Jessica Weiss, MD, MCR; Michele Freeman, MPH; Allison Low, BA; Rochelle Fu, PhD; Amy Kerfoot, MD; Robin Paynter, MLIS; Makalapua Motu'apuaka, BS; Karli Kondo, PhD; Devan Kansagara, MD, MCR
Disclaimer: This article is based on research conducted by the Evidence-based Synthesis Program Center located at the Veterans Affairs Portland Health Care System, Portland, Oregon. The findings and conclusions in this article are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of the U.S. Department of Veterans Affairs or the U.S. government. Therefore, no statement in this article should be construed as an official position of the U.S. Department of Veterans Affairs.
Financial Support: This research was funded by the U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative.
Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-1754.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: Available at www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015017677. Statistical code: Available from Dr. Kansagara (e-mail, email@example.com). Data set: Supplementary data are available in the Supplement.
Requests for Single Reprints: Devan Kansagara, MD, MCR, Veterans Affairs Portland Health Care System, Mail Code RD71, 3710 SW US Veterans Hospital Road, Portland, OR 97239; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Weiss: Oregon Health & Science University, Mail Code SJH6, 3181 SW Sam Jackson Park Road, Portland, OR 97239.
Ms. Freeman; Ms. Low; Drs. Kerfoot, Kondo, and Kansagara; Ms. Paynter; and Ms. Motu'apuaka: Veterans Affairs Portland Health Care System, Mail Code RD71, 3710 SW US Veterans Hospital Road, Portland, OR 97239.
Dr. Fu: Oregon Health & Science University, Mail Code CB669, 3181 SW Sam Jackson Park Road, Portland, OR 97239.
Author Contributions: Conception and design: J. Weiss, A. Low, R. Paynter, M. Motu'apuaka, K. Kondo, D. Kansagara.
Analysis and interpretation of the data: J. Weiss, M. Freeman, R. Fu, A. Kerfoot, M. Motu'apuaka, K. Kondo, D. Kansagara.
Drafting of the article: J. Weiss, M. Freeman, R. Paynter, M. Motu'apuaka, K. Kondo, D. Kansagara.
Critical revision of the article for important intellectual content: J. Weiss, M. Freeman, A. Low, R. Fu, A. Kerfoot, M. Motu'apuaka, K. Kondo, D. Kansagara.
Final approval of the article: J. Weiss, M. Freeman, A. Low, R. Fu, A. Kerfoot, R. Paynter, M. Motu'apuaka, K. Kondo, D. Kansagara.
Statistical expertise: R. Fu.
Obtaining of funding: D. Kansagara.
Administrative, technical, or logistic support: M. Freeman, A. Low, R. Paynter, M. Motu'apuaka.
Collection and assembly of data: J. Weiss, M. Freeman, A. Low, R. Paynter, M. Motu'apuaka, K. Kondo, D. Kansagara.
This article has been corrected. The original version (PDF) is appended to this article as a Supplement.
Recent guidelines recommend a systolic blood pressure (SBP) goal of less than 150 mm Hg for adults aged 60 years or older, but the balance of benefits and harms is unclear in light of newer evidence.
To systematically review the effects of more versus less intensive BP control in older adults.
Multiple databases through January 2015 and MEDLINE to September 2016.
21 randomized, controlled trials comparing BP targets or treatment intensity, and 3 observational studies that assessed harms.
Two investigators extracted data, assessed study quality, and graded the evidence using published criteria.
Nine trials provided moderate- to high-strength evidence that BP control to less than 150/90 mm Hg reduces mortality (relative risk [RR], 0.93 [95% CI, 0.85 to 1.00]), cardiac events (RR, 0.83 [CI, 0.71 to 0.96]), and stroke (RR, 0.77 [CI, 0.65 to 0.91]). Six trials overall provide low-strength evidence that lower targets (≤140/85) do not reduce mortality (RR, 0.93 [CI, 0.75 to 1.14]), cardiac events (RR, 0.91 [CI, 0.77 to 1.04]), or stroke (RR, 0.86 [CI, 0.64 to 1.07]). However, there were important inconsistencies across these studies, and one large trial showed targeting SBP less than 120 mm Hg in patients at high cardiovascular risk reduced mortality and cardiac events.
Data relevant to frail elderly adults and the effect of multimorbidity are limited.
