IVUS indicates intravascular ultrasound.
Over time, the SDs for systolic blood pressure ranged from 13.3 to 15.5
mm Hg for the amlodipine group, 15.6 to 16.5 mm Hg for the placebo group,
and 16.1 to 18.0 mm Hg for the enalapril group. The SDs for diastolic blood
pressure ranged from 8.4 to 9.5 mm Hg for the amlodipine group, 8.9 to 9.8
mm Hg for the placebo group, and 9.4 to 10.5 mm Hg for the enalapril group.
Box sizes indicate proportion of the total study population (ie, smaller
boxes have fewer patients relative to other subgroups).
The solid line represents the continuous relationship, surrounded by
the dashed lines representing 95% confidence intervals. LOWESS indicates locally
weighted scatterplot smoothing.
Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, Berman L, Shi H, Buebendorf E, Topol EJ, CAMELOT Investigators FT. Effect of Antihypertensive Agents on Cardiovascular Events in Patients With Coronary Disease and Normal Blood PressureThe CAMELOT Study: A Randomized Controlled Trial. JAMA. 2004;292(18):2217–2225. doi:10.1001/jama.292.18.2217
Author Affiliations: Department of Cardiovascular
Medicine, Cleveland Clinic Lerner School of Medicine, Cleveland, Ohio (Drs
Nissen, Tuzcu, and Topol); Brigham and Women’s Hospital, Boston, Mass
(Dr Libby); Department of Cardiology, Hartford Hospital, Hartford, Conn (Dr
Thompson); Department of Cardiology, Iowa Heart Center, Des Moines (Dr Ghali);
and Pfizer Inc, New York, NY (Drs Garza and Berman and Mr Shi and Ms Buebendorf).
Context The effect of antihypertensive drugs on cardiovascular events in patients
with coronary artery disease (CAD) and normal blood pressure remains uncertain.
Objective To compare the effects of amlodipine or enalapril vs placebo on cardiovascular
events in patients with CAD.
Design, Setting, and Participants Double-blind, randomized, multicenter, 24-month trial (enrollment April
1999-April 2002) comparing amlodipine or enalapril with placebo in 1991 patients
with angiographically documented CAD (>20% stenosis by coronary angiography)
and diastolic blood pressure <100 mm Hg. A substudy of 274 patients measured
atherosclerosis progression by intravascular ultrasound (IVUS).
Interventions Patients were randomized to receive amlodipine, 10 mg; enalapril, 20
mg; or placebo. IVUS was performed at baseline and study completion.
Main Outcome Measures The primary efficacy parameter was incidence of cardiovascular events
for amlodipine vs placebo. Other outcomes included comparisons of amlodipine
vs enalapril and enalapril vs placebo. Events included cardiovascular death,
nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization,
hospitalization for angina pectoris, hospitalization for congestive heart
failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis
of peripheral vascular disease. The IVUS end point was change in percent atheroma
Results Baseline blood pressure averaged 129/78 mm Hg for all patients; it increased
by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4
mm Hg in the amlodipine and enalapril groups, respectively (P<.001 for both vs placebo). Cardiovascular events occurred in 151
(23.1%) placebo-treated patients, in 110 (16.6%) amlodipine-treated patients
(hazard ratio [HR], 0.69; 95% CI, 0.54-0.88 [P = .003]),
and in 136 (20.2%) enalapril-treated patients (HR, 0.85; 95% CI, 0.67-1.07
[P = .16]. Primary end point comparison
for enalapril vs amlodipine was not significant (HR, 0.81; 95% CI, 0.63-1.04
[P = .10]). The IVUS substudy showed a
trend toward less progression of atherosclerosis in the amlodipine group vs
placebo (P = .12), with significantly less
progression in the subgroup with systolic blood pressures greater than the
mean (P = .02). Compared with baseline,
IVUS showed progression in the placebo group (P<.001),
a trend toward progression in the enalapril group (P = .08),
and no progression in the amlodipine group (P = .31).
For the amlodipine group, correlation between blood pressure reduction and
progression was r = 0.19, P = .07.
Conclusions Administration of amlodipine to patients with CAD and normal blood pressure
resulted in reduced adverse cardiovascular events. Directionally similar,
but smaller and nonsignificant, treatment effects were observed with enalapril.
For amlodipine, IVUS showed evidence of slowing of atherosclerosis progression.
Despite more than 30 years of clinical trials, uncertainty still exists
regarding the optimal use of antihypertensive drugs in patients with coronary
artery disease (CAD).1- 3 Several
classes of pharmacological agents have shown benefits in patients with CAD,
but most studies enrolled patients with an elevated or borderline blood pressure.
