Bangalore, Sripal

Messerli, Franz H.

Ruschitzka, Frank

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ESC HOT LINE COMMENTARYAngiotensin receptor blockers: baselinetherapy in hypertension?Franz H. Messerli1*, Sripal Bangalore2, and Frank Ruschitzka31St. Luke’s Roosevelt Hospital and Columbia University, New York, NY 10019, USA; 2Brigham and Women’s Hospital, Boston, MA, USA; and 3University Hospital,Zurich, SwitzerlandOnline publish-ahead-of-print 31 August 2009This commentary refers to ‘Effects of valsartan on mor-bidity and mortality in uncontrolled hypertensive patientswith high cardiovascular risks: KYOTO HEART Study’†,by T. Sawada et al., on page 2461The provocative editorial by Verma and Strauss in the BMJ 5 yearsago1 stating that angiotensin receptor blockers (ARBs) ‘mayincrease myocardial infarction—and patients may need to betold’ caused a tempest in the teapot and led to extensive scrutinyof outcome data with this drug class. In 2007 the blood pressure-lowering treatment trialists collaboration found that there weresimilar blood pressure-dependent effects of angiotensin-convertingenzyme (ACE) inhibitors and ARBs for the risk of stroke, coronaryheart disease, and heart failure.2 The authors cautioned, however,that only for ACE inhibitors but not for ARBs, was there evidenceof a blood pressure-independent effect on the risk of major coron-ary disease events. Also, ONTARGET, a thorough, double-blindprospective randomized trial, documented equal outcome efficacyof an ARB and an ACE inhibitor in a high-risk population, althoughthere was a trend for better stroke prevention in the ARB (telmi-sartan) arm and better coronary artery disease prevention in theACE inhibitor (ramipril) arm.3 When analysing these studies andincluding the most recent ARB trials such as TRANSCEND,4PRoFESS,5 CASE-J trial,6 HIJ-CREATE,7 JIKEI,8 and KYOTO,9 wefound, in a database of 100 000 patients from 26 randomizednon-heart failure trials of ARBs, a 13% reduction in the risk ofstroke (P ¼ 0.022) (Figure 1) but a trend towards increased riskof myocardial infarction, especially when compared with activetreatment (P ¼ 0.06) (Figure 2).Much ink has been wasted on the outcome of TRANSCENDand PRoFESS, in both of which telmisartan, despite a fall inblood pressure, did not reduce cardiovascular events better thanplacebo. We perhaps also should consider that a majority ofpatients in both of these trials were pre-treated with a blockerof the renin–angiotensin system (RAS). Thus, both trials were eval-uating the effects of discontinuation of RAS blockade rather thanthe effects of starting RAS blockade. Conceivably we are observing,in both of these studies, a ‘legacy effect’ of pre-randomization RASblockade. Also, we should not forget that several ACE inhibitortrials such as QUIET,10 PEACE,11 PROGRESS,12 and CAMELOT13did not beat placebo despite a significant fall in blood pressure.For once, in the present KYOTO study, there was no significantdifference in blood pressure between the two treatment arms. Atstudy end, 50% more patients were treated with a calcium antag-onist in the non-ARB arm. Thus, KYOTO is somewhat reminiscentof VALUE14 in which patients were, in a double-blind prospectivestudy design, randomized to either valsartan or amlodipine.However, the results of KYOTO are diametrically different fromthose of VALUE in that KYOTO, for a given blood pressurereduction, showed a 45% reduction of the primary endpoint com-pared with the non-ARB arm. This benefit was driven mainly bystroke and, somewhat surprisingly, angina, while there was no sig-nificant difference in myocardial infarction, heart failure, and all-cause mortality. In contrast, in VALUE, stroke, if anything, wasreduced less well in the valsartan arm than in the amlodipinearm. While the disparity in blood pressure control in favour ofamlodipine may have confounded the interpretation of theresults of the (double-blind) VALUE trial, in (open label)KYOTO, despite the difference in treatment options, surprisinglyexactly the same blood pressure reduction was achieved in theARB and non-ARB arm throughout the study. Similar toVALUE,14 the risk of new-onset diabetes was significantly less inthe valsartan than in the non-ARB arm.Could the different results of VALUE and KYOTO be explainedby