doi: 10.1161/CIRCULATIONAHA.105.594978
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(Circulation. 2006;114:855-860.)
© 2006 American Heart Association, Inc.
Controversies in Cardiovascular Medicine |
Angiotensin Receptor Blockers Do Not Increase Risk of Myocardial Infarction
From EPICORE Centre, Division of Cardiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Correspondence to Dr Ross T. Tsuyuki, Professor of Medicine, EPICORE Centre, Division of Cardiology, Faculty of Medicine and Dentistry, University of Alberta, 220 College Plaza, University of Alberta Campus, Edmonton, Alberta, Canada T6G 2C8. E-mail ross.tsuyuki{at}ualberta.ca
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Introduction |
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The efficacy and safety of angiotensin-converting enzyme (ACE) inhibitors has been well established; these agents have shown an overwhelming and unequivocal benefit in placebo-controlled trials across a spectrum of patients at risk for cardiovascular events.1–9 What has been less clear, however, is whether inhibition of the renin-angiotensin-aldosterone system with angiotensin receptor blockers (ARBs) yields benefits of comparable scale. ARBs selectively inhibit the angiotensin II type 1 receptor, and it is axiomatic that this might offer theoretical advantages over ACE inhibitors by preventing the effects of angiotensin II generated by non–ACE-dependent pathways.10–12 In large-scale clinical trials, ARBs have been shown to effectively lower blood pressure,13–15 prevent progression to renal failure in patients with diabetes mellitus and proteinuria,16–18 and reduce the incidence of major cardiac events in patients with heart failure.19,20 These medications are also better tolerated than ACE inhibitors and are recommended in the American College of Cardiology/American Heart Association guidelines for patients with chronic heart failure or left ventricular dysfunction after myocardial infarction (MI) who are unable to tolerate ACE inhibitors and by the 2006 Canadian Cardiovascular Society consensus conference recommendations on heart failure.21–23
Response by Strauss and Hall p 860
Debate has surfaced recently on the relative safety of ARBs with respect to MI. In a controversial editorial in the British Medical Journal,24 Verma and Strauss drew attention to results from certain individual trials and concluded that ARBs increase MI, and they suggested that patients may need to be informed of these risks. Although supported by some,25 many members of the scientific community criticized the editorial for its nonsystematic approach to the existing data.26,27 As a "negative" editorial, it received significant attention in the medical community, and concerns about ARB safety were widely reported by the media both locally and internationally.
Our group was concerned about these conclusions drawn from selected studies and recently published a systematic review using all published data on the risk of MI and ARBs, and this review showed no increase in risk.28 Since then, independent systematic reviews and further data have been published that support our assertion that ARBs do not increase the risk of MI.29–31 This review will outline the available evidence for ARB safety with respect to MI events in a broad group of high-risk patients. We will also provide our perspective on questions surrounding the role of ARBs for important patient subpopulations.
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Need for a Systematic Review of All ARB Data on MI Risk |
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Simply put, the best way to answer a clinical question is to systematically and thoroughly evaluate all available data in an unbiased fashion. This is the premise behind the science of systematic reviews or meta-analysis. When we read the editorial by Verma and Strauss that concluded that ARBs cause MI,24 we were both intrigued and puzzled; intrigued because, like ACE inhibitors, ARBs were expected to reduce MI, yet puzzled because they had only reported data from trials that supported their conclusion. As such, we decided to conduct our own formal systematic review. Our question was: "Do ARBs increase the risk of MI?" We conducted a thorough search of the published literature using Medline, Embase, and the Cochrane register of controlled trials and by hand-searching the reference lists of retrieved articles. We included all trials that compared the use of ARBs with ACE inhibitors or placebo that reported MI events. Two reviewers decided which trials to include and abstracted the data, with any disagreements resolved by the vote of a third reviewer. We used standard Cochrane techniques to combine the data, using a random effects model to account for potential variations between studies.
