 |
|
The Role of Angiotensin Receptor Blockers in the Management of Chronic Heart Failure
Aamer H. Jamali, MD;
W. H. Wilson Tang, MD;
Umesh N. Khot, MD;
Michael B. Fowler, MB, FRCP
Arch Intern Med. 2001;161:667-672.
ABSTRACT
Clinical and basic science research has repeatedly confirmed the importance
of the renin-angiotensin-aldosterone system in the pathophysiology of chronic
heart failure. Accordingly, blockade of this system by angiotensin-converting
enzyme (ACE) inhibitors has assumed a central role in the treatment of heart
failure. Recently, angiotensin II receptor blockers (ARBs) have gained prominence
as a possible substitute for ACE inhibitors in therapy for heart failure.
However, clinical data compiled on this use of ARBs have shown them to be
useful only as alternative therapy in ACE inhibitor–intolerant patients.
Continuing large-scale clinical investigations may lead to an expansion of
their role in therapy for various cardiovascular diseases.
INTRODUCTION
Angiotensin-converting enzyme (ACE) inhibitors have been shown to decrease
morbidity and mortality in virtually all types of heart failure.1-8
The ability of ACE inhibitors to suppress neurohormonal activation in the
renin-angiotensin-aldosterone (RAA) system has been presumed to be the principal
mechanism for their therapeutic activity.9
A combination of actions that function to improve hemodynamic variables as
well as to regulate the unfavorable trophic actions of angiotensin II (A-II)
are considered to encompass much of their benefit.10
Concern that ACE inhibitors produce inadequate long-term suppression
of the RAA system has become an important issue.11-12
Intolerance of ACE inhibitors by as much as 10% of patients with heart failure
has also hindered their routine use, despite evident indications.13-14 Such limitations have prompted an
interest in the search for better therapeutic strategies to counteract the
adverse effects of RAA system activation in heart failure.
Recent studies on a new generation of drugs that directly block the
actions of A-II have sparked much excitement in heart failure research.13 These A-II receptor blockers (ARBs) specifically
block the A-II type 1 (AT1) receptor,15
which is responsible for many of the deleterious effects of A-II (Figure 1).10, 16
Since the discovery of losartan potassium in 1992, the Food and Drug Administration
has approved 6 new ARBs for the treatment of essential hypertension. Their
potential role in patients with heart failure is an area of active investigation.
|
|
|
|
The renin-angiotensin-aldosterone system. ACE indicates angiotensin-converting
enzyme; tPA, tissue plasminogen activator; ARB, angiotensin II receptor blocker;
AT1, angiotensin II type 1; AT2, angiotensin II type
2; PAI, plasminogen activator inhibitor; up arrows, increased level or activity;
and down arrows, decreased level or activity.
|
|
|
EXPERIMENTAL CONSIDERATIONS
Bradykinin
Angiotensin-converting enzyme inhibitors also inhibit the enzyme kininase
II, which is responsible for the degradation of bradykinin.17
Recent studies have emphasized the possible role of elevated bradykinin levels
in the benefits of ACE inhibitor therapy for heart failure. Beneficial hemodynamic
effects mediated by bradykinin may include venodilation,18
vasodilation (coronary and systemic),19 and
improved left ventricular relaxation and contractile function.20
Other potential benefits of bradykinin include a reduction in ventricular
dilatation and cardiac hypertrophy, an increase in levels of endogenous tissue
plasminogen activator, and an improvement in abnormal endothelial function.21-23 Such effects may
be especially important in the 60% of patients with heart failure who have
an ischemic cause of their heart failure.14
Additional evidence of the importance of the bradykinin system in ACE
inhibition comes from a study by Guazzi et al.24
Their group showed that although losartan and enalapril maleate had similar
hemodynamic and clinical effects, the action of enalapril was antagonized
by aspirin, whereas that of losartan was not.24
This may be related to the role of the bradykinin in mediating prostaglandin
release (Figure 1). This has potentially
profound implications for most cardiac patients who are concurrently receiving
daily aspirin therapy. Although still preliminary, these results underscore
