I. Introduction

Conventional clinic measurements of blood pressure recorded by physicians or nurses using mercury sphygmomanometers has long been the clinical standard (blood pressure measurement”). However this technique has several important limitations, including the potential for misclassification of hypertensive status in individuals and incorrect prediction of cardiovascular risk. The rationale of the sub study is to complete the goals of the INVIEST trial utilizing the advantages of ambulatory blood pressure monitoring in the determination of the efficacy of two different antihypertensive treatment strategies.

2. Background

The diagnosis and treatment of hypertension has traditionally been based on office blood pressure measurements, although it is well-known since decades, that a single office reading is influenced by several factors, like emotional state, time of the day, physical activity (1,2). It is also well established, that office blood pressure readings overestimate the patient’s average blood pressure outside the medical setting (3). Since the availability of accurate, small and inexpensive ambulatory blood pressure monitors improved dramatically in the 1990s, several studies were performed to examine the predictive value of such devices in the determination of the risk of cardiovascular morbidity in patients with hypertension. It has been found, that ambulatory blood pressure is an independent predictor of prognosis in essential hypertension (4). and more valuable in prognosticating the cardiovascular risk (5) and treatment-induced regression of left ventricular hypertrophy in hypertensive patients (6). The use of ABFM revealed the percentage of white coat hypertensive subjects among the patients with high blood pressure helping the accurate diagnosis of hypertension (7). This has important implications, since inadequate use of drugs in one hand frequently causes bothersome symptoms. Adverse effects. On the other hand it can lead to insufficient therapy, particularly at 16-24 hours post dose. These effects worsen the compliance of patients; can lead more often to otherwise unnecessary visits at the doctor’s office (S). This is especially substantial in antihypertensive trials, since the inadequate inclusion of patients can increase the number of drop-outs”. It is also important. that by improving the precision of a trial, the number of subjects can be minimized. (9) The determination of the duration of activity of an antihypertensive drug and the evaluation of the trough / peak ratio also implicates extra information about the value of the treatment (10). Limited information is available about face to face comparisons of a calcium antagonist vs. beta blocker based strategy on the more fine blood pressure control which can be obtained by ABPM only.

3. Aim of the study

The first objective of this supplementary study is to determine the circadian systolic and diastolic blood pressure parameters and heart rate in patients before nd after 1 year of randomized treatment. The second goal is to see, if there is any difference between daytime and nighttime blood pressure values arid blood pressure variability between the two investigated anti-hypertensive therapy: the calcium antagonist strategy compared to the non- calcium antagonist strategy,

4. Study design

Ambulatory blood pressure monitoring will be performed two times: at the randomization (at visit 1/week 0) and at the 52 week in the same patient group.

5. Study population

Number of patients

200 hypertensive patients (100 per treatment group) should be enrolled; the demographic characteristics of the patients should be representative to the whole IN’VEST population (gender, age, office blood pressure values, and clinical characteristics).

Inclusion criteria (same as the general INVEST population.)

1. Male or female,

2. Age 50 to no upper limit.

3. Hypertension, documented according to the 6th report of the Joint National Committee on Detection and Evaluation of the treatment of high blood pressure (JNC V and the need for drug therapy.

4. Documented coronary artery disease (e.g. classic angina pectoris); myocardial. Infarction three or more month ago; abnormal coronary angiography, or concordant abnormalities on two different types of stress tests.

5. Willingness to sign informed consent.

Exclusion criteria

1. Unstable angina, angioplasty, CABG or stoke within one month. Patients taking beta blockers after myocardial infarction are excluded if study enrollment is planned within 12 months of myocardial infarction. No time limitation if not taking beta blocker.

2. Use of beta blocker within past two weeks.

3. Patients without a pacemaker and any of the following: sinus Bradycardia, sick sinus syndrome, AV-block higher than l degree.

4. Documented contraindication to verapamil, atenolol and hydrochlorothiazide

5. Any kind of Atrial fibrillation

6. Severe heart failure (NYHA IV).

7. Concomitant severe illnesses, which may affect outcome variables or where life expectancy is two year or less, or which are likely to require frequent hospitalizations and / or treatment adjustments.

