Philip B Gorelick
MD MPH FACP
John S Garvin
Professor and Head
Center of Stroke Research
Department of Neurology and Rehabilitation
University of Illinois College of Medicine at Chicago
High blood pressure (BP) is the most important modifiable risk factor for stroke prevention.(1–3) Hypertension has the highest population-attributable risk for stroke and, in observational epidemiological studies, it makes stroke risk rise by three to four times. Meta-analyses of observational epidemiological studies show that long-term lowering of diastolic blood pressure (DBP) by about 5–6mmHg is associated with an estimated 35–40% fewer strokes – a statistic that is similar to the 42% stroke reduction observed in randomised trials of antihypertensive drugs. Our focus, however, has begun to shift. Because there is a continuous association between BP and cardiovascular disease risks, simple categorisation to define “hypertensives” vs “nonhypertensives” may not be adequate.(4) For example, the association between BP and stroke is continuous down to levels of at least 115/75mmHg,(5) and the majority of strokes occur in patients with only mild to normal BP level. Furthermore, there is evidence that some of the detrimental actions of angiotensin II (Ang II), a key mediator of hypertension, may be independent of elevation in BP.(6)
In this article we review the results of the MOrbidity and mortality after Stroke, Eprosartan compared with nitrendipine for Secondary prevention (MOSES) study. The main hypothesis of the study was that in hypertensive stroke patients, for the same level of BP control, the angiotensin receptor blocker (ARB) eprosartan would be more effective than nitrendipine in reducing cerebrovascular and cardiovascular events.(7)
MOSES was a prospective, randomised, controlled, multicentre study that followed a prospective, randomised, open, blinded endpoint (PROBE) design.(7) It was an investigator-initiated study of 1,405 hypertensive patients from internal medicine, general medicine and hospitals in Germany and Austria. Patients enrolled had a history of cerebrovascular events (transient ischaemic attack [TIA], ischaemic stroke and cerebral haemorrhage) documented by cranial computed tomography or magnetic resonance scan (within the past 24 months before inclusion). Exclusion criteria were internal carotid artery occlusion or stenosis >70%, manifest heart failure, age >85 years, treatment with anticoagulants for cardiac arrhythmia, high-grade aortic or mitral valve stenosis, or unstable angina pectoris. The study was initiated in October 1998, and inclusion of subjects ended in February 2002. The follow-up period was from two years and above, and up to four years.
Patients were randomised to receive eprosartan (600mg) or nitrendipine (10mg) once a day. The target BP goal was systolic BP (SBP) <140mmHg and DBP <90mmHg to be reached for two-thirds of entrants within three months. To reach the BP goal, the following add-on combinations were recommended, in order of priority: diuretics, followed by beta-blockers, and then alpha-blockers or centrally acting drugs. Use of angiotensin-converting enzyme inhibitors (ACEIs), Ang II type I (AT(1)) receptor antagonists or calcium antagonists were to be avoided.
Selected baseline characteristics of the study subjects are listed in Table 1.(7) The authors reported no significant differences in terms of demographic characteristics, severity of hypertension and frequency of coexisting cardiovascular conditions. BP reduction was similar in the two treatment groups. During the study an average of 76% had normalised BP in the eprosartan group, compared with 78% in the nitrendipine group. Combination antihypertensive therapy was necessary in about two-thirds of subjects in each treatment group.
Key primary and secondary outcome endpoints are listed in Table 2.(7) There were 461 total fatal and nonfatal events (206 in the eprosartan group and 255 in the nitrendipine group) for an incidence of 13.3 vs 16.7 per 100 patient years (incidence density ratio [IDR], 0.79; 95% confidence interval [CI], 0.66, 0.96; p=0.014). There were a total of 236 cerebrovascular events, 102 in the eprosartan group and 134 in the nitrendipine group (IDR, 0.75%; 95% CI, 0.58, 0.97; p=0.026). In the eprosartan and nitrendipine groups there were, respectively:
- 31 vs 39 ischaemic strokes.
- 66 vs 92 TIAs.
- 5 vs 3 intracerebral haemorrhages.
There were 178 cardiovascular events, 77 in the eprosartan group and 101 in the nitrendipine group (IDR, 0.75%; 95% CI 0.55, 1.02; p=0.061). At the end of the study there were no significant differences in the Mini-Mental State Exam, Barthel or Rankin scores. In addition, the frequency of relevant adverse events was comparable in the two treatment groups.
In the MOSES study, about three-quarters of patients in each treatment group reached the BP goal of <140/90mmHg, and at the end of the study or at the final study visit, mean values of SBP and DBP in the eprosartan and nitrendipine treatment groups were approximately the same (133.2/80.4 and 132.7/80.2mmHg, respectively).(7) Therefore, BP control was achieved in a similar time frame and degree in the two treatment arms. The MOSES study provides several key lessons for the general practitioner. First, the study adds to a growing body of knowledge supporting possible beneficial nonblood- pressure-lowering effects of ARBs.(8–10) Such effects could be mediated by blockage of the AT(1) receptor with sparing of the AT(2) receptor, which may mediate beneficial effects on the vascular endothelium through decreased coagulation, inflammation and altered vessel structure, and also protection of brain tissue from ischaemia.(6,11) Secondly, the main efficacy advantage of eprosartan over nitrendipine appears to be for secondary prevention in stroke patients in which multiple recurrent events may occur. Whereas there were fewer first cardiovascular endpoints in the MOSES study, this was not the case for first cerebrovascular events. The trial, however, was limited by a relatively small number of subjects for a comparison of two active treatments, which may have influenced the results. Finally, although ARBs may have beneficial nonblood-pressure-lowering effects, it is important to get BP to goal after stroke to ensure prevention of recurrent vascular events.(1,3,12)
- Gorelick PB. Lancet Neurol 2002;1:149-56.
- Gorelick PB. Stroke 2002; 33:862-75.
- Pedelty L, Gorelick PB. Hypertension 2004;44:1-5.
- MacMahon S, Neal B, Rodgers A. Lancet 2005;365:1108-9.
- Lawes CMM, Bennett DA, Feigin VL, Rodgers A. Stroke 2004;35:1024-33.
- Iadecola C, Gorelick PB. Stroke 2004;35:348-50.
- Schrader J, Luders S, Kulschewski A, et al for the MOSES Study Group. Stroke 2005;36:1218-26.
- Dahlof B, Devereux RB, Kjeldsen SE, et al. Lancet 2002;359:995-1003.
- Schrader J, Luders S, Kulschewski A, et al. Stroke 2003;34:1699-703.
- Trenkwalder P, Elmfeldt D, Hofman A, et al. Blood Press 2005;14:31-7.
- Strandberg TE. Stroke 2005;36:1225-6.
- PROGRESS Collaborative Group. Lancet 2001;358:1033-41.