Letters
ticipating registry hospitals enrolled at least 1 patient in a clinical trial during the study period, potentially limiting extrapolation to nonparticipating hospitals. Information about socioeconomic status, individual trials, and protocol inclusion or exclusion criteria were not available. Lack of information on the specific timing and reason for trial participation at the patient, physician, and hospital level limited determination of the cause for infrequent trial enrollment, such as patients refusing to participate, researchers not enrolling patients, or no trial being conducted at the hospital. Efforts to improve trial participation are needed to enhance generalizability of results. Nesting trials within existing registries may help meet this goal.
Dr Udell was supported in part by a postdoctoral research fellowship from the Canadian Institutes for Health Research and the Canadian Foundation for Women’s Health. Role of the Sponsors: The study was designed by Drs Udell and Wiviott and approved by the NCDR. The ACTION Registry–GWTG research and publications subcommittee reviewed and approved the proposal and final draft of the manuscript. The funding agency had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The views expressed in this manuscript represent those of the authors, and do not necessarily represent the official views of the NCDR or its associated professional societies identified at http://www.ncdr.com. Additional Contributions: We thank Elliott M. Antman, MD (Brigham and Women’s Hospital, Boston, Massachusetts), for review of the manuscript, for which he received no compensation. 1. Humphreys K, Maisel NC, Blodgett JC, Fuh IL, Finney JW. Extent and reporting of patient nonenrollment in influential randomized clinical trials, 2002 to 2010. JAMA Intern Med. 2013;173(11):1029-1031.
Jacob A. Udell, MD, MPH Tracy Y. Wang, MD, MHS, MSc Shuang Li, MS Payal Kohli, MD Matthew T. Roe, MD, MHS James A. de Lemos, MD Stephen D. Wiviott, MD
2. Antman EM, Harrington RA. Transforming clinical trials in cardiovascular disease. JAMA. 2012;308(17):1743-1744. 3. Chin CT, Chen AY, Wang TY, et al Risk adjustment for in-hospital mortality of contemporary patients with acute myocardial infarction. Am Heart J. 2011;161(1): 113-122,e2.
Author Affiliations: Women’s College Hospital, University of Toronto, Toronto, Ontario, Canada (Udell); Duke Clinical Research Institute, Duke University, Durham, North Carolina (Wang, Li, Roe); Division of Cardiology, University of California, San Francisco (Kohli); Division of Cardiology, University of Texas Southwestern Medical Center, Dallas (de Lemos); Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts (Wiviott). Corresponding Author: Jacob A. Udell, MD, MPH, Women’s College Hospital, University of Toronto, 76 Grenville St, Toronto, ON M5S 1B1, Canada (jay.udell @utoronto.ca). Author Contributions: Ms Li had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Udell, Kohli, Roe, Wiviott. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Udell. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Li, Roe. Obtained funding: Udell, Roe. Administrative, technical, or material support: Udell, Wang, Kohli, Roe. Study supervision: Wang, Roe. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Udell reported receiving honoraria from the American College of Cardiology Foundation. Dr Wang reported receiving honoraria from the American College of Cardiology Foundation and AstraZeneca; and research funding to Duke Clinical Research Institute from Lilly USA, Daiichi Sankyo, GlaxoSmithKline, and Gilead Science. Dr Kohli reported serving as a consultant to Live and Jeffries Research. Dr Roe reported receiving grants from Eli Lilly & Company, Daiichi Sankyo, sanofi-aventis, the American College of Cardiology, the American Heart Association, and the Familial Hypercholesterolemia Foundation; and personal fees from Merck, Janssen Pharmaceuticals, Regeneron, AstraZeneca, and Amgen outside the submitted work. Dr de Lemos reported receiving lecture honoraria from AstraZeneca; consulting income from Janssen Pharmaceuticals, Diadexus, St Jude Medical, and Roche Diagnostics; and grant support and consulting income from Roche Diagnostics and Abbott Diagnostics. Dr Wiviott reported receiving grants from Arena, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Merck, and sanofi-aventis; and consulting fees from Aegerion, Angelmed, Arena, AstraZeneca, Boston Clinical Research Institute, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, ICON Clinical, Janssen, and Xoma. No other disclosures were reported. Funding/Support: This research was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR). The Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry–Get With The Guidelines (GWTG) is sponsored in part by the partnership between Bristol-Myers Squibb and sanofi pharmaceuticals.
4. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015. 5. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009; 361(11):1045-1057. 6. Mehta SR, Bassand JP, Chrolavicius S, et al; CURRENT-OASIS 7 Investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. 2010;363(10):930-942.
