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Calcium Channel Blockers and Hypertension

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Effective treatment of high blood pressure (BP) represents a key strategy for reducing the burden of hypertension-related cardiovascular and renal diseases. In spite of these well-established concepts, hypertension remains poorly controlled worldwide. In order to improve BP control in patients with hypertension, several interventions have been proposed, among which (1) preferred use of more effective, sustained, and well-tolerated antihypertensive drug aimed to ensure adherence to prescribed medications and (2) extensive use of rational, integrated, and synergistic combination therapies, even as first-line strategy, aimed to achieve the recommended BP targets. Within the possible antihypertensive drug classes currently available for the clinical management of hypertension, both in monotherapy and in combination therapy, drugs inhibiting the renin-angiotensin system and calcium channel blockers (CCBs) have demonstrated to be effective and safe in lowering BP levels and achieving the recommended BP targets with a good tolerability profile. In particular, CCBs have been one of the most widely used classes of antihypertensive agents in the last 20 years, based on their effectiveness in reducing BP levels, good tolerability, and abundant evidence on reducing cardiovascular and renal consequences of hypertension. This article provides an updated overview of the evidence supporting the use of CCBs-based antihypertensive regimen, both in monotherapy and in combination therapies with different classes of antihypertensive drugs.
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Journal of Cardiovascular Pharmacology and
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DOI: 10.1177/1074248414555403
published online 14 November 2014J CARDIOVASC PHARMACOL THER
Massimo Volpe
Giuliano Tocci, Allegra Battistoni, Jasmine Passerini, Maria Beatrice Musumeci, Pietro Francia, Andrea Ferrucci and
Calcium Channel Blockers and Hypertension
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Calcium Channel Blockers and Hypertension
Giuliano Tocci, MD, PhD
1,2
, Allegra Battistoni, MD
1
,
Jasmine Passerini, MD
1
, Maria Beatrice Musumeci, MD
1
,
Pietro Francia, MD
1
, Andrea Ferrucci, MD
1
,
and Massimo Volpe, MD, FAHA, FESC
1,2
Abstract
Effective treatment of high blood pressure (BP) represents a key strategy for reducing the burden of hypertension-related cardio-
vascular and renal diseases. In spite of these well-established concepts, hypertension remains poorly controlled worldwide. In order
to improve BP control in patients with hypertension, several interventions have been proposed, among which (1) preferred use of
more effective, sustained, and well-tolerated antihypertensive drug aimed to ensure adherence to prescribed medications and (2)
extensive use of rational, integrated, and synergistic combination therapies, even as first-line strategy, aimed to achieve the recom-
mended BP targets. Within the possible antihypertensive drug classes currently available for the clinical management of hypertension,
both in monotherapy and in combination therapy, drugs inhibiting the renin–angiotensin system and calcium channel blockers
(CCBs) have demonstrated to be effective and safe in lowering BP levels and achieving the recommended BP targets with a good
tolerability profile. In particular, CCBs have been one of the most widely used classes of antihypertensive agents in the last 20 years,
based on their effectiveness in reducing BP levels, good tolerability, and abundant evidence on reducing cardiovascular and renal
consequences of hypertension. This article provides an updated overview of the evidence supporting the use of CCBs-based anti-
hypertensive regimen, both in monotherapy and in combination therapies with different classes of antihypertensive drugs.
Keywords
hypertension, blood pressure control, antihypertensive therapy, combination therapy, calcium channel blockers, calcium
antagonists
Introduction
Hypertension is a major modifiable risk factor, which signifi-
cantly and independently increases the risk of developing major
cardiovascular, cerebrovascular, and renal complications.
1
On
the other hand, an effective treatment of hypertension substan-
tially reduces the risk of developing such complications and
improves cardiovascular prognosis.
2
However, the control of
blood pressure (BP) remains largely unsatisfactory world-
wide.
3,4
In particular, analyses of data collected across different
Western countries on BP control rates have consistently and
independently confirmed that only 20%to 30%of treated
patients with hypertension achieve the recommended BP tar-
gets.
5-8
Inadequate BP control increases the risk of developing
hypertension-related cardiovascular diseases, including myo-
cardial infarction, ischemic stroke, end-stage renal disease, and
congestive heart failure, and explains the persistently high bur-
den of cardiovascular death related to hypertension.
9
Current recommendations from international guidelines
stated that in all patients with hypertension, it is important to
reduce BP until systolic and diastolic BP values below 140/
90 mm Hg are achieved.
10,11
These BP goals are recommended
for all adult patients with hypertension, regardless of gender,
age, ethnicity, or other concomitant clinical conditions.
10,11
Results of large, randomized, controlled clinical trials demon-
strated that it is possible to reach these BP targets in large pro-
portions of treated patients with hypertension having different
cardiovascular risk profiles.
12-14
Indeed, the design of these
clinical trials systematically included antihypertensive thera-
pies based on drugs inhibiting the renin–angiotensin system
(RAS) and calcium channel blockers (CCBs) compared to
b-blockers and diuretics.
12-14
On the basis of these findings,
a preferred use of these antihypertensive drug classes have been
pursued by recent hypertension guidelines, in order to bridge
the gap between the attained and expected BP control rates,
1
Division of Cardiology, Department of Clinical and Molecular Medicine,
Faculty of Medicine and Psychology, University of Rome Sapienza, Sant’Andrea
Hospital, Rome
2
IRCCS Neuromed, Pozzilli (IS), Italy
Manuscript submitted: June 10, 2014; accepted: August 8, 2014.
Corresponding Author:
Massimo Volpe, Division of Cardiology, Department of Clinical and Molecular
Medicine, Faculty of Medicine, University of Rome ‘‘Sapienza’’, Sant’Andrea
Hospital, Rome, Via di Grottarossa 1035-39, 00189 Rome, Italy.
Email: massimo.volpe@uniroma1.it
Journal of Cardiovascular
Pharmacology and Therapeutics
1-10
ªThe Author(s) 2014
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to ensure adequate adherence and persistence to prescribed
medications and to improve cardiovascular outcomes in treated
patients with hypertension.
10,11
Being the vast majority of these evidence based on the use of
dihydropyridinic CCBs, these drugs are now recommended
both as first-line therapy and as an ideal partner for dual or tri-
ple combination therapies for the clinical management of
hypertension and hypertension-related comorbidities.
10,11
The aim of this article is to provide an updated overview of
the evidence supporting the use of CCBs-based antihyperten-
sive regimen, both in monotherapy and in combination thera-
pies with different classes of antihypertensive drugs.
