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1 Powered by Neurology TOP ARTICLE SUPPLEMENTS Stroke TOP ARTICLE SUPPLEMENTS CONTENTS SYSTEMATIC REVIEW: The effect of antihypertensive treatment on the incidence of stroke and cognitive decline in the elderly: a meta-analysis Future Cardiology Vol. 12 Issue 2 EDITORIAL: Central post-stroke pain: theories, diagnosis and treatment Future Neurology Vol. 11 Issue 1 RESEARCH ARTICLE: Efficacy, safety and tolerability of rivaroxaban for the secondary prevention of stroke in patients with atrial fibrillation in clinical practice Future Neurology Vol. 10 Issue 6

2 SYSTEMATIC REVIEW For reprint orders, please contact: The effect of antihypertensive treatment on the incidence of stroke and cognitive decline in the elderly: a meta-analysis Christine Parsons 1, Mohammad Hassan Murad 2, Stuart Andersen 1, Farouk Mookadam*,3 & Helene Labonte 1 Aim: To evaluate the effectiveness of antihypertensives in reducing neurocognitive outcomes in elderly patients. Patients & methods: We conducted a systematic literature search of randomized trials in which hypertensive patients with a mean age 65 years received antihypertensive or control treatment. Outcomes were stroke, transient ischemic attack, cognitive decline and dementia. We included 14 trials for meta-analysis. Results: Compared to placebo, antihypertensive treatment reduced the risk of stroke (RR: 0.67 [95% CI: ]). Reduced risk was significant for transient ischemic attack, fatal stroke, nonfatal stroke and total stroke. There were insufficient data to compare individual agents. Conclusion: Antihypertensive treatment is associated with a significant reduction in stroke in elderly individuals. Reductions in dementia and cognitive decline were not significant; however, there was short follow-up. Comparative effectiveness evidence is limited. First draft submitted: 28 August 2015; Accepted for publication: 21 December 2015; Published online: 26 February 2016 Background Cardiovascular disease is the leading cause of mortality worldwide [1]. Chronic disease is on the rise due to the growing elderly population. One aim of the WHO is to reduce the burden of chronic diseases through drug therapy, especially to reduce the prevalence of risk factors for myocardial infarction and stroke [2]. Hypertension is an established risk factor for cerebrovascular and ischemic heart disease and abundant evidence from clinical trials shows that treatment of hypertension of all degrees of severity reduces cardiovascular morbidity and mortality [3]. The elderly population has a higher prevalence of hypertension and is more likely to have isolated systolic hypertension, which is more closely related to cardiovascular risks than diastolic hypertension [4,5]. The absolute risk associated with hypertension and adverse cardiovascular and stroke outcomes is highest in elderly patients [5]. Studies have also shown significant relationships between hypertension and cognitive decline, although the relationship between blood pressure, cognition and dementia is complex and not fully established. Study results on the efficacy of blood pressure control in the elderly in preventing cognitive decline are inconsistent [6]. Despite the higher incidence of hypertension and associated complications, the elderly population is less well represented in clinical trials assessing the effect of antihypertensive treatment on cardiovascular and cerebrovascular outcomes. We designed the present study to systematically review randomized trials on the effect of antihypertensive treatment on stroke, transient ischemic attack, dementia and cognitive decline in hypertensive patients with a mean age of 65 years. 1 Deptartment of Internal Medicine, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ 85054, USA 2 Division of Preventive Medicine, Mayo Clinic, st St SW, Rochester, MN 55905, USA 3 Division of Cardiovascular Diseases, Mayo Clinic, E Shea Blvd, Scottsdale, AZ 85259, USA *Author for correspondence: Tel.: ; Fax: ; mookadam.farouk@mayo.edu KEYWORDS aged cognition dementia hypertension stroke part of /fca Future Medicine Ltd Future Cardiol. (2016) 12(2), ISSN

