- Email: [email protected]
Blood pressure lowering and cardiovascular risk – Authors' reply
Correspondence
The meta-analysis by the Blood Pressure Lowering Treatment Trialists’ Collaboration1 sought to ascertain whether the predicted absolute risk of cardiovascular events should be used to inform blood pressure-lowering treatment decisions, rather than a single risk factor (ie, blood pressure thresholds). This Article is particularly timely, considering the fact that the revised blood pressure guidelines from the Eighth Joint National Committee (JNC8) 2 maintains a focus on blood pressure in isolation. The revised guidelines have led to some controversy,3 particularly the recommendation for less conservative treatment for older populations and for patients with diabetes and renal disease. The less conservative recommendations stem from the lack of randomised control trials to confirm blood pressure threshold targets. Collectively, these works1,2 indicate an opportunity for a shift. Specifically, peripheral blood pressure measurements could have little usefulness as a single risk factor because they do not accurately show the effects of peak blood pressure on centrally located organs. Alternatively, central blood pressure has been reported to be a stronger determinant of cardiovascular events than are peripheral blood pressure,4 and a recent study5 reported that monitoring central blood pressure, compared with peripheral monitering methods, led to decreased use of blood pressure-lowering drug without adverse effects of left ventricular mass. Oscillometric pulse wave analysis devices have emerged, which are user friendly and suitable for routine measurements of central blood pressure in clinical practice. Therefore, given the known limitations of peripheral blood pressure measurements, the absence of randomised controlled trials that support specific thresholds, and the availability of oscillometric pulse wave analysis devices, perhaps it is time to advocate longitudinal randomised trials to assess the comparative clinical usefulness of central blood pressure. 1746
We declare no competing interests.
*Lee Stoner, Brian Wu [email protected] School of Sport and Exercise, Massey University, Wellington 6140, New Zealand (LS); and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA (BW) 1
2
3
4
5
Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 2014; 384: 591–98. James PA, Oparil S, Carter BL, et al. 2014 evidencebased guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311: 507–20. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes? JAMA 2014; 311: 474–76. Vlachopoulos C, Aznaouridis K, O’Rourke MF, Safar ME, Baou K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis. Eur Heart J 2010; 31: 1865–71. Sharman JE, Marwick TH, Gilroy D, et al. Randomized trial of guiding hypertension management using central aortic blood pressure compared with best-practice care: principal findings of the BP GUIDE study. Hypertension 2013; 62: 1138–45.
In their meta-analysis, the Blood Pressure Lowering Treatment Trialists’ Collaboration 1 conclude that the use of cardiovascular risk equations to guide blood pressure-lowering treatment decisions is likely to be more cost effective than a blood pressure-based approach. This conclusion might depend on the way that blood pressure is measured. In the trials included in their meta-analysis, treatment decisions were based on a small number of blood pressure readings. Conventional blood pressure measurements might both be inaccurate and imprecise, especially in young individuals with hypertension who were at low cardiovascular risk. A modelling study showed that, when an average of three blood pressure measurements were used to diagnose hypertension, the false-positive rate increased from 14% in men and 21% in women aged 45–54 years to 69% in men and 74% in women younger than 35 years.2 Increases in either the number of blood pressure measurements or number of visits decreases variability,
but still results in a systematic overestimation of hypertension compared with measurements of ambulatory blood pressure.3 Because it prevents unnecessary treatment, such a blood pressure-guided approach that uses ambulatory measurements is probably cost effective. Perhaps more so when combined with a strategy based on individual cardiovascular risk prediction. I declare no competing interests.
Bert-Jan H van den Born [email protected] Department of Internal Medicine, Division of Internal and Vascular Medicine, Academic Medical Center, Amsterdam 1100 DD, Netherlands 1
2
3
Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 2014; 384: 591–98. Marshall T. When measurements are misleading: modelling the effects of blood pressure misclassification in the English population. BMJ 2004; 328: 933. Little P, Barnett J, Barnsley L, Marjoram J, Fitzgerald-Barron A, Mant D. Comparison of agreement between different measures of blood pressure in primary care and daytime ambulatory blood pressure. BMJ 2002; 325: 254.
