Proceedings from Duke Resistant Hypertension Think Tank

Proceedings from Duke Resistant Hypertension Think Tank Sreekanth Vemulapalli, MD, a Jamy Ard, MD, b George L. Bakris, MD, c Deepak L. Bhatt, MD, MPH, d Alan S. Brown, MD, e William C. Cushman, MD, f Keith C. Ferdinand, MD, g John M. Flack, MD, MPH, h Jerome L. Fleg, MD, i Barry T. Katzen, MD, j John B. Kostis, MD, k Suzanne Oparil, MD, l Chet B. Patel, MD, a,m Carl J. Pepine, MD, n Ileana L. Piña, MD, MPH, o Krishna J. Rocha-Singh, MD, p Raymond R. Townsend, MD, q Eric D. Peterson, MD, MPH, a,m Robert M. Califf, MD, a,m and Manesh R. Patel, MD a,m Durham, and Winston Salem, NC; Chicago, and Springfield, IL; Boston, MA; Park Ridge, IL; Memphis, TN; New Orleans, LA; Detroit, MI; Bethesda, MD; Miami, and Gainesville, FL; New Brunswick, NJ; Birmingham, AL; New York, NY; Philadelphia, PA

To identify patients at increased risk for cardiovascular outcomes, apparent treatment resistant hypertension (aTRH) is defined as having a blood pressure (BP) above goal despite the use of ≥3 antihypertensive therapies of different classes at maximally tolerated doses, ideally including a diuretic. In light of growing scientific interest in the treatment of this group, a multistakeholder think tank was convened to discuss the current state of knowledge, improve the care of these patients, and identify appropriate study populations for future observational and randomized trials in the field. Although recent epidemiologic studies in selected populations estimate that the prevalence of aTRH is 10% to 15% of hypertensive patients, further large-scale observational studies will be needed to better elucidate risk factors. To spur the development of therapies for aTRH, the development of an “aTRH” label for pharmacologic and device therapies with a developmental pathway including treatment added to the use of existing therapies is favored. Although demonstration of adequate BP lowering should be sufficient to gain Food and Drug Administration approval for therapies targeting aTRH, assessment of improvement in quality of life and cardiovascular outcomes is also desirable and considered in Centers for Medicare and Medicaid Services coverage decisions. Device trials under the aTRH label will need uniform and consistent processes for defining appropriate patient populations as well as postapproval registries assessing both long-term safety and duration of responses. Finally, patients with aTRH are likely to benefit from evaluation by a hypertension team to assure proper patient identification, diagnostic work-up, and therapeutic management before consideration of advanced or novel therapies to lower BP. (Am Heart J 2014;0:1-14.e1.)

The worldwide burden of hypertension is considerable, with 26.4% of the adult population or 972 million patients

From the aDivision of Cardiology, Duke University Medical Center, Durham, NC, b Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston Salem, NC, cDepartment of Medicine, Hypertensive Diseases Unit, University of Chicago, Pritzker School of Medicine, Chicago, IL, dBrigham and Women’s Hospital and Harvard Medical School, Boston, MA, eDivision of Cardiology, Advocate Lutheran General Hospital, Park Ridge, IL, fSection of Preventive Medicine, Veterans Affairs Medical Center– Memphis, Memphis, TN, gTulane Heart and Vascular Institute and Tulane University School of Medicine, New Orleans, LA, hDepartment of Medicine, Wayne State University, Detroit, MI, iDivision of Cardiovascular Sciences, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, jBaptist Cardiac and Vascular Institute, Miami, FL, kDepartment of Medicine, UMDNJ-RWJ Medical School, New Brunswick, NJ, lSection of Vascular Biology and Hypertension, University of Alabama–Birmingham, Birmingham, AL, mDuke Clinical Research Institute, Durham, NC, nDivision of Cardiology, University of Florida, Gainesville, FL, oDivision of Cardiology, Montefiore Medical Center, New York, NY, pPrairie Heart Institute at St John’s Hospital, Springfield, IL, and qPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Submitted February 21, 2014; accepted February 21, 2014. Reprint requests: Manesh R. Patel, MD, Duke Clinical Research Institute, Duke University, 2400 Pratt St Durham, NC 27710. E-mail: [email protected] 0002-8703/$ - see front matter © 2014, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.02.008

having a diagnosis of hypertension in 2000. 1 Hypertension is the number one attributable risk factor for cardiovascular (CV) disease and is estimated to be responsible for over half of the estimated 17 million deaths per year resulting from CV disease worldwide. 2 Beyond mortality, hypertension is a significant risk factor for CV morbidity, including stroke, myocardial infarction (MI), renal failure, and heart failure. 3 Because CV mortality and morbidity increase with blood pressure (BP), with every 20/10-mm Hg increase in BP, CV mortality doubles. 4 Patients with severe, poorly controlled hypertension are of special concern, and there is particular interest in identifying patients whose BP control is difficult. To identify high-risk patients who may benefit from special therapeutic considerations, the American Heart Association (AHA) defined resistant hypertension in a 2008 scientific statement. 5 Years after resistant hypertension was defined, the epidemiology, CV outcomes, and patterns of care in this group remain poorly understood. With multiple new device-based therapies to treat high-risk hypertension on the horizon, including renal denervation and carotid baroreceptor

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activation and growing public interest in improving the care and outcomes of patients with hypertension, 6 a multistakeholder resistant hypertension think tank was conducted. Participants were convened to discuss the current state of knowledge of resistant hypertension with the expressed goals of (1) improving the systems of care designed to diagnose and treat patients with resistant hypertension, (2) improving adherence to evidenceand guideline-based therapies for resistant hypertension, (3) defining appropriate patient populations for future clinical trials and observational studies, and (4) defining appropriate trial designs and trial metrics and identifying stakeholders.

Process The think tank was convened on August 1 to 2, 2013 in Washington, DC. The participants included representatives from industry, academia, the Food and Drug Administration (FDA), National Institutes of Health (NIH), and Centers for Medicare and Medicaid Services (CMS). The meeting format included brief presentations followed by discussion about each of the central themes identified. Questions and answers were encouraged among all the participants, and summary sessions were held at the end of each specific topic.

