Chronic kidney disease and stroke: more observations but no trials

Stroke is the second most common cause of death and the leading cause of neurological disability worldwide [1, 2]. Chronic kidney disease (CKD) is associated with an increased risk of stroke; stroke risk increases linearly and additively with declining glomerular filtration rate (GFR) and increasing albuminuria [3, 4]. Both CKD and stroke are associated with premature death, falls, cognitive impairment, dementia and decreased quality of life [3]. Increasing age, diabetes, male gender, a positive family history, non-white ethnicity, smoking, hypercholesterolaemia or atrial fibrillation are well-known risk factors for stroke in the general population. Several important additional factors are described in CKD populations: anaemia, malnutrition or hyperhomocysteinaemia—all associated with increased risk of stroke [5]. Hypertension remains the major modifiable risk factor in the general population: each 20 mmHg increase in systolic blood pressure (SBP) is associated with more than a 2-fold increase in stroke death rate [6]. The benefit of blood pressure (BP)-lowering therapy for stroke risk reduction is well established, but the optimal BP target is still lacking. For primary stroke prevention—early and strict BP control within the normal range can be likely to be successful for long-term primary cerebrovascular prevention in ‘newly diagnosed young and middle-aged hypertensive patients’ [7]. In a recent updated meta-analysis of 123 randomized controlled trials (RCTs) (53 RCTs for stroke endpoint), every 10 mmHg reduction in SBP significantly reduced the risk of stroke [hazards ratio (HR) 0.73; 95% confidence ineterval (CI) 0.68–0.77] [8]. This benefit was consistent across diverse baseline SBP levels. Moreover, strict BP goals below 130/80 mmHg are associated with a superior reduction in stroke risk in diabetic and non-diabetic middle-aged patients. In ‘ageing hypertensive individuals’, achieving current guideline standards for BP (<150/90 mmHg) substantially reduces the risk of primary stroke in older adults [9]. In a recent systematic review, the authors founded high-strength evidence that BP control to <150/90 mmHg reduces stroke [risk ratio (RR) 0.74; 95% CI 0.65–0.84] [10]. Additionally, six trials yielded low- to moderate-strength evidence that even lower targets (≤140/85 mmHg) are associated with marginally significant decreases in stroke (RR 0.79; 95% CI 0.59–0.99) [10]. Guidelines for the prevention of recurrent stroke and transient ischaemic attack (TIA) recommend initiation of BP therapy for previously untreated patients with ischaemic stroke or TIA who, after the first several days, have an established BP of ≥140 mmHg systolic or ≥90 mmHg diastolic [11]. The BP target and degree of reduction are uncertain, and treatment should be individualized, but it is reasonable to achieve an SBP of <140 mmHg and a diastolic BP (DBP) of <90 mmHg [11]. In the three largest placebo-controlled trials [Perindopril Protection against Recurrent Stroke Study (PROGRESS), prevention regimen for effectively avoiding second strokes (PRoFESS) and post-stroke antihypertensive treatment (PATS) trial], antihypertensive therapy reduced the rate of recurrent stroke, independent of the baseline BP (see Table 1); however, the stroke prevention benefit was related to the degree of BP reduction, being most prominent in patients who had an important mean reduction in BP compared with placebo [12–16]. The same significant reduction in recurrent stroke was described in several recently published meta-analyses (Table 1) [15, 16]. Secondary stroke prevention in the general population Secondary stroke prevention in the general population In CKD patients, the association between BP and stroke is less clear, with some studies reporting no association [3, 17]. Nevertheless, despite less than definitive evidence, BP control remains the cornerstone of stroke prevention also for this increasing category of patients. Importantly, the optimal BP target for cardiovascular events (including stroke prevention) was not determined specifically in CKD populations.There has never been a stroke RCT in CKD patients. Almost all the data are provided by post hoc or subgroup analysis. The only few RCTs conducted in CKD patients, including the Modification of Diet in Renal Disease (MDRD) [18], the Blood Pressure Control for Renoprotection in Patients with Non-diabetic Chronic Renal Disease (REIN-2) Study [19] and the African-American Study of Kidney Disease and Hypertension (AASK) [20], had renal outcomes as the primary outcome. Furthermore, these trials failed to demonstrate benefits of BP lowering for reducing cardiovascular morbidity and mortality. Similarly, in diabetic patients with CKD enrolled in the action to control cardiovascular risk in diabetes (ACCORD) trial, an SBP to <120 mmHg (as compared with <140 mmHg) did not reduce the composite outcome of fatal and non-fatal major cardiovascular events [21]. Nevertheless, at a significance level of <0.05, intensive BP management did reduce the rate total stroke and non-fatal stroke. Assuming that this finding was real, the number needed to undergo intensive BP management to prevent one stroke over the course of 5 years was 89 [21]. Finally, among patients at high risk for cardiovascular events but without diabetes, from a randomized trial of intensive versus standard blood-pressure control (SPRINT) cohort, targeting an SBP of <120 mmHg, as compared with <140 mmHg, resulted in lower rates of fatal and non-fatal major cardiovascular events and death from any cause [22], even in subgroup analyses of CKD patients [23]. After a median follow-up of 3.3 years, the intensive BP CKD group had a lower rate of all-cause death (HR 0.72; 95% CI 0.53–0.99) [23]. However, the total number of deaths was low, and the trial excluded persons with diabetes, proteinuria >1000 mg/g and prior stroke [24]. Besides, the risk of stroke was similar in both groups (HR 0.99; 95% CI 0.57–1.70), P = 0.96. Additionally, intensive BP control caused a higher risk of a 30% decline in eGFR, as well as more acute kidney injury events (irrespective of CKD at baseline). Of note, the method of measuring BP in this study, while correct, is not typically used in practice and yields systolic readings that are at least 7–10 mmHg lower than in usual clinical practice. A lower BP value may be protective for an increased risk of ‘recurrent stroke’, in patients with coexisting CKD and cerebrovascular disease. These data were provided by the post hoc analysis of the PROGRESS study—a randomized, placebo-controlled trial including 6105 participants with prior cerebrovascular disease: CKD patients with baseline SBP <140 mmHg had a 35% lower risk of stroke, while those with the lowest achieved follow-up BP level (particularly with SBP levels below 120 mmHg) had the lowest incidence of secondary stroke [25]. The stringent necessity for new studies to provide definitive information regarding achieved BP and the benefits for cardiovascular events (including stroke prevention) is obvious. In this context, the post hoc analysis of the China Stroke Primary Prevention Trial (CSPPT), published in this issue of Nephrology Dialysis Transplantation, which contributes to filling (albeit only partially) the gap of knowledge in this area is more than welcomed [26]. The CSPPT was designed to test the effect of the combination of antihypertensive drug (e.g. enalapril) with folic acid for primary stroke prevention (significantly reduction in the risk of first stroke by 21%) [27]. Surprisingly, only the post hoc analysis of this trial explored the relationship between the average follow-up SBP level and the risk of first stroke, in the general population [28]. The stroke risk was lowest in patients with an average SBP level of 120–130 mmHg, and the risk increased in those with SBP <120 mm Hg (HR 4.37; 95% CI 2.10–9.07) as well as those with SBP 130–135 mmHg (HR 1.63), 135–140 mmHg (HR 1.85) and >140 mmHg (HR 3.83), indicating a J-curve relationship. Still, for DBP, patients with DBP <80 mmHg had the lowest stroke risk, compared with those with DBP 80–90 mmHg (HR 2.14) and DBP >90 mmHg (HR 5.55) [28]. The current analysis published in this issue of Nephrology Dialysis Transplantation is a second post hoc analysis, involving the ‘renal sub-study’ of the CSPPT, aimed to test the impact of achieved BP on first stroke and renal function decline among hypertensive patients with mild-to-moderate CKD [26]. In total, 3230 hypertensive patients with eGFR 30–60 mL/min/1.73 m2 and/or proteinuria were included. This new analysis demonstrates for the first time that a SBP treatment level of 135 mmHg, compared with an SBP treatment level of 135–140 mmHg, was significantly associated with a decreased risk of first stroke, especially ischaemic stroke. Compared with participants with a time-averaged on-treatment SBP of 135 to ≤140 mmHg, the incidence of total first stroke (1.7% vs 3.3%; HR 0.51; 95% CI 0.26–0.99) and ischaemic stroke (1.3% versus 2.8%; HR 0.46; 95% CI 0.22–0.98) diminished significantly in patients with a time-averaged SBP of ≤135 mmHg. Additionally, a time-averaged DBP of ≤80 mmHg, compared with a time-averaged DBP level of 80 to ≤90 mmHg, was significantly linked to a diminished risk of haemorrhagic stroke (0.2% versus 0.9%; HR 0.18; 95% CI 0.04–0.80). This study is particularly important for several reasons: first of all, it adds new information regarding BP and primary stroke prevention in patients with moderate CKD after almost 10 years from the last article addressing this issue; secondly it complements a few significant articles published in the last 12 months that suggest lowering BP target for cardiovascular protection in the general population and particularly in CKD patients. The current study also had several notable limitations. First and foremost, this was a posthoc analysis of a study subgroup and despite extensive adjustments for known factors; the authors could not exclude the possibility that unrecorded risk factors may explain some findings. Second, only 393 patients with eGFR <60 mL/min/1.73 m2 (out of 3230) were actually included. Furthermore, although a linear association between time-averaged SBP and the risk of stroke was observed, the number of events in the lower BP categories (<130 mmHg) was rather low. Additionally, due to the small number of participants and events in the subgroup with time-averaged SBP <120 mmHg or DBP <70 mmHg, the current study could not evaluate the possible U-shaped relationship between achieved BP and the risk of stroke or all-cause death in hypertensive patients with CKD. Finally, these findings should be replicated in non-Asian, more diverse populations. In conclusion, these recent studies suggested that lowering elevated BP to a target of below 140 mmHg and possibly closer to 130 mmHg could improve cardiovascular outcomes in patients with CKD. In the same direction, the new hypertension guide published this month recommends a BP goal of <130/80 mmHg. However, more information regarding BP control and stroke prevention, provided by large scale, randomized controlled trials in patients with CKD, are urgently needed. The authors had not received any financial support for writing this manuscript. A.C. was an honorary speaker for Fresenius Medical Care. (See related article by Li et al. Impact of achieved blood pressure on renal function decline and first stroke in hypertensive patients with chronic kidney disease.