Authors’ reply With individual participant data from 11 trials in the Blood Pressure Lowering Treatment Trialists’ Collaboration,1 we recently showed that blood pressure-lowering treatment yields similar reductions in relative risk at all levels of baseline estimated cardiovascular risk, which, as the figure from Ian Roberts and David Prieto-Merino shows, implies progressively greater absolute risk reductions as baseline risk increases.1 Bert-Jan van den Born proposes that increases in blood pressure measurements will decrease costs. We agree that for the diagnosis of hypertension, as many blood pressure measurements as possible might be desirable;2 however, inclusion of multiple blood pressure measurements (even the results of 24 h monitoring) in a multifactorial risk assessment increases costs and appears to add little clinical usefulness.3 www.thelancet.com Vol 384 November 15, 2014
Correspondence
We declare no competing interests.
*Johan Sundström, Rod Jackson, Mark Woodward, Colin Baigent, Bruce Neal [email protected] Uppsala University, Uppsala 75185, Sweden (JS); School of Population Health, University of Auckland, Auckland, New Zealand (RJ); The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia (MW, BN); and University of Oxford, Oxford, UK (CB) 1
2
Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 2014; 384: 591–98. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: Meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009; 338: b1665.
www.thelancet.com Vol 384 November 15, 2014
3
4
5
Bell KJ, Beller E, Sundström J, et al. Ambulatory blood pressure adds little to Framingham risk score for the primary prevention of cardiovascular disease in older men: Secondary analysis of observational study data. BMJ Open 2014; 4: e006044. Tzoulaki I, Liberopoulos G, Ioannidis JP. Assessment of claims of improved prediction beyond the Framingham risk score. JAMA 2009; 302: 2345–52. Mihaylova B, Emberson J, Blackwell L, et al, for the Cholesterol Treatment Trialists’ Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: Meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380: 581–90.
Mosquito control might not bolster imperfect dengue vaccines The most recent dengue vaccine trial data from Asia claims 40–70% efficacy in children aged 2–14 years.1 This is a substantial advance in dengue prevention but clearly falls short of the levels of protection required for a standalone intervention. The dengue vaccine initiative and other consortia have emphasised the benefits of integrating vaccines with mosquito control measures,2,3 which infers that vector control can bolster the effect of imperfect vaccines. This theory is logical but is based on a patchy understanding of the extent to which a number of partly effective measures can be combined to create a comprehensive disease control strategy. Neither conventional insecticidals nor novel technologies under development (eg, transgenic sterile releases and disease-refractory Wolbachia infections) can show universally replicable effects on transmission. Assumptions that vector control can reinforce partly effective vaccines are therefore very optimistic. Insecticidal control can reduce dengue transmission, notably after large-scale eradication campaigns and targeted coverage of adult mosquitoes in response to urban outbreaks.4 Conventional mosquito management therefore has the potential to complement partly effective vaccines,
but our understanding of how to guarantee that effect is inadequate. Despite the increasing global incidence of dengue, chikungunya, and other arboviruses, many large health initiatives have lost enthusiasm for mosquito-related research. This is most recently illustrated by the absence of funding opportunities offered under the European Union’s Horizon 2020 programme. This omission implies that few options remain regarding the development of new mosquito control paradigms for disease management. It ignores the fact that novel ideas for disease control include not only novel genetically modified constructs and transinfection by endosymbionts but also novel insecticides and application techniques that offer substantial improvements in insecticide coverage.5,6 We believe there is a pressing need to pursue all those options and to develop an evidence base for their effects. Until such careful characterisations exist, it would be wise to consider whether the registration of partly effective vaccines can be justified by a panglossian interpretation of vector control efficacy.
