1 Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China;
2 Clinical Medicine Research Center, the Affiliated Hospital at Shunde, Southern Medical University (the First People's Hospital of Shunde), Foshan, China
* The authors contributed equally.
Corresponding author: Professor Dingli Xu, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China. Tel.: + 86 20 61641493, Fax: + 86 20 61360416, email: dinglixu@fimmu.com
We are so thankful for the commentary by Dr Meier et al. [1] on our recently published paper on BMC medicine [2]. We believe the commentary is very important in the field of hypertension, and it is helpful to health professionals and those engaged in the primary prevention of cardiovascular disease (CVD).
Epidemiological studies have showed that individuals with blood pressure (BP) of 120-139/80-89mmHg are with a high risk to progress to sustained hypertension. However, arguments against using the definition of prehypertension include that this term would create anxiety among the general population, and there is heterogeneity within this category of prehypertension, because the risk of progressing to hypertension and developing CVD is higher in patients with BP 130-139/85-89 mmHg range (high range) than in those with BP 120-129/80-84 mmHg (low range) [3]. In contrast to the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), other international and national hypertension guidelines did not adopt the term of "prehypertension" [4, 5]. In our study, we found that prehypertension, even in the low range, elevates the risk of CVD after adjusting for multiple cardiovascular risk factors. These findings reaffirms the importance of the definition of "prehypertension" rather than being "normal" for individuals with systolic BP of 120 to 139 mm Hg or diastolic BP of 80 to 89 mm Hg. Furthermore, our data also indicated the inhomogeneity of the prehypertension category, as the risk of CVD was significantly higher in paticipants with high-range prehypertension than those with low-range prehypertension.
Dr Meier et al have discussed that one endpoint that was not assessed in the included studies was the impact of prehypertension on the kidneys. This is a very interesting topic. Actually, we had performed another systematic review and meta-analysis on the topic of prehypertension and incidence of end-stage renal disease (ESRD). Data from 1, 003,793 participants were derived from six prospective cohort studies. Our results showed that even low-range prehypertension increased the risk of ESRD compared with optimal blood pressure (RR 1.44, 95% CI 1.19-1.74), and the risk further increased with high-range prehypertension (RR 2.02, 95% CI 1.70-2.40). The relative risk was significantly higher in the high-range than in the low-range prehypertensive populations (P = 0.01). This paper was just published online [6]. These results further support the findings of our study on CVD and the definition of "prehypertension".
Furthermore, Dr Meier et al have discussed therapeutic implications of our study on prehypertension. We agree that whether treatment of pre-hypertension can reduces cardiovascular risk is still with controversies. Considering the great incidence of prehypertension is up to 30-50% [7] and the robust and significant association between prehypertension and CVD incidence documented in our study, successful intervention in such a large population could therefore have a major public health impact. Based on the lack of prospective, randomized trials examining the effects of anti-hypertensive therapy on reducing cardiovascular events specifically in prehypertensives, professional societies do not recommend drug treatment in prehypertension, even in high-range prehypertension [5]. A recent meta-analysis showed that in patients with clinical history of CVD but without hypertension, antihypertensive treatment was associated with decreased risk of stroke, CHF, composite CVD events, and all-cause mortality [8]. However, the recently published study-the AQUARIUS randomized clinical trial [9], showed that among participants with pre-hypertension and coronary artery disease, the use of aliskiren compared with placebo did not result in improvement or slowing of progression of coronary atherosclerosis. This study should be interpreted with caution that the negative results maybe caused by the small sample (458 cases) and short follow-up duration (104 weeks), as well as the dilution effect of broadly use of statins, beta-blockers and anti-platelets medicine.