the importance of understanding the differences between these classes of drugs.25
The ACE inhibitor–mediated increase in bradykinin levels is believed
to be responsible for the associated cough, which may occur in up to 10% of
the population,26-27 as well as
angioedema, a potentially lethal complication.28-30
By directly blocking AT1, ARBs can inhibit the action of A-II while
having little or no bearing on the bradykinin system.31
Thus, the incidence of angioedema associated with ARB use is limited to case
reports.32 Improvement in tolerability using
ARBs can be seen in the Study of Patients Intolerant of Converting Enzyme
Inhibitors (SPICE) Registry, where patients with heart failure intolerant
of ACE inhibitors were randomized to candesartan vs placebo. Tolerability
of candesartan was comparable to that of placebo at 3 months (83% vs 87%,
respectively).14
Escape Phenomenon
There is growing evidence that ACE inhibitors provide incomplete long-term
suppression of A-II and aldosterone.11-12,33
This is likely due to inadequate suppression of ACE in target tissues, as
well as alternative (non-ACE) pathways of A-II production.34
Direct blockade of the action of A-II by ARBs may attenuate this "escape"
phenomenon by circumventing problems related to non-ACE production of A-II.
This issue has raised concerns about the completeness of the benefit obtained
with ACE inhibitor monotherapy, and has prompted investigations into various
combination therapies.
Sympathetic Nervous System
Sympathetic nervous system hyperactivity is a short-term compensatory
mechanism for cardiac dysfunction, but its prolonged activation may lead to
worsening of heart failure.35 Angiotensin-converting
enzyme inhibitors have been demonstrated to reduce overall sympathetic tone
in heart failure36 and enhance baroreflex control,37-39 but they can increase
plasma norepinephrine levels through the bradykinin cascade.40-42
Similarly, ARBs attenuate sympathetic tone and increase baroreflex control.37, 43 However, their selective blockade
of AT1 increases A-II levels and allows for greater occupancy at
the A-II type 2 (AT2) receptor. This can increase adrenal catecholamine
release,44-45 counteracting other
more beneficial effects (Figure 1).
The clinical implication of these concepts remains to be elucidated.
CLINICAL TRIALS
The early studies on the use of ARBs in heart failure focused on surrogate
outcomes such as hemodynamic effects and neurohormonal activation. Few looked
at clinical outcomes such as exercise tolerance, and none were powered to
study mortality differences.46-59
Consistent hemodynamic improvement was observed when ARBs were compared
with placebo.46-50
Reductions in blood pressure and pulmonary capillary wedge pressure were sustained
after up to 12 weeks of therapy.47, 49
Increased exercise capacity was also demonstrated in short-term studies.46, 51
When ARBs were compared with ACE inhibitors in relatively small-scale
clinical trials, however, the results consistently yielded no significant
differences between ARBs and ACE inhibitors. At the end of follow-ups as long
as 12 weeks, patients treated with losartan fared no better on results of
objective exercise testing or quality-of-life indexes than those treated with
enalapril.52-54
Several trials evaluated the result of combining ACE inhibition with
ARBs (Table 1). This combination
theoretically provides the most complete and sustained blockade of the angiotensin
system, while still affecting the bradykinin system favorably. In small-scale
studies, combination therapy consistently showed superior results to ACE inhibitor
monotherapy with regard to exercise tolerance,55-57
hemodynamic effects,58 and neurohormonal activation.55, 58-59 In the study by Hamroff
et al,56 more than half of the patients receiving
combination therapy (9/16) had an improvement of at least 1 New York Heart
Association (NYHA) class, compared with only 1 of 17 patients receiving ACE
inhibitors alone.
|
|
|
|
Table 1. Comparison of Combination Therapy With ACE Inhibitor Monotherapy*
|
|
|
The recently published Randomized Evaluation of Strategies for Left
Ventricular Dysfunction (RESOLVD) pilot study by McKelvie et al55
is an ambitious attempt to study increasing levels of neurohormonal blockade.