COMMENT & RESPONSE
Bioprosthetic Valves for Transcatheter Aortic Valve Replacement To the Editor Dr Abdel-Wahab and colleagues 1 reported a head-to-head comparison between currently available bioprostheses for transcatheter aortic valve replacement (TAVR). In the Comparison of Transcatheter Heart Valves in High Risk Patients With Severe Aortic Stenosis: Medtronic CoreValve vs Edwards SAPIEN XT (CHOICE) trial, a higher rate of device success was obtained with a balloonex p a n d a b l e p ro s t h e s i s t h a n w it h a s e l f - ex p a n d i ng prosthesis. This finding was partly driven by “a lower frequenc y of residual more-than-mild paravalv ular aortic regurgitation. . . .” However, we believe that some limitations hamper this interpretation, particularly with regard to the assessment of postprocedural paravalvular regurgitation. First, the CHOICE investigators1 selected angiography2 as the main tool to grade paravalvular regurgitation and used this grading as a criterion for determining the composite primary end point. Although angiography is the easiest and quickest method for assessing the degree of paravalvular regurgitation during catheterization (particularly when performed without transesophageal echocardiography), its main drawback is its reliance on subjective interpretation of unidimensional images and the difficulty of determining the relative contribution of paravalvular and central regurgitation.3
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Second, the scale by Sellers et al 2 adopted by the CHOICE investigators 1 was originally intended to grade regurgitation of native valves, while it represents a lessestablished method for paravalvular regurgitation assessment. Third, from a technical standpoint, unlike the balloon-expandable valve that reaches its final expansion right after deployment, the self-expandable prosthesis keeps on expanding for a few hours after implant, so it is not uncommon to observe a reduction in paravalvular regurgitation at discharge. 3,4 Consequently, echocardiographic evaluation of paravalvular regurgitation at discharge provides more reliable grading, particularly when 2 different prostheses are compared. Fo u r t h , t h e C H O I C E i nve s t i g a t o r s 1 s t a t e d t h a t consistent results were seen when aortic regurgitation was assessed by echocardiography. However, the rates of more-than-moderate paravalvular regurgitation was 18.3% in the self-expandable group vs 4.1% in the balloonexpandable group on angiography and was 5.8% in the selfexpandable group vs 1.6% in the balloon-expandable group on echocardiography. Reporting of the composite end point with paravalvular regurgitation assessed by echocardiography might have resulted in no statistically significant difference between groups and changed the conclusion of the trial. Fifth, all national TAVR registries, randomized trials, and studies published after Conformité Européene report the end points of device success and paravalvular regurgitation as assessed by echocardiography, thus making the results of this trial difficult to put into the perspective of existing literature. For all these reasons, we believe that data on device success should also be presented using paravalvular regurgitation grading based on echocardiography, as recommended by the Valve Academic Research Consortium (VARC).5 Marco Barbanti, MD Davide Capodanno, MD, PhD Corrado Tamburino, MD, PhD Author Affiliations: Division of Cardiology, Ferrarotto Hospital, University of Catania, Catania, Italy. Corresponding Author: Marco Barbanti, MD, Division of Cardiology, Ferrarotto Hospital, University of Catania, Via Citelli 1, 95100 Catania, Italy (mbarbanti83 @gmail.com). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Abdel-Wahab M, Mehilli J, Frerker C, et al; CHOICE investigators. Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement: the CHOICE randomized clinical trial. JAMA. 2014;311(15):1503-1514. 2. Sellers RD, Levy MJ, Amplatz K, Lillehei CW. Left retrograde cardioangiography in acquired cardiac disease: technic, indications and interpretations in 700 cases. Am J Cardiol. 1964;14:437-447. 3. Généreux P, Head SJ, Hahn R, et al. Paravalvular leak after transcatheter aortic valve replacement: the new Achilles’ heel? J Am Coll Cardiol. 2013;61(11): 1125-1136. 4. Buellesfeld L, Gerckens U, Schuler G, et al. 2-year follow-up of patients undergoing transcatheter aortic valve implantation using a self-expanding valve prosthesis. J Am Coll Cardiol. 2011;57(16):1650-1657. 844
5. Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol. 2012;60(15): 1438-1454.
To the Editor The CHOICE trial1 is the first randomized trial comparing balloon-expandable and self-expandable valves for TAVR. This trial used the VARC definition of device success as a composite primary end point. It found a higher device success with the balloon-expandable valve, driven largely by a lower frequency of aortic regurgitation. There are several serious flaws in the trial design that call these conclusions into question. For the self-expandable valve, the standard procedure for valve sizing uses 3-dimensional computed tomography (CT), which was required in the US pivotal Investigational Device Exemption CoreValve trials.2,3 In the CHOICE study, such imaging was only recommended and not used for 20% of patients. The CHOICE investigators1 reported they used the VARC definition of device success as their primary end point, but VARC recommends echocardiography and not aortography to measure aortic regurgitation. The CHOICE investigators1 also reported that angiography was used because echocardiography has not been validated as a quantitative test with transcatheter valves. However, aortography standards were developed in the 1960s, and aortography is only a qualitative test and has never been validated as a quantitative test. When using echocardiography as VARC recommends, the difference between the valves was markedly diminished. Moreover, the echocardiography results were not adjudicated by a central, independent echocardiographic core laboratory, but all aortic regurgitation was adjudicated in the US pivotal trial for CoreValve2,3 and the Placement of Aortic Transcatheter Valves IA and IB (PARTNER IA and IB) trials4,5 for the precursor balloon-expandable valve. In the CHOICE trial, no moderate or severe paravalvular regurgitation was found at 1 month for the balloon-expandable valve compared with the PARTNER IA and I B trials, which found 1-month paravalvular regurgitation rates of 12.2% and 11.8%. Why are the CHOICE paravalvular regurgitation rates so much lower? In addition, the outcomes of survival, stroke, myocardial infarction, and bleeding, which clinicians and their patients are really concerned with, were no different between the 2 valves evaluated in this study at 30 days. Michael J. Reardon, MD Author Affiliation: Department of Cardiothoracic Surgery, Houston Methodist DeBakey Heart and Vascular Center, Houston, Texas. Corresponding Author: Michael J. Reardon, MD, Department of Cardiothoracic Surgery, Houston Methodist DeBakey Heart and Vascular Center, 6550 Fannin, Ste 1401, Houston, TX 77030 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported serving on the executive committee of the CoreValve US Pivotal IDE trial; serving as the national principal investigator on the CoreValve SurTAVI trials; and serving on the advisory board for Medtronic.
