0
Original Contribution |

Principal Results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) Trial FREE

Henry R. Black, MD; William J. Elliott, MD, PhD; Gregory Grandits, MS; Patricia Grambsch, PhD; Tracy Lucente, MPH; William B. White, MD; James D. Neaton, PhD; Richard H. Grimm, Jr, MD, PhD; Lennart Hansson, MD, PhD; Yves Lacourcière, MD; James Muller, MD; Peter Sleight, MD, DM; Michael A. Weber, MD; Gordon Williams, MD; Janet Wittes, PhD; Alberto Zanchetti, MD; Robert J. Anders, PharmD; for the CONVINCE Research Group
[+] Author Affiliations

Author Affiliations: Department of Preventive Medicine, Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill (Drs Black and Elliott and Ms Lucente); Division of Biostatistics (Mr Grandits and Drs Grambsch and Neaton) and Center for Evidence-Based Medicine (Dr Grimm), University of Minnesota, Minneapolis; Section of Hypertension and Clinical Pharmacology, Department of Medicine, University of Connecticut School of Medicine, Farmington (Dr White); Department of Geriatrics, University of Uppsala, Uppsala, Sweden (Dr Hansson); Centre Hospitalier Universitaire de Québec, Québec (Dr Lacourcière); Department of Medicine, Massachusetts General Hospital, Boston, Mass (Dr Muller); Department of Medicine, Oxford University, and John Radcliffe Hospital, Oxford, England (Dr Sleight); Department of Medicine, State University of New York, and Brookdale Hospital, Brooklyn (Dr Weber); Brigham and Women's Hospital and Harvard Medical School, Boston, Mass (Dr Williams); Statistics Collaborative, Washington, DC (Dr Wittes); Ospedale Maggiore and Istituto Auxologico Italiano and University of Milan, Milan, Italy (Dr Zanchetti); and Clinical Research, Searle Laboratories, Skokie, Ill (Dr Anders).
Dr Hansson is deceased.


JAMA. 2003;289(16):2073-2082. doi:10.1001/jama.289.16.2073.
Text Size: A A A
Published online

Context Hypertensive patients are often given a calcium antagonist to reduce cardiovascular disease risk, but the benefit compared with other drug classes is controversial.

Objective To determine whether initial therapy with controlled-onset extended-release (COER) verapamil is equivalent to a physician's choice of atenolol or hydrochlorothiazide in preventing cardiovascular disease.

Design, Setting, and Participants Double-blind, randomized clinical trial conducted at 661 centers in 15 countries. A total of 16 602 participants diagnosed as having hypertension and who had 1 or more additional risk factors for cardiovascular disease were enrolled between September 1996 and December 1998 and followed up until December 31, 2000. After a mean of 3 years of follow-up, the sponsor closed the study before unblinding the results.

Intervention Initially, 8241 participants received 180 mg of COER verapamil and 8361 received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. Other drugs (eg, diuretic, β-blocker, or an angiotensin-converting enzyme inhibitor) could be added in specified sequence if needed.

Main Outcome Measures First occurrence of stroke, myocardial infarction, or cardiovascular disease–related death.

Results Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 mm Hg for partcipants assigned to the atenolol or hydrochlorothiazide group. There were 364 primary cardiovascular disease–related events that occurred in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.88-1.18; P = .77). For fatal or nonfatal stroke, the HR was 1.15 (95% CI, 0.90-1.48); for fatal or nonfatal myocardial infarction, 0.82 (95% CI, 0.65-1.03); and for cardiovascular disease–related death, 1.09 (95% CI, 0.87-1.37). The HR was 1.05 (95% CI, 0.95-1.16) for any prespecified cardiovascular disease–related event and 1.08 (95% CI, 0.93-1.26) for all-cause mortality. Nonstroke hemorrhage was more common with participants in the COER-verapamil group (n = 118) compared with the atenolol or hydrochlorothiazide group (n = 79) (HR, 1.54 [95% CI, 1.16-2.04]; P = .003). More cardiovascular disease–related events occurred between 6 AM and noon in both the COER verapamil (99/277) and atenolol or hydrochlorothiazide (88/274) groups; HR, 1.15 (95% CI, 0.86-1.53).

Conclusions The CONVINCE trial did not demonstrate equivalence of a COER verapamil–based antihypertensive regimen compared with a regimen beginning with a diuretic or β-blocker. When considered in the context of other trials of calcium antagonists, these data indicate that the effectiveness of calcium-channel therapy in reducing cardiovascular disease is similar but not better than diuretic or β-blocker treatment.