CDC/Science Photo Library
Similarly, Lee Stoner and Brian Wu propose measurement of central blood pressure instead of peripheral blood pressure. Central blood pressure is associated with the risk of adverse outcomes, but this does not mean that it would necessarily add value in the routine clinical setting. Evidence of discrimination of risk beyond existing risk assessment methods would be needed. Unfortunately few studies properly address this question,4 and the cost-effectiveness of any new strategy must also be assessed. The key point is that our metaanalysis,1 combined with previous evidence,2 implies that the protective effects of blood pressure-lowering treatment are probably worthwhile in people who are at increased vascular disease risk, even if they do not meet the standard, albeit somewhat arbitrary, definitions of hypertension. A similar observation has been for made for statin therapy; a meta-analysis of randomised trials showed that such treatment yields benefit in high-risk patients, even if their LDL cholesterol was average or below average.5 That study directly affected cholesterol treatment guidelines, and our study now provides similar support for risk-based blood pressure-lowering treatment decisions.
RP and AS acknowledge support from the Seventh Framework Programme under Grant Agreement number 282378. CS acknowledges the support of the Government of Portugal (FCT-PTDC/SAU-EPI/ 115853/2009). We declare no competing interests.
Richard Paul, Carla Sousa, Anavaj Sakuntabhai, *Gregor Devine [email protected] Institut Pasteur, Unité de Génétique Fonctionnelle des Maladies Infectieuses, Paris, France (RP, AS); Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal (CS); and Mosquito Control Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia (GD) 1
2
3
Capeding MR, Tran NH, Hadinegoro SR, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebocontrolled trial. Lancet 2014; 384: 1358–65. Anon. Dengue vaccine initiative: integrated control of dengue through vaccines and vector control. Oct 18–19, 2013. http://www. denguevaccines.org/sites/default/files/files/ DengueBoardReport_long_finalv2.pdf (accessed Oct 15, 2014). Knerer G, Currie CS, Brailsford SC. Impact of combined vector-control and vaccination strategies on transmission dynamics of dengue fever: a model-based analysis. Health Care Manag Sci 2013; published online Dec 27. http://dx.doi.org/ 10.1007/s10729-013-9263-x.
1747
The meta-analysis by the Blood Pressure Lowering Treatment Trialists’ Collaboration1 sought to ascertain whether the predicted absolute risk of cardiovascular events should be used to inform blood pressure-lowering treatment decisions, rather than a single risk factor (ie, blood pressure thresholds). This Article is particularly timely, considering the fact that the revised blood pressure guidelines from the Eighth Joint National Committee (JNC8) 2 maintains a focus on blood pressure in isolation. The revised guidelines have led to some controversy,3 particularly the recommendation for less conservative treatment for older populations and for patients with diabetes and renal disease. The less conservative recommendations stem from the lack of randomised control trials to confirm blood pressure threshold targets. Collectively, these works1,2 indicate an opportunity for a shift. Specifically, peripheral blood pressure measurements could have little usefulness as a single risk factor because they do not accurately show the effects of peak blood pressure on centrally located organs. Alternatively, central blood pressure has been reported to be a stronger determinant of cardiovascular events than are peripheral blood pressure,4 and a recent study5 reported that monitoring central blood pressure, compared with peripheral monitering methods, led to decreased use of blood pressure-lowering drug without adverse effects of left ventricular mass. Oscillometric pulse wave analysis devices have emerged, which are user friendly and suitable for routine measurements of central blood pressure in clinical practice. Therefore, given the known limitations of peripheral blood pressure measurements, the absence of randomised controlled trials that support specific thresholds, and the availability of oscillometric pulse wave analysis devices, perhaps it is time to advocate longitudinal randomised trials to assess the comparative clinical usefulness of central blood pressure. 1746
We declare no competing interests.
*Lee Stoner, Brian Wu [email protected] School of Sport and Exercise, Massey University, Wellington 6140, New Zealand (LS); and Keck School of Medicine, University of Southern California, Los Angeles, CA, USA (BW) 1
2
3
4
5
Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 2014; 384: 591–98. James PA, Oparil S, Carter BL, et al. 2014 evidencebased guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311: 507–20. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes? JAMA 2014; 311: 474–76. Vlachopoulos C, Aznaouridis K, O’Rourke MF, Safar ME, Baou K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis. Eur Heart J 2010; 31: 1865–71. Sharman JE, Marwick TH, Gilroy D, et al. Randomized trial of guiding hypertension management using central aortic blood pressure compared with best-practice care: principal findings of the BP GUIDE study. Hypertension 2013; 62: 1138–45.