Definition of resistant hypertension The primary reason to define resistant hypertension is to identify those patients at elevated CV risk. Accordingly, the original definition of resistant hypertension was advanced by Tarazi and Gifford 7 in the late 1970s as a “failure to control BP adequately with a good regimen (diuretic, sympathetic depressant, and guanethidine or vasodilator), provided that medications are taken as prescribed". It is notable that this definition appeared before the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), and calcium-channel blockers for the treatment of hypertension. Furthermore, the original definition predates the era of multiple medical therapies that have reduced rates of absolute CV morbidity and mortality, including statin therapy, acute MI reperfusion, and routine coronary revascularization. Reflecting improvements in CV mortality and the introduction of multiple new classes of antihypertensive medications, the definition of resistant hypertension evolved with the Joint National Committee 7 8 and the 2008 AHA Scientific Statement on Resistant Hypertension 5 to include patients with BP above goal despite adherence to treatment with 3 different classes of antihypertensive therapy, inclusive of a diuretic, at maximal tolerated doses.

The definition of resistant hypertension forms the basis for studies examining its epidemiology, outcomes, and potential therapies. Considerable confusion exists regarding the definition because (1) multiple definitions have been proposed 5,9-11 and (2) multiple terminologies exist with overlapping definitions. The Joint National Committee 7 and AHA have defined resistant hypertension as a failure to achieve goal BP when a patient adheres to the maximum tolerated doses of drugs from 3 antihypertensive drug classes, ideally including a diuretic. 5,8 In contrast, “pseudoresistance” may refer to patients who meet the definition of resistant hypertension due to poor adherence or issues related to measurement such as incorrect BP measurement technique or white coat hypertension. The broader term uncontrolled hypertension is often used for all patients with hypertension not at goal for any reason, including pseudoresistance or resistant hypertension (Figure 1). By these definitions, a patient with BP “at or below goal” on 4 antihypertensive medications, including a diuretic, has resistant hypertension but not uncontrolled hypertension. To focus on patients with resistant hypertension with uncontrolled BP, the term apparent treatment resistant hypertension (aTRH) has been used in the literature to encompass patients with BP ≥140/90 mm Hg who take ≥3 antihypertensive medications, including those with white coat hypertension and suboptimal medical adherence. 12,13 Lastly, the term refractory hypertension may refer to patients whose BP remains uncontrolled after ≥3 visits to a hypertension clinic over 6 months. 14 Although each of these terms describes differing but overlapping populations of patients with difficult to control hypertension (Figure 1), for the purposes of this meeting, the participants focused their discussion on the subset of patients with aTRH, unless otherwise stated. As new therapies continue to reduce overall cardiac risk and new therapies for hypertension emerge, the definition of resistant hypertension and its related subgroups will likely continue to evolve to reflect these changes.

Summary For the purpose of future studies, the consensus definition of aTRH included patients with a systolic BP ≥140 mm Hg on ≥3 BP medications of different classes (including a diuretic) at maximal tolerable doses.

Disease prevalence Early cohort and retrospective studies of aTRH focused on the epidemiology of uncontrolled hypertension. An analysis of the National Health and Nutrition Examination Survey found that the prevalence of uncontrolled hypertensive patients taking ≥3 antihypertensive medications has increased from 15.9% (1998-2004) to 28.0% (2005-2008) of treated patients (P b .001). 12 Accordingly, there is a large pool of potential patients with

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Figure 1

Hypertension terminology.

uncontrolled BP treated with 1 or 2 antihypertensive drugs who, with more intense treatment, might fulfill diagnostic criteria for resistant hypertension. More recently, multiple large cohort studies have investigated the incidence and prevalence of aTRH. Daugherty et al 15 examined the incidence of aTRH among newly diagnosed hypertensive patients in the combined Kaiser Northern California and Kaiser Colorado databases. Among 205,750 newly diagnosed hypertensive patients in the combined Kaiser databases, 1.9% were found to have aTRH, defined as uncontrolled BP on ≥3 antihypertensive medications or controlled BP on ≥4 antihypertensive medications, plus ≥80% medication adherence at one-and-a-half years of follow-up. Over a median follow-up of 3.8 years, CV events, defined as death, MI, congestive heart failure, stroke, or chronic kidney disease, were significantly higher in the aTRH group (18% vs 13.5%; P b .001); after adjustment for patient and clinical characteristics, aTRH remained associated with a higher risk of CV events (hazard ratio [HR] 1.47; 95% CI 1.33-1.62). 15 A subsequent analysis of 69,055 patients from the international Reduction of Atherothrombosis for Continued Health Registry of individuals with known

atherothrombotic CV disease or multiple risk factors for atherosclerosis found that the prevalence of aTRH, defined as BP above goal on ≥3 antihypertensive medications, was 12.7% among those with hypertension. As compared with hypertensive patients without aTRH, patients with aTRH had a higher risk of CV death, MI, or stroke on multivariable analysis (HR 1.11; 95% CI 1.021.20) (P = .017), as well as an increased risk of nonfatal stroke (HR 1.26; 95% CI 1.10-1.45) (P = .0008) and hospitalization due to heart failure (HR 1.36; 95% CI 1.231.51) (P b .0001). 16 To address the possibility that undertreatment of hypertension masks the true prevalence of aTRH, Bakhtar et al 17 assessed the prevalence of aTRH in a referral clinic. Although the prevalence of aTRH was 14.7% at the initial visit, it increased to 43.6% at 7-month follow-up. The striking increase in prevalence over time was likely explained by aggressive up-titration of antihypertensive medications and the addition of diuretics. Although these cohort studies represent a significant step forward in our understanding of the epidemiology of aTRH, they do have limitations. The Kaiser study represents incidence data from a geographically homogenous population within a closed health system, whereas the

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Reduction of Atherothrombosis for Continued Health Registry contains a significant proportion of international patients. Despite these analyses, there remains a need for additional ethnically, geographically, and socioeconomically diverse epidemiologic data because (1) there are varying practice patterns and racial compositions within different parts of the United States and (2) hypertension control varies across patient subgroups 18-20 and medical centers. 21

Summary It was clear from our review that there is a need for additional large-scale observational studies to provide more generalizable information on the prevalence of aTRH and its associated CV outcomes. In addition, such data could provide a better elucidation of risk factors and causal factors for aTRH.

