A Randomized Controlled Phase Ⅳ Trial With Two Equally Sized Treatment Groups: Amlodipine And Nifedipine GITS

1. Study name: Amlodipine Prevents Morning Blood Pressure Surge Study (ARMORS)
2. Study drugs: amlodipine (Norvasc®) and nifedipine GITS (Adalat®)
3. Rationale:

Previous meta-analyses of randomized controlled trials have demonstrated that the long acting dihydropyridine calcium channel blocker amlodipine (Norvasc®), compared with other antihypertensive drugs, provides more protection against stroke. The benefit of amlodipine against stroke is approximately 10% greater than diuretics/β-blockers, and 20% greater than angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Of all the dihydropyridine calcium channel blockers, only amlodipine provides protection against myocardial infarction similar as angiotensin-converting enzyme inhibitors, diuretics and β-blockers, and more than angiotensin receptor blockers. The benefit of amlodipine in the prevention of stroke might be attributable to its 24-h blood pressure control.

24-h ambulatory blood pressure is more predictive of cardiovascular events than clinic pressure measured in doctor's office. The smoother the 24-h ambulatory blood pressure control, the lower the risk of target organ damage. Both systolic and diastolic blood pressure show a circadian rhythm with a nocturnal blood pressure fall and a morning blood pressure surge. The incidence of cardiovascular complications of hypertension, such as myocardial infarction and stroke, is higher in the early morning hours than the rest of the day. Several previous studies have demonstrated that an exaggerated morning blood pressure surge is associated with the incidence of stoke and with cardiovascular structural remodeling. Moreover, non-dipping of blood pressure at night (non-dipper, nighttime blood pressure fall less than 10%) is prevalent and is associated with a higher risk of cardiovascular event. In a recent study of controlled hypertensive patients, the prevalence of non-dipping of blood pressure at night was 62%. In our JingNing population study, we found that Chinese had a higher nighttime diastolic blood pressure than White populations, and the prevalence of isolated nocturnal hypertension was 10.9%. Patients with isolated nocturnal hypertension compared with normotensive subjects had an increased arterial stiffness. Thus, a preferable antihypertensive drug should not only reduce the 24-h mean level of blood pressure, but should also effectively control morning blood pressure surge and reduce nighttime blood pressure.

At present, there are two mechanisms of long-acting antihypertensive agents. One is that the compound itself has a long half life time and hence shows a long term effect. Another is that the efficacy of a short-acting drug is elongated by using a slow release or a controlled release (such as GITS) technique. However, the latter mechanism may vary between individuals because of the difference in the gastrointestinal function. Therefore, a long-acting compound should be more reliable in the maintenance of long term efficacy than slow release or controlled release agents. In the class of dihydropyridine calcium channel blockers, amlodipine is a long-acting compound because of a long half life time (up to 50 hours), and nifedipine GITS uses a controlled release technique. Several recent studies compared 24-h blood pressure lowering effect of these 2 drugs, but produced inconsistent results. At least one study suggested that amlodipine may prevent morning blood pressure rise more effectively than nifedipine GITS. However, other studies demonstrated similar effect on morning blood pressure control of these 2 drugs. The inconsistency might be attributable to a chance finding, because of the small sample size (less than 100). Therefore, a randomized controlled trial with a larger sample size is required to compare these 2 dihydropyridines in the blood pressure control over 24 hours in general and during early morning hours and at night in particular.

4. Objective: The primary objective of this study is to test the hypothesis that amlodipine compared with nifedipine GITS has a stronger effect in preventing morning blood pressure surge (4 am to 8 am) in mild to moderate hypertensive patients.