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Value Based Personalized CVD Care - Multimodality Strategy for Cardiovascular Risk Assessment: Performance in Two Population-Based Cohorts -
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".....an individualized, risk-based approach utilizing traditional risk factors plus biomarkers may be appropriate......[This] multimodality strategy could also facilitate targeting of global and disease-specific CVD prevention efforts as population health care becomes an increasing focus of health care delivery."
from Jules: the Framingham & ACC heart disease algorithm equations are used very widely to evaluate risk for heart disease and when to intervene with therapy (statins), yet there are a lot of debates about their overall utility and in recommending statin therapy, and in HIV there are further questions about these equations & their effectiveness in evaluating risk for heart disease and when to use statin therapy, as HIV+ do not fit the algorithms very well. Yet as I say there are debates & doubts about these equations in the general public. Understandably everyone wants a simple equation, because the healthcare system is under such economic stress, and of much note in HIV our healthcare system is under more economic stress than outside HIV which dimities the quality of care patients receive. Today - its 10-15 in and out with the HIV doctor - this is no way to address what has become a much more complicated disease - its no longer writing a prescription for a HAART regimen - now 80% of HIV= are over 40-45, 50% over 50 & 20% over 60. Most of these patients have comorbidities including heart disease, diabetes, bone disease and as they age over 60 many patients will have 3-6 comorbidities and 12 comedications to take. HIV clinicians and the HIV healthcare system is UNPREPARED to take care of these patients properly for many reasons - including - that the doctors & clinicians are not trained to evaluate & treat cardiovascular disease or bone disease, for example, yet some of them try to do it, and do it wrong; or, they can refer a patient who may or may not be able to navigate a very difficult healthcare system with economic limitations, and do the HIV doctor and the referred to experts adequately communicate? all too often NO. Of course I am probably wasting my time, because the HIV healthcare system & the RWCA is supported & implemented by many from different points if view including staff in cities at DOHs who are remote from the real world of care & patient's reality and this healthcare system is based more on trying to balance care & economics but economics appears to be the main scale influencer, not the patients, and this will worsen as care necessities intensify with the aging population and with big hospitals & care systems & RWCA systems under increasingly greater economic pressure, who loses, as usual the little guy, in this case the patient. All too often the patient is left out on the limb trying to navigate & understand their healthcare & a system, for which the patient is not prepared.
"Conclusions
A novel multi-modality CVD risk assessment strategy using the non-redundant markers of ECG LVH, CAC, NT-proBNP, hs-cTnT, and hs-CRP substantially improved global and atherosclerotic CVD risk stratification among individuals from the general population free from CVD at study entry. Additional study of preventive strategies incorporating these complementary tests is indicated."
"Current consensus recommendations support only selective additional testing beyond traditional
cardiovascular risk factors.1, 22......However, combinations of tests were not assessed in these guidelines,
and the gradients of risk seen with the individual tests considered in these documents were not aslarge in magnitude as those seen with the multimodality risk score in the current study. Our robust
findings support the potential value of a multimodality testing strategy using these markers in
selected individuals in whom additional risk stratification is desired........These findings provide strong evidence that a simple strategy
including the most promising biomarkers from several different testing modalities substantially
improves CVD risk prediction among individuals without known CVD.......The multimodality testing strategy may help to individualize and more efficiently target cardiovascular prevention efforts in primary care.....Importantly, the multimodality strategy provided robust discrimination and reclassification for ASCVD as well as global CVD events. Thus, this strategy may contribute to more accurate identification of appropriate candidates for ASCVD preventive therapies, while at the same time capturing risk for broader CVD events......Importantly, global CVD risk assessment should be considered as a complement and not a replacement for cause-specific risk estimation (i,e for ASCVD)."
