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ONTARGET study editorial

T h e ne w engl a nd jour na l o f medicine

n engl j med 359;4 https://www.wendangku.net/doc/f513833079.html, july 24, 2008

426Telmisartan, Ramipril, or Both in Patients at High Risk of Vascular Events

To the Editor: The investigators of the Ongoing

Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) (April 10 issue)1 report that telmisartan is equiv-alent to ramipril in patients with vascular disease or high-risk diabetes. However, the primary com-posite end point of death from cardiovascular causes, myocardial infarction, stroke, or hospi-talization for heart failure was not lower in the combination-therapy group than in the group re-ceiving ramipril alone, even though blood-pres-sure levels in the combination-therapy group were 2.4/1.4 mm Hg lower than those in the ramipril group throughout the study period. Still more dis-turbing was a trend in the combination-therapy group toward even more deaths from cardiovas-cular and noncardiovascular causes than in the ramipril or telmisartan group (deaths from car-diovascular causes, 620 vs. 603 and 598, respec-tively; deaths from noncardiovascular causes, 445 vs. 411 and 391, respectively). Given that the number of patients with hyperkalemia was much higher in the combination-therapy group than in the ramipril or telmisartan group (480 vs. 283 and 287, respectively), as was the number of patients with hypotensive symptoms (406 vs. 149 and 229, respectively), we wonder whether a specific cause of death (i.e., sudden death or death from arrhyth-mia) can be identified in the combination-therapy group. Data from such an analysis should be provided .

Nikolaus Büchner, M.D.

Bochum University Hospital

44625 Herne, Germany Bernhard Banas, M.D.University of Regensburg 93042 Regensburg, Germany Bernhard K. Kr?mer Bochum University Hospital

44625 Herne, Germany

bernhard.kraemer@marienhospital-herne.de The ONTARGET Investigators. Telmisartan, ramipril, or both 1. in patients at high risk for vascular events. N Engl J Med 2008; 358:1547-59.To the Editor: We are puzzled by the conclud-ing statement of McMurray,1 in his editorial ac-companying the report on the ONTARGET trial, that “Because ARBs [angiotensin-receptor block-ers] are more costly than ACE [angiotensin-con-verting–enzyme] inhibitors and have more side effects, their primary value is as an alternative for patients who cannot tolerate ACE inhibitors.” The ONTARGET trial directly contradicts this state-ment. Although 621 patients permanently discon-tinued ramipril, only 438 patients permanently discontinued telmisartan. When hypotensive symp-toms of an antihypertensive drug (an expected effect) are omitted, more than twice as many pa-tients discontinued ramipril as discontinued telmi-sartan. Also, so-called hypotensive symptoms have little meaningful value unless the corre-sponding blood pressure is recorded. In addition, several randomized trials have shown that ARBs have fewer adverse effects than ACE inhibitors (Table 1). Notably, in ONTARGET, angioedema, which can be fatal, was 2.5 times as common in patients receiving ramipril as in those receiving telmisartan. These findings clearly do not attest to the conclusion that ARBs have a greater num-ber of adverse effects than ramipril, as stated by McMurray.Franz H. Messerli, M.D. Sripal Bangalore, M.D., M.H.A.St. Luke’s–Roosevelt Hospital New York, NY 10025Venkata S. Ram, M.D.University of Texas Southwestern Medical Center Dallas, TX 75240 fmesserl@https://www.wendangku.net/doc/f513833079.html, Dr. Messerli reports serving on speakers’ bureaus for Abbott, GlaxoSmithKline, Novartis, Pfizer, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Forest, Sankyo, and Sanofi-Aventis and receiving research grants from GlaxoSmithKline, Pfizer, Novartis, and CV Therapeutics. Dr. Ram reports serving on speakers’ bureaus for Advanced Health Media, COGENIX, and GENESIS, which conduct educational programs for companies that manufacture pharmaceuticals and medical devices. No other potential conflict of interest relevant to this letter was reported.

McMurray JJV. ACE inhibitors in cardiovascular disease — 1. unbeatable? N Engl J Med 2008;358:1615-6.

Matchar DB, McCrory DC, Orlando LA, et al. Systematic re-2. view: comparative effectiveness of angiotensin-converting en-zyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med 2008;148:16-29.

Pitt B, Segal R, Martinez FA, et al. Randomised trial of losar-3. tan versus captopril in patients over 65 with heart failure (Evalu-

ation of Losartan in the Elderly Study, ELITE). Lancet 1997;349: 747-52.Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan 4. compared with captopril on mortality in patients with sympto-

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correspondence

n engl j med 359;4 https://www.wendangku.net/doc/f513833079.html, july 24, 2008427matic heart failure: randomized trial — the Losartan Heart Fail-ure Survival Study ELITE II. Lancet 2000;355:1582-7.Dickstein K, Kjekshus J. Effects of losartan and captopril on 5. mortality and morbidity in high-risk patients after acute myo-cardial infarction: the OPTIMAAL randomized trial: Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002;360:752-60.Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, 6. captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906. [Erratum, N Engl J Med 2004;350:203.]The editorialist replies: I referred to the only two trials that showed noninferiority of an ARB as compared with an ACE inhibitor and therefore permit a legitimate comparison of tolerability.1 In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), valsartan led to significantly more reductions in the dose of the study drug because of hypotension and renal dysfunction than did captopril. Treatment discontinuation because of hypotension was also significantly more common with valsartan (and discontinua-tion due to renal dysfunction was numerically

more frequent with valsartan). As expected, cough was much less common with valsartan.

Only study-drug discontinuations were report-ed (as multiple episodes) in ONTARGET, but ex-actly the same pattern was observed. It is impor-tant to note that the net difference of 137 more discontinuations for any reason with ramipril reflected the balance of 267 fewer discontinua-tions because of cough with telmisartan, offset by other adverse effects that in my opinion may be more clinically significant (e.g., hypotension, for which there was a net excess of 80 cases with telmisartan).John J.V. McMurray, M.D.

University of Glasgow

Glasgow G12 8QQ, United Kingdom

Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, 1. captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906. [Erratum, N Engl J Med 2004;350:203.]

Anesthesia Awareness and the Bispectral Index

To the Editor: Avidan et al. (March 13 issue)1 confirm that bispectral index (BIS)–guided care achieves a 0.2% incidence of awareness during anesthesia in high-risk patients, as previously re-ported,2 but further conclusions and recommen-dations are not supported. Despite the investiga-tors’ original hypothesis “that the incidence of awareness [with an end-tidal protocol] will be equivalent to or lower” than that with a BIS-guided protocol,3 the sample-size calculation erroneous-ly assumed no treatment effect for the anesthetic protocol (Table 1). Consequently, this study had an 80% probability of missing a 50% difference in the relative efficacy of the two interventions.4Unexplained gaps in BIS trends suggest that

inadequate training or vigilance and poor proto-

* The numbers for each adverse effect represent the incidence with ACE inhibitors versus the incidence with ARBs. ELITE denotes Evaluation of Losartan in the Elderly, MI myocardial infarction, OPTIMAAL Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan, and VALIANT Valsartan in Acute Myocardial Infarction Trial.? P<0.05. Only significant P values were reported.