Letters
Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Hsia. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Le. Obtained funding: Hsia. Administrative, technical, or material support: Hsia. Study supervision: Hsia. Conflict of Interest Disclosures: None reported. Funding/Support: This study was supported by an American Heart Association National Clinical Research Program Award (Dr Hsia). Role of the Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Sun BC, Hsia RY, Weiss RE, et al. Effect of emergency department crowding on outcomes of admitted patients. Ann Emerg Med. 2013;61(6):605-611.e6. doi: 10.1016/j.annemergmed.2012.10.026. 2. Guttmann A, Schull MJ, Vermeulen MJ, Stukel TA. Association between waiting times and short term mortality and hospital admission after departure from emergency department: population based cohort study from Ontario, Canada. BMJ. 2011;342:d2983. doi:10.1136/bmj.d2983. 3. Centers for Medicare & Medicaid Services. Data updates. 2013. http://www.medicare.gov/hospitalcompare/Data/Data-Updates.html. Accessed October 1, 2013. 4. Chan TC, Killeen JP, Kelly D, Guss DA. Impact of rapid entry and accelerated care at triage on reducing emergency department patient wait times, lengths of stay, and rate of left without being seen. Ann Emerg Med. 2005;46(6):491497. 5. Falvo T, Grove L, Stachura R, et al. The opportunity loss of boarding admitted patients in the emergency department. Acad Emerg Med. 2007;14(4):332-337. 6. Fee C, Burstin H, Maselli JH, Hsia RY. Association of emergency department length of stay with safety-net status. JAMA. 2012;307(5):476-482. 7. Hsia RY, Asch SM, Weiss RE, et al. Hospital determinants of emergency department left without being seen rates. Ann Emerg Med. 2011;58(1):24-32.e3. doi:10.1016/j.annemergmed.2011.01.009. 8. American Hospital Association. AHA Annual Survey Database. Chicago, IL: American Hospital Association; 2012. 9. US Department of Agriculture. Measuring rurality: Rural-urban commuting area codes. http://www.ers.usda.gov/data-products/rural-urban-commuting -area-codes.aspx#.U6_kDvldUWI. Accessed June 29, 2014. 10. Centers for Medicare & Medicaid Services. Hospital cost reports. 2011. http: //www.cms.gov/Research-Statistics-Data-and-Systems/Files-for-Order /CostReports/Cost-Reports-by-Fiscal-Year-Items/HOSP-DL-2011.html?DLPage =6&DLSort=0&DLSortDir=ascending. Accessed August 18, 2013. 11. Centers for Medicare & Medicaid Services. Impact File for IPPS FY 2012 final rule. 2011. http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment /AcuteInpatientPPS/Historical-Impact-Files-for-FY-1994-through-Present -Items/Impact-File-for-IPPS-FY2012-Final-Rule.html?DLPage=1&DLSort=1 &DLSortDir=descending. Accessed August 18, 2013.
Renal Artery Revascularization: Updated Meta-analysis With the CORAL Trial Arguments for renal artery revascularization include blood pressure control, stabilization of renal function, and reduction in adverse cardiovascular events. We previously reported on the randomized clinical trial data to 2009 regarding renal artery revascularization compared with medical therapy.1 That Related article page 1815 and report concluded that renal Invited Commentary page 1851 artery revascularization was associated with marginal improvement in serum creatinine levels (P = .06) and no improvement in systolic blood pressure (P = .32), although there was need for fewer antihypertensive medications (P < .001). Since then, the Cardiovascu-
lar Outcomes in Renal Atherosclerotic Lesions (CORAL) Trial has been published.2 Methods | Details of the previous meta-analysis have been described.1 Briefly, the MEDLINE database was searched for trials published from study inception through June 2010. We required that patients were randomized to percutaneous revascularization of a renal artery stenosis with or without stenting vs medical therapy alone. Three independent reviewers extracted data elements. Summary relative risks and 95% CIs were calculated for dichotomous variables using a DerSimonian and Laird random-effects model. For continuous variables, the weighted mean difference (WMD) and 95% CIs were computed using a random-effects model. The Begg funnel plot assessed for publication bias, while heterogeneity was assessed by the I2 measure. An updated search of the MEDLINE database was performed from June 2010 to November 2013, which revealed 2 additional trials.2,3 Data from these trials were extracted (by 2 of us: A.A.B. and D.J.K.) and added to our preexisting database. One minor discrepancy was resolved by discussion. Analyses were performed with STATA statistical software (version 12.0; StataCorp LP). Overall, there were 8 studies in 2223 patients. The 5 later studies routinely used stents. The mean age ranged from 59 to 72 years, and the proportion of women ranged from 27% to 50%. At baseline, the mean number of antihypertensive medications was 2.43, and the mean systolic blood pressure ranged