Driving Blood Pressure Targets Down the BPROAD (Again)

EBM Focus - Volume 21, Issue 13

Reference: N Engl J Med. 2025 Mar 27;392(12):1155-1167

Practice Point: Another trial of intensive blood pressure control suggests a small reduction in nonfatal stroke with systolic blood pressure target ≤ 120 mm Hg in patients with diabetes at elevated cardiovascular risk.

EBM Pearl: Beware of inflated composite outcomes with significance driven by a single outcome, especially if it is a nonfatal event.

George Washington Carver once said, "In the garden of science, even weeds can become flowers with enough tending." As the eleventh trial looking for a benefit of intensive blood pressure control over standard targets, the BPROAD trial may be seen as that flower. If that’s the case, would that make the ACCORD trial a weed? We will come back to that. For now, buckle up.

When it comes to managing hypertension, many clinicians presume that because there is a link between relatively low (i.e. normal) blood pressure and longevity, lowering blood pressure further will continue to benefit patients. Many work to drive down blood pressures to meet ever-lowered targets, never questioning the dogmatic "the lower, the better" approach, despite a lack of evidence from randomized trials supporting that strategy. There is a difference between a patient so healthy that they naturally have a systolic blood pressure (SBP) of 110 mm Hg and a patient who is medicated to an SBP of 110. And, importantly, there is a difference in their outcomes, including iatrogenic harms. While high-quality evidence supports that some degree of BP control (< 140/90) leads to better outcomes in patients with hypertension, the majority of studies and systematic reviews have yet to demonstrate a clinically important benefit of more intensive SBP targets like < 120, even in patients who we think should benefit, like those with diabetes. And perhaps that is one reason researchers keep repeating essentially the same study—because the results hadn’t yet proven what they have long believed to be true.

For context, let us highlight a few of the major developments in hypertension management that preceded the BPROAD trial:

  • JNC 1-3 (1977-1984): Observational-only studies focused on diastolic blood pressures (DBPs) that informed treatment goal of DBP < 90
  • JNC 4-6 (1988-1997): First studies to include SBP but still no clinical trials; first systolic target in 1993 of < 140/90
  • JNC 7 (2003): Limited trial data, targets < 140/90 or < 130/80 if chronic kidney disease (CKD)
  • JNC 8 (2014): First to reflect systematic review of only trial data (no observational data); resulted in recommended targets of < 140/90 for age < 60 or any age with diabetes or CKD; < 150/90 for age ≥ 60
  • UKPDS 38 (1998):
    • Large, unblinded trial of adults with newly diagnosed diabetes comparing intensive (< 150/85) to standard (< 180/105) blood pressure targets over ~ 8 years, although achieved BPs were 144/82 and 154/87, respectively
    • Primary outcome: Composite of 21 individual macrovascular and microvascular outcomes
    • Results: More intensive BP control was associated with a reduction in the composite outcome, driven mainly by reduction in stroke and diabetes-related complications, including death.
    • Caveat: Blood pressure targets were much higher than today’s standards, making it hard to compare to newer data.
  • ACCORD BP Trial (2010):
    • Large trial primarily designed to evaluate tight vs. standard glucose control in adults with diabetes, but with parallel evaluation of the effects of intensive (< 120) vs. standard (< 140) SBP targets
    • Primary outcome: Composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke
    • Results: No difference in primary outcome; small reduction in any or nonfatal stroke
  • SPRINT Trial (2015):
    • Large trial evaluating intensive SBP target (< 120) vs. standard (< 140) in patients ≥ 50 years old without diabetes at increased cardiovascular risk that was ended early due to benefit
    • Primary outcome: Composite of MI, acute coronary syndrome, stroke, acute decompensated heart failure, and cardiovascular death
    • Results: Intensive group had significantly reduced composite outcome, with significantly reduced all-cause and cardiovascular mortality, and reduced heart failure.
    • Caveats:
      • Blood pressure was measured as an average of 3 measurements using an unattended automated device after 5 minutes of quiet rest, which is different from any other study and is likely to result in significantly lower BPs than what would be expected in a typical clinic setting or in other studies. Meaning, SPRINT’s SBPs of 120 and 140 are likely equivalent to another study’s 130 and 150. Importantly, the details of this method were buried in supplemental information.
      • Findings are discordant with many previous studies and lead to wide confidence intervals (i.e. less confidence in results) when included in systematic reviews.
  • Systematic Reviews:
    • Cochrane Review 2009:
      • Systematic review and meta-analysis of 7 trials comparing different diastolic targets (no trials of systolic targets found!)
      • Compared < 135/85 vs. < 140-160/90-100; found no reduction in morbidity or mortality with lower target
    • Systematic Review for ACC/AHA guideline update 2018:
      • Systematic review of 15 randomized controlled trials, including SPRINT trial
      • Generally compared < 130 vs. < 140 SBP targets; found no mortality benefit but reduction in stroke, MI, and heart failure with lower target
    • Cochrane Review 2020:
      • Update of 2009 Cochrane meta-analysis with 7 new trials, including the SPRINT trial
      • Compared standard (< 140) vs. "lower" targets; found no reduction in mortality or serious adverse events, but moderate reduction in nonfatal MI and heart failure

