Trial Registration: SPRINT (Systolic Blood Pressure Intervention Trial); ClinicalTrials.gov Identifier: NCT01206062, https://clinicaltrials.gov/ct2/show/NCT01206062.
Hypertension is a risk factor for both the occurrence and rupture of abdominal aortic aneurysms, is present in most individuals with acute aortic dissection, and has been linked with an increased risk of peripheral artery disease (PAD).1–3 Limited data are available to inform whether lower blood pressure (BP) treatment targets affect the risk of peripheral vascular events. We examined the risk of vascular procedures (as a proxy of progression of PAD) with intensive vs. standard BP control in The Systolic Blood Pressure Intervention Trial (SPRINT).4
SPRINT was a randomized, controlled, open-label trial in which 9361 individuals ≥50 years of age, at high cardiovascular risk (cardiovascular disease except stroke, chronic kidney disease, ≥15% 10-year risk of cardiovascular disease based on the Framingham risk score, or age ≥75 years), and without diabetes, were randomized to intensive (systolic BP target <120mmHg; n = 4678) or standard BP control (systolic BP target 135–139 mmHg; n = 4683).4 We used Kaplan–Meier analyses and Cox proportional-hazards regression to evaluate the risk of vascular procedures, information on which was obtained during scheduled study visits, with intensive vs. standard BP control. We further examined subgroup heterogeneity for treatment effect using likelihood-ratio test-based interaction analysis on the prespecified subgroups listed in the primary outcome paper as well as baseline PAD. The SPRINT clinical data set is available from the National Institutes of Health Biologic Specimen and Data Repository Information Coordination Center. The Brigham and Women’s Hospital Institutional Review Board waived approval for secondary data utilization.
At baseline, 503 (5.3%) participants had a self-reported history of lower limb PAD, with no significant difference between the intensive and standard treatment groups [250 (5.3%) vs. 253 (5.4%); P = 0.90]. During a median of 3.3 years (range 0–5.5 years), 174 (1.9%) composite vascular procedures were recorded. Such procedures were significantly more common among individuals with baseline PAD vs. those without [60 (11.9%) vs. 114 (1.3%), hazard ratio 10.23, 95% confidence interval 7.48–13.99]. The risk of composite and most individual vascular procedures was numerically, though not significantly, lower with intensive BP control (Figure 1 and Table 1). Intensive BP control significantly reduced the risk of peripheral vascular surgery, although this event was infrequent [7 (0.1%) vs. 21 (0.4%), hazard ratio 0.33, 95% confidence interval 0.14–0.77]. The effect of intensive BP lowering was not modified by chronic kidney disease, age, sex, race, previous cardiovascular disease, baseline systolic BP, or history of PAD.
Figure 1.
Kaplan–Meier survival curve showing the risk of vascular procedures with intensive vs. standard blood pressure control in patients with and without peripheral artery disease. PAD, peripheral artery disease.
Table 1.
The risk of incident composite and individual vascular procedures in patients with and without peripheral artery disease.
| Patients with peripheral artery disease |
Patients without peripheral artery disease |
|||||
|---|---|---|---|---|---|---|
| Procedure | Intensive BP control (no. of patients) | Standard BP control (no. of patients) | Hazard ratio (95% confidence interval) | Intensive BP control (no. of patients) | Standard BP control (no. of patients) | Hazard ratio (95% confidence interval) |
| All participants | 250 | 253 | 4416 | 4418 | ||
| Any vascular procedure (composite) | 25 | 35 | 0.70 (0.42–1.18) | 51 | 63 | 0.80 (0.55-1.15) |
| Carotid angioplasty | 1 | 3 | 0.33 (0.03–3.18) | 5 | 3 | 1.64 (0.39-6.87) |
| Carotid endarterectomy | 3 | 6 | 0.48 (0.12–1.93) | 14 | 21 | 0.66 (0.33-1.29) |
| Peripheral angioplasty | 11 | 16 | 0.68 (0.32–1.46) | 20 | 22 | 0.90 (0.49-1.64) |
| Peripheral vascular surgery | 5 | 10 | 0.50 (0.17–1.46) | 2 | 11 | 0.18 (0.04-0.81) |
| Lower limb amputation | 2 | 3 | 0.66 (0.11–3.96) | 3 | 1 | 2.97 (0.31-28.52) |
| Surgical or vascular procedure for AAA | 4 | 1 | 3.96 (0.44–35.43) | 8 | 13 | 0.60 (0.25-1.46) |
| Surgical or vascular procedure for TAA | 0 | 0 | – | 4 | 1 | 3.92 (0.44-35.09) |
| Surgical or vascular procedure for other problem | 3 | 1 | 2.92 (0.30–28.05) | 3 | 2 | 1.47 (0.25-8.81) |
AAA, abdominal aortic aneurysm; BP, blood pressure; TAA, thoracic aortic aneurysm.
