SPRINT: The Study Nephrologists Might Take With a Grain of Salt

Abstract

Patients with chronic kidney disease (CKD) experience several comorbidities, one of the most important being cardiovascular (CV) disease (CVD). For example, patients with stage IIIa/b CKD are more likely to die from CVD than to survive to reach end‐stage renal disease. Management of hypertension, a major determinant of CV outcomes and progressive renal dysfunction, remains elusively controversial in the CKD population. In an effort to clarify this, the National Institutes of Health–funded Systolic Blood Pressure Intervention Trial (SPRINT) compared the traditional systolic 140 mm Hg goal with a more aggressive systolic goal of 120 mm Hg in a cohort of nondiabetic patients at elevated CV risk. SPRINT showed statistically significant reductions in combined CV events across all prespecified subgroups, including patients with CKD. However, SPRINT did not systematically include CKD patients, and the CKD data are merely offered as a convenience sampling. This directly limits external generalizability to CKD patients since only approximately 30% of SPRINT patients in the 120 mm Hg arm had CKD. SPRINT reaffirms the need for blood pressure control, especially in CKD patients, but is not a sufficient standalone guideline for nephrologists treating CKD in the community. A SPRINT‐style study dedicated to the CKD population would be more appropriate if traditional CKD guidelines are to be challenged conclusively.

Chronic kidney disease (CKD) affects 8% to 16% of the world's population.1, 2, 3 The major cause of death in this population is CV events4, which exceeds the rate of survival to reach end‐stage renal disease (ESRD) for patients with stage IIIa/b CKD.

There is clinicopathologic overlap between CKD and CVD at many levels, from oxidative stress and anemia to hypertension and diabetes mellitus. Hypertension is both a precipitant and a product of CKD pathophysiology and has received much focus in the literature. However, consensus regarding blood pressure (BP) goals in CKD has not yet been reached, even in the relatively well‐studied mature adult CKD population.5, 6, 7 In fact, assigning a single BP goal to CKD may oversimplify treatment and expected outcomes from a population that ranges in age from young to elderly adults.

After years of recommending lower BP targets for diabetic and CKD patients, major guidelines after 2013 challenged the “lower is always better” mantra (in a fashion especially controversial for high‐risk patients). As such, the European Society of Hypertension/European Society of Cardiology guidelines now recommend a BP goal of 140/90 mm Hg for CKD patients.7 In response, the Eighth Joint National Committee (JNC 8) report issued in 2014 relaxed BP guidelines in nondiabetic patients older than 60 years to 150/90 mm Hg6 without modifying goals for diabetic or CKD patients. Similarly, guidelines from Kidney Disease Improving Global Outcomes (KDIGO) recommended a 140/90 mm Hg goal for CKD patients, suggesting a stricter 130/80 mm Hg goal in patients with >30 mg albuminuria per day (regardless of diabetic status)5 based on a very low quality of evidence (grade D). Survival outcomes remain forthcoming, as well as the direct effects of hypertensive control on stratified CKD and CV outcomes, especially for this particular BP goal. One important concept to bear in mind is whether, in 2016, we can confidently assert that the same BP target is effective BOTH in arresting future loss of kidney function and in protecting patients from CV events driven by raised BP.

Should All Patients Have Stricter BP Goals?

There is a literature trend toward recommending stricter BP goals, with discordance between observational reports and randomized controlled trials. For example, the Action to Control Cardiovascular Risk in Diabetes (ACCORD)⁸ was a randomized trial showing that a stricter systolic goal of 120 mm Hg reduced stroke rate (but no other CV events) compared with 140 mm Hg, which has prompted guideline shifts toward 135 to 140 mm Hg for diabetic patients.9 ACCORD had a low event rate that may have been confounded by interactions between BP and glucose regulation (possibly due to the 2×2 factorial design that assumed these two interventions would not confound each other) whereby tighter glucose regulation was ironically associated with a higher event rate. A proposed mechanism is arteriolar dysregulation as a result of glycemic pathophysiology.10, 11

SPRINT also compared 120 mm Hg with 140 mm Hg but showed more benefits than did ACCORD (so much so that SPRINT was ethically stopped12 approximately 3 years into its projected 5‐year duration because of significant composite endpoint benefits). SPRINT predefined three subgroups (CKD, CV history, and age older than 75), studying approximately 10,000 nondiabetic but cardiovasculopathic adults older than 50 years.12 SPRINT patients had on‐target BPs with mean systolic BP 121.5 mm Hg and 134.6 mm Hg, using 2.8 and 1.8 medications per subject, in the two groups, respectively.

