Correspondence
Pasieka/Science Photo Library
Authors’ reply
Published Online December 4, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)62348-X
600
We concur with David van Klaveren and colleagues that the projected treatment effect for an individual given his or her risk factors is of considerable importance since net benefit is a function of the person’s absolute risk, the projected individual benefit, as well as potential harms of therapy. We have collaborated previously using this methodology to estimate individualised benefits of statin therapy1 and in work describing the individualised numberneeded-to-treat. As noted in our Comment,2 we further concur that contemporary cohorts should be used to update and recalibrate risk equations when such data are available,3 although we recognise that methods to develop and assess prediction models from multiple studies are quite complex, and should explore and allow for heterogeneity across studies.4 Using the new American Heart Association (AHA) and American College of Cardiology (ACC) algorithms, virtually all men older than 66 years and women older than 70 years have a calculated 10-year risk greater than 7·5%, even with optimal risk factors. Nicholas Wald and Joan Morris thus suggest that screening for age alone is a simpler way to prescribe statin therapy. However, as noted in our Comment,2 these risk estimates are likely to be artificially high. Further, the approach of treating all individuals older than a given age exposes the largest number to therapy, including many who have never been studied in clinical trials. This approach could lead to exposure to potential hazards of statin therapy among some individuals without clear evidence of benefit, and to many others where the number-needed-to-treat to prevent one vascular event is quite large. James McCormack and colleagues present data suggesting that the new AHA/ACC risk calculator has a similar average agreement to other commonly used risk calculators. However, we respectfully believe such risk calculators cannot be directly compared because they vary greatly
in terms of outcome definitions, years of follow-up, and absolute risk categories. Failure to take such major differences into account can lead to serious, but legitimate, discrepancies between estimates, as discussed in our comparison of calculators within the Women’s Health initiative.5 We believe randomised trials should provide the underlying structure for statin guidelines,6 but share William Feeman’s view that experimental data, observational studies, and genetics should inform thoughtful application of those guidelines to individual patients. We are less concerned about elimination of LDL treatment targets since the new AHA/ ACC guidelines strongly emphasise the use of more intensive statins for more patients. This latter approach is consistent with available evidence and will clearly improve patient care. PMR receives investigator initiated research support from the National Heart Lung and Blood Institute, Amgen, AstraZeneca, Novartis, and Pfizer, and is listed as a co-inventor on patents held by the Brigham and Women’s Hospital that relate to inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to Seimens and AstraZeneca. NRC declares that she has no conflicts of interest.
*Paul M Ridker, Nancy R Cook [email protected] Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine and Cardiology, Brigham and Women’s Hospital, Boston, MA 02215, USA 1
2
3
4
5
6
Dorresteijn JA, Boekholdt SM, van der Graaf Y, et al. High-dose statin therapy in patients with stable coronary artery disease: treating the right patients based on individualized prediction of treatment effect. Circulation 2013; 127: 2485–93. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 2013; 382: 1762–65. Janssen KJM, Moons KGM, Kalkman CJ, Grobbee DE, Vergouwe Y. Updating methods improved the performance of a clinical prediction model in new patients. J Clin Epidemiol 2008; 61: 76–86. Pennells L, Kaptoge S, White IR, Thompson SG, Wood AM, and the Emerging Risk Factors Collaboration. Assessing risk prediction models using individual participant data from multiple studies. Am J Epidemiol 2013; published online Dec 22. DOI:10.1093/aje/kwt298. Cook NR, Paynter NP, Eaton CB, et al. Comparison of the Framingham and Reynolds Risk Scores for global cardiovascular risk prediction in the multiethnic Women’s Health Initiative. Circulation 2012; 125: 1748–56. Ridker PM, Wilson PWF. A trial-based approach to statin guidelines. JAMA 2013; 310: 1123–24.
