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Original Contribution |

Effect of Antihypertensive Agents on Cardiovascular Events in Patients With Coronary Disease and Normal Blood Pressure:  The CAMELOT Study: A Randomized Controlled Trial FREE

Steven E. Nissen, MD; E. Murat Tuzcu, MD; Peter Libby, MD; Paul D. Thompson, MD; Magdi Ghali, MD; Dahlia Garza, MD; Lance Berman, MD; Harry Shi, MS; Ethel Buebendorf, BSN; Eric J. Topol, MD; for the CAMELOT Investigators
[+] Author Affiliations

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).

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JAMA. 2004;292(18):2217-2225. doi:10.1001/jama.292.18.2217.
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Published online

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 volume.

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.

Figures in this Article

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).13 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.46

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.

Study Design

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.

Intravascular Ultrasound Substudy

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.

Treatments

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, if possible.

Randomization and Allocation Concealment

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.

Outcomes

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 – PAV baseline).

Statistical Methods

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 at P<.05.

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.

Baseline Characteristics

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 groups.

Figure 1. Flow of Patients Through the Study
Graphic Jump Location

IVUS indicates intravascular ultrasound.

Table Graphic Jump LocationTable 1. Baseline Characteristics, Treatments, and Concomitant Medications
Treatments and Blood Pressure Changes

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).

Figure 2. Mean Patient Blood Pressure at Baseline and During Treatment
Graphic Jump Location

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.

Primary Efficacy Measure

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.

Figure 3. Cumulative Event Rates for All 3 Treatment Groups
Graphic Jump Location
Table Graphic Jump LocationTable 2. Cardiovascular Event Rates and Hazard Ratios

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.

Subgroup Analyses

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.

Figure 4. Adverse Cardiovascular Events in Amlodipine vs Placebo Groups, by Subgroup
Graphic Jump Location

Box sizes indicate proportion of the total study population (ie, smaller boxes have fewer patients relative to other subgroups).

IVUS Results

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).

Table Graphic Jump LocationTable 3. Intravascular Ultrasound (IVUS) Results

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.

Figure 5. LOWESS Plot of Change in Percent Atheroma Volume vs Change in Blood Pressure in the Combined Drug Treatment Groups
Graphic Jump Location

The solid line represents the continuous relationship, surrounded by the dashed lines representing 95% confidence intervals. LOWESS indicates locally weighted scatterplot smoothing.

Exploratory (Post Hoc) Analyses

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]).

Adverse Events

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.35 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.13 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 active treatment.

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 with amlodipine.14

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 (nissens@ccf.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, Buebendorf, Topol.

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, Berman, Topol.

Statistical analysis: Nissen, Thompson, Berman, Shi.

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. Baumgart, MD).

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).

Veterans Administration Cooperative Study Group on Antihypertensive Agents.  Effect of treatment on morbidity in hypertension: results in patients with diastolic blood pressure averaging 115 through 129 mm Hg.  JAMA. 1967;202:116-122
PubMed   |  Link to Article
Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and blood pressure reduction: a meta-analysis.  Lancet. 2001;358:1305-1315[published correction appears in Lancet. 2002;359:360]
PubMed   |  Link to Article
Blood Pressure Lowering Treatment Trialists' Collaboration.  Effects of ACE inhibitors, calcium antagonists, and other blood pressure-lowering drugs: results of prospectively designed overviews of randomised trials.  Lancet. 2000;355:1955-1964
PubMed   |  Link to Article
Heart Outcomes Prevention Evaluation Study Investigators.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.  N Engl J Med. 2000;342:145-153
PubMed   |  Link to Article
Fox KM.European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease Investigators.  Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).  Lancet. 2003;362:782-788
PubMed   |  Link to Article
Pitt B, Byington RP, Furberg CD.  et al. PREVENT Investigators.  Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events.  Circulation. 2000;102:1503-1510
PubMed   |  Link to Article
Chobanian AV, Bakris GL, Black HR.  et al. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.  Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.  JAMA. 2003;289:2560-2572[published correction appears in JAMA. 2003;290:197]
PubMed   |  Link to Article
Nissen SE, Tuzcu EM, Brown BG.  et al.  Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.  JAMA. 2004;291:1071-1080
PubMed   |  Link to Article
Nissen SE, Tsunoda T, Tuzcu EM.  et al.  Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial.  JAMA. 2003;290:2292-2300
PubMed   |  Link to Article
Chambers JM, Cleveland WS, Kleiner B, Tukey PA. Graphical Methods for Data AnalysisBoston, Mass: Duxbury Press; 1983
Lewington S, Clarke R, Qizilbash N.  et al. Prospective Studies Collaboration.  Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.  Lancet. 2002;360:1903-1913
PubMed   |  Link to Article
Jorgensen B, Simonsen S, Endresen K.  et al.  Restenosis and clinical outcome in patients treated with amlodipine after angioplasty: results from the Coronary Angioplasty Amlodipine Restenosis Study (CAPARES).  J Am Coll Cardiol. 2000;35:592-599
PubMed   |  Link to Article
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group.  Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).  JAMA. 2002;288:2998-3007
PubMed   |  Link to Article
Julius S, Kjeldsen SE, Weber M.  et al. VALUE Trial Group.  Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.  Lancet. 2004;363:2022-2031
PubMed   |  Link to Article
MacFadyen RJ, Meredith PA, Elliott HL. Enalapril clinical pharmacokinetics and pharmacokinetic-pharmacodynamic relationships: an overview.  Clin Pharmacokinet. 1993;25:274-282
PubMed   |  Link to Article
Poole-Wilson PA, Lubsen J, Kirwan BA.  et al. Nifedipine Gastrointestinal Therapeutic System Investigators.  Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial.  Lancet. 2004;364:849-857
PubMed   |  Link to Article
Mason RP. Mechanisms of plaque stabilization for the dihydropyridine calcium channel blocker amlodipine: review of the evidence.  Atherosclerosis. 2002;165:191-199
PubMed   |  Link to Article
Cannon CP, Braunwald E, McCabe CH.  et al.  Intensive versus moderate lipid lowering with statins after acute coronary syndromes.  N Engl J Med. 2004;350:1495-1504
PubMed   |  Link to Article

