Pooled analysis of ACCORD-BP/SPRINT data teases out specifics of who benefits from intensive BP lowering

In a pooled analysis of data from the ACCORD-BP and SPRINT trials, researchers found no evidence of a significant interaction between baseline diastolic blood pressure (DBP) and the intensity of blood pressure lowering treatment for all-cause death or for a composite cardiovascular endpoint (CVE) that included cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.

They did find, however, that intensive therapy toward a target systolic BP of 120 mmHg in patients with baseline DBPs of 80-100 mmHg may lower the risk for a composite CVE, while an SBP target of 120 mmHg in patients with baseline DBPs <60 mmHg may increase the risk of all-cause death.

Their findings are published in JAMA Network Open.

“Since the publication of the landmark Systolic Blood Pressure Intervention Trial (SPRINT), the focus in treating hypertension has been on systolic blood pressure (SBP). However, this ignores observational data showing a J-shaped curve for diastolic blood pressure (DBP), where adverse cardiovascular events and mortality increase as DBP decreases below critical levels (<60 mm Hg). It has been postulated that pharmacological treatment to achieve a lower SBP target in persons whose DBP is already low may worsen patient outcomes,” wrote Andrew J. Foy, MD, Penn State University Heart and Vascular Institute, Hershey, Pennsylvania, and fellow researchers.

For their pooled cohort analysis, they included 14,094 patients (mean age: 66.2 years; 60.4% men) who were randomized to either intensive or standard BP control in the ACCORD-BP and the SPRINT trials. Median baseline DBP was 77 mmHg. In all, 4.8% of patients died and 6.3% experienced the combined CVE. More patients died of non-cardiovascular causes than cardiovascular, the authors noted.

When modeled nonlinearly, baseline DBP was found to be significantly associated with all-cause mortality and the composite CVE. For example, when comparing baseline DBP of 50 mmHg versus 80 mmHg, the hazard ratio (HR) for all-cause mortality was 1.48 (95% CI: 1.06-2.08; P=0.02), and for composite CVE, 1.45 (95% CI: 1.27-3.04; P=0.003); corresponding HRs for composite CVE in comparisons of baseline DBP 100 versus 80 mmHg were 2.15 (95% CI, 1.30-3.56; P=0.003) and 1.96 (95% CI: 1.27-3.04; P=0.003), respectively.

But, the researchers noted, “When analyzed as a continuous variable, findings for the association between baseline DBP and treatment group assignment for the outcome of all-cause death did not reach statistical significance. No interaction was seen between baseline DBP and treatment group for the composite CVE.”

When they compared intensive versus standard antihypertensive therapy for death, Foy and colleagues found the following HRs for baseline DBPs:

  • 50 mmHg: HR: 1.80 (95% CI: 0.95-3.39; P=0.07).
  • 60 mmHg: HR:1.12 (95% CI: 0.84-1.50; P=0.43).
  • 70 mmHg: HR: 0.82 (95% CI: 0.65-1.02; P=0.08).
  • 80 mmHg: HR: 0.77 (95% CI: 0.59-1.01; P=0.05).
  • 90 mmHg: HR: 0.85 (95% CI: 0.59-1.20; P=0.35).
  • 100 mmHg: HR: 0.79 (95% CI: 0.48-1.28; P=0.34).
  • 110 mmHg: HR: 0.64 (95% CI: 0.25-1.64; P=0.35).

Finally, in comparisons of intensive versus standard treatment, Foy and fellow researchers observed significant reductions in composite CVE for participants with baseline DBPs of 80 mmHg (HR: 0.78; 95% CI: 0.62-0.98; P=0.03), 90 mmHg (HR: 0.74; 95% CI: 0.55-0.98; P=0.04), and 100 mmHg (HR: 0.67; 95% CI: 0.45-1.01; P=0.05).

“Our results confirm prior observations of a nonlinear association between DBP and patient outcomes that appears U-shaped. No statistically significant interactions were observed, however, with respect to DBP and treatment group assignment for all-cause mortality or the composite CVE. This undermines the traditional J-curve hypothesis relating low DBP with reduced coronary perfusion and events,” Foy et al concluded.

“Although we acknowledge our findings do not establish the existence of an interaction between baseline DBP and treatment group assignment for the outcome of all-cause death, we think it would be imprudent to dismiss possible associations altogether,” they added.

In patients with lower baseline DBPs, Foy and colleagues noted that other factors may come into play.

“In individuals with lower baseline DBP values, factors unrelated to blood pressure may be associated with death more so than for individuals with higher DBP. Patients whose baseline DBP was less than 60 mmHg compared with those with higher values were at 3-fold higher risk of dying (9% vs 3%), were significantly older (73.6 vs 65.7 years), and had higher rates of all comorbid conditions. It is also not implausible to speculate that such individuals would be at increased risk of treatment-related harm, both measured and unmeasured and that they would not recover the same from adverse events as healthier subjects (adverse events were significantly increased in ACCORD-BP and SPRINT in the intensive therapy groups), and finally, that lowering blood pressure would not yield the same benefits as in those generally healthier subjects,” they wrote.

In an accompanying editorial, Sydney E. Hartsell, MD, MPH, and Srinivasan Beddhu, MD, both of the University of Utah School of Medicine, Salt Lake City, wrote:

“Similar to many prior observational analyses, the study by Foy et al found in an observational analysis that lower baseline DBP was significantly associated with a higher risk of both all-cause death and a composite cardiovascular end point of cardiovascular death, nonfatal MI, and nonfatal stroke in pooled study participants. However, when Foy et al tested for a continuous interaction between SBP intervention and baseline DBP on outcomes, there was no statistically significant interaction for all-cause death or the composite cardiovascular end point.”

Hartsell and Beddhu also noted that “…the study by Foy et al renews the attention on the potential increase in all-cause mortality associated with intensive SBP lowering in patients with low baseline DBP and diabetes using strict glycemic control. It should be noted that intensive glycemic control in ACCORD-BP was achieved with insulin and other older agents. With the recent advances in glycemia management with sodium/glucose cotransporter 2 inhibitors and glucose-like peptide-1 analogs in type 2 diabetes, randomized clinical trials of SBP lowering in patients with type 2 diabetes and low baseline DBP are warranted.”

Study limitations include the low numbers of patients with stroke at baseline and those with a baseline DBP of ˂60 mmHg, as well as an intentional exclusion of any analysis of serious adverse events as related to baseline DBP.

  1. Among patients whose baseline DBP was >60 mmHg, intensifying therapy to achieve an SBP target of 120 mmHg may reduce risks of cardiovascular events, according to a pooled cohort analysis of patients enrolled in the ACCORD-BP and SPRINT trials.

  2. In patients with baseline DBPs <60 mmHg, intensive BP lowering therapy may increase the risk of death.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This research was supported by an Innovation Award grant from the Penn State Milton S. Hershey Medical Center Department of Medicine.

Foy reported no disclosures.

Beddhu reported receiving grants from the National Institutes of Health related to the Systolic Blood Pressure Intervention Trial, Novo Nordisk, Boehringer Ingelheim, and Bayer and royalties from UpToDate.

Hartsell reported no disclosures.

Cat ID: 102

Topic ID: 74,102,730,102,6,410,142,192,916,925