Figures in this Article

The background and scientific rationale, inclusion and exclusion criteria, baseline characteristics, and early blood pressure control data regarding the participants for the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) Trial have been previously published.1,2 CONVINCE was planned in 1994 as a large, simple trial3 to assess the equivalence of controlled-onset extended-release (COER) verapamil and standard therapy in preventing cardiovascular disease–related events. It was also the first prospective study of the timing of acute myocardial infarction (MI), cardiovascular event–related death, and stroke—all of which have their highest incidence during the early morning hours (6 AM to noon).4,5 Planned mean follow-up was 5 years; however the trial was stopped 2 years early by the sponsor for commercial reasons.

Study Participants

Participants were randomized from 661 clinical sites in 15 countries.2 All had signed informed consent, were 55 years or older, and had at least 1 other established risk factor (eg, diabetes or cigarette smoker) for cardiovascular disease, in addition to hypertension.1

Study Design

CONVINCE was a randomized, double-blind, active-controlled, multicenter, international clinical trial (Figure 1). One group initially received COER verapamil (Covera-HS in the United States, Chronovera in other countries; Pharmacia Corp, Peapack, NJ), which exerts its major antihypertensive effect 6 to 12 hours after administration.6,7 The active-control group began with either hydrochlorothiazide or atenolol. The choice was made by the investigator prior to randomization, based on which treatment the investigator thought would be more suitable for the individual participant, should the participant be randomized to the atenolol or hydrochlorothiazide group.

Figure 1. Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) Trial
Graphic Jump Location

The primary objective was to compare the 2 regimens in preventing acute MI, stroke, or cardiovascular disease–related death.1 Major secondary outcomes included (1) an expanded cardiovascular disease end point, which included hospitalization for angina, cardiac revascularization or transplant, heart failure, transient ischemic attack or carotid endarterectomy, accelerated or malignant hypertension, or renal failure in addition to the primary outcome; (2) all-cause mortality; (3) cancer; (4) hospitalization for bleeding (excluding hemorrhagic stroke); and (5) incidence of primary end points occurring between 6 AM and noon.1

The design of CONVINCE assumed 2024 participants would develop a primary end point, which provided 84% power for detecting a 14% difference between regimens at a 2-sided significance level of .05. Estimates of noncompliance to COER verapamil (7.5 in first year; 3% each subsequent year) and lost to follow-up rates (1% per year) were incorporated in the sample size and power calculations. It was estimated that 15 000 participants would have to be enrolled to obtain the 2024 events over a 5-year mean follow-up. The sample size was increased to 16 600 (with a target of 2246 events) when it became apparent early in the study that the withdrawal rate from study medication was greater than initially assumed. Equivalence bounds for the hazard ratio (HR) were prespecified as 0.86 to 1.16.1

The randomization schedule was stratified by site and atenolol or hydrochlorothiazide choice in successive permuted blocks of 2, 4, or 6, selected randomly. Schedules were prepared by the statistical center at the Division of Biostatistics at the University of Minnesota, Minneapolis, and provided only to a contract research organization (Parexel International, Waltham, Mass), which used them to implement a transtelephonic interactive voice response system, whereby participants could be randomized by calling a toll-free number.1

Treatments

Participants received 2 bottles for initial treatment (step 1). One bottle contained tablets, 1 to be taken at bedtime, of either placebo or 180 mg of COER verapamil, which provides plasma levels of verapamil that peak8 at about the same time as the early morning increase in blood pressure, pulse rate, and risk of cardiovascular disease–related events.4,5 The other bottle contained tablets, 1 to be taken each morning, of placebo or 50 mg of atenolol, or 12.5 mg of hydrochlorothiazide. The dose of step 1 medication was doubled if systolic blood pressure remained at or above 140 mm Hg and/or diastolic blood pressure remained at or above 90 mm Hg. If blood pressure still was not controlled after increasing the dose, 12.5 mg of hydrochlorothiazide could be added to either the initial dose of either atenolol or COER verapamil. Or 50 mg of atenolol could be added to the initial dose of hydrochlorothiazide (step 2 treatment). The added drug could also be doubled in dose if needed. All step 1 and 2 drugs were blinded. Any additional antihypertensive agent (except a nondihydropyridine calcium antagonist, thiazide diuretic, or β-blocker) could be added as a step 3 medication (nonblinded) if needed. An angiotensin-converting enzyme inhibitor was recommended (but not mandated). The study physician could change doses or medications at any time during follow-up.

All study medication for a participant was obtained by using the interactive voice response system, which provided the appropriate bottles of medication based on the step and dose of treatment the participant was currently taking. Each bottle used in the study was assigned a unique number to maintain blinding.

Data Collection and Monitoring

Participants were seen at least semiannually for blood pressure measurements, treatment dispensing, and end point surveillance. On-site data verification was performed at least annually by the contract research organization. An independent data and safety monitoring board met semiannually to review accumulating data. Confidence intervals (CIs) based on the Lan-DeMets version9 of the O'Brien-Fleming group sequential boundaries were used as guidelines for early termination.10 The data and safety monitoring board met 8 times and recommended continuation of the trial after each meeting. All analyses were performed independently of the sponsor by the statistical center at the Division of Biostatistics at the University of Minnesota. All study investigators and the study sponsor were blinded to all between-treatment comparisons until completion of end point data collection and review.