SPRINT showed that a 120 mm Hg goal reduced all‐cause mortality by 27% and composite CV outcomes by approximately 25% compared with the 140 mm Hg goal (with composite outcomes including myocardial infarction, nonmyocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, and CVD death. There was a trend toward increased treatment‐related adverse events (eg, hypotension and acute kidney injury) in the aggressively treated group, but this did not reach significance (38.3% vs 37.1%, respectively). Treatment compliance was adequate regardless of age.

SPRINT did not include diabetic patients, limiting external generalizability. ACCORD tried to address this shortcoming (and the ACCORD‐SPRINT discordance) by performing long‐term follow‐up (up to 60 months), which was presented at the American Heart Association 2015 Scientific Session.13 The data showed noncompliance with the aggressive 120 mm Hg goal after a median of 4.9 years. As a result, at a median 8.8‐year follow‐up, BP differences between the intent‐for‐120 mm Hg and the intent‐for‐140 mm Hg groups shrank from 14.5 to 4.2 mm Hg and there was no significant difference in mortality or nonfatal CV events. Post hoc analysis showed a benefit in the intent‐for‐120 mm Hg group in participants randomized to standard glycemia therapy (hazard ratio, 0.79; 95% confidence interval, 0.65–0.96).13

SPRINT subgrouped CKD patients but this was merely a convenience sampling, not a systematic CKD inclusion or progression study (advanced CKD or proteinuria >1 g/d were exclusion criteria). Unexpectedly, patients without CKD experienced estimated glomerular filtration rate (eGFR) reduction (reaching eGFR <60 mL/min/1.73 m²) in excess of 30% for the 120 mm Hg group vs the 140 mm Hg group (1.21% per year vs 0.35% per year, respectively). For all SPRINT patients, adverse renal events and electrolyte abnormalities were more frequent in the 120 mm Hg group (4.1% vs 2.5%, respectively, for renal adverse events [P<.001]; 3.1% vs 2.3%, respectively, for electrolyte abnormalities [P=.02]). Baseline proteinuria and albuminuria were similar between the 120 mm Hg and 140 mm Hg groups.

As always, subgroup analyses should be interpreted with caution. SPRINT suggests that aggressive (120 mm Hg) systolic control equally benefits baseline CKD and non‐CKD (P value for interaction reported at 0.36) but reaches this conclusion with a 71.6% non‐CKD population.

In a recent large meta‐analysis pooling data from 613,815 patients enrolled in 123 large‐scale trials of BP lowering, Ettehad and colleagues14 showed that a 10 mm Hg reduction in systolic BP reduced the risk of major CVD events by 20%, coronary heart disease by 17%, stroke by 27%, heart failure by 28%, and all‐cause mortality by 13%. Similar to SPRINT findings, the efficacy of the lowered BP in ameliorating the outcomes was consistent even in trials that included people with lower baseline systolic BP (<130 mm Hg) or who were at high risk. Furthermore, significant relative risk reductions for patients with CKD were shown, although proportional risk reductions were smaller in patients with CKD than in those without CKD.14

Pressure Control for Renal Preservation

The pathophysiologic process between BP treatment goals and CKD outcomes remains unclear.5 Observational studies have shown a positive relationship between systolic pressure and CKD progression (the Kidney Early Evaluation Program and the Chronic Renal Insufficiency Cohort reporting elevated renal dysfunction rates in their >150 mm Hg and >130 mm Hg systolic patient groups, respectively).15, 16 Again, there is discordance between observational and randomized studies, with the two major randomized trials on the topic17, 18 showing similar rates of renal dysfunction progression at mean 125/75 mm Hg vs mean 140/90 mm Hg control (both studies were underpowered for CV outcomes).