Recent clinical trials have demonstrated benefits for both angiotensin-converting
enzyme (ACE) inhibitors and calcium channel blockers in patients with CAD
with relatively normal or borderline blood pressures.4- 6
However, few studies have specifically targeted patients with angiographically
documented coronary obstructions and restricted enrollment to patients with
entry blood pressures significantly less than 140/90 mm Hg. Therefore, no
consensus exists regarding administration of antihypertensive drugs to normotensive
patients with CAD.7
Antihypertensive drugs have a variety of potentially beneficial properties
that might favorably affect cardiovascular event rates. We sought to address
these issues by studying the effects of antihypertensive drugs in patients
with CAD and customary blood pressure of less than 140/90 mm Hg. The Comparison
of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study
compared treatment using either of 2 classes of antihypertensive drugs, a
calcium channel blocker (amlodipine) and an ACE inhibitor (enalapril), with
placebo in normotensive patients with CAD. The primary end point was the time
to first occurrence of an adverse cardiovascular event. In addition, a subset
of patients underwent serial intravascular ultrasound (IVUS) to determine
if either or both agents exhibited antiatherosclerotic effects.
The CAMELOT study was a multicenter, double-blind, placebo-controlled
randomized trial involving 100 study sites in North America (United States
and Canada) and Europe. The institutional review boards of participating centers
approved the protocol and all patients provided written informed consent.
Men and women, aged 30 through 79 years, requiring coronary angiography for
evaluation for chest pain or percutaneous coronary intervention were eligible.
During a screening period, sitting and standing blood pressures were measured
using a manual cuff and stethoscope. Study eligibility required a diastolic
pressure lower than 100 mm Hg, with or without treatment. ACE inhibitors,
angiotensin receptor blockers, and calcium channel blockers were discontinued
over a 2- to 6-week period and were prohibited during the study (with the
exception of study medications). β-Blockers, α1-blockers,
and diuretics were permitted. Angiographic inclusion criteria required 1 or
more lesions in a native coronary artery with greater than 20% stenosis by
visual (angiographic) estimation. Patients with a left main coronary artery
obstruction greater than 50%, left ventricular ejection fraction (EF) less
than 40%, or moderate to severe congestive heart failure were excluded. Information
on race/ethnicity was collected via self-report by the patient. This information
was thought pertinent to the study because antihypertensive agents may have
different effects on different racial groups.
At 38 sites, an IVUS substudy was performed. Following diagnostic angiography,
ultrasound examination was performed in the longest and least angulated target
vessel meeting inclusion criteria. The “target vessel” for interrogation
must not have undergone angioplasty nor have a luminal narrowing of more than
50% throughout a segment with a minimum length of 30 mm. The IVUS procedure
has been described in detail previously.8,9 After
a 24-month treatment period, actively participating patients underwent repeat
IVUS of the originally imaged vessel.
All patients participated in a 2-week placebo run-in period. Patients
were instructed to take 1 placebo tablet and 1 placebo capsule daily (in the
morning) and return in 2 weeks. Patients demonstrating at least 80% compliance
by pill count were randomly assigned to 1 of the following combinations of
study medications: 1 amlodipine tablet (5 mg) plus 1 placebo enalapril capsule,
1 placebo amlodipine tablet and 1 enalapril capsule (10 mg), or 1 placebo
amlodipine tablet plus 1 placebo enalapril capsule. At the end of the second
week, if the initial dose level was tolerated, the participant was instructed
to double the daily dose of study medication. If during the treatment period
a participant was taking the full dose and experienced an intolerable adverse
effect believed to be related to the study drug, he/she was instructed to
take only 1 tablet and 1 capsule of study medication each day. Investigators
attempted to reinstitute the higher dose of study medication at a later date,
The patients and all study personnel were blinded to treatment assignment.
The randomization code was generated using a block size of 6 (stratified in
3 groups: no coronary intervention, stent placement, or non-stent intervention
at baseline). Patients participating in the IVUS substudy were separately
randomized in the same 3 strata.
All events were independently adjudicated by a blinded end point committee.
The primary outcome was the incidence of adverse cardiovascular events in
patients treated with amlodipine compared with placebo. Events included in
the end point were cardiovascular death, nonfatal myocardial infarction, resuscitated
cardiac arrest, coronary revascularization, hospitalization for angina pectoris,
hospitalization for congestive heart failure, fatal or nonfatal stroke or
transient ischemic attack (TIA), and any new diagnosis of peripheral vascular
disease. Secondary outcomes included the incidence of adverse events for enalapril
treatment compared with placebo and comparison of the amlodipine treatment
group with the enalapril group. Additional prespecified secondary end points
included all-cause mortality and the incidence of revascularization in vessels
that had undergone previous stent placement.
