Author's Accepted Manuscript
Prevention of cardiovascular disease Jay N. Cohn M.D.
PII: DOI: Reference:
www.elsevier.com/locate/tcm S1050-1738(14)00241-2 http://dx.doi.org/10.1016/j.tcm.2014.12.005 TCM6089
To appear in: trends in cardiovascular medicine
Cite this article as: Jay N. Cohn M.D., Prevention of cardiovascular disease, trends in cardiovascular medicine, http://dx.doi.org/10.1016/j. tcm.2014.12.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
PREVENTION OF CARDIOVASCULAR DISEASE
Jay N. Cohn, M.D. Professor of Medicine Director, Rasmussen Center for Cardiovascular Disease Prevention University of Minnesota Medical School Minneapolis, Minnesota Dr. COHN reports other from CVC-HS, LLC, outside the submitted work; In addition, Dr. COHN has a patent A method for identifying early cardiovascular disease issued.
Correspondence to:
Jay N. Cohn, M.D. Cardiovascular Division
Mayo Mail Code 508 University of Minnesota Medical School 420 Delaware Street Southeast Minneapolis, MN 55455, USA Tel: 612.625.5646 Fax: 612.626.4411 E‐mail: [email protected]
2 Cardiovascular morbid events have served as the clinical marker for the presence of cardiovascular disease. These markers include not only death from cardiovascular causes but also symptoms of obstructive coronary artery disease (CAD), neurological deficits of cerebrovascular disease, claudication in the lower extremities from peripheral vascular disease, renal failure from kidney vascular disease, and dyspnea, fatigue or rhythm disturbances related to myocardial disease. These clinical syndromes are the leading cause of morbidity and mortality in the developed world and consume a large fraction of our health care expenditures. Efforts over the last several decades to reduce the burden of cardiovascular disease have therefore been focused on reduction of the frequency of these morbid events in defined populations (1‐6). The abnormalities of the vasculature and heart that underlie these morbid events are present and progressing for years prior to the events. Since these functional and structural abnormalities of the arteries and heart can be detected long prior to the occurrence of the morbid events, recent debate has centered on whether identification of early disease and treatment to slow its progression should take precedence over the traditional approach of risk factor assessment and treatment (7, 8). This latter approach has been based on the epidemiologic data from large populations demonstrating a significant relationship between smoking, obesity, a sedentary lifestyle, blood pressure levels, cholesterol levels, and blood sugar levels with the incidence of cardiovascular morbid events (9, 10). Efforts at the community level to favorably affect these so‐called risk factors are designed to reduce the population incidence of these events. Nonetheless, this population‐based approach has been widely advocated for adoption by health care providers to steer preventive intervention in their otherwise healthy patients (11, 12). The effort to prevent symptomatic cardiovascular disease in 2014 therefore involves several alternative or complementary approaches:
3 1. Screening in primary care offices to assess risk factors, encourage behavior to reduce them, and intervene pharmacologically when they are above an accepted threshold for treatment. 2. Community‐wide intervention with pharmacotherapy (a so‐called polypill) that should reduce the incidence in the population of morbid events. 3. Screening of individuals in the population to detect early, asymptomatic vascular or cardiac disease with individually‐guided treatment aimed at slowing progression of the disease. We shall review the strengths and weaknesses of these approaches and consider future strategies aimed at fostering a significant prolongation of life free of cardiovascular morbid events. RISK FACTOR ASSESSMENT AND INTERVENTION For the last several decades, the emphasis in cardiovascular disease prevention has focused on the role of risk factors in influencing the occurrence of cardiovascular morbid events, and on lifestyle interventions aimed at reducing these risk factor levels. This approach has been driven by examination of large data bases that have revealed that such lifestyle‐affected measurements as body weight, smoking, cholesterol levels, fat consumption, exercise infrequency and blood pressure correlate significantly with the frequency of these morbid events. This powerful demonstration of an influence on relative risk has led to the public perception that cardiovascular diseases are largely self‐induced and that their frequency can be dramatically reduced by changes in diet and lifestyle. This inflation of public perception of the role of modifiable risk factors as the cause of cardiovascular disease may be viewed as an appropriate tool to encourage behavior patterns that can reduce the community incidence of morbid events. However, the effort involves the blurring of the distinction between absolute risk and relative risk. The statistical power of these risk factors is assessed by their influence on relative risk in populations. The magnitude of that relative risk increment may, however, be only modest, whereas the absolute risk in individuals is highly variable and largely
4 dependent on non‐measured factors, including inherited genomic characterization. Lifestyle modifications alone are unlikely to alter absolute risk by enough to alter the individual’s prospects for a disease‐free life. The other component of this traditional approach to disease prevention has been the establishment of thresholds of blood pressure and cholesterol, above which the view has been that the likelihood of a morbid event is high enough to justify pharmacologic intervention to lower the risk factor to some target level. The use of an algorithm to calculate the risk, such as that derived from the Framingham data (13), a European data base (14), or the more recent AHA/ACC database (12), has provided another means of identifying risk high enough to justify pharmacologic intervention. Most of these risk algorithms are calculated from time‐limited data. The most commonly used is 10‐year risk. A 10‐year risk over 20% using the Framingham assessment is considered high and in need of intervention. A risk below 10% is considered low and in no immediate need. A value between 10 and 20% is considered moderate and requires other considerations in determining the need for therapy. The AHA/ACC algorithm focuses on treatment for risk >7.5%. The weakness of this time‐ limited assessment is that the time frame of interest for any individual is rarely 10 years. A 35‐year‐old is anxious to prevent morbid events not for 10 years but more likely for 40 or more years. Even a 60‐ year‐old might well have a future horizon of more than 10 years. By this longer perspective, the data from 10‐year risk are not helpful. According to the data used for the algorithm development, 10 years free of morbid events may inappropriately label the patient as at low risk. The strategy of measuring risk factors and using either risk factor thresholds or derived algorithms for calculating risk and using these measurements to drive lifestyle or pharmacologic intervention has undoubtedly contributed to the fall over the last 20 years in the incidence of major cardiovascular morbid events. But the majority of these morbid events are now occurring in individuals with measured risk factors below the threshold required for aggressive pharmacotherapy. Thus,
5 continued reliance on the risk factor model is unlikely to further reduce the incidence of major events and is highly unlikely to prolong disease‐free life to an attainable target such as 90 or 100 years. POPULATION TREATMENT WITH A POLYPILL The demonstration in recent years of the powerful effect of drugs on established risk factors, and the effectiveness of these drugs in reducing morbidity and mortality in high risk individuals, has led to proposals for population treatment to reduce the community incidence of cardiovascular morbid events (15, 16). Such a strategy overcomes one weakness of the risk factor model described above because it would mandate treatment of all individuals above a certain age regardless of the level of the risk factor. It would therefore be aimed at reducing the absolute risk of vascular or cardiac disease, not the incremental relative risk of specific risk factors. The attractiveness of this strategy to reduce the population incidence of morbid events is counterbalanced by a number of confounding factors: 1. Most polypill designs include several drugs‐‐usually a statin, a renin‐angiotensin inhibitor, sometimes a diuretic and aspirin‐‐ representing classes of agents with demonstrated effectiveness in clinical trials. These drugs are usually included in the polypill in doses below those that have been effective in order to minimize side‐effects, so their efficacy in these doses has not been established. 2. Treatment of an entire population, whereas it might reduce the population event rate, may induce side‐effects in individuals who cannot benefit from the treatment because of a low absolute risk. 3. The absence of an indication for treatment and of a personal caregiver may lead to serious adverse events for which there would be inadequate oversight and no justification.