In conclusion, there is a great gap to be covered between epidemiological studies and randomized controlled studies in prehypertension. Prehypertensive individuals are at a high risk to progress to sustained hypertension, as well as CVD and renal damage, so we agree with Dr Meier et al that periodic screening is important. For therapeutic implications, we believe that lifestyle intervention is the mainstay of treatment for prehypertension for the general population. However, since the incidence of CVD increased across the whole range of prehypertension, high-risk subpopulations with prehypertension are need to be selected for future controlled trials of pharmacological treatment. Many risk factors, such as elevated C-reactive protein, glucose abnormality, and dyslipidemia had been reported to be associated with prehypertension and CVD [10-12]. These associated risk factors are indicators for selection of subpopulations, especially in high-range prehypertension, for future controlled trials of pharmacological treatment.
References:
1. Meier P, Messerli FH, Baumbach A, Lansky AJ: Pre-hypertension: another `pseudodisease'? BMC Med 2013, 11:211.
2. Huang Y, Wang S, Cai X, Mai W, Hu Y, Tang H, Xu D: Prehypertension and incidence of cardiovascular disease: a meta-analysis. BMC Med 2013, 11:177.
3. Gupta P, Nagaraju SP, Gupta A, Mandya CK: Prehypertension - time to act. Saudi J Kidney Dis Transpl 2012, 23(2):223-233.
4. National Clinical Guideline Centre (UK): Hypertension: The Clinical Management of Primary Hypertension in Adults: Update of Clinical Guidelines 18 and 34 [Internet]. London: Royal College of Physicians (UK); 2011 Aug.
5. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A et al: 2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013, 34(28):2159-2219.
6. Huang Y, Cai X, Zhang J, Mai W, Wang S, Hu Y, Ren H, Xu D: Prehypertension and Incidence of ESRD: A Systematic Review and Meta-analysis. Am J Kidney Dis 2013, http://dx.doi.org/10.1053/j.ajkd.20 13.07.024
7. Elliott WJ, Black HR: Prehypertension. Nat Clin Pract Cardiovasc Med 2007, 4(10):538-548.
8. Thompson AM, Hu T, Eshelbrenner CL, Reynolds K, He J, Bazzano LA: Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: a meta-analysis. JAMA 2011, 305(9):913-922.
9. Nicholls SJ, Bakris GL, Kastelein JJ, Menon V, Williams B, Armbrecht J, Brunel P, Nicolaides M, Hsu A, Hu B et al: Effect of aliskiren on progression of coronary disease in patients with prehypertension: the AQUARIUS randomized clinical trial. JAMA 2013, 310(11):1135-1144.
10. Tanaka F, Makita S, Onoda T, Tanno K, Ohsawa M, Itai K, Sakata K, Onodera M, Koeda Y, Kawarura K et al: Prehypertension subtype with elevated C-reactive protein: risk of ischemic stroke in a general Japanese population. Am J Hypertens 2010, 23(10):1108-1113.
11. Kokubo Y, Okamura T, Watanabe M, Higashiyama A, Ono Y, Miyamoto Y, Furukawa Y, Kamide K, Kawanishi K, Okayama A et al: The combined impact of blood pressure category and glucose abnormality on the incidence of cardiovascular diseases in a Japanese urban cohort: the Suita Study. Hypertens Res 2010, 33(12):1238-1243.
12. Egan BM, Julius S: Prehypertension: risk stratification and management considerations. Curr Hypertens Rep 2008, 10(5):359-366.
