血管紧张素ii受体拮抗剂卒中防治专家共识（Angiotensin II receptor antagonists, stroke prevention, expert consensus）

1、血管紧张素ii受体拮抗剂卒中防治专家共识（Angiotensin II receptor antagonists, stroke prevention, expert consensus）Angiotensin II receptor antagonists, stroke prevention, expert consensusBeijing Tiantan Hospital Author: Wang YongjunAbstract hypertension is the most important risk factors of stroke and hypertension contr

2、ol in China is unfavorable the incidence of stroke is one of the main reasons for the high levels of blood pressure control, to prevent the occurrence and recurrence of stroke is very important. Therefore, the editorial department of the organization of national cardiovascular and neurological exper

3、ts in the field of Chinese Journal of internal medicine, on the application of angiotensin II receptor antagonists in patients with cerebral vascular disease in the heated debate and reach a consensus.1 PrefaceStroke is a very serious public health problem. In Europe and the United States, stroke ac

4、counts for third of the causes of death, 1. The mortality rate of stroke in China is second only to that of malignant tumors. However, both in Europe and the United States or China, the incidence of stroke disability is the first. Hypertension is the most important risk factor for stroke. Now there

5、are about 1% hypertension patients in China, and the prevalence rate of hypertension is 18.8% in 160 million and over 18. Compared with 1991, the prevalence rate of hypertension increases by 2%. The awareness rate of hypertension in Chinese population was 30.2%, the treatment rate was 24.7%, the con

6、trol rate was 6.1%, and the ratio was higher than that in 1991, but it was still at a poor level, 2. Controlling blood pressure is important to prevent stroke and recurrence. In recent years, a new generation of antihypertensive drugs, angiotensin II receptor antagonists (ARB), has gained more and m

7、ore evidence in the prevention and treatment of stroke. Therefore, it is necessary to determine the status of ARB in stroke prevention and treatment.2 hypertension and stroke2.1 hypertension and stroke correlation: the risk of stroke in hypertensive patients is 3 to 4.5 times as high as that in the

8、control group. Studies have shown that systolic blood pressure increases by 1O mm Hg (1 mmHg=0.133kPa) every day, the incidence of ischemic stroke increases by 47%, bleeding stroke increases by 54%, diastolic pressure by 5 mmHg, and stroke risk increases by 46%. Statistics show that the risk of stro

9、ke is 1.5 times greater in Asian populations than in the western population. 40% to 50% of risk factors for stroke in China are attributed to hypertension 3.2.2 managing blood pressure effectively reduces stroke incidence: a number of studies have shown that antihypertensive treatment reduces stroke

10、 incidence and recurrence. A meta-analysis of 29 randomized trials of antihypertensive treatment in 2003 showed that 4 treatment significantly reduced the relative risk of ischemic or hemorrhagic stroke. Systolic blood pressure decreased by 5 to 6mm, Hg and / or diastolic blood pressure decreased by

11、 23 mmHg, and relative risk (RR) decreased by 40%. An absolute risk reduction of 0.5%requires (NNT) =200, which means that 1 stroke patients can be prevented with each treatment of 200 hypertensive patients. For hypertensive patients with diabetes, the target blood pressure should be lower BP130/8Om

12、m, Hg). Because the effect of stroke prevention is linearly related to the degree of hypotension, in other words, when treatment is tolerated, target blood pressure should be controlled at ideal blood pressure 120/8O, mm, Hg, or 5. Hypertension control was an independent risk factor for increased st

13、roke 6. The correct management of blood pressure involves dropping from high blood pressure to higher target values and then to ideal target values,And try to make the fluctuation of blood pressure in 24h within 20/8, mm and Hg.3 overview of ARB drugs3.1 overview: ARB by selective blockade of angiot

14、ensin II (Ang II) type 1 (AT1) receptor, blocked AngII vasoconstriction, increased blood pressure and aldosterone secretion, water retention, sympathetic excitement and other adverse effects on the body; on the other hand, due to the increased synthesis of AngII feedback, and increased blood tissue