6 4. The strategy is based on the assumption that there is no satisfactory and practical method for screening that could better identify those in need of preventive therapy and no better way to focus specific pharmacologic interventions on specific individuals. Pilot studies of a polypill given to populations of men and women above some cut‐off age have been conducted (17, 18). They have documented the feasibility of such a strategy and have calculated the potential benefit to the population of an hypothesized reduction in morbid events. The enthusiasts for this approach appear to have minimized the population resistance to taking a medication in the absence of an established individual need. EARLY DISEASE DETECTION AND TREATMENT The focus over the last 50 years on risk factors to identify individuals in need of treatment to prevent cardiovascular morbid events reflects the role of the scholarly forces that have dominated the field. Morbid events became the end‐point of all preventive studies, and this required large populations to accumulate enough events for analysis. The Framingham Study and other large data bases became the laboratory for analysis, and the search began for markers that were predictive of such morbid events. The biologic process was largely disregarded, so identification of early disease and the monitoring of its progression were not a high priority, even though the ability to carry out such studies became available in the last 20 years. Cancer research followed a different path, not the search for risk factors associated with cancer mortality but the search for early, asymptomatic tumors that might advance to invasive cancer. By documenting the statistical relationship between the identified risk factor and the relative risk of morbid events, the investigators dedicated themselves to the task of demonstrating that treatment of the risk factors would reduce the frequency of the morbid events. Multiple controlled clinical trials were carried out to confirm that blood pressure reduction and cholesterol reduction were
7 associated with fewer morbid events than in the control arms. These large‐scale trials over the last 50 years have galvanized the medical and public health community to view risk factors as the cause of cardiovascular morbid events and to the mandate for lowering these risk factors as the goals of treatment. The biological processes leading to these morbid events have largely been disregarded in the effort to gain adherence to appropriate risk factor intervention. Nearly all cardiovascular morbid events occur in the setting of functional and structural abnormalities of the arterial vasculature or left ventricle that can be detected long before the symptomatic event occur. Most of these morbid events occur as a complication of two distinct but related processes, atherosclerosis and arteriosclerosis. Atherosclerosis is a disease characterized by lipid‐rich plaque formation in conduit arteries, but it has its origin in endothelial dysfunction that expresses itself as dysfunction and structural remodeling of the small arteries (19). Arteriosclerosis, on the other hand, involves thickening and stiffening of the large conduit arteries and associated hypertrophy and remodeling of the left ventricle. These processes are age‐ dependent and progress in concert, but the individual rate of progression of atherosclerosis may be quite different than that of arteriosclerosis and that of left ventricular remodeling. These functional and structural abnormalities of the arterial vasculature and the left ventricle provide an opportunity to identify disease long before morbid events occur and to track and slow the progression of disease in asymptomatic individuals. Since the ultimate goal of therapy is to prevent morbid events, not to reduce risk factors, the identification and monitoring of the underlying disease process should provide a more sensitive and specific guide to the risk for morbid events and a more individualized guide to the effectiveness of interventions to prevent such events. Thus, early disease detection should outperform the usual risk algorithms that depend predominantly on risk factors, and knowledge of the biological process affecting
8 an individual should provide the opportunity for specific therapy that can be individualized. Clinical trials to document effectiveness of this approach are urgently needed. A number of techniques have been utilized to assess early disease in order to improve the precision in identifying individuals at risk for morbid events. Radiographic identification of coronary calcium is the most widely utilized, and serves as a specific indicator of coronary atherosclerotic plaques. (7). A high calcium score confirms the presence of coronary disease that mandates intervention with drugs to slow its progression. The future hope is that the atherosclerotic process can be identified earlier, before the appearance of extensive calcification, when preventive therapy can likely be more effective, Other methods, such as carotid ultrasound for identifying increased carotid wall thickness or carotid artery plaque formation, provide an alternate vascular bed for assessing arteriosclerosis or atherosclerosis (20). Microalbuminuria occurs as a consequence of small vessel disease in the kidney (21). Attempts to quantitate endothelial dysfunction, as the first stage of atherosclerosis, have also been promoted by some investigators (22). Our approach is based on the concept that the vascular diseases, arteriosclerosis and atherosclerosis, and the cardiac diseases that lead to morbid events are expressed variably in individual patients. Early detection, therefore, requires a comprehensive evaluation of vascular and cardiac health using more than one methodology. This concept has led to a panel of 10 tests that we perform on all patients who seek knowledge and management of their individual risk (Table 1) (23). These non‐invasive tests are all performed in one room by one technician in one hour (Table 1). The testing results in a disease score in each patient based on the sum of the abnormalities (0‐20) detected in the 10‐test panel (24). These tests provide an assessment of health of the large conduit arteries, health of the small arteries, and health of the left ventricle, the primary target organs of cardiovascular morbid events. Preliminary observations using data collected over the first seven years of clinical experience with this program have confirmed two major hypotheses: (1) Assessment of early disease using this
