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A Calcium Antagonist vs a Non–Calcium Antagonist Hypertension Treatment Strategy for Patients With Coronary Artery Disease
The International Verapamil-Trandolapril Study (INVEST): A Randomized Controlled Trial
Carl J. Pepine, MD;
Eileen M. Handberg, PhD;
Rhonda M. Cooper-DeHoff, PharmD;
Ronald G. Marks, PhD;
Peter Kowey, MD;
Franz H. Messerli, MD;
Giuseppe Mancia, MD;
José L. Cangiano, MD;
David Garcia-Barreto, MD;
Matyas Keltai, MD;
Serap Erdine, MD;
Heather A. Bristol, MS;
H. Robert Kolb, RN;
George L. Bakris, MD;
Jerome D. Cohen, MD;
William W. Parmley, MD; for the INVEST Investigators
JAMA. 2003;290:2805-2816.
ABSTRACT
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Context Despite evidence of efficacy of antihypertensive agents in treating hypertensive patients, safety and efficacy of antihypertensive agents for coronary artery disease (CAD) have been discerned only from subgroup analyses in large trials.
Objective To compare mortality and morbidity outcomes in patients with hypertension and CAD treated with a calcium antagonist strategy (CAS) or a non–calcium antagonist strategy (NCAS).
Design, Setting, and Participants Randomized, open label, blinded end point study of 22 576 hypertensive CAD patients aged 50 years or older, which was conducted September 1997 to February 2003 at 862 sites in 14 countries.
Interventions Patients were randomly assigned to either CAS (verapamil sustained release) or NCAS (atenolol). Strategies specified dose and additional drug regimens. Trandolapril and/or hydrochlorothiazide was administered to achieve blood pressure goals according to guidelines from the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) of less than 140 mm Hg (systolic) and less than 90 mm Hg (diastolic); and less than 130 mm Hg (systolic) and less than 85 mm Hg (diastolic) if diabetes or renal impairment was present. Trandolapril was also recommended for patients with heart failure, diabetes, or renal impairment.
Main Outcome Measures Primary: first occurrence of death (all cause), nonfatal myocardial infarction, or nonfatal stroke; other: cardiovascular death, angina, adverse experiences, hospitalizations, and blood pressure control at 24 months.
Results At 24 months, in the CAS group, 6391 patients (81.5%) were taking verapamil sustained release; 4934 (62.9%) were taking trandolapril; and 3430 (43.7%) were taking hydrochlorothiazide. In the NCAS group, 6083 patients (77.5%) were taking atenolol; 4733 (60.3%) were taking hydrochlorothiazide; and 4113 (52.4%) were taking trandolapril. After a follow-up of 61 835 patient-years (mean, 2.7 years per patient), 2269 patients had a primary outcome event with no statistically significant difference between treatment strategies (9.93% in CAS and 10.17% in NCAS; relative risk [RR], 0.98; 95% confidence interval [CI], 0.90-1.06). Two-year blood pressure control was similar between groups. The JNC VI blood pressure goals were achieved by 65.0% (systolic) and 88.5% (diastolic) of CAS and 64.0% (systolic) and 88.1% (diastolic) of NCAS patients. A total of 71.7% of CAS and 70.7% of NCAS patients achieved a systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg.
Conclusion The verapamil-trandolapril–based strategy was as clinically effective as the atenolol-hydrochlorothiazide–based strategy in hypertensive CAD patients.
INTRODUCTION
The prevalence of coronary artery disease (CAD) is increasing, as are major CAD risk factors (hypertension, aging, diabetes, obesity, and inactivity).1 Blood pressure is important in the progression of CAD, yet no large trials have evaluated blood pressure management in only patients with CAD. Thus, blood pressure management in CAD patients2 must be guided by data from relatively small subsets of high-risk patients from other trials.3-6
Current trends in hypertension management emphasize multidrug regimens rather than monotherapy. Combinations of antihypertensive drugs with complementary actions may minimize adverse effects and reduce clinical outcomes by improving blood pressure control and organ protection.7-10  -Blockers are effective in hypertension treatment and reduce incidence of death and reinfarction in patients who have had a myocardial infarction (MI).11 Along with diuretics, -blockers became the standard of care for hypertensive CAD patients.12 However, -blockers may be less effective antihypertensive agents in older patients, who are also more likely to have CAD.13-14 The possibility that other antihypertensive regimens, particularly those containing calcium antagonists and/or angiotensin II active agents, might be as or more effective than -blocker and/or diuretic regimens has not been convincingly demonstrated.15-16 Previous trials were performed predominantly in populations with low frequencies of CAD and used dihydropyridine calcium antagonists.5-6,16-17 A recent trial in high-risk hypertensive patients showed that a combination of an angiotensin II-receptor blocker and a diuretic was more effective than a combination of a -blocker and a diuretic.14
Heart rate–reducing nondihydropyridine calcium antagonists, on the other hand, have rarely been studied in large randomized hypertension trials,18-21 although verapamil appears to reduce the risk of death and reinfarction in acute CAD trials.20 The combination of a nondihydropyridine calcium antagonist and an angiotensin-converting enzyme (ACE) inhibitor may provide better blood pressure control and organ protection than monotherapies.22-25 Many recent trials8, 10, 14, 24, 26-30 indicate that drugs influencing the actions of angiotensin II can be beneficial in high-risk patients, but no hypertension trial has prospectively used these agents for CAD patients with diabetes, renal impairment, or heart failure.
We designed a randomized trial, the International Verapamil-Trandolapril Study (INVEST), to compare outcomes in older hypertensive patients with CAD treated with a calcium antagonist strategy (CAS; verapamil sustained release [SR]) or a non–calcium antagonist strategy (NCAS; atenolol). Because most older hypertensive patients require more than 1 agent to adequately control blood pressure, INVEST was intended to compare multidrug strategies rather than individual agents.
METHODS
Study Design
The INVEST design and methods have been published.31 INVEST was an international, multicenter study with a prospective, randomized, open blinded end-point evaluation design32 conducted according to principles of the Declaration of Helsinki. The institutional review boards and ethics committees at participating sites approved the protocol and patients provided written informed consent.
We tested the hypothesis that risk for adverse outcomes is equivalent to a verapamil SR–based regimen compared with an atenolol-based regimen. Clinically stable CAD patients with hypertension were randomly assigned to either verapamil SR or atenolol for blood pressure treatment according to the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) (target: systolic blood pressure [SBP] <140 and diastolic blood pressure [DBP] <90 mm Hg or SBP <130 mm Hg and DBP <85 mm Hg when diabetes or renal impairment is present).9 Addition of trandolapril and/or hydrochlorothiazide was recommended when necessary to achieve blood pressure goals. Trandolapril also was recommended for patients with heart failure, diabetes, or renal insufficiency. Thus, this was not simply a comparison of verapamil SR with atenolol because it was anticipated that few patients would be treated with only those drugs. Ultimately, it was expected that most would be using the combination of verapamil SR plus trandolapril or atenolol plus hydrochlorothiazide.
