(Circulation. 1999;99:990-992.)
© 1999 American Heart Association, Inc.
Brief Rapid Communication |
Addition of Angiotensin II Receptor Blockade to Maximal Angiotensin-Converting Enzyme Inhibition Improves Exercise Capacity in Patients With Severe Congestive Heart Failure
From the Departments of Medicine, Divisions of Cardiology, The Albert Einstein College of Medicine, Bronx, NY (G.H., I.B., R.B., R.P., S.T., T.H.L.); Columbia Presbyterian Medical Center, New York, NY (S.D.K., D.M.); Hôpital Ambroise Paré, Paris, France (G.J.); and the University of Nebraska Medical Center, Omaha (M.T.O.).
Correspondence to Thierry H. Le Jemtel, MD, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Background—Incomplete suppression of the renin-angiotensin system during long-term ACE inhibition may contribute to symptomatic deterioration in patients with severe congestive heart failure (CHF). Combined angiotensin II type I (AT1) receptor blockade and ACE inhibition more completely suppresses the activated renin-angiotensin system than either intervention alone in sodium-depleted normal individuals. Whether AT1 receptor blockade with losartan improves exercise capacity in patients with severe CHF already treated with ACE inhibitors is unknown.
Methods and Results—Thirty-three patients with severe CHF despite
treatment with maximally recommended or tolerated doses of ACE
inhibitors were randomized 1:1 to receive 50 mg/d
losartan or placebo for 6 months in addition to standard
therapy in a multicenter, double-blind trial. Peak aerobic capacity
(
O2) during symptom-limited treadmill
exercise and NYHA functional class were determined at baseline and
after 3 and 6 months of double-blind therapy. Peak
O2 at baseline and after 3 and 6 months
were 13.5±0.6, 15.1±1.0, and 15.7±1.1 mL ·
kg-1 · min-1, respectively, in
patients receiving losartan and 14.1±0.6, 14.3±0.9, and
13.6±1.1 mL · kg-1 · min-1,
respectively, in patients receiving placebo (P<0.02 for
treatment group–by-time interaction). Functional class improved by at
least one NYHA class in 9 of 16 patients receiving losartan and
1 of 17 patients receiving placebo.
Conclusions—Losartan enhances peak exercise capacity and alleviates symptoms in patients with CHF who are severely symptomatic despite treatment with maximally recommended or tolerated doses of ACE inhibitors.
Key Words: angiotensin • heart failure • trials • exercise
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Marked elevation of angiotensin II, norepinephrine, and aldosterone plasma levels and progression of left ventricular dilatation in patients with congestive heart failure (CHF) treated with recommended doses of ACE inhibitors suggests that long-term ACE inhibition may only partially suppress the activated renin-angiotensin system.1 2 3 Mild activation of the renin-angiotensin system in sodium-depleted normotensive volunteers is more completely suppressed by combined administration of losartan, an angiotensin II type I (AT1) receptor antagonist, and captopril, an ACE inhibitor, than by either intervention alone.4
Losartan is well tolerated by patients with severe CHF who are maximally treated with ACE inhibitors in addition to standard therapy,5 but the effects of combined therapy on functional capacity in patients with severe CHF are unknown. Accordingly, the present study was undertaken to determine the effects of losartan versus placebo on exercise capacity and functional class in patients with CHF who were severely symptomatic despite treatment with optimal doses of ACE inhibitors, digoxin, and diuretics.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
The study was a prospective, double-blind, randomized, placebo-controlled trial conducted at 4 centers (Appendix). The study was approved by the ethical review board at each site; all patients gave written informed consent before participation.