9 comprehensive disease score outperforms the traditional risk factor algorithms in predicting future morbid events (25) (Figures 1 and 2), and (2) interventions known to reduce the occurrence of morbid events have a favorable effect on the disease score in placebo‐controlled studies (26, 27). THERAPEUTIC GOALS The goal of clinical trials has been to reduce morbid events over a truncated time interval designed to accumulate enough events to allow documentation of the effectiveness of therapy. A popular calculation in such trials has been the number needed to treat (NNT), the number of patients who must be treated with the experimental intervention to prevent one morbid event over the duration of follow‐up (28). This trial design depends for its success on enough morbid events to power the outcome analysis. It therefore requires randomizing patients who have a high likelihood of suffering morbid events during the designated follow‐up period. Patients with prior events and those with advanced disease are the ideal candidates for such event‐driven trials. In this design the individuals who do not suffer an event during the study period represent “noise” in the final outcome analysis, since they do not contribute to the end‐point. Such a design does not address the needs of asymptomatic patients who want to slow progression of early disease to delay or prevent future morbid events. A 40‐year‐old, for example, has a much longer horizon of interest than 5 or 10 years, the duration of most randomized, placebo‐controlled studies. The absence of a morbid event over that interval may be interpreted as success, but if disease is progressing and bringing the patient closer to a morbid event the treatment may actually have been a failure. Slowing of progression of disease can be assessed most effectively by monitoring the vascular and cardiac disease itself, not by waiting for morbid events. Indeed, the only reasonable long‐term goal for intervention to prevent cardiovascular disease is to delay events, not prevent them. If all events
10 could be delayed to the target age of 90 or 100, it is likely that other disease process morbidity would predominate over cardiovascular disease and that health insurance policies could ration care for the very elderly. This revised concept would change the agenda from preventing morbid events, an activity that is traditionally not well reimbursed by health insurance, to slowing disease progression, a measurable and reimbursable activity. This will require a focus on the underlying disease, not on risk factors. POPULATION VS. INDIVIDUAL MANAGEMENT Population‐based management strategies have dominated guidelines in recent decades. The concept of “matching the intensity of risk factor management to the estimated risk for CVD” (12, 29) is a populations‐based approach to treatment. Using thresholds for treatment, whether these thresholds are based on blood pressure, cholesterol levels or algorithm‐based scores, does not imply that those above the threshold will all benefit, and those below the threshold not, but that this approach will likely reduce the fraction of individuals who will be treated unnecessarily and increase the fraction of those who need treatment and will receive therapy. This population‐based approach fails those below the threshold who actually need treatment for advancing disease and exposes others who are above the threshold, but have no disease, to needless therapy. In the year 2015 it seems antiquated to use population statistics to drive clinical management when it is possible to individualize therapy based on the detection and sequential monitoring of the health of the arteries and heart, the source of all cardiovascular morbid events. The argument that the population approach has had a favorable impact on cardiovascular morbidity and mortality, and that early disease detection and treatment has not yet been subjected to rigorous controlled clinical trials, should serve as a cautionary note and a stimulus to research, but not as a vendetta against the modernization of medical care.
11 A STRATEGY FOR THE 21st CENTURY Medical care for cardiovascular morbid events currently consumes a large fraction of our health care expenditures, and these events are a major cause of disability and premature deaths in the developed world. Since the progression of the disease leading to this morbidity is largely preventable, the goal for the 21st century should be to halt its progression and delay morbid events until an age when full life expectancy has been achieved. Although this age defining premature morbidity and mortality is at best arbitrary, our Center has set an immediate goal of 90 years and a long‐term goal of 100 years. For this strategy to be successful we must have therapy that can slow progression. The administration of statin drugs and certain antihypertensive drugs has been demonstrated to reduce morbid events in numerous controlled trials (1‐6). The magnitude of that reduction in events has varied considerably, dependent on the effectiveness of the intervention and on the patient population exposed. For example, statin trials carried out in hyperlipidemic patients who had already suffered a morbid event resulted in a significant reduction in future events (5), but the magnitude of benefit was actually lower than in apparently healthy non‐hyperlipidemic individuals (30). The simplest explanation for that apparent paradox is that in individuals with advanced disease slowing of progression may merely delay morbid events, whereas in those with early disease intervention may prevent events (Figure 3). Evidence that drugs can slow the progression of functional and structural abnormalities of the arteries and heart provides further support for the potential of drug therapy introduced into individuals with advancing but asymptomatic disease. Slowing progression of early disease in individuals who present with that phenotype, as displayed in Figure 3, may not reveal a large benefit in event reductions over 10 years but may profoundly reduce the incidence of lifetime morbid events. A second prerequisite for this strategy is that criteria for selection of patients for preventive therapy be available to primary care providers. This requirement has fueled the use of standard risk factor assessment, which includes demographic data as well as blood pressure and cholesterol
12 measurements that are usually available on all adults in primary care practice. If early disease detection measures are to serve as a guide to intervention, then they must be made available to primary care providers. Is this additional diagnostic testing justified and practical? The approach we have used requires 10 non‐invasive and non‐radiographic tests of vascular and cardiac health. These can be accomplished in one hour in a single room by one technologist using equipment that can be purchased for less than $100,000. Nonetheless, there has been reluctance of the health care system to advocate that screening for all adults, and in the absence of such widespread screening this approach to early disease detection cannot be made available. We have therefore set out to develop a two‐tiered evaluation strategy that provides a preliminary, simple screen to exclude from further evaluation most of the patients who are unlikely to require therapeutic intervention (27). This strategy is based on our observations that a simple 4‐test screen, which can be accomplished in 10 minutes in a clinic setting, quite effectively discriminates between individuals unlikely to harbor early disease from those more likely to have early or advancing disease. Our preliminary data suggesting 90% sensitivity seem to provide adequate justification for screening out as many as 60% of the population from the need for more extensive evaluation at that point in time. A key part of this new strategy is an attempt to individualize management based on the abnormalities detected in the evaluation. Cardiovascular disease presents differently from individual to individual, either because of different vascular beds involved or different manifestations of the disease. This variability must relate to individual differences in the progression of functional and structural disease. Our preliminary observations suggest that four distinct phenotypes of cardiovascular abnormalities can be detected and are likely to respond to different therapeutic regimens. These phenotypes can be characterized as: (1) Small artery disease, a manifestation of endothelial dysfunction and characterized by stiff small arteries, retinal vascular changes and microalbuminuria; (2) large artery disease, a manifestation of arteriosclerosis and characterized by systolic hypertension at rest or during