A total of 24 studies met our inclusion criteria, and 19 had data on MI, representing a total of 31 569 patients.13,16–19,32–46 Use of ARBs was not associated with an increased risk of MI compared with placebo (odds ratio [OR] 0.94, 95% confidence interval [CI] 0.75 to 1.16) nor when compared with ACE inhibitors (OR 1.01, 95% CI 0.87 to 1.16).28 With ORs very close to unity and narrow CIs, we concluded that the use of ARBs is not associated with an increased risk of MI. Our conclusions are consistent with those of similar meta-analyses conducted by Verdeccia et al,29 who reported ORs of 1.02 to 1.03 (95% CIs of 0.96 to 1.11 and 0.96 to 1.09, respectively) for MI with ARBs compared with any control, and Volpe et al,30 who reported a relative risk of 1.036 (95% CI 0.966 to 1.110) for ARBs compared with any control.
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Effect of ARBs on MI in Important Subpopulations |
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ARBs in Patients With Hypertension
Much of the concern over ARB use and the association with increased rates of MI stems from the results of recent hypertension trials. In particular, the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial,14 which involved 15 245 patients, found no significant difference in a composite cardiac mortality and morbidity outcome between the ARB valsartan and amlodipine. However, patients randomized to treatment with amlodipine had 19% fewer MIs, a finding that may31 or may not47 be attributable to the consistent, modest blood pressure–lowering advantage of amlodipine at all time points throughout the study. Further insights in hypertensive patients have come from a Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) presentation at the 2005 European Society of Hypertension meeting that focused on blood pressure–independent effects of ACE inhibitors and ARBs in reducing major cardiac events.48 In this analysis, meta-regression plots of blood pressure reduction from individual trials versus relative risk of cardiac events were constructed to tease out whether there was a protective effect of the medications beyond blood pressure reduction. For stroke and heart failure events, no difference was seen for ACE inhibitors and ARBs, which suggests that clinical benefits of these agents in hypertensive patients are attributable to the blood pressure–lowering effects alone. For coronary heart disease, a statistically significant 9% (95% CI 14% to 3%) reduction in risk of events beyond blood pressure lowering was seen with ACE inhibitors, whereas no such effect was seen with ARBs. This simply suggests that the efficacy of ARBs is dependent only on blood pressure lowering.
Although the BPLTTC analysis is elegant, some caveats are worth noting. First, there is still no suggestion that ARBs are associated with an increased incidence of MI, only that there is no evidence to support a blood pressure–independent effect on coronary heart disease outcomes. Second, an acknowledged limitation of the study is the relative paucity of ARB trials. Sixteen ACE inhibitor trials of 104 993 subjects were available for analysis compared with 5 trials of ARBs with 32 603 subjects. The ARB trials included Irbesartan Diabetic Nephropathy Trial (IDNT),17 Losartan Intervention For Endpoint reduction in hypertension (LIFE),15 Reduction of Endpoints in Non–insulin-dependent diabetes mellitus with Angiotensin II Antagonist Losartan (RENAAL),16 Study on COgnition and Prognosis in the Elderly (SCOPE),13 and VALUE,14 each of which was a major component of the neutral systematic reviews discussed above.28–30
ARBs in Patients With Diabetes Mellitus
The value of ARB medications in patients with type 2 diabetes mellitus and nephropathy has been well established in several landmark studies. IDNT17 was a randomized evaluation of 1715 patients with type 2 diabetes mellitus that compared irbesartan with amlodipine and placebo. In this study, irbesartan was associated with a lower incidence of heart failure than either amlodipine or placebo, but it was not associated with a significant difference in the rate of MI. Similarly, in the RENAAL study of 1513 patients with diabetes mellitus and nephropathy, losartan conferred significant benefits over placebo with respect to progression of renal disease, without any suggestion of increased MI events in the treatment group.16 These trials have also been included in the systematic reviews presented.
A prior systematic review by Strippoli and colleagues49 assessing ACE inhibitors and ARBs in diabetic nephropathy concluded that the data for ACE inhibitors are far more robust than for ARBs and that their comparative effect on overall survival cannot yet be ascertained. While demonstrating a reduction in mortality in the ACE inhibitor trials only, this review has been criticized for combining heterogeneous patient populations. Most of the ACE inhibitor data come from studies in type 1 diabetes mellitus, and the ARB data come from studies in type 2 diabetes mellitus, 2 patient groups with strikingly different baseline risk profiles.50
Data that specifically examined MI rates in diabetic patients are also wanting. No difference in event rates was seen, however, in the 250-patient Diabetic Exposed to Telmisartan and Enalapril (DETAIL) study between ACE inhibitor– and ARB-treated groups.18 Currently, it would appear that ARBs are proven efficacious therapies for patients with type 2 diabetes mellitus and proteinuria and that despite their relative safety with regard to MI risk, further research is required to delineate the potential benefits of ARBs on atherosclerotic heart disease events.