Populations for further study Patients with aTRH are at increased risk for CV morbidity and mortality and represent a subgroup of patients that may be amenable to novel treatment strategies and therapies. Other hypertensive subgroups are of interest as well. Apparent treatment resistant hypertension patients with pseudoresistance due to medication nonadherence are still at risk for significant CV morbidity and mortality and may benefit from alternative therapeutic options. Although not well studied, some patients with controlled resistant hypertension may have medicationinduced reduced quality of life and may also benefit from alternative options. Although medication nonadherence is still frequently attributed by the medical profession to a fault of the patient, its etiologies are multifold and include patientrelated, condition-related, therapy-related, socioeconomic-related, and health system–related factors. 22-24 Patientrelated variables in medication adherence include race and depression as well as difficulty in sustaining complex therapies for chronic conditions. Furthermore, care for aTRH in the United States is currently fragmented between primary care physicians, nephrologists, endocrinologists, cardiologists, and hypertension specialists. As a result, evidence-based efforts focused on the coordination of care and the use of allied health professionals 25-28 to deliver integrated care focused on improved medication and lifestyle adherence may be difficult to implement in aTRH. Among medically adherent patients with aTRH, there is a presumed burden imposed by polypharmacy on patient quality of life. Although existing data in hypertension clinical trials have generally failed to show a decrement in quality of life among those taking 1 or 2 antihypertensive medications, 29-31 wide interpatient and intermedication class variation in quality of life exists. 32 Furthermore, data in patients with aTRH are lacking. Given the presump-

tion that polypharmacy is linked to decreased quality of life, implementation of novel therapeutic strategies and systems of care may prove beneficial to those with both aTRH and controlled resistant hypertension.

Summary The think tank participants agreed that, in addition to currently studied populations, future studies of aTRH should be more inclusive of minorities, the elderly, women, and populations of patients with significant comorbidities such as heart failure and chronic kidney disease. Specific inclusion of patients with pseudoresistant hypertension due to medication nonadherence was also favored.

Pharmacotherapy in aTRH The mainstay of treatment for patients with aTRH is currently a combination of lifestyle interventions and optimization of pharmacotherapy. A retrospective analysis of patients referred to a hypertension center indicated that suboptimal medical therapy was most often responsible for uncontrolled hypertension. This was most frequently rectified by addition of a diuretic, increase in diuretic dose, or change in diuretic class. 33 Although thiazide-type diuretics are typically recommended in patients without renal insufficiency, the loop diuretics are often reserved for effective volume and BP control in patients with severe renal dysfunction or heart failure. The comparative effectiveness of various classes of thiazide-type diuretics has not been well studied. Although hydrochlorothiazide 12.5 to 25 mg is the most commonly prescribed antihypertensive worldwide, a meta-analysis of randomized trials with ambulatory blood pressure monitoring (ABPM) outcomes indicated that it was less efficacious at these doses than at 50 mg. 34 In addition, a single, small, blinded study comparing hydrochlorothiazide 50 mg and chlorthalidone 25 mg daily indicated that chlorthalidone provided greater 24-hour ambulatory BP reduction, most notably at night. 35 Given the outcome benefits associated with chlorthalidone 36,37 and availability of single and combination formulations of hydrochlorothiazide, future studies in pharmacotherapy of aTRH should address the comparative effectiveness of thiazide and thiazide-type diuretics for controlling BP and reducing clinical events. Beyond the acknowledged importance of diuretic therapy in aTRH, limited data exist to guide the clinician in choosing among various multidrug combinations of antihypertensive therapy. The Veterans Affairs Single Drug Therapy Cooperative Study randomized ambulatory men to a single antihypertensive from 1 of 6 different classes (diuretic, β blocker, calcium-channel blocker, α blocker, ACE inhibitor, or a centrally acting α agonist) in a double-blind prospective trial. 38 Subsequently, if BP remained uncontrolled, patients were rerandomized to an alternative single drug. Nonresponders to the second

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drug received the first and second drugs in combination. Although not specifically tested in an aTRH population, combinations including diuretics were found to be more effective at achieving goal BP than those without a diuretic (77% vs 46%; P = .002). 38 In addition, multiple studies have demonstrated enhanced efficacy of β blockers, ACE inhibitors, and ARBs in blacks taking a concurrent diuretic. 39 Given a prevalence of subclinical or clinically apparent mineralocorticoid excess of up to 20% within the aTRH population, the 2008 AHA Scientific Statement on Resistant Hypertension proposes the use of aldosterone antagonists as part of a multidrug regimen. 5,40 Nonrandomized trial evidence for this strategy includes a study of 76 patients both with and without hyperaldosteronism referred to a hypertension clinic for aTRH while on a regimen of a diuretic plus an ACE inhibitor/ARB. Addition of 12.5 to 50 mg/day of spironolactone was associated with a mean 21/10 mm Hg reduction in BP at 6 weeks and a mean 25/12 mm Hg reduction in BP at 6-months. 41 In a secondary analysis of the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm, spironolactone was associated with a 21.9/9.5 mm Hg reduction in BP (95% CI: 20.8-23.0/9.0-10.1 mm Hg; P b .001) in the approximately 1,400 patients who received this agent as their fourth-line drug. 42 Although the recent interest in therapeutics for aTRH has centered on device-based therapies, many unanswered questions remain about drug therapy in this cohort. A key question, the comparative effectiveness of thiazide-type diuretics and the role of aldosterone antagonists or epithelial sodium channel antagonists in multidrug therapy, highlights the need for continued investigation of multidrug-based treatment strategies. Although multiple potential funding mechanisms for this type of research exist, recent and likely continuing cuts in government agency research budgets suggest that it will be necessary to create mechanisms to incentivize pharmaceutical companies to invest in the development of pharmaceuticals for aTRH. To this end, creation of a specific “aTRH” approval label for pharmaceuticals tested in the aTRH population may incentivize ongoing drug development and testing (Table I).

Summary The think tank participants diverged in recommendations about the specific thiazide-type diuretic to be used, but all agreed that a thiazide-type diuretic should usually be included in the drug regimen. Most participants also recommend the development of an “aTRH” label for pharmaceutical therapies with a developmental pathway that would include treatment added to the use of existing therapies.

