The Systolic Blood Pressure Intervention Trial (SPRINT) found that intensive versus standard blood pressure (BP) control reduced cardiovascular morbidity and mortality in high-risk patients.1 Effects were consistent among patients with and without prevalent cardiovascular disease. Patients with heart failure may benefit from intensive BP control by slowing the adverse cardiac remodelling associated with high BP. Conversely, some studies have suggested better outcomes among patients with heart failure who have higher BP.2 Therefore, it remains unknown whether a history of heart failure modifies the risks and benefits of intensive BP control.
SPRINT randomized 9361 individuals who were ≥50 years of age, at high cardiovascular risk, and had a systolic BP of 130–180 mmHg to intensive or standard BP control.1 Pertinent exclusion criteria included diabetes, prior stroke, and known symptomatic heart failure within the past 6 months or a left ventricular ejection fraction <35%. The primary endpoint was the composite of acute coronary syndromes, stroke, acute decompensated heart failure, or death from cardiovascular causes. The principal safety endpoint was composite serious adverse events. We used multivariable Cox proportional hazards regression to determine the risk of efficacy and safety events in patients with baseline heart failure. We then calculated the efficacy and safety of intensive versus standard BP control in patients with and without baseline heart failure and examined subgroup heterogeneity using the likelihood-ratio test. A waiver for secondary use of the SPRINT data set was obtained from the Brigham and Women's Hospital Institutional Review Board.
Of the 9361 participants, 326 (3.5%) reported a history of heart failure. The prevalence did not significantly differ between patients randomized to intensive versus standard BP control [166 (3.6%) vs. 160 (3.4%); P = 0.73]. Median follow-up duration was 3.26 years (range 0–4.77 years). A history of heart failure was independently associated with
the primary endpoint (adjusted hazard ratio: 2.34; 95% confidence interval: 1.75–3.13; P < 0.001) and with composite serious adverse events (adjusted hazard ratio: 1.41; 95% confidence interval: 1.21-1.64; P < 0.001). No significant interactions were detected for any of the endpoints (Table 1). Patients with a history of heart failure had higher risks and greater absolute risk reductions in several efficacy endpoints, including the primary endpoint and all-cause death. The risk of safety endpoints was also higher in patients with heart failure, but mostly similar between the intensive and standard groups (Table 1).
Table 1.
Efficacy and safety events with intensive vs. standard blood pressure control in patients with and without heart failure
| Patients with heart failure (n = 326) | Patients without heart failure (n = 9035) | ||||||
|---|---|---|---|---|---|---|---|
| Endpoint | 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) | P-value for interaction |
| All participants | 166 | 160 | 4512 | 4523 | |||
| Primary endpoint | 22 (13.3%) | 34 (21.3%) | 0.58 (0.34–0.99) | 221 (4.9%) | 285 (6.3%) | 0.77 (0.65–0.92) | 0.33 |
| Secondary endpoints | |||||||
| Myocardial infarction | 3 (1.8%) | 8 (5.0%) | 0.34 (0.09–1.29) | 94 (2.1%) | 108 (2.4%) | 0.87 (0.66–1.15) | 0.16 |
| Other acute coronary syndrome | 3 (1.8%) | 5 (3.1%) | 0.56 (0.13–2.35) | 37 (0.8%) | 35 (0.8%) | 1.06 (0.67–1.68) | 0.40 |
| Stroke | 6 (3.6%) | 6 (3.8%) | 0.92 (0.30–2.85) | 56 (1.2%) | 64 (1.4%) | 0.87 (0.61–1.25) | 0.92 |
| Acute decompensated heart failure | 12 (7.2%) | 18 (11.3%) | 0.61 (0.29–1.27) | 50 (1.1%) | 82 (1.8%) | 0.61 (0.43–0.86) | >0.99 |
| Death from cardiovascular causes | 5 (3.0%) | 7 (4.4%) | 0.66 (0.21–2.08) | 32 (0.7%) | 58 (1.3%) | 0.55 (0.36–0.85) | 0.76 |
| Death from any cause | 12 (7.2%) | 18 (11.3%) | 0.62 (0.30–1.29) | 143 (3.2%) | 192 (4.2%) | 0.74 (0.60–0.92) | 0.64 |
| Primary endpoint with death from any cause | 26 (15.7%) | 42 (26.3%) | 0.55 (0.34–0.90) | 306 (6.8%) | 381 (8.4%) | 0.80 (0.69–0.93) | 0.17 |
| Composite serious adverse events | 97 (58.4%) | 90 (56.3%) | 1.01 (0.76–1.35) | 1696 (37.6%) | 1646 (36.4%) | 1.04 (0.97–1.11) | 0.83 |
| Emergency department visit or serious adverse events | |||||||
| Hypotension | 13 (7.8%) | 6 (3.8%) | 2.07 (0.79–5.44) | 145 (3.2%) | 87 (1.9%) | 1.68 (1.29–2.19) | 0.71 |
| Syncope | 8 (4.8%) | 7 (4.4%) | 1.08 (0.39–2.97) | 155 (3.4%) | 106 (2.3%) | 1.47 (1.15–1.88) | 0.53 |
| Bradycardia | 11 (6.6%) | 8 (5.0%) | 1.29 (0.52–3.21) | 93 (2.1%) | 75 (1.7%) | 1.24 (0.92–1.68) | 0.95 |
| Electrolyte abnormality | 8 (4.8%) | 8 (5.0%) | 0.92 (0.34–2.45) | 169 (3.8%) | 121 (2.7%) | 1.40 (1.11–1.77) | 0.43 |
| Injurious fall | 18 (10.8%) | 19 (11.9%) | 0.86 (0.45–1.64) | 316 (7.0%) | 313 (6.9%) | 1.01 (0.86–1.18) | 0.59 |
| Acute kidney injury or renal failure | 18 (10.8%) | 13 (8.1%) | 1.30 (0.63–2.64) | 186 (4.1%) | 107 (2.4%) | 1.75 (1.38–2.22) | 0.41 |