Patient inclusion and exclusion criteria have been described previously.31 Briefly, patients were eligible if they were aged 50 years or older and had documented CAD, with essential hypertension as defined by JNC VI9 requiring drug therapy. Documented CAD was defined as any of the following: remote ( 3 months prior to enrollment) confirmed MI, coronary angiogram with more than 50% narrowing of at least 1 major coronary artery, diagnosis of classic angina pectoris, or concordant abnormalities on 2 different types of signals (electrocardiograms, echocardiograms, and/or radionuclide scans) from stress tests provided that 2 different signals showed findings consistent for ischemia (eg, ST-segment depression and/or perfusion defects by radionuclide, and/or wall-motion abnormalities by echocardiogram or radionuclide). Patients with heart failure classes I through III were included. Patients taking -blockers within 2 weeks of randomization or taking -blockers for an MI that occurred in the previous 12 months were excluded to avoid withdrawal phenomena in patients randomized to the CAS group.
Following validity checks of eligibility data, an Internet-based management system automatically randomized each patient to a treatment strategy. The randomization scheme used a standard C routine and blocked by site using randomly permuted block sizes of 4 and 6. The randomization result was automatically stored in the central database as part of the patient's record and was also returned to the site investigator for electronic signature of strategy drugs in accordance with the protocol.
Interventions
Figure 1 outlines the protocol-recommended treatment schedule for each strategy to achieve JNC VI blood pressure targets.9 The blood pressure target was determined from a mean of 2 sitting cuff blood pressure measurements as described in JNC VI.9
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Figure 1. Treatment Strategies
The drugs, order of addition, and recommended doses for each step of each strategy are summarized. Nonstudy antihypertensive drugs could be added to control blood pressure except for -blockers in those assigned to the calcium antagonist strategy and calcium antagonists for those assigned to the non–calcium antagonist strategy. Titration ranges: atenolol, 25-200 mg/d; hydrochlorothiazide, 12.5-100 mg/d; trandolapril, 1-8 mg/d; and verapamil sustained release, 120-480 mg/d. *For patients with creatinine levels of 2.0 mg/dL or higher (177 µmol/L), the recommended starting dose was 0.5 mg/d of trandolapril.
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Patients allocated to the CAS group were given 240 mg/d of verapamil SR while patients allocated to the NCAS group were given 50 mg/d of atenolol (step 1). If patients did not achieve target blood pressure, in step 2 the CAS group also could receive trandolapril (an ACE inhibitor) and the NCAS group also could receive hydrochlorothiazide. The rationale for this was to maximize use of the combination of calcium antagonist and ACE inhibitor while minimizing diuretic use for the CAS group and maximizing use of the combination of -blocker and diuretic for NCAS group. In step 3, doses were increased in both groups. In step 4, the CAS group also could receive hydrochlorothiazide and the NCAS group also could receive trandolapril. Trandolapril was recommended for all patients with renal impairment, diabetes, or heart failure.9 If the dose was not well tolerated or the target blood pressure was not achieved, verapamil SR could be titrated to between 120 and 480 mg/d and atenolol could be titrated to between 25 and 200 mg/d. The recommended starting dose for trandolapril was 2 mg/d and it could be titrated to between 0.5 and 8 mg/d. For patients in the CAS group, a fixed combination was available for verapamil SR and trandolapril in doses of 180 mg/d and 2 mg/d, respectively; 240 mg/d and 1 mg/d; and 240 mg/d and 4 mg/d. The recommended starting dose for hydrochlorothiazide was 25 mg/d and it could be titrated between 12.5 and 100 mg/d. Doses greater than 25 mg of hydrochlorothiazide were provided to limit the need for nonstudy diuretics in patients with heart failure or edema. If the blood pressure goal was not achieved and adverse effects had not occurred, doses were titrated to those shown in Figure 1 before a patient was moved to the next step.
Additional nonstudy antihypertensive drugs, except -blockers for CAS patients and calcium antagonists for NCAS patients, could be added when needed to reach blood pressure targets or minimize adverse effects. Patients were considered to have crossed over from their randomized treatment strategy if they received a -blocker during the trial and were in the CAS group or received a calcium antagonist and were in the NCAS group. Standard of care nonpharmacological JNC VI guidelines9 and secondary prevention according to the National Cholesterol Education Program were provided online to physicians, which could be printed and given to patients.
Patient Monitoring and Follow-up
Protocol visits were scheduled every 6 weeks for the first 6 months and then biannually until 2 years after the last patient was enrolled. Patients were assessed for response to treatment, occurrence of symptoms, treatment compliance, and adverse effects at each visit and at study close as detailed elsewhere.31
Patient follow-up was complete when a final assessment form was received via the online data system or a death report was received. For all patients not completing the final assessment visit, lost to follow-up, or withdrawn, data were censored according to last visit date.
Study Outcomes
The primary outcome was the first occurrence of death (all-cause), nonfatal MI, or nonfatal stroke by intention-to-treat analysis. The MI and stroke definitions are detailed on the INVEST Web site.33 These 3 components individually were the main secondary outcomes. Additional outcomes included time to most serious event (ranked from death as most serious, to MI, to stroke as least serious), cardiovascular death (definite or presumed), angina, cardiovascular hospitalizations, blood pressure control, cancer, Alzheimer disease, Parkinson disease, and gastrointestinal tract bleeding.34 Shortly after the study started, new information became available on the potential for ACE inhibitors to prevent or delay the onset of diabetes.8, 10 Accordingly, at the recommendation of the independent data safety and monitoring committee, new diagnosis of diabetes was added as an outcome early in the recruitment phase of the study.
Outcomes such as death, MI, stroke, and cardiovascular hospitalization were reported within 24 hours using the online adverse event reporting system and then appropriate documentation was gathered. Adverse experiences were collected from responses to open, active questioning not restricted to those events known to be associated with the drugs taken. Three members of the events committee, masked to treatment assignment, confirmed all outcome events by reviewing documentation and other pertinent patient records. The data safety and monitoring committee reviewed efficacy and safety data at regular intervals throughout the trial.
Sample Size
It was decided a priori that a 20% difference in primary outcome between the treatment strategies would be clinically relevant31 using the intention-to-treat population. Therefore, the equivalence bound for the risk ratio was a confidence interval (CI) of 1.20 to 0.83. We assumed an annual primary outcome rate of no less than 2%,31 an  of .05 (2-sided), and 90% power when estimating the number of patients required. On this basis, a tentative sample size of 27 000 patients was calculated, with an anticipated yearly drop-out rate of 5% to 10%. Because the enrollment period was longer than initially planned, patient-years of follow-up were greater than those used for initial power estimates. At the recommendation of the INVEST study biostatisticians and the data safety and monitoring committee, the steering committee reduced the sample size to 22 000 patients.
Statistical Analysis
All of the main analyses were completed as specified in the protocol with the intention-to-treat population, including patients withdrawn or lost to follow-up censored at the time of the last visit (unless the patient was known to be dead based on death records). One planned interim analysis was performed in August 2001 and the prespecified stopping rules33 were not met.
The final significance level for the primary outcome, adjusted for the single interim analysis, was P = .04806 for a 2-sided test. For the secondary outcomes of death, nonfatal MI, and nonfatal stroke, a Bonferroni adjustment was made to the same P = .04806 significance level (P = .02 for each outcome). All other analyses are reported at the P<.05 significance level. Kaplan-Meier survival analysis was used to assess time to first event for the primary outcome and the main secondary outcomes. The primary outcome was analyzed both unadjusted and adjusted for 5 prespecified covariates: age, race, sex, previous MI, and prior heart failure. Standard relative risk (RR) estimates and 95% CIs were also calculated.
