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.
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 β-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, β-blockers became the
standard of care for hypertensive CAD patients.12 However, β-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 β-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 β-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.
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 β-blockers within 2 weeks of randomization or taking β-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.
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
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 β-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 β-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 β-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.
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.
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 α
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.
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.
χ2 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.
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.
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.
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 β-blocker use was more frequent in the NCAS group (Table 4). Crossover to β-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, β-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).
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).
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).
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.
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).
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).
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).
We tested the hypothesis that treatment of hypertensive CAD patients
with either a verapamil SR–based strategy (CAS group) or a β-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 β-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 β-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 β-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 β-blockers cannot be excluded, particularly
because patients recently taking β-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 β-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 β-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.
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