Age as the only meaningful predictive tool for cardiovascular disease: another blow to personalized medicine?
Today, we published the article, Screening for Future Cardiovascular Disease Using Age by Nicholas J. Wald, Mark Simmonds, and Joan K. Morris. The following Perspective is by Giuseppe Biondi-Zoccai, the academic editor of this manuscript.
In this issue of PLoS ONE Nick Wald and colleagues challenge us again.  After having developed the triple test for Down syndrome,  the polypill,  and teleoanalysis,  they go as far as to question the practical role of risk prognostication with one of the pillars of cardiovascular medicine, the Framingham risk score.  In their elegant simulation work, Wald et al show that using only age as a screening tool in a hypothetical sample of 500,000 subjects at risk for cardiovascular disease provides largely similar results in comparison to screening based on the Framingham risk score. For instance, the area under the curve (AUC) of the receiver operator characteristic (ROC) of the two tests suggested similar discriminatory performance: 89% for age screening, 90% for Framingham risk score assessment every 5 years, and 91% for Framingham risk score assessment every year.
The first key message of this work is that we are not in an era of personalized medicine, after all. As even the respected and validated Framingham risk score fails to provide meaningful incremental insight on top of age screening alone,  we should not put too much faith in other more complex and expensive tests such as those focusing on genotyping or platelet responsiveness.   The second key message of this paper is more practical, but nonetheless crucial. We can maximize patient wellbeing and minimize cost by applying simple risk stratification tools and universally treating (in the context of primary prevention) all those at risk of cardiovascular disease.  For instance, we should propose treatment with a statin and a combination of anti-hypertension agents for everyone older than 55 or 60 years. Accordingly, we should be reserve a more personalized, complex, and expensive approach (e.g. C-reactive protein assessment) to those failing basic preventive means (thus in the context of secondary prevention) or with uncommon and rare conditions. 
Of course this paper has, despite the careful work of the authors, several shortcomings. First, it is a Monte Carlo simulation study and thus does not include any real person. Second, even a 1% improvement in prognostic performance might be worthwhile to some or most decision makers, especially if accompanied by improved reclassification: aren’t we happy when gasoline price decrease even if by 1%?  Third, the Framingham risk score is the best known prediction tool for cardiovascular disease, but others, possibly more precise ones, are also available, such as the QRISK2.  Fourth, any prediction tool may perform well for some end-points, and worse for other. For instance, the EuroSCORE predicts reasonably well death after coronary revascularization, but its performance when focusing on myocardial infarction or repeat revascularization is much poorer.  Nonetheless, we find the message conveyed by Wald et al very intriguing, and in keeping with similar efforts conducted by anesthesiologists and intensive care specialists. 
In conclusion, Wald and colleagues should be commended for demonstrating that, even in the 21st century, Occam’s razor and the law of parsimony still remain valid: less is indeed more. Or in other words: go get your polypill if over 55 years!
1. Wald NJ, Simmonds M, Morris JK (2011) Screening for Future Cardiovascular Disease Using Age Alone Compared with Multiple Risk Factors and Age. PLoS ONE 6(4): e18742. doi:10.1371/journal.pone.0018742
2. Wald NJ (2010) Prenatal screening for open neural tube defects and Down syndrome: three decades of progress. Prenat Diagn 30(7): 619-21.
3. Wald NJ, Law MR (2003) A strategy to reduce cardiovascular disease by more than 80%. BMJ 326(7404): 1419.
4. Wald NJ, Morris JK (2003) Teleoanalysis: combining data from different types of study. BMJ 327(7415): 616-8.
5. Lloyd-Jones DM, Wilson PWF, Larson MG, Beiser A, Leip EP, D’Agostino RB, Levy D. Framingham risk score and prediction of lifetime risk for coronary heart disease. Am J Cardiol 94(1): 20-4.
6. Tzoulaki I, Liberopoulos G, Ioannidis JP (2009) Assessment of claims of improved prediction beyond the Framingham risk score. JAMA 302(21): 2345-52.
7. Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS (2010) Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 304(16): 1821-30.
8. Biondi-Zoccai G, Lotrionte M (2008) Aspirin resistance in cardiovascular disease. BMJ 336(7637): 166-7.
9. Schnabel RB, Schulz A, Messow CM, Lubos E, Wild PS, Zeller T, Sinning CR, Rupprecht HJ, Bickel C, Peetz D, Cambien F, Kempf T, Wollert KC, Benjamin EJ, Lackner KJ, Münzel TF, Tiret L, Vasan RS, Blankenberg S (2010) Multiple marker approach to risk stratification in patients with stable coronary artery disease. Eur Heart J 31(24): 3024-31.
10. Capodanno D, Tamburino C (2011) Integrating the Synergy between percutaneous coronary intervention with Taxus and Cardiac Surgery (SYNTAX) score into practice: use, pitfalls, and new directions. Am Heart J 161(3): 462-70.
11. Hippisley-Cox J, Coupland C, Vinogradova Y, Robson J, Minhas R, Sheikh A, Brindle P (2008) Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2. BMJ 336(7659): 1475-82.
12. Biondi-Zoccai GG, Lotrionte M, Moretti C, Meliga E, Agostoni P, Valgimigli M, Migliorini A, Antoniucci D, Carrie´ D, Sangiorgi G, Chieffo A, Colombo A, Price MJ, Teirstein PS, Christiansen EH, Abbate A, Testa L, Gunn JP, Burzotta F, Laudito A, Trevi GP, Sheiban I (2008) A collaborative systematic review and meta-analysis on 1278 patients undergoing percutaneous drug-eluting stenting for unprotected left main coronary artery disease. Am Heart J 155:274–283.
13. Ranucci M, Castelvecchio S, Menicanti L, Frigiola A, Pelissero G (2009) Risk of assessing mortality risk in elective cardiac operations: age, creatinine, ejection fraction, and the law of parsimony. Circulation 119(24): 3053-61.
By: Giuseppe Biondi-Zoccai, MD, FSICI-GISE
Division of Cardiology, University of Modena and Reggio Emilia, Modena, and Meta-analysis and Evidence based medicine Training in Cardiology (METCARDIO), Ospedaletti, both in Italy
Conflicts of interest: none
Address for correspondence: Division of Cardiology, University of Modena and Reggio Emilia, Via Del Pozzo 71, 41124 Modena Italy. Email: firstname.lastname@example.org