 2 Analysis was used to compare CAS with NCAS on percentage occurrence of different outcomes. Cox proportional hazard models were used to evaluate potential interactions in the reported prespecified subgroup analyses (by baseline characteristic). All data were captured and stored in database tables (Version 7.1, Oracle, Redwood Shores, Calif). Data management and statistical analyses were performed using SAS statistical software (Version 8.2, SAS Institute Inc, Cary, NC). The database was maintained at the University of Florida, Division of Biostatistics, Gainesville.
RESULTS
Patient Enrollment
The pilot phase (30 selected sites) started in September 1997. Full-scale site recruitment and patient enrollment began in January 1998, and patient follow-up was completed on February 14, 2003. A total of 22 576 patients at 862 sites in 14 countries provided informed consent, satisfied administrative requirements, and completed randomization; 11 267 were assigned to the CAS group and 11 309 to the NCAS group (Figure 2). A total of 594 patients had all assigned drugs withdrawn due to an adverse experience. A total of 568 patients failed to return for final assessment and did not appear in death searches (withdrawals or lost to follow-up). These latter patients were censored at the time of their last visit. Mean follow-up was 2.7 years (range, 1 day to 5.4 years) in each strategy. A total of 30 829 patient-years were accumulated in the CAS group and 31 006 patient-years in the NCAS group.
Baseline Characteristics
At baseline, patient characteristics were well-balanced (Table 1). The study population included a large proportion of elderly, Hispanic, diabetic, and female patients. Blood pressure levels were similar between groups (Table 2). Overall, only 4267 patients (18.9% of all patients) had controlled blood pressure.
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Table 1. Patient Characteristics at Baseline*
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Table 2. Baseline Blood Pressure and Antihypertensive Medications
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Treatment
At 24 months, 6391 (81.5%) of CAS patients were taking verapamil SR and 6083 (77.5%) of NCAS patients were taking atenolol (Table 3). As expected from the recommended order of additional drug treatment by strategy, usage of trandolapril and hydrochlorothiazide differed significantly (P<.001). The distribution of number of study drugs used was similar between strategies as was the distribution of total antihypertensive medications. At 24 months, only 2.1% of patients in each group (CAS, 145; NCAS, 141) were taking no antihypertensive medications. At final assessment, nonstudy antihypertensive drug use was observed in 5873 patients (43%) in both strategies (Table 4). As expected, calcium antagonist use was more frequent in the CAS group and -blocker use was more frequent in the NCAS group (Table 4). Crossover to -blocker use in the CAS group (373 [5.5%]) was less than crossover to calcium antagonist use in the NCAS group (479 [7.0%]). This difference persisted over the entire duration of follow-up, -blocker use at any time in the CAS group was 1305 (11.6%) of 11 267 and calcium antagonist use in the NCAS group was 1862 (16.5%) of 11 309 (P<.001). Nonstudy diuretic use was also more frequent in the NCAS group. The percentage of patients taking antidiabetic medications was significantly lower in the CAS group (23.2%; n = 1574) compared with the NCAS group (24.7%; n = 1682) (P = .04). The frequencies of other medication use were similar between strategies (Table 4).
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Table 3. Strategy Antihypertensive Medication Use
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Table 4. Nonstrategy Medication Frequencies at 24 Months
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Blood Pressure and Heart Rate
Figure 3 presents SBP and DBP data by treatment strategy over 48 months (error bars in the upward direction represent 1 SD for CAS and bars in the downward direction represent 1 SD for NCAS). Mean (SD) SBP reduction at 24 months was 18.7 (22.2) mm Hg in the CAS group compared with 19.0 (22.6) mm Hg in the NCAS group (P = .41). The mean (SD) DBP reduction at 24 months was 10.0 (12.4) mm Hg in the CAS group compared with 10.2 (12.4) mm Hg in the in the NCAS group (P = .26). A reduction of 90% of the maximum achieved in SBP and 100% in DBP occurred in the first 6 months of treatment; the reductions were maintained throughout the trial. Mean resting heart rate at 24 months was significantly lower (P<.001) in NCAS patients (69.2/min) compared with CAS patients (72.8/min).
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Figure 3. Mean Systolic and Diastolic Blood Pressure During the Trial
There were no significant differences in systolic or diastolic blood pressure.
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Outcomes
Figure 4 presents the primary outcome and Figure 5 presents the patients with events comprising the primary and other outcomes. A total of 2456 events were reported (CAS, 1214; NCAS, 1242) and the events committee confirmed 2380 of the events (96.9%; CAS, 1171; NCAS, 1209). Sites reported that 2333 patients (CAS, 1153; NCAS, 1180) experienced an event in the primary outcome cluster during follow-up and the events committee confirmed that an event had occurred in 2269 of those patients (97.3%; CAS, 1119; NCAS, 1150). Death (all-cause) occurred in 1766 patients (CAS, 873; NCAS, 893); 304 were nonfatal MIs (CAS, 151; NCAS, 153); and 279 were nonfatal strokes (CAS, 131; NCAS, 148). Of the 1766 confirmed deaths, 862 were classified as definitely or presumed cardiovascular (CAS, 431; NCAS, 431); 701 were noncardiovascular (CAS, 350; NCAS, 351); and 203 could not be classified (CAS, 92; NCAS, 111). Of the 1563 classifiable deaths, 862 (55.2%) were cardiovascular. The analyses reported herein were performed only on events confirmed by the events committee, but analyses of site-investigator reported events yielded similar results (data not shown).
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Figure 4. Primary Outcome by Treatment Strategy
The relative risk was 0.98 (95% confidence interval, 0.90-1.06).
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Figure 5. Primary and Secondary Outcomes by Treatment Strategy
CI indicates confidence interval; RR, relative risk. P value from Kaplan-Meier survival analysis.
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Kaplan-Meier analysis (unadjusted) of time to first primary outcome event demonstrated no difference comparing the CAS group with the NCAS group for a primary outcome (Figure 4; RR, 0.98 [95% CI, 0.90-1.06]). A sensitivity analysis in which the 568 patients who were lost to follow-up or withdrew were all presumed to have died produced an RR of 1.00 (95% CI, 0.94-1.08). When adjusted for the prespecified covariates of age, race, sex, previous MI, and previous heart failure, the CAS and NCAS groups were not different (hazard ratio [HR], 0.98; 95% CI, 0.91-1.07; P = .69). Other outcomes were also similar in frequency between strategies (Figure 5). Time to death (all cause) did not differ between treatment groups (P = .72), nor did time to nonfatal MI (P = .95), or time to nonfatal stroke (P = .33). Time to the most serious event also did not differ between treatment groups (P = .58). Fatal and nonfatal MI occurred in 452 CAS patients (4.01%) and 441 NCAS patients (3.90%) (RR, 1.03; 95% CI, 0.90-1.17). Fatal and nonfatal stroke occurred in 176 CAS patients (1.56%) and 201 NCAS patients (1.78%) (RR, 0.88; 95% CI, 0.72-1.07). Subgroup analyses by baseline characteristics showed consistency for the primary outcome in both high- and low-risk subgroups (Figure 6). Of particular note were the similar event rates for each strategy among patients with prior MI as well as those with prior coronary revascularization. The exception was patients with prior heart failure, for which those assigned to the NCAS strategy appeared to have fewer events (P = .03 for interaction). Also important was the marked difference in the event rate of 14.3% (913/6400) for those with diabetes compared with 8.4% (1356/16 176) for those without diabetes.
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Figure 6. Effects of Treatment Strategy on Primary Outcome in Subgroups of Patients at Baseline
Other race/ethnicity indicates Asian or multiracial. All medical conditions were present at baseline. CI indicates confidence interval; RR, relative risk.
