Supplemental File METHODS
Blood Pressure Measurement in INVEST
Manual office BP was measured in accordance with JNC VI recommendations [1]. At each visit, patients entered a quiet room with minimal extraneous activity and temperature fluctuations. Patients were seated, with legs uncrossed and feet flat on the floor, and the arm rested at heart level, with the patient’s hands pointing upwards. Blood pressure was measured with a standard mercury sphygmomanometer and appropriately-sized cuff. At the baseline visit, BP was measured in both arms by auscultation at the brachial artery, systolic pressure was recorded at the first Korotkoff sound and diastolic pressure was recorded at the disappearance of the fifth Korotkoff sound. If a difference of >5 mmHg was found in either SBP or DBP, the arm with the higher reading was used for that visit and all subsequent visits. At each visit, BP was measured twice in the same brachial artery using the above method, at least 2 minutes apart.
These measurements were averaged for a final study visit BP. Investigators were instructed to measure BP at approximately the same time of day in a given patient throughout the trial.
Blood pressure goals in INVEST were based on then-current JNC VI targets [1]. These goals were systolic BP <140 mmHg and diastolic BP <90 mmHg for the general population and systolic BP <130 mmHg and diastolic BP <85 mmHg for patients with diabetes or renal
impairment.
Antihypertensive Treatment Protocol in INVEST
The Supplemental Figure describes the stepped treatment protocol employed in INVEST [2]. Following randomization, patients had baseline antihypertensive medications discontinued.
Those that were randomly allocated to a calcium channel blocker (CCB) strategy were prescribed 240 mg/day of verapamil-SR, whereas patients allocated to the β-blocker strategy were prescribed 50 mg/day of atenolol (step 1). If patients did not achieve target BP, step 2 entailed adding trandolapril for the CCB group and hydrochlorothiazide (HCTZ) for the β- blocker group. The rationale for this approach was to maximize use of the combination of calcium antagonist and ACE inhibitor while minimizing diuretic use for the CCB group and maximizing use of the combination of β-blocker and diuretic for β-blocker group. In step 3, doses were increased in both groups. In step 4, the CCB group also could receive HCTZ and the β-blocker group also could receive trandolapril.
If the dose was not well-tolerated or target BP was not achieved, verapamil-SR could be titrated to between 120 and 480 mg/day and atenolol could be titrated to between 25 and 200 mg/day. The recommended starting dose for trandolapril was 2 mg/day and it could be titrated to between 0.5 and 8 mg/day. For patients in the CCB group, a fixed combination was available for verapamil SR and trandolapril in doses of 180 mg/day and 2 mg/day, respectively; 240 mg/day and 1 mg/day; and 240 mg/day and 4 mg/day. The recommended starting dose for HCTZ was 25 mg/day and it could be titrated between 12.5 and 100 mg/day. Doses >25 mg of HCTZ were provided to limit the need for nonstudy diuretics in patients with heart failure or edema. If the target BP was not achieved and adverse effects had not occurred, doses were titrated as in the Supplemental Figure before a patient was moved to the next step. Nonstudy antihypertensive drugs, except β-blockers for patients in the CCB group, and calcium antagonists for the β- blocker group, could be added when needed to reach BP targets or minimize adverse effects.
Trandolapril was recommended for all patients with renal impairment, diabetes, or heart failure as early as step 1. Standard of care nonpharmacological JNC VI guidelines [1] and secondary prevention according to National Cholesterol Education Program [3,4] were provided online to physicians, which could be printed and given to patients.
Supplemental Figure. Treatment protocol following randomization in the INternational VErapamil-trandolapril STudy (INVEST). DM, diabetes mellitus; HF, heart failure; SR, sustained release. The white boxes indicate the initial treatment after randomization, at which time home antihypertensive medications were discontinued. Shaded boxes represent
antihypertensive regimen titration steps.
References:
1. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157(21):2413–46.
2. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, et al.;
INVEST Investigators. 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. JAMA 2003;290:2805–2816.
3. National Cholesterol Education Program. Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II).
Circulation 1994;89:1333-445.
4. Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
Circulation 2002;106:3143–421.