Patient Population
Thirty-three patients whose symptoms of CHF were compatible with
functional class III to IV of the New York Heart Association (NYHA)
were studied. In addition to digoxin and diuretics, all
patients had been treated with ACE inhibitors at maximally
recommended or tolerated doses for 
3 months. Clinical characteristics
and medications are detailed in Tables 1
and 2. None of the patients had
participated in a physical conditioning program. Patients randomized to
losartan and placebo were similar except for a preponderance of
men and a higher dose of captopril in the losartan group.
|
|
Study Design
Randomization to losartan or placebo was preceded by a
2-week single-blind tolerability phase, which has been reported
previously.5 All patients tolerated losartan 50
mg/d. Patients were then randomized to therapy with losartan 50
mg or placebo for 6 months. Clinical assessments and laboratory
evaluations were performed weekly for 1 month and monthly thereafter.
Peak oxygen uptake (O2,
mL · kg-1 ·
min-1) during symptom-limited maximal
treadmill exercise was measured at baseline in duplicate and
subsequently after 3 and 6 months of double-blind therapy.
Study End Points and Data Analysis
The primary end points of the study were peak
O2 and NYHA functional class.
Secondary end points were laboratory safety parameters and
doses of concomitant background medications. Prerandomization peak
O2 was determined as the
highest value of 2 exercise tests with <10% variation. Peak
O2 at months 3 and 6 was
derived from a single maximal exercise test.
Case reports were centrally collected, and data were analyzed
by Lynn Sleeper, ScD (New England Research Institute, Watertown, Mass).
Repeated-measures ANOVA (SAS Institute Inc, PROC MIXED) was used to
analyze peak O2,
laboratory safety parameters, and doses of background
medications. An SAS macro for repeated-measures cumulative logistic
regression was used to analyze NYHA functional class. The daily
dose of furosemide was square root–transformed to meet the normality
assumption because of the wide dosing range for this agent. Probability
values reported are from models that incorporate time as a continuous
covariate. Values are expressed as mean±SEM.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Primary End Points
Peak
O2 at baseline and
after 3 and 6 months was 13.5±0.6, 15.1±1.0, and 15.7±1.1 mL
· kg-1 · min-1,
respectively, in patients receiving losartan and 14.1±0.6,
14.3±0.9, and 13.6±1.1 mL · kg-1
· min-1, respectively, in patients receiving
placebo (P<0.02 for treatment group–by-time interaction,
Figure 1). Functional class improved by
1 NYHA class in 9 of 16 patients receiving losartan and 1 of
17 patients receiving placebo. Functional class at baseline and after 3
and 6 months was 3.2±0.4, 2.9±0.6, and 2.5±0.8, respectively, in
patients receiving losartan and 3.0±0.4, 3.0±0.5, and
3.0±0.5, respectively, in patients receiving placebo
(P<0.001 for treatment group–by-time interaction, Figure 2).
|
) and
placebo (
).
|
Secondary End Points
Serum electrolytes, creatinine, and blood urea
nitrogen were unchanged in both treatment groups. The furosemide dose
(square root–transformed) at baseline and after 3 and 6 months was
11.5±1.1, 10.9±1.1, and 10.5±1.2, respectively, in patients
receiving losartan and 9.9±1.0, 10.0±1.1, and 10.8±1.1,
respectively, in patients receiving placebo (P<0.05 for
treatment group–by-time interaction). Doses of other background
medications were unchanged in both treatment groups. The combination of
study drug and ACE inhibitors in both treatment groups was
well tolerated, without adverse side effects.
Four patients in the placebo group and 3 patients in the losartan group did not complete the study. In the placebo group, 1 patient died suddenly, 1 underwent cardiac transplantation, 1 was no longer willing to take the study drug because of impotence, and 1 was lost to follow-up. In the losartan group, 2 patients withdrew from the study (1 was diagnosed with AIDS; the other experienced nausea), and 1 was lost to follow-up.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
The present data indicate that losartan improves peak aerobic capacity and relieves symptoms in patients with CHF who are severely symptomatic despite treatment with optimal doses of ACE inhibitors, digoxin, and loop diuretics.
