The recently released American College of Cardiology

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1 Data Report Atherosclerotic Cardiovascular Disease Prevention A Comparison Between the Third Adult Treatment Panel and the New 2013 Treatment of Blood Cholesterol Guidelines Andre R.M. Paixao, MD; Colby R. Ayers, MS; Jarett D. Berry, MD, MS; James A. de Lemos, MD; Amit Khera, MD, MSc Downloaded from by guest on May 3, 2018 The recently released American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines on the Treatment of Blood Cholesterol propose significant changes to current practice patterns. 1 The adoption of these new guidelines in place of the National Cholesterol Education Program/Third Adult Treatment panel (ATPIII) 2 recommendations has recently been estimated to result in an 11% increase in statin eligibility, representing 12.8 million Americans. 3 Although the magnitude of change in statin eligibility has been a topic of focus, the impact of the new guidelines on atherosclerotic cardiovascular disease (ASCVD) event rates and efficiency of additional statin use cannot be determined from the studies published to date. Knowledge of ASCVD event rates among reclassified individuals is essential to fully understand the implications of adopting the ACC/AHA guidelines. We sought to assess the implications of applying this new paradigm in place of the ATPIII recommendations on ASCVD event reduction and efficiency of statin utilization. Methods and Results The Dallas Heart Study is a multiethnic cohort of Dallas County residents, age 30 to 65 years, examined between 2000 and 2002 and actively followed for cardiovascular outcomes. 4 All participants provided informed consent, and the study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center. Sampling weights were applied to generate unbiased estimates of population frequencies in Dallas County. 4 The primary outcome of ASCVD was defined as coronary heart disease (CHD) death, myocardial infarction, and fatal and nonfatal stroke. 1 Secondary analysis was performed for CHD events (ie, CHD death and myocardial infarction). 2 Participants were classified as statin eligible or ineligible using (1) ATPIII recommendations including the Framingham Risk Score and low-density lipoprotein cholesterol levels and (2) ACC/AHA algorithm including the Pooled Cohort Equations (Table I in the Data Supplement). 1,2 Similar to prior studies, individuals on statins at baseline were considered eligible by both guidelines. 3 Reclassification of statin eligibility from ATPIII to the AHA/ ACC guidelines was determined, and ASCVD event rates were assessed among newly statin-eligible individuals. Net reclassification improvement was calculated as previously described. 5 Using the same framework applied in the ACC/ AHA guidelines, the number of prevented ASCVD events was estimated based on the number of events that occurred among statin-eligible individuals and assuming a relative risk reduction of 30% to 35% for moderate-intensity statin therapy and 45% for high-intensity statin therapy. 1 The number of statin-related excess cases of diabetes mellitus was estimated assuming 0.1 and 0.3 extra cases per 100 person-years for moderate- and high-intensity statin therapy, respectively. 1 Analyses were performed comparing the ACC/AHA guidelines with both the standard and optional low-density lipoprotein cholesterol goals from ATPIII. 2 A total of 2848 participants were assessed for statin eligibility according to both guidelines. Over a mean follow-up of 9.1±1.3 years, 129 ASCVD events including 70 CHD events occurred. After the application of sample weights, the median age of the population was 43 years, 49.9% were women, 19.0% were black, 7.9% had diabetes mellitus, and 3.4% had prior ASCVD (Table II in the Data Supplement). Overall, 17.2% of individuals were classified as statin eligible by ATPIII and 22.0% by the ACC/AHA guidelines (net increase 4.8%, relative increase 27.9%). The ASCVD event rate among newly statin-eligible individuals was 15.8% with an estimated one ASCVD event prevented for each additional 14 patients treated with high-dose statins and 21 treated with moderate-dose statins (Table). The net increase in statin eligibility was 37.1% among participants with ASCVD events and 3.9% among participants without ASCVD events, resulting in a net reclassification improvement of (P<0.001; Table III in the Data Supplement). Excluding individuals on statins at baseline resulted in a net 5.2% increase in statin eligibility with a 15.8% ASCVD event rate among the newly statin eligible and a similar number needed to treat. Results were also similar when the analysis was restricted to individuals 40 years old (Table; Table III in the Data Supplement). Received May 17, 2014; accepted June 25, From the Division of Cardiology (A.R.M.P., J.D.B., J.A.d.L., A.K.) and Department of Clinical Sciences (C.R.A., J.D.B.) at the University of Texas Southwestern Medical Center, Dallas. The Data Supplement is available at Correspondence to Amit Khera, MD, MSc, Division of Cardiology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX amit.khera@utsouthwestern.edu (Circ Cardiovasc Qual Outcomes. 2014;7: ) 2014 American Heart Association, Inc. Circ Cardiovasc Qual Outcomes is available at DOI: /CIRCOUTCOMES