The sponsor closed the study 2 years earlier than originally planned for commercial reasons. A common calendar date of December 31, 2000, was chosen through which all participants would be followed up. Clinical sites were asked to verify the end point status (primary end point and survival status) of each participant as of this date. In addition, in the United States, vital status was determined through the National Death Index for 263 participants whose vital status was unknown through other sources at the end of the trial. Four previously unknown decedents and 15 individuals with previously unknown cause of death were identified as having died from cardiovascular disease.

Primary End Point Review and Adjudication

All possible primary end points were reviewed by an end points committee that was blinded to treatment assignment. This committee consisted of 7 experts in cardiovascular medicine. Two members of the committee independently reviewed documentation provided by the clinical sites for each event to assess whether the event met prespecified criteria. When the 2 reviewers did not agree, the full committee reviewed and adjudicated the case. If documentation was insufficient to confirm (or reject) the event, the site clinician's diagnosis was used. For deaths found only through the National Death Index, the coded cause of death provided was used. Of the 729 participants with a primary event included in the analysis, the end point committee confirmed 651 (89%).

Acute MI required 2 of the following 3 conditions (1) symptoms compatible with acute MI (eg, chest pain) lasting longer than 15 minutes; (2) electrocardiographic changes (new persistent ST-segment elevation or pathological Q waves in 2 contiguous leads); or (3) increased cardiac enzymes (more than twice the upper limit of normal). A diagnosis of stroke required the presence of focal neurological deficit lasting longer than 24 hours. Imaging studies were not required to document a stroke. Any death thought to be compatible with coronary heart disease (eg, heart failure, sudden death) or cardiovascular disease was counted as a cardiovascular disease–related death.

Statistical Methods

Time to event methods (Cox proportional hazards model and Kaplan-Meier curves) were used to compare outcomes for participants randomly assigned COER verapamil with those assigned atenolol or hydrochlorothiazide. Analyses were by modified intent to treat (modified by the exclusion of 2 sites with data integrity concerns), unless otherwise specified, and were stratified by the choice of standard of care and geographic region (United States, Canada, Western Europe, and other [Eastern Europe, Mexico, Israel, or Brazil]) in which the participant's clinical site was located. Analyses of primary and secondary events considered censoring due to losses to follow-up (ie, participants for whom the primary event status was unknown on the closing date), noncardiovascular disease–related deaths (as appropriate), and the closing date of the study. Losses were censored at the date the primary event status was last known (either the date provided by the site during the closeout process; or the date of the last follow-up visit). The HR for COER verapamil vs atenolol or hydrochlorothiazide was estimated from a stratified Cox model with a binary indicator (COER verapamil vs atenolol or hydrochlorothiazide) as the sole covariate. The proportional hazards assumption was tested by including an interaction term between the randomized treatment indicator and log-transformed follow-up time. Heterogeneity of HR for selected prespecified baseline subgroups was assessed by inclusion of an interaction term (randomized treatment by subgroup variable) in the Cox model. To determine whether HRs for the primary end point varied according to time of day of the event, a competing risk analysis was performed for 4 time intervals: midnight to 6 AM; 6 AM to noon; noon to 6 PM; and 6 PM to midnight.11 This analysis allows simultaneous estimation of the HRs for each time interval. The homogeneity of HRs across intervals was tested using a χ23 statistic. For the secondary outcome of primary events that occurred between 6 AM and noon, events with other times or unknown times were censored at the date of the event. P values are 2-tailed.

Blood pressure changes from baseline were compared between the 2 treatment groups using the t test. All analyses were performed using SAS statistical software (Version 8.0, SAS Institute Inc, Cary, NC).

Enrollment

Between September 1996 and December 1998, 16 602 participants were randomized. Participants from 2 sites (n = 126; 62 randomized to COER verapamil) were excluded because of data integrity concerns. Thus, our report is based on 16 476 randomized participants (Figure 1). The mean age was 66 years; 56% of participants were women.2 Most participants (84%) had previously been prescribed antihypertensive drugs; hydrochlorothiazide was chosen over atenolol for 7617 (46.2%) participants; 49% had 2 or more risk factors (Table 1).2

Table Graphic Jump LocationTable 1. Baseline Characteristics of Randomized Groups
Visit Attendance and Lost to Follow-up Rates

Participants were followed up for at least 2 years and a maximum of 4.25 years; the median follow-up was 3 years. Among the participants who were alive at the time of each visit, attendance was 92% for the COER verapamil group compared with 93% for the atenolol or hydrochlorothiazide group at 12 months; 86% for both groups at 24 months; and 79% for the COER verapamil group compared with 80% for the atenolol or hydrochlorothiazide group at 36 months. On the closing date of the trial, the primary end point status was unknown for 570 participants assigned to the COER verapamil group compared with 563 assigned to atenolol or hydrochlorothiazide (P = .52 by log-rank test for time to lost to follow-up). Corresponding percentages for unknown vital status were 1.5% for COER verapamil and 1.6% for the atenolol or hydrochlorothiazide group (P = .67). In both treatment groups, those lost to follow-up were older; had higher baseline blood pressure levels; were more likely to smoke cigarettes; and have a history of MI, stroke, or transient ischemic attacks compared with participants followed up through the closing date.