Strategies for cardiovascular disease (CVD) risk assessment among adults without known CVD remain largely based on traditional atherosclerosis risk factors.1 However, these risk prediction equations provide only moderate discrimination of atherosclerotic cardiovascular disease (ASCVD) risk. .....We hypothesized that a panel combining non-redundant CVD biomarkers across multiple different testing modalities would overcome these limitations and improve CVD risk prediction. The tests prospectively selected included 12-lead electrocardiography (ECG) for assessment of left ventricular hypertrophy (ECG-LVH),30-32 coronary artery calcium (CAC) measurement by computed tomography (CT),11-13 and measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP)14-16 high sensitivity cardiac troponin T (hs-cTnT)17-20 and high sensitivity C-reactive protein (hs-CRP).9, 10 These tests were selected because they reflect distinct and relevant pathological processes, multiple reports from population-based studies demonstrate independent associations of these measurements with CVD outcomes, and sufficient data exist from which to generate a priori thresholds to define abnormal test results.......In MESA, each of the 5 tests was associated with the primary global CVD outcome after adjustment for traditional risk factors and the other test results, with results consistent whether the tests were considered as continuous variables or using the prospective dichotomous cutpoints (Table 2)......Associations of the test results with the secondary composite ASCVD outcomes are shown in Table 3. In MESA, each of the test results except hs-CRP was independently associated with ASCVD......CAC was most strongly associated with coronary heart disease events, followed by NT-proBNP and hs-cTnT, with no association seen for ECG-LVH or hs- CRP (Supplementary Table 3). All 5 test results were independently associated with incident heart failure, with largest hazards seen for NT-proBNP, ECG-LVH, and hs-cTnT. NT-proBNP....demonstrated the largest hazard ratio for fatal outcomes, followed by hs-cTnT. ECG-LVH associated with CVD mortality, but not all-cause mortality......As expected, higher scores were associated with a greater burden of traditional risk factors (Supplementary Tables 9 and 10). However, in multivariable analyses accounting for traditional risk factors, compared with those with a score of 0 in MESA, CVD risk increased among participants with a score of 1 (HR 1.9, 95% CI 1.4-2.6), 2 (HR 3.2, 95% CI 2.3-4.4), 3 (HR 4.7, 95% CI 3.4, 6.5) and > 4 (HR 7.5, 95% CI 5.2-10.6) (Figure 3). Similar graded associations across higher scores were seen for the secondary ASCVD endpoint and with tertiary endpoints, with findings most robust for incident heart failure (Figure 3).
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Multimodality Strategy for Cardiovascular Risk Assessment: Performance in Two Population-Based Cohorts
Circulation March 2017 - James A. de Lemos, MD1; Colby R. Ayers, MS2; Benjamin Levine, MD1,3; Christopher R. deFilippi, MD4; Thomas J. Wang, MD5; W. Gregory Hundley, MD6; Jarett D. Berry, MD, MS1,2; Stephen L. Seliger, MD7; Darren K. McGuire, MD, MHSc1,2; Pamela Ouyang, MBBS8; Mark H. Drazner, MD, MSc1; Matthew Budoff, MD9; Philip Greenland, MD10; Christie M. Ballantyne, MD11; Amit Khera, MD, MSc1
1Department of Medicine; 2Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX; 3Institute for Exercise and Environmental Medicine, Texas Health 4Inova Heart and Vascular Institute, Fall Church VA; 5Department of Medicine, Vanderbilt University Medical Center, Nashville TN; 6Departments of Medicine and Radiological 7Department of Medicine, University of Maryland School of Medicine, Baltimore, MD; 8Johns Hopkins University School of 9Los Angeles Biomedical Research Institute, Los Angeles, CA; 10Departments of Preventive Medicine and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL; 11Baylor College of Medicine, Houston TX
Introduction
Strategies for cardiovascular disease (CVD) risk assessment among adults without known CVD remain largely based on traditional atherosclerosis risk factors.1 However, these risk prediction equations provide only moderate discrimination of atherosclerotic cardiovascular disease (ASCVD) risk.1-3 Moreover, these algorithms typically do not consider risk for additional cardiovascular events, such as heart failure and atrial fibrillation, which are increasingly important contributors to the overall burden of CVD in the population.4, 5 A growing body of evidence suggests that preventive interventions such as weight loss, exercise, and more aggressive blood pressure control may favorably impact not only ASCVD, but also these other highly relevant CVD outcomes.6-8 Prior studies have evaluated individual novel risk markers in an attempt to improve CVD risk prediction, 9-20 However, for individual biomarkers, even those independently associated with outcomes, the incremental improvement in discrimination and risk classification is typically modest.21, 22 As a result, investigators have explored combinations of biomarkers as a potential strategy to augment CVD risk prediction, with mixed results.23-28 Importantly, these prior studies have mostly combined biomarkers within the same testing modality, such as panels of genetic variants or circulating protein biomarkers, have frequently studied biomarkers with limited specificity for cardiovascular disease, and have included combinations of highly correlated biomarkers.29 To our knowledge, no large studies have combined the most promising individual biomarkers across multiple different testing modalities in an attempt to create a risk prediction tool that augments traditional risk factor strategies.