The end point for the IVUS substudy was the nominal change in percent
atheroma volume (PAV) for all slices of anatomically comparable segments of
the target coronary artery from baseline to month 24 visit calculated as follows:
PAV = [∑ (EEMarea−LCSarea)/ ∑ EEMarea] × 100
where EEM represents external elastic membrane area and LCS represents lumen
cross-sectional area. Nominal change in PAV = (PAV month 24 –
Baseline characteristics are reported as means (SDs) and percentages
with P values calculated by 1-way analysis of variance
(ANOVA) or χ2 test. Data were analyzed according to patients’
treatment assignments regardless of their subsequent medications (intent-to-treat
analysis). The log-rank test and Cox proportional hazards model were used
for the three 2-treatment comparisons (amlodipine vs placebo, enalapril vs
placebo, and amlodipine vs enalapril).
The IVUS results are reported as means (SDs). IVUS efficacy analysis
was tested using analysis of covariance (ANCOVA), adjusting for baseline values
and randomization strata as covariates. To further describe the bivariate
relationship between blood pressure and IVUS progression rates, the locally
weighted scatterplot smoothing (LOWESS) technique was used.10 This
technique is designed to produce a smooth fit to the data that also reduces
the influence of extreme outliers. Analyses were performed using SAS version
8.2 (SAS Institute Inc, Cary, NC). Statistical significance was set a priori
The study was originally powered at 90% for a sample size of 3000 patients.
However, enrollment progressed slowly following the publication of a clinical
trial suggesting a benefit for routine administration of ACE inhibitors to
high-risk patients.4 The data and safety monitoring
board observed a greater than anticipated rate of accumulation of events and
recommended that the steering committee reduce the sample size to 2000 patients
and power to 80%. The amended protocol assumed a dropout rate lower than 1%
and an incidence rate of adverse outcomes after 24 months of 0.229 for placebo
and 0.167 for amlodopine. Using the log-rank test, a sample size of 672 randomized
patients per treatment group was specified to provide 80% power to detect
a difference between the groups.
Between April 1999 and March 2004, 1997 patients, aged 32 to 82 years,
were randomized and 1856 completed the protocol (1991 included in the efficacy
analysis). The placebo group included 655 participants, the enalapril group
673, and the amlodipine group 663. Of the 1991 participants in CAMELOT, 274
completed the IVUS substudy: 95 in the placebo group, 88 in the enalapril
group, and 91 in the amlodipine group. The numbers of patients screened, randomized,
and reasons for discontinuation are reported in Figure 1. The baseline characteristics of patients included in efficacy
analyses are reported in Table 1. There
were no clinically meaningful differences in characteristics between treatment
Table 1 also shows the treatments
and concomitant medications for patients in the 3 treatment groups. Crossover
rates were low with 7.4% of amlodipine patients receiving an angiotensin-converting
enzyme (ACE) inhibitor, 1.7% receiving an angiotensin II receptor blocker
(ARB), and 6.1% of enalapril patients receiving a calcium channel blocker.
More patients in the placebo group received a calcium channel blocker, ACE
inhibitor, or ARB.
Figure 2 illustrates the mean
systolic and diastolic blood pressures for the 3 treatment groups. Mean sitting
blood pressure at baseline averaged 128.9/77.6 mm Hg in the placebo group,
128.9/77.2 mm Hg in the enalapril group, and 129.5/77.7 mm Hg in the amlodipine
group. The mean blood pressure during follow-up increased 0.7/0.6 mm Hg in
the placebo group and was reduced 4.8/2.5 mm Hg in the amlodipine group and
4.9/2.4 mm Hg in the enalapril group (P<.001 for
both vs placebo).
Amlodipine vs Placebo. Cardiovascular events
occurred in 151 (23.1%) patients in the placebo group and 110 (16.6%) in the
amlodipine group. Table 2 illustrates
the point estimates and 95% confidence intervals (CIs) for the primary end
point, individual components of this end point, and secondary end points.
The primary efficacy measure was reduced in the amlodipine group compared
with placebo, a hazard ratio (HR) of 0.69 (95% CI, 0.54-0.88, P = .003). The most frequent component of the primary end
point, coronary revascularization, was reduced in the amlodipine group from
15.7% to 11.8% (HR, 0.73; 95% CI, 0.54-0.98, P = .03).
Hospitalization for angina was reduced in the amlodipine group from 12.8%
to 7.7% (HR, 0.58; 95% CI, 0.41-0.82, P = .002). Figure 3 illustrates the cumulative event rates
for the primary composite end point for all 3 treatment groups.
Amlodipine vs Enalapril.Table 2 illustrates the comparisons between amlodipine and enalapril.