13 exercise, stiff large arteries and thickened carotid arteries; (3) atherosclerosis, manifested by small artery disease and carotid or aortic plaque formation; and (4) left ventricular disease, with increased LV mass, elevated NT Pro‐BNP and ECG abnormalities. These phenotypes are of course overlapping but they can provide insights that can lead to different therapeutic recommendations. Clinical trials are needed to determine if this individualized therapy is better at modifying outcomes compared to the present strategy of a more non‐selective approach to treatment. We are in the process of establishing a program of clinic screening and center assessment of high risk patients to determine if such a program can be effective in evaluating and managing a community population. If so, this approach has the potential of providing the long‐sought individualized approach to cardiovascular disease management based on 21st century testing that could replace the population‐based risk factor approach that characterized the 20th century. Legends Figure 1 Predictive value of the Disease Score (DS) calculated from 10 tests of vascular and cardiac health. One year, three years and six years after initial assessment, the occurrence of cardiovascular morbid events was directly related to the DS, which was grouped into nearly equal terciles of scores of 0‐2, 3‐5, and 6+. Note that individuals with DS 0‐2, the non‐disease phenotype, sustained no morbid events during 6 years follow‐up. (With permission from Duprez et al. (Reference 25). Figure 2 Blood pressure (BP) and LDL cholesterol levels (LDL) do not discriminate risk for morbid events. BP (I=84 mmHg); LDL(I=129 mg/dL). Note that although the percentage of patients with morbid events in the normal blood pressure group was lower, the absolute number of events in this group was higher because of its higher frequency in the population. Figure 3
14 The natural history of cardiovascular disease. Those without the phenotype of early disease may live 100 years without a morbid event. Those with the phenotype may alter their risk by therapeutic intervention. If treatment is started after a morbid event (A) life may be prolonged modestly. If treatment is initiated in advanced disease (B) morbid events may be delayed. If treatment is initiated in early disease morbid events may be prevented until age 100. Table 1 10 tests performed in the Rasmussen Center 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Resting sitting blood pressure Small artery elasticity (pulsewave analysis) Large artery elasticity (pulse wave analysis) Exercise (3 minutes, 5 METS) BP response Carotid intima‐medial thickness + plaques Retinal digital photograph Urine sample for albumin/creatinine ratio Electrocardiogram Left ventricular ultrasound for thickness, mass Blood sample for NT‐ProBNP
15 REFERENCES 1. Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta analysis. Lancet 2001;358:1305–15. 2. Turnbull F; Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood‐pressure lowering regimens on major cardiovascular events: results of prospectively‐ designed overviews of randomised trials. Lancet 2003;362:1527–35. 3. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin‐ converting enzyme inhibitor, ramipril, on cardiovascular events in high‐risk patients. N Engl J Med 2000;342:145–53. 4. The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double‐blind, placebo‐ controlled, multicenter trial (the EUROPA study). Lancet 2003;362:782–8. 5. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol lowering treatment: prospective meta‐analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78. 6. Cholesterol Treatment Trialists’ (CTT) 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. 7. Peters SAE, den Ruijter HM, Bots ML, Moons KGM. Improvements in risk stratification for the occurrence of cardiovascular disease by imaging subclinical atherosclerosis: a systematic review. Heart 2012;98:177–84.
16 8. Cohn JN, Duprez DA. Time to foster a rational approach to preventing cardiovascular morbid events. J Am Coll Cardiol 2008;52:327–9. 9. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age‐specific relevance of usual blood pressure to vascular mortality: a meta‐analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13. 10. Prospective Studies Collaboration, Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta‐ analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007;370:1829–39. 11. James PA, Oparil S, Carter BL, Cushman WC, Dennison‐Himmelfarb C, Handler J, et al. 2014 Evidence‐ based 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. 12. Goff Jr DC, Lloyd‐Jones DM, Bennett G, Coady S, D’Agostino RB, Gibbons R, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:S49‐S73. 13. D’Agostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care: The Framingham Heart Study. Circulation 2008;117:743–53. 14. Kotseva K, Wood D, De Backer G, De Bacquer D, Pyörälä K, Keil U; EUROASPIRE Study Group. Cardiovascular prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, and III surveys in eight European countries. Lancet 2009;373:929–40. 15. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. British Med J 2003;326:1419‐23.
17 16. Lonn E, Bosch J, Teo KK, Pais P, Xavier D, Yusuf S. The polypill in the prevention of cardiovascular diseases: Key concepts, current status, challenges and future directions. Circulation 2010;122:2078‐ 88. 17. The Indian Polycap Study (TIPS)* Effects of a polypill (Polycap) on risk factors in middle‐aged individuals without cardiovascular disease (TIPS): a phase II, double‐blind, randomized trial. Lancet 2009;373:1341‐51. 18. Castellano JM, Sanz G, Ortiz AF, Garrido E, Bansilal S, Fuster V. A polypill strategy to improve global secondary cardiovascular prevention: From concept to reality. J Am Coll Cardiol 2014;64:613‐21. 19. Gilani M, Kaiser DR, Bratteli CW, Alinder C, Rajala S, Bank AJ, et al. Role of nitric oxide deficiency and its detection as a risk factor in pre‐hypertension. J Amer Soc Hypertens 2007;1(1):45‐55. 20. Den Ruijter HM, Peters SAE, Anderson TJ, Britton AR, Dekker JM, Eijkemans MJ, et al. Common carotid intimamedia thickness measurements in cardiovascular risk prediction: a meta‐analysis. JAMA. 2012;308:796–803. 21. Weir MR. Microalbuminuria and cardiovascular disease. Clin J Am Soc Nephrol 2007;2:581‐90. 22. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al. Non‐invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111‐15. 23. Cohn JN, Hoke L, Whitwam W, Sommers PA, Taylor AL, Duprez D, et al. Screening for early detection of cardiovascular disease in asymptomatic individuals. Am Heart J 2003;146:679‐85. 24. Duprez DA, Cohn JN. Identifying early cardiovascular disease to target candidates for treatment. J Clin Hypertension 2008;10(3):226‐31. 25. Duprez DA, Florea N, Zhong W, Grandits GA, Hawthorne CK, Hoke L, et al. Vascular and cardiac functional and structural screening to identify risk of future morbid events: preliminary observations. J Amer Soc Hypertens 2011;5:401‐9.