General Considerations on CCBs
Within the drug class, CCBs showed several important differ-
ences from the pharmacokinetic
15
and pharmacodynamic
16
point of views as well as for selectivity and duration of pharma-
cological action,
17-19
although sharing the same ability to inter-
act with L-type voltage-dependent transmembrane calcium
channels (Figure 1). As expected, these differences impact both
clinical and therapeutic effectiveness as well as tolerability and
safety profile in different clinical settings.
Several classifications have been proposed to distinguish dif-
ferent compounds within this drug class. Among these, CCBs
may be classified into 3 groups according to their selectivity for
interactions with either cardiac or vascular (or both) L-type
voltage-dependent transmembrane calcium channels,
20,21
as
reported in Table 1. According to this classification, CCBs may
be stratified into 3 groups, namely (1) dihydropyridinic agents,
which mostly act as dilating agents at peripheral vessel level,
(2) phenilalchilaminic agents, which predominantly act as nega-
tive inotropes and chronotropes at cardiac level, and (3) ben-
zothiazepinic agents, which have an intermediate profile.
The first generation of the compounds of these 3 groups
included nifedipine, verapamil, and diltiazem, respectively.
They were characterized by short-acting therapeutic actions,
which have limited their clinical effectiveness due to potential
risk of drug-related adverse reactions (eg, peripheral edema,
reflex tachycardia, skin reactions). Following the availability
of the first-generation molecules, over the years several other
compounds have been developed for widespread use in treat-
ing hypertension and cardiovascular diseases. In particular,
among dihydropyridinic agents, second-generation CCBs,
including manidipine,
22,23
felodipine,
24,25
and nicardipine,
26
and third-generation CCBs, including lacidipine,
27
lercanidi-
pine
28
barnidipine,
29
and amlodipine,
30
were characterized by
high selection for vascular calcium channels and favorable
pharmacokinetic and pharmacodynamic profile.
From a clinical point of view, dihydropyridinic CCBs are
considered one of the first-line therapeutic options to treat
hypertension and reduce hypertension-related cardiovascular
morbidity and mortality.
10,11
According to the recommendations from the European
guidelines,
10
all CCBs can be effectively and safely used for
the treatment of hypertension, both in monotherapy and in
combination therapies (Figure 2). In particular, according
with the compelling indications (Table 2), they are now
Figure 1. Schematic representation to explain the molecular mechanisms of actions of calcium channel blockers (CCBs).
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recommended for lowering BP levels in black individuals,
elderly patients with isolated systolic hypertension as well as
in patients with hypertension having metabolic syndrome, car-
diac (left ventricular hypertrophy) or vascular (atherosclerosis)
organ damage, previous stroke, or peripheral artery disease. In
addition, nondihydropyridinic CCBs are also recommended for
treating patients with hypertension having angina pectoris and
for those with atrial fibrillation, with the aim of achieving ven-
tricular rate control.
10
Finally, they are recommended for treat-
ing gestational hypertension or for preventing eclampsya.
10
On
the other hand, dihydropyridinic CCBs are contraindicated for
those patients with hypertension having tachycardia or conges-
tive heart failure, while nondihydropyridinic CCBs are contrain-
dicated for those patients with hypertension having grade 2 to 3
atrioventricular block, severe left ventricular dysfunction, or
congestive heart failure.
According to the recommendations from the evidence-based
guidelines in the United States,
11
some selected dihydropyridi-
nic CCBs (ie, amlodipine 2.5-10 mg and nitrendipine 10-20
mg) and only 1 nondihydropyridinic CCB (diltiazem extended
release120-360 mg) may be used for lowering BP levels and
reducing incidence of hypertension-related cardiovascular
Table 1. Classification of Different Compounds Within the CCB Drug Class, According to Their Selectivity for Interactions With Either
Cardiac or Vascular (or Both) L-Type Voltage-Dependent Transmembrane Calcium Channels.
a
Group
First Generation
(Original Formulations)
Second Generation
(Extended-Release Formulations)
Third Generation
(New Formulations)
Dihydropiridinic Nifedipine Nifedipine SR/GITS
Felodipine ER
Nicardipine SR
Nicardipine
Isradipine
Manidipine
Nilvadipine
Nimodipine
Nisoldipine
Nitrendipine
Amlodipine
Felodipine
Lacidipine
Barnidipine
Benzotiazepinic Diltiazem Diltiazem SR
Fenilalchilaminic Verapamil Verapamil SR
Abbreviations: SR, slow release; GITS, gastrointestinal-transport system; ER, extended release.
a
Derived from Reference
20,21
.
Figure 2. Schematic representation illustrating the different therapeutic options (monotherapy vs combination therapy) for the clinical
management of hypertension, according to current European guidelines.
10
Tocci et al 3
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events. With the only exception of renal diseases, in which
RAS-blocking agents should be preferred, CCBs are now rec-
ommended as first-line therapy in all stages of hypertension,
independent of age, gender, race, and other comorbidities
(Figure 3). They may be used both in monotherapy and in com-
bination therapies with either angiotensin-converting enzyme
(ACE) inhibitors or angiotensin receptor blockers (ARBs) or
thiazide diuretics.
11
Table 2. Compelling Indications and Contraindications for Using CCBs in the Clinical Management of Hypertension, According to Current
European Guidelines.
10
Compelling Indications CCB Other Drugs
Asymptomatic organ damage
LVH Dihydropyridinic CCB ACE inhibitor, ARB
Asymptomatic atherosclerosis Dihydropyridinic CCB ACE inhibitor
Clinical CV event
Previous stroke Any agent effectively lowering BP, including CCB
Angina pectoris Dihydropyridinic CCB BB
Atrial fibrillation, ventricular rate control Non-dihydropyridinic CCB BB
Peripheral artery disease Dihydropyridinic CCB ACE inhibitor
Other conditions
ISH (elderly) Dihydropyridinic CCB Diuretic
Metabolic syndrome Dihydropyridinic CCB ACE inhibitor, ARB
Pregnancy Dihydropyridinic CCB Methyldopa, BB
Blacks Dihydropyridinic CCB Diuretic
Contraindications
Tachycardia Dihydropyridinic CCB
Congestive heart failure Dihydropyridinic CCB
AV block (grade 2 or 3, trifascicular block) non-dihydropyridinic CCB (verapamil, diltiazem)
Severe LV dysfunction Nondihydropyridinic CCB (verapamil, diltiazem)
Heart failure Nondihydropyridinic CCB (verapamil, diltiazem)
Abbreviations: CCBs, calcium-channel blockers; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; BB, b-blockers, LVH, left ventricular
hypertrophy; CV, cardiovascular, ISH, isolated systolic hypertension; AV, atrioventricular.