Although much of the data were not statistically significant, combination
therapy was superior to monotherapy in lowering blood pressure and in preventing
left ventricular dilatation in the long term. In addition, the benefit in
ejection fraction achieved with combination therapy was significantly greater
than that achieved with either therapy alone. However, the combination therapy
cohort was the only one to have a decreased exercise tolerance at 18 and 43
weeks.
THE EVALUATION OF LOSARTAN IN THE ELDERLY STUDIES
Evaluation of Losartan in the Elderly Trial
The original Evaluation of Losartan in the Elderly (ELITE) study13 was a double-blind, randomized, captopril-controlled
trial initially designed to compare the tolerability of losartan potassium
(titrated to 50 mg once daily) with that of captopril (titrated to 150 mg/d)
in 722 elderly patients with heart failure. The primary end point, a persistent
increase in serum creatinine level, was not significantly different between
groups (10.5%; P = .63). More patients receiving
captopril discontinued therapy because of adverse effects (20.8% vs 12.2%; P = .002). The most intriguing results came in analysis
of the secondary end points. Death or hospitalization for heart failure occurred
in 49 of 370 patients receiving captopril and 33 of 352 patients receiving
losartan (P = .08). Although this particular result
was not statistically significant, the difference in all-cause mortality (not
a prespecified end point) was statistically significant and showed a reduction
in absolute risk of 3.9%, which translated into a relative risk reduction
of 44% (P = .04). Most of this difference was due
to the rate of sudden death (3.8% in the captopril vs 1.4% in the losartan
groups). There was no significant difference in deaths due to progressive
heart failure, myocardial infarction, or other vascular causes.
Unfortunately, the ELITE trial did not have the statistical power to
determine mortality differences, as only a very small number of events (49
total deaths in the study population) occurred during a relatively short 48-week
follow-up. The study supported the theoretical notion that selective blockade
of A-II action would be better tolerated than ACE inhibition and certainly
implied that it may be more effective.
ELITE II Trial
The follow-up to the ELITE trial, ELITE II, was a direct comparison
of losartan vs captopril in a trial designed and powered to detect mortality
differences from the outset.60 The ELITE II
trial was a randomized, double-blind, multicenter trial with 3152 patients
followed up for 2 years. Inclusion criteria included patients who were older
than 60 years, with NYHA classes II to IV heart failure and ejection fractions
of less than 0.40. One thousand five hundred seventy-four patients were randomized
to receive captopril, whereas 1578 were randomized to receive losartan, all
in a manner similar to that of the ELITE trial. Both arms were similar in
all measured characteristics.
Of the 530 deaths during the 2-year follow-up, 250 occurred in the captopril
arm, whereas 280 occurred in the losartan arm (P
= .16). In addition, sudden cardiac death occurred more frequently in the
losartan arm (9.0% vs 7.3%), although this result was not statistically significant
(P = .08). This is particularly interesting because
it was in sudden cardiac death that losartan achieved most of the mortality
benefit noted in the original ELITE trial. The combination end point of mortality
and hospitalization showed no significant difference between losartan and
captopril, although it also favored the captopril arm (47.7% vs 44.9%; P = .21).
The single result that showed concordance with the original ELITE trial
was the issue of tolerability. Both trials showed losartan to be significantly
better tolerated than captopril. In ELITE II, 14.5% of the patients receiving
captopril had to discontinue the drug because of adverse effects, whereas
only 9.0% of those receiving losartan had to discontinue treatment (P = .001).
The ELITE II study showed that ARBs appear to be equally as effective
as ACE inhibitors in heart failure therapy. Before this result, the only clinical
trial support for alternatives to ACE inhibitors had been for hydralazine
hydrochloride and isosorbide dinitrate, although this combination was shown
to be less effective than ACE inhibitors.6
SUMMARY AND FUTURE DIRECTIONS
Most of the data available show a benefit to ARB use compared with placebo
in patients with left-ventricular systolic dysfunction. However, at present,
the ELITE II trial remains the only large-scale trial to assess mortality
differences between ARBs and ACE inhibitors in these patients. Because of
considerable variation in pharmacodynamics and sympathetic modulation between
ARBs,61 it is unclear whether results from
particular studies can be generalized to a class effect. In contrast, a large
and growing body of clinical trial experience supports the use of ACE inhibitors
in heart failure. Thus, further studies are necessary to define accurately
the role ARBs should play in therapy for heart failure.
