| Objectives:To compare the difference and trend of homocysteine(Hcy)reduction and blood pressure reduction between enalapril folic acid tablets and angiotensin converting enzyme inhibitor(ACEI)alone;to assess the ischemic stroke risk reduction with enalapril folic acid tablets;and explore the confounding factors which may distort the association of treatment and ischemic stroke risk.Methods:A comparative effectiveness research was conducted with two-stage historical prospective cohort study in the real clinical circumstance.In the first stage,the data were collected from the historical clinical registration information.The retrospective comparison,of which Hcy reduction,blood pressure reduction,primary ischemic stroke incidence and ischemic stroke risk reduction between ACEI plus folic acid tablet group and ACEI group,was conducted,respectively.In the second stage,the data were collected with follow-up method.The prospective comparison,of which Hcy reduction,blood pressure reduction,primary ischemic stroke incidence and ischemic stroke risk reduction between enalapril folic acid tablets group and ACEI group,was conducted,respectively.The effectiveness of each treatment was evaluated.Results:First Stage Historical cohort studyA total of 2038 inpatient medical records,which were of all hypertensive patients aged 40 years and more and accepted continuously ACEI antihypertensive drugs plus folic acid or alone,and had at least once blood pressure and Hcy records during 1 January 2015 and 31 December 31 2018,were reviewed.There were no statistically differences among the five groups’characteristics,which included mean age,family history of stroke,baseline mean Hcy,mean systolic blood pressure,mean diastolic blood pressure,hypertension grade and cardiovascular risk level,etc.(all P>0.05).Compared with the baseline,the average levels of Hcy,which were in the enalapril folic acid group,perindopril plus folic acid group,and benazepril puls folic acid group,were reduced after 1-year,2-year and 3-year treatment.The average levels of Hcy,which were in the benazepril group,after 1-year and 2-year treatment were lower than the baseline,however,after 3-year treatment,it elevated to a level that no different with the baseline.After 1-year,2-year and 3-year treatment,the average level of Hcy,which were in the enalapril folic acid group,perindopril plus folic acid group,and benazepril plus folic acid group were lower than those in the perindopril group and benazepril group.The average levels of Hcy,which were in the enalapril folic acid group,benazepril folic acid group and perindopril folic acid group,had a reduction trend with the prolonging treatment time(all P<0.05).Compared with baseline,the means of systolic blood pressure,which were in the enalapril folic acid group,perindopril folic acid group,and benazepril group,were reduced after 1-year,2-year and 3-year treatment;the means of systolic blood pressure,which were in the perindopril group and the benazepril folic acid group,were reduced after 1-year and 2-year treatment;the means of diastolic blood pressure,which were in the enalapril folic acid group and the benazepril group,were reduced after 1-year,2-year and 3-year treatment;the means of systolic blood pressure,which were in the perindopril folic acid group,perindopril group and benazepril folic acid group,were reduced after 1-year and 2-year treatment.The means of systolic blood pressure and average diastolic blood pressure in the five groups had a reduction trend with the prolonging treatment time(all P<0.05).After 3 years treatment,the rate of reaching the lowering blood pressure standard in the enalapril folic acid group was higher than those in the perindopril plus folic acid group,benazepril puls folic acid group and benazepril group,and that in the benazepril group was higher than those in all other groups(all P<0.05).The rates of reaching the lowering blood pressure standard in five groups had an escalating trend with the prolonging treatment time(all P<0.05).The review period of five groups ranged from 1 month to 36 months.During a median 21-month follow-up time,the cumulative incidence and incidence density of the enalapril folic acid tablet group was 5.5%and 3.250 per 1000 person-months,respectively;during a median 27-month follow-up time,the cumulative incidence and incidence density of the perindopril plus folic acid group was 6.3%and 4.898 per 1000 person-months,respectively;during a median 28-month follow-up time,the cumulative incidence and incidence density of the perindopril group was 1 1.5%and 6.809 per 1000 person-months,respectively;during a median 25-month follow-up time,the cumulative incidence and incidence density of the benazepril plus folic acid group was 6.5%and 3.298 per 1000 person-months,respectively;during a median 25-month follow-up time,the cumulative incidence and incidence density of the benazepril group was 10.8%and 6.073 per 1000 person-months,respectively.Based on the cumulative incidence,the ischemic stroke risk in the enalapril folic acid group was 0.475 times(95%CI:0.280-0.805)to that in the perindopril group.Compared to the perindopril group,the absolute risk and relative risk of ischemic stroke in the enalapril folic acid group was reduced 6.0%and 52.5%,respectively.The ischemic stroke risk in the enalapril folic acid group was 0.506 times(95%CI:0.288-0.889)to that in the benazepril group.Compared to the benazepril group,the absolute risk and relative risk of ischemic stroke in the enalapril folic acid group was reduced 5.3%and 49.4%,respectively.The ischemic stroke risk in the perindopril plus folic acid group was 0.547 times(95%CI:0.313-0.958)to that in the perindopril group.Compared to the perindopril group,the absolute risk and relative risk of ischemic stroke in the perindopril plus folic acid group was reduced 5.2%and 45.3%,respectively.The ischemic stroke risk in the benazepril plus folic acid group was 0.599 times(95%CI:0.362-0.992)to that in the benazepril group.Compared to the benazepril group,the absolute risk and relative risk of ischemic stroke in the benazepril plus folic acid group was