In comparison with enalapril, the primary end point was reduced in the amlodipine
group, from 20.2% to 16.6% (HR, 0.81; 95% CI, 0.63-1.04, P = .10). For components of the primary end point, only the
rate of hospitalization for angina showed a statistically significant difference
between amlodipine and enalapril (HR, 0.59; 95% CI, 0.42-0.84, P = .003). A trend toward fewer episodes of revascularization
in patients undergoing intervention at baseline was observed (HR, 0.66; 95%
CI, 0.40-1.06, P = .09).
Enalapril vs Placebo.Table 2 also illustrates the comparisons of enalapril with placebo.
Cardiovascular events were reduced from 23.1% to 20.2% of patients in the
enalapril treatment group (HR, 0.85; 95% CI, 0.67-1.07, P = .16). Individual components of the primary end point
and secondary end points generally showed fewer events with enalapril treatment,
but none of the comparisons reached statistical significance.
The outcomes for prespecified subgroups for the primary end point comparing
amlodipine with placebo are reported in Figure
4. Most point estimates showed similar HRs. There was no statistical
heterogeneity among subgroups.
Table 3 summarizes the IVUS results.
The mean (SD) change in PAV was 0.5% (3.9%) for amlodipine, 0.8% ( 3.7%)
for enalapril, and 1.3% (4.4%) for placebo. Comparison of amlodipine
with placebo showed a trend toward statistical significance (P = .12). Comparison of enalapril with placebo was not statistically
significant (P = .32). In the prespecified
subgroup with systolic blood pressure greater than the mean, the amlodipine
group showed significantly slower progression (0.2% [ 3.9%]) compared
with placebo (2.3% [ 4.7%]) (P = .02).
No treatment effects were evident in the subgroup with baseline blood pressure
below the mean. Paired analyses comparing change from baseline in each of
the treatment groups showed progression for placebo (P = .001),
a trend toward progression for enalapril (P = .08),
and absence of progression for amlodipine (P = .31).
Figure 5 shows the relationship
(LOWESS plots) between IVUS-derived progression rates and change in systolic
blood pressure for the combined drug treatment groups. Using linear regression
analysis, adjusting for baseline blood pressures, the correlation between
blood pressure reduction and progression rate was r = 0.19, P = .07 in the amlodipine group. In the enalapril
and placebo groups, there was no statistically significant correlation between
blood pressure reduction and progression rate.
The event rates for the more restrictive end point of all-cause mortality,
nonfatal myocardial infarction, and nonfatal stroke were also computed. The
event rate was 3.3% in the amlodipine group, 4.7% in the placebo group, and
3.4% in the enalapril group. Comparison of amlodipine vs placebo revealed
an HR of 0.70 (95% CI, 0.41-1.21; P = .20).
Comparison of enalapril vs placebo revealed an HR of 0.71 (95% CI, 0.41-1.21; P = .20). Comparing the combined treatment groups
(amlodipine or enalapril) vs placebo, the HR was 0.70 (95% CI, 0.45-1.11; P = .13). In the subgroup of patients with diabetes
at baseline, the primary composite end point occurred in 19.1% of amlodipine-treated
patients, 29.2% of placebo patients, and 29.7% of enalapril-treated patients
(amlodipine vs enalapril: HR, 0.58; 95% CI, 0.34- 0.99 [P = .04]).
Both active treatment regimens were well tolerated. Discontinuation
from the study for treatment-emergent adverse events was low, averaging 0.4%
and not statistically different between the 3 treatment groups. Discontinuations
of study drug for adverse events occurred in 13% of patients (Figure 1). Investigators reported hypotension in 3.3% of amlodipine-treated
patients, 3.2% of placebo patients, and 9.5% of enalapril-treated patients.
Peripheral edema occurred in 32.4% of amlodipine-treated patients, 9.6% of
placebo patients, and 9.5% of enalapril-treated patients. Amlodipine was discontinued
for edema in 5.0% of patients. Cough occurred in 5.1% of amlodipine-treated
patients, 5.8% of placebo patients, and 12.5% of enalapril-treated patients.
Enalapril was discontinued for cough in 3.9% of patients.
Recent studies have demonstrated benefits for both ACE inhibitors and
calcium channel blockers in patients with established CAD and relatively normal
blood pressures.3- 5 However,
the optimal strategy for administration of these agents to patients with CAD
has not been established. Most large hypertension trials restricted enrollment
to patients with blood pressures higher than 140/90 mm Hg, and few trials
studied patients with angiographically documented CAD.1- 3 Strong
epidemiological data suggest that the lowest cardiovascular event rates occur
in patients with systolic blood pressures much lower than the current treatment
guidelines.7,11 The CAMELOT trial
was designed to determine whether either or both of these 2 therapeutic approaches
would reduce adverse cardiovascular events in patients with CAD and a “normal”
blood pressure by current standards.
