More Intensive Blood Pressure Control Associated with Lower All-Cause Mortality Risk

Chronic kidney disease affects an estimated 26 million people in the United States and 200 million individuals worldwide. The risks for cardiovascular disease, progression to end-stage renal disease (ESRD), and mortality are increased in people with CKD. Hypertension is a risk factor for cardiovascular disease and there have been several studies designed to identify the optimal blood pressure target in patients with CKD; however, to date there has been no clear consensus on the best blood pressure target in this patient population.

Current guidelines from the Kidney Disease: Improving Global Outcomes (KDIGO) on blood pressure call for a goal <130/80 mm Hg for patients with CKD and moderate-to-severe albuminuria <30 mg/g. The Eighth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and the 2013 European Society of Hypertension/European Society of Cardiology Task Force recommend a blood pressure target of <140/90 mm Hg for patients with CKD with no distinction based on albuminuria level.

The SPRINT (Systolic Blood Pressure Intervention Trial) enrolled hypertensive individuals without diabetes and at high risk for CKD; in patients treated to a systolic blood pressure target of <120 mm Hg compared with <140mm HG, the risks of CKD and all-cause mortality were significantly lower, but there was a significant excess of acute kidney injury. Approximately 30% of SPRINT participants had CKD (defined as estimated glomerular filtration rate [eGFR] of 20-59 mL/min/1.73 m2), and trial results were similar to those with CKD compared with patients without CKD. The trial was not specifically powered to define the risks and benefits of intensive blood pressure control in CKD patients, however.

Rakesh Malhotra, MD, MPH, and colleagues recently conducted a systematic review and meta-analysis of randomized controlled trials to investigate if there is
an association between more intensive blood pressure control compared with less intensive control and reduced mortality
risk in individuals with CKD stages 3 to 5. The primary outcome of interest was all-cause mortality; mortality events that occurred during extended follow-up following the active phase of each trial were not included. Results were reported online in JAMA Internal Medicine [doi:10.1001/jamainternmed.2017.4377].

Using the keywords randomized controlled trials, intensive blood pressure treatment, intensive blood pressure control, strict blood pressure treatment, strict blood pressure
control, tight blood pressure treatment,
or tight blood pressure control,
the researchers searched Ovid MEDLINE, Cochrane Library, EMBASE, PubMed, Science
Citation Index, Google Scholar, and
clinicaltrials.gov electronic databases between January 1, 1950, and June 1, 2016. The initial search yielded 4416 citations.

Following a review of abstracts and application of more limited criteria, there were 407 potentially eligible abstracts for inclusion; subsequent review excluded 377 studies that did not meet inclusion criteria. The remaining 30 studies were reviewed in full text; upon final application of inclusion and exclusion criteria, the meta-analysis included 18 randomized controlled trials involving 15,924 participants with CKD; complete data were included in the meta-analysis.

The blood pressure targets varied across the 18 trials. Mean baseline blood pressure was 148 mm Hg in both the intensive and less intensive arms. In the more intensive arms, mean systolic blood pressure decreased by 16 mm Hg to 132 mm Hg; in the less intensive arms, mean systolic blood pressure decreased by 8 mm Hg to 140 mm Hg.

In the 18 trials, there were 584 deaths among 7451 participants in the more intensive blood pressure arm and 709 among the 8473 participants in the less intensive blood pressure arm. Using the random-effects model, the odds ratio (OR) for death among participants with CKD randomized to the more intensive blood pressure lowering arm was 0.86 (95% confidence interval [CI], 0.76-0.97; P=.01), compared with those in the less intensive blood pressure lowering arm. Because results of SPRINT showing that mortality was improved with intensive blood pressure control, and because those results added substantial statistical significance to the meta-analysis, the researchers evaluated the remaining trials with the exclusion of SPRINT in a sensitivity analysis. Results were similar: OR, 0.88; 95% CI, 0.78-0.99; P=.05.

The study had some limitations, according to the authors, including the inability to obtain data on mortality in individuals with CKD in several prior clinical trials, requiring the exclusion of those trials in the meta-analysis; the researchers noted that there was no evidence of heterogeneity in the 18 included studies, making it likely that results would have been similar with the inclusion of additional studies. Further, there were no data on the severity of CKD limiting the ability to assess the effect of more intensive blood pressure control on mortality stratified by CKD severity; most participants in the meta-analysis had CKD stage 3. The risks and benefits of intensive blood pressure control in patients with more advanced CKD may differ, limiting the ability of the researchers to provide an estimate of an optimal blood pressure target in CKD patients.

In conclusion, the researchers said, “Among trial participants with hypertension and an eGFR less than 60 mL/min/1.73 m2, randomization to more intensive blood pressure lowering was associated with lower risk of all-cause mortality. This finding was consistent across trials, with no evidence of heterogeneity. A nonsignificant suggestion of greater mortality benefit was observed in trials that achieved the greatest difference in blood pressure across arms. Although additional studies and intensive monitoring for safety are warranted, these data support that the net benefits may outweigh the net harms of more intensive blood pressure lowering in persons with CKD.”

TAKEAWAY POINTS

It is unclear whether intensive blood pressure lowering is associated with a mortality benefit in patients with prevalent chronic kidney disease (CKD).

Researchers conducted a systematic review and meta-analysis designed to determine if more intensive blood pressure control is associated with reduced mortality risk compared with less intensive blood pressure control in a patient population with CKD.

The meta-analysis included 18 randomized controlled trials involving 15,924 participants. Individuals in the more intensive blood pressure lowering arms had lower mortality risk compared with those in the less intensive blood pressure lowering arms (odds ratio, 0.86; 95% confidence interval, 0.76-0.97; P=.01).

 

“The risks and benefits of intensive blood pressure lowering in CKD patients is unclear.  In the SPRINT trial within the subset of patients with CKD, those randomized to intensive blood pressure control had lower mortality than those in the standard arm, but this had not been seen previously. In this meta-analysis, which was limited to persons who had CKD at baseline within 18 prior clinical trials, we demonstrate that those randomized to the more intensive blood pressure arm within each trial were at lower risk of mortality. The results were similar irrespective of inclusion or exclusion of the SPRINT trial in the analysis, showing that this result appears robust across randomized trials. However, the target blood pressure varied across studies so the meta-analysis does not allow refinement in regards to the most optimal blood pressure target in CKD patients.”
—Joachim H. Ix, MD, MAS