, Neumann FJ, Schulz S, et al. Abciximab and heparin versus bivalirudin
for non-ST-elevation myocardial infarction. N Engl J Med 2011; 365: 1980–1989 .
60. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI
in acute myocardial infarction. N Engl J Med 2008; 358: 2218–2230 .
61. Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enox-
aparin in acute coronary syndromes. N Engl J Med 2006; 354: 1464–1476 .
62. Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and
reinfarction in patients with acute ST-segment elevation myocardial infarction:
the OASIS-6 randomized trial. JAMA 2006; 295: 1519–1530 .
63. Rothberg MB, Celestin C, Fiore LD, et al . Warfarin plus aspirin after myocardial
infarction or the acute coronary syndrome: meta-analysis with estimates of risk
and benefi t. Ann Intern Med 2005; 143: 241–250 .
64. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent
acute coronary syndrome. N Engl J Med 2012; 366: 9–19 .
65. Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after
acute coronary syndrome. N Engl J Med 2011; 365: 699–708 .
66. Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with
cangrelor during PCI. N Engl J Med 2009; 361: 2330–2341 .
67. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in
patients undergoing PCI. N Engl J Med 2009; 361: 2318–2329 .
68. Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging antiplatelet therapy with
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69. Neri Serneri GG, Coccheri S, Marubini E, Violi F . Picotamide, a combined
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2004; 25: 1845–1852 .
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129129
Chapter 9
Treatment of Primary
Hypertension
Alexandros Briasoulis and George Bakris
Epidemiology
Analysis of data from the National Health and Nutrition Examination Survey
(NHANES) data has provided important epidemiologic information on the
prevalence and control of hypertension (HTN) in the United States.
Prevalence rates of HTN in the U.S. adult population have risen remark-
ably over the past two decades but appear to have remained unchanged over
the past 10 years, according to NHANES data. The prevalence rates of HTN
among U.S. adults were 27 percent in 1999–2000, 26 percent in 2001–2002,
29 percent in 2003–2004, and 29 percent in 2005–2006.
1
An additional 25 to
37 percent of U.S. adults had pre-HTN during this period. HTN contributes
to one out of every seven deaths in the United States and to nearly half of
all cardiovascular disease–related deaths, including stroke. There is signifi cant
variation in the prevalence of disease with age, gender, and ethnicity: overall,
the prevalence is higher in older individuals, non-Hispanic blacks, women. and
patients with chronic kidney disease.
The rising prevalence of HTN with advanced age appears more prominent
in females than in males, to the extent that diagnosed HTN is more common
among older women than among older men. Whereas HTN rates among men
aged 20 to 44 ranges from 13 to 23 percent compared to rates of 6 to 17 per-
cent among comparably aged women, the prevalence of HTN among women
65 and older is over 70 percent compared to a prevalence rate of approxi-
mately 65 percent among men 65 and older.
1
The prevalence of HTN among American blacks is one of the highest in the
world, and it continues to rise. Moreover, HTN tends to be both more com-
mon
2
and more severe
3
in blacks, and progression from pre-HTN to HTN is
accelerated. The reasons for the observed associations are not clear, but inges-
tion of a high-sodium/low-potassium diet, lower socioeconomic status, and
genetic–environmental interactions might contribute. Finally, the prevalence
of HTN rises among patients with reduced renal function; up to 75 percent of
patients with moderate to severe kidney disease have HTN.
Despite the success of drug therapy in treating HTN and reducing associated
adverse cardiovascular effects, the percentage of patients achieving adequate
blood pressure (BP) control worldwide remains unacceptably low. Recent data
do suggest an improvement in treatment and control of HTN; however, about
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CHAPTER 9 Treatment of Primary Hypertension
48 percent of those treated are not at a BP goal of less than 140/90 mmHg in the
United States.
1
These numbers are even higher among hypertensive patients in
Europe.
4
In 10 to 20 percent of hypertensive patients, adequate BP control is
not correctable by drug therapy optimization and better compliance.
Selecting patients who require treatment
Before antihypertensive medications are initiated, the potential risks and antici-
pated benefi ts should be taken into consideration.