ARBs in Patients With Heart Failure and After MI
A meta-analysis of heart failure trials demonstrated a reduction in all-cause mortality and heart failure hospitalizations with ARB therapy compared with placebo, with no significant outcome difference between ARBs and ACE inhibitors.51 Our own analysis that specifically examined MI events included a large number of heart failure trials and similarly showed no increased risk of MIs with ARB use versus placebo or versus ACE inhibitors.28 That many of the ARB versus placebo heart failure trials evaluated in this systematic review included patients cotreated with ACE inhibitors raises the possibility that the absence of MI risk in the ARB arms (and by extension, the benefits of ARBs observed in some of the trials) may have been confounded by the background ACE inhibitor therapy. In the VALIANT (VALsartan In Acute myocardial iNfarcTion) trial52 of very high-risk patients with left ventricular dysfunction/heart failure after MI, combination therapy with captopril and valsartan did not demonstrate any benefit compared with captopril alone (hazard ratio 0.98, 97.5% CI 0.89 to 1.09) for mortality, and no difference was seen between the captopril and valsartan monotherapy groups (hazard ratio 1.00, 97.5% CI 0.90 to 1.11). A recently published evaluation of atherosclerotic events in VALIANT53 demonstrated no significant difference in the rate of adjudicated MI between captopril, valsartan, and combination therapy subgroups, which suggests that concomitant ACE inhibitor therapy does not appreciably affect risk of death in ARB-treated patients. In support of this observation, an analysis from the overall CHARM (Candesartan in Heart failure Assessment in Reduction of Mortality) program actually showed a reduction in the outcome of cardiovascular death or nonfatal MI in the candesartan group over placebo (hazard ratio 0.87, 95% CI 0.79 to 0.96) that was similar across the predetermined subgroups, which included patients taking background ACE inhibitors.54 The authors concluded that inhibition of the renin-angiotensin-aldosterone system with candesartan offers additional protection against cardiac events that is similar in magnitude to the protection offered by ACE inhibition alone in SOLVD (Studies Of Left Ventricular Dysfunction) and other heart failure trials.
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Do ARBs Increase the Risk of MI? |
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If an agent causes harm, it is likely that it would produce its deleterious effects across a wide spectrum of patients. In the case of ARBs and MI risk, one would expect to observe an increase in MI across the entire spectrum of cardiovascular risk and with a variety of background therapies. We have updated our 2005 systematic review by comparing ARBs with any control, and we have now included VALIANT,53 MOSES (MOrbidity and mortality after Stroke–Eprosartan vs nitrendipine for Secondary prevention)55 (MI data from S. Luders, MD, e-mail communication, March 13, 2006), ALPINE (Antihypertensive treatment and Lipid Profile In a North of Sweden Efficacy evaluation),56 LIFE,15 VALUE,14 a study by Kondo et al,57 and combined comparative arms from a study by Bakris et al46 and IDNT.17 The results were combined with a random effects model and are shown in the Figure.
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In our inclusive, systematic review of 25 trials,13–19,32–46,53,55–57 68 711 patients at risk for MI, and >4000 events, we now have even stronger evidence that ARBs do not increase the risk of MI, with a pooled OR of 1.03 (95% CI 0.93 to 1.13). Although few of these studies were designed to test equivalence, with a point estimate very close to unity and narrow CIs, it is clear that there is no increased risk of MI associated with ARB use. Thus, it appears reasonable to conclude that ARBs are a safe and efficacious alternative to ACE inhibitors for patients at high risk for ischemia and MI. We are not advocating the superiority of ARBs over ACE inhibitors, only stating that they do not increase the risk of MI. ACE inhibitors remain the agents of choice for reducing MI.
Optimal neurohormonal blockade in this era of ever-evolving cardiovascular therapy is a moving target. Results from the prospective ONTARGET and TRANSCEND trials (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE-iNtolerant subjects with cardiovascular Disease)58 are eagerly awaited to better define the role of ARBs in protecting patients at risk for MI and other atherosclerotic heart disease–related events. In the interim, however, we find no evidence that these agents increase the risk of MI based on a systematic review of all published trials of ARBs. This highlights the importance of assessing all available evidence by systematic methods before drawing any conclusions.
