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Screening for Cardiovascular Disease
The widely used Framingham Risk Score is no more accurate in predicting the odds of a cardiovascular event than age alone, according to a 2011 PLoS ONE article. The Framingham Risk Score is based on age, gender, cholesterol, smoking status, systolic blood pressure, and whether a person is taking blood pressure medication. The score indicates the odds of having a cardiovascular event within the next 10 years. Treatment is recommended when the calculated risk is 20% or more. The risk score's role in preventing cardiovascular morbidity and mortality has never "been tested in a rigorous way," says Michael S. Lauer, MD, at the National Heart, Lung, and Blood Institute (Bethesda, Maryland).
Nicholas J. Wald, Mark Simmonds, and Joan K. Morris used statistical modeling, based on observed data, to compare age screening and the Framingham Risk Score. The three British researchers identified age 55 as the point at which people have a 20% risk of a cardiovascular event within the next 10 years. Age screening would catch 86% of cardiovascular events with a 24% false-positive rate, according to their analysis. The Framingham Risk Score, with its 20% risk cut-off, also gives an 86% detection rate but with a false positive of 21%. Age screening, the researchers argue, would save time and health care dollars. Repeated blood tests to assess cholesterol levels and multiple doctor visits to discuss risk assessment would no longer be necessary.
"One implication of the new study is that everybody might begin treatment at 55," Richard Smith, director of UnitedHealth Chronic Disease Initiative, wrote in his commentary on the PLoS ONE study. "This fits with the strategy proposed by Wald and Law in 2000 and in 2003 in the BMJ to take a polypill containing blood pressure lowering drugs, a statin, and possibly aspirin and folic acid." Research studies show that polypills can reduce blood pressure and serum cholesterol, but it will take years to assess their ability to reduce cardiovascular events and mortality rates. Long-term tests that track the medication's effect on actual disease and mortality and its adverse effects have not yet been performed.
Instead of using risk factors to screen for cardiovascular disease, some are advocating the routine use of imaging technology, says Laurer. Laurer, however, is concerned that imaging screening will lead to overdiagnosis. He says, "Many, often most, people with abnormal screening test findings will nonetheless remain free of clinical disease; for example, among adults with high coronary calcium scores in the MESA (Multi-Ethnic Study of Atherosclerosis), 95% remained asymptomatic over the next 5 years." A positive screen often propels worried practitioners and patients to commence a series of "potentially risky" tests and treatments. He calls for "definitive large-scale randomized trials" to determine the most accurate means of assessing cardiovascular disease risk.
Lauer MS. Screening asymptomatic subjects for subclinical atherosclerosis. J Am Coll Cardiol. 2010;56(2). Available at http://content.onlinejacc.org/article.aspx?articleid=1142958&issueno=2. Accessed February 20, 2013.
(Editor note: Access via http://content.onlinejacc.org/article.aspx?articleid=1142971)
Smith R. Screening for cardiovascular disease using age alone: reflections on a paper peer-reviewed as both 'radical' and 'unsurprising.' J Med Screen. 2011;18:113–114. Available at http://188.8.131.52/content/18/3/113.full.pdf&html. Accessed February 20, 2013.
(Editor note: Access via http://msc.sagepub.com/content/18/3/113.full.pdf+html)
Wald NJ, Simmonds M, Morris JK. Screening for future cardiovascular disease using age alone compared with multiple risk factors and age. PLoS ONE. May 2011;6(5): e18742. Available at www.plosone.org/article/info:doi/10.1371/journal.pone.0018742. Accessed February 20, 2013.
C-Reactive Protein and Cardiovascular Disease
When the FDA approved the statin Crestor in 2010, for use in men over 50 and women over 60 with normal cholesterol levels but high C-reactive protein (>2.0 mg/dL) and one additional cardiovascular risk factor, the agency was acknowledging inflammation's role in cardiovascular disease. C-reactive protein (CRP) appears in serum when inflammation or necrosis is present and "disappears when an inflammatory process is suppressed by salicylates, steroids, or both" (Mosby's). Although C-reactive protein is an accurate biomarker for inflammation, two recent studies cast doubt on its usefulness in predicting cardiovascular disease.
As part of the Dallas Heart Study, Nitin K. Gupta and colleagues decided to investigate the relationship of CRP, cardiovascular disease, and body mass index (BMI). The body produces CRP in response to interleukin (IL)-6, a cytokine produced by leukocytes and smooth muscle cells in atherosclerotic plaques; but atherosclerotic plaque is not the only source of IL-6. Adipose tissue (body fat) also produces IL-6. The researchers point out that most studies showing a correlation between CRP and cardiovascular disease have involved subjects "who are less obese than the current U.S. population, where now more than two-thirds of adults are overweight or obese."