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Letters
1. Abdel-Wahab M, Mehilli J, Frerker C, et al; CHOICE investigators. Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement: the CHOICE randomized clinical trial. JAMA. 2014;311(15):1503-1514. 2. Popma JJ, Adams DH, Reardon MJ, et al. CoreValve United States Clinical Investigators. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol. 2014;63(19):1972-1981. . 3. Adams DH, Popma JJ, Reardon MJ, et al. US CoreValve Clinical Investigators. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med.2014;370(19):1790-1798. . 4. Smith CR, Leon MB, Mack MJ, et al; PARTNER Trial Investigators. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364(23):2187-2198. 5. Leon MB, Smith CR, Mack M, et al; PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363(17):1597-1607.
In Reply We do not share the concerns of Dr Barbanti and colleagues or of Dr Reardon about the use of angiography as the primary tool for assessment of aortic regurgitation after TAVR in the CHOICE trial. Aortic regurgitation after TAVR is commonly paravalvular. These paravalvular jets are usually eccentric with crescentic, irregular orifices and may become entrained along the left ventricular wall, altering their appearance and the perception of severity, particularly with echocardiography. Although VARC suggests using the circumferential extent of the regurgitant jet as a semiquantitative measure of severity, this parameter has limitations when compared with quantitative regurgitant volume and regurgitant fraction estimated using cardiac magnetic resonance (CMR) imaging. 1 Furthermore, quantitative echocardiographic grading of aortic regurgitation severity using regurgitant volume or fraction requires the definition of 4 parameters, any of which may be affected by measurement inaccuracies, with considerable intraobsever and interobserver variability when compared with CMR.1 Comparisons of aortic regurgitation using quantitative measurements by CMR vs angiography showed better correlations than with echocardiography.2 In the CHOICE trial, sitereported echocardiography underestimated the degree of aortic regurgitation, whereas adjudicated angiographic grading was corroborated by CMR in a prespecified subgroup. In addition, the presence of significant aortic regurgitation after prosthesis implant has an immediate effect on the course of the procedure. Considering the increasing proportion of TAVR procedures performed with local anesthesia (without transesophageal echocardiography), the use of angiography to determine aortic regurgitation severity has practical advantages. It can be quickly and safely performed and provides essential information to initiate adjunctive maneuvers if needed. Of 4 major European registries mentioned by Barbanti and colleagues, both the German and the United Kingdom registries have reported on aortic regurgitation using angiography.3,4 Considering these advantages, we chose angiography as the main tool for evaluating aortic regurgitation in the CHOICE trial. To avoid the possible confounding factors
mentioned by Barbanti and colleagues and by Reardon, the angiographic acquisition was standardized. However, the rate of device success remained higher with balloonexpandable valves, even if echocardiographic grading was used instead of angiography (98.3% vs 88.3%, P = .003). Improvement over time in paravalvular regurgitation after implanting a self-expandable device is commonly explained by the self-expanding nature of the stent frame. However, full expansion usually occurs within minutes after placement, while further expansion and improvement in the degree of regurgitation was not shown in a recent study.5 We acknowledge the superiority of 3-dimensional CT for valve sizing, but we did not observe any interaction between the use of CT and the rate of device success (77.9% for selfexpandable valves vs 94.9% for balloon-expandable valves in 193 patients with CT, and 76% vs 100% in 48 patients without CT; P = .99 for interaction). The lower rate of aortic regurgitation in the CHOICE trial compared with the PARTNER I trial may be related to improved sizing algorithms and an optimized implantation technique with the liberal use of balloon after dilatation. The superiority hypothesis in the CHOICE trial was based on the results of large European registries that have suggested a lower rate of aortic regurgitation with balloonexpandable valves.4,6 Despite similar death and stroke rates at 30 days, rehospitalization for heart failure only occurred in patients receiving self-expandable valves, and further follow-up will provide insight into the clinical relevance of our findings. Mohamed Abdel-Wahab, MD Julinda Mehilli, MD Gert Richardt, MD Author Affiliations: Heart Center, Segeberger Kliniken, Bad Segeberg, Germany (Abdel-Wahab, Richardt); Munich University Clinic, Munich, Germany (Mehilli). Corresponding Author: Mohamed Abdel-Wahab, MD, Heart Center, Segeberger Kliniken GmbH, Academic Teaching Hospital of the Universities of Kiel and Hamburg, Am Kurpark 1, 23795 Bad Segeberg, Germany (mohamed [email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr AbdelWahab reported receiving a grant from Medtronic; and receiving lecture fees from Edwards Lifesciences and Boston Scientific. Dr Mehilli reported serving on advisory boards for Abbott Vascular and Terumo; and receiving personal fees from Abbott Vascular, Terumo, Lilly/Daiichi Sankyo, and Biotronik. Dr Richardt reported receiving a grant from Medtronic; and receiving lecture fees from Boston Scientific. 1. Altiok E, Frick M, Meyer CG, et al. Comparison of two- and three-dimensional transthoracic echocardiography to cardiac magnetic resonance imaging for assessment of paravalvular regurgitation after transcatheter aortic valve implantation. Am J Cardiol. 2014;113(11):1859-1866. 2. Sherif MA, Abdel-Wahab M, Beurich HW, et al. Haemodynamic evaluation of aortic regurgitation after transcatheter aortic valve implantation using cardiovascular magnetic resonance. EuroIntervention. 2011;7(1):57-63. 3. Zahn R, Gerckens U, Grube E, et al; German Transcatheter Aortic Valve Interventions-Registry Investigators. Transcatheter aortic valve implantation: first results from a multi-centre real-world registry. Eur Heart J. 2011;32(2):198204.