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Acknowledgments |
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The authors would like to recognize the contributions of their colleagues from their original systematic review: Drs Scot H. Simpson, Gabor Gyenes, and Justin A. Ezekowitz.
Disclosures
Dr Tsuyuki has received honoraria and research grants from Merck Frosst, Merck-Schering, Pfizer, Sanofi-Aventis, Ortho Biotech, Apotex, AstraZeneca, Bristol-Meyers Squibb, and Novartis. Dr McDonald has nothing to disclose.
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References |
|---|
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TopIntroductionNeed for a Systematic...Effect of ARBs on...Do ARBs Increase the...References |
|---|
1. 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]
2. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987; 316: 1429–1435.[Abstract]
3. 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]
4. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC; for 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]
5. 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.[Medline] [Order article via Infotrieve]
6. Swedberg K, Held P, Kjekshus J, Rasmussen K, Ryden L, Wedel H. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med. 1992; 327: 678–684.[Abstract]
7. Ambrosioni E, Borghi C, Magnani G. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med. 1995; 332: 80–85.
8. Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G, Torp-Pedersen C, Ball S, Pogue J, Moye L, Braunwald E. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. Lancet. 2000; 355: 1575–1581.[CrossRef][Medline] [Order article via Infotrieve]
9. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000; 342: 145–153.
10. Silverstein RL, Fenves AZ, Ram VS. ARBs and target organ protection: exploring benefits beyond their hypertensive effects. Postgrad Med. 2004; 116: 31–41.[CrossRef][Medline] [Order article via Infotrieve]
11. McMurray JJV, Pfeffer MA, Swedberg K, Dzau VJ. Which inhibitor of the rennin-angiotensin system should be used in chronic heart failure and acute myocardial infarction? Circulation. 2004; 110: 3281–3288.
12. Levy BI. Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the rennin-angiotensin system. Circulation. 2004; 109: 8–13.
13. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003; 21: 875–886.[CrossRef][Medline] [Order article via Infotrieve]
14. Julius S, Kjeldsen E, Weber M, Brunner HR, Edkman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004; 363: 2022–2031.[CrossRef][Medline] [Order article via Infotrieve]
15. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H. Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension (LIFE): a randomised trial against atenolol. Lancet. 2002; 359: 995–1003.[CrossRef][Medline] [Order article via Infotrieve]
16. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345: 861–869.
17. Berl T, Hunsicker LG, Lewis JB, Pfeffer MA, Porush JG, Rouleau JL, Drury PL, Esmatjes E, Hricik D, Parikh CR, Raz I, Vanhille P, Wiegmann TB, Wolfe BM, Locatelli F, Goldhaber SZ, Lewis EJ. Cardiovascular outcomes in the irbesartan diabetic nephropathy trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med. 2003; 138: 542–549.
18. Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, Mustonen J. Angiotensin-receptor blockade versus converting enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med. 2004; 351: 1952–1961.
19. Cohn JN, Tognoni G. A randomized trial of the angiotensin receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001; 345: 1667–1675.
20. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, Michelson EL, Olofsson B, Ostergren J, Yusuf S. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM Overall programme. Lancet. 2003; 362: 759–766.[CrossRef][Medline] [Order article via Infotrieve]
21. Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2005; 46: 1–82.
22. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz H, Kushner FG. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol. 2004; 44: 671–719.
23. Arnold JMO, Liu P, Demers C, Dorian P, Giannetti N, Haddad H, Heckman GA, Howlett JG, Ingaszewski A, Johnstone DE, Jong P, McKelvie RS, Moe GW, Parker JD, Rao V, Ross HJ, Sequeira EJ, Svendsen AM, Teo K, Tsuyuki RT, White M. Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management. Can J Cardiol. 2006; 22: 23–45.[Medline] [Order article via Infotrieve]
24. Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. BMJ. 2004; 329: 1248–1249.
25. Yousef ZR, Leyva F, Gibbs C. Angiotensin receptor blockers and myocardial infarction: cautions voiced are biologically credible. BMJ. 2005; 330: 1270. Comment.
26. McMurray JJ. Angiotensin receptor blockers and myocardial infarction: analysis of evidence is incomplete and inaccurate. BMJ. 2005; 330: 1269. Comment.