from 131 to 182 mm Hg. The mean duration of follow-up was 34.2 months. Renal artery revascularization was not associated with a change in systolic blood pressure from baseline when compared with medical therapy (WMD, 0.12; 95% CI, −0.97 to 1.21; P = .83) but was associated with a reduction in the number of antihypertensive medications required at follow-up (2.96 vs 3.18; WMD, −0.23; 95% CI, −0.33 to −0.12; P < .001). There was no evidence of heterogeneity (I2 = 0) or publication bias (P = .45 for change in systolic blood pressure; P = .85 for medications at follow-up). Revascularization was not associated with a reduction in adverse cardiovascular or renal outcomes compared with medical therapy (Figure). Results were similar when restricted to stent-only trials. Discussion | Among patients with renal artery stenosis and hypertension and/or chronic kidney disease, revascularization was of marginal benefit. This therapy slightly reduced the need for antihypertensive medications. However, revascularization did not reduce adverse cardiovascular or renal outcomes compared with medical therapy over a mean follow-up of 34 months. Patients enrolled in the CORAL Trial likely mirrored clinical practice in that the degree of renal artery stenosis was somewhat modest, and the frequency of bilateral renal artery stenosis was low.2 Also, in the CORAL Trial, the average blood pressure at baseline was 150 mm Hg, a value at which revascularization may be unlikely to provide much benefit. It still remains plausible that revascularization could benefit patients with severe bilateral stenoses, or a critical stenosis that supplies a solitary kidney; however, such a trial is unlikely to be performed. Currently, the only class I recommendation for
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Figure. Summary Estimates of Cardiovascular Outcomes for Revascularization vs Medical Therapy A Mortality
Source STAR ASTRAL SNARSCG NITER CORAL RASCAD DRASTIC EMMA Overall (I 2 = 0.0%; P = .98)
Favors Revascularization
RR (95% CI) 0.99 (0.32-3.09) 0.98 (0.74-1.29) 0.60 (0.12-3.01) 0.86 (0.19-3.86) 0.85 (0.63-1.16) 0.95 (0.14-6.46) (Excluded) (Excluded) 0.91 (0.75-1.11) 0.1
Favors Medical Therapy
1.0
10
RR (95% CI) B
Congestive heart failure
Source STAR ASTRAL SNARSCG CORAL RASCAD Overall (I 2 = 0.0%; P = .80)
Favors Revascularization
RR (95% CI) 0.40 (0.04-3.71) 0.80 (0.55-1.16) 0.90 (0.22-3.65) 1.03 (0.67-1.57) 1.91 (0.18-20.24) 0.89 (0.68-1.17) 0.1
Favors Medical Therapy
1.0
10
RR (95% CI) C
Stroke
Source STAR ASTRAL SNARSCG NITER CORAL RASCAD Overall (I 2 = 0.0%; P = .85)
Favors Revascularization
RR (95% CI) 0.39 (0.02-9.53) 1.06 (0.56-1.98) 0.30 (0.04-2.51) 0.64 (0.16-2.59) 0.72 (0.38-1.34) 0.95 (0.06-14.75) 0.80 (0.54-1.21) 0.1
Favors Medical Therapy
1.0
10
RR (95% CI) D Worsening renal function
Source STAR ASTRAL DRASTIC SNARSCG EMMA NITER CORAL Overall (I 2 = 0.0%; P = .91)
Favors Revascularization
RR (95% CI) 0.74 (0.36-1.52) 0.98 (0.67-1.43) 0.30 (0.03-2.77) 1.20 (0.18-7.92) 0.38 (0.02-8.78) 1.07 (0.50-2.28) 0.99 (0.76-1.27) 0.96 (0.79-1.16) 0.1
Favors Medical Therapy
1.0
10
RR (95% CI)
renal revascularization is in the setting of recurrent pulmonary edema.4 In conclusion, routine revascularization of a renal artery stenosis does not seem to be clinically beneficial. Anthony A. Bavry, MD, MPH Samir R. Kapadia, MD Deepak L. Bhatt, MD, MPH Dharam J. Kumbhani, MD, SM, MRCP 1850
A, Mortality incidence was 14.0% for revascularization vs 15.3% for medical therapy (P = .37). B, Hospitalization for heart failure was 9.4% vs 10.4% (P = .40); C, for stroke: 4.1% vs 5.1% (P = .30); and D, for worsening renal function: 15.3% vs 16.1% (P = .67), respectively. ASTRAL indicates Angioplasty and Stenting for Renal Artery Lesions; CORAL, Cardiovascular Outcomes in Renal Atherosclerotic Lesions; DRASTIC, Dutch Renal Artery Stenosis Intervention Cooperative; EMMA, Essai Multicentrique Medicaments vs Angioplastie; NITER, Nephropathy Ischemic ThERapy; RASCAD, Renal Artery Stenosis in Coronary Artery Disease; RR, risk ratio; SNARSCG, Scottish and Newcastle Renal Artery Stenosis Collaborative Group; STAR, STent placement and blood pressure and lipid-lowering for the prevention of progression of renal dysfunction caused by Atherosclerotic ostial stenosis of the Renal artery.
Author Affiliations: Department of Medicine, University of Florida, Gainesville (Bavry); Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio (Kapadia); Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Bhatt); Department of Medicine, University of Texas Southwestern Medical Center, Dallas (Kumbhani). Corresponding Author: Anthony A. Bavry, MD, MPH, Cardiology Section, Medical Service, North Florida/South Georgia Veterans Health System (Malcolm Randal Veterans Administration Medical Center), 1601 SW Archer Rd, Gainesville, FL 32608 ([email protected]). Published Online: September 15, 2014. doi:10.1001/jamainternmed.2014.4332.
