Doi:10.1016/s0140-6736(08)61243-x

The power to TRANSCEND
The role of angiotensin-receptor blockers in primary older and intolerant to angiotensin-converting-enzyme Published Online
or secondary prevention of cardiovascular disease inhibitors. The population was similar in some but not August 31, 2008
has been unclear. Speculation about equivalence to all respects to that of HOPE.3 In TRANSCEND, there were 6736(08)61243-X
angiotensin-converting-enzyme inhibitors exists more women, patients were more ethnically diverse, and See Online/Articles
because of sim ilar pharmacology, such as truncation more patients were on statins (55% in TRANSCEND vs 6736(08)61242-8of eff ects on angiotensin II. Conversely, speculation 28% in HOPE), β blockers (58% vs 39%), and antiplatelet also exists about superiority of angiotensin-receptor drugs (85% vs 75%). There was no diff erence in the blockers over angiotensin-converting-enzyme inhibitors primary composite endpoint of cardiovascular death, because of diff erences in pharmacology: angiotensin- myocardial infarction, stroke, or admission to hospital receptor blockers block angiotensin II at the receptor for heart failure (events: telmisartan 465 [15·7%] and theoretic ally attenuate the eff ects of angiotensin vs placebo 504 [17·0%]; hazard ratio 0·92, 95% CI II arising from non-angiotensin-converting-enzyme 0·81–1·05) (table, which also spells out trial acronyms). pathways.1 Yet, angiotensin II and aldosterone return Although a diff erence was found in the prespecifi ed to pre treatment levels irrespective of treatment composite secondary outcome of cardiovascular death, with an angiotensin-converting-enzyme inhibitor, an myocardial infraction, and stroke (events, respectively: angio tensin-receptor blocker, or both.2 Angiotensin- 384 [13·0%] vs 440 (14·8%); 0·87, 0·76–1·00, p=0·048), converting-enzyme inhibitors reduce cardiovascular this diff erence became non-signifi cant after statistical outcomes in patients at risk for and with cardiovascular adjustments were made for multiple comparisons disease;3 accordingly, they are the current standard. (p=0·068). None of these endpoints were individually Evidence showing similar clinical eff ectiveness in signifi cant. There was no diff erence in several other patients with heart failure has augmented discussion endpoints, including development of heart failure, about comparison with angiotensin-converting-enzyme new diabetes, and total mortality. Telmisartan did inhibitors in other cardiovascular conditions. Whether reduce hospitalisations for cardiovascular reasons, left-angiotensin-receptor blockers are equivalent, an altern- ventricular hypertrophy, and fewer patients had the ative, or even superior is fi nally starting to be addressed combination of macrovascular and microvascular by outcomes data.
events plus microalbuminuria. A prespecifi ed com- Today’s Lancet presents results from the TRANSCEND bined analysis with data from PRoFESS (not published study,4 which compared telmisartan (an angiotensin- in full at the time of writing, but data were cited in receptor blocker) 80 mg daily with placebo in almost TRANSCEND) showed signifi cant benefi t on cardio-6000 high-risk patients who were aged 55 years or vascular death, myocardial infarction, and stroke, Trial and endpoints
Intervention
Relative-risk reduction
p value Number needed
(95% CI on hazard ratio)
TRANSCEND (Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease)
Primary: cardiovascular death, myocardial infacrtion, stroke, or admission for Telmisartan vs placebo Secondary: cardiovascular death, myocardial infarction, or stroke HOPE (Heart Outcomes Prevention Evaluation)3
Primary: cardiovascular death, myocardial infacrtion, or stroke EUROPA (EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease)6
Primary: cardiovascular death, myocardial infarction, or cardiac arrest PEACE (Prevention of Events with Angiotensin Converting Enzyme inhibition)7
Primary: cardiovascular death or non-fatal myocardial infraction Other trial acronyms mentioned in text: PRoFESS=Prevention Regimen for Eff ectively avoiding Second Strokes; ONTARGET=ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial.
Table: Comparative eff ect of renin-active agents vs placebo in prevention of cardiovascular events
www.thelancet.com Published online August 31, 2008 DOI:10.1016/S0140-6736(08)61243-X
but not for admission for heart failure. Telmisartan The safety information from TRANSCEND must not was well tolerated, even in patients who had angio- oedema, hypotension, and renal dysfunction on an had previously had severe reactions to angiotensin-angiotensin-converting-enzyme inhibitor before study converting-enzyme inhibitors that would, until these data, preclude use of an angiotensin-receptor blocker. The non-signifi cant relative reduction of 8% by Of those patients, two had hypotension and one had telmisartan in TRANSCEND was unexpected, especially renal dysfunction, although none had angio-oedema because telmisartan was recently shown to be non- while on telmisartan. These data, in addition to inferior to ramipril in ONTARGET.5 There are several CHARM-Alternative,8 support use of an angiotensin-possible reasons TRANSCEND did not show a statistic- receptor blocker in those with an intolerance to an ally signifi cant diff erence in the primary endpoint. angiotensin-converting-enzyme inhibitor for reasons The investigators ambitiously powered TRANSCEND beyond cough.