Treatment to at least current guideline standards for BP (<150/90 mm Hg) substantially improves health outcomes in older adults. There is less consistent evidence, largely from 1 trial targeting SBP less than 120 mm Hg, that lower BP targets are beneficial for high-risk patients. Lower BP targets did not increase falls or cognitive decline but are associated with hypotension, syncope, and greater medication burden.
U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. (PROSPERO 2015: CRD42015017677)
Literature flow diagram.
BP = blood pressure; EBM = Evidence-Based Medicine; RCT = randomized, controlled trial.
* All databases were searched through 30 January 2015. The Ovid MEDLINE search was updated on 15 September 2016.
Appendix Table. Characteristics of Trials Included in the Meta-analysis
RRs for death, stroke, and cardiac events, with trials combined by mean baseline SBP ≥160 or <160 mm Hg.
ACCORD = Action to Control Cardiovascular Risk in Diabetes; ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron - MR Controlled Evaluation; Cardio-Sis = Italian Study on the Cardiovascular Effects of Systolic Blood Pressure Control; EWPHE = European Working Party on High Blood Pressure in the Elderly; FEVER = Felodipine Event Reduction; HOT = Hypertension Optimal Treatment; HYVET = Hypertension in the Very Elderly Trial; JATOS = Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; RR = relative risk; SBP = systolic blood pressure; SCOPE = Study on Cognition and Prognosis in the Elderly; SHEP = Systolic Hypertension in the Elderly Program; SPRINT = Systolic Blood Pressure Intervention Trial; Syst-Eur = Systolic Hypertension in Europe; VALISH = Valsartan in Elderly Isolated Systolic Hypertension.
RRs for death, stroke, and cardiac events in trials in which the intervention group had a target of SBP <140 mm Hg or DBP ≤85 mm Hg and the control group had a less strict target.
ACCORD = Action to Control Cardiovascular Risk in Diabetes; BP = blood pressure; Cardio-Sis = Italian Study on the Cardiovascular Effects of Systolic Blood Pressure Control; DBP = diastolic blood pressure; HOT = Hypertension Optimal Treatment; JATOS = Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients; RR = relative risk; SBP = systolic blood pressure; SPRINT = Systolic Blood Pressure Intervention Trial; VALISH = Valsartan in Elderly Isolated Systolic Hypertension.
Table. Summary of the Evidence on More Versus Less Intensive Treatment for Hypertension in Elderly Adults
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Gulistan Bahat1, Birkan İlhan2, Asli Tufan3, Mehmet Akif Karan4
1 Associate Professor, M.D, Department of Internal Medicine, Division of Geriatrics, Istanbul Medical School, Istanbul University, Capa, 34390, Istanbul, Turkey, email@example.com
February 6, 2017
Treatment of hypertension in frail, functionally limited older adults
We have read the article entitled “Benefits and Harms of Intensive Blood Pressure Treatment in Adults Aged 60 Years or Older” by Weiss et al. with great interest (1). In their valuable systematic review and meta-analysis, the authors reviewed a large number of studies regarding optimal management strategies of hypertension in older adults. We would like to give a few comments on this valuable review.Authors stated that in 2 trials (2,3), antihypertensive treatment effects did not differ according to frailty status. However, when we go into the second report of the SPRINT (2), primary composite cardiovascular outcomes and all-cause mortality was not better in subjects with frailty (p=0.06, 0.05; respectively) or slow gait speed (p=0.05, 0.28; respectively) when they get intensive treatment compared with standard treatment (4). In the other one HYVET trial (3), both the frailer and the fitter older adults with hypertension appeared to gain from treatment. Here frailty was evaluated by Frailty Index (FI) but there were about or less than 5% participants having limitation in walking and activities of daily living. Hence, in the HYVET study, the reported lack of modification of positive impact of antihypertensive treatment by FI, does not supply data on the older adults specifically having low gait speed and/or functional limitation. However, the specific investigation of the impact of antihypertensive treatment in the older adults having low gait speed and/or functional limitation would give a better view (4). In accordance with this argument, in 2016 the European Society of Hypertension (ESH) and the European Union Geriatric Medicine Society have published