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4. Moat NE, Ludman P, de Belder MA, et al. Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: the UhK TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry. J Am Coll Cardiol. 2011;58(20):2130-2138. 5. Merten C, Beurich HW, Zachow D, et al. Aortic regurgitation and left ventricular remodeling after transcatheter aortic valve implantation: a serial cardiac magnetic resonance imaging study. Circ Cardiovasc Interv. 2013;6(4): 476-483. 6. Gilard M, Eltchaninoff H, Iung B, et al; FRANCE 2 Investigators. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med. 2012; 366(18):1705-1715.
Patients Affected by Changes to Hypertension Guideline To the Editor A recent study by Dr Navar-Boggan and colleagues1 used data from the National Health and Nutrition Examination Survey to estimate changes in the proportion of US adults who would be recommended for hypertension treatment based on the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults by Panel Members Appointed to the Eighth Joint National Committee (JNC 8). There may be several errors in Table 1 of the article by Navar-Boggan et al.1 The analysis could have led to overestimates in the proportion of older adults who would now meet blood pressure goals but would have been considered to have uncontrolled hypertension according to the previous national guideline.2 In the bottom half of Table 1 in the section for people aged 60 years or older, in the row for people with chronic kidney disease aged 70 years or older, there is a typographical error in the blood pressure range given in the third column. It reads diastolic blood pressure of 150 mm Hg or greater when it should be systolic blood pressure of 150 mm Hg or greater. Also, I do not believe any blood pressure range should be given because the JNC 8 does not recommend any specific treatment goal (recommendation 4) for patients aged 70 years or older with chronic kidney disease.3 In addition, in the same section, in the row for people with diabetes mellitus and no chronic kidney disease, the blood pressure range given in the third column is systolic blood pressure of 150 mm Hg or greater. However, the JNC 8 does not suggest a systolic blood pressure goal of 150 mm Hg or greater for people with diabetes mellitus no matter what their age. According to recommendation 5, this should be systolic blood pressure of 140 mm Hg or greater.3 Karen L. Margolis, MD, MPH Author Affiliation: HealthPartners Institute for Education and Research, Minneapolis, Minnesota. Corresponding Author: Karen L. Margolis, MD, MPH, HealthPartners Institute for Education and Research, 8170 33rd Ave S, MS 21111R, Minneapolis, MN 55425 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Navar-Boggan AM, Pencina MJ, Williams K, Sniderman AD, Peterson ED. Proportion of US adults potentially affected by the 2014 hypertension guideline. JAMA. 2014;311(14):1424-1429.
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2. Chobanian AV, Bakris GL, Black HR, et al; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-1252. 3. James PA, Oparil S, Carter BL, 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 (5):507-520.
In Reply Dr Margolis raised a few concerns regarding our interpretations of the 2014 blood pressure guideline1 and our calculations of patients who would be affected by the changes. Specifically, she questioned our use of a cutoff of 150 mm Hg for systolic blood pressure and 90 mm Hg for diastolic blood pressure for initiation of treatment in adults aged 70 years or older with chronic kidney disease and in those aged 60 years or older with diabetes. For both of these issues, the guideline is somewhat vague. When discussing blood pressure goals in patients with chronic kidney disease, the 2014 guideline text states: “Based on available evidence the panel cannot make a recommendation for a BP [blood pressure] goal for people aged 70 years or older with GFR [glomerular filtration rate] less than 60 mL/min/1.73m2. … Thus, when weighing the risks and benefits of a lower BP goal for people aged 70 years or older with estimated GFR less than 60 mL/min/1.73m2, antihypertensive treatment should be individualized, taking into consideration factors such as frailty, comorbidities, and albuminuria.” 1 Based on this, we elected to use a higher systolic/diastolic blood pressure threshold of 150/90 mm Hg for adults aged 70 years or older with chronic kidney disease. Similarly, when discussing blood pressure cutoffs in adults aged 60 years or older, the guideline authors note: “While all panel members agreed that the evidence supporting recommendation 1 is very strong, the panel was unable to reach unanimity on the recommendation of a goal SBP [systolic blood pressure] of lower than 150 mm Hg. Some members recommended continuing the JNC 7 SBP goal of lower than 140 mm Hg for individuals older than 60 years based on expert opinion. These members concluded that the evidence was insufficient to raise the SBP target from lower than 140 to lower than 150 mm Hg in high-risk groups, such as black persons, those with CVD [cardiovascular disease] including stroke, and those with multiple risk factors. The panel agreed that more research is needed to identify optimal goals of SBP for patients with high BP.”1 Given this uncertainty, we again elected to evaluate the higher systolic/diastolic blood pressure threshold of 150/90 mm Hg for adults aged 60 years or older with diabetes. However, to address the concerns of Margolis, we analyzed our sample using a systolic/diastolic blood pressure cutoff of 140/90 mm Hg or greater for all adults aged 60 years or older with diabetes or chronic kidney disease. Overall, our results were largely unchanged. The percentage of adults with treatment-eligible hypertension using the 2014
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ticipating registry hospitals enrolled at least 1 patient in a clinical trial during the study period, potentially limiting extrapolation to nonparticipating hospitals. Information about socioeconomic status, individual trials, and protocol inclusion or exclusion criteria were not available. Lack of information on the specific timing and reason for trial participation at the patient, physician, and hospital level limited determination of the cause for infrequent trial enrollment, such as patients refusing to participate, researchers not enrolling patients, or no trial being conducted at the hospital. Efforts to improve trial participation are needed to enhance generalizability of results. Nesting trials within existing registries may help meet this goal.