Adherence to Study Medication

Median time receiving blinded treatment was 2.2 years for both the COER verapamil group and the atenolol or hydrochlorothiazide group. By the close of the trial, 39.4% of COER verapamil group and 39.7% of the atenolol or hydrochlorothiazide group had discontinued blinded study medication. The proportion was identical for both groups at 1 year (27%). Reasons for withdrawal were available for 78% of those withdrawing in each treatment group. Participants assigned COER verapamil withdrew more often due to adverse signs or symptoms compared with those assigned atenolol or hydrochlorothiazide (P = .02); the most common reason was constipation (216 in the COER verapamil group compared with 28 in the atenolol or hydrochlorothiazide group). However, fewer participants assigned COER verapamil (n = 115) withdrew because of poor blood pressure control (treatment failures) compared with those assigned atenolol or hydrochlorothiazide (n = 207) (P<.001 by log-rank).

Blood Pressure Control and Step of Medication

Both regimens lowered blood pressure significantly.2 Averaged over the entire follow-up period, systolic blood pressure was reduced by 13.6 mm Hg and diastolic blood blood pressure by 7.8 mm Hg from baseline in the COER verapamil group. In the atenolol or hydrochlorothiazide group, systolic blood pressure was reduced by 13.5 mm Hg and diastolic by 7.1 mm Hg. The mean differences in blood pressure change (COER verapamil minus atenolol or hydrochlorothiazide) were small for systolic blood pressure (0.06 mm Hg; 95% CI, −0.44 to 0.56 mm Hg) and diastolic blood pressure (0.67 mm Hg; 95% CI, 0.38-0.95 mm Hg). At the last follow-up visit attended, a systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg was achieved in 65.5% of the COER verapamil group and 65.9% of the atenolol or hydrochlorothiazide group.

During follow-up, the prescribed antihypertensive regimen was similar across randomized groups (Figure 2). In both groups, the proportion of participants prescribed more than 1 antihypertensive medication increased with longer follow-up.

Figure 2. Participants Taking Determined Level of Therapy
Graphic Jump Location
Asterisk indicates angiotensin-converting enzyme inhibitor primarily; COER, controlled-onset extended-release. During 6 to 36 months of follow-up, 41 (0.8%) to 105 (1.7%) of participants in either randomized group reported taking no antihypertensive medications.

At the last visit, 28.4% of the COER verapamil group and 26.1% of the atenolol or hydrochlorothiazide group were taking only the initially assigned medication. The percentages of participants taking step 2 or step 3 treatment or nonblinded medication only were similar between treatment groups. For step 2, 15.5% of the COER verapamil group were receiving treatment compared with 16.1% of the atenolol or hydrochlorothiazide group; step 3, 16.7 vs 18.2%; and no blinded medication, 39.4% vs 39.7%, respectively. Since β-blockers, by design, were not used with COER verapamil, the 2 treatment groups differed more with respect to blinded β-blocker use (0% of the COER verapamil group vs 43% of the atenolol or hydrochlorothiazide group) than with diuretic use (26% vs 44%, respectively).

Primary End Point and Its Components

There were 364 first primary events in the group randomized to COER verapamil compared with 365 among the atenolol or hydrochlorothiazide group (Table 2). Figure 3 shows the Kaplan-Meier curves for the primary end point. Among those assigned COER verapamil, 1.51% of participants had an event after 12 months of follow-up, 3.12% after 24 months, and 4.94% after 36 months. Among those assigned atenolol or hydrochlorothiazide, 1.69% of participants had an event after 12 months of follow-up, 3.10% after 24 months, and 4.73% after 36 months. The HR for COER verapamil group compared with the atenolol or hydrochlorothiazide group was 1.02 (95% CI, 0.88-1.18; P = .77). There was no evidence that this HR varied over follow-up (proportional hazards P = .36).

Table Graphic Jump LocationTable 2. Primary and Secondary Events by Treatment Assignment
Figure 3. Incidence of Primary Outcome Measure Over Time
Graphic Jump Location
COER indicates controlled-onset extended-release. The COER verapamil group experienced 364 cardiovascular disease–related events and the atenolol or hydrochlorothiazide group experienced 365 (hazard ratio, 1.02; 95% confidence interval, 0.88-1.18).