the study populations? Asians may be particularly receptive tothe protective effects of ARBs, as was shown in RENAAL15where most of the benefits occurred in the Asian subpopulation.Cerebrovascular disease is more prevalent and coronary arterydisease less prevalent in Asians than in western societies. Not sur-prisingly, therefore, a reduction of strokes is easier to documentthan a reduction of coronary artery disease, as was shown inboth the JIKEI-Heart Study and KYOTO. With regard to angina,we should remember that this is a rather soft endpoint and thatbecause of the open label design, investigators were fully aware* Corresponding author. Tel: þ1 212 523 7373, Fax: þ1 212 523 7765, Email: messerli.f@gmail.com† doi:10.1093/eurheartj/ehp363The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.European Heart Journal (2009) 30, 2427–2430doi:10.1093/eurheartj/ehp364of the treatment being administered. We find it somewhat difficultto believe that an ARB should be better in preventing angina than acalcium antagonist, as was observed in both KYOTO and the JIKEI-Heart Study.In contrast to JIKEI and KYOTO, in the other two similarlydesigned ARB studies in the Asian population, i.e. CASE-J andHIJ-CREATE, ARB treatment with candesartan did not reducemorbidity and mortality better than non-ARB therapy. Whetherthe difference in outcome between the two valsartan and thetwo candesartan studies is due to chance or to differences in theARB molecule, in study design, in the patient population, or inthe concomitant medication cannot be determined.In KYOTO, adverse events were uncommon and medicationwas well tolerated. This is not surprising since many studies havedocumented that ARBs are exceedingly well tolerated. In fact, ina few studies in which ARBs were compared with a placebo,patients on ARB therapy had significantly fewer headaches thanthose on placebo. In a thorough Cochrane meta-analysis, withdra-wal rates due to adverse effects in a total of 46 studies and 13 451patients were significantly lower on ARBs than on placebo [RR0.68 (95% CI 0.54–0.87)].16 In contrast, the Cochranemeta-analysis of 92 studies and 12 954 patients documented thatACE inhibitors are not better tolerated than placebo [RR0.85(95% CI 0.67–1.07)].17The low withdrawal rates in the ARB arm would indicate thathypertension is perhaps not necessarily such an asymptomaticdisease as we thought and taught. Low-grade headache, fatigue,and other non-specific symptoms may be associated with sustainedblood pressure elevation. A reduction of blood pressure by anARB or an ACE inhibitor may reduce such low-grade symptomsbetter than does placebo. However, the inherent adverse effectsof the ACE inhibitor (cough and, uncommonly, angioedema)seem to abolish the overall achieved benefit. Indeed, head tohead comparisons suggest a better tolerability of ARBs than ofACE inhibitors.18The impressive results of the KYOTO study lead to the questionof whether ARBs as a class have come of age and should now be con-sidered as preferred or baseline therapy in hypertension. Theanswer, with regard to safety and efficacy, could be a resoundingyes, i.e. if efficacy were defined as blood pressure reduction.However, blood pressure is merely a surrogate endpoint which cor-relates to some extent with the true endpoint, i.e. heart attack,stroke, and death. As the above meta-analysis demonstrates, ARBsare efficacious and even superior to other drug classes in strokeFigure 1 Odds ratio for stroke. There was a significant reduction in the risk of stroke with ARBs compared with controls. The size of themarkers represents the weight of each trial. Meta-analysis was performed using the search terms ‘angiotensin receptor blockers’ with theinclusion criteria of being a randomized comparison with follow-up for at least 1 year, enrolling non-heart failure patients and evaluating out-comes of interest.Commentary2428prevention but their efficacy with regard to coronary events remainsuncertain. Thus, if efficacy is defined as reduction in overall cardio-vascular events and mortality, the answer, in view of the data inaggregate, remains no, or perhaps, not yet.Conflict of interest: none declared.References1. Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. BMJ2004;329:1248–1249.2. Turnbull F, Neal B, Pfeffer M, Kostis J, Algert C, Woodward M, Chalmers J,Zanchetti A, MacMahon S. Blood pressure-dependent and independent effectsof agents that inhibit the renin–angiotensin system. J Hypertens 2007;25:951–958.3. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P,Anderson C. Telmisartan, ramipril, or both in patients at high risk for vascularevents. N Engl J Med 2008;358:1547–1559.4. Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, Schumacher H,Dagenais G, Sleight P. Effects of the angiotensin-receptor blocker telmisartanon cardiovascular events in high-risk patients intolerant to angiotensin-convertingenzyme inhibitors: a randomised controlled trial. Lancet 2008;372:1174–1183.5. Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, Palesch Y,Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L,Dahlof B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K,Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P,Toni D, VanderMaelen C,VoigtT, WeberM,Yoon BW. Telmisartan toprevent recur-rent stroke and cardiovascular events. N Engl J Med 2008;359:1225–1237.6. Ogihara T, Nakao K, Fukui T, Fukiyama K, Ueshima K, Oba K, Sato T, Saruta T.Effects of candesartan compared with amlodipine in hypertensive patients withhigh cardiovascular risks: candesartan antihypertensive survival evaluation inJapan trial. Hypertension 2008;51:393–398.7. Kasanuki H, Hagiwara N, Hosoda S, Sumiyoshi T, Honda T, Haze K, Nagashima M,Yamaguchi J, Origasa H, Urashima M, Ogawa H. Angiotensin II receptor blocker-based vs. non-angiotensin II receptor blocker-based therapy in patients withangiographically documented coronary artery disease and hypertension: theHeart Institute of Japan Candesartan Randomized Trial for Evaluation in CoronaryArtery Disease (HIJ-CREATE). Eur Heart J 2009;30:1203–1212.8. Mochizuki S, Dahlof B, Shimizu M, Ikewaki K, Yoshikawa M, Taniguchi I, Ohta M,Yamada T, Ogawa K, Kanae K, Kawai M, Seki S, Okazaki F, Taniguchi M, Yoshida S,Tajima N. Valsartan in a Japanese population with hypertension and other cardi-ovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpointmorbidity–mortality study. Lancet 2007;369:1431–1439.9. Sawada T, Yamada H, Dahlo¨f B, Matsubara H, for the KYOTO HEART StudyGroup. Effects of valsartan on morbidity and mortality in uncontrolled hypertensivepatients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J 2009;30:2461–2469. First published on 31 August 2009. doi:10.1093/eurheartj/ehp363.10. Pitt B, O’Neill B, Feldman R, Ferrari R, Schwartz L, Mudra H, Bass T, Pepine C,Texter M, Haber H, Uprichard A, Cashin-Hemphill L, Lees RS. The QUinaprilIschemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy inpatients with ischemic heart disease and preserved left ventricular function. AmJ Cardiol 2001;87:1058–1063.11. Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, Pfeffer MA,Rice MM, Rosenberg YD, Rouleau JL. Angiotensin-converting-enzyme inhibitionin stable coronary artery disease. N Engl J Med 2004;351:2058–2068.12. Randomised trial of a perindopril-based blood-pressure-lowering regimen among6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033–1041.13. Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, Berman L, Shi H,Buebendorf E, Topol EJ. Effect of antihypertensive agents on cardiovascular eventsin patients with coronary disease and normal blood pressure: the CAMELOTstudy: a randomized controlled trial. JAMA 2004;292:2217–2225.14. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, Hua T, Laragh J,McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A. Outcomes in hyper-tensive patients athigh cardiovascular risk treated with regimens based onvalsartanoramlodipine: the VALUE randomised trial. Lancet 2004;363:2022–2031.15. 