Dr Udell was supported in part by a postdoctoral research fellowship from the Canadian Institutes for Health Research and the Canadian Foundation for Women’s Health. Role of the Sponsors: The study was designed by Drs Udell and Wiviott and approved by the NCDR. The ACTION Registry–GWTG research and publications subcommittee reviewed and approved the proposal and final draft of the manuscript. The funding agency had no role in the conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The views expressed in this manuscript represent those of the authors, and do not necessarily represent the official views of the NCDR or its associated professional societies identified at http://www.ncdr.com. Additional Contributions: We thank Elliott M. Antman, MD (Brigham and Women’s Hospital, Boston, Massachusetts), for review of the manuscript, for which he received no compensation. 1. Humphreys K, Maisel NC, Blodgett JC, Fuh IL, Finney JW. Extent and reporting of patient nonenrollment in influential randomized clinical trials, 2002 to 2010. JAMA Intern Med. 2013;173(11):1029-1031.
Jacob A. Udell, MD, MPH Tracy Y. Wang, MD, MHS, MSc Shuang Li, MS Payal Kohli, MD Matthew T. Roe, MD, MHS James A. de Lemos, MD Stephen D. Wiviott, MD
2. Antman EM, Harrington RA. Transforming clinical trials in cardiovascular disease. JAMA. 2012;308(17):1743-1744. 3. Chin CT, Chen AY, Wang TY, et al Risk adjustment for in-hospital mortality of contemporary patients with acute myocardial infarction. Am Heart J. 2011;161(1): 113-122,e2.
Author Affiliations: Women’s College Hospital, University of Toronto, Toronto, Ontario, Canada (Udell); Duke Clinical Research Institute, Duke University, Durham, North Carolina (Wang, Li, Roe); Division of Cardiology, University of California, San Francisco (Kohli); Division of Cardiology, University of Texas Southwestern Medical Center, Dallas (de Lemos); Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts (Wiviott). Corresponding Author: Jacob A. Udell, MD, MPH, Women’s College Hospital, University of Toronto, 76 Grenville St, Toronto, ON M5S 1B1, Canada (jay.udell @utoronto.ca). Author Contributions: Ms Li had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Udell, Kohli, Roe, Wiviott. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Udell. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Li, Roe. Obtained funding: Udell, Roe. Administrative, technical, or material support: Udell, Wang, Kohli, Roe. Study supervision: Wang, Roe. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Udell reported receiving honoraria from the American College of Cardiology Foundation. Dr Wang reported receiving honoraria from the American College of Cardiology Foundation and AstraZeneca; and research funding to Duke Clinical Research Institute from Lilly USA, Daiichi Sankyo, GlaxoSmithKline, and Gilead Science. Dr Kohli reported serving as a consultant to Live and Jeffries Research. Dr Roe reported receiving grants from Eli Lilly & Company, Daiichi Sankyo, sanofi-aventis, the American College of Cardiology, the American Heart Association, and the Familial Hypercholesterolemia Foundation; and personal fees from Merck, Janssen Pharmaceuticals, Regeneron, AstraZeneca, and Amgen outside the submitted work. Dr de Lemos reported receiving lecture honoraria from AstraZeneca; consulting income from Janssen Pharmaceuticals, Diadexus, St Jude Medical, and Roche Diagnostics; and grant support and consulting income from Roche Diagnostics and Abbott Diagnostics. Dr Wiviott reported receiving grants from Arena, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Merck, and sanofi-aventis; and consulting fees from Aegerion, Angelmed, Arena, AstraZeneca, Boston Clinical Research Institute, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, ICON Clinical, Janssen, and Xoma. No other disclosures were reported. Funding/Support: This research was supported by the American College of Cardiology Foundation’s National Cardiovascular Data Registry (NCDR). The Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry–Get With The Guidelines (GWTG) is sponsored in part by the partnership between Bristol-Myers Squibb and sanofi pharmaceuticals.
4. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015. 5. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009; 361(11):1045-1057. 6. Mehta SR, Bassand JP, Chrolavicius S, et al; CURRENT-OASIS 7 Investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med. 2010;363(10):930-942.