In this secondary analysis of the large SPRINT trial, incident composite vascular procedures were numerically reduced with intensive vs. standard BP lowering, and with an effect, estimate mimicking that of the primary efficacy endpoint; however, the difference did not meet statistical significance. While the study was randomized, and analyses were conducted using the intention-to-treat principle, it was not powered for vascular endpoints. The evidence for antihypertensive treatment for limiting the expansion of aortic aneurysms is equivocal, and optimal BP targets are not known.2 Conversely, more data regarding secondary prevention are available for PAD.1 A post hoc analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) demonstrated a J-shaped relationship between systolic BP and PAD-related events, with an optimum of 120–129 mmHg.3 A diastolic BP <70 mmHg was also associated with a high risk of PAD-related events. Although that analysis had suggested that lower BP targets in this population may impair blood flow to the lower limb, data regarding baseline PAD were not available. Furthermore, a meta-analysis suggested that BP lowering might even increase maximal walking distance in patients with PAD.5 In our study, intensive BP control reduced the risk of peripheral vascular surgery to a similar degree among individuals with and without known PAD. However, this was based on a limited number of events, and the treatment group did not significantly affect the risk of peripheral angioplasty or thrombolysis and lower limb amputation. Nevertheless, it seems reasonable to treat individuals with hypertension and PAD in a similarly aggressive manner as supported by SPRINT as those who have hypertension without PAD.1
Funding
SPRINT was supported by the National Heart, Lung, and Blood Institute. This exploratory analysis was unfunded.
Conflict of interest: M.P. discloses the following relationships – Advisory Board: AstraZeneca; Speaker Honorarium: AstraZeneca; Bayer; Boehringer Ingelheim. M.V. is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst (NIH/NCATS Award UL 1TR002541), serves on advisory boards for Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, and Boehringer Ingelheim, and participates on clinical endpoint committees for studies sponsored by Novartis and the NIH. T.B.-S. discloses the following relationships – Steering Committee member of the Amgen financed GALACTIC-HF trial; Advisory Board: Sanofi Pasteur, Amgen; Speaker Honorarium: Novartis, Sanofi Pasteur. M.H.O. discloses that he has received a part-time clinical research grant from the Novo Nordisk Foundation. D.L.B. discloses the following relationships – Advisory Board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. The other authors declare no conflicts of interest.