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The effect of the treatment strategies using an overall SBP control goal of less than 140 mm Hg and DBP control goal of less than 90 mm Hg was similar. A total of 5625 patients (71.7%) in the CAS group and 5553 (70.7%) in the NCAS group achieved overall blood pressure control at 24 months (P = .18). Based on JNC VI blood pressure goals, SBP control was achieved by 65.0% of CAS patients (n = 5093) compared with 64.0% of NCAS patients (n = 5025) (P = .23); DBP control was achieved by 88.5% of CAS patients (n = 6937) compared with 88.1% of NCAS patients (n = 6914) (P = .46).
At baseline, angina was reported in 66.2% of CAS patients (n = 7463) compared with 67.0% of NCAS patients (n = 7582). At 24 months, these percentages decreased to 27.3% in the CAS group (n = 2055) and 28.3% in the NCAS group (n = 2136) (P = .18). Angina and unstable angina were infrequently reported as adverse experiences and rates were similar in both groups (Table 5). At baseline (based on the previous 4 weeks), there was a mean (SD) of 1.5 (2.33) angina episodes/wk in the CAS group and 1.5 (2.43) in the NCAS group. At 24 months, angina episodes decreased in both groups, but the mean (SD) frequency was lower in the CAS group (0.77 [1.31] episodes/wk) compared with the NCAS group (0.88 [1.62] episodes/wk) (P = .02). Revascularization was required in only 2% of patients in each group (Table 5). Nitrate use was the same in each strategy (Table 4).
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Table 5. Adverse Experiences*
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Analysis of the development of diabetes revealed significant differences between the treatment strategies. Of the 8098 CAS patients without diabetes at entry, 569 (7.03%) were diagnosed as having diabetes during follow-up. Of the 8078 NCAS patients without diabetes at entry, 665 (8.23%) were diagnosed as having diabetes during follow-up (RR, 0.85; 95% CI, 0.77-0.95). Patients in the CAS group were also less likely to die or develop diabetes compared with patients in the NCAS group (1050 [12.97%] vs 1177 [14.57%]; RR, 0.89; 95% CI, 0.82-0.96) and less likely to have an event in the primary outcome cluster or develop diabetes (1185 [14.63%] vs 1313 [16.25%]; RR, 0.90; 95% CI, 0.84-0.97). To explore possible explanations for reduced risk of diabetes, we conducted preliminary analyses adjusting for the 5 prespecified baseline covariates (age, race, sex, prior MI, and prior heart failure) and included factors for average daily dose of add-on medication (trandolapril and/or hydrochlorothiazide). In these analyses, trandolapril appeared to confer a protective effect in the CAS group. Compared with those in the NCAS group not taking either trandolapril or hydrochlorothiazide, those in the CAS group not taking trandolapril had a HR of developing diabetes of 0.95 (95% CI, 0.82-1.10). A 2-mg dose of trandolapril was associated with a HR of 0.86 (95% CI, 0.74-1.00) and a 4-mg dose was associated with a HR of 0.77 (95% CI, 0.62-0.96). In the NCAS group, a 2-mg dose of trandolapril was associated with a HR of 0.99 (95% CI, 0.90-1.08) and a 4-mg dose was associated with a HR of 0.98 (95% CI, 0.82-1.18). On the other hand, hydrochlorothiazide appeared to confer a nonstatistically significant increased risk of diabetes. Compared with those in the NCAS group not taking either trandolapril or hydrochlorothiazide, the addition of 12.5 mg of hydrochlorothiazide was associated with a HR of 1.17 (95% CI, 1.09-1.25) and 25 mg of hydrochlorothiazide was associated with a HR of 1.36 (95% CI, 1.18-1.57). Those in the CAS group not taking hydrochlorothiazide had a HR of 0.95 (95% CI, 0.82-1.10); the addition of 12.5 mg of hydrochlorothiazide was associated with a HR of 1.11 (95% CI, 0.95-1.29) and 25 mg of hydrochlorothiazide was associated with a HR of 1.28 (95% CI, 1.05-1.57).
Adverse Experiences
Both drug combinations were generally well tolerated in each treatment group. Cancer was reported in 192 patients (1.70%) in the CAS group compared with 186 patients (1.64%) in the NCAS group (P = .73). Alzheimer disease, gastrointestinal tract bleeding, and Parkinson disease were reported in 1% or less of patients in each group and incidence did not differ between groups. Patients in the CAS group reported constipation and cough more frequently than patients in the NCAS group, while NCAS patients had more dyspnea, lightheadedness, symptomatic bradycardia, and wheezing (Table 5).
COMMENT
We tested the hypothesis that treatment of hypertensive CAD patients with either a verapamil SR–based strategy (CAS group) or a -blocker–based strategy (atenolol; NCAS group) would result in equivalent clinical outcomes. Our findings demonstrated that these treatment strategies were equivalent in the prevention of the outcome of all-cause mortality, nonfatal MI, or nonfatal stroke. Furthermore, similar results were observed comparing the treatment strategies for all-cause mortality, cardiovascular death, cardiovascular hospitalization, and blood pressure control. Significant differences were observed between strategies that favored the verapamil SR plus trandolapril strategy (CAS group) for lower angina frequency and new diagnoses of diabetes. There was a significant interaction between treatment group and prior heart failure, suggesting that those randomized to the atenolol plus hydrochlorothiazide strategy (NCAS group) had better outcomes than those randomized to the verapamil SR plus trandolapril strategy (CAS group). Both strategies were well tolerated.
INVEST is the first, to our knowledge, large randomized, prospective trial to focus on CAD patients with hypertension and to follow JNC VI guidelines,9 which recommend use of an ACE inhibitor for special populations and lower blood pressure goals than other guidelines. It is important to note that this was not simply a comparison of verapamil SR with atenolol because it was anticipated that few patients would be treated with only those drugs. At study end, most were taking the combination of verapamil SR plus trandolapril (CAS group) or atenolol plus hydrochlorothiazide (NCAS group). Also, the study population included a high percentage of elderly, female, nonwhite, and diabetic patients. Thus, the results reported herein should be clinically applicable.
Although other trials3, 5, 16, 21 have investigated use of calcium antagonists in hypertensive patients, the frequency of CAD in these trials was too low to reach any relevant conclusions. For example, the Nordic Diltiazem (NORDIL) study demonstrated equivalence between diltiazem and diuretics and/or -blockers for cardiovascular morbidity and mortality and showed a reduction in incidence of fatal and nonfatal stroke in the diltiazem group, but only a small proportion of those patients (4.5%; n = 496) had coronary heart disease.21 Results from several hypertension trials, including LIFE14 and ALLHAT,16 have been confounded by differences in achieved blood pressure level, which influences outcomes. In our study, the reductions and achieved levels for SBP and DBP were similar in both treatment groups. Most INVEST patients achieved JNC VI goals for blood pressure control. These findings in patients with CAD extend those from LIFE14 and ALLHAT,16 demonstrating that even lower blood pressure targets are achievable with more aggressive management. However, ALLHAT neither tested a -blocker arm nor used an angiotensin II active agent for organ protection for patients with diabetes, renal impairment, or heart failure. Thus, INVEST results complement ALLHAT by including a -blocker–based strategy plus organ protection in an elderly population with CAD. The INVEST data also confirm and extend the suggestions of others7, 35 that monotherapy is not necessarily sufficient for optimal treatment of hypertension.