COMMENT & RESPONSE
Bioprosthetic Valves for Transcatheter Aortic Valve Replacement To the Editor Dr Abdel-Wahab and colleagues 1 reported a head-to-head comparison between currently available bioprostheses for transcatheter aortic valve replacement (TAVR). In the Comparison of Transcatheter Heart Valves in High Risk Patients With Severe Aortic Stenosis: Medtronic CoreValve vs Edwards SAPIEN XT (CHOICE) trial, a higher rate of device success was obtained with a balloonex p a n d a b l e p ro s t h e s i s t h a n w it h a s e l f - ex p a n d i ng prosthesis. This finding was partly driven by “a lower frequenc y of residual more-than-mild paravalv ular aortic regurgitation. . . .” However, we believe that some limitations hamper this interpretation, particularly with regard to the assessment of postprocedural paravalvular regurgitation. First, the CHOICE investigators1 selected angiography2 as the main tool to grade paravalvular regurgitation and used this grading as a criterion for determining the composite primary end point. Although angiography is the easiest and quickest method for assessing the degree of paravalvular regurgitation during catheterization (particularly when performed without transesophageal echocardiography), its main drawback is its reliance on subjective interpretation of unidimensional images and the difficulty of determining the relative contribution of paravalvular and central regurgitation.3
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Second, the scale by Sellers et al 2 adopted by the CHOICE investigators 1 was originally intended to grade regurgitation of native valves, while it represents a lessestablished method for paravalvular regurgitation assessment. Third, from a technical standpoint, unlike the balloon-expandable valve that reaches its final expansion right after deployment, the self-expandable prosthesis keeps on expanding for a few hours after implant, so it is not uncommon to observe a reduction in paravalvular regurgitation at discharge. 3,4 Consequently, echocardiographic evaluation of paravalvular regurgitation at discharge provides more reliable grading, particularly when 2 different prostheses are compared. Fo u r t h , t h e C H O I C E i nve s t i g a t o r s 1 s t a t e d t h a t consistent results were seen when aortic regurgitation was assessed by echocardiography. However, the rates of more-than-moderate paravalvular regurgitation was 18.3% in the self-expandable group vs 4.1% in the balloonexpandable group on angiography and was 5.8% in the selfexpandable group vs 1.6% in the balloon-expandable group on echocardiography. Reporting of the composite end point with paravalvular regurgitation assessed by echocardiography might have resulted in no statistically significant difference between groups and changed the conclusion of the trial. Fifth, all national TAVR registries, randomized trials, and studies published after Conformité Européene report the end points of device success and paravalvular regurgitation as assessed by echocardiography, thus making the results of this trial difficult to put into the perspective of existing literature. For all these reasons, we believe that data on device success should also be presented using paravalvular regurgitation grading based on echocardiography, as recommended by the Valve Academic Research Consortium (VARC).5 Marco Barbanti, MD Davide Capodanno, MD, PhD Corrado Tamburino, MD, PhD Author Affiliations: Division of Cardiology, Ferrarotto Hospital, University of Catania, Catania, Italy. Corresponding Author: Marco Barbanti, MD, Division of Cardiology, Ferrarotto Hospital, University of Catania, Via Citelli 1, 95100 Catania, Italy (mbarbanti83 @gmail.com). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Abdel-Wahab M, Mehilli J, Frerker C, et al; CHOICE investigators. Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement: the CHOICE randomized clinical trial. JAMA. 2014;311(15):1503-1514. 2. Sellers RD, Levy MJ, Amplatz K, Lillehei CW. Left retrograde cardioangiography in acquired cardiac disease: technic, indications and interpretations in 700 cases. Am J Cardiol. 1964;14:437-447. 3. Généreux P, Head SJ, Hahn R, et al. Paravalvular leak after transcatheter aortic valve replacement: the new Achilles’ heel? J Am Coll Cardiol. 2013;61(11): 1125-1136. 4. Buellesfeld L, Gerckens U, Schuler G, et al. 2-year follow-up of patients undergoing transcatheter aortic valve implantation using a self-expanding valve prosthesis. J Am Coll Cardiol. 2011;57(16):1650-1657. 844
5. Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol. 2012;60(15): 1438-1454.
To the Editor The CHOICE trial1 is the first randomized trial comparing balloon-expandable and self-expandable valves for TAVR. This trial used the VARC definition of device success as a composite primary end point. It found a higher device success with the balloon-expandable valve, driven largely by a lower frequency of aortic regurgitation. There are several serious flaws in the trial design that call these conclusions into question. For the self-expandable valve, the standard procedure for valve sizing uses 3-dimensional computed tomography (CT), which was required in the US pivotal Investigational Device Exemption CoreValve trials.2,3 In the CHOICE study, such imaging was only recommended and not used for 20% of patients. The CHOICE investigators1 reported they used the VARC definition of device success as their primary end point, but VARC recommends echocardiography and not aortography to measure aortic regurgitation. The CHOICE investigators1 also reported that angiography was used because echocardiography has not been validated as a quantitative test with transcatheter valves. However, aortography standards were developed in the 1960s, and aortography is only a qualitative test and has never been validated as a quantitative test. When using echocardiography as VARC recommends, the difference between the valves was markedly diminished. Moreover, the echocardiography results were not adjudicated by a central, independent echocardiographic core laboratory, but all aortic regurgitation was adjudicated in the US pivotal trial for CoreValve2,3 and the Placement of Aortic Transcatheter Valves IA and IB (PARTNER IA and IB) trials4,5 for the precursor balloon-expandable valve. In the CHOICE trial, no moderate or severe paravalvular regurgitation was found at 1 month for the balloon-expandable valve compared with the PARTNER IA and I B trials, which found 1-month paravalvular regurgitation rates of 12.2% and 11.8%. Why are the CHOICE paravalvular regurgitation rates so much lower? In addition, the outcomes of survival, stroke, myocardial infarction, and bleeding, which clinicians and their patients are really concerned with, were no different between the 2 valves evaluated in this study at 30 days. Michael J. Reardon, MD Author Affiliation: Department of Cardiothoracic Surgery, Houston Methodist DeBakey Heart and Vascular Center, Houston, Texas. Corresponding Author: Michael J. Reardon, MD, Department of Cardiothoracic Surgery, Houston Methodist DeBakey Heart and Vascular Center, 6550 Fannin, Ste 1401, Houston, TX 77030 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported serving on the executive committee of the CoreValve US Pivotal IDE trial; serving as the national principal investigator on the CoreValve SurTAVI trials; and serving on the advisory board for Medtronic.