reduced 4.3%and 40.1%,respectively.Based on the incidence density,the ischemic stroke risk in the enalapril folic acid group was 0.477 times(95%CI:0.392-0.581)to that in the perindopril group.Compared to the perindopril group,the absolute risk and relative risk of ischemic stroke in the enalapril folic acid group was reduced 3.599 per 1000 person-months and 52.3%,respectively.The ischemic stroke risk in the enalapril folic acid group was 0.535 times(95%CI:0.443-0.647)to that in the benazepril group.Compared to the benazepril group,the absolute risk and relative risk of ischemic stroke in the enalapril folic acid group was reduced 2.823 per 1000 person-months and 46.5%,respectively.The ischemic stroke risk in the perindopril plus folic acid group was 0.719 times(95%CI:0.582-0.889)to that in the perindopril group.Compared to the perindopril group,the absolute risk and relative risk of ischemic stroke in the perindopril plus folic acid group was reduced 1.910 per 1000 person-months and 28.1%,respectively.The ischemic stroke risk in the benazepril plus folic acid group was 0.543 times(95%CI:0.449-0.656)to that in the benazepril group.Compared to the benazepril group,the absolute risk and relative risk of ischemic stroke in the benazepril plus folic acid group was reduced 2.775 per 1000 person-months and 45.7%,respectively.The results of survival analysis showed that the cumulative disease-free probability of the enalapril folic acid group was higher than that of the perindopril group(the time corresponding to 90%cumulative disease-free probability:17 months vs.11 months),and the cumulative disease-free probability of the enalapril folic acid group was higher than that of the benazepril group(the time corresponding to 90%cumulative disease-free probability:17 months vs.13 months).The results of a Cox regression model,which had been adjusted the potential confounding factors involving age,sex,baseline hypertension level and so on,showed that the ischemic stroke risk in the enalapril folic acid group was 0.330 times(95%CI:0.174-0.624)to that in the perindopril group and 0.320 times(95%CI:0.164-0.626)to that in the benazepril group.Second stage Prospective cohort studyFrom 1 January 2019 to 31 December 2020,852 subjects accepted the enalapril folic acid tablet and 1203 subjects accepted the ACEI antihypertensive drugs were recruited and followed up prospectively.There were no statistical differences between two groups’baseline characteristics,which included average age,average Hcy,average systolic blood pressure,average diastolic blood pressure,heart disease history,liver disease history,family history of stroke,hypertension grade and cardiovascular risk level,etc.(all P>0.05).Compared with the baseline,the average level of Hcy in the enalapril folic acid group was reduced after 1-year and 2-year treatment,and the average level of Hcy in the ACEI antihypertensive drug group was reduced after 1-year treatment as well;After 1-year and 2-year treatment,the average levels of Hcy in the enalapril folic acid group were lower than that in the ACEI antihypertensive drug group.The average levels of Hcy in the enalapril folic acid group had a reduction trend with the prolonging treatment time(all P<0.05).Compared to the baseline,the means of systolic blood pressure and the average diastolic blood pressure,which were in the enalapril folic acid group and the ACEI antihypertensive drug group,were reduced after 1-year and 2-year treatment.The mean of systolic blood pressure and mean of diastolic blood pressure in the two groups had a reduction tendency with the prolonging treatment time(all P<0.05).After 1-year and 2-year treatment,there were no statistical differences between two groups’ rates,which were of reaching the lowering blood pressure standard in the enalapril folic acid group and the ACEI antihypertensive drug group.Compared to 1-year treatment,the rate of reaching the lowering blood pressure standard in the two groups were elevated after 2-year treatment(all P<0.05).The follow-up duration of the two groups was range from 1 month to 24 months.During a median 22-month follow-up time,the cumulative incidence and incidence density of the enalapril folic acid tablet group was 3.1%(95%CI:1.9%-4.3%)and 1.599 per 1000 person-months,respectively;during a median 21-month follow-up time,the cumulative incidence and incidence density of the ACEI antihypertensive group was 6.7%(95%CI:5.3%-8.1%)and 3.369 per 1000 person-months,respectively.Based on the cumulative incidence,the ischemic stroke risk in the enalapril folic acid group was 0.460 times(95%CI:0.294-0.720)to that in the ACEI antihypertensive group.Compared to the ACEI antihypertensive group,the absolute risk and relative risk of ischemic stroke in the enalapril folic acid group was reduced 3.6%and 54.0%,respectively.Based on the incidence density,the ischemic stroke risk in the enalapril folic acid group was 0.475 times(95%CI:0.413-0.545)to that in the ACEI antihypertensive group.Compared to the ACEI anti-hypertensive group,the absolute risk and relative risk of ischemic stroke in the enalapril folic acid group was reduced 1.770 per 1000 person-months and 52.5%,respectively.The results of survival analysis showed that the cumulative disease-free probability of the enalapril folic acid group was higher than that of the ACEI antihypertensive group(the time corresponding to 97%cumulative disease-free probability:15 months vs.10 months).The results of a Cox regression model,which had been adjusted the potential confounding factors involving age,sex and baseline hypertension level and so on,showed that the ischemic stroke risk in the enalapril folic acid group was 0.387 times(95%CI:0.242-0.620)to that in the ACEI antihypertensive group.Conclusions:Enalapril Maleate-Folate Tablets could effectively reduce blood pressure and Hcy levels.As a single-pill combination,it has a better cardiovascular risk reduction effect and preventive effect on hypertensive ischemic stroke than the free combination of ACEI and folic acid.It is worthy of clinical application. |
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