In their meta-analysis, the Blood Pressure Lowering Treatment Trialists’ Collaboration 1 conclude that the use of cardiovascular risk equations to guide blood pressure-lowering treatment decisions is likely to be more cost effective than a blood pressure-based approach. This conclusion might depend on the way that blood pressure is measured. In the trials included in their meta-analysis, treatment decisions were based on a small number of blood pressure readings. Conventional blood pressure measurements might both be inaccurate and imprecise, especially in young individuals with hypertension who were at low cardiovascular risk. A modelling study showed that, when an average of three blood pressure measurements were used to diagnose hypertension, the false-positive rate increased from 14% in men and 21% in women aged 45–54 years to 69% in men and 74% in women younger than 35 years.2 Increases in either the number of blood pressure measurements or number of visits decreases variability,
but still results in a systematic overestimation of hypertension compared with measurements of ambulatory blood pressure.3 Because it prevents unnecessary treatment, such a blood pressure-guided approach that uses ambulatory measurements is probably cost effective. Perhaps more so when combined with a strategy based on individual cardiovascular risk prediction. I declare no competing interests.
Bert-Jan H van den Born [email protected] Department of Internal Medicine, Division of Internal and Vascular Medicine, Academic Medical Center, Amsterdam 1100 DD, Netherlands 1
2
3
Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 2014; 384: 591–98. Marshall T. When measurements are misleading: modelling the effects of blood pressure misclassification in the English population. BMJ 2004; 328: 933. Little P, Barnett J, Barnsley L, Marjoram J, Fitzgerald-Barron A, Mant D. Comparison of agreement between different measures of blood pressure in primary care and daytime ambulatory blood pressure. BMJ 2002; 325: 254.
Authors’ reply With individual participant data from 11 trials in the Blood Pressure Lowering Treatment Trialists’ Collaboration,1 we recently showed that blood pressure-lowering treatment yields similar reductions in relative risk at all levels of baseline estimated cardiovascular risk, which, as the figure from Ian Roberts and David Prieto-Merino shows, implies progressively greater absolute risk reductions as baseline risk increases.1 Bert-Jan van den Born proposes that increases in blood pressure measurements will decrease costs. We agree that for the diagnosis of hypertension, as many blood pressure measurements as possible might be desirable;2 however, inclusion of multiple blood pressure measurements (even the results of 24 h monitoring) in a multifactorial risk assessment increases costs and appears to add little clinical usefulness.3 www.thelancet.com Vol 384 November 15, 2014
Correspondence
We declare no competing interests.
*Johan Sundström, Rod Jackson, Mark Woodward, Colin Baigent, Bruce Neal [email protected] Uppsala University, Uppsala 75185, Sweden (JS); School of Population Health, University of Auckland, Auckland, New Zealand (RJ); The George Institute for Global Health, University of Sydney, Sydney, NSW, Australia (MW, BN); and University of Oxford, Oxford, UK (CB) 1
2
Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 2014; 384: 591–98. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: Meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009; 338: b1665.
www.thelancet.com Vol 384 November 15, 2014
3
4
5
Bell KJ, Beller E, Sundström J, et al. Ambulatory blood pressure adds little to Framingham risk score for the primary prevention of cardiovascular disease in older men: Secondary analysis of observational study data. BMJ Open 2014; 4: e006044. Tzoulaki I, Liberopoulos G, Ioannidis JP. Assessment of claims of improved prediction beyond the Framingham risk score. JAMA 2009; 302: 2345–52. Mihaylova B, Emberson J, Blackwell L, et al, for the Cholesterol Treatment Trialists’ Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: Meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380: 581–90.