a common expert opinion article on the management of hypertensive very old, frail subjects and suggested that in these patients, therapeutic decisions should be preceded by accurate information on their functional capacity (5).Weiss et al. stated the lack of data to assess the risks and benefits of antihypertensive treatment among institutionalized elderly patients or those with multiple comorbidities. We would like to point out the PARTAGE study which assessed all-cause mortality in institutionalized individuals older than 80 years according to systolic blood pressure levels and number of antihypertensive drugs (6). They reported higher risk of mortality in patients with low systolic blood pressure (<130 mmHg) who were receiving multiple antihypertensive agents compared with the other participants. This longitudinal study gives weighty data regarding the harms of antihypertensive agent use in frail older adults.REFERENCES1. Weiss J, Freeman M, Low A, Fu R, Kerfoot A, Paynter R, Motu'apuaka M, Kondo K, Kansagara D. Benefits and Harms of Intensive Blood Pressure Treatment in Adults Aged 60 Years or Older: A Systematic Review and Meta-analysis. Ann Intern Med. 2017 Jan 17. 2. Williamson JD,Supiano MA,Applegate WB,Berlowitz DR,Campbell RC,Chertow GM et al;SPRINT Research Group.Intensive vs Standard Blood Pressure Control and Car-diovascular Disease Outcomes in Adults Aged ≥75 Years:A Randomized Clinical Trial.JAMA.2016Jun 28;315(24):2673-82.3. Warwick J,Falaschetti E,Rockwood K,Mitnitski A,Thijs L et al:No evidence that frail-ty modifies the positive impact of antihypertensive treatment in very elderly people:an investigation of the impact of frailty upon treatment effect in the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind,placebo-controlled study of anti-hypertensives in people with hypertension aged 80 and over. BMC Med 2015Apr 9;13:78.4. Bahat G, Ilhan B, Tufan A, Karan MA. Blood pressure goals in functionally limited elderly patients. The American Journal of Medicine 2017, in press.5. Benetos A, Bulpitt CJ, Petrovic M, Ungar A, Agabiti Rosei E, Cherubini A, Redon J, Grodzicki T, Dominiczak A, Strandberg T, Mancia G. An Expert Opinion From the European Society of Hypertension-European Union Geriatric Medicine Society Work-ing Group on the Management of Hypertension in Very Old, Frail Subjects. Hyperten-sion. 2016 May;67(5):820-5.6. Benetos A, Labat C, Rossignol P, Fay R, Rolland Y, Valbusa F, Salvi P, Zamboni M, Manckoundia P, Hanon O, Gautier S. Treatment With Multiple Blood Pressure Medi-cations, Achieved Blood Pressure, and Mortality in Older Nursing Home Residents: The PARTAGE Study. JAMA Intern Med. 2015 Jun;175(6):989-95.
Alain Braillon MD, PhD
February 22, 2017
The American College of Physicians and the American Academy of Family Physicians must be commended for their “clinical practice guideline” about blood pressure goals for adults aged 60 years or older based with only three simple recommendations.(1) First, they ended the Byzantine debate about additional benefits from aggressive control by daring to clearly illustrate the size of benefit obtained with moderate targets (<150/90 mm Hg): reduction in mortality (ARR, 1.64), stroke (ARR, 1.13), and cardiac events (ARR, 1.25).(1) That means 61 patients should be treated to avoid one premature death. Could they indicate the mean duration of the time frame to obtain this benefit and also expressed the benefit in weeks of life gained per patient per year of treatment. Second, they highlighted the limitations of the trials with their highly selected, motivated and captive patients treated for free by top-notch investigators monitored with a costly quality assurance program. This has little to do with the real life setting.This guideline fulfils the 3U rules: being unbiased, usable and, useful. Accordingly, it will be used and not shelved as too many. The next step should be a “public health policy guideline” to address the barriers at the patient, healthcare provider and health system level. The list of recommendations will be much longer: training for motivational interviewing to improve adherence, simplifying delivery of healthcare through task-sharing with non-physician health workers, optimizing self-management with treatment supporters and new technologies, improving affordability of treatment and monitoring … 1 Qaseem A, Wilt TJ, Rich R et al. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: A clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 2017. Online Jan 17. doi: 10.7326/M16-1785.