So, the recently published BPROAD trial is the latest to assess the clinical benefit of intensive (< 120 mm Hg) compared to standard (< 140 mm Hg) SBP control, this time in older adults (average age 63 years) with diabetes in China. At the beginning of the trial, the 13,000 patients enrolled had an average BP of 140/76, an A1c of 7.6, and took 1-2 antihypertensives (mostly ARBs and CCBs). One quarter had a history of clinical cardiovascular disease. All patients were continued on usual treatment, but half of them were given an SBP goal of < 120 and the other half given a goal of < 140. Patients were blinded, but treating clinicians were aware of allocation. Patients in the intensive target group ended up on about one additional antihypertensive.

After about 4 years of follow-up, investigators found a small benefit of intensive control for the composite of nonfatal MI, nonfatal stroke, treatment or hospitalization due to heart failure, or death from cardiovascular cause (hazard ratio [HR] 0.79 [0.69-0.90]), driven almost entirely by a reduction in nonfatal stroke (HR 0.79 [0.67-0.92]). This outcome mirrors those demonstrated in previous systematic reviews in which more intensive control demonstrated no effect on mortality, but when components of a composite were analyzed individually, a reduction in nonfatal events was found.

Allow us to remind you of the EBM Focus: Nonfatal MI — Death of a Surrogate, which discusses exactly how including nonfatal events can inflate the perceived benefit of a treatment when aggregated with death rates, and therefore why we should not be routinely combining mortality and nonfatal events in composite analyses. Although it seems like it would make sense that a reduction in nonfatal events would be a good surrogate for a reduction in related fatal events, the evidence suggests this isn’t the case often enough to be any kind of reliable surrogate. Essentially, we can’t assume anything. What plays out in trials is sometimes not at all what we expected to happen. Here’s an example: The arm of the ACCORD trial that studied effects of more intensive glucose control actually found increased, not decreased, mortality as was expected.

The devil is in the details (which are often buried in the supplement, as was the case with the BP measurement technique in the SPRINT trial). In the case of the BPROAD trial, the achieved BPs at the end of the 4-year follow-up period were never mentioned. We managed to extrapolate them from a figure in the supplement: the intensive group averaged an SBP of 117, and the standard group, 133. This is interesting, because the BPs achieved at one year, 121 and 133, respectively, were reported in the prime real estate of the text. Related, symptomatic hypotension occurred significantly more often in the intensive treatment group, although no increase in falls was reported. Why are we making a big deal about driving pressures past the targets and not being forthcoming with that information? Well, an average SBP of 117 in the trial really means a) about half the participants had measured pressures lower than that, and b) home blood pressures were likely to be about 102-112 based on an established 5- to 15-point difference between in-clinic and home BPs. An older person with diabetes and likely other comorbidities walking around with an SBP of 102 that we gave them is not necessarily something that deserves a pat on the back. (Hello! Hip fractures have a 5-year mortality rate of 18%-26%).

So, are the studies that found no significant benefit of intensive blood pressure control "weeds," and the SPRINT and BPROAD trials "flowers" because they’ve finally "proven" what was believed to be true all along—the lower, the better? The evidence isn’t quite so simple. The BPROAD trial is hanging its hat on what comes down to a reduction in nonfatal stroke, which again, we know puts the primary outcome data into question because it was included in a composite outcome with death. Even if we accept the statistical analysis and outcome data as is, what we are talking about here is a small absolute benefit: 0.4 composite events (almost all likely to be nonfatal strokes) per 100 person-years, inextricably bundled with some additional harms.

Rather than weeds and flowers, perhaps it is all one garden, a body of evidence if you will. When we zoom out and look at the big picture, our caption might say that SBP targets closer to 120 mm Hg might make sense for some patients, including those with diabetes at particularly increased risk of stroke, but alas, lower has still not actually been proven to be better.

For more information, see the topic Hypertension in DynaMed.

DynaMed EBM Focus Editorial Team

This EBM Focus was written by Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, MPH, FACP, Senior Deputy Editor at DynaMed; McKenzie Ferguson, PharmD, BCPS, Senior Clinical Writer at DynaMed; Rich Lamkin, MPH, MPAS, PA-C, Clinical Writer at DynaMed; Matthew Lavoie, BA, Senior Medical Copyeditor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor II at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.