18 26. Duprez DA, Florea ND, Jones K, Cohn JN. Beneficial effects of valsartan in asymptomatic individuals with vascular or cardiac abnormalities: The DETECTIV Pilot Study. J Am Coll Cardiol 2007;50:835‐9. 27. Saul SM, Duprez DA, Zhong W, Grandits GA, Cohn JN. Effect of carvedilol, lisinopril and their combination on vascular and cardiac health in patients with borderline blood pressure: The DETECT study. J Human Hypertension 2013;27:362‐7. 28. Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med 1988;318:1728‐33. 29. 27TH Bethesda Conference. Matching the intensity of risk factor management with the hazard for coronary disease events. September 14‐15, 1995. J Am Coll Cardiol 1996;27:957‐1047. 30. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto Jr AM, Kastelein JJP, et al for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C‐reactive protein. N Engl J Med 2008;359:2195‐207. Fig 1
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Prevention of cardiovascular disease Jay N. Cohn M.D.
PII: DOI: Reference:
www.elsevier.com/locate/tcm S1050-1738(14)00241-2 http://dx.doi.org/10.1016/j.tcm.2014.12.005 TCM6089
To appear in: trends in cardiovascular medicine
Cite this article as: Jay N. Cohn M.D., Prevention of cardiovascular disease, trends in cardiovascular medicine, http://dx.doi.org/10.1016/j. tcm.2014.12.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
PREVENTION OF CARDIOVASCULAR DISEASE
Jay N. Cohn, M.D. Professor of Medicine Director, Rasmussen Center for Cardiovascular Disease Prevention University of Minnesota Medical School Minneapolis, Minnesota Dr. COHN reports other from CVC-HS, LLC, outside the submitted work; In addition, Dr. COHN has a patent A method for identifying early cardiovascular disease issued.
Correspondence to:
Jay N. Cohn, M.D. Cardiovascular Division
Mayo Mail Code 508 University of Minnesota Medical School 420 Delaware Street Southeast Minneapolis, MN 55455, USA Tel: 612.625.5646 Fax: 612.626.4411 E‐mail: [email protected]
2 Cardiovascular morbid events have served as the clinical marker for the presence of cardiovascular disease. These markers include not only death from cardiovascular causes but also symptoms of obstructive coronary artery disease (CAD), neurological deficits of cerebrovascular disease, claudication in the lower extremities from peripheral vascular disease, renal failure from kidney vascular disease, and dyspnea, fatigue or rhythm disturbances related to myocardial disease. These clinical syndromes are the leading cause of morbidity and mortality in the developed world and consume a large fraction of our health care expenditures. Efforts over the last several decades to reduce the burden of cardiovascular disease have therefore been focused on reduction of the frequency of these morbid events in defined populations (1‐6). The abnormalities of the vasculature and heart that underlie these morbid events are present and progressing for years prior to the events. Since these functional and structural abnormalities of the arteries and heart can be detected long prior to the occurrence of the morbid events, recent debate has centered on whether identification of early disease and treatment to slow its progression should take precedence over the traditional approach of risk factor assessment and treatment (7, 8). This latter approach has been based on the epidemiologic data from large populations demonstrating a significant relationship between smoking, obesity, a sedentary lifestyle, blood pressure levels, cholesterol levels, and blood sugar levels with the incidence of cardiovascular morbid events (9, 10). Efforts at the community level to favorably affect these so‐called risk factors are designed to reduce the population incidence of these events. Nonetheless, this population‐based approach has been widely advocated for adoption by health care providers to steer preventive intervention in their otherwise healthy patients (11, 12). The effort to prevent symptomatic cardiovascular disease in 2014 therefore involves several alternative or complementary approaches:
3 1. Screening in primary care offices to assess risk factors, encourage behavior to reduce them, and intervene pharmacologically when they are above an accepted threshold for treatment. 2. Community‐wide intervention with pharmacotherapy (a so‐called polypill) that should reduce the incidence in the population of morbid events. 3. Screening of individuals in the population to detect early, asymptomatic vascular or cardiac disease with individually‐guided treatment aimed at slowing progression of the disease. We shall review the strengths and weaknesses of these approaches and consider future strategies aimed at fostering a significant prolongation of life free of cardiovascular morbid events. RISK FACTOR ASSESSMENT AND INTERVENTION For the last several decades, the emphasis in cardiovascular disease prevention has focused on the role of risk factors in influencing the occurrence of cardiovascular morbid events, and on lifestyle interventions aimed at reducing these risk factor levels. This approach has been driven by examination of large data bases that have revealed that such lifestyle‐affected measurements as body weight, smoking, cholesterol levels, fat consumption, exercise infrequency and blood pressure correlate significantly with the frequency of these morbid events. This powerful demonstration of an influence on relative risk has led to the public perception that cardiovascular diseases are largely self‐induced and that their frequency can be dramatically reduced by changes in diet and lifestyle. This inflation of public perception of the role of modifiable risk factors as the cause of cardiovascular disease may be viewed as an appropriate tool to encourage behavior patterns that can reduce the community incidence of morbid events. However, the effort involves the blurring of the distinction between absolute risk and relative risk. The statistical power of these risk factors is assessed by their influence on relative risk in populations. The magnitude of that relative risk increment may, however, be only modest, whereas the absolute risk in individuals is highly variable and largely
4 dependent on non‐measured factors, including inherited genomic characterization. Lifestyle modifications alone are unlikely to alter absolute risk by enough to alter the individual’s prospects for a disease‐free life. The other component of this traditional approach to disease prevention has been the establishment of thresholds of blood pressure and cholesterol, above which the view has been that the likelihood of a morbid event is high enough to justify pharmacologic intervention to lower the risk factor to some target level. The use of an algorithm to calculate the risk, such as that derived from the Framingham data (13), a European data base (14), or the more recent AHA/ACC database (12), has provided another means of identifying risk high enough to justify pharmacologic intervention. Most of these risk algorithms are calculated from time‐limited data. The most commonly used is 10‐year risk. A 10‐year risk over 20% using the Framingham assessment is considered high and in need of intervention. A risk below 10% is considered low and in no immediate need. A value between 10 and 20% is considered moderate and requires other considerations in determining the need for therapy. The AHA/ACC algorithm focuses on treatment for risk >7.5%. The weakness of this time‐ limited assessment is that the time frame of interest for any individual is rarely 10 years. A 35‐year‐old is anxious to prevent morbid events not for 10 years but more likely for 40 or more years. Even a 60‐ year‐old might well have a future horizon of more than 10 years. By this longer perspective, the data from 10‐year risk are not helpful. According to the data used for the algorithm development, 10 years free of morbid events may inappropriately label the patient as at low risk. The strategy of measuring risk factors and using either risk factor thresholds or derived algorithms for calculating risk and using these measurements to drive lifestyle or pharmacologic intervention has undoubtedly contributed to the fall over the last 20 years in the incidence of major cardiovascular morbid events. But the majority of these morbid events are now occurring in individuals with measured risk factors below the threshold required for aggressive pharmacotherapy. Thus,