HTN predicts cardiovascular events in a continuous, graded manner. With
each 20/10-mmHg increase in BP above the level of 115/75 mmHg, the overall
cardiovascular risk doubles.
5
However, at any BP level the cardiovascular risk
depends on the presence of additional risk factors.
Lowering systolic and diastolic pressure is associated with improved car-
diovascular outcomes. In a post hoc analysis from the International Verapamil
Trandolapril Study (INVEST) trial, which compared the effectiveness of vera-
pamil and atenolol in hypertensive patients with known coronary artery dis-
ease (CAD), major cardiovascular event rates decreased progressively from
the group with the poorest BP control to the groups with better control.
6
The
magnitude of benefi t from antihypertensive treatment is higher in patients with
moderate (systolic 160 to 179 mmHg and/or diastolic 100 to 109 mmHg) to
severe HTN (systolic 180 or above and/or diastolic 110 mmHg or above). The
benefi ts of BP control are less pronounced in patients with mild HTN (systolic
140 to 159 mmHg and/or diastolic 90 to 99 mmHg). The aforementioned data
indicate that failure to control HTN with nonpharmacologic measures should
prompt the initiation of antihypertensive medications in patients with systolic
BP persistently at or above 140 mmHg and/or diastolic BP persistently at or
above 90 mmHg at home or offi ce visits. Isolated systolic HTN at or above
140 mmHg and isolated diastolic HTN at or above 90 mmHg should also be
treated despite the lack of robust data suggesting clinical benefi t. The Systolic
Hypertension in the Elderly Program (SHEP)
7
of elderly patients with isolated
systolic HTN of 170/77 mmHg at baseline showed that the group with lower
BP at treatment (143/68 mmHg) had a lower incidence of both cerebrovascular
and coronary events compared to the control group. The VA Cooperative
evaluated younger individuals with stages I or II diastolic HTN, averaging 90 to
114 mmHg, and reported a signifi cant reduction in cardiovascular events in the
treatment group, compared with placebo.
8
It is proposed that patients with diabetes mellitus, CAD, congestive heart
failure, and proteinuric chronic kidney disease should initiate antihyperten-
sive therapy when the systolic BP is persistently above 130 mmHg and/or the
diastolic BP is above 80 mmHg. This guideline recommendation is not based
on solid evidence but retrospective data from clinical trials and opinion. The
most recent guidelines for kidney disease progression actually recommend with
grade 1B evidence a BP below 140/90 mmHg.
9
Compared to individuals with normal BP (systolic less than 120 mmHg and
diastolic less than 80 mmHg), patients with BP in the pre-HTN range (sys-
tolic 120 to 139 mmHg or diastolic 80 to 89 mmHg) have an increased risk of
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CHAPTER 9 Treatment of Primary Hypertension
cardiovascular events. These observations were confi rmed by an analysis of
data from the Framingham Heart Study, which demonstrated that pre-HTN
was associated with an increased risk of myocardial infarction (relative risk 3.5)
and CAD (relative risk 1.7) but not stroke.
10
As shown in the Atherosclerosis
Risk in Communities (ARIC) study, the elevated cardiovascular risk was more
pronounced among black, obese, and diabetic individuals.
11
Therefore, the iden-
tifi cation and treatment of prehypertensive patients who are at greatest risk
for progression to HTN prolong the duration to onset of HTN and reduce the
cardiovascular event risk.
This hypothesis of early intervention in pre-HTN was tested in the Trial of
Preventing Hypertension (TROPHY) study. This 4-year trial of patients with
systolic BP of 130 to 139 mmHg and/or diastolic BP of 85 to 89 mmHg, ran-
domly assigned to 2 years of therapy with either placebo or candesartan, failed
to show that early initiation of treatment prevents future development of HTN.
In light of these fi ndings, the Joint National Committee (JNC 7)
12
recommended
that patients with pre-HTN who do not have diabetes, CAD, or chronic kidney
disease should not be treated with antihypertensive medications. Instead, life-
style modifi cations should be implemented fi rst.