References
- 1. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, Clement DL, Coca A, de Simone G, Dominiczak A, Kahan T, Mahfoud F, Redon J, Ruilope L, Zanchetti A, Kerins M, Kjeldsen SE, Kreutz R, Laurent S, Lip GYH, McManus R, Narkiewicz K, Ruschitzka F, Schmieder RE, Shlyakhto E, Tsioufis C, Aboyans V, Desormais I, De Backer G, Heagerty AM, Agewall S, Bochud M, Borghi C, Boutouyrie P, Brguljan J, Bueno H, Caiani EG, Carlberg B, Chapman N, Cífková R, Cleland JGF, Collet J-P, Coman IM, de Leeuw PW, Delgado V, Dendale P, Diener H-C, Dorobantu M, Fagard R, Farsang C, Ferrini M, Graham IM, Grassi G, Haller H, Hobbs FDR, Jelakovic B, Jennings C, Katus HA, Kroon AA, Leclercq C, Lovic D, Lurbe E, Manolis AJ, McDonagh TA, Messerli F, Muiesan ML, Nixdorff U, Olsen MH, Parati G, Perk J, Piepoli MF, Polonia J, Ponikowski P, Richter DJ, Rimoldi SF, Roffi M, Sattar N, Seferovic PM, Simpson IA, Sousa-Uva M, Stanton AV, van de Borne P, Vardas P, Volpe M, Wassmann S, Windecker S, Zamorano JL, Windecker S, Aboyans V, Agewall S, Barbato E, Bueno H, Coca A, Collet J-P, Coman IM, Dean V, Delgado V, Fitzsimons D, Gaemperli O, Hindricks G, Iung B, Jüni P, Katus HA, Knuuti J, Lancellotti P, Leclercq C, McDonagh TA, Piepoli MF, Ponikowski P, Richter DJ, Roffi M, Shlyakhto E, Simpson IA, Sousa-Uva M, Zamorano JL, Tsioufis C, Lurbe E, Kreutz R, Bochud M, Rosei EA, Jelakovic B, Azizi M, Januszewics A, Kahan T, Polonia J, van de Borne P, Williams B, Borghi C, Mancia G, Parati G, Clement DL, Coca A, Manolis A, Lovic D, Benkhedda S, Zelveian P, Siostrzonek P, Najafov R, Pavlova O, De Pauw M, Dizdarevic-Hudic L, Raev D, Karpettas N, Linhart A, Olsen MH, Shaker AF, Viigimaa M, Metsärinne K, Vavlukis M, Halimi J-M, Pagava Z, Schunkert H, Thomopoulos C, Páll D, Andersen K, Shechter M, Mercuro G, Bajraktari G, Romanova T, Trušinskis K, Saade GA, Sakalyte G, Noppe S, DeMarco DC, Caraus A, Wittekoek J, Aksnes TA, Jankowski P, Polonia J, Vinereanu D, Baranova EI, Foscoli M, Dikic AD, Filipova S, Fras Z, Bertomeu-Martínez V, Carlberg B, Burkard T, Sdiri W, Aydogdu S, Sirenko Y, Brady A, Weber T, Lazareva I, Backer TD, Sokolovic S, Jelakovic B, Widimsky J, Viigimaa M, Pörsti I, Denolle T, Krämer BK, Stergiou GS, Parati G, Trušinskis K, Miglinas M, Gerdts E, Tykarski A, de Carvalho Rodrigues M, Dorobantu M, Chazova I, Lovic D, Filipova S, Brguljan J, Segura J, Gottsäter A, Pechère-Bertschi A, Erdine S, Sirenko Y, Brady A; ESC Scientific Document Group. ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021–3104. [DOI] [PubMed] [Google Scholar]
- 2. Lederle FA, Noorbaloochi S, Nugent S, Taylor BC, Grill JP, Kohler TR, Cole L.. Multicentre study of abdominal aortic aneurysm measurement and enlargement. Br J Surg 2015;102:1480–1487. [DOI] [PubMed] [Google Scholar]
- 3. Itoga NK, Tawfik DS, Lee CK, Maruyama S, Leeper NJ, Chang TI.. Association of blood pressure measurements with peripheral artery disease events. Circulation 2018;138:1805–1814. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. SPRINT Research GroupWright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff DC Jr, Fine LJ, Cutler JA, Cushman WC, Cheung AK, Ambrosius WT.. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103–2116. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Thomas Manapurathe D, Krishna SM, Dewdney B, Moxon JV, Biros E, Golledge J.. Effect of blood pressure lowering medications on leg ischemia in peripheral artery disease patients: a meta-analysis of randomised controlled trials. PLoS One 2017;12:e0178713. [DOI] [PMC free article] [PubMed] [Google Scholar]