The therapeutic efficacy of losartan has been demonstrated in patients with CHF in the absence of ACE inhibitors.6 7 8 9 10 Acute administration of losartan results in arterial and venous dilatation comparable to that with ACE inhibition.6 The acute hemodynamic effects of losartan are greatest at a dose of 50 mg and persist without attenuation for 12 weeks.7 In patients in whom previous ACE inhibition therapy was withdrawn, losartan and enalapril have comparable effects on exercise performance.8 9
The present study assessed the long-term effects of AT1 receptor blockade in patients with severe CHF receiving optimal doses of ACE inhibitors. Data collected from previous clinical trials have suggested that an escape phenomenon may occur during prolonged ACE inhibition.1 2 3 Whether partial deactivation is attributable to an escape from ACE inhibition during long-term therapy or to other metabolic pathways for biosynthesis of angiotensin II cannot be ascertained from the present study.11 Our findings are consistent with the additive effects of combined ACE inhibition and AT1 receptor blockade on blood pressure and renin release in sodium-depleted normotensives and with the preliminary results of the RESOLVD trial.4 12 In the RESOLVD trial, combined ACE inhibition and AT1 receptor blockade prevented left ventricular dilatation and lowered plasma brain natriuretic peptide levels to a greater extent than either intervention alone.12 Enhanced functional capacity in our patients treated with losartan is thus likely to be, at least in part, centrally mediated. Patients randomized to losartan were receiving higher doses of ACE inhibitors than those randomized to placebo. Whether such baseline imbalance affected our results is difficult to ascertain in view of the small patient population.
In summary, the present data demonstrate that addition of AT1 receptor blockade to optimal ACE inhibition therapy improves peak exercise performance and function capacity in patients with severe heart failure. These striking findings in 33 patients require confirmation in larger trials.
|
Appendix 1 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Trial Centers and Investigators
Albert Einstein College of Medicine: Glenn Hamroff, MD; Ira Blaufarb, MD; Rachel Bijou, MD; Rajoo Patel, MD; Sylvia Thomas, MS, RPh; and Thierry H. Le Jemtel, MD. Columbia Presbyterian Hospital Center: Stuart D. Katz, MD; and Donna Mancini, MD. University of Nebraska Medical Center: Maria-Teresa Olivari, MD. Hôpital Ambroise Paré: Guillaume Jondeau, MD.
Received October 1, 1998; revision received December 22, 1998; accepted January 8, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
1. Rousseau MF, Konstam MA, Benedict CR, Donckier J, Galanti L, Melin J, Kinan D, Ahn S, Ketelslegers JM, Pouleur H. Progression of left ventricular dysfunction secondary to coronary artery disease, sustained neurohormonal activation and effects of ibopamine therapy during long-term therapy with angiotensin-converting enzyme inhibitor. Am J Cardiol. 1994;73:488–493.[Medline] [Order article via Infotrieve]
2. Francis GS, Cohn JN, Johnson G, Rector TS, Goldman S, Simon A, the V-HeFT VA Cooperative Studies Group. Plasma norepinephrine, plasma renin activity, and congestive heart failure: relations to survival and the effects of therapy in V-HeFT II. . Circulation. 1993;87(suppl VI):VI-40–VI-48.
3.
St John Sutton M, Pfeffer MA, Moye L, Plappert T,
Rouleau JL, Lamas G, Rouleau J, Parker JO, Arnold MO, Sussex B,
Braunwald E. Cardiovascular death and left
ventricular remodeling two years after myocardial
infarction: baseline predictors and impact of long-term use of
captopril: information from the Survival and Ventricular
Enlargement (SAVE) trial. Circulation. 1997;96:3294–3299.
4.
Azizi M, Chatellier G, Guyene TT, Murieta-Geoffroy D,
Menard J. Additive effects of combined
angiotensin-converting enzyme inhibition and
angiotensin II antagonism on blood pressure and renin
release in sodium-depleted normotensives. Circulation. 1995;92:825–834.