Overall, adverse experiences reported were minimal and similar in frequency between treatment strategies. Previous articles17, 36-37 have suggested that some calcium antagonists (principally short-acting dihydropyridines) may be associated with an increased risk of cancer, gastrointestinal tract bleeding, and all-cause mortality. Results of ALLHAT,16 STOP-2,5 and INVEST have not confirmed these suggestions. The difference in crossover rates may reflect the consequences of adverse experiences (dyspnea, lightheadedness, symptomatic bradycardia, and wheezing) associated with the combination of atenolol plus hydrochlorothiazide (NCAS group) compared with adverse experiences (constipation and cough) associated with the combination of verapamil SR plus trandolapril (CAS group). The possibility that the higher crossover rate in the atenolol-based strategy is related to previous intolerance or physician bias against -blockers cannot be excluded, particularly because patients recently taking -blockers were excluded from the trial. Another possibility is that the differing drug components of CAS (verapamil SR plus trandolapril) or NCAS (atenolol plus hydrochlorothiazide) could have conferred advantages in addition to blood pressure control. The combination of verapamil SR plus trandolapril could result in fewer metabolic complications, as was observed with reduction of new diagnoses of diabetes. The NCAS might have been expected to have advantages in patients with a prior MI and prior coronary revascularization; however, the results observed were similar with both strategies. Our outcome data for patients with prior heart failure, on the other hand, concur with recent trials documenting benefits of -blockers when added to diuretics and ACE inhibitors,38-40 although not all patients in those trials had hypertension. In light of the results reported herein, management of hypertension must focus on the risk profile of the patient and overall treatment regimen rather than a single drug.
There are some limitations to our study. We used blood pressure goals in accordance with JNC VI; however, JNC VII7 and epidemiological data41 indicate that CHD risk increases with SBP level higher than 115 mm Hg so it could be argued that even lower blood pressure targets may be reasonable. More than half the patients required 3 or more antihypertensive drugs to achieve blood pressure control. Better blood pressure control might have been possible if we had included a fourth drug in each of the specified treatment strategies. The large sample size resulted in a statistically significant difference in angina frequency comparing CAS with NCAS, but this difference may not be clinically significant. The decline in angina prevalence and frequency from entry (only 2% underwent revascularization) is clinically important. This, at least in part, is likely due to the decline in both SBP and heart rate. Lastly, although the new diabetes analysis was not planned before the trial started, we added this outcome early in the recruitment phase. Our findings suggest potential clinical implications that require confirmation. Other analyses of INVEST baseline data indicate that Hispanic ethnicity, heart failure, US residency, hypercholesterolemia, left ventricular hypertrophy, stroke and transient ischemic attack, prior coronary revascularization, and body mass index are linked to risk of developing diabetes.42 In our preliminary analyses herein, administration of trandolapril appeared to confer some protection, as suggested in previous studies of ACE inhibitors.8, 10, 16, 43 Hydrochlorothiazide was associated with a nonsignificantly increased risk of developing diabetes, which is also consistent with previous studies (usually a thiazide diuretic with a -blocker).14, 16, 44 Further analyses are required to better understand the complex interactions among drug, dose, and demographic factors. Patients' potassium levels were not collected in this study, so the role that hypokalemia may have played in precipitating hyperglycemia cannot be determined.
In conclusion, our results indicate that lower targets for blood pressure control can be achieved in most hypertensive patients with CAD using a multidrug strategy that includes administration of ACE inhibitors to patients with heart failure, diabetes, or renal impairment. The clinical equivalence of the CAS and NCAS groups in prevention of death, MI, or stroke supports the use of either strategy in clinically stable patients with CAD who require blood pressure control. The decision regarding which drug classes to use in specific CAD patients should be based on additional factors including adverse experiences, history of heart failure, diabetes risk, and the physician's best judgment. The possibility of delaying the emergence of a diabetes diagnosis with a CAS compared with an NCAS requires further investigation.
AUTHOR INFORMATION
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Corresponding Author and Reprints: Carl J. Pepine, MD, University of Florida College of Medicine, 1600 SW Archer Rd, Gainesville, FL 32610.
Author Contributions: Dr Pepine had full access to all the data in the study and takes responsiblility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Pepine, Handberg, Cooper-DeHoff, Marks, Kowey, Messerli, Mancia, Erdine, Kolb, Bakris.
Acquisition of data: Pepine, Handberg, Cooper-DeHoff, Marks, Kowey, Cangiano, Garcia-Barreto, Keltai, Erdine, Bristol, Kolb, Cohen.
Analysis and interpretation of data: Pepine, Handberg, Cooper-DeHoff, Marks, Kowey, Messerli, Mancia, Keltai, Erdine, Bristol, Bakris, Parmley.
Drafting of the manuscript: Pepine, Handberg, Cooper-DeHoff, Bristol.
Critical revision of the manuscript for important intellectual content: Pepine, Handberg, Cooper-DeHoff, Marks, Kowey, Messerli, Mancia, Cangiano, Garcia-Barreto, Keltai, Erdine, Bristol, Kolb, Bakris, Cohen, Parmley.
Statistical expertise: Marks, Bristol.
Obtained funding: Pepine.
Administrative, technical, or material support: Pepine, Handberg, Cooper-DeHoff, Marks, Kowey, Messerli, Keltai, Erdine, Bristol, Kolb, Bakris, Cohen, Parmley.
Study supervision: Pepine, Handberg, Cooper-DeHoff, Mancia, Cangiano.
Financial Disclosures: Dr Pepine has received grant support from Abbott Laboratories, AstraZeneca, Aventis Pharmaceuticals Inc, Berlex Laboratories Inc, Bristol-Myers Squibb, Sanofi Company, CV Therapeutics, Monarch Pharmaceuticals, Novartis, Pfizer, and Wyeth-Ayerst Laboratories and has been a consultant for Abbott Laboratories, CV Therapeutics, and Pfizer. Dr Handberg has received grant support from Abbott Laboratories. Dr Cooper-DeHoff has received grant support from Abbott Laboratories and Pfizer. Dr Kowey has received grant support and honoraria from and has a consultant agreement with Abbott Laboratories. Dr Messerli has received honoraria from Merck, Pfizer, Abbott Laboratories, Forest, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Biovail, Solvay, Reliant, and Pharmacia. Dr Cangiano has received honoraria from GlaxoSmithKline, Pfizer, Bristol-Myers Squibb, Genzyme, and Merck and research support from Genzyme, Bristol-Myers Squibb, and Abbott Laboratories. Dr Keltai has consultant agreements with and has received honoraria and travel grants from Sanofi-Synthelabo, Pfizer, Abbott Laboratories, Richter, and Servier, and has provided expert testimony for Pfizer. Dr Bakris has consultant agreements with and serves on speakers' bureaus for AstraZeneca, Abbott Laboratories, Amersham, Alteon, Biovail, Boehringer Ingelheim, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Merck, Novartis, Sanofi-Synthelabo, Sankyo and Solvay and has received grant support from AstraZeneca, Abbott Laboratories, Amersham, Alteon, Boehringer Ingelheim, Forest, GlaxoSmithKline, Merck, Novartis, Sankyo, and Solvay. Drs Pepine, Handberg, Cooper-DeHoff, and Marks are coinventors of the online prescribing system used in the INVEST, which is licensed to the University of Florida.