2 Paixao et al Comparison Between Cholesterol Guidelines 779 Downloaded from by guest on May 3, 2018 Table. Additional Statin Eligibility and ASCVD Event Rates Among Newly Statin Eligible Individuals Outcome Additional Statin Eligibility* Event Rate Among Newly Statin Eligible NNT Among Newly Statin Eligible Primary analysis ASCVD 4.8% 15.8% CHD 4.8% 11.7% ATPIII statin eligibility determined by optional cholesterol goals ASCVD 2.8% 15.7% CHD 2.8% 12.4% Restricting to individuals aged 40 years ASCVD 9.0% 15.8% CHD 9.0% 11.6% ASCVD indicates atherosclerotic cardiovascular disease; ATPIII, Third Adult Treatment panel; CHD, coronary heart disease; and NNT, number needed to treat. *Additional statin eligibility is the net product of those newly statin eligible and those no longer statin eligible under the new guidelines. Number needed to treat with moderate to high potency statin to prevent one atherosclerotic cardiovascular event assuming a 30% to 45% relative risk reduction. Applying the ACC/AHA guidelines in place of ATPIII would result in an additional 3.6 to 4.9 prevented ASCVD events for every 1000 individuals screened and accordingly treated with moderate- or high-dose statins, respectively, with 0.5 to 1.5 excess cases of diabetes mellitus (Figure I in the Data Supplement). When applied to the source population of Dallas County residents aged 30 to 65 (n= ), an additional 4479 to 4771 ASCVD events would be prevented. When the ACC/AHA guidelines were compared with the optional ATPIII low-density lipoprotein cholesterol goals, 2 even though a net reduction of 2.8% in statin eligibility was observed, newly statin-eligible individuals had an ASCVD event rate and number need to treat which were comparable to the primary analysis (Table) and a net reclassification improvement of (P<0.001; Table III in the Data Supplement). Restricting the outcome to CHD events yielded similar results (Table; Table III in the Data Supplement). Assuming a more conservative 25% ASCVD relative risk reduction for statin therapy, 6 the number needed to treat to prevent one event among newly statin-eligible individuals would be 25 and 2.7. ASCVD events would be prevented for every 1000 individuals screened and accordingly treated. Comment The release of the ACC/AHA guidelines was followed by a heated debate that was often centered on the expansion of statin eligibility. Our findings are consistent with a recent report from the National Health and Nutrition Examination Surveys and suggest that, among individuals <60 to 65 years, adopting the ACC/AHA guidelines would result in a modest absolute increase in statin eligibility. 3 Beyond reporting on additional statin use, we apply actual event rates to show that in this age group, additional statin use with adoption of the new guidelines seems reasonably efficient and effective. Newly statin-eligible individuals had high ASCVD event rates (15.8%), resulting in an efficient number needed to treat (14 21) to prevent one ASCVD event. Over one third of individuals with ASCVD events were newly classified as statin eligible, and there was an acceptable balance between prevented ASCVD events and new-onset diabetes mellitus. The implications for practitioners who have adopted the ATPIII optional low-density lipoprotein cholesterol goals would be more modest as switching to the ACC/AHA recommendations would actually decrease statin eligibility by 2.8% among individuals in this age range. The new guidelines, however, resulted in a more efficient use of statins with a 15.7% event rate among the newly statin eligible, translating into a persistent but lesser reduction in ASCVD events ( per 1000 screened). Our results from a contemporary, multiethnic, younger population suggest that the application of the ACC/AHA guidelines will have a favorable effect on ASCVD prevention with reasonable efficiency of statin use when compared with the prior ATPIII recommendations. The net effect of the new recommendations should also be assessed in older populations and in those with different ethnic composition. Sources of Funding The Dallas Heart Study was funded by the Donald W. Reynolds Foundation (Las Vegas, NE) and partially supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (Bethesda, MD) under award number UL1TR Disclosures Dr de Lemos has received honoraria and consulting fees from Astra Zeneca and consulting fees from Sanofi/Regeneron and Amgen. Dr Berry is a member of the Speakers Bureau for Merk & Co. The other authors report no conflicts. References 1. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1 S Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ; Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004;44: Pencina MJ, Navar-Boggan AM, D Agostino RB Sr, Williams K, Neely B, Sniderman AD, Peterson ED. Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014;370: Victor RG, Haley RW, Willett DL, Peshock RM, Vaeth PC, Leonard D, Basit M, Cooper RS, Iannacchione VG, Visscher WA, Staab JM, Hobbs HH; Dallas Heart Study Investigators. The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health. Am J Cardiol. 2004;93: Pencina MJ, D Agostino RB Sr, D Agostino RB Jr, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med. 2008;27: Taylor F, Huffman MD, Macedo AF, Moore TH, Burke M, Davey Smith G, Ward K, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;1:CD Key Words: cardiovascular diseases cholesterol