3 Systematic Review Parsons, Murad, Andersen, Mookadam & Labonte Objective In hypertensive elderly patients, to assess the effects of blood pressure lowering treatments for the prevention of stroke, transient ischemic attack, cognitive decline, and dementia. Patients & methods Eligibility criteria We included randomized controlled trials with primary and secondary end points of interest that were published in English. Eligible trials had to fulfill the following criteria: prospective study involving elderly persons with a mean age of 65 years who underwent randomized treatment with antihypertensive monotherapy or combination therapy compared with another antihypertensive therapy or placebo; treatment duration was 2 years and sample size in each treatment arm was 200 subjects; outcomes assessed included cerebrovascular accident, transient ischemic attack (TIA) and dementia or cognitive decline. Dementia was diagnosed according to standard diagnostic criteria and cognitive decline was defined as a negative cognitive change from baseline as assessed by any standardized test of cognition, including the Mini-Mental State Examination (MMSE). Study identification We identified studies by searching electronic databases and manual review of all reference lists from of articles included in the analysis. The search was applied to Embase, MEDLINE and CINAHL (1 January June 2014) by three investigators with a second search completed independently by a medical librarian. The search was limited to studies in human subjects and the English language. We used the following medical subject headings (MeSH) terms: aged ; hypertension ; hypertension, malignant ; vascular resistance ; antihypertensive agents ; stroke ; cerebro vascular disorders ; intracranial embolism ; dementia ; dementia, multi-infarct ; dementia, vascular and cognition disorders. We used the following key terms: geriatric patients ; aging senescence ; high blood pressure hypertensive state ; hypertension drug therapy ; antihypertensive drug treatment and stroke cerebrovascular disorders. Three investigators assessed basic trial eligibility via title and abstract screening utilizing the inclusion criteria. The full text of remaining articles was assessed for eligibility and the reference lists of these articles were reviewed for additional articles. Data collection Data extracted from each trial included: demographic characteristics and baseline blood pressure; intervention (including drug type, dose, duration and protocol for dose titration and addition of other drugs to meet blood pressure goals); and outcome measures (including final blood pressure, how cognitive decline was defined, and how dementia and other neurocognitive outcomes were diagnosed). We assessed the risk of bias in included studies using the Cochrane Collaboration s tool for assessing risk of bias. Statistical analysis An intention-to-treat meta-analysis was performed in accordance with recommendations from the Cochrane Collaboration. Metaanalyses were performed using Comprehensive Meta-analysis, Version 2 (NJ, USA). The I 2 statistic of inconsistency was used to assess heterogeneity between studies. Substantial heterogeneity was defined as an I 2 statistic >50%. Pooled estimates of relative risks (RRs) with their 95% CIs were estimated using the random effects model. Publication bias could not be assessed due to the small number of studies included in each analysis. Results Study identification Figure 1 depicts the search and selection procedures. Thirty-one articles were identified from the screen and 15 new articles were identified from the reference lists of screened articles. Supplementary searches were conducted to capture additional publications of two trials, the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive Patients (JATOS) and the Systolic Hypertension in the Elderly: Long-term Lacidipine treatment (SHELL) trial. Thus, 48 articles in total (25 randomized trials) met our inclusion criteria. The only subanalyses of the main trial results from the 25 identified trials that were of interest and consequently included were those that isolated different treatment regimens within a trial (as a result of add-on therapies in certain trials). Also, subanalyses done by mean age 65 years were included even if the overall trial did not meet the mean age requirement. Fourteen trials were included in the metaanalysis for treatment versus placebo [720]. There were insufficient trials to conduct a 238 Future Cardiol. (2016) 12(2)

4 Antihypertensive treatment on the incidence of stroke & cognitive decline in the elderly Systematic Review Records identified through PubMed and Ovid databases, duplicates removed (n = 626) Records excluded on the basis of PICOT parameters assessed via title (n = 272) Records screened (n = 354) Records excluded on the basis of PICOT parameters assessed via abstract (n = 286) Full text assessed for eligibility (n = 68) Records excluded (n = 37) Records included (n = 48) Article screen (n = 31) References (n = 15) Additional searches (n = 2) Records excluded from data extraction (n = 12) Duplicates of trial results (n = 9) ISH substudy (n = 3) Records included in data extraction (n = 36) (25 trials) Records excluded from meta-analysis (n = 22) Insufficient therapy vs therapy comparisons (n = 18) Same therapy in both arms (difference in treatment duration or BP goal) (n = 3) Substudy duplicate of main trial results (n = 1) Records included in meta-analysis (n =14) (nine trials) Figure 1. Preferred reporting items for systematic reviews and meta-analyses flow diagram of study selection. Additional searches were conducted to capture additional publications of the JATOS and the SHELL trials. BP: Blood pressure; ISH: Isolated systolic hypertension; PICOT: Patient population of interest, intervention of interest, comparison with another intervention, outcome of interest, time frame. network meta-analysis and provide pairwise comparisons. The characteristics of the trials included in the meta-analysis are summarized in Table 1. Those trials reporting stroke had a total of 15,531 placebo control and 15,245 intervention hypertensive subjects, with a mean age 73 years for both groups. The average duration of follow-up was 3.5 years. Those trials reporting dementia outcomes had a total of 7660 placebo control and 7767 intervention hypertensive subjects, with a mean age of 75 years for both groups. The average duration of follow-up was 3.1 years. Those trials reporting cognitive decline had a total of 5375 placebo control and 5471 intervention hypertensive subjects, with a mean age of 77 years for both groups. The average duration of follow-up was 3.5 years