5. Hamroff G, Blaufarb I, Mancini D, Katz SD, Bijou R, Jondeau G, Olivari MT, Thomas S, LeJemtel TH. Angiotensin II-receptor blockade further reduces afterload safely in patients maximally treated with angiotensin-converting enzyme inhibitors for heart failure. J Cardiovasc Pharmacol. 1997;30:533–536.[Medline] [Order article via Infotrieve]
6.
Gottlieb SS, Dickstein K, Fleck E, Kostis J, Levine
TB, LeJemtel T, DeKock M. Hemodynamic and neurohormonal
effects of the angiotensin II antagonist
losartan in patients with congestive heart failure.
Circulation. 1993;88:1602–1609.
7.
Crozier I, Ikram H, Awan N, Cleland J, Stephen N,
Dickstein K, Frey M, Young J, Klinger G, Makris L, Rucinska E,
Losartan Hemodynamic Study Group.
Losartan in heart failure: hemodynamic effects
and tolerability. Circulation. 1995;91:691–697.
8. Dickstein K, Chang P, Willenheimer R, Haunso S, Remes J, Hall C, Kjekshus J. Comparison of the effects of losartan and enalapril on clinical status and exercise performance in patients with moderate or severe chronic heart failure. J Am Coll Cardiol. 1995;26:438–445.[Abstract]
9. Lang RM, Elkayam U, Yellen LG, Krauss D, McKelvie RS, Vaughan DE, Ney DE, Makris L, Chang PI, the Losartan Pilot Exercise Study Investigators. Comparative effects of losartan and enalapril on exercise capacity and clinical status in patients with heart failure. J Am Coll Cardiol. 1997;30:983–991.[Abstract]
10. Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, Deedwania PC, Ney DE, Snavely DB, Chang PI. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE) [see comments]. Lancet. 1997;349:747–752.[Medline] [Order article via Infotrieve]
11. van den Meiracker AH, Man in 't Veld AJ, Admiraal PJ, Ritsema van Eck HJ, Boomsma F, Derkx FH, Schalekamp MA. Partial escape of angiotensin converting enzyme (ACE) inhibition during prolonged ACE inhibitor treatment: does it exist and does it affect the antihypertensive response? J Hypertens. 1992;10:803–812.[Medline] [Order article via Infotrieve]
12. Yusuf S, Maggioni AP, Held P, Rouleau JL. Effects of candesartan, enalapril, or their combination on exercise capacity, ventricular function, clinical deterioration, and quality of life in heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD). Circulation. 1997;96(suppl I):I-452. Abstract.
This article has been cited by other articles:
 |
|
 |
|
  F Gomez-Gallego, C Santiago, M Moran, M Perez, J L Mate-Munoz, M F. del Valle, J C Rubio, I Garcia-Consuegra, C Foster, I A L Andreu, et al. The I allele of the ACE gene is associated with improved exercise capacity in women with McArdle disease Br. J. Sports Med., February 1, 2008; 42(2): 134 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. O. Phillips, A. Kashani, D. K. Ko, G. Francis, and H. M. Krumholz Adverse Effects of Combination Angiotensin II Receptor Blockers Plus Angiotensin-Converting Enzyme Inhibitors for Left Ventricular Dysfunction: A Quantitative Review of Data From Randomized Clinical Trials Arch Intern Med, October 8, 2007; 167(18): 1930 - 1936. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. I. Vinik and D. Ziegler Diabetic Cardiovascular Autonomic Neuropathy Circulation, January 23, 2007; 115(3): 387 - 397. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hang, Z. Huang, S. Jiang, J. Gong, C. Wang, D. Xie, and H. Ren Apoptosis in pressure overload-induced cardiac hypertrophy is mediated, in part, by adenine nucleotide translocator-1. Ann. Clin. Lab. Sci., December 1, 2006; 36(1): 88 - 95. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Tsouli, E. N. Liberopoulos, D. N. Kiortsis, D. P. Mikhailidis, and M. S. Elisaf Combined Treatment With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers: A Review of the Current Evidence Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2006; 11(1): 1 - 15. [Abstract] [PDF]