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Table I. New pharmacologic targets for hypertension Region Global EU US Japan EU US EU NA EU APAC US US EU

Compound

Status

Neutral endopeptidase inhibitor (with ARB) Dopamine β-hydroxylase inhibitor Endothelial nitric oxide synthase modulator IkappaB kinase β inhibitor Na +/K + ATPase modulator Natriuretic peptide receptor agonist Phosphodiesterase 5 inhibitor Uricosuric agent (w/diuretic) Vaccine (angiotensin I) ORL1 receptor agonist (w/ diuretic) Phosphodiesterase 5 inhibitor VIP 2 receptor agonist Vaccine (angiotensin II)

Phase 2/3 Phase 2 Phase 2 Phase 2 Phase 2 Phase 2 Phase 2 Phase 2 Phase 2 Phase 1 Phase 1 Phase 1 Suspended in phase 2

Abbreviations: EU, European Union; US, United States; NA, not applicable; APAC, Asia Pacific; Na + / K +, sodium potassium; ATPase, adenosine triphosphatase.

Device therapy for aTRH Since the convening of this think tank, Medtronic Inc has issued a preliminary announcement regarding the failure of their SYMPLICITY Renal Denervation System to reach its primary efficacy end point in the SYMPLICITY HTN-3 US pivotal trial. 43 Nevertheless, the apparent success of early preclinical and initial clinical studies of device-based sympathetic nervous system modulation for the therapy of aTRH has spawned an explosion of new technologies for this field. A patent search encompassing January 1990 to August 2013 covering the terms resistant hypertension and sympathetic nervous system modulation returns N120,000 patent applications. A survey of publically available information reveals active development of ≥20 device-based systems for the treatment of aTRH (Table II). 44 Devices may be further classified as carotid baroreceptor modulators or renal denervation instruments. Via exogenous stimulation, carotid baroreceptor modulators attempt to reestablish normal carotid sinus nerve activity, which is diminished in chronic hypertension. Given that first generation devices require surgical exposure of the carotid sinuses and the placement of adventitial electrodes, recent design innovations have primarily been aimed at reducing the incidence of surgical complications and transient or permanent nerve injuries. Solutions have included the use of vibrational energy transmitted via bone from electrodes surgically placed on the clavicle instead of directly on the carotid sinus. Devices designed for renal denervation may be further classified by the mechanism by which denervation is achieved. Categories under development include (1) second generation endovascular catheter-based ultrasound or multipolar radiofrequency energy delivery systems aimed at reducing procedural time and

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Table II. Devices in development for the treatment of aTRH Company Energy: RF, ultrasound, radiation Ardian–Medtronic⁎ St Jude Medical⁎ Covidien-Maya Medical⁎ Boston Scientific–Vessix⁎ Vascular⁎ ReCor Medical⁎ Angiocare-Terumo⁎ Cordis CardioSonic Sound Interventions Kona Medical CyberHeart SyMap Medical Cibiem Verve Medical Drugs/agents NorthWind Medical Ablative Solutions, Inc Mercator Medsystems – ApexNano Therapeutics Implants: mechanical, electrical CVRx⁎ Rox Medical Vascular Dynamics Sympara

Device name

Symplicity EnligHTN OneShot Vessix V2 Paradise Iberis RenLane TIVUS Sound 360 Surround Sound – – –

Mechanism

RF renal denervation RF renal denervation RF renal denervation RF renal denervation U/S renal denervation RF renal denervation RF renal denervation U/S renal denervation U/S renal denervation U/S renal denervation Radio-surgical ablation/renal denervation RF renal denervation Carotid body modulation Transurethral RF renal denervation

– Peregrine System Bullfrog/Cricket Microinfusion Catheters – –

Adventitial renal denervation with neurotropic agent Adventitial neurotropic with ethanol Adventitial ethanol with guanethidine

Rheos Coupler MobiusHD

Carotid baroreceptor modulation Creates iliac artery/vein AV fistula Cartid baroreceptor modulation Carotid baroreceptor modulation with vibrational energy

Vincristine guanethidine Adventitial renal denervation with Botox B magnetic nanoparticles placed by magnetic field

Abbreviations: U/S, Ultrasound; RF, radiofrequency; AV, arterovenous. ⁎ Received CE mark.

anatomical contraindications, (2) endovascular catheterbased systems to deliver ablative medications or agents (ethanol, guanethidine, vincristine, and Botox B magnetic nanoparticles), and (3) noninvasive ultrasound ablation systems. Preclinical animal studies evaluating these techniques have generally shown short-term histologic evidence of renal nerve ablation without vessel wall injury in conjunction with reductions in plasma norepinephrine. Regulatory and product development issues may differ between drugs and devices because of the rapid pace of device improvement and iteration. As a result, issues to be considered in device therapy for aTRH include, in part (1) the development of clinically relevant safety outcomes, (2) development and integration of premarket and postmarket surveillance programs in the refinement of future generations of devices, and (3) integration of international safety and efficacy data into regulatory approvals. These issues and the number of potential devices in development for the management of aTRH mandate careful consideration of appropriate clinical trial parameters and associated regulatory concerns.

Summary The think tank participants reviewed the large number of possible device-based therapies for aTRH. The group

agreed on the need for uniform and consistent processes for defining appropriate patient populations for (1) clinical trials of device therapies and (2) postapproval registries assessing both long-term safety and duration of responses.

Considerations in clinical trial design for aTRH Study populations Appropriate patient populations for clinical trials in aTRH have yet to be formally defined. There are multiple hypertensive subpopulations that may derive benefit from new therapies, including aTRH, uncontrolled hypertension, and pseudoresistant hypertension due to medication nonadherence. Given the high burden of hypertension among African Americans 45 and Hispanics 46 , special effort will be required to ensure adequate representation of these groups among study populations. Following the strategy of developing devicebased therapies in the highest risk populations with the fewest alternative treatments, existing and ongoing randomized pivotal trials, such as SYMPLICITY HTN-2 47 and SYMPLICITY HTN-3 48, have enrolled patients with aTRH and systolic BP ≥160 mm Hg. Initial device and pharmacologic pivotal trials rightly focus on this highrisk population. However, should they continue to show

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Figure 2

Mean treatment and placebo effects in randomized controlled trials of hypertensive patients with mean baseline systolic BP ≥150 mm Hg. Ninetyfive percent CI are shown when they could be calculated from the published data. In trials where multiple treatment arms exist, only the arm with the greatest treatment effect is shown.

efficacy in this group, second and third generation studies focused on the broader populations of aTRH (systolic BP ≥140 mm Hg), and uncontrolled hypertension may be of value.