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Author Contributions: Dr Bavry 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: Bavry, Kapadia, Kumbhani. Acquisition, analysis, or interpretation of data: Bhatt, Kumbhani. Drafting of the manuscript: Bavry, Kapadia, Kumbhani. Critical revision of the manuscript for important intellectual content: Kapadia, Bhatt, Kumbhani. Statistical analysis: Bavry. Study supervision: Bavry, Kapadia. Conflict of Interest Disclosures: Dr Bavry has received honoraria from the American College of Cardiology and Gilead and research support from Novartis Pharmaceuticals, Gilead, and Eli Lilly. Dr Bhatt has been on the advisory boards for Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; on the board of directors for the Boston VA Research Institute and the Society of Cardiovascular Patient Care; has been chair of American Heart Association Get With The Guidelines Steering Committee; has received honoraria from the American College of Cardiology (editor, Clinical Trials, Cardiosource), Belvoir Publications (editor-in-chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today’s Intervention), WebMD (CME steering committees); has been senior associate editor, Journal of Invasive Cardiology; has been on the data monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; has received research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic (for his role as co–principal investigator of Symplicity HTN-3 and member of the steering committee of Symplicity HTN-4), Sanofi-Aventis, and The Medicines Company; and has performed unfunded research for FlowCo, PLx Pharma, and Takeda. Dr Kumbhani has received honoraria from the American College of Cardiology and Somahlutions Inc. No other disclosures are reported. 1. Kumbhani DJ, Bavry AA, Harvey JE, et al. Clinical outcomes after percutaneous revascularization versus medical management in patients with significant renal artery stenosis: a meta-analysis of randomized controlled trials. Am Heart J. 2011;161(3):622-630, e1. 2. Cooper CJ, Murphy TP, Cutlip DE, et al; CORAL Investigators. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014; 370(1):13-22. 3. Marcantoni C, Zanoli L, Rastelli S, et al. Effect of renal artery stenting on left ventricular mass: a randomized clinical trial. Am J Kidney Dis. 2012;60(1):39-46. 4. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(13):1425-1443.
Invited Commentary
The Kidney Connection: Holy Grail or Wild Goose Chase? The pathophysiologic mechanisms of renovascular hypertension are well described: Hemodynamically significant renal artery stenosis results in reduced renal perfusion pressure, which in turn leads to activation of the renin-angiotensin system and increased levels of angiotensin II, resulting in systemic vasoconstriction, aldosterone release, sodium retention, and expansion of extracellular fluid volume and blood volume. Logically, reversal of the restriction in flow and establishment of normal renal perfusion pressure should reverse the process and decrease blood pressure. Nevertheless, the clinical benefits of renal artery revascularization in the setting of refractory hypertension have been variable, and largely disappointing. In this issue of JAMA Internal Medicine, Bavry et al1 present an update to their 2011 meta-analysis2 of renal revascularization vs medical therapy for resistant hypertension. Their findings once again suggest no significant difference in sys-
tolic or diastolic blood pressure among patients randomized to renal artery revascularization or medical therapy. Important clinical outcomes such as death, stroke, congestive heart failure, or worsening renal function also did not differ between treatment groups. The only outcome measure that differed significantly between groups in the current analysis was the mean number of antihypertensive medications, which was lower in patients randomized to revascularization (2.96 vs 3.18; weighted mean difference, −0.23; 95% CI, −0.33 to −0.12; P < .001). These results are materially unchanged from those of their prior publication. This update was undertaken owing to the recent publication of the much anticipated Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) Trial,3 which reported only a modest reduction in blood pressure after a median of 43 months of follow-up in patients randomized to renal artery stenting (−2.3 mm Hg; 95% CI, −4.4 to −0.2; P = .03) compared with medical therapy, and no difference in death from cardiovascular or renal causes, myocardial infarction, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy. Why have we been unable to demonstrate a benefit with renal artery revascularization? Prior critiques have focused on patient selection because some studies have included patients with less-than-severe renal artery stenosis and unilateral disease. Logically, stricter inclusion criteria may allow for better identification of patients most likely to benefit from renal artery revascularization. However, while prior studies included patients with stenoses of 50% or greater,4 patients enrolled in the CORAL Trial were required to have at least 80% diameter stenosis or at least 60% stenosis with a pressure gradient of at least 20 mm Hg. We must also acknowledge the high interobserver variability in visual estimation of angiographic lesion severity. In the setting of coronary artery disease, we have learned that revascularization of lesions with objective evidence of ischemia results in improved outcomes compared with the previously standard practice of revascularization of lesions based on angiographic criteria alone. The same might hold true for renal artery stenosis, and accordingly, measures such as fractional flow reserve or the renal resistive index might be useful in identifying patients who truly have a renovascular component to their hypertension and who might benefit from revascularization.5 Furthermore, the technical challenges of treating predominantly aorto-ostial disease must be addressed, and the potential impact of adjunctive technologies, such as intravascular ultrasonography, have not been evaluated in contemporary studies of renal artery revascularization. Finally, restenosis (as high as 15% in prior studies) may temper the clinical benefits of renal artery revascularization, and current-generation drug-eluting stents are not available in the large sizes typically needed for renal artery stenting. There is, however, a deeper reason to question the renalhypertension connection. Another recent publication, the Symplicity 3 HTN (hypertension) study,6 surprisingly demonstrated no significant reduction in blood pressure in patients undergoing renal artery denervation and has generated an uproar in the field of interventional treatment of resistant hypertension. Prior, nonrandomized, studies7,8 suggested signifi-