|
|
|
|
 |
|
 P. K. Jacobsen Review: Preventing End-Stage Renal Disease in Diabetic Patients -- Dual Blockade of the Renin-Angiotensin System (Part II) Journal of Renin-Angiotensin-Aldosterone System, June 1, 2005; 6(2): 55 - 68. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Tachibana, H.-J. Cheng, T. Ukai, A. Igawa, Z.-S. Zhang, W. C. Little, and C.-P. Cheng Levosimendan improves LV systolic and diastolic performance at rest and during exercise after heart failure Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H914 - H922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Funabiki, K. Onishi, K. Dohi, T. Koji, K. Imanaka-Yoshida, M. Ito, H. Wada, N. Isaka, T. Nobori, and T. Nakano Combined angiotensin receptor blocker and ACE inhibitor on myocardial fibrosis and left ventricular stiffness in dogs with heart failure Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2487 - H2492. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J.V. McMurray, M. A. Pfeffer, K. Swedberg, and V. J. Dzau Which Inhibitor of the Renin-Angiotensin System Should Be Used in Chronic Heart Failure and Acute Myocardial Infarction? Circulation, November 16, 2004; 110(20): 3281 - 3288. [Full Text] [PDF]
|
|
|
|
 |
|
 V. C. Lee, D. C. Rhew, M. Dylan, E. Badamgarav, G. D. Braunstein, and S. R. Weingarten Meta-Analysis: Angiotensin-Receptor Blockers in Chronic Heart Failure and High-Risk Acute Myocardial Infarction Ann Intern Med, November 2, 2004; 141(9): 693 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Azizi and J. Menard Combined Blockade of the Renin-Angiotensin System With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Antagonists Circulation, June 1, 2004; 109(21): 2492 - 2499. [Full Text] [PDF]
|
|
|
|
|
|
J. J. McMurray Angiotensin inhibition in heart failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1_suppl): S17 - S22. [Abstract] [PDF]
|
|
|
|
 |
|
 R. S. McKelvie, J.-L. Rouleau, M. White, R. Afzal, J. B. Young, A. P. Maggioni, P. Held, and S. Yusuf Comparative impact of enalapril, candesartan or metoprolol alone or in combination on ventricular remodelling in patients with congestive heart failure Eur. Heart J., October 1, 2003; 24(19): 1727 - 1734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ostergren and J. J. McMurray Angiotensin receptor blockers in heart failure Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 171 - 175. [Abstract] [PDF]
|
|
|
|
|
|
J. Segura, M. Praga, C. Campo, J. L Rodicio, and L. M Ruilope Combination is better than monotherapy with ACE inhibitor or angiotensin receptor antagonist at recommended doses Journal of Renin-Angiotensin-Aldosterone System, March 1, 2003; 4(1): 43 - 47. [Abstract] [PDF]
|
|
|
|
 |
|
 C. Varma, S. Sharma, S. Firoozi, W. J. McKenna, J.-C. Daubert, and Multisite Stimulation in Cardiomyopathy (MUSTIC) S Atriobiventricular pacing improves exercise capacity in patients with heart failure and intraventricular conduction delay J. Am. Coll. Cardiol., February 19, 2003; 41(4): 582 - 588. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kim, Y. Izumi, Y. Izumiya, Y. Zhan, M. Taniguchi, and H. Iwao Beneficial Effects of Combined Blockade of ACE and AT1 Receptor on Intimal Hyperplasia in Balloon-Injured Rat Artery Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1299 - 1304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cicoira, L. Zanolla, A. Rossi, G. Golia, L. Franceschini, G. Brighetti, P. Marino, and P. Zardini Long-term, dose-dependent effects of spironolactone on left ventricular function and exercise tolerance in patients with chronic heart failure J. Am. Coll. Cardiol., July 17, 2002; 40(2): 304 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A Sica Review: The practical aspects of combination therapy with angiotensin receptor blockers and angiotensin-converting enzyme inhibitors Journal of Renin-Angiotensin-Aldosterone System, June 1, 2002; 3(2): 66 - 71. [Abstract] [PDF]