5 continued reliance on the risk factor model is unlikely to further reduce the incidence of major events and is highly unlikely to prolong disease‐free life to an attainable target such as 90 or 100 years. POPULATION TREATMENT WITH A POLYPILL The demonstration in recent years of the powerful effect of drugs on established risk factors, and the effectiveness of these drugs in reducing morbidity and mortality in high risk individuals, has led to proposals for population treatment to reduce the community incidence of cardiovascular morbid events (15, 16). Such a strategy overcomes one weakness of the risk factor model described above because it would mandate treatment of all individuals above a certain age regardless of the level of the risk factor. It would therefore be aimed at reducing the absolute risk of vascular or cardiac disease, not the incremental relative risk of specific risk factors. The attractiveness of this strategy to reduce the population incidence of morbid events is counterbalanced by a number of confounding factors: 1. Most polypill designs include several drugs‐‐usually a statin, a renin‐angiotensin inhibitor, sometimes a diuretic and aspirin‐‐ representing classes of agents with demonstrated effectiveness in clinical trials. These drugs are usually included in the polypill in doses below those that have been effective in order to minimize side‐effects, so their efficacy in these doses has not been established. 2. Treatment of an entire population, whereas it might reduce the population event rate, may induce side‐effects in individuals who cannot benefit from the treatment because of a low absolute risk. 3. The absence of an indication for treatment and of a personal caregiver may lead to serious adverse events for which there would be inadequate oversight and no justification.
6 4. The strategy is based on the assumption that there is no satisfactory and practical method for screening that could better identify those in need of preventive therapy and no better way to focus specific pharmacologic interventions on specific individuals. Pilot studies of a polypill given to populations of men and women above some cut‐off age have been conducted (17, 18). They have documented the feasibility of such a strategy and have calculated the potential benefit to the population of an hypothesized reduction in morbid events. The enthusiasts for this approach appear to have minimized the population resistance to taking a medication in the absence of an established individual need. EARLY DISEASE DETECTION AND TREATMENT The focus over the last 50 years on risk factors to identify individuals in need of treatment to prevent cardiovascular morbid events reflects the role of the scholarly forces that have dominated the field. Morbid events became the end‐point of all preventive studies, and this required large populations to accumulate enough events for analysis. The Framingham Study and other large data bases became the laboratory for analysis, and the search began for markers that were predictive of such morbid events. The biologic process was largely disregarded, so identification of early disease and the monitoring of its progression were not a high priority, even though the ability to carry out such studies became available in the last 20 years. Cancer research followed a different path, not the search for risk factors associated with cancer mortality but the search for early, asymptomatic tumors that might advance to invasive cancer. By documenting the statistical relationship between the identified risk factor and the relative risk of morbid events, the investigators dedicated themselves to the task of demonstrating that treatment of the risk factors would reduce the frequency of the morbid events. Multiple controlled clinical trials were carried out to confirm that blood pressure reduction and cholesterol reduction were
7 associated with fewer morbid events than in the control arms. These large‐scale trials over the last 50 years have galvanized the medical and public health community to view risk factors as the cause of cardiovascular morbid events and to the mandate for lowering these risk factors as the goals of treatment. The biological processes leading to these morbid events have largely been disregarded in the effort to gain adherence to appropriate risk factor intervention. Nearly all cardiovascular morbid events occur in the setting of functional and structural abnormalities of the arterial vasculature or left ventricle that can be detected long before the symptomatic event occur. Most of these morbid events occur as a complication of two distinct but related processes, atherosclerosis and arteriosclerosis. Atherosclerosis is a disease characterized by lipid‐rich plaque formation in conduit arteries, but it has its origin in endothelial dysfunction that expresses itself as dysfunction and structural remodeling of the small arteries (19). Arteriosclerosis, on the other hand, involves thickening and stiffening of the large conduit arteries and associated hypertrophy and remodeling of the left ventricle. These processes are age‐ dependent and progress in concert, but the individual rate of progression of atherosclerosis may be quite different than that of arteriosclerosis and that of left ventricular remodeling. These functional and structural abnormalities of the arterial vasculature and the left ventricle provide an opportunity to identify disease long before morbid events occur and to track and slow the progression of disease in asymptomatic individuals. Since the ultimate goal of therapy is to prevent morbid events, not to reduce risk factors, the identification and monitoring of the underlying disease process should provide a more sensitive and specific guide to the risk for morbid events and a more individualized guide to the effectiveness of interventions to prevent such events. Thus, early disease detection should outperform the usual risk algorithms that depend predominantly on risk factors, and knowledge of the biological process affecting