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cant decreases in blood pressure following renal denervation, but this sham-controlled study identified no such benefit. While these findings also may be influenced by patient selection, they should concern those inclined to recommend interventional treatment of resistant hypertension presumed due to renovascular causes. Keeping in mind that blood pressure reduction can only be considered a surrogate for “hard end points” such as death, myocardial infarction, stroke, congestive heart failure, and renal failure, we seem to be very far removed from any convincing evidence that renal artery interventions reduce cardiovascular or renal morbidity or mortality. With these issues in mind, where do we go from here? While awaiting further studies to investigate the possibility of a clinical benefit to renal artery interventions, we must focus on aggressive medical management of patients with refractory hypertension. We should not overlook the consistent evidence that sodium restriction, increased potassium intake, exercise and weight loss are associated with blood pressure reduction in patients with hypertension. Furthermore, the recent Eighth Joint National Committee guidelines9 suggest that for nonblack patients, first-line therapy for hypertension should consist of 1 or a combination of thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. For black patients, firstline therapy should consist of thiazide diuretics and calcium channel blockers. Emphasis on the importance of lifestyle measures and medication compliance, and consideration of secondary causes such as sleep apnea, drug-induced hypertension, hypercortisolism, hyperaldosteronism, hyperthyroidism or hypothyroidism, or hyperparathyroidism is warranted in patients with resistant hypertension. Focus on proven therapies while we await more concrete data supporting the use of interventional procedures for resistant hypertension is the most reasonable approach, at least until the next big thing comes along. David M. Safley, MD Adnan K. Chhatriwalla, MD Author Affiliations: Saint Luke’s Mid America Heart Institute, Kansas City, Missouri; University of Missouri–Kansas City, Kansas City. Corresponding Author: Adnan K. Chhatriwalla, MD, Saint Luke’s Mid America Heart Institute, 4300 Wornall Rd, Ste 2000, Kansas City, MO 64111 ([email protected]). Published Online: September 15, 2014. doi:10.1001/jamainternmed.2014.3139. Conflict of Interest Disclosures: Dr Chhatriwalla reports travel reimbursements from Edwards Lifesciences Corp, Medtronic Inc, and St Jude Medical Inc. 1. Bavry AA, Kapadia SR, Bhatt DL, Kumbhani DJ. Renal artery revascularization: updated meta-analysis with the CORAL Trial [published online September 15, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014.4332. 2. Kumbhani DJ, Bavry AA, Harvey JE, et al. Clinical outcomes after percutaneous revascularization versus medical management in patients with significant renal artery stenosis: a meta-analysis of randomized controlled trials. Am Heart J. 2011;161(3):622-630, e1. 3. Cooper CJ, Murphy TP, Cutlip DE, et al; CORAL Investigators. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014; 370(1):13-22. 4. Bax L, Woittiez AJ, Kouwenberg HJ, et al. Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial. Ann Intern Med. 2009;150(12):840-848, W150-1.
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5. Leesar MA, Varma J, Shapira A, et al. Prediction of hypertension improvement after stenting of renal artery stenosis: comparative accuracy of translesional pressure gradients, intravascular ultrasound, and angiography. J Am Coll Cardiol. 2009;53(25):2363-2371. 6. Bhatt DL, Kandzari DE, O’Neill WW, et al; SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393-1401. 7. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M; Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376(9756):1903-1909. 8. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275-1281. 9. 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.
LESS IS MORE
Altering Overuse of Cardiac Telemetry in Non–Intensive Care Unit Settings by Hardwiring the Use of American Heart Association Guidelines Arrhythmia detection is reported to affect the clinical management of care in 3.4% to 12.7% of patients.1 The American Heart Association’s (AHA’s)2 published recommendations addressing the use of non–intensive care unit (non-ICU) cardiac telemetry stratify patients into 3 categories: cardiac telemetry Invited Commentary is indicated, may provide benpage 1855 efit, or is unlikely to provide benefit. Clinical-effectiveness studies of implementing these guidelines have either reported the use of labor-intensive strategies3 or nonsustained decreases in non-ICU cardiac telemetry use.4 Various efforts to reduce the perceived overuse of cardiac telemetry at Christiana Care Health System, a 1100-bed tertiary care system, were unsuccessful. In August 2012 we convened a team to increase the appropriate use of non-ICU cardiac telemetry through the integration of AHA guidelines into our electronic ordering system (EOS). This effort was validated in March 2013 when nonICU use of cardiac telemetry appeared on the Society of Hospital Medicine’s top 5 list for the Choosing Wisely campaign.5 Methods | Approval for this study was received from the institutional review board of Christiana Healthcare System; need for patient consent was waived. Our interdisciplinary team redesigned and standardized all cardiac telemetry orders within our EOS. Cardiac telemetry orders were removed from order sets for clinical conditions for which monitoring was not supported by the AHA guidelines.2 The remaining orders for cardiac telemetry required providers to select from a list of clinical indications, each with its AHA guideline–based predetermined telemetry duration (Box). Bedside nurse assessment guidelines were embedded in the EOS to facilitate safe, timely, and automatic discontinuation of cardiac telemetry. When telemetry discontinuation was believed to be unsafe, such as in a patient with unstable blood pressure, the nurse was required to contact the physician, and telemetry could be reordered when appropriate.