Control groups Appropriate control groups for trials in aTRH, uncontrolled hypertension, and pseudoresistant hypertension due to medication nonadherence will necessarily vary by the hypotheses and goals of the trial. However, various potential control groups exist, each with unique strengths and weaknesses with regards to trial design. Initial US pivotal trials in device-based therapy for aTRH have adopted a rigorous active comparison of the experimental intervention with a sham procedure plus optimal care control group. In these control groups, patients undergo a blinded sham procedure that essentially serves as a placebo and assessment of medication compliance via self-reported medication administration logs. Although selection of an optimal therapy comparator group necessarily limits the applicability of the study findings as it may not reflect “real-world” care, the greater clinical trial design challenge may be accounting for “placebo effect.” A review of pharmacotherapeutic hypertension trials in patients with mean initial systolic BP ≥150 mm Hg demonstrates the presence of a notable placebo effect (Figure 2). Although sham procedure

placebo groups have not previously been used in hypertension trials, predicting and accounting for this effect with appropriate statistical powering will be critical. 49 In contrast, the selection of a “usual care” control group will likely prove more appropriate for treatment strategy or comparative effectiveness trials, although this approach is more challenging. Alhough treatment strategy trials necessarily require prior pivotal trials establishing efficacy, in the area of aTRH, multiple potential strategy trials exist, including (1) chlorthalidone versus hydrochlorothiazide as diuretic therapy, (2) spironolactone versus usual care as fourth-line therapy, (3) pharmacotherapy plus a new device or drug versus usual care as fourth-line therapy, (4) care provided by hypertension team approach versus usual care and referral to a certified hypertension specialist (Table III).

Efficacy outcomes Clinical trials in aTRH, like many studies of primary prevention, are plagued by relatively low CV event rates and long expected latency periods between enrollment and effects on CV outcomes. As a result, selection of very high-risk groups or a biomarker-based metric is often necessary. Although the formal criteria for surrogate metrics comprise a high hurdle, 50 BP lowering to b150/ 90 mm Hg, regardless of the pharmacologic mechanism,

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Table III. Suggested strategy trials in aTRH Study population

Intervention tested

aTRH

Diuretic type

aTRH

Fourth-line therapy: spironolactone vs usual care

aTRH

Fourth-line therapy: new drug or device vs usual care

aTRH

Systems of care intervention

Treatment strategy 1

Treatment strategy 2

1. Three antihypertensives of different classes, including a diuretic 2. Chlorthalidone (25 mg) as diuretic 1. Three antihypertensives of different classes, including a diuretic 2. Spironolactone 25-50 mg 1. Three antihypertensives of different classes, including a diuretic 2. New drug or device Care via HTN team

1. Three antihypertensives of different classes, including a diuretic 2. HCTZ (25 mg) as diuretic 1. Three antihypertensives of different classes, including a diuretic 2. Usual care 1. Three antihypertensives of different classes, including a diuretic 2. Usual care Usual care, including referral to HTN specialist

Abbreviation: HCTZ, Hydrochlorothiazide; HTN, Hypertension.

has been reliably associated with a reduction in CV events. 36,51-56 Although multiple studies have failed to show a significant CV or renal benefit with lower goal BP, 31,54,57-60 because of the strong relationship above this threshold, BP lowering has been considered a useful efficacy outcome for trials of pharmacotherapy. As a result, antihypertensive drugs have not traditionally been expected to have outcomes studies. At issue is whether the observed correlation between BP lowering and CV outcomes holds true for the mechanisms of action of device therapies. Current device therapies appear to directly target autonomic activity, a mechanism not used by available pharmacotherapies. As a result, given the lack of overlap in mechanism of action between device and drug therapies, postmarketing studies of clinical outcomes may be necessary for device therapies. Office BP fulfills many of the requirements of an ideal metric, including simple, noninvasive measurement, short latency in response to interventions, and correlation and causality to CV outcomes. The timing of the trial metric is also of critical importance. Although treatment effect in pharmacotherapy may be detectable within hours to weeks depending on half-life, initial clinical data from studies of renal denervation and carotid baroreceptor modulation indicate that treatment effect may require weeks to months to manifest. 61-63 Multiple device trials for aTRH have chosen to measure the primary outcome at 6 months. 47,48,64 This timepoint makes a crossover design feasible, thus allowing all participants the opportunity to receive the intervention. Assuming an efficacious intervention, a 6-month primary outcome minimizes the amount of time that the control group may be “undertreated.” Although 6 months of difference in therapy between the intervention and control groups is unlikely to result in a difference in CV outcomes, based on long-term data from SYMPLICITY HTN-1 and SYMPLICITY HTN-2, 63,65 it allows enough latency to observe a difference in BP. The selection of secondary outcomes is also of importance in clinical trial design because they allow for the investigation of biological mechanism that may

underlie potential treatment effects. Ambulatory blood pressure monitoring with 24-hour, day and night average BP values correlates more closely than office BP to endorgan damage, 66-70 and nighttime BP is more closely related to CV morbidity and mortality than daytime BP. In addition, the placebo effect noted in previous pharmacotherapy hypertension studies is also thought to be mitigated by ABPM as compared with office BP. 71,72 As a result, ABPM may represent an ideal secondary outcome or perhaps, even a primary outcome, for studies of aTRH. Furthermore, the association between high nighttime BP and nondipping patterns and increased sympathetic activity 73 suggests that ABPM may be a tool useful for differentiating responders and nonresponders to therapies targeting autonomic nervous system modulation. Other secondary end points of interest for future studies of autonomic nervous system modulation and other therapies for aTRH should focus on elucidating mechanisms and predictors of response as well as markers of subclinical end-organ damage. Appropriate secondary outcomes in future clinical trials of aTRH should also include quality of life measures. Patients with aTRH often have higher rates of anxiety and depression with lower baseline quality of life than normotensive patients and patients with controlled BP. 74 Multiple retrospective cohort analyses of renal denervation have identified improvement in quality of life measures out of proportion to BP effects. 74-76 Prospective assessment of quality of life using both general and disease-specific instruments in the context of controlled clinical trials will be ideal for a more complete understanding of therapeutic efficacy.

