Two Trials of Intensive BP Lowering, Two Different Outcomes

CHICAGO — Intensive antihypertensive therapy to target systolic blood pressure (BP) less than 120 mm Hg can lower the chance of strokes, heart attacks, or other major cardiovascular events in people who have had a stroke but not so much in people with diabetes, according to twin clinical trials.“We were able to achieve a sustained reduction in systolic BP of 13.1 mm Hg difference at 3.9 years,” said Otavio Berwanger, MD, PhD, co-lead author of both the OPTIMAL-STROKE and OPTIMAL-DIABETES trials. Both trials, presented at the American Heart Association (AHA) Scientific Sessions 2026, randomized patients to the 120 mm Hg target or the standard target of 140 mm Hg.Otavio Berwanger, MD, PhDThe diabetes trial found a similar effect with the intensive therapy group having systolic BP of 13.7 mm Hg lower than the standard therapy group, said Berwanger, the executive director of The George Institute for Global Health in London, England. The OPTIMAL-STROKE and OPTIMAL-DIABETES trials were published simultaneously in The New England Journal of Medicine.In the stroke trial, the intensive treatment group had a statistically significant relative risk reduction of 21.6% for the primary outcome, which was a composite of cardiovascular death, nonfatal heart attack or stroke, or hospitalization for unstable angina or heart failure (HF), Berwanger said (hazard ratio [HR], 0.79; 95% CI, 0.67-0.94; P = .007).The diabetes trial, on the other hand, found no statistically significant difference between the two treatment groups, Berwanger said, with 6% of the intensive group and 6.7% of the standard treatment patients meeting the primary outcome, for a HR of 0.9 (95% CI, 0.77-1.06; P = .2).The outcomes in the diabetes trial, however, may merit a closer look, said Shawna Nesbitt, MD, MS, medical director of the Hypertension Clinic at Parkland Health and a professor at University of Texas Southwestern Medical Center, both in Dallas. “A longer follow-up for this population may have shown us statistically significant differences,” she said. Nesbitt is not affiliated with the study.Both trials randomized patients 1:1 to either intensive treatment to a target systolic BP of 120 mm Hg or treatment to the standard target of 140 mm Hg. OPTIMAL-Stroke randomized 4368 patients; OPTIMAL-Diabetes randomized 9476 patients.OPTIMAL-STROKE ResultsWomen comprised about 48% of the stroke study population, and the average age of participants was 64 years. Among all, 57% of patients were White, 30% mixed-race, and 12% Black. Upon enrollment, average systolic BP was around 146 mm Hg, about 40% had diabetes, and the median time since the cardiovascular event was 1.1 years, said co-lead investigator Gisele Sampaio Silva, MD, MPH, PhD, head of neurology clinical trials at Hospital Israelita Albert Einstein in São Paulo, Brazil.“The right systolic target for patients with a previous stroke remains unclear,” Silva said. She noted the SPRINT trial supported a target systolic BP of less than 120 mm Hg, but that did not include patients who had a previous stroke.Gisele Sampaio Silva, MD, MPH, PhD“And earlier secondary-prevention trials were either underpowered or limited to specific stroke subtypes,” she said. “So our question was simple: In patients with prior ischemic stroke or transient ischemic attack, does a systolic target below 120 mm Hg reduce major cardiovascular events compared with a target below 140?”It does, according to Berwanger, who presented the results. At 4 years, 10.9% of the intensive treatment group and 13.5% of the standard treatment group had one of the composite cardiovascular events (95% CI, 0.67-0.94; P = .007), Berwanger said. Patients in the intensive therapy group took an average of three medications; in the standard treatment group, they averaged 2.2 medications.A hierarchical secondary analysis found no difference between the respective groups in cardiovascular death (4.6% and 4.7%; HR, 0.96; 95% CI, 0.73-1.26), but a 19% relative risk reduction in the 3-point measure of major adverse cardiovascular events (MACEs), including cardiovascular death and nonfatal heart attack or stroke (9.8% vs 11.8%; HR, 