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Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Hsia. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Le. Obtained funding: Hsia. Administrative, technical, or material support: Hsia. Study supervision: Hsia. Conflict of Interest Disclosures: None reported. Funding/Support: This study was supported by an American Heart Association National Clinical Research Program Award (Dr Hsia). Role of the Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Sun BC, Hsia RY, Weiss RE, et al. Effect of emergency department crowding on outcomes of admitted patients. Ann Emerg Med. 2013;61(6):605-611.e6. doi: 10.1016/j.annemergmed.2012.10.026. 2. Guttmann A, Schull MJ, Vermeulen MJ, Stukel TA. Association between waiting times and short term mortality and hospital admission after departure from emergency department: population based cohort study from Ontario, Canada. BMJ. 2011;342:d2983. doi:10.1136/bmj.d2983. 3. Centers for Medicare & Medicaid Services. Data updates. 2013. http://www.medicare.gov/hospitalcompare/Data/Data-Updates.html. Accessed October 1, 2013. 4. Chan TC, Killeen JP, Kelly D, Guss DA. Impact of rapid entry and accelerated care at triage on reducing emergency department patient wait times, lengths of stay, and rate of left without being seen. Ann Emerg Med. 2005;46(6):491497. 5. Falvo T, Grove L, Stachura R, et al. The opportunity loss of boarding admitted patients in the emergency department. Acad Emerg Med. 2007;14(4):332-337. 6. Fee C, Burstin H, Maselli JH, Hsia RY. Association of emergency department length of stay with safety-net status. JAMA. 2012;307(5):476-482. 7. Hsia RY, Asch SM, Weiss RE, et al. Hospital determinants of emergency department left without being seen rates. Ann Emerg Med. 2011;58(1):24-32.e3. doi:10.1016/j.annemergmed.2011.01.009. 8. American Hospital Association. AHA Annual Survey Database. Chicago, IL: American Hospital Association; 2012. 9. US Department of Agriculture. Measuring rurality: Rural-urban commuting area codes. http://www.ers.usda.gov/data-products/rural-urban-commuting -area-codes.aspx#.U6_kDvldUWI. Accessed June 29, 2014. 10. Centers for Medicare & Medicaid Services. Hospital cost reports. 2011. http: //www.cms.gov/Research-Statistics-Data-and-Systems/Files-for-Order /CostReports/Cost-Reports-by-Fiscal-Year-Items/HOSP-DL-2011.html?DLPage =6&DLSort=0&DLSortDir=ascending. Accessed August 18, 2013. 11. Centers for Medicare & Medicaid Services. Impact File for IPPS FY 2012 final rule. 2011. http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment /AcuteInpatientPPS/Historical-Impact-Files-for-FY-1994-through-Present -Items/Impact-File-for-IPPS-FY2012-Final-Rule.html?DLPage=1&DLSort=1 &DLSortDir=descending. Accessed August 18, 2013.
Renal Artery Revascularization: Updated Meta-analysis With the CORAL Trial Arguments for renal artery revascularization include blood pressure control, stabilization of renal function, and reduction in adverse cardiovascular events. We previously reported on the randomized clinical trial data to 2009 regarding renal artery revascularization compared with medical therapy.1 That Related article page 1815 and report concluded that renal Invited Commentary page 1851 artery revascularization was associated with marginal improvement in serum creatinine levels (P = .06) and no improvement in systolic blood pressure (P = .32), although there was need for fewer antihypertensive medications (P < .001). Since then, the Cardiovascu-
lar Outcomes in Renal Atherosclerotic Lesions (CORAL) Trial has been published.2 Methods | Details of the previous meta-analysis have been described.1 Briefly, the MEDLINE database was searched for trials published from study inception through June 2010. We required that patients were randomized to percutaneous revascularization of a renal artery stenosis with or without stenting vs medical therapy alone. Three independent reviewers extracted data elements. Summary relative risks and 95% CIs were calculated for dichotomous variables using a DerSimonian and Laird random-effects model. For continuous variables, the weighted mean difference (WMD) and 95% CIs were computed using a random-effects model. The Begg funnel plot assessed for publication bias, while heterogeneity was assessed by the I2 measure. An updated search of the MEDLINE database was performed from June 2010 to November 2013, which revealed 2 additional trials.2,3 Data from these trials were extracted (by 2 of us: A.A.B. and D.J.K.) and added to our preexisting database. One minor discrepancy was resolved by discussion. Analyses were performed with STATA statistical software (version 12.0; StataCorp LP). Overall, there were 8 studies in 2223 patients. The 5 later studies routinely used stents. The mean age ranged from 59 to 72 years, and the proportion of women ranged from 27% to 50%. At baseline, the mean number of antihypertensive medications was 2.43, and the mean systolic