Competing interests
None declared
Prehypertension: Gap between Epidemiological Studies and Randomized Controlled Studies -The Reply
Pascal Meier, University College London UCL
14 October 2013
Pascal Meier (1), MD, Franz H. Messerli (2), MD, Alexandra J. Lansky (3), MD, Andreas Baumbach (4), MD
1 Institute of Cardiovascular Science, University College London, UCL, London, UK
2 St Luke¿s Roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York, NY 10019, USA
3 Division of Cardiology, Yale Medical School, New Haven, CT, USA;
4 Bristol Heart Institute, Bristol, UK
We thank Dr Huang and colleagues for their comment on our editorial.[1] This group has a great expertise in this field and has contributed to this topic with important publications on the impact of pre-hypertension on clinical outcomes.[2, 3]
We fully agree with their point of view, there is conflicting evidence from epidemiological data based on cohort studies which suggests that blood pressure below the currently defined pathological levels of ¿140/90 mmHg is associated with adverse clinical outcomes and a lack of evidence from and interventional studies which so far could not clearly show a benefit of blood pressure reduction in individuals with prehypertension. In patients with manifest cardiovascular disease, blood pressure therapy in the pre-hypertensive range could be beneficial.[4] However, we have to be aware that many antihypertensives have pleoptropic effects and it is unclear whether the benefit purely derives from the blood pressure lowering effect in this patient group. Dr Huang and colleagues interestingly mention the very recently published AQUARIUS trial (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study) which has not found any advantage of antihypertensive treatment in pre-hypertensive individuals based on the primary endpoint (atherosclerotic plaque volume) . [5] We agree with Dr Huang¿s comment on this study, it was a rather small and therefore possibly underpowered . The study enrolled 613 individuals ¿35 years with coronary artery disease (at least one 20% stenosis on clinically indicated coronary angiography) and a systolic blood pressure between 125 and 139 mm Hg and at least 2 additional cardiovascular risk factors. Their renin-angiotensin-aldosterone system (RAAS) was suppressed with the direct renin inhibitor Aliskiren. While there was no significant regarding the primary endpoint, fewer major cardiovascular events were seen in the aliskiren group (hazard ratio, 0.50 [95% CI, 0.31 to 0.81], P¿ =¿.004), and fewer nonfatal myocardial infarctions (hazard ratio, 0.13 [95% CI, 0.02 to 1.02], P¿=¿.02). The majority of cardiovascular events in the study were coronary revascularizations which is not a very hard endpoint, all events were rather rare and it was not the primary endpoint of the study and the study was rather small. We therefore need to be carefully with strong conclusions. Even if we assume this was a true effect, we also have to avoid generalizing the results to other antihypertensive treatments. Such an impressive effect over a follow up duration of max. 2 years is unlikely to solely due to the minimal blood pressure reduction achieved in this study (- 2.1 mmHg reduction in systolic blood pressure).
Clearly, there still are significant knowledge gaps as stated by Dr Huang and colleagues. We would like to better understand the threshold where blood pressure starts to have a direct, causal negative impact on health and whether there is indeed a universal threshold or whether this rather depends on accompanying risk factors.
¿
References
1. Meier P, Messerli FH, Baumbach A, Lansky AJ: Pre-hypertension: another `pseudodisease'? BMC Med BMC Med 2013, 11(211).
2. Huang Y, Wang S, Cai X, Mai W, Hu Y, Tang H, Xu D: Prehypertension and incidence of cardiovascular disease: a meta-analysis. BMC Medicine 2013, 11(177).
3. Huang Y, Cai X, Zhang J, Mai W, Wang S, Hu Y, Ren H, Xu D: Prehypertension and Incidence of ESRD: A Systematic Review and Meta-analysis. Am J Kidney Dis 2013.
4. Thompson AM, Hu T, Eshelbrenner CL, Reynolds K, He J, Bazzano LA: Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: a meta-analysis. JAMA 2011, 305(9):913-922.
5. Nicholls SJ, Bakris GL, Kastelein JJ, Menon V, Williams B, Armbrecht J, Brunel P, Nicolaides M, Hsu A, Hu B et al: Effect of aliskiren on progression of coronary disease in patients with prehypertension: the AQUARIUS randomized clinical trial. JAMA 2013, 310(11):1135-1144.
Competing interests
FHM: Ad hoc consultant for the following organizations: Novartis, Daiichi Sankyo, Pfizer, Takeda, Abbott, Servier, Medtronic, Ipca Laboratories Ltd.