We hypothesized that a panel combining non-redundant CVD biomarkers across multiple different testing modalities would overcome these limitations and improve CVD risk prediction. The tests prospectively selected included 12-lead electrocardiography (ECG) for assessment of left ventricular hypertrophy (ECG-LVH),30-32 coronary artery calcium (CAC) measurement by computed tomography (CT),11-13 and measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP)14-16 high sensitivity cardiac troponin T (hs-cTnT)17-20 and high sensitivity C-reactive protein (hs-CRP).9, 10 These tests were selected because they reflect distinct and relevant pathological processes, multiple reports from population-based studies demonstrate independent associations of these measurements with CVD outcomes, and sufficient data exist from which to generate a priori thresholds to define abnormal test results.
Abstract
Background-Current strategies for cardiovascular disease (CVD) risk assessment among adults without known CVD are limited by suboptimal performance and a narrow focus on only atherosclerotic CVD (ASCVD). We hypothesized that a strategy combining promising biomarkers across multiple different testing modalities would improve global and atherosclerotic CVD risk assessment among individuals without known CVD.
Methods-We included participants from the Multi-Ethnic Study of Atherosclerosis (MESA, n=6621) and Dallas Heart Study (DHS, n=2202) who were free from CVD and underwent measurement of left ventricular hypertrophy by electrocardiogram (ECG-LVH), coronary artery calcium (CAC), N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT) and high-sensitivity C-reactive protein (hs-CRP). Associations of test results with the global composite CVD outcome (CVD death, myocardial infarction [MI], stroke, coronary or peripheral revascularization, incident heart failure or atrial fibrillation) and ASCVD (fatal or nonfatal MI or stroke) were assessed over > 10 years of follow-up. Multivariable analyses for the primary global CVD endpoint adjusted for traditional risk factors plus statin use and creatinine (base model).
Results-Each test result was independently associated with global composite CVD events in MESA after adjustment for the components of the base model and the other test results (p< 0.05 for each). When the five tests were added to the base model, the c-statistic improved from 0.74 to 0.79 (p=0.001), significant integrated discrimination improvement (0.07, 95% CI 0.06-0.08, p<0.001) and net reclassification improvement (0.47, 95% CI 0.38-0.56, p=0.003) were observed, and the model was well calibrated (χ2=12.2, p=0.20). Using a simple integer score counting the number of abnormal tests, compared with those with a score of 0, global CVD risk was increased among participants with a score of 1 (adjusted HR 1.9, 95% CI 1.4-2.6), 2 (HR 3.2, 95% CI 2.3-4.4), 3 (HR 4.7, 95% CI 3.4, 6.5) and ≥4 (HR 7.5, 95% CI 5.2-10.6). Findings replicated in DHS and were similar for the ASCVD outcome.
Conclusions-Among adults without known CVD, a novel multimodality testing strategy using ECG-LVH, CAC, NT-proBNP, hs-cTnT and hs-CRP significantly improved global CVD and ASCVD risk assessment.
What is new?
⋅ We evaluated a novel strategy for assessment of CVD risk among adults without known CVD
that combined promising biomarkers across multiple different testing modalities, including
12-lead electrocardiography for assessment of left ventricular hypertrophy, coronary artery
calcium, N-terminal pro-brain natriuretic peptide, high sensitivity cardiac troponin T and high
sensitivity C-reactive protein.
⋅ Each test result provided incremental information with regard to global CVD risk in the
Multi-Ethnic Study of Atherosclerosis (MESA), and a score containing the 5 results provided
robust stratification of global and atherosclerotic CVD risk, with findings replicated in the
Dallas Heart Study.