The results of this study showed a relatively large treatment effect
for the primary efficacy measure. For patients with a baseline systolic blood
pressure averaging only 129/78 mm Hg, amlodipine reduced blood pressure an
average of 5/3 mm Hg and produced a 31% relative reduction (6.5% absolute
reduction) in cardiovascular events (P = .003).
The number needed to treat for amlodipine is 16, ie, for every 16 patients
who receive amlodipine, there will be on average 1 adverse cardiovascular
event avoided during the 2-year period compared with patients who receive
placebo. The most frequent component of the primary end point, need for revascularization,
was reduced by 27.4% (absolute reduction, 3.9%). Amlodipine treatment reduced
hospitalization for angina by 42.2% (absolute reduction, 4.1%), nonfatal myocardial
infarction by 26% (absolute reduction, 0.8%), and stroke or TIA by 50.4% (absolute
reduction, 0.9%) (Table 2). Importantly,
the improved clinical outcome was observed in the setting of optimal treatment
of lipids (a mean baseline low-density lipoprotein cholesterol level of approximately
100 mg/dL [2.59 mmol/L]) and very high use of concomitant therapies such as
aspirin (95%), statins (83%), and β-blockers (76%) (Table 1).
Enalapril treatment also reduced blood pressure by an average of 5/2
mm Hg. However, the observed 15.3% relative reduction (2.9% absolute reduction)
in events was not statistically significant. None of individual components
of the composite end point reached statistical significance; however, most
event rates (Table 2) showed directional
changes favoring enalapril treatment compared with placebo.
The mechanism of action of amlodipine in reducing events in patients
with CAD remains uncertain. Two mechanisms seem likely. Since the most frequent
component of the composite outcome was coronary revascularization, the anti-ischemic
properties of amlodipine may have played an important role. Amlodipine is
approved for treatment of angina.12 Conceivably,
a reduction in ischemic chest pain may have prevented hospitalization and
subsequent revascularization procedures. Although enalapril produced similar
blood pressure reductions, it is not approved for treatment of angina, which
may explain its smaller effect on the primary end point. Alternatively, blood
pressure reduction may have contributed to the observed benefits. Supporting
the importance of antihypertensive effects is the observation of a relative
risk reduction similar to the primary outcome for the composite of all-cause
mortality, myocardial infarction, and stroke—end points not likely driven
by antianginal efficacy. Furthermore, in the IVUS substudy, for patients with
systolic blood pressures greater than the mean, amlodipine treatment significantly
slowed atherosclerosis progression. A continuous relationship between reductions
in blood pressure and atherosclerotic progression was observed in the LOWESS
plot for the combined amlodipine and enalapril treatment groups.
The blood pressures in the current trial are, to our knowledge, the
lowest ever studied in a major trial of antihypertensive drug therapy, averaging
only 124 mm Hg during active treatment. The 2 trials using ACE inhibitors
in patients with vascular disease studied patients with initial blood pressure
values approximately 10 mm Hg higher than those in the current study.4,5 In CAMELOT, although initial blood
pressures appeared “normal,” a 5/3-mm Hg decrease in blood pressure
during amlodipine treatment was accompanied by a 31% relative reduction in
morbidity. Although we cannot directly attribute the observed reduction in
cardiovascular events to blood pressure reduction, these findings suggest
the possibility that current target levels for blood pressure are too high
for patients with established CAD. Our findings support the hypothesis that,
even within the normal range, blood pressure represents a continuous risk
factor for adverse cardiovascular outcomes. Although we consider the current
findings important, we acknowledge that our findings are insufficient to recommend
routine administration of antihypertensive agents to all “normotensive”
patients with CAD without further confirmatory trials.
The IVUS substudy provides useful insights into potential mechanisms
of benefit of antihypertensive treatments in a CAD population (Table 2). A trend toward reduced progression was evident for the
amlodipine group compared with placebo (P = .12).
However, in the subgroup with baseline blood pressures above the mean, significant
reduction in progression was observed in the amlodipine group compared with
placebo (P = .02). Furthermore, paired
analysis of each regimen compared with baseline revealed progression in the
placebo group (P<.001) and no progression in either
the amlodipine or enalapril treatment groups (Table 3). The LOWESS plot shows a continuous relationship between
reduction in blood pressure and IVUS-derived progression rates (Figure 5). Linear regression analysis also provides evidence of
a relationship for the amlodipine treatment group. Although not definitive,
the current study provides the first clinical trial evidence that reduction
in blood pressure may decrease progression of coronary atherosclerosis.
The reduction in clinical events with amlodipine, but not enalapril,
will be surprising to many. The value of ACE inhibitors in patients with CAD
has received considerable attention following publication of 2 trials showing
benefits in patients with evidence of vascular disease.4,5 Both
sets of investigators concluded that the benefits observed were unlikely due
to antihypertensive effects of the tested agents, ramipiril and perindopril.