The Dallas Heart Study involves a multiethnic, population-based probability sample of 6101 Dallas County adults, aged 30 to 65 years, who completed a detailed in-home survey. For this investigation of CRP and BMI, Gupta and colleagues used data from 2899 of the subjects who had also provided blood and urine samples and undergone various imaging procedures. The researchers looked for associations between CRP levels, coronary artery calcium (n = 2685), aortic wall thickness (n = 2238), and aortic plaque burden (n = 2224) according to BMI categories (normal, 18.5 to <25 kg/m2; overweight, 25 to <30 kg/m2; obese, ≥30 kg/m2). In this study, 38% of men and 53% of women were obese.
As BMI increased, the correlation between C-reactive protein levels and cardiovascular imaging evaluations decreased. "Increasing CRP levels (<1 mg/l, 1 to 3 mg/l, >3 mg/l) were associated with increased [coronary artery calcium] prevalence in normal and overweight men and in normal weight women (p < 0.01), but not in obese subjects of either sex," say the authors. "Likewise, the correlations between CRP and [aortic wall thickness] and [aortic plaque burden] diminished with increasing BMI and were nonsignificant in obese individuals (p < 0.05 in nonobese, p > 0.1 in obese."
A 2013 study, led by J. S. Ho, investigates the ability of C-reactive protein and coronary artery calcium (CAC) to predict the presence of obstructive coronary artery stenoses. This Texas study involved 1079 people whose traditional cardiovascular risk screening put them at low risk for cardiovascular disease. Coronary computed tomographic angiography found 38 severely obstructive stenoses in the population (3.5%), which were confirmed with invasive coronary angiography. Angina (p < 0.001), an elevated coronary arterial calcium score (p < 0.001), and the use of antihypertensive agents (p = 0.03) were the best predictors of severely obstructed blood flow in coronary arteries. The researchers saw a direct correlation between a rise in coronary artery calcium scores and the frequency of obstructive stenosis. Not all people with high scores had stenosis, but stenosis was uncommon when coronary arterial calcium was not detected. The researchers saw no significant correlation between CRP and stenosis.
The idea of using high-sensitivity C-reactive protein measures to predict cardiovascular disease appears to need rethinking.
C-reactive protein (CRP). Mosby's Medical Dictionary. 6th ed. St. Louis: Mosby Inc.; 2002: 446.
Gupta NK, de Lemos JA, Ayers CR, Abdullah SM, McGuire DK, Khera A. The relationship between C-reactive protein and atherosclerosis differs on the basis of body mass index. J Am Coll Cardiol. 2012;60(13). Available at http://content.onlinejacc.org. Accessed February 22, 2013.
Ho JS, Cannaday JJ, Barlow CE, Reinhardt DB, Wade WA, Ellis JR. Utility of high-sensitivity C-reactive protein versus coronary artery calcium for the detection of obstructive stenoses in stable patients (abstract). Am J Cardiol February 1, 2013: 111(3):328–332. Accessed February 22, 2013.
Klotter J. The rosuvastatin-JUPITER controversy. Townsend Lett. May 2012;346:23–24.
The Challenges of Determining Hypertension
"The current approach to define normal [blood pressure] as less than 120/80 is presumably based on detectable increases in risk above that level," say Brent C. Taylor, PhD; MPH, Timothy J. Wilt, MD, MPH; and H. Gilbert Welch, MD, MPH," … [but] the threshold to label individuals as 'abnormal' ought to require more than simply any detectable effect, in any outcome, in any size sample." Treatment for above-normal blood pressure typically involves medications. A lower cut-off for normal means that more people are treated, potentially leading to more adverse drug effects and higher medical costs. More treatment does not necessarily reduce mortality. In their 2011 research article for the Journal of General Internal Medicine, Taylor, Wilt, and Welch argue, " … the definition of normal blood pressure must be made with careful attention to the trade-off between the desire to identify those at substantially higher risk than average and the need to avoid overdiagnosis and overtreatment." This leads back to the question, what is normal?
In an effort to determine normal blood pressure linked to mortality outcomes, Taylor, Wilt, and Welch decided to investigate the independent effects of diastolic and systolic blood pressure on mortality by using data collected during the first National Health and Nutrition Examination Survey (NHANES I) in the early 1970s. The NHANES I subjects were followed for two decades. Taylor and colleagues chose to use the oldest data that they could find in order to avoid the confounding effect of hypertension treatment as much as possible.
