Jan A. Staessen
Studies Coordinating Centre， Division of Hypertension and Cardiac Rehabilitation， University of Leuven， Belgium

PROSPECTIVE COHORT studies in predominantly Asian1 or Caucasian2 populations unani mously demonstrated strong associations of the incidence of cardiovascular complications with both systolic and diastolic blood pressures.  These associations were present at all ages.1，2  The risk continuously increased with blood pressure without threshold and already started to rise at levels well within the normotensive range， as low as 115 mm Hg systolic or 75 mm Hg diastolic.1，2  More importantly， these prospective studies demonstrated that small gradients in blood pressure might account for substantial differences in cardiovascular outcomes.1，2  In keeping with large-scale prospective observational studies，1，2 meta-regression analyses published by us3-6 and other research consortia7 demonstrated that small gradients in the achieved systolic blood pressure explained most of the differences in the cardiovascular outcomes as observed in randomized clinical trials.  This association was particularly strong for the prevention of stroke，7 the complication most directly associated with blood pressure，8 and weakest for heart failure.7  A recent meta-analysis questioned the specific reno-protective effects of ACE inhibitors and ARBs on renal outcomes in diabetic as well as non-diabetic patients， over and beyond those due to the blood pressure lowering per se.9  In an update of our 20013 and 20034 meta-regression analyses， we accounted not only for the difference in the achieved systolic blood pressure between groups randomized in clinical trials， but also for drug class， the interaction between on-treatment systolic pressure and drug class， age at randomization， year of publication， and duration of follow-up.6  We included trials that compared either CCBs or ACE inhibitors with placebo or older drugs.6  We corroborated that blood pressure reduction was by far the most important determinant of cardiovascular outcome.  In addition， we found that CCBs compared to ACE inhibitors， over and beyond their blood pressure lowering effects， provided a small benefit (~14%; P=0.042) in the prevention of stroke and that the same was true for ACE inhibitors compared to CCBs for the prevention of coronary heart disease (~10%; P=0.028).6  In contrast to ACE inhibitors， ARBs do not produce a blood pressure independent reduction in the relative risk of coronary heart disease.10  

From our previously published meta-regression analyses，4 we could accurately predict the relative risk reduction on treatment with amlodipine vs. valsartan in VALUE11 and with the newer vs. the older antihypertensive drugs in ASCOT.12  These findings13 highlight that blood pressure control must have been the main determinant of cardiovascular outcomes in these two trials.  

In conclusion， we6 and other researchers10 found that it required from 150 00010 to 180 0006 randomized patients followed up from 3 to 5 years to demonstrate a 10% to 15% benefit beyond blood pressure lowering of CCBs or ACE inhibitors over other classes of antihypertensive in the prevention of stroke or myocardial infarction， respectively.  These findings underscore that blood pressure lowering ——not special properties of antihypertensive agents —— are key in cardiovascular prevention.  Moreover， in most patients， optimization of treatment at acceptable tolerance requires rotation through and combination of several drug classes.14  Thus， the discussion which drug should be used to initiate antihypertensive treatment is largely elusive. 

References
1. Asia Pacific Cohort Studies Collaboration. Blood pressure indices and cardiovascular disease in the Asia Pacific region.  A pooled analysis. Hypertension.  2003;42:69-75.
2. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality : a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet.  2002;360:1903-1913.
3. Staessen JA， Wang JG， Thijs L. Cardiovascular prevention and blood pressure reduction .Lancet. 2001;358:1305-1315.
4. Staessen JA， Wang JG， Thijs L. Cardiovascular prevention and blood pressure reduction.J Hypertens.  2003;21:1055-1076.
5. Staessen JA， Li Y， Thijs L， Wang JG. Blood pressure reduction and cardiovascular prevention. Hypertens Res.  2005;28:385-407.
6. Verdecchia P， Reboldi G， Angeli A， et al. Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention. Hypertension.2005;46:386-392.
7. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events : results of prospectively-designed overviews of randomised trials. Lancet.  2003;362:1527-1535.
8. Zhang H， Thijs L， Staessen JA. Blood pressure lowering for the primary and secondary prevention of stroke. Hypertension.  2006;48:187-195.
9. Casas JP， Chua W， Loukogoergakis S， et al.Effects of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes : systematic reveiw and meta-analysis. Lancet.  2005;366:2026-2033.
10. Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens.  2007;25:951-958.
11. Julius S， Kjeldsen SE， Weber M， et al. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens : VALUE， a randomised trial. Lancet.  2004;363:2022-2031.
12. Dahl??f B， Sever PS， Poulter NR， et al.Prevention of cardiovascular events with an amlodipine °?? perindopril strategy compared with an atenolol °?? thiazide strategy.  The Anglo-Scandinavian Cardiac Outcomes Trial - Blood Pressure Lowering Arm (ASCOT-BPLA) : a multicentre randomised controlled trial. Lancet.  2005;366:895-906.
13. Staessen JA， Birkenh??ger WH. Evidence that new antihypertensives are superior to older drugs. Lancet.  2005;366:869-871.
14. Dickerson JEC， Hingorani AD， Ashby MJ， et al.Optimisation of antihypertensive treatment by crossover rotation of four major drug classes. Lancet.  1999;353:2008-2013.