27. Opie L. Angiotensin receptor blockers and myocardial infarction: direct comparative studies are needed. BMJ. 2005; 330: 1270. Comment.
28. McDonald MA, Simpson SH, Ezekowitz JA, Tsuyuki RT. Angiotensin receptor blockers and risk of myocardial infarction: systematic review. BMJ. 2005; 331: 873–878.
29. Verdeccia P, Angeli F, Gattobigio R, Reboldi GP. Do angiotensin II receptor blockers increase the risk of myocardial infarction? Eur Heart J. 2005; 26: 2381–2386.
30. Volpe M, Mancia G, Trimarco B. Angiotensin II receptor blockers and myocardial infarction: deeds and misdeeds. J Hypertens. 2005; 23: 2113–2118.[Medline] [Order article via Infotrieve]
31. Weber MA, Julius S, Kjeldsen SE, Brunner HR, Ekman S, Hansson L, Hua T, Laragh JH, McInnes GT, Mitchell L, Plat F, Schork MA, Smith B, Zanchetti A. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE trial. Lancet. 2004; 363: 2049–2051.[CrossRef][Medline] [Order article via Infotrieve]
32. Haneda M, Kikkawa R, Sakai H, Kawamori R. Antiproteinuric effect of candesartan cilexetil in Japanese subjects with type 2 diabetes and nephropathy. Diabetes Res Clin Pract. 2004; 66: 87–95.[CrossRef][Medline] [Order article via Infotrieve]
33. Matsumori A; on behalf of the Assessment of Response to Candesartan in Heart Failure in Japan (ARCH-J) Study Investigators. Efficacy and safety of oral candesartan cilexetil in patients with congestive heart failure. Eur J Heart Fail. 2003; 5: 669–677.[CrossRef][Medline] [Order article via Infotrieve]
34. McMurray JJV, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA; for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM Added trial. Lancet. 2003; 362: 767–771.[CrossRef][Medline] [Order article via Infotrieve]
35. Granger CB, McMurray JJV, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K; for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM Alternative trial. Lancet. 2003; 362: 772–776.[CrossRef][Medline] [Order article via Infotrieve]
36. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, Michelson EL, Olofsson B, Ostergren J; for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM Preserved trial. Lancet. 2003; 362: 777–781.[CrossRef][Medline] [Order article via Infotrieve]
37. Granger CB, Ertl G, Kuch J, Maggioni AP, McMurray J, Rouleau JL, Stevenson LW, Swedberg K, Young J, Yusuf S, Califf R, Bart BA, Held P, Michelson E, Sellers MA, Ohlin G, Sparapani R, Pfeffer MA. Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors. Am Heart J. 2000; 139: 609–617.[Medline] [Order article via Infotrieve]
38. Targum SL, Hung HMJ. Medical-statistical review: NDA 20-665/SE1-016 and 21-283/SE-001 Diovan (valsartan) capsules and tablets [Food and Drug Administration Web site]. 2001. Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3793B1_03_MEDSTAT.pdf. Accessed April 4, 2005.
39. Pitt B, Segal R, Martinez FA, Cowley AJ, Thomas I, Deedwania PC, Ney DE, Snavely DB, Chang PI; on behalf of the ELITE Study Investigators. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997; 349: 747–752.[CrossRef][Medline] [Order article via Infotrieve]
40. Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, Konstam MA, Riegger G, Klinger GH, Neaton J, Sharma D, Thiyagarajan B; on behalf of the ELITE II Investigators. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial: the losartan heart failure survival study ELITE II. Lancet. 2000; 355: 1582–1587.[CrossRef][Medline] [Order article via Infotrieve]
41. Willenheimer R, Helmers C, Pantev E, Rydberg E, Lofdahl P, Gordon A; for the Heart Failure Valsartan Exercise Capacity Evaluation (HEAVEN) Study Group. Safety and efficacy of valsartan versus enalapril in heart failure patients. Int J Cardiol. 2002; 85: 261–270.[CrossRef][Medline] [Order article via Infotrieve]
42. Dunselman PHJM. Effects of the replacement of the angiotensin converting enzyme inhibitor enalapril by the angiotensin II receptor blocker telmisartan in patients with congestive heart failure: the replacement of angiotensin converting enzyme inhibition (REPLACE) investigators. Int J Cardiol. 2001; 77: 131–138.[CrossRef][Medline] [Order article via Infotrieve]
43. Di Pasquale P, Bucca V, Scalzo S, Cannizzaro S, Giubilato A, Paterna S. Does the addition of losartan improve the beneficial effects of ACE inhibitors in patients with anterior myocardial infarction? A pilot study. Heart. 1999; 81: 606–611.