What are the clinical implications?
⋅ Our findings support the potential value of a multimodality testing strategy in selected
individuals in whom additional risk stratification is desired beyond measurement of traditiona
atherosclerosis risk factors.
⋅ Additional studies are needed to validate the present findings, determine the optimal approach
to implementation, and address direct and indirect cost implications of the additional testing.
DISCUSSION
In the present study, we combined 5 promising tests for cardiovascular risk stratification among adults without known CVD: the 12-lead ECG to assess LVH, CAC scanning, and measurement of NT-proBNP, hs-cTnT, and hs-CRP. Although this combination of tests captures multiple well defined cardiac pathological processes, including cardiac hypertrophy, coronary atherosclerosis, neurohormonal activation, cardiomyoctye injury and inflammation, to our knowledge they have not been considered together previously. Each test provided non-redundant incremental information to traditional risk factors, and when the test results were combined in a simple integer score, a > 20-fold gradient in risk for the primary global CVD outcome was seen across the range of scores after > 10 years of follow-up. The findings were consistent among women, ethnic minorities, younger individuals, and those at low predicted risk for ASCVD. Results were robust to multivariable adjustment, and across different CVD endpoints, and performed similarly in two distinct cohorts with different age ranges and race/ethnic distributions. Discrimination and risk classification were improved for both global and ASCVD outcomes, and models incorporating the screening test results were generally well calibrated. These findings provide strong evidence that a simple strategy including the most promising biomarkers from several different testing modalities substantially improves CVD risk prediction among individuals without known CVD.
CVD risk stratification has traditionally been focused on predicting only CHD events. More recently, in concert with changes in prevention guidelines,1, 50 the focus of CVD risk prediction has expanded to include stroke. It is notable that while rates of MI and stroke have been steadily declining,51 the prevalence of HF is projected to increase by 25% over the next 20 years.4 Among middle-aged adults, the 10-year risk of incident heart failure is approximately 10%,52 with lifetime risks of 30-40%.53 Tools to predict incident HF may allow targeted therapies to prevent its development, which could have important public health implications given its associated morbidity and mortality. To date only a single global CVD risk model has been developed that considers ASCVD and HF together,54 and differs from our approach as it only contained traditional CHD risk factors as covariates and did not include AF as part of the global CVD outcome.54 Like HF, AF is rapidly increasing in prevalence, is difficult to treat once present, and carries substantial costs and morbidity.5, 55 A focus on global CVD risk prediction, incorporating endpoints of HF and AF as was done in the present study, is likely to become increasingly important. Importantly, global CVD risk assessment should be considered as a complement and not a replacement for cause-specific risk estimation (i,e for ASCVD).
Although the individual biomarkers were each associated with the primary composite global CVD endpoint, they differed in their relative associations with secondary and tertiary CVD endpoints, as would be expected based on the pathological processes captured by each biomarker.11, 15, 18, 31, 39 For example, CAC demonstrated the largest hazard ratio for ASCVD and CHD events, while NTproBNP and hs-cTnT were associated with the highest hazards for all-cause and CVD mortality and heart failure. Importantly, although NT-proBNP and hs-cTnT were included to enhance global CVD risk prediction, they also provided independent prognostic value for ASCVD and CHD in MESA. While hs-CRP provided modest incremental information for the global CVD endpoint and HF endpoints, this biomarker generally demonstrated the weakest and least consistent associations across the portfolio of endpoints. Importantly, the multimodality strategy provided robust discrimination and reclassification for ASCVD as well as global CVD events. Thus, this strategy may contribute to more accurate identification of appropriate candidates for ASCVD preventive therapies, while at the same time capturing risk for broader CVD events.
Several limitations of the present study merit consideration. First, this study was not designed to determine the optimal number or combination of the screening tests for risk stratification purposes. The number of potential combinations of the 5 tests is 120, and each potential combination could be considered for multiple endpoints. Second, the number of endpoints in the DHS was too low to perform multivariable adjustment for the tertiary endpoints. However, the adjusted results for the primary and secondary outcomes demonstrated consistent results compared with MESA, as did unadjusted analyses for the tertiary endpoints. Finally, we acknowledge that comparing strength of association between the different tests presents challenges, and can be influenced by the incidence of the different endpoints and the distributions of the test results in the study cohorts.