BP goals in the treatment of HTN
Previous trials have suggested that antihypertensive therapy that results in
adequate BP control is associated with improved cardiovascular outcomes.
However, the optimal level of control may vary with certain patient popula-
tions. In general, the benefi ts of increasingly intensive therapy must be weighed
against the increased incidence of cardiovascular events, particularly in elderly
patients and those with CAD.
In the general population, BP reduction to less than 140 mmHg systolic and
less than 90 mmHg diastolic is associated with a lower incidence of cardiovas-
cular events and strokes. The Felodipine Event Reduction (FEVER) study of
patients with previously treated HTN and baseline BP of 154/91 mmHg showed
that all-cause mortality and stroke rates were decreased in the group of patients
with the lower BP (137/83) compared with the placebo group (143/85) after
40 months of follow-up.
13
Similar benefi cial effects in patients with attained BP
below 140/90 were reported by the MRC trial.
14
Based on the above fi ndings,
major society guidelines recommend a goal BP of less than 140 mmHg systolic/
less than 90 mmHg diastolic in the general hypertensive population.
Systolic BP continues to rise proportionally with increasing age, whereas
diastolic BP peaks in the fi fth decade of life and thereafter decreases, refl ect-
ing the decreased arterial elasticity.
15
Among individuals younger than 65 years,
studies show a progressive increase in the risk of stroke and coronary disease
with increasing BP. The risk is greater for each increment in systolic BP increase
compared to diastolic BP.
16
Among individuals older than 65 years, the risk of cardiovascular events
continues to increase with the rising systolic BP. However, studies have pro-
posed that in people with angina, a J-shaped curve exists such that diastolic
BP reduction to 85 mmHg decreases the risk of cardiovascular events, but
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CHAPTER 9 Treatment of Primary Hypertension
further diastolic reduction below 80 to 85 mmHg increases the event rates.
16–18
A post hoc analysis of the INVEST trial, a cohort of over 22,000 people with
coronary disease, confi rmed a strong J-shaped relationship between a diastolic
BP level of 70 mmHg and adverse outcomes. The J-shaped relationship was
attenuated after adjustment for myocardial infarction and heart failure but per-
sisted between low diastolic BB and adverse events.
6
Similarly, the Action to
Control Cardiovascular Risk in Diabetes (ACCORD) study of patients with
type 2 diabetes at high risk for cardiovascular events suggested that targeting
a systolic BP of less than 120 mmHg, compared with less than 140 mmHg, did
not reduce the rate of cardiac events but did reduce the rate of strokes.
19
In
very old individuals (above 80 years old) with moderate to severe HTN, the
Hypertension in the Very Elderly (HYVET) trial showed that lowering BP to a
goal of 150/80 mmHg with a combination of low-dose thiazide with or without
an angiotensin-converting enzyme (ACE) inhibitor reduced all-cause mortality
and nonfatal strokes.
20
However, a number of studies refute the J-curve association between dia-
stolic BP and cardiovascular events. The Systolic Hypertension in the Elderly
Program (SHEP) study of elderly patients with isolated systolic HTN found a
lower incidence of both cerebrovascular and coronary events despite a reduc-
tion of the diastolic BP to below 70 mmHg.
7
Nonetheless, those who expe-
rienced a cardiovascular event while on antihypertensive drug therapy had
lower diastolic levels than those who did not have an event. The Hypertension
Optimal Treatment (HOT) trial was designed to resolve the controversy on
the existence of the J-curve. The study randomized 19,000 patients to target
diastolic pressures of 90 mmHg or less, 85 mmHg or less, or 80 mmHg or less
and showed that intensive BP lowering was associated with a low rate of cardio-
vascular events.
21
However, HOT did not achieve systolic pressures below the
goal for the general population, since the mean attained BP was 140/81 mmHg
in the lowest group. Finally, a meta-analysis of randomized, placebo-controlled
trials including more than 28,000 patients found that lowering BP was benefi cial
even in individuals with diastolic BP below 70 mmHg, as long as the systolic
blood pressure was lowered.