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 andFigure 2 Odds ratio for myocardial infarction. There was a trend towards increased risk of myocardial infarction with ARBs compared withthe active treatment group. The size of the markers represents the weight of each trial.Commentary 2429cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N EnglJ Med 2001;345:861–869.16. Heran BS, Wong MM, Heran IK, Wright JM. Blood pressure lowering efficacy ofangiotensin receptor blockers for primary hypertension. Cochrane Database SystRev 2008;(4):CD003822.17. Heran BS, Wong MM, Heran IK, Wright JM. Blood pressure lowering efficacy ofangiotensin converting enzyme (ACE) inhibitors for primary hypertension.Cochrane Database Syst Rev 2008;(4):CD003823.18. Messerli FH, Bangalore S, Ram VS. Telmisartan, ramipril, or both in patients athigh risk of vascular events. N Engl J Med 2008;359:426–427; author reply 427.CARDIOVASCULAR FLASHLIGHT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .doi:10.1093/eurheartj/ehp312Online publish-ahead-of-print 14 August 2009Acute episode of an arrhythmogenic right ventricular cardiomyopathy withvast necroses exclusively in right ventricular myocardiumStefan Gattenlo¨hner1*, Philipp Demmer1, Martin Oberhoff2, and Georg Ertl31Institute of Pathology, University of Wu¨rzburg, Josef-Schneiderstr.2, D-97080 Wu¨rzburg, Germany; 2Department of Internal Medicine II, St-Elisabeth Hospital, BadKissingen, Germany; and 3Department of Internal Medicine I, University of Wu¨rzburg, Wu¨rzburg, Germany* Corresponding author. Tel: þ49 931 201 47420, Fax: þ49 931 201 47440, Email: stefan.gattenloehner@mail.uni-wuerzburg.deWe describe the case of an athlete aged 18 yearswho died of sudden cardiac arrest withoutpreviously having been diagnosed with heartdisease. The autopsy did not reveal signs ofintoxication or endo-/myocarditis, including nega-tive results for cardiotropic virus, and coronaryheart disease/vasculitis was excluded by coronaryangiography and histology.In contrast, cardiac morphology showedclassical signs of arrhythmogenic right ventricularcardiomyopathy (ARVC) with diffuse replacementof RV myocardium by fibro-fatty tissue (Panel A),detection of abnormal long desmosomes (PanelA, inset) and immunohistochemical lack ofplakoglobin1 (Panel B) but strong expression ofN-cadherin (Panel B, inset). More interestinglyand exclusively in RV myocardium but not in leftventricle nor both atrias, large areas of acute/subacute cardiomyocyte necroses were detected(Panels C and D) with mild inflammatory infiltrates (Panel C), myocytolysis with loss of myofibrils2 (Panel C, inset) and myocardialcontraction bands (Panel D) with hypercontracted sarcomeres (Panel D, inset)Although death of single myocytes has been reported in ARVC,3 the vast necroses in RV myocardium shown here with an increaseof the MB isoform of creatine kinase (CK-MB 85U/l; CK 530 U/l) detected in a blood sample collected immediately after start ofreanimation have so far not been described and might be the morphological correlate of an acute episode of ARVC. In ouropinion, these data confirm the ‘degenerative hypothesis’4 suggesting that the replacement of the RV myocardium is progressivewith time starting from the epicardium and expanding transmurally to the endocardium3 and underline the relevance of markersas plakoglobin in preventing such fatal courses of ARVC.FundingFunding to pay open access publication charges for this article was provided by the Wilhelm-Sander-Stiftung (grant 2007.068.01) and theDeutsche Forschungs-Gesellschaft (DFG-SFB-Transregio 52, TPA8).References1. Asimaki A, Tandri H, Huang H, Halushka MK, Gautam S, Basso C, Thiene G, Tsatsopoulou A, Protonotarios N, McKenna WJ, Calkins H, Saffitz JE. A new diagnostic testfor arrhythmogenic right ventricular cardiomyopathy. N Engl J Med 2009;360:1075–1084.2. Turillazzi E, Baroldi G, Silver MD, Parolini M, Pomara C, Fineschi V. A systematic study of a myocardial lesion: colliquative myocytolysis. Int J Cardiol 2005;104:152–157.3. Thiene G, Corrado D, Basso C. Arrhythmogenic right ventricular cardiomyopathy/dysplasia. Orphanet J Rare Dis 2007;2:45.4. Thiene G, Corrado D, Nava A, Rossi L, Poletti A, Boffa GM, Daliento L, Pennelli N. Right ventricular cardiomyopathy: is there evidence of an inflammatory aetiology? EurHeart J 1991;12(Suppl. D):22–25.Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: journals.permissions@oxfordjournals.orgThe online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version ofthis article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press areattributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part oras a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.orgCommentary2430

Angiotensin receptor blockers: baseline therapy in hypertension?

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