A regimen that includes ACE inhibitors and ARBs would be expected to
provide potent, sustained suppression of the RAA system while still providing
the benefits of increased activity of bradykinin. Preliminary data on such
combination therapy are promising,55 and a
number of studies now under way should further define the role of combination
therapy (Table 2).62
Indeed, combination therapy could theoretically be augmented further by the
addition of aldosterone antagonists, such as spironolactone. However, such
triple therapy remains untested in clinical trials.
|
|
|
|
Table 2. Ongoing Mortality Trials With ARBs in Heart Failure*
|
|
|
Another area in which the use of ARBs may have specific benefit is in
the setting of ischemic heart disease. Angiotensin-converting enzyme inhibitors
have a proven mortality benefit in coronary artery disease, before and after
myocardial infarction.7-8,63
It is unclear what effect ARBs will have in these settings, especially as
they presumably lack bradykinin-mediated increases in endogenous thrombolysis
and vascular reactivity.21 Trials currently
under way should clarify this topic and may help us understand the role ARBs
can play in patients with a spectrum of cardiovascular diseases.64-65
In conclusion, the use of ACE inhibitors remains the standard of care
in patients with heart failure. In patients intolerant of an ACE inhibitor,
ARBs can provide a safe and efficacious alternative therapy. At present, the
most promising area in which ARBs may assume a role as first-line therapy
is as part of a combination with ACE inhibitors. Such a combination has many
theoretical advantages, and preliminary results are very promising.
AUTHOR INFORMATION
Accepted for publication September 21, 2001.
Corresponding author: Michael B. Fowler, MB, FRCP, Falk-CVRC 295,
Stanford University Medical Center, Stanford, CA 94305 (e-mail: mfowler{at}cvmed.stanford.edu).
From the Division of Cardiovascular Medicine, Department of Medicine,
Stanford University School of Medicine, Stanford, Calif (Drs Jamali, Tang,
and Fowler), and the Department of Cardiology, The Cleveland Clinic Foundation,
Cleveland, Ohio (Dr Khot). Dr Fowler has received grant and research support
from SmithKline Beecham Pharmaceuticals, Merck & Co, Inc, and Novartis;
has acted as a consultant to SmithKline Beecham Pharmaceuticals, Merck &
Co, Inc, and Bristol Myers; and has participated in the speakers bureaus of
Astra Zeneca, Roche, SmithKline Beecham, and Merck & Co, Inc.
REFERENCES
| |
1. Captopril Multicenter Research Group. A placebo-controlled trial of captopril in refractory chronic congestive
heart failure. J Am Coll Cardiol. 1983;2:755-763.
ABSTRACT
2. Sharpe DN, Murphy J, Coxon R, Hannan SF. Enalapril in patients with chronic heart failure: a placebo-controlled,
randomized, double-blind study. Circulation. 1984;70:271-278.
FREE FULL TEXT
3. Swedberg K, Kjekshus J. Effects of enalapril on mortality in severe congestive heart failure:
results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). Am J Cardiol. 1988;62:60A-66A.
4. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular
ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302.
ABSTRACT
5. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure
in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med. 1992;327:685-691.
ABSTRACT
6. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in
the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-310.
ABSTRACT
7. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute
myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821-828.
ISI
| PUBMED
8. Pfeffer MA, Braunwald E, Moye LA, et al (the SAVE Investigators). Effect of captopril on mortality and morbidity in patients with left
ventricular dysfunction after myocardial infarction: results of the survival
and ventricular enlargement trial. N Engl J Med. 1992;327:669-677.