8 an individual should provide the opportunity for specific therapy that can be individualized. Clinical trials to document effectiveness of this approach are urgently needed. A number of techniques have been utilized to assess early disease in order to improve the precision in identifying individuals at risk for morbid events. Radiographic identification of coronary calcium is the most widely utilized, and serves as a specific indicator of coronary atherosclerotic plaques. (7). A high calcium score confirms the presence of coronary disease that mandates intervention with drugs to slow its progression. The future hope is that the atherosclerotic process can be identified earlier, before the appearance of extensive calcification, when preventive therapy can likely be more effective, Other methods, such as carotid ultrasound for identifying increased carotid wall thickness or carotid artery plaque formation, provide an alternate vascular bed for assessing arteriosclerosis or atherosclerosis (20). Microalbuminuria occurs as a consequence of small vessel disease in the kidney (21). Attempts to quantitate endothelial dysfunction, as the first stage of atherosclerosis, have also been promoted by some investigators (22). Our approach is based on the concept that the vascular diseases, arteriosclerosis and atherosclerosis, and the cardiac diseases that lead to morbid events are expressed variably in individual patients. Early detection, therefore, requires a comprehensive evaluation of vascular and cardiac health using more than one methodology. This concept has led to a panel of 10 tests that we perform on all patients who seek knowledge and management of their individual risk (Table 1) (23). These non‐invasive tests are all performed in one room by one technician in one hour (Table 1). The testing results in a disease score in each patient based on the sum of the abnormalities (0‐20) detected in the 10‐test panel (24). These tests provide an assessment of health of the large conduit arteries, health of the small arteries, and health of the left ventricle, the primary target organs of cardiovascular morbid events. Preliminary observations using data collected over the first seven years of clinical experience with this program have confirmed two major hypotheses: (1) Assessment of early disease using this
9 comprehensive disease score outperforms the traditional risk factor algorithms in predicting future morbid events (25) (Figures 1 and 2), and (2) interventions known to reduce the occurrence of morbid events have a favorable effect on the disease score in placebo‐controlled studies (26, 27). THERAPEUTIC GOALS The goal of clinical trials has been to reduce morbid events over a truncated time interval designed to accumulate enough events to allow documentation of the effectiveness of therapy. A popular calculation in such trials has been the number needed to treat (NNT), the number of patients who must be treated with the experimental intervention to prevent one morbid event over the duration of follow‐up (28). This trial design depends for its success on enough morbid events to power the outcome analysis. It therefore requires randomizing patients who have a high likelihood of suffering morbid events during the designated follow‐up period. Patients with prior events and those with advanced disease are the ideal candidates for such event‐driven trials. In this design the individuals who do not suffer an event during the study period represent “noise” in the final outcome analysis, since they do not contribute to the end‐point. Such a design does not address the needs of asymptomatic patients who want to slow progression of early disease to delay or prevent future morbid events. A 40‐year‐old, for example, has a much longer horizon of interest than 5 or 10 years, the duration of most randomized, placebo‐controlled studies. The absence of a morbid event over that interval may be interpreted as success, but if disease is progressing and bringing the patient closer to a morbid event the treatment may actually have been a failure. Slowing of progression of disease can be assessed most effectively by monitoring the vascular and cardiac disease itself, not by waiting for morbid events. Indeed, the only reasonable long‐term goal for intervention to prevent cardiovascular disease is to delay events, not prevent them. If all events
10 could be delayed to the target age of 90 or 100, it is likely that other disease process morbidity would predominate over cardiovascular disease and that health insurance policies could ration care for the very elderly. This revised concept would change the agenda from preventing morbid events, an activity that is traditionally not well reimbursed by health insurance, to slowing disease progression, a measurable and reimbursable activity. This will require a focus on the underlying disease, not on risk factors. POPULATION VS. INDIVIDUAL MANAGEMENT Population‐based management strategies have dominated guidelines in recent decades. The concept of “matching the intensity of risk factor management to the estimated risk for CVD” (12, 29) is a populations‐based approach to treatment. Using thresholds for treatment, whether these thresholds are based on blood pressure, cholesterol levels or algorithm‐based scores, does not imply that those above the threshold will all benefit, and those below the threshold not, but that this approach will likely reduce the fraction of individuals who will be treated unnecessarily and increase the fraction of those who need treatment and will receive therapy. This population‐based approach fails those below the threshold who actually need treatment for advancing disease and exposes others who are above the threshold, but have no disease, to needless therapy. In the year 2015 it seems antiquated to use population statistics to drive clinical management when it is possible to individualize therapy based on the detection and sequential monitoring of the health of the arteries and heart, the source of all cardiovascular morbid events. The argument that the population approach has had a favorable impact on cardiovascular morbidity and mortality, and that early disease detection and treatment has not yet been subjected to rigorous controlled clinical trials, should serve as a cautionary note and a stimulus to research, but not as a vendetta against the modernization of medical care.
11 A STRATEGY FOR THE 21st CENTURY Medical care for cardiovascular morbid events currently consumes a large fraction of our health care expenditures, and these events are a major cause of disability and premature deaths in the developed world. Since the progression of the disease leading to this morbidity is largely preventable, the goal for the 21st century should be to halt its progression and delay morbid events until an age when full life expectancy has been achieved. Although this age defining premature morbidity and mortality is at best arbitrary, our Center has set an immediate goal of 90 years and a long‐term goal of 100 years. For this strategy to be successful we must have therapy that can slow progression. The administration of statin drugs and certain antihypertensive drugs has been demonstrated to reduce morbid events in numerous controlled trials (1‐6). The magnitude of that reduction in events has varied considerably, dependent on the effectiveness of the intervention and on the patient population exposed. For example, statin trials carried out in hyperlipidemic patients who had already suffered a morbid event resulted in a significant reduction in future events (5), but the magnitude of benefit was actually lower than in apparently healthy non‐hyperlipidemic individuals (30). The simplest explanation for that apparent paradox is that in individuals with advanced disease slowing of progression may merely delay morbid events, whereas in those with early disease intervention may prevent events (Figure 3). Evidence that drugs can slow the progression of functional and structural abnormalities of the arteries and heart provides further support for the potential of drug therapy introduced into individuals with advancing but asymptomatic disease. Slowing progression of early disease in individuals who present with that phenotype, as displayed in Figure 3, may not reveal a large benefit in event reductions over 10 years but may profoundly reduce the incidence of lifetime morbid events. A second prerequisite for this strategy is that criteria for selection of patients for preventive therapy be available to primary care providers. This requirement has fueled the use of standard risk factor assessment, which includes demographic data as well as blood pressure and cholesterol
