Published online before print January 5, 2006, doi: 10.1161/01.STR.0000199643.05768.8f
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(Stroke. 2006;37:338.)
© 2006 American Heart Association, Inc.
Letters to the Editor |
MOSES Raises Questions
Division of Cardiology, North York General Hospital, Toronto, Canada
Division of Cardiac Surgery, St Micheal’s Hospital, Toronto, Canada
To the Editor:
The MOSES trial confirms both the safety and efficacy of eprosartan in hypertensive patients with cerebrovascular disease.1 The authors’ conclusion that eprosartan provides "vascular protective effects" above that of nitrendipine, however, is not substantiated by the data. Mortality was not different (57 eprosartan versus 52 nitrendipine; P=0.725), nor was the first occurrence of a cebrovascular event (80 eprosartan versus 89 nitrendipine; P=0.42). Eprosartan did reduce total cerebrovascular events (102 versus 134; P=0.026) but did not result in improvement in either functional or cognitive parameters. Perhaps this is a reflection that nondisabling TIAs rather than stroke drove the benefit. Furthermore, the apparent benefit with eprosartan may have been spurious because a single patient, presumably on nitrendipine, had multiple events.
The cardiovascular end points in MOSES take on a more intriguing significance considering the results of the VALUE trial, which compared the same 2 classes of drugs. In VALUE, the ARB valsartan was associated with a 19% (P=0.02) increase in myocardial infarction (MI) compared with the calcium channel blocker (CCB) amlodipine. A highly controversial editorial addressed the increased MI rate in VALUE, suggesting that ARB as a class may not only lack vascular protection, but may possibly result in increased MI.2 This hypothesis continues to be debated,3 and despite the ongoing analysis of the data,4,5 some have already concluded that an ARB may not have the same "vascular protection" of an angiotensin converting enzyme inhibitor (ACEI).6
Eprosartan, although reducing first time cardiovascular events (CV; 60 versus 84; P=0.03), did not reduce total cardiovascular events. Acute coronary syndrome rates tended to be lower with eprosartan, which is encouraging, but the benefit with eprosartan on cardiovascular end points appears to be primarily related to a reduction in congestive heart failure (CHF). The reduction in CHF with eprosartan, surprisingly, did not correlate with a reduction in mortality. Considering the criterion for diagnosing CHF in MOSES was not reported, one has to wonder whether peripheral edema alone, a common side effect with CCB secondary to vasodilatation, led to an increase in the diagnosis of CHF in the nitrendipine patients. This, of course, would be erroneous in the absence of other symptoms or signs of CHF requiring treatment.
How should the results of MOSES influence clinical practice? Should ARB or CCB be first-line therapy in the hypertensive patient after cerebrovascular accident? Upwards of 64% of the patients in MOSES had a very strong indication for an ACEI becuase their premorbid diagnosis included coronary artery disease or diabetes mellitus.7 Current guidelines8 strongly recommend all patients with coronary artery disease receive ACEI independent of hypertension because of their unique "vascular protective" effects, the benefit which is above that of lowering blood pressure alone.9 Many patients with cerebrovascular disease have concomitant coronary artery disease, which even in the absence of symptoms, will statistically lead to the demise of the patient. Thus, ACEI can reasonably be viewed as the "preferred" cardio-protective agent for a MOSES patient. And finally, a MOSES patient requires aggressive intervention of all vascular risk factors. Only 32% of the hyperlipidemic patients in MOSES received a statin. This suggests a real opportunity for dramatically improving the prognosis of a MOSES patient with a more judicious prescribing of statins.
References
1. Schrader J, Luders S, Kulschewski A, Hammersen F, Plate K, Berger J, Zidek W, Dominiak P, Diener HC. Morbidity and Mortality after Stroke-Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES). Stroke. 2005; 36: 1218–1226.
2. Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. BMJ. 2004; 329: 1248–1249.
3. Strauss M, Verma S. Letters To The Editor. Angiotensin receptor blockers and myocardial infarction. BMJ. 2005; 330: 1269–1271.
4. Verma S, Leiter L, Lonn E, Strauss M. Perindopril in diabetes: perspectiv from the EUROPA substudy, PERSUADE. Eur Heart J. 2005; 26: 1347–1349.
5. Strauss MH, Verma S. Inhibition of the renin-angiotensin system in cardiovascular protection: Is it important to watch C’ARB ‘intake? Can J Cardiol. 2005; 21: 577–580.[Medline] [Order article via Infotrieve]
6. ARB and Myocardial Infarction. The Medical Letter. 2005; 47: 38–39.
7. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000; 342: 145–153.
8. Lopez-Sendon J, Swedberg K, McMurray J, Tamargo J, Maggioni AP, Dargie H, Tendera M, Waagstein F, Kjekshus J, Lechat P, Torp-Pedersen C; Task Force on ACE-inhibitors of the European Society of Cardiology. Expert consensus document on angiotensin converting enzyme inhibitors in cardiovascular disease. The Task Force on ACE-inhibitors of the European Society of Cardiology. Eur Heart J. 2004; 25: 1454–1470.
9. Verdecchia P, Reboldi G, Angeli F, Gattobigio R, Bentivoglio M, Thijs L, Staessen JA, Porcellati C. Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention. Hypertension. 2005; 46: 386–392.
Response:
Department of Internal Medicine, St. Josefs Hospital, Cloppenburg, Germany
Institute for Hypertension and Cardiovascular Research, Cloppenburg, Germany
Medical Biometry and Epidemiology, University Hospital Hamburg-Eppendorf, Germany
Department of Nephrology, Charité Campus Benjamin Franklin, Berlin, Germany
Department of Pharmacology and Toxicology, University of Lübeck, Germany
Department of Neurology, University of Essen, Germany
for the MOSES Study Group
Drs Strauss and Verma discussed several important aspects of the MOSES study results concerning the cardiovascular end points in comparison to other data, especially the increase of myocardial infarction in the valsartan group of the VALUE trial.1 These results could not be supported by the MOSES data.2 In this study, the number of acute coronary syndrome in the eprosartan group was even less than in the nitrendipine group (39 versus 48; but not significant) showing at least the safety of treatment with eprosartan in patients with cerebrovascular disease. Drs Strauss and Verma wondered if the diagnosis of heart failure in the MOSES study could be attributable to peripheral edema alone. This question is of course of great importance because the significant difference in first occurrence of cardiovascular events was attributable to heart failure.
To accept the diagnosis of CHF, more information like hospital demission-letters, echocardiography, chest x-ray, hospitalization and concomitant medication had to be documented and considered by the end point committee. Because of the limited number of words in the original article these methods could not be described in detail.
The benefit for the eprosartan group in terms of reducing cerebral events was not driven by a single patient with multiple events. There was a higher number of patients with >1 event in the same category of end points (TIA, ischemic stroke, acute coronary syndrome, CHF) in the nitrendipine group (16 versus 24; eprosartan versus nitrendipine).
References
1. 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; VALUE trial group. 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]
2. Schrader J, Luders S, Kulschewski A, Hammersen F, Plate K, Berger J, Zidek W, Dominiak P, Diener HC; MOSES Study group. Morbidity and Mortality after Stroke-Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES). Stroke. 2005; 36: 1218–1226.
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