0.81; 95% CI, 0.68-0.98; P = .03), and a 16% risk reduction in 5-point MACEs, which also included unstable angina and hospitalization for HF (17.4% vs 20.2%; HR, 0.84; 95% CI, 0.74-0.97; P = .02).When the MACE components were broken out individually, the rates of all-cause death were similar between the two groups (11.7% and 12.4%), but rates of stroke, ischemic stroke, HF-related hospitalization, and unstable angina all favored intensive therapy. Relative risks ranged from 26% to 47%. The rate of hemorrhagic stroke was higher in the intensive therapy group — 0.2% vs 0.1% — but that affected only five and three patients, respectively.The study provides clarification for BP lowering in patients that can be “very challenging,” said Cheryl Bushnell, MD, MHS, a neurologist at Wake Forest University School of Medicine in Winston-Salem, North Carolina, who was not affiliated with the study.Cheryl Bushnell, MD, MHS“There are a lot of times when patients are discharged from the hospital and they have carotid stenosis, they have a middle cerebral artery stenosis and everybody is nervous about lowering their blood pressure too much, so this kind of abolishes some of the concerns that a lot of physicians have had on cerebral perfusion,” she said.Current guidelines call for lowering BP to less than 130/80 mm Hg, Bushnell noted. “Now we have evidence that perhaps we could do even better in terms of our cardiovascular outcomes by pushing that just a little bit more.”OPTIMAL-DIABETES ResultsThe diabetes trial sought clarifying evidence on the effect of intensive BP lowering in the disease, said Karla Santo, MD, PhD, co-lead investigator. “The optimal systolic blood pressure target in patients with type 2 diabetes is still uncertain and that comes from inconsistent results from previous trials,” said Santo, a researcher at Hospital Israelita Albert Einstein.Two previous trials she focused on were the 2010 ACCORD-BP trial, which found that intensive BP control did not reduce the incidence of cardiovascular events, and the 2024 BPROAD trial in China, which reported an opposite finding.In OPTIMAL-DIABETES, 62% of participants were women, and the average age was 65 years. In all, 42% were White, 42.5% mixed race, and 14.5% Black. Baseline systolic BP was 146 mm Hg. Around 28% of patients had clinical cardiovascular disease, and 4% had subclinical disease.Karla Santo, MD, PhDThe systolic BP outcomes in OPTIMAL-DIABETES tracked the stroke trial: 121.8 mm Hg for intensive treatment and 135.4 mm Hg for standard treatment; as did the variation in BP between the groups — 13.7 mm Hg — and the number of medications — 3.2 vs 2.3, Berwanger said.However, the primary outcome of cardiovascular death, nonfatal MI or stroke, or hospitalization for unstable angina or HF did not favor either group in the diabetes trial, he noted.Likewise, Berwanger said, the individual secondary outcomes were not significantly different across the board with a few exceptions: The intensive therapy group had a lower rate of stroke, 1.1% vs 1.5%, or a 27% lower HR (HR, 0.73; 95% CI, 0.51-1.06), but a 33% higher rate of hospitalization for HF (1.4% vs 1%; HR, 1.33; 95% CI, 0.92-1.93).“This should be interpreted as a neutral trial, but it’s not the only trial,” Berwanger said. When the OPTIMAL-DIABETES results are combined with those from the BPROAD and ACCORD trials, the analysis reveals a 16% relative risk reduction in cardiovascular events, he added.However, Berwanger noted in the BPROAD population in China that most cardiovascular events were strokes, “as expected in that population.” OPTIMAL-DIABETES more closely resembled ACCORD-BP, in which most fatal events were coronary events. “The Brazilian population is much more similar to the North American population than to the Chinese population in terms of risk profile," he said.