Safety outcomes Trials assessing therapies for the primary prevention of CV outcomes will be judged on the balance of benefit and risk over a relevant period of observation. Proper selection of safety measures for trials of novel therapeutic modalities, such as autonomic modulation, are especially important given the potential for unforeseen shortand long-term treatment-related adverse side effects,

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including orthostatic hypotension and impaired stress response. At least 2 major considerations exist in the assessment of safety: the adverse outcome and the timing of the adverse outcome assessment. In device-based trials, 3 particular timepoints are of interest: periprocedural safety, short-term safety, and long-term safety. Precedent has been set in both the SYMPLICITY HTN-3 48 trial of renal denervation and the Rheos Pivotal Trial 64 of carotid baroreceptor modulation to assess 1-month periprocedural safety and 6-month (short-term) safety outcomes. Assessment of longer term safety outcomes in trials of therapies with novel mechanisms, where a lack of clinical experience may make it difficult to anticipate adverse effects, will require longer in trial follow-up as well as a careful strategy for postmarketing registry surveillance. Although device and pharmacologic trials in hypertension face distinct design and assessment challenges, the European Medical Agency guidelines for the assessment of pharmacologic intervention in hypertension trials 77 echo many of the recommendations discussed above (Table IV).

CMS coverage decisions Representatives from the CMS described their procedures for making decisions on coverage. Centers for Medicare and Medicaid Services coverage decisions are made under the framework of whether an item or service is “reasonable and necessary” without consideration of cost. Specifically, the criteria for this determination are whether an item or service (1) improves health outcomes, (2) is generalizable to the Medicare population (generally those who are age ≥65 years), and (3) is generalizable to the general provider community. Health outcomes are weighed on a 2-tiered system. Outcomes demonstrating longer life and improved function, increased quality of life, or symptom improvement are regarded to be superior to longer life with declining function, improved disease-specific survival, or improved surrogate end points. Sources of evidence considered include peer-reviewed journal articles, technology assessments by the Agency for Health Care Research and Quality Evidence-based Practice Centers, and Medicare Evidence Development and Coverage Advisory Committee recommendations. Based on previous coverage decisions, the most commonly encountered evidence deficits are nonstandard or nonvalidated outcome measures, short-term follow-up, lack of comparative effectiveness, and poor generalizability for Medicare beneficiaries and providers. Given the current US government and industryfunding climate, completion of the large and lengthy trials required for the demonstration of improved CV outcomes with adequate follow-up will likely require novel funding mechanisms and cost-saving trial designs (eg, NIH RFA-RM-13-012 for efficient, large-scale prag-

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Table IV. European Medical Agency guidelines for the assessment of pharmacologic intervention in hypertension Study design Blinding/randomization Run-in period Duration Efficacy criteria Morbidity and mortality Reduction in BP Office sphygmomanometry Noninvasive ABPM Intraarterial measurement Target organ damage Long-term safety criteria Nonclinical data Clinical data

Adverse events Hypotension/orthostasis Target organ damage Effects on comorbidities

Effects on risk factors

Double blind/randomized 2-4 weeks Controlled studies with reference agents should last 6 months Would require large-scale, long-term controlled trials Valid surrogate end point Standard method of determining BP in clinical pivotal trials Strongly recommended secondary end point Appropriate for phase II studies Supportive secondary end point Animal studies Patient level meta-analysis or specific long-term controlled outcome study with ≥18-24 months follow-up Drug/intervention specific Symptomatic or asymptomatic Renal function, electrolyte homeostasis, LVH Diabetes, renal impairment, ischemic heart disease, heart failure, cerebrovascular disease, peripheral artery disease, sleep apnea, anxiety Glucose and lipid metabolism

Abbreviation: LVH, Left ventricular hypertrophy.

matic clinical trials focused on management of patients with chronic conditions).

Novel trial designs and funding mechanisms for aTRH With the rising costs of clinical trials, diminishing government and industry funding and rapid development cycles in devices and standards of care, the current models of executing clinical trials are ill suited for the future landscape of clinical research. Specifically, the total cost of developing a single drug for market was estimated to be $1.2 billion in 2003, 78 and a recent survey of pharmaceutical and biotech companies indicated that the per-patient cost of conducting a phase IIIb trial is approximately $48,000. 79 Thus, strategies to share the funding burden among multiple stakeholders and to maintain the scientific validity of randomized clinical trials, while minimizing costs are needed to spur drug and device development in aTRH. The electronic health record (EHR)-based clinical trial provides one strategy to minimize administrative costs and optimize clinical trial recruitment. In this construct, trial recruitment is accomplished either by retrospective EHR search followed by approaching the potential participant for consent or by real-time notification of a clinical provider that his or her patient is eligible for trial inclusion. Point-of-care clinical trials using EHR for