15、Ang II levels, in type 2 (AT2) receptor, pharmacological effect of 7 produce vasodilation, anti cell proliferation and regulate cell apoptosis positive.3.2 commonly used ARB class: ARB class has been listed in China, 6 kinds (including valsartan, losartan, irbesartan, telmisartan, candesartan ester,

16、 olmesartan ester), has been completed clinical trials of valsartan, but not listed.Neuroprotective effect of 4 ARB4.1 the distribution of renin angiotensin system in the central nervous system: angiotensin has a short and long-term effect on osmotic pressure and blood pressure. There is a complete

17、renin angiotensin system in brain tissue, and the distribution of AT1 and AT2 receptors varies according to different sites and nuclei, and AT1 receptor 8 is mainly distributed in most areas.4.2 animal studies: several studies have shown that taking ARB (candesartan, telmisartan, Losartan) for a lon

18、g time can reduce stroke susceptibility in hypertensive rats with stroke 9-10. Pre administration of valsartan 3mg, Kg-1, D-L could significantly reduce the infarct size after cerebral ischemia in the middle cerebral artery occlusion (MCAo) model mice. After the embolization of 24h, the scores of ne

19、urological function in the Valsartan treated group were significantly improved by 11. Similarly, in the cerebral ischemia rat model of MCAo, irbesartan treatment group neurological score was significantly better than the control group, and apoptosis of microglia and macrophage activation decreased,

20、c-fos/C-jun significantly decreased the expression of 12-13. Pre intervention with candesartan did not affect the blood pressure, the infarct size of the treatment group was reduced, and the nerve function defect was 14. Studies using gene technology have shown that the action of the ATl receptor bl

21、ocker, valsartan, is activated by the AT2 receptor, and the effective effect of valsartan is reversed by knocking out the AT2 receptor, 15. Animal experimental evidence supports the neuroprotective effect of ARB on stroke, independent of the hypotensive effect.5 ARB for primary prevention of strokeP

22、rimary prevention of stroke refers to the rational treatment of risk factors for stroke in the absence of stroke in order to reduce the likelihood of stroke. Hypertension, left ventricular hypertrophy, atrial fibrillation, diabetes mellitus are the risk factors of stroke. Extensive clinical trials h

23、ave confirmed that ARB plays a positive role in reducing and controlling blood pressure, reversing left ventricular hypertrophy, preventing and treating diabetes mellitus and preventing atrial fibrillation.5.1 control blood pressure: hypertension is the most important risk factor of cerebral hemorrh

24、age and cerebral infarction. The United States national hypertension prevention, diagnosis, treatment and evaluation of Joint Committee seventh report, European hypertension guidelines and Chinese guidelines for hypertension prevention and treatment are clearly pointed out, ARB and diuretics, self b

25、lockers, calcium antagonists, angiotensin converting enzyme inhibitors (ACEI) are the first-line drugs for the treatment of hypertension. Compared with other types of antihypertensive drugs,The ARB class has at least the same effective hypotensive effect as 16.Evidence based medical evidence of 5.2

26、ARB in primary prevention of stroke:JIKEI HEAART of 17 a prospective, randomized, open and parallel control and blind method end point judgment research design, is one of Asias largest cardiovascular clinical research in Japan, in 3081 cases of hypertension, coronary heart disease and (or) heart fai

27、lure (CHF) patients, treatment of valsartan and non ARB drugs compared to the main research end point was a composite of cardiovascular morbidity and mortality measures including stroke, transient ischemic attack, myocardial infarction, chronic heart failure or angina, aortic dissection, occlusion o

28、f lower extremity muscle, blood dialysis or increased exponentially. The results showed that the relative risk of new stroke in valsartan group was decreased by 40%, and the risk ratio (HR) was =0.60 (P=0.028,95%CI0.38 0.95).LIFE study 18 was a randomized, double-blind, parallel controlled trial inv