‘Skewed’ Outcomes?OPTIMAL-DIABETES had a different population than the other studies it has been referenced against, Nesbitt said. BPROAD had 45% women, and an average age of participants was 64 years. SPRINT had 35% women, and an average age of participants was 68 years. The BPROAD trial in China also had a different ethnic population than the SPRINT trial. The larger proportion of women may have “skewed” OPTIMAL-DIABETES outcomes early on, she said.Shawna Nesbitt, MD, MS“In OPTIMAL, though there’s no statistically significant difference here, we do see a trend beginning early and continuing as the lines are separating further out,” she said, referring to a bar graph that showed the gap between trend for the intensive and standard therapy groups widening over time. “A longer follow-up for this population may have shown us statistically significant differences,” Nesbitt said.Comparing that to BPROAD or SPRINT, the differences appeared early in the trials and stayed consistent to the end, she said. Nesbitt also noted the ESPRIT trial in 2024 concluded that aggressive BP targeting in patients with cardiovascular risk, regardless of their diabetes status or stroke history, prevented major vascular events.OPTIMAL-DIABETES “supports rather than refutes what we already have seen in other trials of treating hypertension more aggressively in patients with diabetes,” Nesbitt said.The trial might call for a more nuanced approach to managing BP in patients with diabetes, she added. “Perhaps we’ve been lumping patients together that may not always be advantageous. Thinking about them more discretely is maybe something that we need to consider as we go forward.”Renal OutcomesIn both trials, the intensive treatment patients had a higher rate of kidney-related complications, Berwanger said.In the stroke trial, 3.9% of patients on intensive treatment met the composite renal outcome vs 2.2% of the standard treatment group (HR, 1.76; 95% CI, 1.24-2.50). In the diabetes trial, the respective proportions were 5.7% vs 3.7% (HR, 1.55; 95% CI, 1.28-1.88). The composite renal outcome in both trials was defined as a sustained reduction 50% or more in the glomerular filtration rate (eGFR) or progression to end-stage kidney disease.In both trials more kidney-related deaths occurred in the intensive treatment group: 0.2% vs 0.1% in the stroke trial (HR, 1.35; 95% CI, 0.3-6.05); and matching percentages in the diabetes trial (HR, 2.66; 95% CI, 0.71-10.02). However, the overall numbers were small: four vs three in the stroke trial and eight vs three in the diabetes trial.Both trials used sustained eGFR reduction of at least 50% in the composite renal outcome. In the stroke trial, 3.6% of the intensive group and 2.2% of the standard group had a sustained eGFR reduction of at least 50% (HR, 1.69; 95% CI, 1.18-2.42), and 0.3% and 0.1% were on long-term dialysis (HR, 2.02; 95% CI, 0.5-8.06). In the diabetes trial, the rate of sustained eGFR reduction was 5.4% in the intensive treatment group and 3.4% in the standard therapy group (HR, 1.59; 95% CI, 1.31-1.93). Significantly more patients in the diabetes study were on long-term dialysis, but the rates were similar in both treatment groups: 0.4% and 0.5%, respectively (HR, 0.95; 95% CI, 0.52-1.73).Renal complications in the diabetes trial were driven by the sustained drop in renal function, Berwanger said. “But we doubt how much that resulted in end-stage renal disease, long-term dialysis or renal mortality,” he added.Many antihypertensive medications are diuretics, which increases creatinine spiking “and that is measurable as a decrease in eGFR,” Nesbitt said. “The long-term consequence that you worry about over time is permanent loss of renal function rather than the intermediate measure in change in eGFR,” which patients can counteract by drinking more water, she said.“In clinical trials we’ve used that because we need a measure of change, but in real clinical treatment of patients it may not necessarily indicate that this is the negative effect of the drug that should dictate a change in therapy,” Nesbitt added.Berwanger reported having financial relationships with AstraZeneca, Bayer, Servier, Amgen, Pfizer, and Novartis. Silva reported having financial relationships with Boehringer Ingelheim, AstraZeneca, and Bayer. Santo reported having financial relationships with Elfie and Servier. Bushnell reported having financial relationships with Bayer and Care Directions. Nesbitt reported no relevant conflicts of interest.Richard Mark Kirkner is a medical journalist based in the Philadelphia area.