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both randomization and ascertainment of outcomes have recently been completed in the Veterans Affairs system for comparing sliding scale and weight-based insulin administration. 80,81 High-risk hypertension interventions are especially well suited to EHR-based trials. Identification of appropriate patient populations based on BP and medication data and International Classification of Diseases, Ninth Revision codes has been achieved in multiple studies. 15,82 Randomization and informed consent may be obtained through web-based or telephone-based systems, whereas outcomes are obtained through EHR and insurance databases. One example of a database randomized clinical trial is the recently reported SAFE-PCI for Women study. 83 This study used the existing National Cardiovascular Data Registry CathPCI Registry and the National Institutes of Health’s Cardiovascular Research infrastructure to randomized 1,787 women to percutaneous coronary intervention through either a radial or femoral access approach. This study was financed via an innovative consortium of academic, industry, and government sponsors at a per-patient cost of approximately $2,800—well below the average for phase IIIb trials. Another strategy to minimize clinical trial costs is the adaptive trial design popular in cancer research. Adaptive trial design seeks to reduce the high economic and time costs of traditional simple randomized clinical trials by changing trial parameters at predefined timepoints in response to interim “looks” at the data. Common adaptations include changing medication dose in a treatment arm, changing trial duration or sample size based on event rate, or eliminating interventions that appear to be ineffective. 84 Because trial adaptations may introduce bias, the resultant trial may not preserve the type I error rate at the prespecified level of significance. To avoid this, proper execution of adaptive trial design requires greater up-front statistical planning and infrastructure. In the setting of trials of renal denervation/carotid baroreceptor modulation or other therapies with an expected delay between treatment and treatment effect, surrogate outcomes that support rapid prediction of primary outcomes may also be necessary. Based on its superior repeatability and prediction of CV outcomes as compared with clinic BP, ABPM may be an appropriate outcome from which to adapt trial design, assuming a primary end point of clinic BP. Although adaptive trial designs are encouraged by FDA, their complexity and uncertainty regarding appropriate adaption points mandate early involvement of FDA in trial design, especially to ensure appropriate assessment of potentially uncommon safety outcomes. Summary for clinical trials. Participants all agreed that BP reduction should remain sufficient for FDA approval of either devices or pharmacotherapy for aTRH. Centers for Medicare and Medicaid Services indicated that the criteria for coverage decisions weighted therapeutic impact on CV outcomes and quality of life

outcomes more heavily than surrogate outcomes. The participants believed that future studies aimed at evaluating improvements in clinical outcomes should be conducted. Finally, the group agreed that there is a need for more studies and measurement instruments to evaluate quality of life outcomes associated with aTRH.

The hypertension team Advancements in multifaceted care for heart failure and valvular heart disease have spawned the creation of a multidisciplinary “heart team” to streamline care coordination and ensure appropriate evaluation for access to novel treatment strategies. In contrast to valve disease or heart failure, where physician care is provided primarily by a cardiologist, hypertension is typically treated by primary care providers, nephrologists, cardiologists, and endocrinologists. To unify this fragmented system, creation of a multidisciplinary “hypertension team” could enable greater efficiency and improved rates of BP control in aTRH patients. The multidisciplinary team could be composed of a primary care provider, a nutritionist, a clinical pharmacist, an exercise specialist, a behavioral scientist, a hypertension specialist, and an interventional physician working in concert. (Figure 3) Ideally, the “hypertension team” would be localized in one site; however, creation of relationships among the component providers of the “hypertension team” is the keystone of the concept and provides for the formation of a virtual clinic. Penetration of this organizational concept into the community and beyond large medical systems and academic medical centers will be necessary to ensure (1) easier implementation of current evidencebased strategies to improve medication and lifestyle adherence, (2) improved provider adherence to guideline- and evidence-based recommendations regarding the work-up and treatment of patients with aTRH, (3) creation of a clinical infrastructure that will serve as the basis for EHR-based observational research registries and clinical trial recruitment, (4) the creation of a clinical infrastructure that permits rapid access to approved novel treatment strategies and therapies, and (5) the careful selection of patients in whom application of these technologies is most likely to be effective.

Summary The think tank participants believed that aTRH patients are likely to benefit from evaluation by a hypertension team to assure proper patient identification, diagnostic work-up, and therapeutic management before consideration of advanced or novel therapies to lower BP.

Conclusion Multiple overlapping populations of hypertensive patients, including aTRH, controlled resistant

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as well as implementation of therapies will be ideal to ensure quality care.

Figure 3

Disclosures

The hypertension team.

hypertension, uncontrolled hypertension, and pseudoresistant hypertension due to medication nonadherence may benefit from novel pharmacologic or device-based therapies. Although distinct, each of these populations may benefit from drug- or device-based therapies due to a failure of available medical options, a failure in medical adherence, or a failure of the current fragmented system of hypertension care to deliver integrated, patientcentered lifestyle therapy, and pharmacotherapy. Creation of a multidisciplinary hypertension team–based system of care for these populations is likely to improve the implementation of currently available treatments and allows for the rapid and efficient implementation of newly approved therapies. To spur the development of novel therapies, a drug and device designation for therapy of aTRH is ideal. To date, studies of aTRH populations have focused on the additive value of device-based therapies to optimal medical therapy. Future studies should test effective devicebased strategies versus usual care and drug-based strategies, stratified by BP. Given that interventions in aTRH are essentially primary prevention for CV events, strategy trials will need to select outcomes that provide an integrated assessment of efficacy and safety. In addition, novel trial strategies, especially EHR-based clinical trials, combined with multiple stakeholder sponsors will be necessary to achieve the requisite efficiencies to make these trials feasible in the current funding climate. Lastly, with the potential emergence of multiple novel pharmacologic and device-based therapies for aTRH, creation of a national registry to track outcomes

The following companies provided unrestricted funding for this meeting: AstraZeneca, Bayer, Boston Scientific, Covidien, Eli Lilly and Company, Medtronic, St. Jude, and Takeda Pharmaceuticals. The views expressed in this manuscript are the authors' and do not necessarily reflect those of the National Institutes of Health or the Department of Health and Human Services. Barry T. Katzen, MD—consultant: Medtronic, St Jude Medical, and Boston Scientific. John M. Flack—grants/research support: NIH, Novartis, and Medtronic; consultant: Novartis, NIH, Medtronic, Back Beat Hypertension, and NIVasc; speaker bureau: Novartis. George L. Bakris—grants/research support: Takeda, Medtronic; consultant: Takeda, AbbVie, CVRx, Janssen, Eli Lilly/Boeringher-Ingelheim, Medtronic, BMS, Novartis, GSK, and Bayer. Dr Deepak L. Bhatt—advisory board: Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; board of directors: Boston VA Research Institute and Society of Cardiovascular Patient Care; chair: American Heart Association Get With The Guidelines Steering Committee; data monitoring committees: Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute (DSMB for EnligHTNment); honoraria: American College of Cardiology (Editor: Clinical Trials and Cardiosource), Belvoir Publications (Editor-in-Chief: Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor-in-Chief: Journal of Invasive Cardiology), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor: Cardiology Today’s Intervention), and WebMD (CME steering committees); other: Clinical Cardiology (Associate Editor) and Journal of the American College of Cardiology (Section Editor: Pharmacology); research grants: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic (co-PI of SYMPLICITY HTN-3 and steering committee member of SYMPLICITY HTN-4), Roche, Sanofi Aventis, and The Medicines Company; and unfunded research: FlowCo, PLx Pharma, and Takeda. Keith Ferdinand—consulting and speaking: Astra Zeneca, Daiichi Sankyo, Forest, Novartis, Arbor, and Boehringer Ingleheim; and research grants: Eli Lilly and Company. Krishna Rocha-Singh—consultant: Medtronic, Boston Scientific, CardioSonics, CiBiem, Cordis, and Covidien. William C. Cushman—consulting: Janssen and Takeda; and grants: Merck and Lilly. Alan S. Brown—consulting and speaking: Merck, Aegerion, Amarin, and Gilead.