Two supplemental on-treatment analyses were performed. In 1 analysis, follow-up was censored 30 days after blinded study medication was discontinued (220 events among participants in the COER verapamil group compared with 217 events in the atenolol or hydrochlorothiazide group; HR, 1.05 [95% CI, 0.87-1.26]; P = .63). A second analysis included only those participants who were still taking blinded study medication 1 year after randomization. The result of this analysis, which only included events after the first year (171 events among participants in the COER verapamil group compared with 157 in the atenolol or hydrochlorothiazide group), yielded a HR of 1.14 (95% CI, 0.91-1.41; P = .25). After adjusting for age, sex, and risk factors at entry, the HRs were 1.06 (95% CI, 0.88-1.28) using the first on-treatment analysis method and 1.12 (95% CI, 0.90-1.40) using the second on-treatment analysis method.

For fatal or nonfatal MI, the HR was 0.82 (95% CI, 0.65-1.03; P = .09); fatal or nonfatal stroke, 1.15 (95% CI, 0.90-1.48; P = .26); and cardiovascular disease–related death, 1.09 (95% CI, 0.87-1.37; P = .47). Among participants in the COER verapamil group, there were 152 cardiovascular disease–related deaths (24 MIs, 18 strokes, and 110 had other cardiovascular disease). There were 143 cardiovascular disease–related deaths among participants in the atenolol or hydrochlorothiazide group (22 MIs, 21 strokes, and 100 had other cardiovascular disease).

Secondary End Points

The HR for the primary end point or cardiovascular-related hospitalization was 1.05 (95% CI, 0.95-1.16; P = .31) and 1.08 (95% CI, 0.93-1.26; P = .32) for death. Hospitalization for heart failure, a component of the secondary cardiovascular disease end point, was 30% higher with COER verapamil compared with atenolol or hydrochlorothiazide (HR, 1.30; 95% CI, 1.00-1.69; P = .05). More participants assigned COER verapamil (n = 118; 1.4%) than atenolol or hydrochlorothiazide (n = 79; 1.0%) died or were hospitalized for bleeding unrelated to stroke (HR, 1.54; 95% CI, 1.15-2.04; P = .003). Six participants in each group died of hemorrhage not related to stroke (HR, 1.02 [95% CI, 0.33-3.17]; P = .97). Cancer incidence did not vary by treatment group (310 participants reported cancer in the COER verapamil group vs 299 in the atenolol or hydrochlorothiazide group; HR, 1.06 [95% CI, 0.91-1.24]; P = .46). About 14% of participants in each treatment group were hospitalized at least once during follow-up (P = .62).

For the primary end point, treatment HRs did not vary significantly by time of day of the event (P = .43). In each treatment group, more participants had primary events between 6 AM and noon than any other 6-hour period (Figure 4). The HR for the 6 AM to noon events was 1.15 (95% CI, 0.86-1.53; P = .34). For an additional analysis that censored participant follow-up 30 days after blinded medication was discontinued, the HR for events occurring between 6 AM and noon was 1.19 (95% CI, 0.84-1.70).

Figure 4. Incidence of Primary End Points by Treatment Assignment and Time of Day
Graphic Jump Location
Time of onset of first cardiovascular disease–related event was determined for 277 participants in the controlled-onset extended-release (COER) verapamil group and 274 participants in the atenolol or hydrochlorothiazide group. There were 178 (24%) events for which time of onset could not be determined (87 among those randomized to COER verapamil and 91 among those randomized to atenolol or hydrochlorothiazide; hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.73-1.32).
Baseline-Defined Subgroup Results

When participants were grouped according to baseline characteristics, there was no evidence of a treatment by subgroup interaction for any of the predefined baseline subgroups (Table 3).

Table Graphic Jump LocationTable 3. Primary Composite End Point by Treatment Assignment

The results of this study indicate thatCOER verapamil is not equivalent to atenolol or hydrochlorothiazide in preventing cardiovascular disease–related events. The upper bound of the 95% CI for the primary end point (1.18) slightly exceeded the prespecified boundary (1.16) for equivalence of COER verapamil and atenolol or hydrochlorothiazide.1,12 All HRs involving efficacy were close to 1.0, including the primary end point (1.02), the major secondary combined cardiovascular disease end point (1.05), and mortality (1.08). Similarly, although the HRs increased slightly in the on-treatment analyses for the primary end point, they remained close to 1.0 (1.06 and 1.12). The relative risks for the primary end point did not differ significantly across multiple subgroups (Table 3), including choice of atenolol or hydrochlorothiazide, suggesting that there was no particular baseline characteristic associated with a different outcome overall. Further analyses by choice of atenolol or hydrochlorothiazide that take into account use of treatment steps 2 and 3 are planned. The HR was also close to unity for all of the prespecified secondary cardiovascular disease–related events, with the exception of heart failure. This was expected because both diuretics and β-blockers are usually recommended for heart failure,13 whereas verapamil has been associated with an increased risk of heart failure in previous studies.14,15