Prehypertension: Gap between Epidemiological Studies and Randomized Controlled Studies
2 October 2013
Yuli Huang, 1, 2 * Xiaoyan Cai, 2 * and Dingli Xu1
1 Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China;
2 Clinical Medicine Research Center, the Affiliated Hospital at Shunde, Southern Medical University (the First People's Hospital of Shunde), Foshan, China
* The authors contributed equally.
Corresponding author: Professor Dingli Xu, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou 510515, China. Tel.: + 86 20 61641493, Fax: + 86 20 61360416, email: dinglixu@fimmu.com
We are so thankful for the commentary by Dr Meier et al. [1] on our recently published paper on BMC medicine [2]. We believe the commentary is very important in the field of hypertension, and it is helpful to health professionals and those engaged in the primary prevention of cardiovascular disease (CVD).
Epidemiological studies have showed that individuals with blood pressure (BP) of 120-139/80-89mmHg are with a high risk to progress to sustained hypertension. However, arguments against using the definition of prehypertension include that this term would create anxiety among the general population, and there is heterogeneity within this category of prehypertension, because the risk of progressing to hypertension and developing CVD is higher in patients with BP 130-139/85-89 mmHg range (high range) than in those with BP 120-129/80-84 mmHg (low range) [3]. In contrast to the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), other international and national hypertension guidelines did not adopt the term of "prehypertension" [4, 5]. In our study, we found that prehypertension, even in the low range, elevates the risk of CVD after adjusting for multiple cardiovascular risk factors. These findings reaffirms the importance of the definition of "prehypertension" rather than being "normal" for individuals with systolic BP of 120 to 139 mm Hg or diastolic BP of 80 to 89 mm Hg. Furthermore, our data also indicated the inhomogeneity of the prehypertension category, as the risk of CVD was significantly higher in paticipants with high-range prehypertension than those with low-range prehypertension.
Dr Meier et al have discussed that one endpoint that was not assessed in the included studies was the impact of prehypertension on the kidneys. This is a very interesting topic. Actually, we had performed another systematic review and meta-analysis on the topic of prehypertension and incidence of end-stage renal disease (ESRD). Data from 1, 003,793 participants were derived from six prospective cohort studies. Our results showed that even low-range prehypertension increased the risk of ESRD compared with optimal blood pressure (RR 1.44, 95% CI 1.19-1.74), and the risk further increased with high-range prehypertension (RR 2.02, 95% CI 1.70-2.40). The relative risk was significantly higher in the high-range than in the low-range prehypertensive populations (P = 0.01). This paper was just published online [6]. These results further support the findings of our study on CVD and the definition of "prehypertension".
Furthermore, Dr Meier et al have discussed therapeutic implications of our study on prehypertension. We agree that whether treatment of pre-hypertension can reduces cardiovascular risk is still with controversies. Considering the great incidence of prehypertension is up to 30-50% [7] and the robust and significant association between prehypertension and CVD incidence documented in our study, successful intervention in such a large population could therefore have a major public health impact. Based on the lack of prospective, randomized trials examining the effects of anti-hypertensive therapy on reducing cardiovascular events specifically in prehypertensives, professional societies do not recommend drug treatment in prehypertension, even in high-range prehypertension [5]. A recent meta-analysis showed that in patients with clinical history of CVD but without hypertension, antihypertensive treatment was associated with decreased risk of stroke, CHF, composite CVD events, and all-cause mortality [8]. However, the recently published study-the AQUARIUS randomized clinical trial [9], showed that among participants with pre-hypertension and coronary artery disease, the use of aliskiren compared with placebo did not result in improvement or slowing of progression of coronary atherosclerosis. This study should be interpreted with caution that the negative results maybe caused by the small sample (458 cases) and short follow-up duration (104 weeks), as well as the dilution effect of broadly use of statins, beta-blockers and anti-platelets medicine.