|
|
|
|
|
|
C. A. J. Farquharson and A. D. Struthers Gradual reactivation over time of vascular tissue angiotensin I to angiotensin II conversion during chronic lisinopril therapy in chronic heart failure J. Am. Coll. Cardiol., March 6, 2002; 39(5): 767 - 775. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. R. Ellis, A. K. Nightingale, D. J. Blackman, R. A. Anderson, C. Mumford, G. Timmins, D. Lang, S. K. Jackson, M. D. Penney, M. J. Lewis, et al. Addition of candesartan to angiotensin converting enzyme inhibitor therapy in patients with chronic heart failure does not reduce levels of oxidative stress Eur J Heart Fail, March 1, 2002; 4(2): 193 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Jong, C. Demers, R. S. McKelvie, and P. P. Liu Angiotensin receptor blockers in heart failure: meta-analysis of randomized controlled trials J. Am. Coll. Cardiol., February 6, 2002; 39(3): 463 - 470. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Massie Neurohormonal blockade in chronic heart failure: How much is enough? can there be too much? J. Am. Coll. Cardiol., January 2, 2002; 39(1): 79 - 82. [Full Text] [PDF]
|
|
|
|
|
|
H. Skali and M. A Pfeffer Review: Prospects for ARB in the next five years Journal of Renin-Angiotensin-Aldosterone System, December 1, 2001; 2(4): 215 - 218. [PDF]
|
|
|
|
|
|
J. E. McDonald, N. Padmanabhan, M. C. Petrie, C. Hillier, J. M.C. Connell, and J. J.V. McMurray Vasoconstrictor Effect of the Angiotensin-Converting Enzyme-Resistant, Chymase-Specific Substrate [Pro11D-Ala12] Angiotensin I in Human Dorsal Hand Veins: In Vivo Demonstration of Non-ACE Production of Angiotensin II in Humans Circulation, October 9, 2001; 104(15): 1805 - 1808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. H. Frishman Update in Cardiology Ann Intern Med, September 18, 2001; 135(6): 439 - 446. [Full Text] [PDF]
|
|
|
|
|
|
N. H. Andersen and C. E. Mogensen Review: Inhibition of the renin-angiotensin system, with particular reference to dual blockade treatment Journal of Renin-Angiotensin-Aldosterone System, September 1, 2001; 2(3): 146 - 152. [PDF]
|
|
|
|
 |
|
 J. J V McMurray HEART FAILURE: Angiotensin receptor blockers for chronic heart failure and acute myocardial infarction Heart, July 1, 2001; 86(1): 97 - 103. [Full Text] [PDF]
|
|
|
|
|
|
S. Mankad, T. A. d'Amato, N. Reichek, W. E. McGregor, J. Lin, D. Singh, W. J. Rogers, and C. M. Kramer Combined Angiotensin II Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Further Attenuates Postinfarction Left Ventricular Remodeling Circulation, June 12, 2001; 103(23): 2845 - 2850. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-P. Cheng, T. Ukai, K. Onishi, N. Ohte, M. Suzuki, Z.-S. Zhang, H.-J. Cheng, H. Tachibana, A. Igawa, and W. C. Little The role of ANG II and endothelin-1 in exercise-induced diastolic dysfunction in heart failure Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1853 - H1860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H. Jamali, W. H. W. Tang, U. N. Khot, and M. B. Fowler The Role of Angiotensin Receptor Blockers in the Management of Chronic Heart Failure Arch Intern Med, March 12, 2001; 161(5): 667 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Burnier Angiotensin II Type 1 Receptor Blockers Circulation, February 13, 2001; 103(6): 904 - 912. [Full Text] [PDF]