blood pressure ranged from 131 to 182 mm Hg. The mean duration of follow-up was 34.2 months. Renal artery revascularization was not associated with a change in systolic blood pressure from baseline when compared with medical therapy (WMD, 0.12; 95% CI, −0.97 to 1.21; P = .83) but was associated with a reduction in the number of antihypertensive medications required at follow-up (2.96 vs 3.18; WMD, −0.23; 95% CI, −0.33 to −0.12; P < .001). There was no evidence of heterogeneity (I2 = 0) or publication bias (P = .45 for change in systolic blood pressure; P = .85 for medications at follow-up). Revascularization was not associated with a reduction in adverse cardiovascular or renal outcomes compared with medical therapy (Figure). Results were similar when restricted to stent-only trials. Discussion | Among patients with renal artery stenosis and hypertension and/or chronic kidney disease, revascularization was of marginal benefit. This therapy slightly reduced the need for antihypertensive medications. However, revascularization did not reduce adverse cardiovascular or renal outcomes compared with medical therapy over a mean follow-up of 34 months. Patients enrolled in the CORAL Trial likely mirrored clinical practice in that the degree of renal artery stenosis was somewhat modest, and the frequency of bilateral renal artery stenosis was low.2 Also, in the CORAL Trial, the average blood pressure at baseline was 150 mm Hg, a value at which revascularization may be unlikely to provide much benefit. It still remains plausible that revascularization could benefit patients with severe bilateral stenoses, or a critical stenosis that supplies a solitary kidney; however, such a trial is unlikely to be performed. Currently, the only class I recommendation for
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Figure. Summary Estimates of Cardiovascular Outcomes for Revascularization vs Medical Therapy A Mortality
Source STAR ASTRAL SNARSCG NITER CORAL RASCAD DRASTIC EMMA Overall (I 2 = 0.0%; P = .98)
Favors Revascularization
RR (95% CI) 0.99 (0.32-3.09) 0.98 (0.74-1.29) 0.60 (0.12-3.01) 0.86 (0.19-3.86) 0.85 (0.63-1.16) 0.95 (0.14-6.46) (Excluded) (Excluded) 0.91 (0.75-1.11) 0.1
Favors Medical Therapy
1.0
10
RR (95% CI) B
Congestive heart failure
Source STAR ASTRAL SNARSCG CORAL RASCAD Overall (I 2 = 0.0%; P = .80)
Favors Revascularization
RR (95% CI) 0.40 (0.04-3.71) 0.80 (0.55-1.16) 0.90 (0.22-3.65) 1.03 (0.67-1.57) 1.91 (0.18-20.24) 0.89 (0.68-1.17) 0.1
Favors Medical Therapy
1.0
10
RR (95% CI) C
Stroke
Source STAR ASTRAL SNARSCG NITER CORAL RASCAD Overall (I 2 = 0.0%; P = .85)
Favors Revascularization
RR (95% CI) 0.39 (0.02-9.53) 1.06 (0.56-1.98) 0.30 (0.04-2.51) 0.64 (0.16-2.59) 0.72 (0.38-1.34) 0.95 (0.06-14.75) 0.80 (0.54-1.21) 0.1
Favors Medical Therapy
1.0
10
RR (95% CI) D Worsening renal function
Source STAR ASTRAL DRASTIC SNARSCG EMMA NITER CORAL Overall (I 2 = 0.0%; P = .91)
Favors Revascularization
RR (95% CI) 0.74 (0.36-1.52) 0.98 (0.67-1.43) 0.30 (0.03-2.77) 1.20 (0.18-7.92) 0.38 (0.02-8.78) 1.07 (0.50-2.28) 0.99 (0.76-1.27) 0.96 (0.79-1.16) 0.1
Favors Medical Therapy
1.0
10
RR (95% CI)
renal revascularization is in the setting of recurrent pulmonary edema.4 In conclusion, routine revascularization of a renal artery stenosis does not seem to be clinically beneficial. Anthony A. Bavry, MD, MPH Samir R. Kapadia, MD Deepak L. Bhatt, MD, MPH Dharam J. Kumbhani, MD, SM, MRCP 1850
A, Mortality incidence was 14.0% for revascularization vs 15.3% for medical therapy (P = .37). B, Hospitalization for heart failure was 9.4% vs 10.4% (P = .40); C, for stroke: 4.1% vs 5.1% (P = .30); and D, for worsening renal function: 15.3% vs 16.1% (P = .67), respectively. ASTRAL indicates Angioplasty and Stenting for Renal Artery Lesions; CORAL, Cardiovascular Outcomes in Renal Atherosclerotic Lesions; DRASTIC, Dutch Renal Artery Stenosis Intervention Cooperative; EMMA, Essai Multicentrique Medicaments vs Angioplastie; NITER, Nephropathy Ischemic ThERapy; RASCAD, Renal Artery Stenosis in Coronary Artery Disease; RR, risk ratio; SNARSCG, Scottish and Newcastle Renal Artery Stenosis Collaborative Group; STAR, STent placement and blood pressure and lipid-lowering for the prevention of progression of renal dysfunction caused by Atherosclerotic ostial stenosis of the Renal artery.
Author Affiliations: Department of Medicine, University of Florida, Gainesville (Bavry); Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio (Kapadia); Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts (Bhatt); Department of Medicine, University of Texas Southwestern Medical Center, Dallas (Kumbhani). Corresponding Author: Anthony A. Bavry, MD, MPH, Cardiology Section, Medical Service, North Florida/South Georgia Veterans Health System (Malcolm Randal Veterans Administration Medical Center), 1601 SW Archer Rd, Gainesville, FL 32608 ([email protected]). Published Online: September 15, 2014. doi:10.1001/jamainternmed.2014.4332.