22
Based on the results of the studies , for hypertensive patients under age 65,
with an elevated systolic pressure above 140/90 mmHg, the goal BP is less than
140/90 mmHg. However, as described above, the diastolic BP should not be
reduced below 60 mmHg, especially in patients with known CAD. The results
of the HYVET study support a target BP of 150/80 mmHg in hypertensive
patients over 80 years old.
In the JNC 7 guidelines, a goal BP of less than 140/90 mmHg in patients
with coronary heart disease is recommended.
12
A more recent statement
published by the American Heart Association suggested a goal of less than
130/80 mmHg for these patients. However, the Avoiding Cardiovascular Events
through Combination Therapy in Patients Living with Systolic Hypertension
(ACCOMPLISH)
23
(weber), ACCORD BP,
19
HOT,
21
and INVEST trials
6
did not
report signifi cant differences in mortality and cardiovascular event rate with
tight BP control (less than 130/80) compared to usual BP control (less than
140/90 mmHg). Therefore, the goal for patients with CAD should be less than
140/90. A target BP of less than 130/80 mmHg can lead to lower stroke rates,
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133
CHAPTER 9 Treatment of Primary Hypertension
if it is achieved without a diastolic BP drop below 70 mmHg or signifi cant side
effects.
23
In patients at high risk for CAD such as patients with diabetes mellitus, and
proteinuric chronic kidney disease, lowering of BP below 130/80 mmHg is
argued as being more benefi cial than below 140/90 mmHg. According to the
results of the African American Study of Kidney Disease and Hypertension
(AASK)
24
as well as the Modifi cation of Diet in Renal Disease (MDRD) trial
25
and a recent meta-analysis,
26
the data for the target BP for patients with pro-
teinuria of less than 1 g/day support less than 140/90 mmHg. These trials, along
with the results from the Ramipril Effi cacy in Nephropathy (REIN-2) trial,
27
demonstrated that randomization to a lower BP control did not further slow
nondiabetic chronic kidney disease progression
Choice of antihypertensive therapy
Nonpharmacologic treatment
Treatment of HTN combines nonpharmacologic approaches as well as pharma-
ceutical interventions. Lifestyle modifi cations such as sodium restriction, weight
loss, smoking cessation, DASH diet, aerobic exercise, and decreased alcohol
intake can effectively reduce BP.
28
Dietary sodium reduction can reduce BP in normotensive, prehypertensive,
and hypertensive individuals, as shown in short-term studies. A meta-analysis of
17 trials of patients with HTN and 11 in patients with normal BP suggested that a
decrease of approximately 75 mEq/day in sodium intake for more than 4 weeks
resulted in a fall in BP of 5/3 mmHg among hypertensives and 2/1 mmHg among
normotensives. In addition to effects on blood pressure, limiting sodium intake
can enhance the response to most antihypertensive drugs, with the exception
of calcium channel blockers (CCBs).
29
Sodium restriction may also diminish the
degree of potassium depletion following treatment with a diuretic.
The DASH diet consists of increased intake of fruits and vegetables, low-fat
dairy products, whole grains, nut, and limited fats and red meat. Hence, the diet
is low in sodium but high in potassium. Note that low potassium can also ele-
vate BP, not just high sodium. The DASH diet, when combined with salt restric-
tion, resulted in a mean systolic BP reduction of 11.5 mmHg.
28
The BP reduction
associated with dietary modifi cations can be augmented by the institution of a
regular aerobic exercise routine. Although the benefi t of sodium restriction,
diet, and exercise on BP control has been well documented, the effects of these
interventions on cardiovascular morbidity and mortality will require prolonged
compliance, large sample sizes, and long-term follow-up.
Monotherapy
Patients with stage I HTN (140 to 159/90 to 99 mmHg) can initially be treated
with a single antihypertensive agent. Among patients who do not have a com-
pelling indication for a specifi c drug class, the major antihypertensive classes
recommended are thiazide-like diuretics (chlorthalidone and indapamide),
long-acting ACE inhibitors or angiotensin II receptor blockers (ARBs), or long-
acting CCBs. If there is a compelling indication for their use, beta-blockers can
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134
CHAPTER 9 Treatment of Primary Hypertension
be used (i.e., congestive heart failure, symptomatic CAD, arrhythmias, hypera-
drenergic states).