The treatment regimens showed some minor and statistically nonsignificant differences in the incidence of each component of the primary end point. The incidence of acute MI was about 18% lower with COER verapamil (P = .09) than with the atenolol or hydrochlorothiazide group; this benefit was offset by a 15% higher risk of stroke (P = .26). Although quite possibly due to chance, these trends are consistent with COER verapamil's ability to inhibit platelet aggregation,1618 leading to both reduced MI incidence and more bleeding. Such a mechanism has been postulated to explain aspirin's tendency to increase hemorrhagic stroke, which is outweighed by a protective effect on MI.19 These trends are opposite to those seen in the Nordic Diltiazem (NORDIL) study, which used the nondihydropyridine calcium antagonist diltiazem.20 A similar contrast is observed when comparing the results of CONVINCE and a recent meta-analysis.21

The prospectively gathered data of Figure 4 confirm previous epidemiological observations concerning the increased risk of cardiovascular events in the early morning hours,4,5 but do not support the concept of chronotherapeutics.22 However, our analyses of this secondary outcome were limited by the smaller than expected number of events, and may be further confounded by nonadherence and use of multiple drugs in each treatment group to control blood pressure.

The findings of CONVINCE are subject to many limitations. The decision to terminate CONVINCE prematurely did not derive from a recommendation of the data and safety monitoring board,2326 nor from review of external data from other clinical trials.27,28 In this respect, the study is flawed. When stopped, the results were still inconclusive with respect to the prespecified equivalence bounds. Less than a third of the planned number of events were observed, which affects the width of the 95% CIs, and limits the ability to make conclusions about any results (which may not be similar) with longer follow-up. More participants than expected discontinued blinded medication, which pushes the overall result toward the null. Approximately 7% of participants were lost to follow-up for the primary end point. In both treatment groups, participants who were lost to follow-up had baseline risk factors that placed them at a higher risk of cardiovascular disease–related events than participants who continued follow-up. Finally, the effectiveness of atenolol or hydrochlorothiazide in the population studied might differ from that in previous clinical trials establishing the efficacy of atenolol or hydrochlorothiazide, which is a common problem in interpreting the results of equivalence trials.

In summary, CONVINCE was unable to demonstrate equivalence of a COER verapamil–based antihypertensive regimen and a regimen beginning with a diuretic or β-blocker. When considered in the context of other trials of calcium antagonists, including the larger Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),29 which found that the calcium channel blocker amlodipine was not superior to the diuretic chlorthalidone, in reducing the rate of coronary heart disease or stroke and was associated with a higher rate of heart failure, these data indicate that the effectiveness of calcium channel blocker therapy in reducing cardiovascular disease–related morbidity and mortality is similar but not better than diuretic or β-blocker treatment. These data support the recommendation of the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure30 for low-dose diuretic (or possibly β-blocker) therapy for hypertensive patients who have no specific indication for another antihypertensive drug.

