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Published on 1 September 2004

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Use of Ang-II antagonists in ISH: the Val-Syst study

teaser

Paolo Palatini
MD
Professor of Emergency Medicine
Dipartimento di Medicina Clinica e Sperimentale
Università di Padova
Padova
Italy
E:palatini@unipd.it

In recent years, evidence has been accumulating that systolic blood pressure (SBP) is more important than diastolic blood pressure (DBP) in determining cardiovascular morbidity and mortality, especially in elderly subjects.(1,2) Isolated systolic hypertension (ISH) is associated with a several-fold excess risk of cardiovascular mortality, and thus a rapid decrease of SBP should be sought in this condition. (3) In fact, a recent meta-analysis showed that treatment of systolic hypertension led to a 30% reduction in combined fatal and nonfatal stroke, a 26% reduction in fatal and nonfatal cardiovascular events, and a 13% reduction in total mortality.(3)

Arterial stiffening through increased pulse wave velocity causes early wave reflection, thereby increasing peak systolic pressure in the aorta. This effect may be partially reversed by antihypertensive treatments, especially drugs acting on the renin–angiotensin system (RAS) or calcium-
channel blockers.

In hypertensive patients, the established therapeutic goal is to reduce BP while causing minimal or no adverse effects. This is particularly important in elderly patients, in whom altered metabolism and an exaggerated response to treatment may, at least partially, modify the risk–benefit profile of different drugs. The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in patients with hypertension have been clearly demonstrated.(4,5) However, the reactive increases in renin and angiotensin (Ang)-I plasma levels may override the ACE inhibition, and Ang-I may be converted into Ang-II by alternative, non-ACE enzymes, including chymase.(6–9) In recent years, evidence has been accumulating on AT(1) (Ang-II type 1) receptor antagonists, showing that these drugs cause more effective RAS suppression than ACE inhibition and could, thus, provide greater benefits.(10,11) Furthermore, Ang-II receptor blockers proved to be better tolerated than other leading classes of antihypertensive agents.(12)

The Val-Syst study
The Val-Syst study was a 24-week, parallel-group, titration-to-effect, double-blind trial that aimed to evaluate whether valsartan, a highly selective AT(1)-subtype Ang-II receptor antagonist, had a better risk–benefit profile than the calcium-entry blocker amlodipine in elderly subjects with ISH.(13) Given the particular population selected for the study, hydrochlorothiazide (12.5mg) was considered a rational choice for the second drug to be added in both groups.

The study involved 421 patients aged 60–80 years with ISH attending 35 outpatient centres in Italy. After a two-week washout period, the patients were randomised to valsartan (80–160mg) once daily or amlodipine (5–10mg) once daily. If adequate BP control was not achieved within 16 weeks, low-dose hydrochlorothiazide (12.5mg) was added for a further eight weeks. In a subset of 187 patients, ambulatory BP monitoring (ABPM) was performed at the baseline and at the end of the treatment period. Sitting SBP was effectively reduced by both treatments throughout the study: –30.7 (13.9)/–5.6 (6.1)mmHg in the valsartan group and –32.2 (11.3)/–6.6 (6.1)mmHg in the amlodipine group at week 16, and, respectively, –33.4 (11.2)/–6.0 (6.0)mmHg and –33.5 (10.0)/–6.5 (6.0)mmHg at week 24. By the end of the study, SBP control (<140mmHg) was achieved in 74.7% of patients on valsartan and 73.0% of patients on amlodipine.

The results of the ABPM substudy(14) confirmed that both valsartan- and amlodipine-based treatments effectively lowered mean 24h, day- and night-time systolic ambulatory BP (all p<0.001). However, among the 138 responders, the valsartan-based treatment had a greater antihypertensive effect during the daytime hours (p=0.02), a difference that was also significant for average 24h BP (p=0.02). It is interesting to note that ambulatory heart rate decreased in the subjects on valsartan and slightly increased in those on amlodipine (the differences in 24h and daytime heart rate were significant, with p-values of 0.008 and 0.002, respectively). Patients reporting at least one adverse event were more frequent (p=0.0026) in the amlodipine group (31.9%) than in the valsartan group (20.2%). Peripheral oedema occurred with greater frequency (p<0.0001) in the patients on amlodipine (26.8%) than in those on valsartan (4.8%).