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1. Abdel-Wahab M, Mehilli J, Frerker C, et al; CHOICE investigators. Comparison of balloon-expandable vs self-expandable valves in patients undergoing transcatheter aortic valve replacement: the CHOICE randomized clinical trial. JAMA. 2014;311(15):1503-1514. 2. Popma JJ, Adams DH, Reardon MJ, et al. CoreValve United States Clinical Investigators. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol. 2014;63(19):1972-1981. . 3. Adams DH, Popma JJ, Reardon MJ, et al. US CoreValve Clinical Investigators. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med.2014;370(19):1790-1798. . 4. Smith CR, Leon MB, Mack MJ, et al; PARTNER Trial Investigators. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364(23):2187-2198. 5. Leon MB, Smith CR, Mack M, et al; PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363(17):1597-1607.
In Reply We do not share the concerns of Dr Barbanti and colleagues or of Dr Reardon about the use of angiography as the primary tool for assessment of aortic regurgitation after TAVR in the CHOICE trial. Aortic regurgitation after TAVR is commonly paravalvular. These paravalvular jets are usually eccentric with crescentic, irregular orifices and may become entrained along the left ventricular wall, altering their appearance and the perception of severity, particularly with echocardiography. Although VARC suggests using the circumferential extent of the regurgitant jet as a semiquantitative measure of severity, this parameter has limitations when compared with quantitative regurgitant volume and regurgitant fraction estimated using cardiac magnetic resonance (CMR) imaging. 1 Furthermore, quantitative echocardiographic grading of aortic regurgitation severity using regurgitant volume or fraction requires the definition of 4 parameters, any of which may be affected by measurement inaccuracies, with considerable intraobsever and interobserver variability when compared with CMR.1 Comparisons of aortic regurgitation using quantitative measurements by CMR vs angiography showed better correlations than with echocardiography.2 In the CHOICE trial, sitereported echocardiography underestimated the degree of aortic regurgitation, whereas adjudicated angiographic grading was corroborated by CMR in a prespecified subgroup. In addition, the presence of significant aortic regurgitation after prosthesis implant has an immediate effect on the course of the procedure. Considering the increasing proportion of TAVR procedures performed with local anesthesia (without transesophageal echocardiography), the use of angiography to determine aortic regurgitation severity has practical advantages. It can be quickly and safely performed and provides essential information to initiate adjunctive maneuvers if needed. Of 4 major European registries mentioned by Barbanti and colleagues, both the German and the United Kingdom registries have reported on aortic regurgitation using angiography.3,4 Considering these advantages, we chose angiography as the main tool for evaluating aortic regurgitation in the CHOICE trial. To avoid the possible confounding factors
mentioned by Barbanti and colleagues and by Reardon, the angiographic acquisition was standardized. However, the rate of device success remained higher with balloonexpandable valves, even if echocardiographic grading was used instead of angiography (98.3% vs 88.3%, P = .003). Improvement over time in paravalvular regurgitation after implanting a self-expandable device is commonly explained by the self-expanding nature of the stent frame. However, full expansion usually occurs within minutes after placement, while further expansion and improvement in the degree of regurgitation was not shown in a recent study.5 We acknowledge the superiority of 3-dimensional CT for valve sizing, but we did not observe any interaction between the use of CT and the rate of device success (77.9% for selfexpandable valves vs 94.9% for balloon-expandable valves in 193 patients with CT, and 76% vs 100% in 48 patients without CT; P = .99 for interaction). The lower rate of aortic regurgitation in the CHOICE trial compared with the PARTNER I trial may be related to improved sizing algorithms and an optimized implantation technique with the liberal use of balloon after dilatation. The superiority hypothesis in the CHOICE trial was based on the results of large European registries that have suggested a lower rate of aortic regurgitation with balloonexpandable valves.4,6 Despite similar death and stroke rates at 30 days, rehospitalization for heart failure only occurred in patients receiving self-expandable valves, and further follow-up will provide insight into the clinical relevance of our findings. Mohamed Abdel-Wahab, MD Julinda Mehilli, MD Gert Richardt, MD Author Affiliations: Heart Center, Segeberger Kliniken, Bad Segeberg, Germany (Abdel-Wahab, Richardt); Munich University Clinic, Munich, Germany (Mehilli). Corresponding Author: Mohamed Abdel-Wahab, MD, Heart Center, Segeberger Kliniken GmbH, Academic Teaching Hospital of the Universities of Kiel and Hamburg, Am Kurpark 1, 23795 Bad Segeberg, Germany (mohamed [email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr AbdelWahab reported receiving a grant from Medtronic; and receiving lecture fees from Edwards Lifesciences and Boston Scientific. Dr Mehilli reported serving on advisory boards for Abbott Vascular and Terumo; and receiving personal fees from Abbott Vascular, Terumo, Lilly/Daiichi Sankyo, and Biotronik. Dr Richardt reported receiving a grant from Medtronic; and receiving lecture fees from Boston Scientific. 1. Altiok E, Frick M, Meyer CG, et al. Comparison of two- and three-dimensional transthoracic echocardiography to cardiac magnetic resonance imaging for assessment of paravalvular regurgitation after transcatheter aortic valve implantation. Am J Cardiol. 2014;113(11):1859-1866. 2. Sherif MA, Abdel-Wahab M, Beurich HW, et al. Haemodynamic evaluation of aortic regurgitation after transcatheter aortic valve implantation using cardiovascular magnetic resonance. EuroIntervention. 2011;7(1):57-63. 3. Zahn R, Gerckens U, Grube E, et al; German Transcatheter Aortic Valve Interventions-Registry Investigators. Transcatheter aortic valve implantation: first results from a multi-centre real-world registry. Eur Heart J. 2011;32(2):198204.