Figure 3. Schematic representation illustrating the different therapeutic options (monotherapy vs combination therapy) for the clinical man-
agement of hypertension, according to current United States guidelines.
11
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Current Recommendations for Hypertension
Treatment and Control
In view of the documented equivalence in terms of antihyper-
tensive efficacy and in terms of reducing the risk of major car-
diovascular events, it is now possible to choose among 5
antihypertensive drug classes, including ACE inhibitors,
ARBs, b-blockers, CCBs, and diuretics, for starting and main-
taining antihypertensive treatment in monotherapy.
10
In the selection ofthe first-choice antihypertensive drug class,
however, it should be noted that, even in the presence of a sub-
stantial equivalence in terms of antihypertensive effectiveness,
there are relevant differences in terms of compelling indications
and contraindications among different antihypertensive drug
classes (Table 2).
10
In addition, beyond evidence in favor of car-
diovascular and renal protection, clinical trials have also demon-
strated a better tolerability profile
31,32
and favorable metabolic
properties
33-35
by RAS-inhibiting drugs, especially ARBs, and
by CCBs, compared to b-blockers and diuretics, thus promoting
the use of these drug classes, both in monotherapy and in com-
bination therapies, for hypertension management and control.
It is documented that only a relatively low proportion of
treated patients with hypertension (20%to 30%) can be main-
tained on a therapy based on a single class of antihypertensive
medication (monotherapy).
36
On the contrary, larger propor-
tions of treated patients with hypertension (70%to 80%)
require a combination therapy based on at least 2 classes of
drugs, in order to achieve the recommended BP goals.
36
In those patients with hypertension who have mild eleva-
tions in systolic/diastolic BP levels (ie stage 1 hypertension),
CCB-based monotherapy can be effectively and safely used
to control hypertension, especially in the presence of compel-
ling indications.
10
Indeed, monotherapy based on CCBs has
demonstrated to provide sustained antihypertensive efficacy
and to reduce cardiovascular and renal complications com-
pared to other antihypertensive drug classes.
37-42
In those patients with hypertension who do not achieve
satisfactory BP control under monotherapy, or in those with
high or very high cardiovascular risk profile, a combination
strategy based on the use of 2 classes of antihypertensive drugs,
including either ARBs or ACE inhibitors plus CCBs or thiazide
diuretics (dual combination therapy) should be used. Rando-
mized clinical trials
43-45
and large meta-analyses
46,47
con-
firmed that these combination strategies are characterized by
an antihypertensive efficacy about 5 times greater than the dou-
bling of the dose of each monotherapy. In particular, among
different combination therapies, those based on RAS blockers
and CCBs are now viewed as the most effective and better tol-
erated antihypertensive strategy compared to other drug classes
in several clinical settings.
48
In those patients with hypertension who do not achieve
satisfactory BP control under a combination therapy based on
the use of 2 classes of antihypertensive drugs, it should be use-
ful to use a combination strategy based on the use of 3 or more
classes of antihypertensive drugs, including either ARBs or
ACE inhibitors, CCBs, and thiazide diuretics (triple
combination therapy).
48
Potential CCB-based combination
therapies, both in dual or in triple combination therapies, are
reported in Table 3.
In this latter regard, dual or triple combination therapies
with CCBs have recently become available in fixed formula-
tions (single pill). These preparations have been demonstrated
to provide effective BP reductions, sustained BP control over
24 h, and improved adherence to prescribed medications com-
pared to free combination therapies. Recent meta-analyses have
consistently demonstrated that fixed combination therapy may
provide effective systolic and diastolic BP control and better
adherence to prescribed medications compared to free combina-
tion therapy.
49-51
In addition, fixed combination therapies have
demonstrated to provide sustained BP control over the 24-hour
period,
52
thus reducing the potential risk of cardiovascular and
cerebrovascular accidents due to partial or limited BP control
during the nighttime period.
53,54
Finally, these formulations
seem to have the advantage of an easier therapeutic regimen to
be taken as a single pill, which of course has relevant conse-
quence on pill burden and improves patient compliance and
adherence to prescribed antihypertensive therapy as demon-
strated even in a setting of real practice.
55,56
Calcium channel blocker-based therapy has also demon-
strated to be very effective and safe for the treatment of patients
with true resistant hypertension, particularly when combined
with RAS-blocking agents (either ACE inhibitors or ARBs),
thiazide diuretic, and antialdosterone agents.
57,58
In these
cases, high-dose, integrated and synergistic antihypertensive
strategies are required to achieve the recommended BP targets,
in the presence of high adherence to prescribed medications
and low risk of drug-related side effects.
48
Thus, CCBs repre-
sent a very attractive and useful partner for any antihyperten-
sive regimen to be used in this clinical setting of high-risk
patients with true resistant hypertension.
Calcium Channel Blockers and Hypertension:
Lessons From Large Randomized Clinical
Trials
Over the last years, several large, randomized, controlled clin-
ical trials have convincingly assessed the ability of CCBs to
Table 3. Potential Combination Therapies Based on CCBs.
CCB-based dual combination therapies (plus one of the following)
a
:
þACE inhibitors
þARBs
þDirect renin inhibitors
þDiuretics (hydrochlorothiazide, indapamide)
CCB-based triple combination therapies (plus one of the following)
a
:
þACE inhibitors þdiuretics (hydrochlorothiazide, indapamide)
þARBs þdiuretics (hydrochlorothiazide)
þDirect renin inhibitors þdiuretics (hydrochlorothiazide)
Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin
receptor blocker; CCBs, calcium-channel blocker.
a
When available and tolerated, fixed combination therapies should be
preferred to ensure adherence to prescribed medications.
Tocci et al 5
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reduce cardiovascular morbidity and mortality, and mostly cer-
ebrovascular events, in patients with hypertension and high car-
diovascular risk (Table 4).
A first evidence suggesting a beneficial effect of an anti-
hypertensive regimen based on CCBs derived from the Sys-
tolic Hypertension in Europe (Syst-Eur) Trial,
37
which
enrolled elderly patients aged 60 to 75 years with isolated
systolic hypertension (as defined for systolic BP values
more than 160 mmHg and diastolic BP lower than 95 mm
Hg), randomly assigned to a CCB-based regimen or to pla-
cebo. As expected, this trial was prematurely interrupted
after an average period of 2 years, due to the significant
reduction in the incidence of the primary composite end
point of both fatal and nonfatal stroke observed in the active
compared to the placebo group.