In conclusion, there is a great gap to be covered between epidemiological studies and randomized controlled studies in prehypertension. Prehypertensive individuals are at a high risk to progress to sustained hypertension, as well as CVD and renal damage, so we agree with Dr Meier et al that periodic screening is important. For therapeutic implications, we believe that lifestyle intervention is the mainstay of treatment for prehypertension for the general population. However, since the incidence of CVD increased across the whole range of prehypertension, high-risk subpopulations with prehypertension are need to be selected for future controlled trials of pharmacological treatment. Many risk factors, such as elevated C-reactive protein, glucose abnormality, and dyslipidemia had been reported to be associated with prehypertension and CVD [10-12]. These associated risk factors are indicators for selection of subpopulations, especially in high-range prehypertension, for future controlled trials of pharmacological treatment.
References:
1. Meier P, Messerli FH, Baumbach A, Lansky AJ: Pre-hypertension: another `pseudodisease'? BMC Med 2013, 11:211.
2. Huang Y, Wang S, Cai X, Mai W, Hu Y, Tang H, Xu D: Prehypertension and incidence of cardiovascular disease: a meta-analysis. BMC Med 2013, 11:177.
3. Gupta P, Nagaraju SP, Gupta A, Mandya CK: Prehypertension - time to act. Saudi J Kidney Dis Transpl 2012, 23(2):223-233.
4. National Clinical Guideline Centre (UK): Hypertension: The Clinical Management of Primary Hypertension in Adults: Update of Clinical Guidelines 18 and 34 [Internet]. London: Royal College of Physicians (UK); 2011 Aug.
5. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A et al: 2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013, 34(28):2159-2219.
6. Huang Y, Cai X, Zhang J, Mai W, Wang S, Hu Y, Ren H, Xu D: Prehypertension and Incidence of ESRD: A Systematic Review and Meta-analysis. Am J Kidney Dis 2013, http://dx.doi.org/10.1053/j.ajkd.20 13.07.024
7. Elliott WJ, Black HR: Prehypertension. Nat Clin Pract Cardiovasc Med 2007, 4(10):538-548.
8. Thompson AM, Hu T, Eshelbrenner CL, Reynolds K, He J, Bazzano LA: Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: a meta-analysis. JAMA 2011, 305(9):913-922.
9. Nicholls SJ, Bakris GL, Kastelein JJ, Menon V, Williams B, Armbrecht J, Brunel P, Nicolaides M, Hsu A, Hu B et al: Effect of aliskiren on progression of coronary disease in patients with prehypertension: the AQUARIUS randomized clinical trial. JAMA 2013, 310(11):1135-1144.
10. Tanaka F, Makita S, Onoda T, Tanno K, Ohsawa M, Itai K, Sakata K, Onodera M, Koeda Y, Kawarura K et al: Prehypertension subtype with elevated C-reactive protein: risk of ischemic stroke in a general Japanese population. Am J Hypertens 2010, 23(10):1108-1113.
11. Kokubo Y, Okamura T, Watanabe M, Higashiyama A, Ono Y, Miyamoto Y, Furukawa Y, Kamide K, Kawanishi K, Okayama A et al: The combined impact of blood pressure category and glucose abnormality on the incidence of cardiovascular diseases in a Japanese urban cohort: the Suita Study. Hypertens Res 2010, 33(12):1238-1243.
12. Egan BM, Julius S: Prehypertension: risk stratification and management considerations. Curr Hypertens Rep 2008, 10(5):359-366.