5 Systematic Review Parsons, Murad, Andersen, Mookadam & Labonte Table 1. Characteristics of studies included in meta-analysis. Study (year) Subgroup Outcome n Mean age (sd) Male (%) Follow-up (years) FEVER (2011) and diuretic Mean initial BP (sd) Mean final BP (sd) Ref. Stroke (3.3) (11.9)/89.1 (8.1) 139.7/81.2 [18] Placebo /83.6 HYVET (2008) Fatal stroke, total stroke (3.2) (8.4)/90.8 (8.5) 143.5/77.9 [19] Placebo (3.1) (8.6)/90.8 (8.5) 158.5/84 HYVET-COG (2008) CD, dementia (3.1) (8.5)/90.8 (8.5) 143.5/77.7 [17] Placebo (8.5)/90.8 (8.5) 158.3/83.6 MRC (1992); MRC and Stroke / /76.2 [15,16] (2012) diuretic BB / /75.6 Placebo / /84.7 SCOPE (2003) ARB CD #, dementia, nonfatal, (8.9)/90.3 (6.6) (16.1)/79.9 (8.7) [13] Placebo fatal and total stroke (9)/90.4 (6.6) (16.8)/81.6 (8.8) SHEP (1991); SHEP (2001) CD, dementia, TIA, (6.7) (9.5)/76.7 (9.6) 144 (19.3)/67.7 (10.2) [7,8] nonfatal, fatal and total Placebo (6.7) (9.2)/76.4 (9.8) (20.9)/71.1 stroke (12.8) STONE (1996) Stroke (5.1) (13)/98.5 (7) 146.8/85.4 [12] Placebo (5) (15)/97.4 (7) 156.3/89.8 STOP-Hypertension BB and TIA, stroke (3.7) (14)/102 (7) 167 (21)/87 (9) [9] (1991) Placebo (3.7) (14)/102 (7) 186 (22)/96 (10) Syst-China (1998) Nonfatal, fatal and total (5.4) (10.9)/86.1 (6.7) 150.7/81.1 [14] Placebo stroke (5.7) (11.4)/85.9 (7) 159.3/84 Syst-Eur (1998) Dementia (6.5) (10.1)/86.1 (5.6) 151.8/79.7 [10] Placebo (6.2) (10.1)/86 (5.7) 160/83.4 Syst-Eur (1997) Nonfatal, fatal and total (6.7) (9.9)/85.5 (5.8) (14.7)/79.4 (8.4) [11,20] Placebo stroke (6.7) (10.1)/85.5 (5.9) (17.2)/83.5 (8.3) Values for combined treatment groups; values for individual treatment groups were not readily available in the literature. Cognitive outcome reporting for HYVET. and/or BB treatment group; n = # ARB n = 2416; placebo n = n = 1368; placebo n = Dementia outcome reporting for Syst-Eur. ARB: Angiotensin receptor blocker; BB: β-blocker; BP: Blood pressure; CD: Cognitive decline; : Dihydropyridine calcium channel blocker; sd: Standard deviation; TIA: Transient ischemic attack. 240 Future Cardiol. (2016) 12(2)