Statins, risk assessment, and the new American prevention guidelines In 2008, the National Heart, Lung and Blood Institute commissioned three expert panels (on cholesterol treatment, blood pressure treatment, and obesity and overweight management) and cross-cutting and supporting work groups (focused on lifestyle and risk assessment) to create updated clinical practice guidelines for cardiovascular disease prevention. The American Heart Association and American College of Cardiology completed and published the guidelines on Nov 12, 2013.1–4 For the first time, these guideline panels and work groups took an approach that was based almost solely on systematic reviews of the medical literature and synthesis of high-quality evidence. In their Comment,5 Paul Ridker and Nancy Cook support many of the recommendations for cardiovascular risk reduction that were made as a result of the prolonged and careful deliberations of these panels. However, they take issue with the risk assessment algorithm provided by the guidelines. For its risk calculator, the work group pooled recent data (mostly derived from the 1990s) from several long-standing, community-based US cohort studies to develop new sexspecific and race-specific equations to predict 10-year risk for atherosclerotic cardiovascular disease (ASCVD).2 These pooled cohort equations represent a major step forward for risk estimation, because, for the first time in a major guideline, they focus on estimation of risk for both heart attacks and strokes and provide estimates applicable to African American people. As a result, they are much better at representing overall, or global, cardiovascular disease risk, especially in women and African Americans, in whom risk for stroke increases earlier in life than does risk for heart attacks. The risk assessment work group considered other potential approaches www.thelancet.com Vol 383 February 15, 2014
Pasieka/Science Photo Library
Authors’ reply
Published Online December 4, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)62348-X
600
We concur with David van Klaveren and colleagues that the projected treatment effect for an individual given his or her risk factors is of considerable importance since net benefit is a function of the person’s absolute risk, the projected individual benefit, as well as potential harms of therapy. We have collaborated previously using this methodology to estimate individualised benefits of statin therapy1 and in work describing the individualised numberneeded-to-treat. As noted in our Comment,2 we further concur that contemporary cohorts should be used to update and recalibrate risk equations when such data are available,3 although we recognise that methods to develop and assess prediction models from multiple studies are quite complex, and should explore and allow for heterogeneity across studies.4 Using the new American Heart Association (AHA) and American College of Cardiology (ACC) algorithms, virtually all men older than 66 years and women older than 70 years have a calculated 10-year risk greater than 7·5%, even with optimal risk factors. Nicholas Wald and Joan Morris thus suggest that screening for age alone is a simpler way to prescribe statin therapy. However, as noted in our Comment,2 these risk estimates are likely to be artificially high. Further, the approach of treating all individuals older than a given age exposes the largest number to therapy, including many who have never been studied in clinical trials. This approach could lead to exposure to potential hazards of statin therapy among some individuals without clear evidence of benefit, and to many others where the number-needed-to-treat to prevent one vascular event is quite large. James McCormack and colleagues present data suggesting that the new AHA/ACC risk calculator has a similar average agreement to other commonly used risk calculators. However, we respectfully believe such risk calculators cannot be directly compared because they vary greatly
in terms of outcome definitions, years of follow-up, and absolute risk categories. Failure to take such major differences into account can lead to serious, but legitimate, discrepancies between estimates, as discussed in our comparison of calculators within the Women’s Health initiative.5 We believe randomised trials should provide the underlying structure for statin guidelines,6 but share William Feeman’s view that experimental data, observational studies, and genetics should inform thoughtful application of those guidelines to individual patients. We are less concerned about elimination of LDL treatment targets since the new AHA/ ACC guidelines strongly emphasise the use of more intensive statins for more patients. This latter approach is consistent with available evidence and will clearly improve patient care. PMR receives investigator initiated research support from the National Heart Lung and Blood Institute, Amgen, AstraZeneca, Novartis, and Pfizer, and is listed as a co-inventor on patents held by the Brigham and Women’s Hospital that relate to inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to Seimens and AstraZeneca. NRC declares that she has no conflicts of interest.
*Paul M Ridker, Nancy R Cook [email protected] Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine and Cardiology, Brigham and Women’s Hospital, Boston, MA 02215, USA 1
2
3
4
5
6
Dorresteijn JA, Boekholdt SM, van der Graaf Y, et al. High-dose statin therapy in patients with stable coronary artery disease: treating the right patients based on individualized prediction of treatment effect. Circulation 2013; 127: 2485–93. Ridker PM, Cook NR. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 2013; 382: 1762–65. Janssen KJM, Moons KGM, Kalkman CJ, Grobbee DE, Vergouwe Y. Updating methods improved the performance of a clinical prediction model in new patients. J Clin Epidemiol 2008; 61: 76–86. Pennells L, Kaptoge S, White IR, Thompson SG, Wood AM, and the Emerging Risk Factors Collaboration. Assessing risk prediction models using individual participant data from multiple studies. Am J Epidemiol 2013; published online Dec 22. DOI:10.1093/aje/kwt298. Cook NR, Paynter NP, Eaton CB, et al. Comparison of the Framingham and Reynolds Risk Scores for global cardiovascular risk prediction in the multiethnic Women’s Health Initiative. Circulation 2012; 125: 1748–56. Ridker PM, Wilson PWF. A trial-based approach to statin guidelines. JAMA 2013; 310: 1123–24.
Statins, risk assessment, and the new American prevention guidelines In 2008, the National Heart, Lung and Blood Institute commissioned three expert panels (on cholesterol treatment, blood pressure treatment, and obesity and overweight management) and cross-cutting and supporting work groups (focused on lifestyle and risk assessment) to create updated clinical practice guidelines for cardiovascular disease prevention. The American Heart Association and American College of Cardiology completed and published the guidelines on Nov 12, 2013.1–4 For the first time, these guideline panels and work groups took an approach that was based almost solely on systematic reviews of the medical literature and synthesis of high-quality evidence. In their Comment,5 Paul Ridker and Nancy Cook support many of the recommendations for cardiovascular risk reduction that were made as a result of the prolonged and careful deliberations of these panels. However, they take issue with the risk assessment algorithm provided by the guidelines. For its risk calculator, the work group pooled recent data (mostly derived from the 1990s) from several long-standing, community-based US cohort studies to develop new sexspecific and race-specific equations to predict 10-year risk for atherosclerotic cardiovascular disease (ASCVD).2 These pooled cohort equations represent a major step forward for risk estimation, because, for the first time in a major guideline, they focus on estimation of risk for both heart attacks and strokes and provide estimates applicable to African American people. As a result, they are much better at representing overall, or global, cardiovascular disease risk, especially in women and African Americans, in whom risk for stroke increases earlier in life than does risk for heart attacks. The risk assessment work group considered other potential approaches www.thelancet.com Vol 383 February 15, 2014