|
|
|
|
|
|
S. Kim, M. Yoshiyama, Y. Izumi, H. Kawano, M. Kimoto, Y. Zhan, and H. Iwao Effects of Combination of ACE Inhibitor and Angiotensin Receptor Blocker on Cardiac Remodeling, Cardiac Function, and Survival in Rat Heart Failure Circulation, January 2, 2001; 103(1): 148 - 154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Mogensen, S. Neldam, I. Tikkanen, S. Oren, R. Viskoper, R. W Watts, and M. E Cooper Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study BMJ, December 9, 2000; 321(7274): 1440 - 1444. [Abstract] [Full Text]
|
|
|
|
|
|
H. Kawai, S. Y. Stevens, and C.-S. Liang Renin-angiotensin system inhibition on noradrenergic nerve terminal function in pacing-induced heart failure Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H3012 - H3019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S Weinberg, A. J Weinberg, and D. H Zappe Effectively targetting the renin-angiotensin-aldosterone system in cardiovascular and renal disease: rationale for using angiotensin II receptor blockers in combination with angiotensin-converting enzyme inhibitors Journal of Renin-Angiotensin-Aldosterone System, September 1, 2000; 1(3): 217 - 233. [PDF]
|
|
|
|
|
|
J. McMurray AT1 receptor antagonists---beyond blood pressure control: possible place in heart failure treatment Heart, September 1, 2000; 84(90001): 42i - 45. [Full Text]
|
|
|
|
|
|
J. McMurray and C. Berry Ongoing clinical trials with angiotensin II receptor antagonists in chronic heart failure and myocardial infarction Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 131 - 136. [PDF]
|
|
|
|
|
|
S. Hanon, P. Vijayaraman, E. H Sonnenblick, and T. H Le Jemtel Persistent formation of angiotensin II despite treatment with maximally recommended doses of angiotensin converting enzyme inhibitors in patients with chronic heart failure Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 147 - 150. [PDF]
|
|
|
|
|
|
J. N Cohn Rationale for angiotensin II receptor blocker therapy in chronic heart failure Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2_suppl): S38 - S40. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Kim, Y. Zhan, Y. Izumi, and H. Iwao Cardiovascular Effects of Combination of Perindopril, Candesartan, and Amlodipine in Hypertensive Rats Hypertension, March 1, 2000; 35(3): 769 - 774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. P. Jorde, P. V. Ennezat, J. Lisker, V. Suryadevara, J. Infeld, S. Cukon, A. Hammer, E. H. Sonnenblick, and T. H. Le Jemtel Maximally Recommended Doses of Angiotensin-Converting Enzyme (ACE) Inhibitors Do Not Completely Prevent ACE-Mediated Formation of Angiotensin II in Chronic Heart Failure Circulation, February 29, 2000; 101(8): 844 - 846. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.J. van Veldhuisen and A.A. Voors Blockade of the renin angiotensin system in heart failure: the potential place of angiotensin II receptor blockers Eur. Heart J., January 1, 2000; 21(1): 14 - 16. [PDF]
|
|
|
|
 |
|
 L. M. Ruilope Is it wise to combine an ACE inhibitor and an angiotensin receptor antagonist? Nephrol. Dial. Transplant., December 1, 1999; 14(12): 2855 - 2856. [Full Text] [PDF]
|
|
|
|
|
|
A. Korzets and U. Gafter Tuberculosis prophylaxis for the chronically dialysed patient--yes or no? Nephrol. Dial. Transplant., December 1, 1999; 14(12): 2857 - 2859. [Full Text] [PDF]
|
|
|
|
 |
|
 Losartan Improves Exercise Capacity in CHF Patients Journal Watch Cardiology, April 16, 1999; 1999(416): 4 - 4. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||