Mosquito control might not bolster imperfect dengue vaccines The most recent dengue vaccine trial data from Asia claims 40–70% efficacy in children aged 2–14 years.1 This is a substantial advance in dengue prevention but clearly falls short of the levels of protection required for a standalone intervention. The dengue vaccine initiative and other consortia have emphasised the benefits of integrating vaccines with mosquito control measures,2,3 which infers that vector control can bolster the effect of imperfect vaccines. This theory is logical but is based on a patchy understanding of the extent to which a number of partly effective measures can be combined to create a comprehensive disease control strategy. Neither conventional insecticidals nor novel technologies under development (eg, transgenic sterile releases and disease-refractory Wolbachia infections) can show universally replicable effects on transmission. Assumptions that vector control can reinforce partly effective vaccines are therefore very optimistic. Insecticidal control can reduce dengue transmission, notably after large-scale eradication campaigns and targeted coverage of adult mosquitoes in response to urban outbreaks.4 Conventional mosquito management therefore has the potential to complement partly effective vaccines,
but our understanding of how to guarantee that effect is inadequate. Despite the increasing global incidence of dengue, chikungunya, and other arboviruses, many large health initiatives have lost enthusiasm for mosquito-related research. This is most recently illustrated by the absence of funding opportunities offered under the European Union’s Horizon 2020 programme. This omission implies that few options remain regarding the development of new mosquito control paradigms for disease management. It ignores the fact that novel ideas for disease control include not only novel genetically modified constructs and transinfection by endosymbionts but also novel insecticides and application techniques that offer substantial improvements in insecticide coverage.5,6 We believe there is a pressing need to pursue all those options and to develop an evidence base for their effects. Until such careful characterisations exist, it would be wise to consider whether the registration of partly effective vaccines can be justified by a panglossian interpretation of vector control efficacy.
CDC/Science Photo Library
Similarly, Lee Stoner and Brian Wu propose measurement of central blood pressure instead of peripheral blood pressure. Central blood pressure is associated with the risk of adverse outcomes, but this does not mean that it would necessarily add value in the routine clinical setting. Evidence of discrimination of risk beyond existing risk assessment methods would be needed. Unfortunately few studies properly address this question,4 and the cost-effectiveness of any new strategy must also be assessed. The key point is that our metaanalysis,1 combined with previous evidence,2 implies that the protective effects of blood pressure-lowering treatment are probably worthwhile in people who are at increased vascular disease risk, even if they do not meet the standard, albeit somewhat arbitrary, definitions of hypertension. A similar observation has been for made for statin therapy; a meta-analysis of randomised trials showed that such treatment yields benefit in high-risk patients, even if their LDL cholesterol was average or below average.5 That study directly affected cholesterol treatment guidelines, and our study now provides similar support for risk-based blood pressure-lowering treatment decisions.
RP and AS acknowledge support from the Seventh Framework Programme under Grant Agreement number 282378. CS acknowledges the support of the Government of Portugal (FCT-PTDC/SAU-EPI/ 115853/2009). We declare no competing interests.
Richard Paul, Carla Sousa, Anavaj Sakuntabhai, *Gregor Devine [email protected] Institut Pasteur, Unité de Génétique Fonctionnelle des Maladies Infectieuses, Paris, France (RP, AS); Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal (CS); and Mosquito Control Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia (GD) 1
2
3
Capeding MR, Tran NH, Hadinegoro SR, et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebocontrolled trial. Lancet 2014; 384: 1358–65. Anon. Dengue vaccine initiative: integrated control of dengue through vaccines and vector control. Oct 18–19, 2013. http://www. denguevaccines.org/sites/default/files/files/ DengueBoardReport_long_finalv2.pdf (accessed Oct 15, 2014). Knerer G, Currie CS, Brailsford SC. Impact of combined vector-control and vaccination strategies on transmission dynamics of dengue fever: a model-based analysis. Health Care Manag Sci 2013; published online Dec 27. http://dx.doi.org/ 10.1007/s10729-013-9263-x.
1747