Funding/Support: INVEST was supported by the University of Florida and grants from BASF Pharma and Abbott Laboratories. Abbott Laboratories provided financial support for all study medications. Dr Pepine is supported by the AHA Sun Coast Chapter Eminent Scholar Chair in Cardiovascular Research and National Heart, Lung, and Blood Institute grants U01HL64924-02 and N01-HV-68163. Dr Handberg received grant support from the Florida Department of Health and National Heart, Lung, and Blood Institute grants U01HL64924-02 and N01-HV-68163. Dr Cooper-DeHoff received grant support from the PA Foote Small Grants Program at the University of Florida.
Role of Sponsor: The study was conceived and designed by the University of Florida investigators prior to seeking sponsorship. After BASF Pharma/Knoll AG (now Abbott Laboratories) agreed to sponsor the study, they provided minor suggestions for the protocol. University of Florida investigators were responsible for identifying the site investigators and for the complete conduct of the study. The University of Florida investigators provided a quarterly report to the sponsor focused primarily on site recruitment and patient enrollment (no study outcome data were provided). The sponsor played no role in collection, analysis, or interpretation of the data. All drafts of the manuscript were prepared by the University of Florida investigators, and in accordance with the contract the sponsor was provided a draft of the manuscript for comment, but the contract specifically excluded the sponsor from making any editorial changes to the results or conclusions set forth in the manuscript. After the analyses were complete and drafts of the manuscript were finished, a final copy of the database was provided to the sponsor in accordance with the contract.
Acknowledgment: We thank Linda Horne, Melanie Fridl Ross, MSJ, ELS, and Michael Raffin for editing assistance. The authors are grateful to Drs Peter Zilles, Peter Volkers, Udo Legler, Peter Iafrate, Michael Conlon, and Stuart Kupfer for their strong support throughout the study. The INVEST Site Investigators, Steering Committee, Event Adjudication Committee, Data Safety and Monitoring Board, and Executive and Publication Committee appear below.
INVEST Site Investigators: Australia: Richard Gordon, Jeff Karrasch, Roger Norman Wyndham. Canada: Steve Blitzer, Hubert Comtois, Paolo Costi, Jean-Marc Decary, Mark Dube, Daniel Gauthier, Raymond Gendreau, Kulwant Gill, Dominique Grandmont, Robert Harvey, J. Keith Hay, John Hunt, Andrew Kuchtaruk, Roger Labonte, Mario Lapointe, Robert Luton, Dennis Malcolm, Garfield McIntosh, Shahid Mecci, Martine Montigny, Champaklal Morar, Shah Nawaz, Shehnaz Pabani, Hyman Reisler, Guy Riendeau, Andre Rioux, Yehudi Shields, Ricki Shore, Gurcharan Syan, Swaran Syan, Ivor Teitelbaum, Timothy Zmijowskyj. Cuba: Jose Bernal, Juan R. Cabrera, Rodolfo Candelario, Alberto Hernandez Canero, Ariadna Concepcion, Javier Garcia, David Garcia-Barreto, Raymid Garcia-Fernandez, Claudio Gonzalez, Alfredo Guadalupe, Roberto Melo, Jose L. Mendoza, Rogelio Perez-Collado. Dominican Republic: Roberto Fernandez de Castro. El Salvador: Ricardo Arce, Juan Daniel Castro, Hugo Villarroel Abrego. Germany: Stephan Beckmann, Rudiger Bernauer, Annelore Buhr, Manfred Deterding, Frank Forquignon, Willi Heepe, Gisela Heinemann, Klaus-Ludwig Jahn, Hans-Peter Kempe, Ronald Luecke, Eberhard Meier, Joachim Minnich, Stefan Schreiber, Christina Ulrich, Wolf-Dietrich von Ohlen, Jorg Walter, Jens Westphal, Conrad Wolfgang. Guatemala: Milton Herrera Rivera. Hungary: Dezso Apro, Richard Asboth, Istvan Barna, Tibor Buza, Istvan Czuriga, Csaba Farsang, Emil Kalo, Andras Katona, Matyas Keltai, Erno Kis, Ferenc Lakatos, Zoltan Nadhazi, Bela Oze, Gyula Polak, Ferene Poor, Judit Rapi, Laszlo Regos, Gyorgy Sallai, Matyas Sereg, Ferenc Szaboki, Jeno Tarjan, Sandor Timar, Kalman Toth, Gabor Veress. Italy: Claudio Bonifazi, Federico Corbara, Giovanni De Rinaldis, Renato Fellin, Sandro Forconi, Ugo Giannuzzi, Vincenzo Inserra, Emilio Iommi, Fausto Marchetta, Aleardo Maresta, Luigi Meniconi, Giovanni Modica, Lucio Mos, Ernesto Mossuti, Giuseppe Nenci, Gian Piero Perna, Umberto Senin, Luigi Tavazzi, Mario Vincenzi. Mexico: Humberto Alvarez-Lopez, Hector Briseno, Alfredo Campoy-Diaz, Ernesto Cardona, Jorge Chavez, Juan Cordero Cabra, Gilberto De La Pena, Maria de Los Angeles Rios Arellano, Carlos Diaz De La Vega, Luis Eng, Jesus Esparragoza, Julio-Ivan Farjat Ruiz, Efrain Gaxiola, Javier Gonzalez Martin, Hugo Hernandez Garcia, J. Jaime Illescas Diaz, Jose Leiva Pons, Alfonso Mojica, Raul Munuzuri Taboada, Sergio Najar, Fernando Ortiz Galvan, Rogelio Peralta, Juan-Carlos Ramirez, Irineo Renteria Ibarra, Francisco Robles, Alberto Romo Jara, Sergio Sanchez, Sergio Varela, Raul Gerardo Velasco-Sanchez, Jesus Zuniga-Sedano. New Zealand: Joe Singh. Panama: Ruben Dario Nieto. Turkey: Ramazan Akdemir, Ahmet Alpman, Bulent Behlul Altunkeser, Suleyman M. Aslan, Bulent Boyaci, Zehra Bugra, Bekir Sitki Cebeci, Cevdet Erdol, Kemal Erol, Cigdem Yazici Ersoy, Yuksel Gokel, Isil Uzunhasan Heybeli, Baris Ilerigelen, Nilgun Incesoy, Celal Kirdar, Serdar Kucukoglu, Akif Turhan Kurum, Osman Mavis, Hasim Mutlu, Aytekin Oguz, Kenan Ovunc, Cetin Ozener, Mustafa Ozkan, Mahmut Sahin, Akin Serdar, Cevad Sekuri, Bilgin Timuralp, Bulent Tokgoz, Nizamettin Toprak, Cavlan Turkoglu, Sennur Unal, Oguz Yavuzgil, Murat Yesil. United States: Gerard Abate, Francisco Abreu, Raghavendra Adiga, Bikash Agarwal, Jorge Aguilera-Montalvo, Masood