The goal of our study was to evaluate prospectively a multimodality risk prediction strategy, and replicate the findings in a second population-based dataset. We did not design our primary analyses to validate the MESA multivariable models in DHS, but rather to determine if the scientific approach replicated in a second data set. We did perform sensitivity analyses in which the MESA models were applied directly to the DHS, and while overall performance of the models was modestly impacted (as would be expected), the improvement in model performance with addition of the 5 tests was generally similar to the primary analysis approach in which the coefficients were derived in the DHS. The models from MESA were also less well calibrated when applied to DHS, particularly for the ASCVD endpoint, although calibration remained adequate. Additional prospective validation is required before the multivariable models can be considered for clinical application.
Clinical Implications
Current consensus recommendations support only selective additional testing beyond traditional cardiovascular risk factors.1, 22 However, combinations of tests were not assessed in these guidelines, and the gradients of risk seen with the individual tests considered in these documents were not as large in magnitude as those seen with the multimodality risk score in the current study. Our robust findings support the potential value of a multimodality testing strategy using these markers in selected individuals in whom additional risk stratification is desired.
The multimodality testing strategy may help to individualize and more efficiently target cardiovascular prevention efforts in primary care. Although current prevention guidelines recommend a risk-based approach only when implementing statin and aspirin therapy, the role for targeting therapy based on risk in primary prevention is likely to expand in the future. For example, the Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that lowering blood pressure below currently recommended targets was associated with reduced rates of heart failure and all-cause mortality,8 endpoints that were predicted well by the tests studied here.
The favorable effects of more aggressive blood pressure lowering in SPRINT were balanced by side effects and some safety concerns, and the resource implications of broad implementation of lower blood pressure targets would be substantial. In addition, a novel agent for the management of diabetes, empagliflozin, recently demonstrated a 38% reduction in death from cardiovascular causes and 35% reduction in heart failure, with lesser impact on ASCVD endpoints.56 Targeting empagiflozin to patients at highest risk for death and heart failure events may be a prudent strategy given the high cost of the drug. Thus, an individualized, risk-based approach utilizing traditional risk factors plus biomarkers may be appropriate when determining blood pressure targets or implementing newer therapies that favorably impact CVD endpoints beyond ASCVD.
The multimodality strategy could also facilitate targeting of global and disease-specific CVD prevention efforts as population health care becomes an increasing focus of health care delivery. For example, among individuals with risk score of 0, global CVD risk was extremely low in both MESA and DHS (<3% over 10 years in each study), and this large group of individuals could be managed with a low intensity/ low cost approach. On the other hand, higher scores clearly captured risk not recognized with traditional risk factor algorithms, as consistent results were seen even among individuals estimated to be at low risk with the pooled cohort equations. Individuals with scores >2, for example, represented fewer than half of MESA participants and 1/4 of the younger DHS cohort, yet accounted for 79% and 58% of global CVD events, respectively. A tailored and incrementally more intensive approach to global CVD risk reduction would be appropriate for individuals with a greater number of abnormal test results. For example, higher risk individuals could be referred to lifestyle intervention programs, focusing on improving low fitness and obesity, which are important contributors to multiple components of the global CVD endpoint. Triage for cardiovascular specialist evaluation may be considered for the highest risk individuals, a strategy recently evaluated for a biomarker screening program in primary care with promising preliminary results.57 Although each of the 5 tests is available clinically and thus measurement is currently feasible, larger studies will be needed both to validate the present findings and also to elucidate the optimal strategy for clinical implementation. Moreover, additional consideration of costs, both those directly related to the tests and those engendered by abnormal test results, would be necessary prior to implementation.
Conclusions
A novel multi-modality CVD risk assessment strategy using the non-redundant markers of ECG LVH, CAC, NT-proBNP, hs-cTnT, and hs-CRP substantially improved global and atherosclerotic CVD risk stratification among individuals from the general population free from CVD at study entry. Additional study of preventive strategies incorporating these complementary tests is indicated.
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