1. Systolic hypertension not an isolated problem Michael Weber, MD Professor of Medicine Associate Dean Downstate College of Medicine State University of New York Brooklyn, NY George L Bakris, MD Director Hypertension-Clinical Research Center Rush Medical College Chicago, IL

2. Cardiovascular risk Systolic hypertension The association between systolic hypertension and cardiovascular risk is well recognized and has been seen in: prospective clinical trials (eg, SHEP) multiple retrospective analyses (eg, Framingham data) analyses of cardiovascular risk data from renal patients with systolic hypertension

3. Relative risk Systolic hypertension The evidence suggests that systolic blood pressure (SBP), especially in people > 55 is a relatively more powerful predictor of cardiovascular events than is diastolic blood pressure (DBP). The Framingham data suggest that this difference in relative risk is 2-3 fold higher for SBP compared to DBP.

4. The lower the better Systolic hypertension The old adage that systolic blood pressure should equal “100 plus your age” is false. Prospective investigation has shown that in the older age groups, reducing SBP to 130- 140 mm Hg reduces risk for cardiovascular events and mortality.

5. Pathophysiology Systolic hypertension As the vasculature ages, relaxation is less likely to occur, and DBP rises. SBP pressure is also a reflection of the hardened posture of the vessels. Older vessels are less pliable and contribute to an increased pulse pressure which may be as important a predictor for cardiovascular events as an elevated SBP.

6. Conclusions for management Systolic hypertension 1) Reducing SBP to around 140 or less gives better cardiovascular risk reduction than maintaining the SBP at 160-170. 2) The population that benefits the most from this reduction is the elderly.

7. The aging of America “The population that will get the greatest benefit are actually the oldest patients, that is those patients that are 75-80 years of age, and with the aging of America, for that matter the world, at least the Western world, I think those are significant findings.” George L Bakris, MD Director of the Hypertension/Clinical Research Center at Rush Medical College Chicago, IL

8. Meeting the JNC-VI guidelines Systolic hypertension The JNC-VI (Joint National Commission) guidelines state that SBP should be less than 140 for everyone regardless of age. In the presence of comorbid conditions (diabetes, diabetic nephropathy), lower values (eg, 130) are recommended. Reaching these values is one of the most difficult tasks in clinical medicine.

9. Treatment recommendations Systolic hypertension Prospective treatment trials (SHEP, Systolic Hypertension in the elderly program and Syst-Eur, Systolic Hypertension in Europe trial) used calcium channel blockers (CCB’s) and diuretics to reduce SBP. Combination therapy, such as the additional use of ACE inhibitors in diabetics, or beta- blockers in patients with angina, is often required. Most patients will need to be controlled with 2-4 different medications.

10. Which antihypertensive? “So we shouldn't be arguing should it be a calcium channel blocker, should it be an ACE inhibitor, should it be a diuretic – the fact is that most of our patients are going to require 2 if not all 3 of those drugs. And sometimes even that isn't quite enough.” Michael Weber, MD Immediate past president of the American Society of Hypertension

11. Treat the elderly Systolic hypertension There does not appear to be an upper age limit for benefit in the treatment of SBP. The goal is to reduce stroke risk. A linear correlation exists between the level to which you've reduced blood pressure and the relative risk for stroke.

12. SBP as an endpoint Systolic hypertension SBP and renal disease endpoints are becoming more important in drug development. The FDA approves medications for “the treatment of hypertension” which may be the treatment of DBP, SBP or both.

13. CCB’s inferior? “To say they provide no benefit is at best a stretch and the analysis used to come up with that conclusion is flawed in many respects, not the least of which being the trials that were selected.” George L Bakris, MD … on a meta-analysis showing CCB’s to be inferior, presented by Dr Curt Furberg at the recent 2000 ESC meeting in Amsterdam

14. Ongoing clinical trials The first interim analysis from a prospective WHO/ISH meta-analysis of “ongoing” clinical trials (trials not published before 1995) in hypertension, coronary artery disease, and CHF analysis was reported at the International Society of Hypertension meeting (Chicago, August 24, 2000). This interim analysis is based on 14 clinical trials involving 75 000 patients and >6000 cause-specific cardiovascular events. Meta-analysis

15. The debate over CCB’s Dr Steven MacMahon (Institute for International Health, University of Sydney, Australia) reported on the interim analysis. and drew two conclusions, as follows: 1) the newer agents, such as CCBs and ACE inhibitors, reduce cerebrovascular and cardiovascular complications, and 2) only small differences exist between the different classes of drugs - diuretics, beta blockers, calcium antagonists and ACE inhibitors Heartwire/Sep 1, 2000/Experts condemn Furberg's meta- analysis showing calcium channel blockers to be inferior.

16. NORDIL study Systolic hypertension The Nordic Diltiazem (NORDIL) study group enrolled 10 881 patients aged 50 - 74 years with a diastolic BP of > 100 mm Hg. Patients were randomly assigned to receive diltiazem, diuretics, beta blockers, or a diuretic/beta blocker combination. Endpoints included the incidence of fatal and nonfatal stroke, MI, and other cardiovascular death. The mean duration of follow-up was 4.5 years.

17. NORDIL results Systolic hypertension SBP and DBP were lowered effectively in all groups, and diltiazem was as effective as diuretics, beta blockers or both in preventing all stroke, MI and other cardiovascular death. All regimens were equally well-tolerated. Hansson L, et al. Lancet 2000; 356: 359-365

18. INSIGHT study Systolic hypertension The Intervention as a Goal in Hypertension Treatment, or INSIGHT trial compared the effects of nifedipine with the combination amiloride and hydrochlorothiazide on cardiovascular death, MI, heart failure, or stroke. The trial randomized 6321 patients aged 55 to 80 years with BP >150/95 mm Hg or >160 mm Hg systolic and at least one additional cardiovascular risk factor to either of the two treatment arms.

19. INSIGHT results Systolic hypertension As in the NORDIL trial, the effect on primary outcomes was similar in the two groups, there were an equal number of deaths, and both drugs lowered BP equally effectively. Brown MJ, et al. Lancet 2000; 356: 366-372