Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study: reply In the KYOTO HEART study, stroke was diagnosed by sudden onset of neurological deficit (showing apparent cognitive or physical disabilities) and the presence of intracranial lesions corresponding to the neurological deficit and hospitalization (not for just diagnosis but for treatment). This is an ordinary diagnosis process for stroke treatment by Japanese physicians, and an isolated computed tomography/magnetic resonance imaging abnormality alone was not used to suffice the diagnosis. Although PROBE method was used in this study, the investigators were kept uninformed about the diagnostic criteria which had been independently determined by the Endpoint committee. In fact, among 558 provisional reports, only 238 (42.7%) were accepted as the primary endpoint by the endpoint committee [valsartan add-on: 83 (41.3%); non-angiotensin receptor blocker (ARB) group: 155 (43.4%)]. We believe that the possible bias would be highly unlikely to account for differences. Rather, the PROBE design may put the study close to daily clinical practice. This was described in detail in the ‘Limitation of this study’ in our publication. Regarding the utilization of aspirin and statins at Trial’s end, we at presence have not the data except anti-hypertensive drugs; however, there was no significant difference at baseline between both groups. The result with regard to stroke in KYOTO HEART study appears to be inconsistent with a recent meta-analysis by Messerli et al. of randomized ARB trials with active comparators (RR, 0.86; CI, 0.72–1.02) or placebo (RR, 0.89; CI, 0.78–1.02), although either meta-analysis showed a trend for better stroke prevention in the ARB arm, and the meta-analyses including both placebo and active treatment exhibited a significant reduction (RR, 0.87; CI, 0.77–0.98). Few Asians (especially Japanese) have participated to the large EU/US trials except RENAAL trial, in which subanalyses in Asian and Japanese subpopulations have reported that relative risk reduction rates in the primary endpoint are 35 and 45%, respectively, much higher than 16% in the whole RENAAL. Messerli et al. also commented that Asians may be particularly receptive to the protective effects of ARBs, as shown in RENAAL. Furthermore, mortality by coronary artery disease is one-third of that in USA, and cerebrovascular disease mortality is over 1.5 times higher than in USA. The percentage of cerebral bleeding is two or three times greater in Japan than in Western countries, and cerebral infarction is mostly caused by lacunar type ischaemic stroke due to hypertensive small vessel disease. It is possible that Asians are more susceptible to hypertension-related vascular disease rather than hyperlipidaemiaassociated vascular disease seen in Western countries. Together with JIKEI Heart Study showing impressive stroke benefits of valsartan in Japanese, a drug-specific molecule effect that stimulates preferentially AT2 receptor/NO-mediated vascular protective action (due to higher AT1 selectivity vs. AT2 compared with other ARBs) may be more apparently emerged in Japanese patients and yield an impressive stroke benefit above and independent of blood pressure lowering.