By Dr. Christopher Cheung (biography and no disclosures) and Dr. Kenneth Gin (biography and disclosures, disclosures: Research for Bayer, Ad board Bayer, BI, Pfizer)
Mitigating potential bias: Only published trial data is presented. Recommendations are consistent with current practice patterns. References are made to published guidelines (i.e. CHEP, JNC8, ESC – see references)
What I did before
Hypertension affects over 1 in 5 Canadians and is one of the leading causes of cardiovascular disease, including coronary artery disease and heart failure.1,2 Uncontrolled hypertension is a risk factor for stroke (both ischemic and hemorrhagic), retinopathy, chronic kidney disease (CKD), and peripheral vascular disease. Epidemiologic studies show that the risk of cardiovascular disease increases above a blood pressure of 115/75 mmHg.3
The 2015 CHEP guidelines recommended a blood pressure treatment target of 140/90 mmHg or less in most individuals with hypertension (Table 1).4-6 Elderly populations, particularly patients 80 years and older, may benefit from a more conservative target of 150/80 mmHg, according to the HYVET study.7 Patients with diabetes may benefit from a lower blood pressure target of 130/80 mmHg, although this recommendation remains controversial.4 In the ACCORD study, intensive blood pressure targets (systolic less than 120 mmHg) in diabetic patients did not demonstrate any significant benefit over standard targets (systolic less than 140 mmHg).8
What changed my practice
The SPRINT trial was recently published in the New England Journal of Medicine and compares intensive versus standard blood pressure control in patients with increased cardiovascular risk.9 In SPRINT, 9361 patients with a systolic blood pressure between 130 to 180 mmHg were randomized to an intensive treatment target (systolic less than 120 mmHg) or standard target (systolic less than 140 mmHg).9 Patients were selected to have an increased cardiovascular risk, defined as one or more of the following: clinical or subclinical cardiovascular disease other than stroke, previous CKD (eGFR 20-60 mL/min/1.73 m2), 10-year Framingham risk of 15% or greater, or greater than 75 years of age.9 Patients with diabetes or prior stroke were excluded from the study. Adverse events, including acute kidney injury, were identified from the hospital discharge summary, adjudicated by a safety officer, and reviewed by a safety committee.
After a median follow-up of 3.26 years, the mean systolic blood pressures were 121.5 mmHg and 134.6 mmHg in the intensive and standard treatment groups, respectively.9 Patients in the intensive group were taking one additional anti-hypertensive medication (2.8 vs. 1.8), with the relative distribution of agents similar (no restriction in type of medications used).9 The trial was terminated early due to a significant reduction in the composite primary outcome of myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, and death from cardiovascular causes in the intensive treatment group (5.2% vs. 6.8%, HR 0.75, p<0.001).9 These findings were present in all subgroups, irrespective of age, sex, ethnicity, baseline systolic blood pressure, previous cardiovascular disease, or previous CKD. The authors also reported a reduction in secondary outcomes, including death from any cause (3.3% vs. 4.5%, HR 0.73, p=0.003), death from cardiovascular causes (0.8% vs. 1.4%, HR 0.57, p=0.005), and heart failure (1.3% vs. 2.1%, HR 0.62, p=0.002).9
There was no difference in the overall serious adverse events between the two groups (38.3% vs. 37.1%, HR 1.04, p=0.25). However, hypotension (2.4% vs. 1.4%, HR 1.67, p=0.001), syncope (2.3% vs. 1.7%, HR 1.33, p=0.05), electrolyte abnormality (3.1% vs. 2.3%, HR 1.35, p=0.02), and acute kidney injury (4.1% vs. 2.5%, HR 1.66, p<0.001) were more common in the intensive treatment group.9 There was no difference in injurious falls (2.2% vs. 2.3%, HR 0.95, p=0.71).9
What I do now
The SPRINT trial brings into question the optimal blood pressure target in the hypertensive patient and reflects a departure from the targets currently recommended in North American and European guidelines (Table 1).4-6 The authors reported an absolute risk reduction of 1.6% in their primary outcome with intensive treatment, translating to a number needed-to-treat of 61 to prevent one primary outcome, and 90 to prevent one death (from any cause).9 These findings were present in all subgroups, with potentially a stronger signal in those 75 years and older, with a baseline systolic blood pressure ≤132 mmHg, and without previous CKD. Notably, there was no reduction in stroke as a single endpoint (1.3% vs. 1.5%, HR 0.89, p=0.50).9