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Raymond R Townsend—consulting: GSK, Merck, Janssen, and Medtronic; grants: NIH; travel support: American Society of Nephrology, American Society of Hypertension, National Kidney Foundation, and American Heart Association; royalties: UpToDate; and honorarium: PriMED. Robert Califf—research grants: Amylin, BMS, Eli-Lilly & Company, Janssen Research & Development, LLC, Merck, and Novartis; and consultant: BMS, Genentech, GSK, HeartOrg-Diaichi Sankyo, Janssen Research & Development, LLC, Kowa, Les Laboratoires Servier, Medscape LLC/heart.org, and Roche. Carl Pepine—research grants: Abbott, Actelion Pharmaceuticals, Amarin, Amgen, Amorcyte, Angioblast/ Mesoblast, AstraZeneca, Baxter Healthcare, Brigham and Women’s Hospital, Capricor, Inc, Catabasis Pharmaceuticals, Cytori, Daiichi Sankyo, Esperion Therapeutics, Genentech, Gilead, GlaxoSmithKline, InfraReDx Inc, Isis Pharmaceuticals, Lilly, Medtronic, NeoStem Inc, NIH/ NHLBI, Regeneron Pharmaceuticals, Sanofi, and United Therapeutics Corp; and consultant: Lilly/CCF-DSMB, Mesoblast-DSMB, Servier, and SLACK Inc. Eric Peterson—research grants: Janssen Pharmaceutical Products, Society of Thoracic Surgeons, and American Heart Association; and consultant: Merck & Co, SanofiAventis, Genentech, and Boehringer Ingelheim. Manesh Patel—research grants: NHLBI, Johnson and Johnson, Astra Zeneca, Baxter Healthcare, AHRQ, Medtronic; and consultant: Bayer Healthcare, Baxter, Genzyme, Otsuka, and Cardiostem. Funding: The Duke Resistant Hypertension Think Tank was supported by unrestricted grants from AstraZeneca, Bayer, Boston Scientific, Covidien, Eli Lilly and Company, Medtronic, St Jude, and Takeda Pharmaceuticals.

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Appendix. Think Tank Participants: Jamy Ard, MD, Associate Professor, Epidemiology & Prevention Wake Forest School of Medicine. George Bakris, MD, Professor of Medicine, Director, Comprehensive Hypertension Center, University of Chicago. Deepak Bhatt, MD, MPH, Chief of Cardiology Executive Director of Interventional Cardiovascular Programs, Brigham and Women’s Hospital, Heart and Vascular Center; Professor of Medicine, Harvard Medical School. Steven Brooks, MD, Medical Officer, Division of Cardiovascular Devices Food and Drug Administration, CDRH. Alan S. Brown, MD, Division of Cardiology, Advocate Lutheran General Hospital. Robert Califf, MD, Vice Chancellor for Clinical & Translational Research Duke Medical Center, DTMI. Todd Courtney, MS, FDA, CDRH. William Cushman, MD, Chief, Preventive Medical Section Veterans Affairs Medical Center, Memphis. John M. Flack, MD, MPH, CECA Director and Associate Chairman for Clinical Research and Interim Chair, Dept. of Internal Medicine, Wayne State University. Jerome L. Fleg, MD, Medical Officer Division of Cardiovascular Sciences NIH, NHLBI. Barry Katzen, MD, Founder and Medical Director, Baptist Cardiac & Vascular Institute. John B. Kostis, MD, Director of Cardiovascular Institute, UMDNJ-RWJ Medical School. Lisa M. Lim, PhD, Acting Chief, Peripheral Interventional Devices Branch FDA, CDRH. Suzanne Oparil, MD, Professor of Medicine and Physiology & Biophysics University of Alabama, Birmingham. Chet Patel, MD, Assistant Professor of Medicine, Cardiology/Transplant Duke University Medical Center.

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Manesh Patel, MD, Associate Professor of Medicine, Director of Interventional Cardiology, Duke Health System Duke Clinical Research Institute. Carl Pepine, MD, Professor of Medicine, Cardiology University of Florida. Eric Peterson, MD, MPH, Director Duke Clinical Research Institute, Duke University Medical Center. Ileana L. Piña, MD, MPH, Associate Chief for Academic Affairs, Cardiology Montefiore Medical Center. Krishna J. Rocha- Singh, MD, Interventional Cardiology & Vascular Medicine Prairie Heart Institute at St John’s Hospital. Jyme H. Schafer, MD, MPH, Director, Division of Medical and Surgical Services CMS/OSCQ/Coverage and Analysis Group. Kimberly Smith, MD/CMS, Medical Officer Centers for Medicaid and Medicare Services Centers for Clinical Standards and Quality Coverage and Analysis Group. Norman Stockbrige, MD, PhD, Division Director Division of Cardiovascular and Renal Products, FDA, CDER. John Sundy, MD, Associate Professor of Medicine, Director of the DCRU Director, Center for Educational Excellence, Duke Clinical Research Institute Duke University Medical Center. Robert Temple, MD, FDA, Center for Drug Evaluation and Research Deputy Director for Clinical Science. Raymond R. Townsend, MD, Professor of Medicine, Associate Director, Clinical & Translational Research Center/CTSA, Perelman School of Medicine University of Pennsylvania. Sreekanth Vemulapalli, MD, Instructor of Medicine, Division of Cardiology Duke University Medical Center. Bram Zuckerman, MD, Director, FDA Division of Cardiovascular Devices.