Discussion
The results of the Val-Syst study show that, in ISH subjects, valsartan, alone or combined with a diuretic, is as active on SBP as amlodipine-based treatment, with a lower proportion of subjects experiencing adverse events.(13)

An interesting finding of the ABPM substudy is that, among treatment responders, the combination valsartan– hydrochlorothiazide reduced SBP (mainly during the daytime) to a greater extent than amlodipine– hydrochlorothiazide, which led to a significantly greater decrease in average 24h values.(14) To improve compliance with treatment of hypertension and control of BP in the general population, more attention should be given to the risk–benefit ratio of the antihypertensive drugs, with this ratio driving doctors’ decisions. There is growing evidence that, in patients with high cardiovascular risk, AT(1) antagonists are well tolerated and may provide additional renal, cardiac and vascular benefits beyond those directly attributable to the reduction in BP, particularly when administered at relatively high doses.(15–17)

Recently, the Valsartan in Acute Myocardial Infarction (VALIANT) study,(18) which compared the effects of valsartan, the ACE inhibitor captopril and their combination in patients with prior myocardial infarction and evidence of heart failure and/or left ventricular dysfunction, showed that valsartan was clinically equivalent to captopril.

References

  1. Kannel WB. Historic perspectives on the relative contributions of diastolic and systolic blood pressure elevation to cardiovascular risk profile. Am Heart J 1999;138:205-10.
  2. He J, Whelton PK. Elevated systolic blood pressure and risk of cardiovascular and renal disease: Overview of evidence from observational epidemiological studies and randomized controlled trials. Am Heart J 1999;138:S211-9.
  3. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet 2000;355:865-72. [Correction in Lancet 2001;357:724.]
  4. Yusuf S, Lonn E, Bosch J, Gerstein H. Summary of randomized trials of angiotensin converting enzyme inhibitors. Clin Exp Hypertens 1999;21:835-45.
  5. Ruschitzka F, Noll G, Luscher TF. Angiotensin converting enzyme inhibitors and vascular protection in hypertension. J Cardiovasc Pharmacol 1999;34 Suppl 1:S3-12.
  6. Wolny A, Clozel JP, Rein J, et al. Functional and biochemical analysis of angiotensin II-forming pathways in the human heart. Circ Res 1997;80:219-27.
  7. Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans. Circulation 1997;95:1115-8.
  8. Gainer JV, Morrow JD, Loveland A, et al. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med 1998;339:1285-92.
  9. Urata H, Boehm KD, Philip A, et al. Cellular localization and regional distribution of an angiotensin II-forming chymase in the heart. J Clin Invest 1993;91:1269-81.
  10. Siragy HM. Angiotensin receptor blockers: how important is selectivity? Am J Hypertens 2002;15:1006-14.
  11. Burnier M, Brunner HR. Angiotensin II receptor antagonists. Lancet 2000;355:637-45.
  12. Black HR, Graff A, Shute D, et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy, tolerability and safety compared to an angiotensin-converting enzyme inhibitor, lisinopril. J Hum Hypertens 1997;11:483-9.
  13. Malacco E, Vari N, Capuano V, et al. A randomized, double-blind, active-controlled, parallel-group comparison of valsartan and amlodipine in the treatment of isolated systolic hypertension in elderly patients: the Val-Syst study. Clin Ther 2003;25:2765-80.
  14. Palatini P, Mugellini A, Spagnuolo V, et al. Comparison of the effects on 24-h ambulatory blood pressure of valsartan and amlodipine, alone or in combination with a low-dose diuretic, in elderly patients with isolated systolic hypertension (Val-syst study). Blood Press Monit 2004;9:91-7.
  15. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003.
  16. Parving HH, Lehnert H, Brochner-Mortensen J, et al. Irbesartan in patients with type 2 diabetes and microalbuminuria study group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870-8.
  17. Dickstein K, Kjekshus J, et al. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 2002; 360:752-60.
  18. Velazquez EJ, Pfeffer MA, McMurray JV, et al. Valsartan in acute myocardial infarction (VALIANT) trial: baseline characteristics in context. Eur J Heart Fail 2003;5:537-44.

Resources
European Society of Hypertension
W:www.eshonline.org
Hypertension network
W:www.bloodpressure.com
European Society of Cardiology
W:www.escardio.org
American Society of Hypertension
W:www.ash-us.org
World Hypertension League
W:www.mco.edu/whl/know.html

Events
58th Annual Fall Conference and Scientific Sessions of the Council for High Blood Pressure Research in
association with the Council on the Kidney in Cardiovascular Disease
9–12 October 2004
Chicago, USA
W:www.americanheart.org/presenter.jhtml?identifier=3015752
14th World Congress of the International Society for the Study of Hypertension in Pregnancy (ISSHP)
14–17 November 2004
Vienna, Austria
W:www.isshp2004-vienna.at



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