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Author Contributions: Dr Bavry 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: Bavry, Kapadia, Kumbhani. Acquisition, analysis, or interpretation of data: Bhatt, Kumbhani. Drafting of the manuscript: Bavry, Kapadia, Kumbhani. Critical revision of the manuscript for important intellectual content: Kapadia, Bhatt, Kumbhani. Statistical analysis: Bavry. Study supervision: Bavry, Kapadia. Conflict of Interest Disclosures: Dr Bavry has received honoraria from the American College of Cardiology and Gilead and research support from Novartis Pharmaceuticals, Gilead, and Eli Lilly. Dr Bhatt has been on the advisory boards for Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; on the board of directors for the Boston VA Research Institute and the Society of Cardiovascular Patient Care; has been chair of American Heart Association Get With The Guidelines Steering Committee; has received honoraria from the American College of Cardiology (editor, Clinical Trials, Cardiosource), Belvoir Publications (editor-in-chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today’s Intervention), WebMD (CME steering committees); has been senior associate editor, Journal of Invasive Cardiology; has been on the data monitoring committees for Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; has received research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic (for his role as co–principal investigator of Symplicity HTN-3 and member of the steering committee of Symplicity HTN-4), Sanofi-Aventis, and The Medicines Company; and has performed unfunded research for FlowCo, PLx Pharma, and Takeda. Dr Kumbhani has received honoraria from the American College of Cardiology and Somahlutions Inc. No other disclosures are reported. 1. Kumbhani DJ, Bavry AA, Harvey JE, et al. Clinical outcomes after percutaneous revascularization versus medical management in patients with significant renal artery stenosis: a meta-analysis of randomized controlled trials. Am Heart J. 2011;161(3):622-630, e1. 2. Cooper CJ, Murphy TP, Cutlip DE, et al; CORAL Investigators. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014; 370(1):13-22. 3. Marcantoni C, Zanoli L, Rastelli S, et al. Effect of renal artery stenting on left ventricular mass: a randomized clinical trial. Am J Kidney Dis. 2012;60(1):39-46. 4. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(13):1425-1443.
Invited Commentary
The Kidney Connection: Holy Grail or Wild Goose Chase? The pathophysiologic mechanisms of renovascular hypertension are well described: Hemodynamically significant renal artery stenosis results in reduced renal perfusion pressure, which in turn leads to activation of the renin-angiotensin system and increased levels of angiotensin II, resulting in systemic vasoconstriction, aldosterone release, sodium retention, and expansion of extracellular fluid volume and blood volume. Logically, reversal of the restriction in flow and establishment of normal renal perfusion pressure should reverse the process and decrease blood pressure. Nevertheless, the clinical benefits of renal artery revascularization in the setting of refractory hypertension have been variable, and largely disappointing. In this issue of JAMA Internal Medicine, Bavry et al1 present an update to their 2011 meta-analysis2 of renal revascularization vs medical therapy for resistant hypertension. Their findings once again suggest no significant difference in sys-
tolic or diastolic blood pressure among patients randomized to renal artery revascularization or medical therapy. Important clinical outcomes such as death, stroke, congestive heart failure, or worsening renal function also did not differ between treatment groups. The only outcome measure that differed significantly between groups in the current analysis was the mean number of antihypertensive medications, which was lower in patients randomized to revascularization (2.96 vs 3.18; weighted mean difference, −0.23; 95% CI, −0.33 to −0.12; P < .001). These results are materially unchanged from those of their prior publication. This update was undertaken owing to the recent publication of the much anticipated Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) Trial,3 which reported only a modest reduction in blood pressure after a median of 43 months of follow-up in patients randomized to renal artery stenting (−2.3 mm Hg; 95% CI, −4.4 to −0.2; P = .03) compared with medical therapy, and no difference in death from cardiovascular or renal causes, myocardial infarction, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy. Why have we been unable to demonstrate a benefit with renal artery revascularization? Prior critiques have focused on patient selection because some studies have included patients with less-than-severe renal artery stenosis and unilateral disease. Logically, stricter inclusion criteria may allow for better identification of patients most likely to benefit from renal artery revascularization. However, while prior studies included patients with stenoses of 50% or greater,4 patients enrolled in the CORAL Trial were required to have at least 80% diameter stenosis or at least 60% stenosis with a pressure gradient of at least 20 mm Hg. We must also acknowledge the high interobserver variability in visual estimation of angiographic lesion severity. In the setting of coronary artery disease, we have learned that revascularization of lesions with objective evidence of ischemia results in improved outcomes compared with the previously standard practice of revascularization of lesions based on angiographic criteria alone. The same might hold true for renal artery stenosis, and accordingly, measures such as fractional flow reserve or the renal resistive index might be useful in identifying patients who truly have a renovascular component to their hypertension and who might benefit from revascularization.5 Furthermore, the technical challenges of treating predominantly aorto-ostial disease must be addressed, and the potential impact of adjunctive technologies, such as intravascular ultrasonography, have not been evaluated in contemporary studies of renal artery revascularization. Finally, restenosis (as high as 15% in prior studies) may temper the clinical benefits of renal artery revascularization, and current-generation drug-eluting stents are not available in the large sizes typically needed for renal artery stenting. There is, however, a deeper reason to question the renalhypertension connection. Another recent publication, the Symplicity 3 HTN (hypertension) study,6 surprisingly demonstrated no significant reduction in blood pressure in patients undergoing renal artery denervation and has generated an uproar in the field of interventional treatment of resistant hypertension. Prior, nonrandomized, studies7,8 suggested signifi-
