Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints Trial - CONVINCE


The goal of the CONVINCE trial was to determine equivalency in the incidence of MI, stroke, or cardiovascular-related death among hypertensive patients randomized to controlled onset-extended release-verapamil vs standard of care (atenolol or hydrochlorothiazide).


Controlled onset-extended release-verapamil will be equivalent to standard of care in the incidence of MI, stroke, or cardiovascular-related deaths. Equivalence bounds for the hazard ratio (HR) were prespecified as 0.86 to 1.16.

Study Design

Study Design:

Patients Enrolled: 16476
Mean Follow Up: mean 3 years
Mean Patient Age: mean 65.6 years
Female: 56%

Patient Populations:

Hypertensive; age >=55 years; and established second risk factor for cardiovascular disease (obesity, diabetes, dyslipidemia, LV hypertrophy, cigarette smoking, prior MI, vascular disease, stroke or TIA).

Primary Endpoints:

First occurrence of stroke, MI, or cardiovascular disease–related death

Secondary Endpoints:

1) 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.

Drug/Procedures Used:

Patients were randomized double-blind to controlled onset-extended release (COER)-verapamil (180 mg/day; n=8241), which has its major antihypertensive effect 6-12 hours after administration; or standard of care (SOC, n=8361) which was defined as either hydrochlorothiazide (HCTZ, 12.5 mg) or atenolol (50 mg), one of which is preselected by the investigator for an individual patient prior to randomization. Initial doses were doubled if blood pressure (BP) did not reach target goals (systolic BP < 140 mm and diastolic BP < 90 mm Hg). If BP is not controlled by the higher dose of the initial medication, HCTZ was added to COER-verapamil, or the SOC choice not initially selected is added in the SOC arm. Third step therapy was ACE-inhibitors.

Principal Findings:

Patients were to be monitored for clinical events for 5 years. However, the trial was discontinued early by the sponsor due to commercial considerations before unblinding the results. At the close of the trial, approximately 40% had discontinued the blinded study medication in each arm. Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg in the COER verapamil group and by 13.5 and 7.1 mm Hg in the atenolol or hydrochlorothiazide group (p=NS for SBP between arms). The primary endpoint occurred in 364 patients in the COER verapamil group vs 365 in atenolol or hydrochlorothiazide group (HR 1.02; 95% CI 0.88–1.18; p=0.77); the upper bound of the 95% CI for the primary endpoint (HR 1.18) exceeded the prespecified boundary (HR 1.16) for equivalence. There were no significant differences in the individual components of the composite: fatal or nonfatal MI (HR=0.82, 95% CI 0.65–1.03; p=0.09); fatal or nonfatal stroke (HR 1.15, 95% CI, 0.90–1.48; p=0.26); and cardiovascular disease–related death (HR=1.09, 95% CI, 0.87–1.37; p=0.47). There was also no difference in the secondary endpoint of primary endpoint events or CV-related hospitalization (HR 1.05, 95% CI 0.95–1.16; p=0.31). However, hospitalization for heart failure, a component of the secondary cardiovascular disease endpoint, was higher with COER verapamil vs atenolol or hydrochlorothiazide (HR 1.30, 95% CI 1.00–1.69; p=0.05).


Among hypertensive patients with 1 or more additional risk factors, the CONVINCE trial did not demonstrate equivalence in the primary endpoint of long acting verapamil-based antihypertensive treatment compared to a regimen beginning with a diuretic or beta-blocker. However, it is unclear if the trial would have met its primary endpoint had it not been discontinued prematurely by the sponsor due to commercial considerations. Given this major flaw, limited conclusions can be drawn from the study. Further analyses are planned by choice of atenolol or hydrochlorothiazide and use of treatment in steps 2 and 3. The only significant benefit observed was with heart failure in the diuretics and beta-blockers arm, which are usual therapy for heart failure, unlike verapamil, which has been associated with an increased risk of heart failure in earlier studies. As the authors note, the data in this trial are similar to the recently published ALLHAT trial, which showed 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.


JAMA 2003;289(16):2073-2082.

Keywords: Stroke, Chlorthalidone, Standard of Care, Diuretics, Coronary Disease, Blood Pressure, Calcium Channel Blockers, Smoking, Dyslipidemias, Heart Failure, Obesity, Verapamil, Hydrochlorothiazide, Amlodipine, Hypertrophy, Hospitalization, Hypertension, Diabetes Mellitus

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