ABSTRACT
9. Sander GE, McKinnie JJ, Greenberg SS, Giles TD. Angiotensin-converting enzyme inhibitors and angiotensin II receptor
antagonists in the treatment of heart failure caused by left ventricular systolic
dysfunction. Prog Cardiovasc Dis. 1999;41:265-300.
FULL TEXT
|
ISI
| PUBMED
10. Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med. 1996;334:1649-1654.
FREE FULL TEXT
11. Pitt B. "Escape" of aldosterone production in patients with left ventricular
dysfunction treated with an angiotensin converting enzyme inhibitor: implications
for therapy. Cardiovasc Drugs Ther. 1995;9:145-149.
FULL TEXT
|
ISI
| PUBMED
12. Struthers AD. Aldosterone escape during ACE inhibitor therapy in chronic heart failure. Eur Heart J. 1995;16(suppl N):103-106.
13. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with
heart failure. Lancet. 1997;349:747-752.
FULL TEXT
|
ISI
| PUBMED
14. Bart BA, Ertl G, Held P, et al. Contemporary management of patients with left ventricular systolic
dysfunction: results from the Study of Patients Intolerant of Converting Enzyme
Inhibitors (SPICE) Registry. Eur Heart J. 1999;20:1182-1190.
FREE FULL TEXT
15. Timmermans PB. Pharmacological properties of angiotensin II receptor antagonists. Can J Cardiol. 1999;15:26F-28F.
16. Timmermans PB, Benfield P, Chiu AT, Herblin WF, Wong PC, Smith RD. Angiotensin II receptors and functional correlates. Am J Hypertens. 1992;5(suppl):221S-235S.
17. Erdos EG. Angiotensin I converting enzyme. Circ Res. 1975;36:247-255.
FREE FULL TEXT
18. Trippodo NC, Panchal BC, Fox M. Repression of angiotensin II and potentiation of bradykinin contribute
to the synergistic effects of dual metalloprotease inhibition in heart failure. J Pharmacol Exp Ther. 1995;272:619-627.
FREE FULL TEXT
19. Hornig B, Arakawa N, Drexler H. Effect of ACE inhibition on endothelial dysfunction in patients with
chronic heart failure. Eur Heart J. 1998;19(suppl G):G48-G53.
20. Cheng CP, Onishi K, Ohte N, Suzuki M, Little WC. Functional effects of endogenous bradykinin in congestive heart failure. J Am Coll Cardiol. 1998;31:1679-1686.
FREE FULL TEXT
21. Remme WJ. Bradykinin-mediated cardiovascular protective actions of ACE inhibitors:
a new dimension in anti-ischaemic therapy? Drugs. 1997;54(suppl 5):59-70.
22. Mancini GB, Henry GC, Macaya C, et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial
vasomotor dysfunction in patients with coronary artery disease: the TREND
(Trial on Reversing ENdothelial Dysfunction) Study. Circulation. 1996;94:258-265.
FREE FULL TEXT
23. Schlaifer JD, Wargovich TJ, O'Neill B, et al for the TREND Investigators. Effects of quinapril on coronary blood flow in coronary artery disease
patients with endothelial dysfunction. Am J Cardiol. 1997;80:1594-1597.
FULL TEXT
|
ISI
| PUBMED
24. Guazzi M, Melzi G, Agostoni P. Comparison of changes in respiratory function and exercise oxygen uptake
with losartan versus enalapril in congestive heart failure secondary to ischemic
or idiopathic dilated cardiomyopathy. Am J Cardiol. 1997;80:1572-1576.
FULL TEXT
|
ISI
| PUBMED
25. Song KH, Fedyk R, Hoover R. Interaction of ACE inhibitors and aspirin in patients with congestive
heart failure. Ann Pharmacother. 1999;33:375-377.
ABSTRACT
26. Fox AJ, Lalloo UG, Belvisi MG, Bernareggi M, Chung KF, Barnes PJ. Bradykinin-evoked sensitization of airway sensory nerves: a mechanism
for ACE-inhibitor cough. Nat Med. 1996;2:814-817.