However, neither trial included a treatment group assigned a non–ACE
inhibitor antihypertensive agent. Accordingly, it was difficult to assess
whether the apparent benefits of ACE inhibition were drug-specific or merely
a reflection of the impact of blood pressure reduction. The CAMELOT study
deliberately included both an ACE inhibitor group and calcium channel blocker
group to further elucidate the relative benefits of these 2 therapeutic strategies
in normotensive patients with CAD. It should be recognized that post hoc analysis
using the more restrictive “hard” combined end point of death,
myocardial infarction, and stroke showed comparable reductions using either
The current study is consistent with other recent clinical trials that
failed to show superior outcomes for antihypertensive agents that modulate
the renin angiotensin system. The Antihypertensive and Lipid Lowering to Prevent
Heart Attack Trial (ALLHAT) showed similar event reduction with lisinopril,
diuretic, and amlodipine therapy.13 The Valsartan
Antihypertensive Long-term Use Evaluation (VALUE) study showed smaller reduction
in blood pressure and less decrease in early events for valsartan compared
However, unlike VALUE and ALLHAT, the current study observed nearly
identical blood pressure reductions in the ACE inhibitor and amlodipine groups.
Amlodipine has a 50-hour half-life, resulting in nearly constant blood pressure
reduction, whereas enalapril has an 11-hour half-life.15 The
current study measured blood pressure during the daytime clinic visits and
may have underestimated nighttime and early morning differences. Since many
coronary events occur in the early morning hours, just prior to awakening,
the continuous effects of amlodipine may have proven advantageous. It is also
possible that twice-daily administration of enalapril might have improved
outcomes in this treatment group, resulting in similar benefits to amlodipine.
A recent study of sustained-release nifedipine failed to show similar benefits.16 However, amlodipine has additional biological effects
not mediated through blood pressure reduction, including antioxidant activity,
inhibition of smooth muscle cell proliferation, and enhancement in endothelial
nitric oxide production.17 Some of these pleiotropic
effects are not shared with all other calcium channel blockers.17
We are cognizant of the limitations of the current study. The sample
size, approximately 2000 patients, was modest and the CIs around the point
estimates for event reductions are relatively large. The application of an
extended composite end point, rather than the narrower end point of cardiovascular
death, nonfatal myocardial infarction, and stroke, is a potential weakness.
However, in recent years, addition of hospitalization for angina and/or revascularization
to the composite end point has become increasingly common.6,18 There
is a reasonable rationale for using a broader end point. Hospitalization for
chest pain and revascularization are undesirable outcomes for patients and
consume substantial health care resources. Because the current study planned
to enroll patients with “normal” blood pressures and appropriate
concomitant therapies, use of a narrow end point would have required a prohibitively
large sample size and longer treatment exposure. Nonetheless, clinical trials
are always more convincing when powered for the traditional narrower end point
of death, myocardial infarction, and stroke.
Despite these limitations, the current study provides important new
findings regarding the administration of antihypertensive agents to patients
with CAD and a “normal” blood pressure. In patients with CAD treated
with a “standard of care” regimen including high rates of statin
and aspirin use, addition of amlodipine for 24 months resulted in a 31% relative
reduction and a 5.6% absolute reduction in adverse cardiovascular outcomes.
In the amlodipine treatment group, the IVUS substudy provides evidence of
a relationship between the magnitude of blood pressure reduction and the rate
of disease progression. These results suggest that the optimal blood pressure
range for patients with CAD may be substantially lower than indicated by current
guidelines. Accordingly, larger and perhaps longer-term studies of antihypertensive
therapies in patients with CAD and a “normal” blood pressure are
essential to further explore these potential benefits.
Corresponding Author: Steven E. Nissen,
MD, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500
Euclid Ave, Cleveland, OH 44195 (firstname.lastname@example.org).
Author Contributions: Dr Nissen had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Nissen, Tuzcu, Garza,
Acquisition of data: Nissen, Tuzcu, Thompson,
Ghali, Garza, Shi, Buebendorf, Topol.
Analysis and interpretation of data: Nissen,
Tuzcu, Libby, Garza, Berman, Shi, Topol.
Drafting of the manuscript: Nissen, Tuzcu,
Thompson, Garza, Berman, Buebendorf, Topol.
Critical revision of the manuscript for important
intellectual content: Nissen, Tuzcu, Libby, Thompson, Ghali, Garza,
Statistical analysis: Nissen, Thompson, Berman,
Obtained funding: Nissen, Tuzcu, Thompson.