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4. Moat NE, Ludman P, de Belder MA, et al. Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: the UhK TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry. J Am Coll Cardiol. 2011;58(20):2130-2138. 5. Merten C, Beurich HW, Zachow D, et al. Aortic regurgitation and left ventricular remodeling after transcatheter aortic valve implantation: a serial cardiac magnetic resonance imaging study. Circ Cardiovasc Interv. 2013;6(4): 476-483. 6. Gilard M, Eltchaninoff H, Iung B, et al; FRANCE 2 Investigators. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med. 2012; 366(18):1705-1715.
Patients Affected by Changes to Hypertension Guideline To the Editor A recent study by Dr Navar-Boggan and colleagues1 used data from the National Health and Nutrition Examination Survey to estimate changes in the proportion of US adults who would be recommended for hypertension treatment based on the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults by Panel Members Appointed to the Eighth Joint National Committee (JNC 8). There may be several errors in Table 1 of the article by Navar-Boggan et al.1 The analysis could have led to overestimates in the proportion of older adults who would now meet blood pressure goals but would have been considered to have uncontrolled hypertension according to the previous national guideline.2 In the bottom half of Table 1 in the section for people aged 60 years or older, in the row for people with chronic kidney disease aged 70 years or older, there is a typographical error in the blood pressure range given in the third column. It reads diastolic blood pressure of 150 mm Hg or greater when it should be systolic blood pressure of 150 mm Hg or greater. Also, I do not believe any blood pressure range should be given because the JNC 8 does not recommend any specific treatment goal (recommendation 4) for patients aged 70 years or older with chronic kidney disease.3 In addition, in the same section, in the row for people with diabetes mellitus and no chronic kidney disease, the blood pressure range given in the third column is systolic blood pressure of 150 mm Hg or greater. However, the JNC 8 does not suggest a systolic blood pressure goal of 150 mm Hg or greater for people with diabetes mellitus no matter what their age. According to recommendation 5, this should be systolic blood pressure of 140 mm Hg or greater.3 Karen L. Margolis, MD, MPH Author Affiliation: HealthPartners Institute for Education and Research, Minneapolis, Minnesota. Corresponding Author: Karen L. Margolis, MD, MPH, HealthPartners Institute for Education and Research, 8170 33rd Ave S, MS 21111R, Minneapolis, MN 55425 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Navar-Boggan AM, Pencina MJ, Williams K, Sniderman AD, Peterson ED. Proportion of US adults potentially affected by the 2014 hypertension guideline. JAMA. 2014;311(14):1424-1429.
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2. Chobanian AV, Bakris GL, Black HR, et al; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-1252. 3. James PA, Oparil S, Carter BL, 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 (5):507-520.
In Reply Dr Margolis raised a few concerns regarding our interpretations of the 2014 blood pressure guideline1 and our calculations of patients who would be affected by the changes. Specifically, she questioned our use of a cutoff of 150 mm Hg for systolic blood pressure and 90 mm Hg for diastolic blood pressure for initiation of treatment in adults aged 70 years or older with chronic kidney disease and in those aged 60 years or older with diabetes. For both of these issues, the guideline is somewhat vague. When discussing blood pressure goals in patients with chronic kidney disease, the 2014 guideline text states: “Based on available evidence the panel cannot make a recommendation for a BP [blood pressure] goal for people aged 70 years or older with GFR [glomerular filtration rate] less than 60 mL/min/1.73m2. … Thus, when weighing the risks and benefits of a lower BP goal for people aged 70 years or older with estimated GFR less than 60 mL/min/1.73m2, antihypertensive treatment should be individualized, taking into consideration factors such as frailty, comorbidities, and albuminuria.” 1 Based on this, we elected to use a higher systolic/diastolic blood pressure threshold of 150/90 mm Hg for adults aged 70 years or older with chronic kidney disease. Similarly, when discussing blood pressure cutoffs in adults aged 60 years or older, the guideline authors note: “While all panel members agreed that the evidence supporting recommendation 1 is very strong, the panel was unable to reach unanimity on the recommendation of a goal SBP [systolic blood pressure] of lower than 150 mm Hg. Some members recommended continuing the JNC 7 SBP goal of lower than 140 mm Hg for individuals older than 60 years based on expert opinion. These members concluded that the evidence was insufficient to raise the SBP target from lower than 140 to lower than 150 mm Hg in high-risk groups, such as black persons, those with CVD [cardiovascular disease] including stroke, and those with multiple risk factors. The panel agreed that more research is needed to identify optimal goals of SBP for patients with high BP.”1 Given this uncertainty, we again elected to evaluate the higher systolic/diastolic blood pressure threshold of 150/90 mm Hg for adults aged 60 years or older with diabetes. However, to address the concerns of Margolis, we analyzed our sample using a systolic/diastolic blood pressure cutoff of 140/90 mm Hg or greater for all adults aged 60 years or older with diabetes or chronic kidney disease. Overall, our results were largely unchanged. The percentage of adults with treatment-eligible hypertension using the 2014
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