44. Dickstein K, Kjekshus J, and the OPTIMAAL Steering Committee, for the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet. 2002; 360: 752–760.[CrossRef][Medline] [Order article via Infotrieve]
45. Spinar J, Vitovec J, Spinarova L, Pluhacek L, Fischerova B, Toman J. A comparison of intervention with losartan or captopril in acute myocardial infarction. Eur J Heart Fail. 2000; 2: 91–100.[Medline] [Order article via Infotrieve]
46. Bakris G, Sica D, Ram V, Fagan T, Vaitkus PT, Anders RJ. A comparative trial of controlled-onset extended-release verapamil, enalapril, and losartan on blood pressure and heart rate changes. Am J Hypertens. 2002; 15: 53–57.[CrossRef][Medline] [Order article via Infotrieve]
47. Staessen JA, Thijs L, Birkenhager WH. VALUE: analysis of results. Lancet. 2004; 364: 931. Comment.[CrossRef][Medline] [Order article via Infotrieve]
48. Turnbull F. Blood pressure-independent effects for agents inhibiting the renin-angiotensin system. In: Program and abstracts from the Fifteenth European Meeting on Hypertension; June 17–21, 2005; Milan, Italy. Plenary Session. Available at: http://www.medscape.com/viewarticle/507293. Accessed February 28, 2006.
49. Strippoli GFM, Craig M, Deeks JJ, Schena FP, Craig JC. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ. 2004; 329: 828–829.
50. Lewis EJ. Angiotensin receptor blockers and myocardial infarction: results reflect different cardiovascular states in patients with types 1 and 2 diabetes. BMJ. 2005; 330: 1269–1270.
51. Lee VC, Rhew DC, Dylan M, Badamgarav E, Braunstein GD, Weingarten SR. Meta-analysis: angiotensin receptor blockers in chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med. 2004; 141: 693–704.
52. Pfeffer MA, McMurray JJV, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JK, Henis M, Edwards S, Zelenkofske S, Sellers Ma, Califf RM. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003; 349: 1893–1906.
53. McMurray JJV, Solomon S, Pieper K, Reed S, Rouleau J, Velazquez E, White H, Howlett J, Swedberg K, Maggioni A, Kober L, Van de Werf F, Califf R, Pfeffer M. The effect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction. An analysis of the valsartan in acute myocardial infarction trial (VALIANT). J Am Coll Cardiol. 2006; 47: 726–733.
54. Demers C, McMurray JJV, Swedberg K, Pfeffer MA, Granger CB, Olofsson B, McKelvie RS, Ostergren J, Michelson EL, Johansson PA, Wang D, Yusuf S. Impact of candesartan on nonfatal myocardial infarction and cardiovascular death in patients with heart failure. JAMA. 2005; 294: 1794–1798.
55. Schrader J, Luders S, Kulschewski A, Hammersen F, Plate K, Berger J, Zidek W, Dominiak P, Diener HC; for the MOSES Study Group. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention. Stroke. 2005; 36: 1218–1226.
56. Lindholm LH, Persson M, Alaupovic P, Carlberg B, Svensson A, Samuelsson O. Metabolic outcome during 1 year in newly detected hypertensives: results of the antihypertensive treatment and lipid profile in a north of Sweden efficacy evaluation (ALPINE study). J Hypertens. 2003; 21: 1563–1574.[CrossRef][Medline] [Order article via Infotrieve]
57. Kondo J, Sone T, Tsuboi H, Mukawa H, Morishima I, Uesugi M, Kono T, Kosaka T, Yoshida T, Numaguchi Y, Matsui H, Murohara T, Okumura K. Effects of low-dose angiotensin II receptor blocker candesartan on cardiovascular events in patients with coronary artery disease. Am Heart J. 2003; 146: e20.[Medline] [Order article via Infotrieve]
58. The ONTARGET/TRANSCEND Investigators. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J. 2004; 148: 52–61.[CrossRef][Medline] [Order article via Infotrieve]
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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