Figures

Figure 1. Flow of Patients Through the Study
Graphic Jump Location

IVUS indicates intravascular ultrasound.

Figure 2. Mean Patient Blood Pressure at Baseline and During Treatment
Graphic Jump Location

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.

Figure 3. Cumulative Event Rates for All 3 Treatment Groups
Graphic Jump Location
Figure 4. Adverse Cardiovascular Events in Amlodipine vs Placebo Groups, by Subgroup
Graphic Jump Location

Box sizes indicate proportion of the total study population (ie, smaller boxes have fewer patients relative to other subgroups).

Figure 5. LOWESS Plot of Change in Percent Atheroma Volume vs Change in Blood Pressure in the Combined Drug Treatment Groups
Graphic Jump Location

The solid line represents the continuous relationship, surrounded by the dashed lines representing 95% confidence intervals. LOWESS indicates locally weighted scatterplot smoothing.

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics, Treatments, and Concomitant Medications
Table Graphic Jump LocationTable 2. Cardiovascular Event Rates and Hazard Ratios
Table Graphic Jump LocationTable 3. Intravascular Ultrasound (IVUS) Results

References

Veterans Administration Cooperative Study Group on Antihypertensive Agents.  Effect of treatment on morbidity in hypertension: results in patients with diastolic blood pressure averaging 115 through 129 mm Hg.  JAMA. 1967;202:116-122
PubMed   |  Link to Article
Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and blood pressure reduction: a meta-analysis.  Lancet. 2001;358:1305-1315[published correction appears in Lancet. 2002;359:360]
PubMed   |  Link to Article
Blood Pressure Lowering Treatment Trialists' Collaboration.  Effects of ACE inhibitors, calcium antagonists, and other blood pressure-lowering drugs: results of prospectively designed overviews of randomised trials.  Lancet. 2000;355:1955-1964
PubMed   |  Link to Article
Heart Outcomes Prevention Evaluation Study Investigators.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.  N Engl J Med. 2000;342:145-153
PubMed   |  Link to Article
Fox KM.European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease Investigators.  Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).  Lancet. 2003;362:782-788
PubMed   |  Link to Article
Pitt B, Byington RP, Furberg CD.  et al. PREVENT Investigators.  Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events.  Circulation. 2000;102:1503-1510
PubMed   |  Link to Article
Chobanian AV, Bakris GL, Black HR.  et al. National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.  Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.  JAMA. 2003;289:2560-2572[published correction appears in JAMA. 2003;290:197]
PubMed   |  Link to Article
Nissen SE, Tuzcu EM, Brown BG.  et al.  Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.  JAMA. 2004;291:1071-1080
PubMed   |  Link to Article
Nissen SE, Tsunoda T, Tuzcu EM.  et al.  Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial.  JAMA. 2003;290:2292-2300
PubMed   |  Link to Article
Chambers JM, Cleveland WS, Kleiner B, Tukey PA. Graphical Methods for Data AnalysisBoston, Mass: Duxbury Press; 1983
Lewington S, Clarke R, Qizilbash N.  et al. Prospective Studies Collaboration.  Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.  Lancet. 2002;360:1903-1913
PubMed   |  Link to Article
Jorgensen B, Simonsen S, Endresen K.  et al.  Restenosis and clinical outcome in patients treated with amlodipine after angioplasty: results from the Coronary Angioplasty Amlodipine Restenosis Study (CAPARES).  J Am Coll Cardiol. 2000;35:592-599
PubMed   |  Link to Article
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group.  Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).  JAMA. 2002;288:2998-3007
PubMed   |  Link to Article
Julius S, Kjeldsen SE, Weber M.  et al. VALUE Trial Group.  Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.  Lancet. 2004;363:2022-2031
PubMed   |  Link to Article
MacFadyen RJ, Meredith PA, Elliott HL. Enalapril clinical pharmacokinetics and pharmacokinetic-pharmacodynamic relationships: an overview.  Clin Pharmacokinet. 1993;25:274-282
PubMed   |  Link to Article
Poole-Wilson PA, Lubsen J, Kirwan BA.  et al. Nifedipine Gastrointestinal Therapeutic System Investigators.  Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial.  Lancet. 2004;364:849-857
PubMed   |  Link to Article
Mason RP. Mechanisms of plaque stabilization for the dihydropyridine calcium channel blocker amlodipine: review of the evidence.  Atherosclerosis. 2002;165:191-199
PubMed   |  Link to Article
Cannon CP, Braunwald E, McCabe CH.  et al.  Intensive versus moderate lipid lowering with statins after acute coronary syndromes.  N Engl J Med. 2004;350:1495-1504
PubMed   |  Link to Article
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