Taylor and colleagues obtained data for 6839 adults whose blood pressure (BP) was taken by a physician at the beginning of a physical exam and twice by nurses at the exam's end. An individual's three BP readings tended to be about the same: systolic blood pressure readings taken at exam's end were an average of 1.5 mm Hg lower than the initial reading, and diastolic pressure readings were an average of 1 mm Hg higher. Taylor and colleagues distributed patients' systolic reading into seven categories: <100 mm Hg, 100–119 mm Hg, 120–139 mm Hg, 140–159 mm Hg, 160–179 mm Hg, 180–199 mm Hg, ≥200. They distributed diastolic blood pressure reading into eight categories: <60 mm Hg, 60–69 mm Hg, 70–79 mm Hg, 80–89 mm Hg, 90–99 mm Hg, 100–109 mm Hg, 110–119 mm Hg, ≥120. After adjusting for several confounders (age, smoking weight and height, BMI, total cholesterol, education, income, race), Taylor and colleagues compared the all-cause mortality rate for each blood pressure category with the "so-called 'normal' blood pressure: less than 120/80."
The results showed an age-based difference in the correlation between blood pressure levels and overall mortality risk. In people over age 50, significant increases in mortality were associated with a systolic pressure above 140. Diastolic pressure had no significant effect on mortality rates in people over 50. For people 50 years or younger, diastolic pressure ≥100 mmHg or systolic blood pressure ≥200 mmHg was "associated with significant increases in mortality." Systolic blood pressure between 140 and 200, in the younger group, made "no significant difference in the relative rate of death" when diastolic pressure under 100.
While the authors are not saying that their findings should lead to a change in the definition of normal blood pressure and hypertension, they do suggest that the current normal may be leading to unnecessary treatment expenses and adverse drug effects in millions of people. "We … recognize that our approach for defining normal adds an additional complexity to the current approach because it is modified by age … " they write. "But even a small simple expansion in the definition of normal – from under 120/80 to under 140/90 – would have a tremendous impact: affecting about 80 million Americans." "Normal" is the bull's-eye that practitioners aim for in treatment. "When abnormal is defined to include values in which the risk itself is ambiguous, the ability of treatment to change that risk becomes even less certain," the authors state. They hope that their findings will be taken into consideration as Joint National Committee works on its eighth report on high blood pressure, now in progress.
The definition of normal is one factor in identifying hypertension, but actual measurement is another. Benjamin J. Powers, MD, and colleagues report, "There is no consensus among clinical guidelines and quality-reporting standards on the setting, timing, and total number of BP measurements that should be used for classifying patients and making treatment decisions." The JNC presently recommends at least two clinical blood pressure readings on separate days in order to make a diagnosis; but that does not take into account the "white coat syndrome," in which a patient's blood pressure increases during office visits, nor does it suggest how best to monitor treatment outcomes. The American Society of Hypertension and the European Society of Hypertension advocate the use of home BP monitoring for people with known or suspected hypertension. These societies recommend using a minimum of 12 home readings for clinical decisions.
A 2011 study, led by Powers, investigated the question, where and how many measures? The researchers followed 444 veterans with hypertension for 18 months using clinical, research, and home measurements. The clinical measurements were taken by nurses using Alaris automated devices during routine visits. Researchers used BpTRU digital BP monitors to take two measurements, 5 minutes apart, at baseline and 6, 12, and 18 months. Patients themselves took at least three measurements per week using A&D digital home BP monitors. Patients were shown how to use the monitor and then how to transmit the time-stamped measurement via a telemedicine device and toll-free telephone number to a secure server.
Mean blood pressure measurements taken at the three locations varied greatly, affecting diagnosis and clinical decision-making: "The proportion of patients who had control of his or her SBP in the first 30 days (<140 mm Hg for clinic or research measurement; <135 mm Hg for home measurement) differed between method of measurement: 28% were in control according to clinic measurement, 47% were in control according to home measurement, and 68% were in control according to research measurement." Overall, mean home systolic blood pressure (SBP) was 9.6 mm Hg less than mean clinical measurement.
Because of natural individual variations in blood pressure as well as the difference between clinic and home measurements, the authors recommend reimbursement for home BP monitors so that multiple measures can be taken and recorded. An average of at least five or six measurements, taken on different days, is needed to give a more accurate view of a patient's need for hypertension treatment. "Patients could not be classified as having BP that was in or out of control with 80% certainty on the basis of a single clinic SBP measurement from 120 mm Hg to 157 mm Hg," the authors state. (Multiple measurements taken within minutes did not vary significantly.) The researchers recognize that averaging multiple measurements is problematic for busy practitioners; "If providers are supposed to rely more on average measurements, new ways of capturing and presenting these data at the point of care are needed."
Powers BJ, Olsen MK, Smith VA, Woolson RF, Bosworth HB, Oddone EZ. Measuring blood pressure for decision making and quality reporting: where and how many measures? Ann Intern Med. 2011;154:781–788. Available at http://annals.org. Accessed February 22, 2013.
Taylor BC, Wilt TJ, Welch HG. Impact of diastolic and systolic blood pressure on mortality: implications for the definition of "normal." J Gen Intern Med. 2011;26(7):685–690. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3138604/pdf/11606_2011_Article_1660.pdf. Accessed February 22, 2013.
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