Highest-Risk Patients Gain the Most From Intensive BP Therapy

Patients in the SPRINT trial with the highest predicted risk of CVD at baseline derived the greatest benefit from intensive blood pressure lowering, but they also faced an increased likelihood of treatment-related adverse events.

Researchers say that since most of those events were mild and fleeting, particularly compared to the severity of the outcomes prevented, intensive therapy is worth the risk. Still, the findings, from a secondary analysis, have important implications for guidelines and practice.

“What we were hoping is that we would find a large number of people who derived a lot of benefit at very low risk of adverse events. And that is what we did not find,” senior author Andrew Moran, MD (Columbia University Irving Medical Center, New York, NY), told TCTMD.

Only 1.8% of patients, in fact, had the ideal combination of large predicted benefit and low predicted risk of adverse events.

The researchers were motivated to try to find a substantial number of patients like that in order to better focus the delivery of intensive therapy as studied in the SPRINT trial. Prior research by a team led by Adam Bress, PharmD (University of Utah, Salt Lake City), lead author of the current analysis, estimated that 8.6 million US adults who would have been eligible for SPRINT were not being treated for hypertension, and that another 8.2 million who were being treated were candidates for more-aggressive therapy.

“For the US health system to shift to taking on intensive treatment for that number of people, it would be a huge burden because it requires more medicines and more visits to the clinic under the model of SPRINT. So that’s a lot of resources,” Moran said.

Because the data do not reveal a large group of patients who would derive a large benefit from intensive treatment without a high risk of adverse events, it places greater importance on shared decision-making between patients and their physicians when it comes to lowering blood pressure, Moran indicated.

“We’re really putting it on the treating doctors to make this a priority and take the adverse event risk in the context of weighing it against the implications of heart attack, stroke, and heart failure,” he said.

The bottom line, Bress told TCTMD, is that “our results support offering intensive treatment to all SPRINT-eligible adults.” But in situations where all such patients can’t be treated, he added, efforts should focus on the highest-risk patients.

Influence of Baseline Risk

Results of the SPRINT trial, released in November 2015, showed that among nondiabetic patients with high CVD risk, treating to a systolic BP goal of less than 120 mm Hg reduced the risk of the primary composite outcome (MI, ACS other than MI, stroke, acute decompensated heart failure, or cardiovascular death) compared with treating to a standard goal of less than 140 mm Hg. All-cause mortality was reduced as well. The overall rate of serious adverse events did not differ between treatment arms, although certain events—like hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure—were increased with intensive therapy.

Despite the positive findings, physicians may be hesitant to take BP too low in certain patients, due to concerns about adverse effects. Several prior studies have explored whether there are particular subsets of patients who derive a particularly high benefit at a low cost of side effects, including the first- and third-place winners of the SPRINT Data Analysis Challenge launched after the main trial was reported.

In this new study, published in the April 27, 2021, issue of the Journal of the American College of Cardiology, Bress, Moran, and colleagues use a risk-modeling approach to examine the same issue. In contrast to previous efforts, they had the advantage of using the complete individual patient data set from SPRINT and getting input from the trial investigators, steering committee, and coordinating center.

The analysis included 8,828 SPRINT participants (mean age 67.9 years; 35% women) after excluding those with missing information on key baseline variables. During a median follow-up of 3.26 years, there were 600 CVD composite events, 363 all-cause deaths, and 481 treatment-related adverse events.

The results showed that patients with a higher predicted CVD risk at baseline had a greater absolute reduction in CVD events with intensive therapy. Adverse event risk tracked with baseline CVD risk as well, and 95% of those in the highest tertile of predicted benefit in terms of composite CVD event reduction also had high or moderate predicted increases in treatment-related adverse event risk. “However,” Bress et al write, “for treatment-related adverse events, the association between baseline risk and the effect of intensive versus standard systolic BP treatment appeared to be attenuated at the highest levels of baseline risk.”

Findings were similar when looking at reductions in all-cause mortality with intensive therapy.

Weighing Benefits and Risks

The authors argue that the predicted CVD benefits and the increased adverse event risks should not be weighted equally, because many of the adverse events in the trial were mild and transient. Moreover, there was greater opportunity to report adverse events in the intensive arm than in the standard arm, because there were about 10% more study visits to handle adjustments to treatment, a bias that should be considered, they indicate.

Bress underscored the point, noting that the outcomes of benefit are life-altering and potentially fatal events like MI, stroke, and heart failure, whereas many of the adverse events were manageable issues like transient rises in creatinine and bradycardia. So rather than incorporating both sides of the equation into a single assessment—as was done in some prior studies—they were reported separately so patients, clinicians, and other researchers can make their own judgments about how the benefits and risks should be weighed, he said.

“We thought it was critically important to present it, of course, because benefit and harm is the marriage that clinicians are faced with in terms of making decisions around intensive treatment, especially among the elderly where the fear of—particularly—injurious falls is greatest,” Bress said.

Though SPRINT enrolled a wide range of patients and showed the benefits of intensive therapy across many subgroups, Moran noted, some physicians remain wary about taking blood pressure too low for certain types of people.

“Individual clinicians, individual patients, have to monitor things closely, have to account for these individual factors and take things slowly, but the results do suggest that in many cases we’re overly cautious and that we might be denying patients a benefit if we don’t even try to intensively manage blood pressure,” he said.

Miguel Camafort, MD, PhD (Hospital Clínic Barcelona, Spain), who was not involved in the study, agreed, although he told TCTMD that in his practice, frailty is a key factor when it comes to deciding on the intensity of blood pressure control.

“In patients similar to those who were in the SPRINT trial, I think it is good to go as low as possible,” he said. Camafort questioned, however, whether there were really many frail patients included in SPRINT, even though a prior analysis of the trial indicated that that frail patients also had much to gain from more-aggressive therapy.

“My suspicion is that there are not so many frail patients in SPRINT, and what we do in our clinic is to see if the patients are frail or not,” Camafort said. “If they are not frail, we are going as low as possible. If they are frail, we are more cautious.”

It’s important, however, to keep trying to get blood pressure under control in all patients, and to make efforts to increase awareness of hypertension in the community, he stressed. “I hope that these data help us to [address] clinical inertia, and that also the health administrations make a big effort in finding those patients with hypertension and to get better control of them.”

It’s good to be cautious about adverse effects, but it’s important to also consider the severity of the events that are being prevented, Camafort said. “I think all physicians should be aware that for lowering blood pressure, when you take into account benefits and risks, it’s more benefit than risk.”

A similar point is made in an editorial by Joseph Diamond, MD (Hofstra Northwell School of Medicine, Hempstead, NY), and colleagues, who discuss the “treatment-risk paradox” that sees patients at higher risk for adverse events getting less-intensive treatment.

“Given the conflicting blood-pressure guidelines that have been issued over the past several years, the results of the current study, in conjunction with other secondary analyses of SPRINT, offer an evidence-based rationale that nudges physicians to overcome the treatment-risk paradox in blood pressure management,” they say.