Despite the potential benefits of intensive blood pressure control, there remain significant risks. We calculated a number needed-to-harm of 106 for hypotension, 172 for syncope, and 61 for acute kidney injury. Thus, patients with a history of hypotension and syncope should be closely followed, and electrolytes and renal function monitored routinely, after the initiation of additional anti-hypertensives medications. We also do not know whether the positive findings in SPRINT represent the benefit from a single class of anti-hypertensives (i.e. ACE inhibitors), as patients in the intensive treatment group used more medications from all drug classes.9
The results of SPRINT also are at odds with previous studies. In patients with diabetes (i.e. ACCORD), there was no difference in the primary outcome between intensive versus standard therapy, but more serious adverse events with intensive therapy.8 However, the ACCORD study may have suffered from insufficient power and poor study design – a combined analysis of the SPRINT and ACCORD data demonstrated a significant reduction in event rate with intensive blood pressure control.10 Furthermore, studies of hypertension management in the elderly have targeted a blood pressure of 150/80 mmHg or less (i.e. HYVET).7 The SPRINT trial sends a strong message that intensive therapy in these individuals may still offer additional benefit, although one must consider the risk of adverse events in this population.
Conclusion
The SPRINT trial brings into question the optimal blood pressure target for the non-diabetic hypertensive patient with increased cardiovascular risk. In SPRINT, the authors demonstrated a significant reduction in their composite primary outcome and death from any cause with an intensive treatment target. Previous, smaller studies in diabetic and elderly patients have not demonstrated such significant reductions in cardiovascular and mortality endpoints.
The results of the SPRINT trial have now been incorporated in the 2016 CHEP guidelines (Table 1).11 Similar to the guidelines, we would consider treating individuals at increased cardiovascular risk to an intensive treatment target, although this decision must be balanced with the increased risk for adverse events, including hypotension, syncope, and acute kidney injury. The practitioner must balance the number needed-to-treat, number needed-to-harm, and patient preferences to determine the optimal blood pressure target and choice of therapy for each individual.
Table 1. 2015 and 2016 CHEP Guidelines4,11
| Population | Target |
| Adults with Hypertension | ≤ 140/90 mmHg |
| Elderly (age ≥ 80 years) | ≤ 150/90 mmHg |
| Diabetes mellitus | ≤ 130/80 mmHg |
| New Recommendation in 2016 CHEP Guidelines: Selected high-risk patients† | SBP ≤ 120 mmHg |
†Selected high-risk patients who may potentially benefit from lower BP targets, referring to patients enrolled in the SPRINT trial.9,11
References and Additional Reading
- Robitaille C, Dai S, Waters C, et al. Diagnosed hypertension in Canada: incidence, prevalence and associated mortality. CMAJ. 2012 Jan 10;184(1):E49-56. (View)
- Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004 Sep 11-17;364(9438):937-52. (View with CPSBC or UBC) DOI: 1016/S0140-6736(04)17018-9
- Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002 Dec 14;360(9349):1903-13. (View with CPSBC or UBC) DOI: 10.1016/S0140-6736(02)11911-8
- Daskalopoulou SS, Rabi DM, Zarnke KB, et al. The 2015 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol. 2015 May;31(5):549-68. (View with CPSBC or UBC) DOI: 10.1016/j.cjca.2015.02.016
- 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 Feb 5;311(5):507-20. (Request with CPSBC or view UBC) DOI: 10.1001/jama.2013.284427
- Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013 Jul;34(28):2159-219.(View)
- Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008 May 1;358(18):1887-98. (View)
- ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010 Apr 29;362(17):1575-85. (View)
- SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015 Nov 26;373(22):2103-16. (View)
- Perkovic V, Rodgers A. Redefining Blood-Pressure Targets–SPRINT Starts the Marathon. N Engl J Med. 2015 Nov 26;373(22):2175-8. (View)
- Leung AA, Nerenberg K, Daskalopoulou SS, et al. Hypertension Canada’s 2016 CHEP Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention and Treatment of Hypertension. Can J Cardiol. 2016. (View with CPSBC or UBC) DOI: 10.1186/s12916-015-0502-5
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I haven’t been in practice too many years but have already had the experience of determining my practice based on a single (not very well designed) RCT and later seeing the evidence pile up to suggest I was too quick to jump on a bandwagon. I worry about this with a trail like SPRINT.