12,15
It is noteworthy that it is the amount of BP reduction rather than the anti-
hypertensive drug class that determines the degree of cardiovascular risk
reduction. In the Captopril Prevention Project (CAPPP), 10,985 patients with
a diastolic BP of at least 100 mmHg were randomly assigned to captopril or
beta-blocker and/or a diuretic.
30
After 6 years of follow-up, no difference was
observed in the risk of a myocardial infarction, stroke, or cardiovascular death
between the two treatment groups. Similarly, the STOP-Hypertension-2 trial
of elderly patients with severe HTN showed that beta-blockers or diuretics,
ACE inhibitors, or dihydropyridine CCBs led to the same cardiovascular event
risk reduction after 4.5 years of follow-up.
31
Additionally, no difference in out-
comes between enalapril and amlodipine was reported in the Comparison of
Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT)
study of normotensive patients with CAD.
32
The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) trial showed a
lower cardiovascular death rate in high-risk hypertensive patients treated with
amlodipine compared with atenolol. Treatment with amlodipine resulted in a
signifi cantly lower mean BP compared to atenolol after 5.5 years of follow-up.
33
In a population similar to that of the ASCOT trial, the authors of the Valsartan
Antihypertensive Long-term Use Evaluation (VALUE) trial
34
suggested bet-
ter outcomes but also greater BP reduction with amlodipine compared to
valsartan.
The fi ndings above were confi rmed by two recent well-conducted meta-
analyses
35,36
that suggested that all the classes of BP-lowering drugs have a simi-
lar effect in reducing cardiovascular events and stroke for a specifi c reduction in
BP. The exception to this statement is the administration of beta-blockers after
a myocardial infarction.
The fi rst trial that reported signifi cant differences between different classes
of antihypertensive medications was the Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial (ALLHAT), which randomized 41,000
hypertensive patients with at least one risk factor to chlorthalidone, amlodipine,
lisinopril, or doxazosin (that arm was prematurely terminated due to increased
heart failure rates).
37
Although CAD-related death or myocardial infarction
rates were the same among the three arms, chlorthalidone was associated with
a signifi cantly lower rate of heart failure and combined cardiovascular events
than lisinopril. These results could, in part, be attributed to a 2-mmHg BP differ-
ence in the general population and a 6-mmHg difference in African Americans
between the chlorthalidone and the lisinopril groups. Based on the results of
the ALLHAT trial and other previous outcome trials, the JNC 7 guidelines
recommended low-dose thiazide-like diuretics as the initial drug treatment of
most patients with stage I HTN, unless there is a specifi c indication for a differ-
ent antihypertensive class.
Signifi cant interpatient variability in response to BP-lowering agents does
exist based on age, race, and ethnicity, in part related to the high sodium con-
tent of various cultural diets. This subsequently affects the actions of different
antihypertensive agents. Specifi cally, patients eating high-sodium diets require
more antihypertensive agents to achieve the same level of BP control than
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135
CHAPTER 9 Treatment of Primary Hypertension
those on lower-sodium diets.
38
Additionally, agents that depend on RAAS
activation such as RAAS blockers will lose more than half their activity as an
antihypertensive in patients on high-sodium diets. Some additional general
observations from subgroup analysis of the previous studies are the following:
(1) black and elderly patients generally respond better to monotherapy with a
thiazide diuretic or CCB and respond relatively poorly to an ACE inhibitor or
beta-blocker; (2) non-black and younger patients respond better to ACE inhibi-
tors or ARBs; (3) the largest BP reduction was observed at half the standard
dose
35
; standard or twice-standard doses resulted in only modestly greater BP
reductions in blood pressures; and (4) the side effect rate increased signifi -
cantly with standard or twice-standard doses compared to half-standard doses
of CCBs, thiazide diuretics, and beta-blockers. The side effect rates with ACE
inhibitors and ARBs were not dose-dependent.