Black HR, Elliott WJ, Neaton JD.  et al. for the CONVINCE Research Group.  Rationale and design for the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) Trial.  Controlled Clinical Trials.1998;19:370-390.
Black HR, Elliott WJ, Neaton JD.  et al.  Baseline characteristics and early blood pressure control in the CONVINCE trial.  Hypertension.2001;37:12-18.
Peto R, Collins R, Gray R. Large-scale randomized evidence: large, simple trials and overviews of trials.  J Clin Epidemiol.1995;48:23-40.
Cohen MC, Rohtla KM, Lavery CE, Muller JE, Mittleman MA. Meta-analysis of the morning excess of acute myocardial infarction and sudden cardiac death.  Am J Cardiol.1997;79:1512-1516.
Elliott WJ. Circadian variation in the timing of stroke onset: a meta-analysis.  Stroke.1998;29:992-996.
White WB, Anders RJ, MacIntyre JM.  et al.  Nocturnal dosing of a novel delivery system of verapamil for systemic hypertension.  Am J Cardiol.1995;76:375-380.
White WB, Black HR, Weber MA, Elliott WJ, Bryzinski B, Fakouhi TD. Comparison of effects of COER-verapamil at bedtime and nifedipine GITS on arising on early morning blood pressure, heart rate and the heart rate blood pressure product.  Am J Cardiol.1998;81:424-431.
Gupta SK, Yih MY, Atkinson L, Longstreth J. The effect of food, time of dosing, and body position on the pharmacokinetics and pharmacodynamics of verapamil and norverapamil.  J Clin Pharmacol.1995;35:1083-1093.
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials.  Biometrika.1983;70:659-663.
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials.  Biometrics.1979;35:549-556.
Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. New York, NY: Springer; 2000:170-179.
Ellenberg SS, Temple R. Placebo-controlled trials and active-control trials in the evaluation of new treatments, part 2: practical issues and specific cases.  Ann Intern Med.2000;133:464-470.
Gomberg-Maitland M, Baran DA, Fuster V. Treatment of congestive heart failure: guidelines for the primary care physician and the heart failure specialist.  Arch Intern Med.2001;161:342-352.
Danish Study Group on Verapamil in Myocardial Infarction (DAVIT-I).  Verapamil in acute myocardial infarction.  Eur Heart J.1984;5:516-528.
Danish Study Group on Verapamil in Myocardial Infarction.  Effect of verapamil on mortality and major events after acute myocardial infarction: the Danish Verapamil Infarction Trial II (DAVIT-II).  Am J Cardiol.1990;66:779-785.
Addonizio Jr VP, Fisher CA, Strauss 3rd JF, Wachtfogel YT, Colman RW, Josephson ME. Effects of verapamil and diltiazem on human platelet function.  Am J Physiol.1986;250:H366-H371.
Lacoste L, Lam JY, Hung J, Waters D. Oral verapamil inhibits platelet thrombus formation in humans.  Circulation.1994;89:630-634.
Ding YA, Chou TC, Lin KC. Effects of long-acting propranolol and verapamil on blood pressure, platelet function, metabolic and rheological properties in hypertension.  J Hum Hypertens.1994;8:273-278.
He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized clinical trials.  JAMA.1998;280:1930-1935.
Hansson L, Hedner T, Lund-Johansen P.  et al.  Randomised trial of effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) Study.  Lancet.2000;356:359-365.
Blood Pressure Lowering Treatment Trialists' Collaborative.  Effects of ACE-inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials.  Lancet.2000;356:1955-1964.
Smolensky MH, Portaluppi F. Chronopharmacology and chronotherapeutics of cardiovascular medications: relevance to prevention and treatment of coronary heart disease.  Am Heart J.1999;137:S14-S24.
The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on death from cardiovascular causes, myocardial infarction, and stroke in high-risk patients.  N Engl J Med.2000;342:145-153.
ALLHAT Collaborative Research Group.  Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT).  JAMA.2000;283:1967-1975.
Staessen JA, Fagard R, Thijs L.  et al. for the Systolic Hypertension Europe (Syst-EUR) Trial Investigators.  Morbidity and mortality in the placebo-controlled European Trial on Isolated Systolic Hypertension in the Elderly.  Lancet.1997;350:757-764.
Agodoa LY, Appel L, Bakris GL.  et al. for the African American Study of Kidney Disease and Hypertension (AASK) Study Group.  Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial.  JAMA.2001;285:2719-2728.
Lewis EJ, Hunsicker LG, Clarke WR.  et al.  Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.  N Engl J Med.2001;345:851-860.
Brenner BM, Cooper ME, de Zeeuw D.  et al. for the Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) Study Group.  Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.  N Engl J Med.2001;345:861-869.
ALLHAT Collaborative Research Group.  Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).  JAMA.2002;288:2981-2997.
 The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI).  Arch Intern Med.1997;157:2413-2446.

Figures

Figure 1. Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) Trial
Graphic Jump Location
Figure 2. Participants Taking Determined Level of Therapy
Graphic Jump Location
Asterisk indicates angiotensin-converting enzyme inhibitor primarily; COER, controlled-onset extended-release. During 6 to 36 months of follow-up, 41 (0.8%) to 105 (1.7%) of participants in either randomized group reported taking no antihypertensive medications.
Figure 3. Incidence of Primary Outcome Measure Over Time
Graphic Jump Location
COER indicates controlled-onset extended-release. The COER verapamil group experienced 364 cardiovascular disease–related events and the atenolol or hydrochlorothiazide group experienced 365 (hazard ratio, 1.02; 95% confidence interval, 0.88-1.18).
Figure 4. Incidence of Primary End Points by Treatment Assignment and Time of Day
Graphic Jump Location
Time of onset of first cardiovascular disease–related event was determined for 277 participants in the controlled-onset extended-release (COER) verapamil group and 274 participants in the atenolol or hydrochlorothiazide group. There were 178 (24%) events for which time of onset could not be determined (87 among those randomized to COER verapamil and 91 among those randomized to atenolol or hydrochlorothiazide; hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.73-1.32).