The Therapeutics Initiaitve at UBC did a good review of this trial and the practical implications here: http://www.ti.ubc.ca/2016/04/07/98-sprint-change-approach-blood-pressure-targets/
I think their review is a bit more balanced, although I appreciate the acknowledgement of harms in this review.
When there are multiple well-designed RCTs all showing similar effects, I’ll be open to changing my practice on this.
Exactly what Joel said.
He beat me to it!
When the SPRINT trial is considered in addition to all existing trials, it doesn’t move the marker for treatment thresholds. Furthermore, there is no convincing evidence that diabetics require more strict control. The TI has some excellent slides covering this specific question as well.
In the spirit of transparency and to allow readers to apply critical thinking, it is important for author’s disclosures to be listed on this site. Unfortunately I believe there have been some (all) omitted for the second author. Hopefully the process of disclosure can be more comprehensive in future.
The SPRINT study was sponsored by Takeda and Arbor Pharmaceuticals, both of which produce anti-hypertensive drugs. Should physicians be suddenly changing their practice based on one industry-sponsored study?
I generally do not change my practice based on a single trial either. I put more emphasis on lifestyle change than on medication to begin with and this was not mentioned in the article at all.
Regarding D. Moore’s comment. The trial was government funded and not sponsored by Takeda ( which was taken over by Arbor. Takeda contributed two study medications (azilsartan alone and azilsartan combined with chlorthalidone), which were two in a formulary of many antihypertensive medications. Azilsartan is an angiotensin II receptor antagonist. Chlorthalidone is a commonly prescribed diuretic. Approximately 5% of participants were on one of these donated drugs. Various classes of standard antihypertensive medications were included in the formulary for the SPRINT trial, including diuretics, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, and beta blockers, among others. At this time, most SPRINT blood pressure medications are generic.
An important note about this significant trial is the that blood pressure measure were take after 5 minutes rest by an automated 3 reading ( 2 minutes apart) Omron model 907 device. This method give lower readings that the the single physician reading reading that most physicians use. I recently switched to an Omron and measure BP in a separate room. I get significantly lower readings this way. This method is recommended in the 2016 CHEP guidelines.
TI thinks there is performance bias as they got such good control with 3 drugs in many patients. I have being able to achieve these numbers in my office after switching to an 3 reading automated device. ( I cycle patients through twice getting 6 readings)
Thanks for the clarification Dr Barrs. It’s all in the detail.
Thank you to all those that have read our article and those who have sent us their comments. We would like to take this opportunity to respond to the submitted comments.
First, there were several concerns regarding the generalizability of the SPRINT trial. The findings in SPRINT do not apply to patients with diabetes, history of stroke, significant proteinuria, one-minute standing SBP less than 110 mmHg, in addition to other exclusion criteria (see SPRINT appendix).(1) The SPRINT results only apply to patients 50 years and older with an SBP between 130-180 mmHg and a predefined risk factor, such as chronic kidney disease, cardiovascular disease, elevated Framingham risk, or age greater than 75 years. While it is the authors’ opinion that the SPRINT trial changes our practice, the Canadian Hypertension Education Program (CHEP) represents a well-respected national authority in the diagnosis, assessment, prevention, and treatment of hypertension. The 2016 CHEP Guidelines have reinforced the importance of applying intensive blood pressure control only in selected high-risk patients.(2)
Epidemiological studies show an increasing risk of cardiovascular events above a blood pressure of 115/75mmHg.(3) Almost half of the blood pressure-related disease burden occurs in people with a SBP less than 140mmHg. The Cochrane systematic review cited by the Therapeutics Initiative was published in 2009, with an updated review unpublished at this time.(4) Recently, there were two meta-analyses published in the Lancet in November 2015 reviewing the effect of intensive blood pressure lowering.(5,6) Xie et al. reviewed 19 trials including 44,989 patients but did not include SPRINT due to publication timing.(5) Despite this, the authors calculated a 14% reduction in major cardiovascular events with intensive blood pressure lowering (RR 0.87), with benefits extending to those with a blood pressure less than 140 mmHg.(5) There was also a reduction in microvascular events including albuminuria and retinopathy progression. This meta-analysis demonstrated an increase in severe hypotensive effects with more intensive BP lowering, but there was no suggestion that these adverse effects would outweigh the benefits of treatment. Over half of the trials included in the Xie et al. systematic review were published after 2009 and were not included in the original Cochrane analysis.