Administrative, technical, or material support:
Nissen, Tuzcu, Thompson, Garza, Berman, Buebendorf, Topol.
Study supervision: Nissen, Tuzcu, Libby, Thompson,
Garza, Berman, Topol.
Steering Committee: E. J. Topol, MD, Cleveland
Clinic, Ohio; B. Pitt, MD, University of Michigan, Ann Arbor; D. Hunninghake,
MD, Minneapolis, Minn; C. O’Connor, MD, Duke University, Durham, NC.
IVUS Substudy Steering Committee: S. E. Nissen,
MD, Cleveland Clinic, Cleveland, Ohio; P. Libby, MD, Brigham and Women’s
Hospital, Boston, Mass; E. Murat Tuzcu, MD, Cleveland Clinic, Cleveland, Ohio;
R. Waksman, MD, Washington Hospital Center, Washington, DC.
Data and Safety Monitoring Board: C. H. Hennekens,
MD, University of Florida, Boca Raton; B. G. Brown, MD, PhD, University of
Washington, Seattle; T. Fleming, PhD, University of Washington, Seattle; D.
O’Leary, MD, New England Medical Center, Boston, Mass.
End Point Adjudication Committee: A. B. Miller,
MD, Jacksonville, Fla; R. Nesto, MD, Boston, Mass; G. Vetrovec, MD, Richmond,
Va; R. DiBianco, MD, Washington, DC; J. Abrams, MD, Albuquerque, NM.
IVUS Core Laboratory: T. Churchill, J. Coughlin,
T. Crowe, D. Hansen, A. Loyd, W. Magyar, P. Schoenhagen, MD, P. Shalling,
C. Werle, B. Wong, J. Zhitnik.
CAMELOT Investigators (by country):Canada: *Laurel Cardiology, Vancouver (D. Ricci, MD); *Montreal Heart
Institute, Montreal (J. Tardif, MD).
France: Groupe Hospitalier Cochin, Paris (S.
Weber, MD); Unite d Hemodinamique et di Cardiologie Interventionnell, Cretiel
(Prof P. Dupuoy); Hospital Cardiologique, Lyon (Prof M. Ovize).
Germany: *Essen University Clinic, Essen (D.
Italy: *Ospedale San Raffaele, Milan (C. DiMario,
MD, F. Arinoldi, MD). *Ospedale San Martino Di Genova, Genova (F. Miccoli,
MD, G. Terzi, MD); *Ospedale San Giovanni–Addolorata, Rome (F. Prati,
MD); *Istituto Clinico Humanitas, Rozzano (P. Presbitero, MD); Divisone di
Cardiolgia–Policlinico Universita Federico II, Napoli (Prof M. Chiariello);
Policlinico Universita Divisone di Cardiolgia, Palermo (Prof E. Hoffman);
*Azienda Osedaliera Deparmento Malatti Cardiovascolari, Siena (Prof A. Bravi).
United States: Alabama:
*University of Alabama, Birmingham (J. Canto, MD, V. K. Misra, MD); Heart
Center, Huntsville (W. H. Haught, MD). Arizona: University
Medical Center Cardiology, Tucson (P. Fenster, MD); Affiliated Cardiologists
of Arizona, Phoenix (N. Laufer, MD); Maricopa Medical Center Cardiology Services,
Phoenix (R. Patel, MD, R. Asher, MD, E. Zavala-Alarcon, MD); Desert Cardiology
of Tucson, Tucson (M. Jerman, MD); Southern Arizona VA Health Care System,
Tucson (D. Morrison, MD); Phoenix Heart, PLLC Cardiovascular Center (F. Cucher,
MD). Arkansas: Heart Center Arkansas, Little Rock
(S. W. Hutchins, MD); Sparks Regional Medical Center, Fort Smith (J. Schwarz,
MD, E. Rivera, MD); *St Edward Mercy Medical Center, Clinical Research, Fort
Smith (R. D. Foreman, DO). California: *San Diego
VA Medical Center, San Diego (W. F. Penny, MD); *San Diego Cardiovascular
Associates, San Diego (G. W. Dennish, MD); *Huntington Memorial Hospital,
Pasadena (J. Heger, MD); Los Angeles Cardiology Associates, Los Angeles (T.
L. Shook, MD); San Diego Cardiac Center, San Diego (L. Favrot, MD, D. Marsh,
MD). Connecticut: Hartford Hospital, Hartford (P.
D. Thompson, MD). District of Columbia: *Washington
Hospital Center (R. Waksman, MD); George Washington University Medical Center
(J. Reiner, MD). Georgia: Atlanta Cardiology Group,
PC (K. McGrath, DO). Florida: *Florida Cardiovascular
Research, Atlantis (M. Lakow, MD); *Florida Cardiovascular Institute, Tampa
(F. Matar, MD); *University of Florida Health Center, Jacksonville (P. S.