29、olving 9193 patients with primary hypertension with left ventricular hypertrophy (confirmed by echocardiography). The results showed that: the treatment group (Losartan group) and control group (atenolol) compared to the main end point events (death, myocardial infarction, stroke) decreased 13%, rel

30、ative risk (RR) 0.87 (95%CI0.77 - 0.98, P=0.021). For fatal or nonfatal stroke, the RR in the treatment group and the control group was 0.75 (95%CI0.63 to 0.89, P=0.001).In the SCOPE of 19, 4964 cases of 79 89 years old patients with hypertension were randomly divided into control group and treatmen

31、t group, the control group using conventional antihypertensive drugs mainly for thiazide diuretics treated by candesartan, an average of 3.7 years of follow-up. The nonfatal stroke RR in the Candesartan treated group and the control group was 0.72 (95%CI0.53 to 0.99; P=0.04); the RR for all stroke e

32、vents was 0.77 (95%CI0.58 to 1.02; P=0.056).6 ARB is used for two stage prevention of strokeThe two stage prevention of stroke is the prevention of recurrent stroke in patients who have had one or more strokes. In the MOSES 20 study included 1405 patients with CT or MRI confirmed for stroke patients

33、, divided into eprosartan treatment group and nitrendipine compared to the control group, the average of 2.5 years of follow-up, there was no significant difference in blood pressure of two groups under the condition of the main end point (death, all stroke events all cause and cardiovascular event)

34、 RR is 0.79 (95%CI0.66 0.96; P=0.014), stroke fell 24%. ACCESS 2l was a multicenter, prospective, randomized, double-blind, placebo-controlled phase II clinical study, a total of 342 patients were enrolled, 175 cases were treated with candesartan, 167 cases in control group were given placebo, the C

35、andesartan group 12 months cumulative mortality rate is similar with the placebo group (P=0.07); candesartan group of vascular events was significantly lower than that of the placebo group (P=0.026), including fatal and nonfatal cerebrovascular events in two groups were 13 cases and 19 cases. The PR

36、OFESS study of 22 is an ongoing trial using 2 * 2 factorial design. Patients were randomly assigned to receive telmisartan or placebo, and 18500 patients from 34 countries and 700 centers participated in the study with Gray or aspirin plus extended release dipyridamole.The treatment will last for 4

37、years until the 2100 cases of patients with fatal or non fatal recurrent Zu Zhong event, the primary end point was a recurrent event in the Zu Zhong time, the secondary end point include vascular events (death, myocardial infarction, Zu Zhong vascular disease) and new onset diabetes.Clinical benefit

38、s of 7 ARB antihypertensiveClinical studies have found that carotid artery structural lesions (thickening and plaques), metabolic syndrome, myocardial hypertrophy and atrial fibrillation (atrial fibrillation) are related to stroke. In ARB step-down at the same time, and delay the increase of the car

39、otid intima-media thickness. Improve insulin resistance, reduce cardiac remodeling, reduce the occurrence and recurrence of atrial fibrillation, in order to prevent the occurrence of stroke and recurrence has important significance.7.1 effect of ARB on carotid atherosclerosis and stroke: progress of

40、 carotid atherosclerosis is directly related to the intima-media thickness of carotid artery atherosclerotic plaque formation and the severity of stroke risk is high, the stability of carotid artery plaque of carotid artery stenosis caused hemodynamic stroke (reduced blood hypoperfusion), broken nec

41、k artery plaque and causing embolic stroke. While the ARB has good anti atherosclerosis effect, found that the subgroup of 23 in the LIFE study, compared with ARB treatment group and atenolol, for follow-up of 3 years in 2 groups of blood pressure reduction is the same, but the Losartan group of car