12 measurements that are usually available on all adults in primary care practice. If early disease detection measures are to serve as a guide to intervention, then they must be made available to primary care providers. Is this additional diagnostic testing justified and practical? The approach we have used requires 10 non‐invasive and non‐radiographic tests of vascular and cardiac health. These can be accomplished in one hour in a single room by one technologist using equipment that can be purchased for less than $100,000. Nonetheless, there has been reluctance of the health care system to advocate that screening for all adults, and in the absence of such widespread screening this approach to early disease detection cannot be made available. We have therefore set out to develop a two‐tiered evaluation strategy that provides a preliminary, simple screen to exclude from further evaluation most of the patients who are unlikely to require therapeutic intervention (27). This strategy is based on our observations that a simple 4‐test screen, which can be accomplished in 10 minutes in a clinic setting, quite effectively discriminates between individuals unlikely to harbor early disease from those more likely to have early or advancing disease. Our preliminary data suggesting 90% sensitivity seem to provide adequate justification for screening out as many as 60% of the population from the need for more extensive evaluation at that point in time. A key part of this new strategy is an attempt to individualize management based on the abnormalities detected in the evaluation. Cardiovascular disease presents differently from individual to individual, either because of different vascular beds involved or different manifestations of the disease. This variability must relate to individual differences in the progression of functional and structural disease. Our preliminary observations suggest that four distinct phenotypes of cardiovascular abnormalities can be detected and are likely to respond to different therapeutic regimens. These phenotypes can be characterized as: (1) Small artery disease, a manifestation of endothelial dysfunction and characterized by stiff small arteries, retinal vascular changes and microalbuminuria; (2) large artery disease, a manifestation of arteriosclerosis and characterized by systolic hypertension at rest or during
13 exercise, stiff large arteries and thickened carotid arteries; (3) atherosclerosis, manifested by small artery disease and carotid or aortic plaque formation; and (4) left ventricular disease, with increased LV mass, elevated NT Pro‐BNP and ECG abnormalities. These phenotypes are of course overlapping but they can provide insights that can lead to different therapeutic recommendations. Clinical trials are needed to determine if this individualized therapy is better at modifying outcomes compared to the present strategy of a more non‐selective approach to treatment. We are in the process of establishing a program of clinic screening and center assessment of high risk patients to determine if such a program can be effective in evaluating and managing a community population. If so, this approach has the potential of providing the long‐sought individualized approach to cardiovascular disease management based on 21st century testing that could replace the population‐based risk factor approach that characterized the 20th century. Legends Figure 1 Predictive value of the Disease Score (DS) calculated from 10 tests of vascular and cardiac health. One year, three years and six years after initial assessment, the occurrence of cardiovascular morbid events was directly related to the DS, which was grouped into nearly equal terciles of scores of 0‐2, 3‐5, and 6+. Note that individuals with DS 0‐2, the non‐disease phenotype, sustained no morbid events during 6 years follow‐up. (With permission from Duprez et al. (Reference 25). Figure 2 Blood pressure (BP) and LDL cholesterol levels (LDL) do not discriminate risk for morbid events. BP (I=84 mmHg); LDL(I=129 mg/dL). Note that although the percentage of patients with morbid events in the normal blood pressure group was lower, the absolute number of events in this group was higher because of its higher frequency in the population. Figure 3
14 The natural history of cardiovascular disease. Those without the phenotype of early disease may live 100 years without a morbid event. Those with the phenotype may alter their risk by therapeutic intervention. If treatment is started after a morbid event (A) life may be prolonged modestly. If treatment is initiated in advanced disease (B) morbid events may be delayed. If treatment is initiated in early disease morbid events may be prevented until age 100. Table 1 10 tests performed in the Rasmussen Center 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Resting sitting blood pressure Small artery elasticity (pulsewave analysis) Large artery elasticity (pulse wave analysis) Exercise (3 minutes, 5 METS) BP response Carotid intima‐medial thickness + plaques Retinal digital photograph Urine sample for albumin/creatinine ratio Electrocardiogram Left ventricular ultrasound for thickness, mass Blood sample for NT‐ProBNP
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17 16. Lonn E, Bosch J, Teo KK, Pais P, Xavier D, Yusuf S. The polypill in the prevention of cardiovascular diseases: Key concepts, current status, challenges and future directions. Circulation 2010;122:2078‐ 88. 17. The Indian Polycap Study (TIPS)* Effects of a polypill (Polycap) on risk factors in middle‐aged individuals without cardiovascular disease (TIPS): a phase II, double‐blind, randomized trial. Lancet 2009;373:1341‐51. 18. Castellano JM, Sanz G, Ortiz AF, Garrido E, Bansilal S, Fuster V. A polypill strategy to improve global secondary cardiovascular prevention: From concept to reality. J Am Coll Cardiol 2014;64:613‐21. 19. Gilani M, Kaiser DR, Bratteli CW, Alinder C, Rajala S, Bank AJ, et al. Role of nitric oxide deficiency and its detection as a risk factor in pre‐hypertension. J Amer Soc Hypertens 2007;1(1):45‐55. 20. Den Ruijter HM, Peters SAE, Anderson TJ, Britton AR, Dekker JM, Eijkemans MJ, et al. Common carotid intimamedia thickness measurements in cardiovascular risk prediction: a meta‐analysis. JAMA. 2012;308:796–803. 21. Weir MR. Microalbuminuria and cardiovascular disease. Clin J Am Soc Nephrol 2007;2:581‐90. 22. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al. Non‐invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111‐15. 23. Cohn JN, Hoke L, Whitwam W, Sommers PA, Taylor AL, Duprez D, et al. Screening for early detection of cardiovascular disease in asymptomatic individuals. Am Heart J 2003;146:679‐85. 24. Duprez DA, Cohn JN. Identifying early cardiovascular disease to target candidates for treatment. J Clin Hypertension 2008;10(3):226‐31. 25. Duprez DA, Florea N, Zhong W, Grandits GA, Hawthorne CK, Hoke L, et al. Vascular and cardiac functional and structural screening to identify risk of future morbid events: preliminary observations. J Amer Soc Hypertens 2011;5:401‐9.
18 26. Duprez DA, Florea ND, Jones K, Cohn JN. Beneficial effects of valsartan in asymptomatic individuals with vascular or cardiac abnormalities: The DETECTIV Pilot Study. J Am Coll Cardiol 2007;50:835‐9. 27. Saul SM, Duprez DA, Zhong W, Grandits GA, Cohn JN. Effect of carvedilol, lisinopril and their combination on vascular and cardiac health in patients with borderline blood pressure: The DETECT study. J Human Hypertension 2013;27:362‐7. 28. Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med 1988;318:1728‐33. 29. 27TH Bethesda Conference. Matching the intensity of risk factor management with the hazard for coronary disease events. September 14‐15, 1995. J Am Coll Cardiol 1996;27:957‐1047. 30. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto Jr AM, Kastelein JJP, et al for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C‐reactive protein. N Engl J Med 2008;359:2195‐207. Fig 1
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