37
The Swedish Trial in Old Patients with Hypertension-2
Study (STOP Hypertension-2)
38
was a prospective, rando-
mized clinical trial, which enrolled elderly patients aged 70
to 84 years with severe hypertension (defined for systolic
BP more than 180 mm Hg and diastolic BP more than 105
mmHg, or both). Patients were randomized to an antihyper-
tensive strategy based on either b-blockers and diuretics or
ACE inhibitors or CCBs. In the presence of comparable BP
reductions among 3 groups during an average follow-up of
54 months, there was a trend toward reduction in the relative risk
of fatal and nonfatal stroke in the overall comparison between
either CCBs or ACE inhibitors and b-blockers plus diuretics.
38
However, when considering the comparison between CCBs or
ACE inhibitors versus conventional drugs, no significant differ-
ence was observed for fatal and nonfatal stroke nor in the com-
parison between CCBs and ACE inhibitors.
38
The International Nifedipine GITS Study: Intervention as a
Goal in Hypertension Treatment (INSIGHT) Study
39
was a
prospective, double-blind, randomized clinical trial that
enrolled adult patients aged 55 to 80 years with stage 1 to 2
hypertension (as defined for BP levels more than 150/95
mmHg) or isolated systolic hypertension (systolic BP more
than 160 mmHg) and at least 1 additional cardiovascular risk
factor. Patients were randomly assigned to either a CCB or a
diuretic.
39
Even in this trial, in the presence of comparable
BP reductions during an average follow-up of 4 years, no sig-
nificant differences were observed in the 2 treatment groups in
terms of primary composite end point, all-cause mortality, non-
fatal events, both fatal and nonfatal stroke.
39
Table 4. Stroke Incidence in Randomized Clinical Trials in Hypertension, Performed With CCBS Versus Either Placebo or Other
Antihypertensive Drugs.
a,b
RCT
Publication,
year
Population,
Num Active Drug (CCB) Comparator
BP
Difference,
mm Hg
Risk Reduction
(Fatal and
Nonfatal Stroke)
P
Value
Syst-Eur 1997 4695 Nitrendipine 10-40 mg Placebo 10/527% (62% to 39%) .33
STOP2 1999 6614 Felodipine 2.5 mg OR
Isradipine 2.5 mg
beta-blockers (atenolol
50 mg, or metoprolol
100 mg, or indolol 5 mg)
PLUS diuretics (hydro-
clorothiazide 25 mg plus
amiloride 2.5 mg)
0.3/þ0.9 0.88 (0.73 to 1.06) .16
ACE inhibitors (enalapril
10 mg or lisinopril
10 mg)
Felodipine 2.5 mg OR
Isradipine 2.5 mg
nr 1.02 (0.84 to 1.24) .84
INSIGHT 2000 6321 Nifedipine 30-60 mg GITS Hydrochlorothiazide
25-50 mg plus
amiloride 2.5 mg
0.0/0.0 0.87 (0.61 to 1.26) .52
NORDIL 2000 10 881 Diltiazem BB +Diuretics 3.0/0.0 0.80 (0.65 to 0.99) .04
SHELL 2003 1882 Lacidipine 4 mg Clorthalidone 12.5 mg 1.6/þ0.2 0.96 (0.61 to 1.51) .87
CONVINCE 2003 16 476 Verapamil 120-240 mg Atenolol 50-100 mg 0.1/0.7 1.15 (0.90 to 1.48) .11
INVEST 2003 22 576 Verapamil SR 120-240 mg Atenolol 50-100 mg þ0.3/0.2 0.89 (0.70 to 1.12) .33
ALLHAT 2004 33 357 Amlodipine 2.5-10 mg Chlorthalidone,
12.5-25 mg
þ0.8/0.7 0.93 (0.82 to 1.06) .28
VALUE 2004 15 245 Valsartan 80-160 mg Amlodipine 5-10 mg þ2.2/þ1.6 1.15 (0.98 to 1.35) .08
ASCOT-BPLA 2005 19 257 Amlodipine 5-10 mg Atenolol 50-100 mg 1.6/1.8 0.77 (0.66 to 0.89) .0003
FEVER 2005 9800 Felodipine ER 5 mg Placebo 4.2/2.1 0.73 (0.60 to 0.89) .0019
MOSES 2005 1405 Eprosartan 600 mg Nitrendipine 10 mg þ1.5/þ0.6 0.75 (0.58 to 0.97) .026
ACCOMPLISH 2008 11 506 Amlodipine 5-10 mg plus
benazepril
Hydroclorothiazide 25 mg
plus benazepril
0.9/1.1 0.84 (0.65 to 1.08) .17
Abbreviations: nr, not reported; ACEI, angiotensin-converting enzyme; CCB, calcium channel blockers; BB, beta-blockers.
a
In the Syst-Eur,
37
STOP Hypertension-2,
38
INSIGHT,
39
SHELL,
40
NORDIL,
41
CONVINCE,
42
FEVER,
59
ALLHAT,
44
ASCOT-PBPLA,
43
ACCOMPLISH,
45
SCOPE
(49) and VALUE
60
trials, number of events included fatal and non-fatal stroke; in the INVEST trial,
61
number of events included non-fatal stroke; in the MOSES
study,
62
number of events included fatal and nonfatal stroke and recurrent events.
b
Adapted from Reference
14
.
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Even in the Systolic Hypertension in the Elderly (SHELL)
trial,
40
which enrolled patients aged older than 60 years with
stage 1 to 2 hypertension (as defined for systolic BP more than
160 mmHg and diastolic BP more than 95 mm Hg) randomly
assigned to receive an antihypertensive treatment based on the
CCB or the diuretic, no difference in any cardiovascular or cer-
ebrovascular event and in total mortality was observed between
the 2 treatment groups. Substantial similar results were also
observed in other clinical trials, performed with nondihydropir-
idinic CCBs, such as in the Nordic Diltiazem Study (NOR-
DIL)
41
and in the Controlled Onset Verapamil Investigation
of Cardiovascular End-Points (CONVINCE) trial.
42
Calcium Channel Blockers, Hypertension,
and High Cardiovascular Risk: Lessons From
Large Randomized Clinical Trials
Several international, randomized, controlled clinical trials have
tested the antihypertensive efficacy, safety and tolerability of
CCB-based therapy in patients with hypertension at high or very
high cardiovascular risk. The results of these trials have consis-
tently and independently confirmed the greater efficacy of CCBs
in lowering BP levels and reducing incidence of major cardio-
vascular events compared to either diuretics or b-blockers and
substantial equivalence to RAS-blocking agents (Table 4).
The International Verapamil-Trandolapril Study (INVEST)
61
was a randomized, open-label, clinical trial, which enrolled
patients aged 50 years or older, with hypertension and coron-
ary artery disease. Patients were randomly assigned to receive
a nondihydropiridinic CCB or a b-blocker. After a 2-year
follow-up and in the presence of similar BP reductions, no
significant difference was observed between the 2 treatment
regimens in terms of main cardiovascular outcomes, includ-
ing fatal and nonfatal stroke.