at 94% to fi nd a 19% relative-risk reduction. This was Overall, data supporting use of angiotensin- a higher power and more robust eff ect size than in receptor blockers to prevent vascular events in various HOPE, in which more patients were enrolled, event cardiovascular groups, other than heart failure, are rates were higher, and use of other life-saving drugs incomplete. TRANSCEND’s results challenge the non-was lower. Although ramipril reduced the primary inferiority shown in ONTARGET and suggest no more composite endpoint in HOPE by 22%, the higher use than a modest eff ect, if any at all. Other evidence on of lipid-lowering therapy, β blockers, and antiplatelet angiotensin-receptor blockers is also limited. Losartan drugs in TRANSCEND refl ects the current standard of showed benefi t in patients with hypertension and care and would be expected to lower event rates and left-ventricular hypertrophy,9 but it was compared infl uence the size of eff ect from additional therapies. with atenolol, a β blocker with questionable effi However, perindopril did reduce cardiovascular death, and possible harm in some groups;10 one Japanese trial myocardial infarction, and cardiac arrest by 20% in showed that valsartan reduced cardiovascular events.11 EUROPA,6 despite the patients being on similar drugs Angiotensin-receptor blockers that have been studied to those in TRANSCEND. It is unclear if this result in coronary disease are safe, but possibly less eff ective refl ects a lesser eff ect of telmisartan or if the benefi t alternatives in patients with intolerance to angiotensin-in EUROPA was driven by a sicker population (all had converting-enzyme inhibitors. Although data are too coronary disease in EUROPA vs 75% in TRANSCEND). limited to reach defi nitive conclusions, the clinical Conversely, trandolapril showed no benefi t in PEACE eff ect of angiotensin-receptor blockers seems less in patients with stable coronary disease.7 Despite being robust than that of angiotensin-converting-enzyme the largest placebo-controlled trial of this nature to inhibitors. There fore angiotensin-converting-enzyme date, TRANSCEND was underpowered to test this inhibitors should remain the preferred renin-active robust eff ect. The non-signifi cant trend in favour of agent to prevent vascular events in patients with or at telmisartan suggests there may be a more modest but high risk for cardiovascular disease.
signifi cant eff ect in a trial designed to detect a smaller risk reduction. At present, a statistical and clinical *Toni L Ripley, Donald Harrisonbenefi t from telmisartan cannot be ruled in or out.
University of Oklahoma College of Pharmacy, Oklahoma City, It is unclear why telmisartan did not reduce the OK 73190, USA incidence of diabetes or admissions for heart failure, We declare that we have no confl ict of interest.
when other angiotensin-receptor blockers have shown 1 Jorde UP, Ennezat PV, Lisker J, et al. Maximally recommended doses of some benefi t in post-hoc analysis (especially when angiotensin-converting-enzyme (ACE) inhibitors do not completely telmisartan did reduce development of left-ventricular prevent ACE-mediated formation of angiotensin II in chronic heart failure.
Circulation 2000; 101: 844–46.
hypertrophy). Although this fi nding might be due to 2 McKelvie RS, Yusuf S, Pericak D, et al, for the RESOLVD Pilot Study Investigators. Comparison of candesartan, enalapril, and their chance (these were secondary and tertiary endpoints), combination in congestive heart failure: Randomized Evaluation of the results may also refl ect heterogeneity in the Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study.
Circulation 1999; 100: 1056–64.
www.thelancet.com Published online August 31, 2008 DOI:10.1016/S0140-6736(08)61243-X
The Heart Outcomes Prevention Evaluation Study Investigators. Eff ects The Prevention of Events with Angiotensin Converting Enzyme Inhibition of an angiotensin-converting-enzyme inhibitor, ramipril, on (PEACE) Investigators. Angiotensin-converting-enzyme inhibition in stable cardiovascular events in high risk patients. N Engl J Med 2000; coronary artery disease. N Engl J Med 2004; 351: 2058–68.
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Granger CB, McMurray JJV, Yusuf S, et al, for the CHARM Investigators The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects and Committees. Eff ects of candesartan in patients with chronic heart with cardiovascular Disease (TRANSCEND) Investigators. Eff ects of the failure and reduced left-ventricular systolic function intolerant to angiotensin-receptor blocker telmisartan on cardiovascular events in angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. high-risk patients intolerant to angiotensin-converting enzyme inhibitors: Lancet 2003; 362: 772–76.
a randomised controlled trial. Lancet 2008; published online Aug 31. Dahlöf, B, Devereux RB, Kjeldsen SE, et al, for the LIFE study group. Cardiovascular morbidity and mortality in the Losartan Intervention For The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint reduction in hypertension study (LIFE): a randomised trial against Endpoint Trial (ONTARGET) Investigators. Telmisartan, ramipril, or both atenolol. Lancet 2002; 359: 995–1003.
in patients at high risk for vascular events. N Engl J Med 2008; 10 Kahn N, McAlister FA. Re-examining the effi 358: 1547–59.
treatment of hypertension: a meta-analysis. CMAJ 2006; 174: 1737–42.
The EURopean trial On reduction of cardiac events with Perindopril in 11 Mochizuki S, Dahlöf B, Shimizu M, et al, for the Jikei Heart Study group. stable coronary Artery disease Investigators. Effi Valsartan in a Japanese population with hypertension and other reduction of cardiovascular events among patients with stable coronary cardiovascular disease (Jikei Heart Study): a randomised, open-label, artery disease: randomised, double-blind, placebo-controlled, multicentre blinded endpoint morbidity-mortality study. Lancet 2007; 369: 1431–39.
trial (the EUROPA study). Lancet 2003; 362: 782–88.
www.thelancet.com Published online August 31, 2008 DOI:10.1016/S0140-6736(08)61243-X

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