FULL TEXT
|
ISI
| PUBMED
27. Takahama K, Araki T, Fuchikami J, Kohjimoto Y, Miyata T. Studies on the magnitude and the mechanism of cough potentiation by
angiotensin-converting enzyme inhibitors in guinea-pigs: involvement of bradykinin
in the potentiation. J Pharm Pharmacol. 1996;48:1027-1033.
ISI
| PUBMED
28. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting
enzyme inhibitor therapy: a review of the literature and pathophysiology. Ann Intern Med. 1992;117:234-242.
29. Nielsen EW, Stenberg PA, Einarsen E, Johansen HT, Mollnes TE. Angioedema associated with ACE inhibitors [in Norwegian]. Tidsskr Nor Laegeforen. 1994;114:804-806.
PUBMED
30. Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angio-oedema. Lancet. 1998;351:1693-1697.
FULL TEXT
|
ISI
| PUBMED
31. Brooks DP, Ruffolo RR Jr. Pharmacological mechanism of angiotensin II receptor antagonists: implications
for the treatment of elevated systolic blood pressure. J Hypertens Suppl. 1999;17(suppl):S27-S32.
32. van Rijnsoever EW, Kwee-Zuiderwijk WJ, Feenstra J. Angioneurotic edema attributed to the use of losartan. Arch Intern Med. 1998;158:2063-2065.
FREE FULL TEXT
33. MacFadyen RJ, Lee AF, Morton JJ, Pringle SD, Struthers AD. How often are angiotensin II and aldosterone concentrations raised
during chronic ACE inhibitor treatment in cardiac failure? Heart. 1999;82:57-61.
FREE FULL TEXT
34. Liao Y, Husain A. The chymase-angiotensin system in humans: biochemistry, molecular biology
and potential role in cardiovascular diseases. Can J Cardiol. 1995;11(suppl F):13F-19F.
35. Francis GS, Goldsmith SR, Levine TB, Olivari MT, Cohn JN. The neurohumoral axis in congestive heart failure. Ann Intern Med. 1984;101:370-377.
36. Licker M, Neidhart P, Lustenberger S, et al. Long-term angiotensin-converting enzyme inhibitor treatment attenuates
adrenergic responsiveness without altering hemodynamic control in patients
undergoing cardiac surgery. Anesthesiology. 1996;84:789-800.
FULL TEXT
|
ISI
| PUBMED
37. Yee KM, Struthers AD. Endogenous angiotensin II and baroreceptor dysfunction: a comparative
study of losartan and enalapril in man. Br J Clin Pharmacol. 1998;46:583-588.
FULL TEXT
|
ISI
| PUBMED
38. Grassi G, Cattaneo BM, Seravalle G, et al. Effects of chronic ACE inhibition on sympathetic nerve traffic and
baroreflex control of circulation in heart failure. Circulation. 1997;96:1173-1179.
FREE FULL TEXT
39. Dusing R, Kayser G, Wagner S, et al. Baroreflex setting and sensitivity in normal subjects: effects of pharmacologic
inhibition of the angiotensin I converting enzyme. Am J Cardiol. 1987;59:50D-54D.
FULL TEXT
|
ISI
| PUBMED
40. Rump LC, Berlit T, Schwertfeger E, Beyersdorf F, Schollmeyer P, Bohmann C. Angiotensin converting enzyme inhibition unmasks the sympathofacilitatory
effect of bradykinin in human right atrium. J Hypertens. 1997;15:1263-1270.
FULL TEXT
|
ISI
| PUBMED
41. Dominiak P. Modulation of sympathetic control by ACE inhibitors. Eur Heart J. 1993;14(suppl I):169-172.
42. Schwieler JH, Kahan T, Nussberger J, Hjemdahl P. Converting enzyme inhibition modulates sympathetic neurotransmission
in vivo via multiple mechanisms. Am J Physiol. 1993;264:E631-E637.
43. Ma R, Zucker IH, Wang W. Central gain of the cardiac sympathetic afferent reflex in dogs with
heart failure. Am J Physiol. 1997;273:H2664-H2671.