Could pressure control save lives despite not saving the kidneys? The extended follow‐up analysis of the Modification of Diet in Renal Disease (MDRD) trial (median follow‐up of 19.3 years) showed that strict BP control during the CKD phase of disease was strongly associated with lower risk of all‐cause mortality after ESRD onset (significant unadjusted hazard ratio for death 0.72; 95% confidence interval, 0.58–0.89).19 In contrast, many other interventions such as hematocrit normalization,20 aggressive dialysis,21 the use of high flux hemodialysis membranes,21 and calcimimetic use22 have not yet been shown to improve mortality rates in this population. Lead‐time bias (giving a false impression that an intervention prolongs survival when in fact patients with earlier disease detection simply live longer with that disease) may account for these discrepant results in terms of outcome between pre‐ESRD and ESRD; thus, differential gains in pressure control for pre‐ESRD CKD patients remain forthcoming.

Arterial stiffness may confound CV outcomes in CKD patients23 via renal microvascular pressure dysregulation resulting in ischemic fibrosis.24 Studies on this topic remain underpowered with inconsistent inclusion criteria. The more recent Rotterdam study (n=3666) and meta‐analysis concluded that arterial stiffness causes renal functional decline25 but it is not clear how “stiffness” can be prevented or treated. Finally, a study of living renal donors26 showed that GFR reduction was associated with increased aortic stiffness, but those patients remained normotensive. In summary, the exact relationship between arterial stiffness, BP, renal outcomes, and CV outcomes remains elusive.

Current Directions

Lifestyle modifications fail to bring BP to goal for most patients27, 28, 29 but remain a reasonable first‐line recommendation. The SPRINT cohort included 13% active smokers and a large proportion of overweight individuals. Although SPRINT patients were closely monitored, almost half of the patients could not achieve the <120 mm Hg systolic BP goal, a disheartening result for the community practitioner facing a less compliant patient population. This rather implies the need for population‐level initiatives (eg, reduced sodium content in food), new therapies, and most of all, multifactorial intervention to attain the BP targets of SPRINT. However, the lesson from the successful multiple‐risk targeting STENO‐2 study30 in diabetic patients, remains underappreciated, and underemulated, in CKD.

Entry BP in SPRINT was only modestly elevated at 139.7±15.8 in the intent‐for‐120 mm Hg group and 139.7±15.4 mm Hg in the intent‐for‐140 mm Hg group, respectively (while patients in the community may have systolic pressures of ≥170 mm Hg). Furthermore, systolic pressure <120 mm Hg may increase polypharmacy, fall risk, electrolyte imbalances, and arrhythmias. However, despite including patients at high CV risk, the adverse event rate in SPRINT was somehow lower than expected in the aggressive treatment population, reporting hypotension in 2.4% vs 1.4% (P=.001), syncope in 2.3% vs 1.7% (P=.05), electrolyte imbalance in 3.1% vs 2.3% (P=.02), and acute kidney injury in 4.1% vs 2.5% (P<.001) for the 120 mm Hg and 140 mm Hg groups, respectively. Hypertension in the Very Elderly Trial (HYVET)31 reported similar results, with both frailer and fitter older adults with hypertension deriving benefit from BP treatment.

In future SPRINT analyses and publications it will be important to probe more deeply into outcomes. Thus, it is possible that the independent, established, cardioprotective effects of the SPRINT medications confounded positive outcomes beyond mere BP control (for example, angiotensin‐converting enzyme inhibitors or angiotensin II antagonists that were used more frequently in the intensive group).

Cost‐effectiveness of aggressive pressure control remains understudied, including medication costs, office visits, and days lost from work for those visits. Bress and colleagues32 suggest that 16.8 million US adults meet the SPRINT eligibility criteria for antihypertensive treatment initiation or intensification, raising questions of feasibility of treatment for such a broad population with a success rate of less than 50% reaching goal pressure.33

Follow‐up and subanalyses from several trials suggest that patients with heavier proteinuria (>1 g/d) may benefit from lower BP targets.18 However, SPRINT excluded these patients, hampering efforts to study these lower targets for proteinuria patients (an especially relevant population for individualized treatment planning by clinical nephrologists). Therefore, the authors suggest a holistic approach targeting multiple risk factors with a focus on nephroprotection, rather than focusing solely on numeric BP goals.

Conclusions

SPRINT brings attention to the need for individualized BP management without including enough CKD patients to rigorously challenge the established status quo guidelines for CKD. Therefore, clinical nephrologists remain in search of a study dedicated to CKD to prove that relaxing guidelines in CKD is an acceptable evidence‐based practice.

J Clin Hypertens (Greenwich). 2016; 18:1185–1188. DOI: 10.1111/jch.12866. © 2016 Wiley Periodicals, Inc.