Thiazide and thiazide-like diuretics
Thiazide diuretics (hydrochlorothiazide [HCTZ], chlorothiazide) effectively
reduce HTN-associated cardiovascular morbidity and mortality
37
and exhibit
additive BP-lowering effects when combined with ACE inhibitors or ARBs.
Chlorthalidone, a thiazide-like diuretic, at the same dose as HCTZ is far more
effective at lowering BP. The reason for these differences is a signifi cantly lon-
ger half-life and different chemistry than basic thiazide diuretics; there is no
difference in potency between these agents.
39,40
This is clearly associated with
better BP control than HCTZ throughout the day, as was exemplifi ed in a
substitution study where chlorthalidone decreased systolic BP by 8 mmHg on
average compared to HCTZ and 5 mmHg when compared to HCTZ paired
with the same ARB.
39,41
Although higher doses of thiazide diuretics produce
little further antihypertensive response, metabolic complications (hypokalemia,
hypomagnesemia, glucose intolerance, hyperlipidemia, and hyperuricemia) are
dose-dependent.
35
Thiazides are generally considered ineffective when the
glomerular fi ltration rate (GFR) is less than 40 mL/min/1.73 m
2
, and for chlo-
rthalidone and indapamide less than 30 mL/min/1.73 m
2
, and they should be
substituted with a long-acting loop diuretic (torsemide) or, if unavailable, furo-
semide twice daily. One exception to this general rule is metolazone, a thiazide
diuretic that acts on both the proximal and distal tubule and can be used in
concert with a loop diuretic in patients with advanced kidney disease and heart
disease for diuresis.
Renin angiotensin aldosterone system (RAAS)
blockade
The RAAS is a major neurohormonal pathway that helps regulate BP as well as
fl uid and electrolyte balance. Upregulation of RAAS results in potent vasocon-
striction and sodium retention, thus raising BP. Therefore, it is considered one
of the key systems in the pathogenesis of HTN and presents an optimal treat-
ment target. Blockade of the RAAS has, until recently, been accomplished by
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136
CHAPTER 9 Treatment of Primary Hypertension
inhibiting formation of angiotensin II and stimulating bradykinin. ACE inhibitors
stimulate bradykinin, while ARBs inhibit the actions of angiotensin II at the type
I angiotensin II (AT
1
) receptor by directly inhibiting the receptor. Renin inhibi-
tion with direct renin inhibitors, such as aliskiren, prevents the ability to convert
angiotensinogen to angiotensin I. Blocking the effects of aldosterone with a
mineralocorticoid receptor blocker such as spironolactone or eplerenone also
blocks part of the effects of this system downstream.
ACE inhibitors and ARBs must be part of all therapy in patients with systolic
left ventricular dysfunction, patients with congestive heart failure, patients who
have had a myocardial infarction, patients with type 2 diabetes mellitus, and
patients with proteinuric chronic kidney disease, unless contraindicated.
The fi ndings of the Ongoing Telmisartan Alone and in Combination with
Ramipril Global Endpoint Trial (ONTARGET) show that ACE inhibitors and
ARBS are equivalent in the secondary prevention of cardiovascular events.
42
However, the combination of ACE inhibitors and ARBs is associated with more
adverse events without an increase in benefi t to high-risk hypertensive patients.
Moreover, many of the adverse effects seen in this trial came from those who
were normotensive and randomized to the combination. Untoward effects
could have been anticipated in such people and could have been avoided.
43
The antihypertensive effect of different ACE inhibitors and ARBs is not
equivalent. In comparison with losartan, telmisartan provides superior control
of offi ce and 24-hour ambulatory BP (~2.5/1.5 mmHg mean difference) with-
out an increased risk of adverse events.
44
A newer ARB, azilsartan, exhibited
superior effi cacy to both olmesartan and valsartan (~3- to 4-mmHg difference
in systolic BP) at their maximal, approved doses without increasing adverse
events.
45
Aliskiren, the only available direct renin inhibitor, lowers BP to a degree
similar to other ACE inhibitors and ARBs. Although studies have shown that
aliskiren is associated with a greater reduction in proteinuria compared with
losartan in patients with type 2 diabetes mellitus and nephropathy
46
there are
no prospective randomized studies demonstrating cardiovascular benefi ts of
aliskiren in hypertensive patients.