42、otid artery intima media cross-sectional area (IMA) decreased significantly (P0.05), progress losartan can make the carotid intima-media thickness was delayed by 7.9%, while only 1.7% of the atenolol group delay rate. SILVHIA 24 was selected to study 108 cases of patients with hypertension and left

43、ventricular hypertrophy, respectively Maher Bbe Chatain and atenolol in the treatment group were followed up for 1 years, the blood pressure decreased in similar circumstances, irbesartan group of carotid artery IMT decreased significantly. At the same time, basic research also confirmed that ARB ca

44、n reduce the activity and content of PAI at the same time, which suggests that ARB may play a role in the prevention and treatment of thrombosis. These mechanisms and clinical findings provide better data for the long-term treatment of ARB to prevent stroke.7.2 effects of ARB on glucose metabolism:

45、recent studies have found that compared with other antihypertensive drugs, ARB drugs have special advantages in improving glucose metabolism disorders. Top 25 study found that in patients with primary hypertension has decreased insulin sensitivity, valsartan 8Omg/d treatment can significantly reduce

46、 the HOMA index (hyperinsulinemia and insulin sensitivity index based on steady-state model), so as to improve insulin sensitivity in patients with primary hypertension. VALUE study 26 found that compared with amlodipine, valsartan can reduce the risk of new onset diabetes in hypertensive patients b

47、y 23%.7.3 effects of ARB on left ventricular hypertrophy: numerous clinical trials have demonstrated that left ventricular hypertrophy is significantly associated with various cardiac events and is an independent predictor of stroke. The incidence of cerebrovascular adverse events in hypertensive pa

48、tients with left ventricular hypertrophy was significantly higher than that in patients without left ventricular hypertrophy. Early effective antihypertensive intervention can prevent the progression of left ventricular hypertrophy, and further reduce the occurrence of cardiovascular events. Yasunar

49、i and other 27 studies have found that valsartan and amlodipine are similar in the treatment of hypertensive patients with similar antihypertensive efficacy,Valsartan is superior to amlodipine in reducing left ventricular hypertrophy. In the Val-HEFT study, 28 was added to ACEI or B receptor blocker

50、s, and valsartan or placebo was added to the antihypertensive treatment, which proved that valsartan reversed the left ventricular remodeling. LIFE of 29 showed that after adjustment for baseline and after treatment, blood pressure, electrocardiogram, compared to treatment with atenolol based antihy

51、pertensive therapy with losartan based. The effect of reversing left ventricular hypertrophy is stronger.7.4 ARB impact on atrial fibrillation: studies have shown that atrial fibrillation is highly associated with stroke, and that the risk of stroke in patients with atrial fibrillation is 4 times hi

52、gher than in patients without atrial fibrillation, and that patients with new onset atrial fibrillation are at higher risk of stroke. Val-HEFT study 30 showed that plasma BNP levels were independent risk factors for atrial fibrillation, whereas valsartan in patients with HF significantly lowered pla

53、sma BNP levels compared with placebo. Subgroup analysis showed that valsartan was significantly lower in patients without atrial fibrillation at baseline and 37% of newly developed atrial fibrillation. 31 of subgroup LIFE showed that compared with atenolol group, losartan group of patients with left

54、 atrial diameter decreased more significantly (P0.001), atrial fibrillation (P0.001), to further reduce the 33% previous history of atrial fibrillation stroke risk is reduced by 45% (P=0.045). Fogari 32 study included 250 patients with at least 2 times and the history of atrial fibrillation patients

55、 taking amiodarone, respectively with losartan and amlodipine gradually increase the amount of treatment, follow-up of 12 months, results showed that the level of blood pressure control under the same condition, losartan inhibits the recurrence of atrial fibrillation and most with dose correlation, and amlodipine there were no obvious improvement in atrial fibrillation. MMadrid and other 33 investigated the role of Maher Bbe Chatain in maintaining sinus rhythm after cardioversion of persistent atrial fibrillation, and found t