Ahmed, Kamran Akhtar, Nancy Akins, Abdul Ali, Alexander Alperovich, Larry Alton, Jerome Anderson, Nabil Andrawis, Jerome Andres, Luis Anez, Muhammad Anwar, Jose Aponte, Juan Aranda, Jr, Anthony Arevalos, Kevin Ariani, Marc Armstrong, William Arnett, Anita Arnold, Carlos Arroyo, Moogali (Mark) Arvind, Manuel Ascano, Joseph Asch, Antoine Atallah, Osama Ayad, Bonita Aycock, Betsy Babcock, Ladan Bakhtari, Karam Bansel, Chowdry Bashir, Marin Bautista-Rosas, Richard Beasley, Lou Anne Beauregard, Garry Becker, Rajendra Bellam, Carl Bengs, Milton Bergal, Frederick Berry, Mark Bertoglio, Barry Bertolet, Bruce Bethancourt, Brijesh Bhambi, Thayyullathil Bharathan, Sanjay Bharti, Girish Bhaskar, Mohammad Bhidya, Lester Bickford, Steven Bimson, Jack Birge, Jeffrey Bishop, Neville Bittar, Lawrence Blacher, Scott Blair, Ronald Bloom, Michael Boland, Joseph Bonanno, John Borkovec, Edwin Bosa-Osorio, David Bosscher, Robert Brahan, A. Gordon Brandau, Jr, Ray Breitenbach, Robert Briskin, Hal Brodsky, Mark Brooks, Raymond Broughton, Nate Brown, Josephine Brown, Colleen Browne, Errol Bryce, Linda Buster, Daniel Butler, James Butler, David Byler, Jean-Felert Cadet, Glenn Caine, William Calhoun, Daryl Callahan, Richard Callihan, Edwin Camilo Vazquez, William Campbell, Jr, Jose Cangiano, David Capper, Ulises Caraballo, Scott Carlton, Michael Carney, George Carr, Robert Carter, James Carter, Jr, Elizabeth Cato, Michael Caveness, Robert Cesarec, Billy Chacko, Matthew Chamberlain, Marlene Chance, Harish Chandna, Martin Charlat, Francois Charles, Eric Cheng, Tien Cheng, Alan Cherkasky, Michael Chidester, Suk Choi, Jerry Ciocon, Carlton Clarke, Jaime Claudio, Adam Cohen, Barton Cohen, Jerome Cohen, Paul Cohen, David Colan, Maria Collazo Garcia, Pedro Colon, Donald Conerly, Susan Courtnage, John Cox, Deena Craig, William Curry, Jeffrey Daniels, Robert Davis, William Davis, Rosalind Dawson, Virgil Dawson, Jr, Thomas Deering, Andy Delwadia, Christopher Demas, George Dennish, III, Kirit Desai, Marcos Devarie, Candido Diaz, Brooks Dickerson, Emily Diltz, Jose Dimen, Richard DiMonte, Sr, Paul Dixon, Vien Doan, Frederick Doerfler, Jr, Bipin Doshi, John Drury, Michael Duren, Allan Durfey, Jr, George Dy, W. Kirby Edge, D. William Edgren, Frood Eelani, Leo Egbujiobi, Norman Eisenstadt, Mahfouz El Shahawy, Dunk Ellis, III, Howard Ellison, Nina Ellison, Betty Erb, John Estess, Kimball Ewell, James Farrell, John Faulkner, William Feeman, Jr, Alicia Feliberti-Irizarry, Pedro Felix, David Feller, Thimjon Ferguson, Joaquin Fernandez-Quintero, Lee Fischer, Russell Fisher, Bret Fisher, Patrick Flamion, Jorge Flechas, Harold Fleming, Cornelius Flowers, Kent Ford, Jack Foster, Jr, Dana Fouchi, Richard Fowler, F. Jeffrey Friedlin, Burton Friedman, John Funai, Allan Furman, Manuel Galceran, Walter Gaman, Shyamala Ganti, David Gaskin, Samuel Gaskins, Jalal Ghali, James Giuliani, Howard Glass, Stephen Glasser, F. Michael Gloth, Gary Goforth, Sudhir Gogu, Ivan Goldsmith, Reynaldo Gomez-Adrover, Elena Gonzalez-Ortiz, Dennis Goodman, Santosh Gopalakrishnan, Jeffrey Gorwit, Susan Graham, Douglas Grant, Jeffrey Greiff, Rodney Grogan, Carolyn Guidot, Jyotsna Gupta, Ambrish Gupta, Alok Gupta, T. Eric Hale, Alexander Halkos, Anthony Hall, Arthur Hall, Jack Hall, Karen Hall, Michael Hall, Robert Hanlon, Stephan Hanna, Thomas Harakal, Michael Hardy, Gerald Harmon, Arthur Harrow, Steven Hartz, Greg Hayes, Robert Heath, Robert Heckey, Charles Heinsen, Robert Herrington, III, David Hill, Donald Hilliard, Shobha Hiremagalur, Michael Holland, Laura Hong, Stanley Horowitz, Michael Horseman, Lawrence Horwitz, Mark Houston, John Howard, Mark Hughes, Catherine Hunt, Joseph Hura, Yoichi Imamura, Ijaz Iqbal, Carmen Irizarry, Phillip Isbell, Tetsuo Ishimori, Peter Jacobson, Jay Jaikishen, Avanindra Jain, Usha Jain, Kassamali Jamal, Mohan Jesrani, Osvaldo Jimenez, Gary Johnson, James Jones, Mary Jones, Jeffrey Kagan, Cezary Kakol, Mark Kantzler, James Karas, Parvez Karim, Robert Karns, Adam Karns, Carol Kavanaugh, Ashok Kejriwal, Andrew Keller, Robert Keller, John Kemerer, Anton Kemps, Arthur Kennedy, Richard Kerensky, Nicholas Kerin, Nancy Kern, William Kerr, Aamir Khan, Azhar Khan, M. Naeem Khan, Mahmood Khan, Misal Khan, Rashid Khan, Ravi Khant, Ganesh Kini, Robert Kirstein, Kitturah Klaiss, Cameron Knackstedt, Christopher Koeppl, Linda Korman, David Kresnicka, Mark Krotowski, Mariananda Kumar, Kulmeet Kundlas, Muthu Kuttappan, Ronald Langman, Noel Lasala, Confesor LaSalle-Ruiz, Milanieva Latorre, Nathan Laufer, Sally Lawson, J. W. Randolph Lawson, Thomas Leahey, T. Glenn Ledbetter, R. Lee-Pack, Gary Lehman, Anthony Leone, Gary Lessmann, Raphael Levine, Derek Lewis, Kristine Lewis, Charles Li, David Lichtinger, David Liporace, Bruce Lipschutz, Fernando Lopez, Francisco Lopez, Mel Lucas, Benjamin Lumicao, James Lynch, Nasirdin Madhany, Antonio Maisonet, Paul Malen, Jane Mallet, Jose Manautou Godreau, Daniel Mangum, Manoucher Manoucheri, Mohammed Mansuri, Vincent Marino, Timothy Marshall, Craig Martin, Philemon Marvell, Sr, Walter Mashman, Arshad Masood, Mukesh Mathur, Robert Matthews, Francisco Mayorquin, Brian McCarroll, James McCauley, Linda McCauley, William McGarity, Jr, Jerry McKnight, Ravi Mehra, Romulo Mella, Sattar Memon, Mario Mendizabal, Franz Messerli, Delbert Meyer, Raymond Mikelionis, Marcia Miller, Kelly Mills, Thulmon Mills, Chester Miltenberger, Stefano Mion-Bet, Michael Mirro, Robin Mitchell, Kevin Mocklin, Kiran Modi, Usha Modi, Morgan Moncada, Michael Monroe, Steve Monroe, Baxter Montgomery, David