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cant decreases in blood pressure following renal denervation, but this sham-controlled study identified no such benefit. While these findings also may be influenced by patient selection, they should concern those inclined to recommend interventional treatment of resistant hypertension presumed due to renovascular causes. Keeping in mind that blood pressure reduction can only be considered a surrogate for “hard end points” such as death, myocardial infarction, stroke, congestive heart failure, and renal failure, we seem to be very far removed from any convincing evidence that renal artery interventions reduce cardiovascular or renal morbidity or mortality. With these issues in mind, where do we go from here? While awaiting further studies to investigate the possibility of a clinical benefit to renal artery interventions, we must focus on aggressive medical management of patients with refractory hypertension. We should not overlook the consistent evidence that sodium restriction, increased potassium intake, exercise and weight loss are associated with blood pressure reduction in patients with hypertension. Furthermore, the recent Eighth Joint National Committee guidelines9 suggest that for nonblack patients, first-line therapy for hypertension should consist of 1 or a combination of thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. For black patients, firstline therapy should consist of thiazide diuretics and calcium channel blockers. Emphasis on the importance of lifestyle measures and medication compliance, and consideration of secondary causes such as sleep apnea, drug-induced hypertension, hypercortisolism, hyperaldosteronism, hyperthyroidism or hypothyroidism, or hyperparathyroidism is warranted in patients with resistant hypertension. Focus on proven therapies while we await more concrete data supporting the use of interventional procedures for resistant hypertension is the most reasonable approach, at least until the next big thing comes along. David M. Safley, MD Adnan K. Chhatriwalla, MD Author Affiliations: Saint Luke’s Mid America Heart Institute, Kansas City, Missouri; University of Missouri–Kansas City, Kansas City. Corresponding Author: Adnan K. Chhatriwalla, MD, Saint Luke’s Mid America Heart Institute, 4300 Wornall Rd, Ste 2000, Kansas City, MO 64111 ([email protected]). Published Online: September 15, 2014. doi:10.1001/jamainternmed.2014.3139. Conflict of Interest Disclosures: Dr Chhatriwalla reports travel reimbursements from Edwards Lifesciences Corp, Medtronic Inc, and St Jude Medical Inc. 1. Bavry AA, Kapadia SR, Bhatt DL, Kumbhani DJ. Renal artery revascularization: updated meta-analysis with the CORAL Trial [published online September 15, 2014]. JAMA Intern Med. doi:10.1001/jamainternmed.2014.4332. 2. Kumbhani DJ, Bavry AA, Harvey JE, et al. Clinical outcomes after percutaneous revascularization versus medical management in patients with significant renal artery stenosis: a meta-analysis of randomized controlled trials. Am Heart J. 2011;161(3):622-630, e1. 3. Cooper CJ, Murphy TP, Cutlip DE, et al; CORAL Investigators. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014; 370(1):13-22. 4. Bax L, Woittiez AJ, Kouwenberg HJ, et al. Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial. Ann Intern Med. 2009;150(12):840-848, W150-1.
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5. Leesar MA, Varma J, Shapira A, et al. Prediction of hypertension improvement after stenting of renal artery stenosis: comparative accuracy of translesional pressure gradients, intravascular ultrasound, and angiography. J Am Coll Cardiol. 2009;53(25):2363-2371. 6. Bhatt DL, Kandzari DE, O’Neill WW, et al; SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393-1401. 7. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M; Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376(9756):1903-1909. 8. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275-1281. 9. 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.
LESS IS MORE
Altering Overuse of Cardiac Telemetry in Non–Intensive Care Unit Settings by Hardwiring the Use of American Heart Association Guidelines Arrhythmia detection is reported to affect the clinical management of care in 3.4% to 12.7% of patients.1 The American Heart Association’s (AHA’s)2 published recommendations addressing the use of non–intensive care unit (non-ICU) cardiac telemetry stratify patients into 3 categories: cardiac telemetry Invited Commentary is indicated, may provide benpage 1855 efit, or is unlikely to provide benefit. Clinical-effectiveness studies of implementing these guidelines have either reported the use of labor-intensive strategies3 or nonsustained decreases in non-ICU cardiac telemetry use.4 Various efforts to reduce the perceived overuse of cardiac telemetry at Christiana Care Health System, a 1100-bed tertiary care system, were unsuccessful. In August 2012 we convened a team to increase the appropriate use of non-ICU cardiac telemetry through the integration of AHA guidelines into our electronic ordering system (EOS). This effort was validated in March 2013 when nonICU use of cardiac telemetry appeared on the Society of Hospital Medicine’s top 5 list for the Choosing Wisely campaign.5 Methods | Approval for this study was received from the institutional review board of Christiana Healthcare System; need for patient consent was waived. Our interdisciplinary team redesigned and standardized all cardiac telemetry orders within our EOS. Cardiac telemetry orders were removed from order sets for clinical conditions for which monitoring was not supported by the AHA guidelines.2 The remaining orders for cardiac telemetry required providers to select from a list of clinical indications, each with its AHA guideline–based predetermined telemetry duration (Box). Bedside nurse assessment guidelines were embedded in the EOS to facilitate safe, timely, and automatic discontinuation of cardiac telemetry. When telemetry discontinuation was believed to be unsafe, such as in a patient with unstable blood pressure, the nurse was required to contact the physician, and telemetry could be reordered when appropriate.
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