42
The Felodipine Event Reduction (FEVER) trial
59
was a
prospective, double-blind, parallel group, placebo-controlled,
randomized clinical trial, which enrolled patients aged 50 to
79 years, with 1 or 2 additional cardiovascular risk factors or
disease. Patients, whose BP levels remained uncontrolled after
6-week therapy based on thiazide diuretic, were randomly
assigned either to CCB or to placebo. In the presence of a small
difference in BP levels, the primary end point (fatal and nonfa-
tal stroke) was significantly reduced in the felodipine compared
to the placebo group. Among secondary end points, all cardio-
vascular events were reduced by 27%(P< .001), all cardiac
events by 35%(P¼.012), death by any cause by 31%(P¼
.006), coronary events by 32%(P¼.024), heart failure by
30%(P¼.239), and cardiovascular death by 33%(P¼
.019) were reduced in active compared to placebo group.
The Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT),
44
was a double-blind,
active-controlled, randomized clinical trial, which enrolled
patients, aged 55 years or older, with a history of hypertension
and at least 1 additional vascular risk factor. Patients were ran-
domly assigned to receive thiazide diuretic, CCB, ACE
inhibitor, or a-blocker in a setting of general practice for
planned follow-up of approximately 4 to 8 years. At the end
of the follow-up period, systolic BP levels were significantly
higher in the amlodipine (þ0.8 mm Hg, P¼.03) and lisinopril
(þ2 mm Hg, P< .001) groups compared with chlorthalidone,
whereas diastolic BP was significantly lower with amlodipine
(0.8 mmHg, P< .001 for both comparisons). These BP differ-
ences, however, were paralleled with no differences between
treatment groups for the incidence of the primary composite
end point as well as for that of all-cause mortality.
The Anglo-Scandinavian Cardiac Outcomes Trial – Blood
Pressure Lowering Arm (ASCOT-BPLA) was a prospective,
randomized, clinical trial, which enrolled patients with hyperten-
sion and at least 3 cardiovascular risk factors.
43
Patients were
randomized to either a CCB-based regimen or a b-blocker-
based regimen.
43
Compared with the atenolol-based regimen,
BP values were lower throughout the follow-up in those patients
allocated to the amlodipine-based regimen. In particular, these
differences were largest (5.9/2.4 mm Hg) at 3 months, and the
average difference throughout the study was 2.7/1.9 mm Hg.
By the end of the trial, about 53%patients had reached both the
systolic and the diastolic BP targets, and about 78%were taking
at least 2 antihypertensive agents. This trial (originally powered
for an estimated 1150 primary end points) was prematurely
stopped when only 903 primary end points had occurred. Thus,
the primary end point of fatal cardiovascular disease and nonfa-
tal myocardial infarction was not achieved (HR 0.90 [95%CI:
0.79-1.02]; P¼.1052). However, when the components of
the primary and secondary end points were considered, the
amlodipine-based regimen was consistently better than the com-
parator, by significantly reducing all-cause mortality by 11%
(P¼.0247), cardiovascular mortality by 24%(P¼.0010),
total cardiovascular events and procedures by 16%(P<
.0001), total coronary end points by 13%(P¼.0070), fatal
and nonfatal stroke by 23%(P¼.003) as compared to the
atenolol/thiazide regimen. Also, amlodipine-based regimen
significantly reduced incidence of new-onset diabetes by
30%(P< .0001) compared to the atenolol-based regimen.
Two additional trials have tested the clinical efficacy and
safety of CCB-based compared to ARB-based regimen in
patients with hypertension at high cardiovascular risk.
The Valsartan Antihypertensive Long-term Use Evaluation
(VALUE) trial
60
was a prospective, multinational, double-
blind, randomized, active-controlled, parallel group trial,
which enrolled high-risk patients aged 50 years or older, with
a history of hypertension and predefined combinations of car-
diovascular risk factors or cardiovascular diseases. Patients
were randomly assigned to valsartan-based regimen or to
amlodipine-based regimen during a mean follow-up period of
4.2 years.
60
As observed for the ASCOT-BPLA,
63
even in this
trial the amlodipine-based regimen induced greater BP reduc-
tions than valsartan-based regimen throughout the study, and
especially during the first 6 months of the follow-up, during
which the highest frequency of cardiovascular events, includ-
ing stroke, was recorded. Authors interpreted the slightly
reduced incidence of fatal and nonfatal stroke observed in the
Tocci et al 7
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amlodipine group compared to the valsartan group as a conse-
quence of these BP differences.
60
Subsequent analysis of the
study population, stratified according to the same degree of
BP reductions in both treatment groups, seems to confirm sim-
ilar beneficial effects provided by both ARB-based and CCB-
based therapy in terms of cardiovascular protection and
reduced incidence of cerebrovascular events, mostly stroke.
64
The MOrbidity and mortality after Stroke—Eprosartan
compared with nitrendipine in Secondary prevention (MOSES)
trial
62
enrolled patients with hypertension having a history of
cerebrovascular events. Patients were randomized to either
ARB or CCB.
62
In the presence of comparable BP reductions,
the eprosartan-based regimen reduced the incidence of the pri-
mary composite end point, including cardiovascular and cere-
brovascular events and noncardiovascular death, significantly
more than the nitrendipine group.
62
However, no significant
differences were observed between 2 treatment groups in terms
of incidence of cerebrovascular events.
62
More recently, the Avoiding Cardiovascular Events through
Combination Therapy in Patients Living with Systolic Hyperten-
sion (ACCOMPLISH) trial
45
was a double-blind, randomized
clinical trial, which enrolled patients with hypertension at high
cardiovascular risk. Patients were randomized to receive a
first-line combination therapy based on the association of the
ACE inhibitor plus either the CCB amlodipine or the thiazide
diuretic hydrochlorothiazide once daily.
45
Even in this case,
the trial course was terminated early after a mean follow-up
of 36 months because of the documented superior efficacy
of benazepril plus amlodipine compared with benazepril plus
hydrochlorothiazide.
45
At the time of trial interruption, com-
bination therapy with benazepril-amlodipine significantly
reduced the incidence of both primary (hazard ratio [HR]
0.80, [95%confidence interval, CI: 0.72 to 0.90]; P< .001)
and secondary (HR 0.79, [95%CI: 0.67 to 0.92]; P¼.002)
end points compared to combination therapy with benaze-
pril-hydrochlorothiazide.