Jessica Weiss, MD, Devan Kansagara, MD
OHSU and VA Portland
February 24, 2017
We appreciate the comments by Dr. Bahat and colleagues regarding the data available to inform blood pressure targets among older adults with frailty, poor functional status, and multi-morbidity. The two randomized controlled trials in our review which provided analyses of frail versus non-frail subgroups, SPRINT and HYVET, did identify comparable benefits of lower blood pressure targets regardless of frailty status within their patient populations (1-3). We did not feel it was statistically sound to pool these study results because of the heterogeneity in study design, patient populations, and blood pressure targets, as well as potential differences in frailty identification. While both trials used a frailty index to assess frailty, the two indexes likely differed somewhat in terms of included characteristics and there were a significant number of patients excluded from the HYVET frailty analysis due to missing data. Moreover, based on the modest frailty index levels reported (median 0.17 and 0.18 for HYVET and SPRINT, respectively), as well as the reported study exclusion characteristics, it is unlikely that either study enrolled patients with levels of frailty or functional status seen among patients who require a higher level of care, such as that of patients in a skilled nursing facility. Cesari and colleagues recently reported a mean frailty index of 0.4 among patients in skilled nursing facilities; these researchers used a frailty index that was likely comparable in design to those used by investigators in SPRINT and HYVET (4). While it is important and novel that SPRINT and HYVET investigators incorporated any analyses related to frailty and functional status in their evaluation of the benefits of different blood pressure targets, these data alone cannot speak to the most frail and fragile – the patients for whom providers may harbor the greatest uncertainty about the balance of benefit versus harm from lower blood pressure targets. We did not find data from randomized controlled trials to inform whether or not multi-morbidity may mitigate or adjust the relationship between lower blood pressure targets and our specified outcomes (mortality, stroke, cardiovascular events) in older adults. Our review excluded observational studies in considering these primary health outcomes, given the risk of residual confounding in observational studies of blood pressure targets as well as the existence of many controlled trials. In the PARTAGE study, Dr. Benetos and colleagues used observational data to identify an increased risk of all-cause mortality among multi-morbid older adults in a skilled nursing facilities who experienced baseline systolic blood pressure (SBP) <130 mmHg with concurrent use of two or more antihypertensive medications compared to the risk of death for those multi-morbid older adults with SBP >130 mmHg and/or use of fewer than 2 antihypertensive medications (5). As is true for all observational studies of blood pressure targets, however, it is difficult to escape concerns about residual confounding - in particular the idea that patients with the lowest achieved SBP levels may experience lower blood pressures due to greater disease burden, greater severity of disease, and greater likelihood of particular diseases which both lower blood pressure and associate with increased risk of death, such as heart failure and cirrhosis. In the PARTAGE study, 34.8% of patients with SBP <130 and use of two or more antihypertensive medications had a diagnosis of heart failure at baseline, compared to only 14.2% in the remainder of their patient population. Patients with SBP <130 mmHg were also more likely to be on loop diuretics and potassium sparing diuretics as compared to those older adults with SBP >130 mmHg. We do feel that observational studies of blood pressure targets in older adults are very useful to identify harms associated with higher versus lower blood pressures, in particular because of the potential for longer observational periods when harms may become more apparent. We look forward to the pending publication from Dr. Bahat and colleagues to continue this discussion about blood pressure targets for the important and growing population of older adults with frailty, poor functional status, and complex multi-morbidity.Jessica Weiss, MD, MCRDevan Kansagara, MD, MCRReferences:1. Weiss J, Kerfoot A, Freeman M, Motu’apuaka M, Fu R, Low A, et al. Benefits and harms of treating blood pressure in older adults: a systematic review and meta-analysis. VA ESP Project #05-225. http://www.hsrd.research.va.gov/publications/esp/bloodpressure.pdf. 2015.2. Wright JT, Jr., Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. New England Journal of Medicine. 2015;373(22):2103-16.3. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. Treatment of hypertension in patients 80 years of age or older. New England Journal of Medicine. 2008;358(18):1887-98.4. Fougere B, Kelaiditi E, Hoogendijk EO, Demougeot L, Duboue M, Vellas B, et al. Frailty Index and Quality of Life in Nursing Home Residents: Results From INCUR Study. J Gerontol A Biol Sci Med Sci. 2016;71(3):420-4.5. Benetos A, Labat C, Rossignol P, Fay R, Rolland Y, Valbusa F, et al. Treatment With Multiple Blood Pressure Medications, Achieved Blood Pressure, and Mortality in Older Nursing Home Residents: The PARTAGE Study. JAMA Internal Medicine. 2015;175(6):989-95.
Weiss J, Freeman M, Low A, Fu R, Kerfoot A, Paynter R, et al. Benefits and Harms of Intensive Blood Pressure Treatment in Adults Aged 60 Years or Older: A Systematic Review and Meta-analysis. Ann Intern Med. ;166:419–429. doi: 10.7326/M16-1754
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Published: Ann Intern Med. 2017;166(6):419-429.
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