| Orthostatic hypotension alone | 40 (24.1%) | 42 (26.3%) | 0.74 (0.47–1.41) | 737 (16.3%) | 815 (18.0%) | 0.89 (0.81–0.98) | 0.37 |
| Orthostatic hypotension with dizziness | 4 (2.4%) | 2 (1.3%) | 1.87 (0.34–10.21) | 58 (1.3%) | 69 (1.5%) | 0.83 (0.58–1.17) | 0.50 |
BP, blood pressure.
Our study showed a greater risk of both efficacy and safety events among individuals with heart failure, but no significant differences in the risk–benefit profile of intensive BP control. Effects were virtually identical in patients with vs. those without heart failure. Nevertheless, data regarding the exact phenotype, disease severity, or functional status of individuals with heart failure were not available. It seems likely that a significant proportion of these patients had heart failure with mildly reduced ejection fraction, heart failure with preserved ejection fraction (HFpEF), or heart failure with recovered ejection fraction, and our data support the class I guideline recommendation to control BP in patients with HFpEF.3 Other limitations were the small sample size, exclusion of other specific high-risk conditions, and that heart failure was self-reported. In conclusion, a specific subgroup of patients with heart failure faces excess risks of clinical adverse events but appears to benefit from intensive BP control to attenuate this risk. Future prospective clinical trials are needed to establish optimal BP targets in HFpEF.
Contributor Information
Manan Pareek, Heart & Vascular Center, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA; Department of Internal Medicine, Yale New Haven Hospital, Yale School of Medicine, New Haven, CT, USA; Department of Cardiology, Herlev and Gentofte Hospital, Copenhagen, Denmark.
Muthiah Vaduganathan, Heart & Vascular Center, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA.
Christina Byrne, Department of Cardiology, Herlev and Gentofte Hospital, Copenhagen, Denmark.
Astrid Duus Mikkelsen, Department of Cardiology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
Anna Meta Dyrvig Kristensen, Department of Cardiology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark.
Tor Biering-Sørensen, Department of Cardiology, Herlev and Gentofte Hospital, Copenhagen, Denmark; Institute of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Kristian Hay Kragholm, Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.
Massar Omar, Department of Cardiology, Odense University Hospital, Odense, Denmark.
Michael Hecht Olsen, Division of Cardiology, Department of Internal Medicine, Holbæk Hospital, Holbæk, Denmark.
Deepak L Bhatt, Heart & Vascular Center, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA.
Funding
SPRINT was supported by the National Heart, Lung, and Blood Institute. This exploratory analysis was unfunded.
Trial registration number: NCT01206062
Conflict of interest: M.P. discloses the following relationships—advisory board: AstraZeneca and Janssen-Cilag; speaker honorarium: AstraZeneca, Bayer, Boehringer Ingelheim, and Janssen-Cilag.
M.V. has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Relypsa, and Roche Diagnostics; had speaker engagements with Novartis and Roche Diagnostics; and participates in clinical endpoint committees for studies sponsored by Galmed and Novartis.
T.B.S. discloses the following relationships—steering committee member of the Amgen-financed GALACTIC-HF trial; advisory board: Sanofi Pasteur and Amgen; and speaker honorarium: Novartis and 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: Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Janssen, Level Ex, Medscape Cardiology, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, and Stasys; board of directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; chair: inaugural 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), Boston Scientific (chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Novartis, and Population Health Research Institute; honoraria: American College of Cardiology (senior associate editor, Clinical Trials and News, acc.org; chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), 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), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, 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), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Piper Sandler, 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), and WebMD (CME steering committees); others: Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), and VA CART Research and Publications Committee (chair); research funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Lexicon, Lilly, Medtronic, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, and 89Bio; royalties: Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); site co-investigator: Abbott, Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Philips, and Svelte; trustee: American College of Cardiology; and unfunded research: FlowCo, Merck, and Takeda.
The other authors report no conflict of interest.
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