45
Conclusions
In conclusion, the benefits obtained by achieving effective and
persistent BP control in patients with hypertension having dif-
ferent cardiovascular risk profile in terms of reduction in cardi-
ovascular morbidity and mortality have been repeatedly
demonstrated. Despite such solid evidence, large international
surveys still document persistently low rates of BP control in
the general population with hypertension. The relatively low
use of combination therapy and the lack of drug dosage optimi-
zation during chronic antihypertensive treatment represents 2
of the plausible reasons for this paradox.
Antihypertensive strategy based on the use of dihyropyridi-
nic CCBs, both in monotherapy and in combination therapy
with drugs inhibiting the RAS and/or thiazide diuretics, have
demonstrated that this approach may significantly contribute
to improvement in BP control in the presence of a good toler-
ability profile. In particular, fixed combination therapies based
on RAS-blocking agents and CCBs have proven to be effective
and safe in different clinical settings over the cardiovascular
and renal continuum. Hence, this strategy could be viewed as
a viable way to improve BP control rates in general outpatients
with hypertension and to ensure effective and sustained BP
control over the 24 h.
On the basis of the currently available clinical evidence, this
strategy is particularly indicated for elderly patients with iso-
lated systolic hypertension, in patients with hypertension hav-
ing metabolic disorders (dyslipidemia, metabolic syndrome,
hyperuricemia),in those with diabetes mellitus, and in those
with renal impairment or diabetic nephropathy.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship,
and/or publication of this article.
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10 Journal of Cardiovascular Pharmacology and Therapeutics
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... These i n c l u d e C i l n i d i p i n e , L a c i d i p i n e , Felodipine, Lercanidipine, Isradipine, N i s o l d i p i n e , N i c a r d i p i n e a n d Benidipine. 8,9 Cilnidipine is a newer member of the calcium channel blocker family, which blocks N-type calcium channels as well as L-type calcium channels. This N-type channel blockade can be used as a fresh approach to treat cardiovascular disease. ...
... Thus the measurement of uric acid levels could be possibly used as a marker of oxidative stress in patients with sepsis. 9,10 We conducted the present study to find association of hyperuricemia with severity of disease and outcome in patients of scrub typhus. ...
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Full-text available
Background: Cilnidipine, an upcoming anti-hypertensive drug, is a combined Land N-type calcium channel blocker. It is proposed to be more efficacious and safer due to its two-pronged approach in treating hypertension. Methods: The study was a randomized open-label parallel-group study, conducted in the Department of General Medicine, Sri Ramachandra Medical College Hospital, Chennai, during the period September 2014 to May 2015. 50 patients were randomized to the amlodipine group and 50 to the cilnidipine group. The blood pressure, pulse rate and adverse effects were monitored in each patient over 12 weeks. The difference in the Systolic Blood Pressure(SBP), Diastolic Blood Pressure(DBP) and Heart Rate(HR) before and after treatment within each group, and between the two groups were analyzed using paired and unpaired t tests respectively. The adverse effects reported in each group were analyzed using Chi-square test. Results: There was no statistically significant difference in the reduction of SBP and DBP between the two groups (p>0.05). The HR however, showed an increase of 1.07/min in the amlodipine group and decreased by 1.16/min in the cilnidipine group. The patients in the cilnidipine group experienced significantly less adverse effects such as pedal edema and palpitations when compared to those in the amlodipine group (p<0.05). Conclusions: Cilnidipine therapy is an effective and safe alternative in the treatment of essential hypertension. It can be used as a first line antihypertensive drug since its efficacy is comparable to that of amlodipine with a better safety profile than amlodipine.
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... Among them, an increase in intracellular calcium ion (CA 2+ ) concentration can directly influence VSMCs. And calcium channel blockers (CCBs), which are widely used in clinical settings, are to reduce intracellular calcium concentration in SMCs (14) and thus controlling BP. The nitric oxide (NO)-nitric oxide-sensitive guanylate cyclase (NOsGC)-cGMP pathway is also a well-studied pathway that is closely related to the contractile function of VSMCs. ...
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... CCBs, also called calcium channel antagonists, have been widely used to treat hypertension for several decades [7]. This group of agents is often divided into two classes: non-dihydropyridines (e.g., verapamil and diltiazem) and dihydropyridines (e.g., nifedipine and amlodipine) (Fig. 1). ...
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The prevalence of hypertension and comorbidities such as metabolic syndrome, diabetes mellitus, and chronic kidney disease in India is alarmingly high. Amlodipine, an older-generation calcium channel blocker (CCB), is currently the gold standard for hypertension management in India. However, it has several disadvantages, including reflex tachycardia and pedal edema. Therefore, an effective antihypertensive agent that does not cause these adverse effects and provides end-organ protection is required for the holistic management of hypertension in the country. Azelnidipine is a new-generation CCB that has recently been approved for the treatment of hypertension in India. This review provides an overview of the utility of azelnidipine for hypertension control, including comparisons with traditional CCBs such as amlodipine. It discusses the key antihypertensive effects of azelnidipine as well as its advantages in the prevention of tachycardia and associated complications. In addition, this review highlights the extensive cardio- and renoprotective activities of azelnidipine, including its effects on systolic and diastolic function and urinary albumin excretion. Overall, this substantial body of evidence supports the use of azelnidipine for the treatment of hypertension, especially in India. It suggests that the adoption of azelnidipine as the new gold standard CCB could help India battle its hypertension epidemic.
... These compounds, such as propranolol, are commonly used combined with other drugs and their proposed mechanism of action includes heart rate and cardiac output reduction, renin release inhibition, venous return and plasma volume reduction and vascular compliance improvement, among others [140]. Furthermore, during recent decades, calcium channel blockers (amlodipine, felodipine, isradipine) have been widely used (monotherapy or combined therapy) because of their good tolerability by hypertensive patients and their effectiveness in reducing BP via blocking calcium entry into cardiovascular cells and thus triggering a vasodilator effect [141]. Moreover, different diuretic drugs are used in several cases of HTN, acting in several areas of nephrons. ...
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Hypertension (HTN) is one of the main cardiovascular risk factors and is considered a major public health problem. Numerous approaches have been developed to lower blood pressure (BP) in hypertensive patients, most of them involving pharmacological treatments. Within this context, natural bioactive compounds have emerged as a promising alternative to drugs in HTN prevention. This work reviews not only the mechanisms of BP regulation by these antihypertensive compounds, but also their efficacy depending on consumption time. Although a plethora of studies has investigated food-derived compounds, such as phenolic compounds or peptides and their impact on BP, only a few addressed the relevance of time consumption. However, it is known that BP and its main regulatory mechanisms show a 24-h oscillation. Moreover, evidence shows that phenolic compounds can interact with clock genes, which regulate the biological rhythm followed by many physiological processes. Therefore, further research might be carried out to completely elucidate the interactions along the time–nutrition–hypertension axis within the framework of chrononutrition.