Competing interests
None declared
Prehypertension: Gap between Epidemiological Studies and Randomized Controlled Studies -The Reply
14 October 2013
Pascal Meier (1), MD, Franz H. Messerli (2), MD, Alexandra J. Lansky (3), MD, Andreas Baumbach (4), MD
1 Institute of Cardiovascular Science, University College London, UCL, London, UK
2 St Luke¿s Roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York, NY 10019, USA
3 Division of Cardiology, Yale Medical School, New Haven, CT, USA;
4 Bristol Heart Institute, Bristol, UK
We thank Dr Huang and colleagues for their comment on our editorial.[1] This group has a great expertise in this field and has contributed to this topic with important publications on the impact of pre-hypertension on clinical outcomes.[2, 3]
We fully agree with their point of view, there is conflicting evidence from epidemiological data based on cohort studies which suggests that blood pressure below the currently defined pathological levels of ¿140/90 mmHg is associated with adverse clinical outcomes and a lack of evidence from and interventional studies which so far could not clearly show a benefit of blood pressure reduction in individuals with prehypertension. In patients with manifest cardiovascular disease, blood pressure therapy in the pre-hypertensive range could be beneficial.[4] However, we have to be aware that many antihypertensives have pleoptropic effects and it is unclear whether the benefit purely derives from the blood pressure lowering effect in this patient group. Dr Huang and colleagues interestingly mention the very recently published AQUARIUS trial (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study) which has not found any advantage of antihypertensive treatment in pre-hypertensive individuals based on the primary endpoint (atherosclerotic plaque volume) . [5] We agree with Dr Huang¿s comment on this study, it was a rather small and therefore possibly underpowered . The study enrolled 613 individuals ¿35 years with coronary artery disease (at least one 20% stenosis on clinically indicated coronary angiography) and a systolic blood pressure between 125 and 139 mm Hg and at least 2 additional cardiovascular risk factors. Their renin-angiotensin-aldosterone system (RAAS) was suppressed with the direct renin inhibitor Aliskiren. While there was no significant regarding the primary endpoint, fewer major cardiovascular events were seen in the aliskiren group (hazard ratio, 0.50 [95% CI, 0.31 to 0.81], P¿ =¿.004), and fewer nonfatal myocardial infarctions (hazard ratio, 0.13 [95% CI, 0.02 to 1.02], P¿=¿.02). The majority of cardiovascular events in the study were coronary revascularizations which is not a very hard endpoint, all events were rather rare and it was not the primary endpoint of the study and the study was rather small. We therefore need to be carefully with strong conclusions. Even if we assume this was a true effect, we also have to avoid generalizing the results to other antihypertensive treatments. Such an impressive effect over a follow up duration of max. 2 years is unlikely to solely due to the minimal blood pressure reduction achieved in this study (- 2.1 mmHg reduction in systolic blood pressure).
Clearly, there still are significant knowledge gaps as stated by Dr Huang and colleagues. We would like to better understand the threshold where blood pressure starts to have a direct, causal negative impact on health and whether there is indeed a universal threshold or whether this rather depends on accompanying risk factors.
¿
References
1. Meier P, Messerli FH, Baumbach A, Lansky AJ: Pre-hypertension: another `pseudodisease'? BMC Med BMC Med 2013, 11(211).
2. Huang Y, Wang S, Cai X, Mai W, Hu Y, Tang H, Xu D: Prehypertension and incidence of cardiovascular disease: a meta-analysis. BMC Medicine 2013, 11(177).
3. Huang Y, Cai X, Zhang J, Mai W, Wang S, Hu Y, Ren H, Xu D: Prehypertension and Incidence of ESRD: A Systematic Review and Meta-analysis. Am J Kidney Dis 2013.
4. Thompson AM, Hu T, Eshelbrenner CL, Reynolds K, He J, Bazzano LA: Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: a meta-analysis. JAMA 2011, 305(9):913-922.
5. Nicholls SJ, Bakris GL, Kastelein JJ, Menon V, Williams B, Armbrecht J, Brunel P, Nicolaides M, Hsu A, Hu B et al: Effect of aliskiren on progression of coronary disease in patients with prehypertension: the AQUARIUS randomized clinical trial. JAMA 2013, 310(11):1135-1144.
Competing interests
FHM: Ad hoc consultant for the following organizations: Novartis, Daiichi Sankyo, Pfizer, Takeda, Abbott, Servier, Medtronic, Ipca Laboratories Ltd.