8. Patients with psychiatric, cognitive or social conditions that would interfere with giving consent cooperating or remaining available for follow up for two years.

9. Unableness to wear blood pressure monitoring device,*

10. Severe muscular tremor (e.g. Parkinsonism),*

    * in addition to the exclusion criteria of the general IN VEST population

6. Methods

Devices

Meditech ABPM-02, 03, 04 devices will be used. These automatic non-invasive ambulatory blood pressure monitors are validated according to the British Hypertension Society (11).

Measurements

Blood pressure and heart rate measurements will be taken by oscillometric method, uniformly in every 30 minutes during a 24 hours period. The patients will be provided with the monitors in the morning, after the determination of office blood pressure and heart rate. Investigators should ensure that measurements are taken at .00 and .30 of each hour, preferably starting at 900 a.m, Patients will have to make notes about their daily activity according to a simplified diary (without making any attempt to control behavior) and they will be asked to try to spend the day like any other “average day”, They will be asked to keep their arn still during cuff inflation (to avoid false readings). The patients will be asked to return to the hospital at the end of the 24 hour to take the monitor off.

7. Data analysis

The recorded and stored data will be edited to remove artifacts according to predetermined criteria ,l2), Only dose recordings can be included and further evaluated in the study, which have 8B9/ valid data of the 24 hours measurements (38 measurements or above). If this is not fulfilled, the recording should be repeated. 24 hours, daytime and rii average systolic, diastolic blood pressure and heart rate values will be calculated.)The number of elevated systolic and diastolic blood pressure measurements [ in % of the total number of measurements] and systolic and diastolic pressure load during daytime and nighttime will be determined as well, Pressure load is the area under the systolic/diastolic blood pressure curve above normal blood pressure level [ The cutoff values for daytime systolic, diastolic, and nighttime systolic, diastolic blood pressure are 135 Hgmm, 85 l-Hgmm. 120 Hgmm, 75 Hgmm, respectively pressure variability will be characterized as systolic and diastolic diurnal index =/- SDs{(1- nighttime BP average / daytime BP average) x 100%} Data are stored on floppy disks in the study center until it is collected by the Principal Investigator for further analysis.

8. References

1. Mancia G et al. Effects of blood pressure measurement by the doctor on patient’s
   blood pressure and heart rate. Lancet, 1983; ii:695-698.

2. Pickering TO at al. Blood pressure during normal daily activities, sleep and exercise; comparison of values in normal and hypertensive subjects. JAMA, 1982; 247:992-996.

3. Pickering TG et al, How common is white coat hypertension JAMA 1988;
   258:225- 228,

4. Verdecchia P et al, Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension. Hypertension, 1994 ;24 :793 -801.

5. Staessen IA et al. Predicting cardiovascular risk using conventional vs ambulatory
   blood pressure in older patients with systolic hypertension. JAA’L4, 1 999

6. Maricia G et al. Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricular hypertrophy. Circulation, 1997; 95:1464. 1470.

7. Sheps SG et al, Current role of automated ambulatory blood pressure and self-measured pressure determinations in clinical practice. Mayo C/in Proc. 1994; 69; l000-1005

8. Appel U et al Ambulatory blood pressure monitoring and blood pressure self Measurement in the diagnosis and management of hypertension. Ann of Int Medicine, 1993; 1lS:S67-882.

9. Purcell HJ et al. Ambulatory blood pressure monitoring and circadian variation of Cardiovascular disease; clinical and research application mt .1 Cardiology, 1992 ;3 6:135-149,

10. White WB. Analysis of ambulatory blood pressure data in antihypertensive drug Trials. J. Hypertension. 1991; 9(S I):S27-S32,

11. Barna I at a]. Evaluation of the Meditech ABPM-04 ambulatory blood pressure Measuring device according to the British Hypertension Society protocol. Blood Pressure Monitoring, 1998 3(6)363-368.

12. Berardi L et al. Ambulatory blood pressure monitoring; a critical review of the current methods to handle outliers. .J Hypertension, 1992; 10:1243-1 248.