... Heart failure (HF) is a chronic condition that results from any structural or functional cardiac disorders, leading to reduced cardiac output. 1,2 The prevalence of HF is increasing and despite advances in pharmacotherapy, the disease is still associated with high morbidity and mortality. 3,4 A developing body of evidence suggests that mediators involved in the control of myocardial function and vascular tone may contribute to the pathophysiology of HF. ...
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Background: Mebudipine, a dihydropyridine calcium-channel blocker (CCB), shows greater time- and voltage-dependent inhibitory effects than nifedipine. Its significant negative chronotropic effects without having considerable negative inotropic properties may make it a suitable candidate for the pharmacotherapy of heart failure (HF). This study aimed to investigate the possible beneficial action of mebudipine in a rat model of HF. Methods: The present study carried out in the Department of Pharmacology at the Iran University of Medical Sciences during the years of 2009-2011. An experimental model of HF was induced in male Wistar rats using doxorubicin (DOX). The rats were divided into five groups with seven animals in each group: normal control group, DOX-induced HF control groups, and treatment groups. The animals were administered DOX for 15 days. A consistent deterioration occurred after a four-week rest period. The animals were then treated with intraperitoneal mebudipine (0.5 mg/kg) and intraperitoneal amlodipine (0.35 mg/kg), as well as an equal volume of distilled water for 15 days. The plasma levels of big endothelin-1 (BET-1), creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), as well as the clinical status (heart rate and blood pressure), were assessed before and after treatment. Statistical analysis was performed with SPSS software using parametric and nonparametric ANOVA. Results: Mebudipine and amlodipine reversed the increased plasma BET-1 values in the treated animals when compared with the HF control group (0.103 and 0.112 vs 0.231 pg/mL, respectively). The increased plasma levels of AST, ALT, CK-MB, and LDH were also reversed in the HF animals that received mebudipine or amlodipine. Conclusion: The administration of mebudipine to HF animals, akin to amlodipine, palliated the clinical and biochemical signs of the disease in the present study. The abstract was presented in the Iranian Congress of Physiology and Pharmacology as a poster and published in the Scientific Information Database as a supplement (2015; Vol 22).
... This is the most common chronic disease [1] and it is commonly treated using synthetic chemical drugs. The classifications of drugs commonly used for hypertension therapy include angiotensin II receptor blockers (ARBs), angiotensin-I-converting enzyme (ACE) inhibitors, [2] combined ARBs and ACE-inhibitors, [3] diuretics, [4] beta-blockers, [5] calcium channel blockers, [6] alphaadrenergic receptor agonists, [7] combined alpha-and beta-blockers, [8] inhibitors of renin, [9] vasodilators, [10] and others. ACE inhibitors are the most widely used type of antihypertensive drugs after diuretics. ...
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Hypertension is a condition, in which a patient’s systolic blood pressure reaches ≥140 mmHg and/or the diastolic blood pressure reaches ≥90 mmHg. The disease is generally treated using synthetic chemical drugs such as angiotensin- converting enzyme (ACE) inhibitors. In Indonesia, especially the island of Java, people often use medicinal plants called Jamu (herbs) to treat hypertension. One of the most often used medicinal plants to treat hypertension is cantaloupe (Cucumis melo var. cantalupensis) or Blewah in Javanese. However, thus far, the mechanism of how cantaloupe reduces blood pressure is still unknown. Materials and Methods: This research aimed to investigate the working mechanism of cantaloupe in reducing blood pressure through an in silico approach. Results: An enzyme activity analysis showed that the methanol extract from cantaloupe inhibited the activity of ACE in a dose-dependent manner. Moreover, the mapping analysis of the interaction between the bioactive compounds and their target proteins, using the STITCH and STRINGdb databases, suggested that L-glutathione (GSH) (reduced) interacted with proteins that are members of the superfamily of GSH S-transferase (GST). Conclusion: This protein family acts in detoxification and radical scavenging. Thus, the possible working mechanism of cantaloupe in reducing blood pressure is through the detoxification and radical scavenging pathways by GST.
... The relationship between hypertension and intracellular calcium concentration has been confirmed by a large number of experiments [4][5][6][7]. Therefore, changes in the function of calcium channel proteins, which have a regulatory effect on intracellular calcium concentration, may be closely related to the abnormal changes in blood pressure and the development of hypertension. ...
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Background : Abnormal calcium homeostasis related to the development of hypertension. As the key regulator of intracellular calcium concentration, voltage-gated calcium channels (VDCCs), the variations in these genes may have important effects on the development of hypertension. Here we evaluate VDCCs variability with respect to hypertension in the Dai ethnic group of China. Methods : A total of 1034 samples from Dai individuals were collected, of which 495 were used as cases, and 539 were used as controls. Blood pressure was measured using a standard mercury measurement method, three times with a rest for 5 min, and the average was used for analyses. Seventeen single nucleotide polymorphisms (SNPs) in the four protein-coding genes ( CACNA1A, CACNA1C, CACNA1S, CACNB2 ) of VDCCs were identified by multiplex PCR-SNP typing technique. Chi-square tests and regression models were used to analyse the associations of SNPs with hypertension. Results: The results of chi-square tests showed that the allele frequencies of 5 SNPs were significantly different between the case and the control groups (P
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Introducción: la hipertensión arterial sistémica (HTA) constituye el principal factor de riesgo para morbilidad y mortalidad cardiovascular a nivel global, afecta a todas las edades, sin distinción de género y etnicidad. Su tratamiento continúa constituyendo un reto, dada la persistencia del pobre control, especialmente en países como Colombia. Objetivo: mostrar la evidencia disponible respecto al tratamiento actualizado de la HTA y la elección certera de los agentes antihipertensivos acorde con la individualidad de cada paciente. Asimismo, consolidar y comparar el efecto hipotensor de cada agente antihipertensivo más usado. Metodología: se realizó una búsqueda avanzada con los términos DeCS y MeSH: hipertensión, agentes antihipertensivos, hipertensión esencial y terapia combinada, en los motores de búsqueda PubMed, Clinical Key, Lilacs, Scielo. Un total de 109 artículos se seleccionaron para elaborar en la presente revisión de la literatura. Conclusiones: la individualización del manejo de la HTA lleva al reconocimiento de los distintos fenotipos, la presencia de complicaciones, el examen físico, el género y la raza como puntos fundamentales para elegir el agente antihipertensivo más adecuado que permita alcanzar las metas de control y propenda por la reducción y prevención de las complicaciones derivadas de un control no óptimo.