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of Randomized Groups
Table Graphic Jump LocationTable 2. Primary and Secondary Events by Treatment Assignment
Table Graphic Jump LocationTable 3. Primary Composite End Point by Treatment Assignment

References

Black HR, Elliott WJ, Neaton JD.  et al. for the CONVINCE Research Group.  Rationale and design for the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) Trial.  Controlled Clinical Trials.1998;19:370-390.
Black HR, Elliott WJ, Neaton JD.  et al.  Baseline characteristics and early blood pressure control in the CONVINCE trial.  Hypertension.2001;37:12-18.
Peto R, Collins R, Gray R. Large-scale randomized evidence: large, simple trials and overviews of trials.  J Clin Epidemiol.1995;48:23-40.
Cohen MC, Rohtla KM, Lavery CE, Muller JE, Mittleman MA. Meta-analysis of the morning excess of acute myocardial infarction and sudden cardiac death.  Am J Cardiol.1997;79:1512-1516.
Elliott WJ. Circadian variation in the timing of stroke onset: a meta-analysis.  Stroke.1998;29:992-996.
White WB, Anders RJ, MacIntyre JM.  et al.  Nocturnal dosing of a novel delivery system of verapamil for systemic hypertension.  Am J Cardiol.1995;76:375-380.
White WB, Black HR, Weber MA, Elliott WJ, Bryzinski B, Fakouhi TD. Comparison of effects of COER-verapamil at bedtime and nifedipine GITS on arising on early morning blood pressure, heart rate and the heart rate blood pressure product.  Am J Cardiol.1998;81:424-431.
Gupta SK, Yih MY, Atkinson L, Longstreth J. The effect of food, time of dosing, and body position on the pharmacokinetics and pharmacodynamics of verapamil and norverapamil.  J Clin Pharmacol.1995;35:1083-1093.
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials.  Biometrika.1983;70:659-663.
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials.  Biometrics.1979;35:549-556.
Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. New York, NY: Springer; 2000:170-179.
Ellenberg SS, Temple R. Placebo-controlled trials and active-control trials in the evaluation of new treatments, part 2: practical issues and specific cases.  Ann Intern Med.2000;133:464-470.
Gomberg-Maitland M, Baran DA, Fuster V. Treatment of congestive heart failure: guidelines for the primary care physician and the heart failure specialist.  Arch Intern Med.2001;161:342-352.
Danish Study Group on Verapamil in Myocardial Infarction (DAVIT-I).  Verapamil in acute myocardial infarction.  Eur Heart J.1984;5:516-528.
Danish Study Group on Verapamil in Myocardial Infarction.  Effect of verapamil on mortality and major events after acute myocardial infarction: the Danish Verapamil Infarction Trial II (DAVIT-II).  Am J Cardiol.1990;66:779-785.
Addonizio Jr VP, Fisher CA, Strauss 3rd JF, Wachtfogel YT, Colman RW, Josephson ME. Effects of verapamil and diltiazem on human platelet function.  Am J Physiol.1986;250:H366-H371.
Lacoste L, Lam JY, Hung J, Waters D. Oral verapamil inhibits platelet thrombus formation in humans.  Circulation.1994;89:630-634.
Ding YA, Chou TC, Lin KC. Effects of long-acting propranolol and verapamil on blood pressure, platelet function, metabolic and rheological properties in hypertension.  J Hum Hypertens.1994;8:273-278.
He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized clinical trials.  JAMA.1998;280:1930-1935.
Hansson L, Hedner T, Lund-Johansen P.  et al.  Randomised trial of effects of calcium antagonists compared with diuretics and β-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) Study.  Lancet.2000;356:359-365.
Blood Pressure Lowering Treatment Trialists' Collaborative.  Effects of ACE-inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials.  Lancet.2000;356:1955-1964.
Smolensky MH, Portaluppi F. Chronopharmacology and chronotherapeutics of cardiovascular medications: relevance to prevention and treatment of coronary heart disease.  Am Heart J.1999;137:S14-S24.
The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on death from cardiovascular causes, myocardial infarction, and stroke in high-risk patients.  N Engl J Med.2000;342:145-153.
ALLHAT Collaborative Research Group.  Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT).  JAMA.2000;283:1967-1975.
Staessen JA, Fagard R, Thijs L.  et al. for the Systolic Hypertension Europe (Syst-EUR) Trial Investigators.  Morbidity and mortality in the placebo-controlled European Trial on Isolated Systolic Hypertension in the Elderly.  Lancet.1997;350:757-764.
Agodoa LY, Appel L, Bakris GL.  et al. for the African American Study of Kidney Disease and Hypertension (AASK) Study Group.  Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial.  JAMA.2001;285:2719-2728.
Lewis EJ, Hunsicker LG, Clarke WR.  et al.  Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.  N Engl J Med.2001;345:851-860.
Brenner BM, Cooper ME, de Zeeuw D.  et al. for the Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) Study Group.  Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.  N Engl J Med.2001;345:861-869.
ALLHAT Collaborative Research Group.  Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).  JAMA.2002;288:2981-2997.
 The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI).  Arch Intern Med.1997;157:2413-2446.
CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 336

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...