3 Atherosclerotic Cardiovascular Disease Prevention: A Comparison Between the Third Adult Treatment Panel and the New 2013 Treatment of Blood Cholesterol Guidelines Andre R.M. Paixao, Colby R. Ayers, Jarett D. Berry, James A. de Lemos and Amit Khera Downloaded from by guest on May 3, 2018 Circ Cardiovasc Qual Outcomes. 2014;7: ; originally published online August 5, 2014; doi: /CIRCOUTCOMES Circulation: Cardiovascular Quality and Outcomes is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2014 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at: Data Supplement (unedited) at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Cardiovascular Quality and Outcomes can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Circulation: Cardiovascular Quality and Outcomes is online at:

4 Supplemental Material 1

5 Supplemental Table 1: ATPIII and ACC/AHA Guidelines Statin Eligibility Criteria ATPIII statin eligibility 1 Risk Category High risk (Clinical CVD*, diabetes or 2 risk Consider drug therapy LDL-C 2.6mmol/L (100mg/dL) Optional LDL-C 1.8mmol/L (70mg/dL) factors and FRS >20%) Moderately high risk ( 2 risk factors and FRS 10%-20%) Moderate risk LDL-C 3.4mmol/L (130mg/dL) Optional LDL-C 2.6mmol/L (100mg/dL) LDL-C 4.1mmol/L (160 mg/dl) ( 2 risk factors and FRS <10%) Low risk (0-1 risk factor ) LDL-C 4.9mmol/L (190 mg/dl) Optional LDL-C 4.1mmol/L (160mg/dL) 2013 ACC/AHA statin eligibility 2 Statin eligible groups Clinical CVD* LDL-C 4.9mmol/L (190 mg/dl) Diabetes and age 40 years PCE risk 7.5% and age 40 years and LDL-C 1.8mmol/L (70mg/dL) ATPIII = Third Adult Treatment panel, ACC = American College of Cardiology, AHA = American Heart Association, CVD = cardiovascular disease, FRS = Framingham Risk Score, LDL-C = low density lipoprotein cholesterol, PCE = Pooled Cohort Equations. 2

6 * Cardiovascular disease was defined as prior history of myocardial infarction, coronary revascularization or stroke. Risk factors include cigarette smoking, hypertension (blood pressure 140/90 mmhg or on antihypertensive medication), high density lipoprotein cholesterol <1.0mmol/L (40mg/dL), family history of premature coronary disease, and age (men 45 years; women 55 years). 3

7 Supplemental Table 2: Sample Weight-Adjusted Baseline Characteristics Characteristics Study population N 2848 Age* 43 [36, 52] Women 49.9% Race Black 19.0% White 54.9% Hispanic 23.2% Other 2.9% Smokers 24.1% Hypertension 26.3% TC (mg/dl) * 182 [159, 208] LDL-C (mg/dl) * 108 [86, 131] HDL-C (mg/dl) * 46 [38, 56] Triglycerides (mg/dl) * 105 [72, 159] Statins 6.2% Hypertension 18.3% medications 4

8 Diabetes 7.9% CVD 3.4% FRS * 1% [0,4] PCE * 1.7% [0.6, 4.4] TC = total cholesterol, LDL-C = low density lipoprotein, HDL-C = high density lipoprotein, CVD = Cardiovascular disease, FRS = Framingham risk score, PCE = Pooled Cohort Equations. Cardiovascular disease was defined as prior history of myocardial infarction, coronary revascularization or stroke. Framingham risk score and Pooled Cohort Equations are reported as 10 year risk estimates. *median [interquartile range] 5

9 Supplemental Table 3: Net Reclassification of Statin Eligibility among Individuals with and without ASCVD Events Outcome Additional statin Additional statin NRI p-value eligibility among events eligibility among nonevents Primary analysis ASCVD 37.1% 3.9% <0.01 CHD 40.4% 4.1% <0.01 ATPIII statin eligibility determined by optional cholesterol goals ASCVD 16.5% -3.4% <0.01 CHD 19.1% -3.2% <0.01 Restricting to individuals 40 years of age ASCVD 37.8% 7.6% <0.01 CHD 41.3% 8.0% <0.01 ASCVD = atherosclerotic cardiovascular disease, NRI = net reclassification improvement, CHD = coronary heart disease, ATPIII = Third Adult Treatment panel. 6

10 Supplemental Figure Implications of Applying the ACC/AHA Guidelines in Place of the ATPIII Recommendations per 1000 Individuals Screened AHA = American Heart Association, ACC = American College of Cardiology, ATPIII = Third Adult Treatment panel, ASCVD = atherosclerotic cardiovascular disease, LDL-C = low density lipoprotein cholesterol 7

11 References 1. Grundy SM, Cleeman JI, Merz CN, Brewer HB, Jr., Clark LT, Hunninghake DB, Pasternak RC, Smith SC, Jr., Stone NJ. Implications of recent clinical trials for the national cholesterol education program adult treatment panel iii guidelines. Journal of the American College of Cardiology. 2004;44: Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC, Jr., Watson K, Wilson PW ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the american college of cardiology/american heart association task force on practice guidelines. Circulation. 2014;129:S1 S45 8