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Context. Hypertensive patients are often given a calcium antagonist to reduce cardio-vascular disease risk, but the benefit compared with other drug classes is controversial. Objective. To determine whether initial therapy with controlled-onset extended- release (COER) verapamil is equivalent to a physician’s choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease. Design, Setting, and Participants. Double-blind, randomized clinical trial conducted at 661 centers in 15 countries. A total of 16602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31, 2000. After a mean of 3 years of follow-up, the sponsor closed the study before unblinding the results. Intervention. Initially, 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. Other drugs (eg, diuretic, beta-blocker, or an angiotensin-converting enzyme inhibitor) could be added in specified sequence if needed. Main Outcome Measures. First occurrence of stroke, myocardial infarction, or cardiovascular disease–related death. Results. Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 nomm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group. There were 364 primary cardiovascular disease–related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.88-1.18; P=.77). For fatal or nonfatal stroke, the HR was 1.15 (95% CI, 0.90-1.48); for fatal or nonfatal myocardial infarction, 0.82 (95% CI, 0.65-1.03); and for cardiovascular disease–related death, 1.09 (95% CI, 0.87-1.37). The HR was 1.05 (95% CI, 0.95-1.16) for any prespecified cardiovascular disease–related event and 1.08 (95% CI, 0.93-1.26) for all-cause mortality. Non-stroke hemorrhage was more common with participants in the COER-verapamil group (n=118) compared with the atenolol or hydrochlorothiazide group (n=79) (HR, 1.54[95% CI, 1.16-2.04]; P=.003). More cardiovascular disease–related events occurred between 6 AM and noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups; HR, 1.15 (95% CI, 0.86-1.53). Conclusions. The CONVINCE trial did not demonstrate equivalence of a COER verapamil–based antihypertensive regimen compared with a regimen beginning with a diuretic or beta-blocker. When considered in the context of other trials of calcium antagonists, these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or �beta-blocker treatment.
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The safety and tolerability of lacidipine was assessed in a volunteer population, and its pharmacodynamic and pharmacokinetic profiles evaluated. In nor-motensive subjects, single oral doses of 3-5 mg of lacidipine produced a dose-related fall in peripheral vascular resistance. This was accompanied by reflex-mediated increases in heart rate and cardiac output to maintain blood pressure. Adverse events were those typically related to the vasodilatory action of lacidipine. such as flushing and headache. A 4-mg dose of lacidipine elicited a cardiovascular response equivalent to that with 10 mg of nifedipine, given as a single oral dose. Lacidipine did not affect sinoatrial or atrioventricular conduction in the healthy subjects studied. Two specialized electrophysiologic studies in patients confirmed that lacidipine does not affect pacemaker tissue and that it exhibits relative selectivity for the vascular smooth muscle. Lacidipine is eliminated primarily by hepatic metabolism, and extensive first-pass loss occurs after oral dosing. Absolute bioavailability is less than 10%. The systemic availability of lacidipine was increased in healthy elderly subjects and in patients with impaired hepatic function, but not in patients with impaired renal function. Copyright
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The age-specific relevance of blood pressure to cause-specific mortality is best assessed by collaborative meta-analysis of individual participant data from the separate prospective studies. Methods Information was obtained on each of one million adults with no previous vascular disease recorded at baseline in 61 prospective observational studies of blood pressure and mortality. During 12.7 million person-years at risk, there were about 56 000 vascular deaths (12 000 stroke, 34000 ischaemic heart disease [IHD], 10000 other vascular) and 66 000 other deaths at ages 40-89 years. Meta-analyses, involving "time-dependent" correction for regression dilution, related mortality during each decade of age at death to the estimated usual blood pressure at the start of that decade. Findings Within each decade of age at death, the proportional difference in the risk of vascular death associated with a given absolute difference in usual blood pressure is about the same down to at least 115 mm Hg usual systolic blood pressure (SBP) and 75 mm Hg usual diastolic blood pressure (DBP), below which there is little evidence. At ages 40-69 years, each difference of 20 mm Hg usual SBP (or, approximately equivalently, 10 mm Hg usual DBP) is associated with more than a twofold difference in the stroke death rate, and with twofold differences in the death rates from IHD and from other vascular causes. All of these proportional differences in vascular mortality are about half as extreme at ages 80-89 years as at,ages 40-49 years, but the annual absolute differences in risk are greater in old age. The age-specific associations are similar for men and women, and for cerebral haemorrhage and cerebral ischaemia. For predicting vascular mortality from a single blood pressure measurement, the average of SBP and DBP is slightly more informative than either alone, and pulse pressure is much less informative. Interpretation Throughout middle and old age, usual blood pressure is strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold down to at least 115/75 mm Hg.
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Background The benefits of reducing blood pressure on the risks of major cardiovascular disease are well established, but uncertainty remains about the comparative effects of different blood-pressure-lowering regimens. We aimed to estimate effects of strategies based on different drug classes (angiotensin-converting-enzyme [ACE] inhibitors, calcium antagonists, angiotensin-receptor blockers [ARBs], and diuretics or P blockers) or those targeting different blood pressure goals, on the risks of major cardiovascular events and death. Methods We did seven sets of prospectively-designed overviews with data from 29 randomised trials (n=162 341). The trial eligibility criteria, primary outcomes, and main hypotheses were specified before the result of any contributing trial was known. Findings In placebo-controlled trials the relative risks of total major cardiovascular events were reduced by regimens based on ACE inhibitors (22%; 95% Cl 17-27) or calcium antagonists (18%; 5-29). Greater risk reductions were produced by regimens that targeted lower blood pressure goals (15%; 5-24). ARB-based regimens reduced the risks of total major cardiovascular events (10%; 4-17) compared with control regimens. There were no significant differences in total major cardiovascular events between regimens based on ACE inhibitors, calcium antagonists, or diuretics or P blockers, although ACE-inhibitor-based regimens reduced blood pressure less. There was evidence of some differences between active regimens in their effects on cause-specific outcomes. For every outcome other than heart failure, the difference between randomised groups in achieved blood pressure reduction was directly related to the observed difference in risk. Interpretation Treatment with any commonly-used regimen reduces the risk of total major cardiovascular events, and larger reductions in blood pressure produce larger reductions in risk.
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The benefits of reducing blood pressure on the risks of major cardiovascular disease are well established, but uncertainty remains about the comparative effects of different blood-pressure-lowering regimens. We aimed to estimate effects of strategies based on different drug classes (angiotensin-converting-enzyme [ACE] inhibitors, calcium antagonists, angiotensin-receptor blockers [ARBs], and diuretics or β blockers) or those targeting different blood pressure goals, on the risks of major cardiovascular events and death.