Moore, Ali Moosvi, Steve Morris, III, Herbert Moskow, Gonzalo Mosquera, Jack Mourad, William Mroczek, Marek (Mark) Mrzyglocki, Farzana Mumtaz, Sanjay Muttreja, Seymour Myers, Ronald Myers, Mohammad Nadeemullah, Gule Naeem, Rameschandran Nair, Peter Nalos, Alfred Narraway, Anna Naumovich, Jorge Navas, Selim Newaz, Ngai Nguyen, Thach Nguyen, Sunil Nihalani, John Nobel, Raymond Noel, Thomas Noonan, Nabil Nouna, Glenn Novak, Okechi Nwabara, Joseph Nystrom, James O'Brien, Ronald Oglesby, Gisela Okonski, William Olney, Stephen Ong, James Oppy, Terry Ostrowski, Kuang-Yu Ou, Shirley Pagan, Amita Patel, Bhasker Patel, Mitchell Patt, Henry Patton, Hernando Payne, Philip Pearlstein, Juan Perez, Charles Pettus, Huong Phan, Andrea Phillips, James Pickens, Keith Pierce, Manuel Pimentel, Parag Pitroda, Peter Platzer, Richard Polakoff, Maryanna Polukhin, Malcolm Pond, Paul Popper, Myriam Portilla, Scott Posgai, Charles Powers, Jr, Jan Prasad, Sudhir Prasada, Nalini Premsingh, LeRoi Price, Donald Pritchard, Michelle Putnam, David Questell, Joseph Ragno, Kosuri Raju, William Rawlings, Jr, Michael Ray, Abi Rayner, Tito Razdan, Mahender Reddy, Malladi Reddy, Venugopala Reddy, Robert Remler, Joseph Resendiz, Leonel Reyes, Jr, Jerry Rhodes, William Rhodes, Jr, Maria Rios, Maritza Rivera, Fernando Rivera, Charles Robinson, M. Charlene Robinson, Luis Rodriguez, Roque Rodriguez, Joseph Roell, Michael Romanowsky, Philip Romm, Jose Rosado, Louis Rosenfield, Robert Ross, David Ross, Jr, David Rothman, Jerry Routh, Michael Rubin, Philip Rubin, Emir Rubio, Mario Ruiz, Roberto Ruiz, Lieu Rupp, Harvey Sabbota, Laurie Sadler, Mohammad Saklayen, Bradley B. Sakran, Ayaz Samadani, Michael Samalik, Smita Sampat, Wayne Sampson, Sergio Sanchez-Zambrano, Bharat Sangani, Deepak Sant Ram, Jose Santana, Joseph Saponaro, Chandresh Saraiya, Gregory Saric, Pete Sarmiento, Louis Sasser, III, Brent Savelli, Paul Sawrey, Sergio Schabelman, Norbert Scharff, David Scheer, Jay Schlaifer, Seigfried Schmidt, J. David Schmitz, Allan Schonberg, Martin Schwarze, Martin Scott, Cranford Scott, Edwin Searcy, Georgina Sehapayak, Paul Seigel, Munni Selagamsetty (Setty), Robert Sepulveda, M. Saleem Seyal, Gaurang Shah, Avani Shah, Dhiren Shah, Rakesh Sharma, Khalid Sheikh, David Sheps, James Shoemaker, Jaleel Siddiqui, Yolanda Sierra Quinones, Keith Simnicht, Lawrence Sinatra, Vibhuti Singh, Sudeep Singh, Domingo Singson, Jose Soba, Miguel Sosa-Padilla, Edwin Soto, Carlos Sotolongo, Jerome Spruill, Jagwinder Sraow, Gerard Stanley, Robert Steinberg, Mary Stiles, John Stokes, Randall Stoltz, David Stricklin, Joyce Stroud, Barbara Stryjewska, Wayne Stuart, David Subich, Leonard Sukienik, William Sullivan, Din-On Sun, William Swagler, III, Joseph Szgalsky, Jose Tavarez-Valle, Earle Taylor, Malcolm Taylor, George Thomas, Vincent Thompson, Robert Thompson, II, Raghdaa Toban, Sanjay Tomar, Frederic Tommey, Ramul Torres, Maylynn Tossas, Bao Cong Tran, Tan Tran, Nori Trehan, Paul Trentham, Mildred Trevett, N. Tucker, III, Samuel Turner, Ross Tye, Stephen Ulrich, Patricia Van Diepen, Shalendra Varma, Jose Vazquez-Tanus, George Vellanikaran, Joseph Vento, Thomas Verdin, III, Zaida Vidal, Elvin Vigo Paredes, Alex Villacastin, Anicia Villafria, Ramon Villafria, Dhruv Vyas, Stephen Wagner, Brent Walker, Julia A. Walker, Jesse Wallace, Steven Wallach, Franklin Waller, Jr, Leslie Walter, Gary Walton, Chok Wan, Sun-King Wan, Dana Ware, Lewis Weaver, Randall Weaver, Rachael Weiderhold, Robert Weiss, Frank Westmeyer, Earlene Whaley, Milton White, John Wilker, Benjamin Williams, Dean Williams, Michael Williams, Joseph Wilson, Elsie Witt-Bockler, Leonard Wojonowich, Elzbieta Wozniak, Janet Wright, Rathna Yallapragada, Greigstone Yearwood, Turgut Yetil, Lynn Yontz, NP, Dionisio Yorro, Jr, Shug-Hong Young, Jerry Zang, Khin Zaw, Demetrios Zerefos, Joseph Zizzi, Jr, Frederick Zugibe, Jr, Namir Zukkoor, Dianne Zwicke.
Steering Committee: G. Bakris, A. Benetos, J. Cangiano, A. Chobanian, A. Coca, J. Cohen, R. Davies, V. DeQuattro, S. Erdine, D. Garcia-Barreto, E. Gaxiola, M. Keltai, W. Klinke, R. Kolloch, P. Kowey, G. Mancia, R. Marks, F. Messerli, W. Parmley, C. Pepine (chair).
Event Adjudication Committee: E. Haththotuwa, K. Jayaram, P. Kowey (chair), G. von Mering.
Data Safety and Monitoring Committee: C. Conti (chair), E. Davis, L. Hansson, N. Kaplan, T. Ryan, P. Sleight.
Executive and Publication Committee: G. Bakris, H. Bristol, J. Cohen, R. Cooper-DeHoff, E. Handberg, G. Mancia, R. Marks, C. Pepine (chair).
Deceased.
Author Affiliations: Division of Cardiovascular Medicine, Departments of Medicine (Drs Pepine, Handberg, Cooper-DeHoff and Mr Kolb) and Statistics (Dr Marks and Ms Bristol), University of Florida College of Medicine, Gainesville; Department of Medicine, Lankenau Hospital, Wynnewood, Pa (Dr Kowey); Department of Medicine, Ochsner Clinic, New Orleans, La (Dr Messerli); Department of Medicine, Universita Degli Studi, Monza, Italy (Dr Mancia); Clinica Las Americas, Hat Rey, Puerto Rico (Dr Cangiano); Instituto de Cardiologia y Cirugia Cardiovascular, Havana, Cuba (Dr Garcia-Barreto); Department of Cardiology, Semmelweis University, Budapest, Hungary (Dr Keltai); Cardiology Institute, University of Istanbul, Istanbul, Turkey (Dr Erdine); Department of Preventive Medicine, Rush University, Chicago, Ill (Dr Bakris); Department of Medicine, Saint Louis University, St Louis, Mo (Dr Cohen); and Department of Medicine, University of California, San Francisco (Dr Parmley).
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