Aldosterone antagonists are effective adjuncts to fi rst-line antihypertensive
regimens, particularly in patients with resistant HTN. Spironolactone is associ-
ated with a signifi cantly greater fall in 24-hour ambulatory BP compared to ACE
inhibitors/ARBs in overweight or obese individuals.
47
Eplerenone is more spe-
cifi c for the mineralocorticoid receptor than spironolactone and as a result has
a low occurrence of breast tenderness, gynecomastia, and sexual dysfunction.
Calcium channel blockers
Long-acting CCBs are effective antihypertensive agents that can be used as
monotherapy or in combination RAAS blockers for the treatment of HTN.
Both dihydropyridine CCBs (amlodipine, nifedipine) and non-dihydropyridine
CCBs (verapamil, diltiazem) are effective in lowering BP and reducing the
rate of cardiovascular events in high-risk populations.
36
Recently, the Avoiding
Cardiovascular Events through Combination Therapy in Patients Living with
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CHAPTER 9 Treatment of Primary Hypertension
Systolic Hypertension (ACCOMPLISH) study randomized 11,506 patients with
HTN at high risk for cardiovascular events to receive either benazepril plus
amlodipine or benazepril plus hydrochlorothiazide.
48
This trial, despite similar
BP reductions in both arms (both offi ce and 24-hour measurements), reported
an approximately 20 percent lower risk of primary outcome events—a com-
posite of death from cardiovascular causes, nonfatal myocardial infarction, non-
fatal stroke, hospitalization for angina, resuscitation after cardiac arrest, and
coronary revascularization—in subjects treated with the benazepril and amlo-
dipine combination.
In patients with proteinuric kidney disease, dihydropyridine CCBs do not
reduce albuminuria to the same extent as do non-dihydropyridine CCBs.
49
However, dihydropyridine CCBs can also be used in combination with ACE
inhibitors or ARBs to maximally reduce BP and slow nephropathy progression,
as reported by ACCOMPLISH.
50
CCBs are associated with lower-extremity edema, particularly in younger,
Asian, overweight female patients. CCBs might be preferred in older individu-
als, blacks, patients with obstructive airways disease, or individuals not main-
taining a low-sodium diet or being treated with nonsteroidal anti-infl ammatory
drugs.
Beta-blockers
In the presence of tachyarrhythmias, chronic stable angina, heart failure, or
asymptomatic left ventricular dysfunction or after an acute myocardial infarc-
tion, beta-blockers without intrinsic sympathomimetic activity are indicated. In
the absence of these indications, and particularly in patients over 60 years old,
other fi rst-line antihypertensive medications offer superior protection against
stroke risk.
33,51
The Losartan Intervention For Endpoint (LIFE) trial demon-
strated that losartan-based regimens prevented more cardiovascular morbidity
and death than atenolol-based regimens despite similar BP reduction.
52
Beta-blockers are also associated with metabolic problems, specifi cally
impaired glucose tolerance and an increased risk of new-onset diabetes higher
than the risk associated with thiazide diuretics.
53–55
Newer beta-blockers, particularly agents with vasodilatory properties, may
have less metabolic and heart-rate–related side effects than traditional beta-
blockers. In the GEMINI trial of diabetic, hypertensive patients, carvedilol was
associated with better glycemic control, increased insulin sensitivity, and no
change in HgbA1c compared to metoprolol
54
after 5 months of follow-up.
Despite the favorable safety profi le and the improved effi cacy of newer beta-
blockers, there are no prospective randomized studies evaluating their long-
term effects on HTN-related cardiovascular morbidity and mortality.
Combination therapy
Each of the antihypertensive agents discussed above, when used as mono-
therapy, produces an adequate antihypertensive effect in 40 to 60 percent of
the patients.
56
If the goal BP is not achieved with nonpharmacologic interven-
tions or monotherapy or if BP is more than 20/10 mmHg above the goal of
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