Gilmore, MD); *Florida Heart Associates, Fort Myers (J. F. Butler, DO, M.
Rubin, MD); *MIMA Regional Research Associates, Melbourne (R. Vicari, MD);
Pharmquest Clinical Research, Leesburg (D. Lew, MD); Greater Fort Lauderdale
HeartGroup Research, Fort Lauderdale (A. L. Niederman, MD); Mediquest Research
Group Inc, Ocala (R. L. Feldman, MD); South Florida Research Group, LLC, Miami
(P. Seigel, MD); Watson Clinic, LLP, Lakeland (C. L. Simek, MD); Charlotte
Heart Group, Port Charlotte (M. Lopez, MD); Ocala Research Institute, Ocala
(R. Prashad, MD). Hawaii: St Francis Hospital, Honolulu
(S. Dacanay, MD). Illinois: *Rush-Presbyterian-St
Luke’s Medical Center, Chicago (R. J. Snell, MD); *Loyola University
Medical Center, Maywood(Mirck Sochanski, MD); Heart Care Midwest, Peoria (B.
S. Clemson, MD); Carter Cardiovascular Clinic, Calumet City (J. E. Carter,
Jr, MD). Indiana: *Care Group, LLC, Indianapolis
(M. N.Walsh, MD); *Midwest Medical Group, LLC, South Bend (M. Lampert, MD,
D. R. Westerhausen, MD); Heart Group, Evansville (J. Becker, MD). Iowa: *Iowa Heart Center, Des Moines (M. G. H. Ghali, MD); Iowa Heart
Center Research Center, Des Moines (P. Bear, MD). Kentucky: Cardiovascular Associates, PSC, Louisville (W. Dillon, MD, D. A.
Dangeforde, MD). Louisiana:*Tulane University School
of Medicine, New Orleans (J. G. Diez, MD, A. N. Tenaglia, MD); Cardiovascular
Institute of the South, Thibodaux (B. G. Denys, MD); Cardiovascular Institute
of the South, Houma (P. S. Fail, MD); Cardiovascular Institute of the South,
Morgan City (P. Abel, MD); Cardiovascular Institute of the South, New Iberia
(M. Changlani, MD). Maine: *Androscoggin Cardiology
Associates, Auburn (R. J. Weiss, MD). Maryland: University
of Maryland, Baltimore (J. L. Stafford, MD). Massachusetts: Boston Medical Center, Boston (R. Falk, MD). Michigan: *University of Michigan Medical Center, Division of Cardiology, Ann
Arbor (S. Werns, MD, S. Chetcuti, MD); *Mc MD); Cardiology Consultants Ltd,
Norfolk (R. Stine, MD). Washington : *VA Puget Sound Health Care
Center, Seattle (K. Lehmann, MD, S. Kapadia, MD). Wisconsin: Cardiovascular Associates of Northern Wisconsin SC, Wausau (T. N.
Logemann, MD); Kenosha Hospital and Medical Center, Kenosha (K. J. Fullin,
MD); Marshfield Clinic Wausau Center, Wausau (R. Srivastava, MD).
*Indicates IVUS site.
Funding/Support: This study was funded by Pfizer.
Role of the Sponsor: The sponsor, Pfizer, participated
in discussions regarding study design and protocol development and provided
logistical support during the trial. Monitoring of the study was performed
by a contract research organization, Covalent, under contract with the sponsor,
and maintained the trial database. The IVUS end points were prepared by the
Intravascular Ultrasound Core Laboratory at the Cleveland Clinic. Primary
statistical analysis was performed by Pfizer. All tables, listings, and analyses
were performed and created by the writing group. After completion of the trial,
as specified in the study contract, a complete copy of the database was transferred
to the Cleveland Clinic Cardiovascular Coordinating Center, in which primary
efficacy analyses were verified by independent statisticians (Marlene Goormastic,
MPH, Kathy Wolski, MPH, and Craig Balog, BS). The manuscript was prepared
by the corresponding author and modified after consultation with coauthors.
The sponsor was permitted to review the manuscript and suggest changes, but
the final decision on content was exclusively retained by the authors.
Acknowledgment: We acknowledge the contributions
made by Nadine Juran, RN (study coordinator; Cleveland Clinic), Tim Crowe,
BS (IVUS laboratory manager), Marlene Goormastic, MPH, Kathy Wolski, MPH,
Craig Balog, BS (statisticians; Cleveland Clinic), Mathieu Ghadanfar, MD,
David J. Frid, MD (medical officer; Pfizer), Rebecca Scherzer, MS, Sarah Young,
PhD, Michael Gaffney, PhD, (statisticians; Pfizer).