44. Martineau D, Lamouche S, Briand R, Yamaguchi N. Functional involvement of angiotensin AT2 receptor in adrenal catecholamine
secretion in vivo. Can J Physiol Pharmacol. 1999;77:367-374.
FULL TEXT
|
ISI
| PUBMED
45. Mazzocchi G, Gottardo G, Macchi V, Malendowicz LK, Nussdorfer GG. The AT2 receptor–mediated stimulation of adrenal catecholamine
release may potentiate the AT1 receptor–mediated aldosterone secretagogue
action of angiotensin-II in rats. Endocr Res. 1998;24:17-28.
ISI
| PUBMED
46. Warner JG Jr, Metzger DC, Kitzman DW, Wesley DJ, Little WC. Losartan improves exercise tolerance in patients with diastolic dysfunction
and a hypertensive response to exercise. J Am Coll Cardiol. 1999;33:1567-1572.
FREE FULL TEXT
47. Crozier I, Ikram H, Awan N, et al for the Losartan Hemodynamic Study Group. Losartan in heart failure: hemodynamic effects and tolerability. Circulation. 1995;91:691-697.
FREE FULL TEXT
48. Gottlieb SS, Dickstein K, Fleck E, et al. Hemodynamic and neurohormonal effects of the angiotensin II antagonist
losartan in patients with congestive heart failure. Circulation. 1993;88:1602-1609.
FREE FULL TEXT
49. Havranek EP, Thomas I, Smith WB, et al. Dose-related beneficial long-term hemodynamic and clinical efficacy
of irbesartan in heart failure. J Am Coll Cardiol. 1999;33:1174-1181.
FREE FULL TEXT
50. Parker AB, Azevedo ER, Baird MG, et al. ARCTIC: assessment of haemodynamic response in patients with congestive
heart failure to telmisartan: a multicentre dose-ranging study in Canada. Am Heart J. 1999;138:843-848.
FULL TEXT
|
ISI
| PUBMED
51. Riegger GA, Bouzo H, Petr P, et al. Improvement in exercise tolerance and symptoms of congestive heart
failure during treatment with candesartan cilexetil. Circulation. 1999;100:2224-2230.
FREE FULL TEXT
52. Lang RM, Elkayam U, Yellen LG, et al. Comparative effects of losartan and enalapril on exercise capacity
and clinical status in patients with heart failure: the Losartan Pilot Exercise
Study Investigators. J Am Coll Cardiol. 1997;30:983-991.
ABSTRACT
53. Dickstein K, Chang P, Willenheimer R, et al. 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
54. Cowley AJ, Wiens BL, Segal R, Rich M. Quality of life in elderly patients with symptomatic heart failure:
losartan versus captopril [abstract]. Eur Heart J. 1998;19:134.
55. McKelvie RS, Yusuf S, Pericak D, et al for the RESOLVD Pilot Study Investigators. Comparison of candesartan, enalapril, and their combination in congestive
heart failure: Randomized Evaluation of Strategies for Left Ventricular Dysfunction
(RESOLVD) pilot study. Circulation. 1999;100:1056-1064.
FREE FULL TEXT
56. Hamroff G, Katz SD, Mancini D, et al. Addition of angiotensin II receptor blockade to maximal angiotensin-converting
enzyme inhibition improves exercise capacity in patients with severe congestive
heart failure. Circulation. 1999;99:990-992.
FREE FULL TEXT
57. Houghton AR, Harrison M, Perry AJ, Evans AJ, Cowley AJ. Combined treatment with losartan and an angiotensin-converting enzyme
inhibitor in chronic heart failure: a randomised, double-blind, placebo-controlled
trial [abstract]. Eur Heart J. 1998;19:302.
58. Baruch L, Anand I, Cohen IS, Ziesche S, Judd D, Cohn JN. Augmented short- and long-term hemodynamic and hormonal effects of
an angiotensin receptor blocker added to angiotensin converting enzyme inhibitor
therapy in patients with heart failure: Vasodilator Heart Failure Trial (V-HeFT)
|