The second meta-analysis (Ettehad et al.) reviewed 123 studies (including SPRINT) with 613,815 patients.(6) The authors included all trials comparing blood pressure treatment versus placebo, trials comparing different blood pressure targets (i.e. SPRINT), and trials comparing different classes of blood pressure medications. The authors demonstrated a 20% reduction in major cardiovascular events (RR 0.80) for every 10 mmHg blood pressure reduction, with benefits extending to blood pressures less than 130 mmHg.(6) There was also a reduction in all-cause mortality (RR 0.87) for every 10 mmHg reduction, and all findings were demonstrated independent of baseline cardiovascular disease.
Interestingly, the systolic blood pressure target of less than 140 mmHg that is most often followed is based on only Grade C evidence (2015 CHEP Guidelines), compared to the current intensive treatment recommendation (2016 CHEP Guidelines), which reflects Grade B evidence.(2)
It is important to evaluate the potential funding biases that can influence a study. As stated by Dr. Barss, the SPRINT trial was funded by the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institutes on Aging, and the National Institute of Neurological Disorders and Stroke. The provision of study medications and method of blood pressure measurement has been clearly explained in Dr. Barss’ response. In British Columbia, the provincial drug formulary has just announced price reductions for most commonly prescribed anti-hypertensive medications, making these medications affordable for most patients. The method of anti-hypertensive monitoring, as noted by Dr. Barss, is also an important point.
Finally, we agree that lifestyle remains an important pillar of anti-hypertensive treatment. Space limitations in our original article precluded the discussion of lifestyle and non-pharmacologic therapies. Previous studies, such as the DASH (Dietary Approaches to Stop Hypertension) trial, have demonstrated marked reductions (up to 12 mmHg) with dietary changes in hypertensive patients.(7) Exercise has been demonstrated to reduce blood pressure (4-5 mmHg) in pre-hypertensive and hypertensive adults, with higher intensity exercise showing greater benefit.(8) Likewise, excess alcohol consumption has a marked effect on blood pressure and the risk of hypertension, in addition to other cardiovascular and systemic risks.(9)
Thank you for your questions and comments. We hope that our responses have sufficiently addressed your concerns.
Drs. Christopher Cheung and Kenneth Gin
References:
(1) SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015 Nov 26;373(22):2103-16.
(2) Leung AA, Nerenberg K, Daskalopoulou SS, et al. Hypertension Canada’s 2016 CHEP Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention and Treatment of Hypertension. Can J Cardiol. 2016 May;32(5):569-88.
(3) Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002 Dec 14;360(9349):1903-13.
(4) Arguedas JA, Perez MI, Wright JM. Treatment blood pressure targets for hypertension. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD004349.
(5) Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2016 Jan 30;387(10017):435-43.
(6) Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016 Mar 5;387(10022):957-67.
(7) Sacks FM, Appel LJ, Moore TJ, et al. A dietary approach to prevent hypertension: a review of the Dietary Approaches to Stop Hypertension (DASH) Study. Clin Cardiol. 1999 Jul;22(7 Suppl):III6-10.
(8) Williamson W, Foster C, Reid H, et al. Will Exercise Advice Be Sufficient for Treatment of Young Adults With Prehypertension and Hypertension? A Systematic Review and Meta-Analysis. Hypertension. 2016 Jul;68(1):78-87.
(9) Chen L, Smith GD, Harbord RM, et al. Alcohol intake and blood pressure: a systematic review implementing a Mendelian randomization approach. PLoS Med. 2008 Mar 4;5(3):e52.
i will change my practice
An interesting summary of the discussion regarding SPRINT at the European Society of Cardiology meeting in Rome posted yesterday on the MedPage Today website: http://www.medpagetoday.com/meetingcoverage/esc/59908 discussing the controversy surrounding the method of BP monitoring used in the trial.