6 Antihypertensive treatment on the incidence of stroke & cognitive decline in the elderly Systematic Review Excluded studies Of the 48 studies that met inclusion criteria, nine were excluded in the analysis as they reported the same main trial results as in other included studies. Three studies were excluded as they reported isolated systolic hypertension subanalyses of certain main trial results, which were not a variable of particular interest in this review. Three studies were excluded because they either had the same treatment strategy for both arms for strict versus mild blood pressure targets or a different duration of therapy for both arms. One study was excluded as it reported a subgroup of the main trial. Risk of bias The domains of random sequence generation, allocation concealment, blinding (participants, personnel, outcome assessment), incomplete outcome data (loss to follow-up) and reporting bias (selective reporting) were assessed for each included study. The risk of bias was generally low and is summarized in Supplementary Tables 2 & 3. Paired reviewers demonstrated adequate chance-adjusted agreement (k) for the different components of the risk of bias assessment (0.78 overall). Of studies included in the metaanalysis (Supplementary Table 2), all were randomized, most concealed allocation via central allocation (including telephone and web-based controlled randomization), and all blinded participants although some studies had a proportion of participants with eventual open-label followup (i.e., withdrew from study medication). Most blinded personnel had a centralized group of blinded investigators that evaluated end points. Stroke and dementia outcomes were less likely to be influenced by a lack of blinding as these outcomes are largely physiologic with standardized diagnostic criteria. However, cognitive decline as assessed by various screening exams is more likely to be influenced by lack of participant blinding. Most trials in the meta-analysis had small loss to follow-up that were comparable across the active treatment and placebo groups. The Medical Research Council (MRC) Elderly Hypertension trial had a high loss to follow-up (25%); however, the RR was similar to that of the other studies included in the meta-analysis and thus would not be expected to skew the overall result or conclusion. The risk of bias due to incomplete outcome data in the MRC trial was also thought to be lower as the loss to follow-up was balanced across the three treatment groups and the authors employed an intention-to-treat analysis. The authors thought that the loss to follow-up was likely due to a long duration of follow-up (mean: 5.8 years) compared with other similar studies. Furthermore, it was noted that definitions used in the MRC trial to define loss to follow-up were broader than those used in similar studies and that redefinition of MRC losses in terms used by European trialists (such as in the European Working Party on High Blood Pressure in the Elderly [EWPHE] trial) reduces the figure from 25 to 11.7% [21]. The loss to follow-up for the cognitive assessment of participants in the Systolic Hypertension in the Elderly Program (SHEP) trial was not reported, although 219 (16.0%) and 266 (20.1%) participants in the active treatment and placebo groups were not assessed during the fourth year of the study. The authors stated that there was possible selective attrition as the behavioral assessment was frequently limited to those who were healthier and able to reach the study clinic. The group not assessed was not differentiated, thus the loss to followup may have been less and the trial results were similar to those of the Hypertension in the Very Elderly Trial Cognitive Function Assessment (HYVET-COG), which also employed a diuretic regimen for the active treatment. The risk of bias due to incomplete outcome data was also thought to be lower as the loss to follow-up was relatively balanced across the treatment groups and the authors employed an intention-to-treat analysis. The Systolic Hypertension in China (Syst-China) trial had a 9.3 and 10.7% loss to follow-up in the active treatment and placebo groups; however, the associated risk of bias was judged to be low as the RR was similar to that of the Shanghai Trial of Nifedipine in the Elderly (STONE) and Systolic Hypertension in Europe (Syst-Eur) trial, which also utilized a dihydropyridine calcium channel blocker () regimen for the active treatment group. Also, attrition was similar across groups and the analysis was by the intention-to-treat principle. Of studies evaluating treatment versus treatment comparisons (Supplementary Table 3), all were randomized, concealed allocation via central allocation (including telephone and webbased controlled randomization) and had a centralized group of blinded investigators that evaluated end points. Nine of these studies did not blind participants and personnel, employing the Prospective Randomized Open-label 241

7 Systematic Review Parsons, Murad, Andersen, Mookadam & Labonte Group by intervention Study (year) Outcome ARB ARB BB BB BB and BB and and diuretic and diuretic and diuretic and/or BB and/or BB Overall SCOPE (2003) MRC BB (2012) STOP-HTN (1991) STONE (1996) Syst-China (1998) Syst-Eur (1999) MRC (2012) FEVER (2011) HYVET (2008) SHEP (1991) MRC (1992) Stroke Stroke Stroke Stroke Stroke Stroke Stroke Stroke Stroke Stroke Stroke Risk ratio Statistics for each study Lower limit Upper Limit p-value Risk ratio and 95% CI < <0.001 < < Favors antihypertensive Favors placebo Statistics for each study Group by intervention Study (year) Outcome Risk ratio Lower limit Upper limit p-value Risk ratio and 95% CI ARB ARB Overall SCOPE (2003) Syst-China (1998) Syst-Eur (1997) HYVET (2008) SHEP (1991) Fatal stroke Fatal stroke Fatal stroke Fatal stroke Fatal stroke Favors antihypertensive Favors placebo Group by intervention Study (year) Outcome ARB ARB Overall SCOPE (2003) SHEP (1991) Syst-China (1998) Syst-Eur (1999) Nonfatal stroke Nonfatal stroke Nonfatal stroke Nonfatal stroke Risk ratio Statistics for each study Lower limit Upper limit p-value Risk ratio and 95% CI < <0.001 < Favors Favors antihypertensive placebo Group by intervention Study (year) Outcome BB and BB and Overall STOP-HTN (1991) SHEP (1991) TIA TIA Risk ratio Statistics for each study Lower limit Upper limit p-value Risk ratio and 95% CI Favors Favors antihypertensive placebo 242 Future Cardiol. (2016) 12(2)

8 Antihypertensive treatment on the incidence of stroke & cognitive decline in the elderly Systematic Review Figure 2. Meta-analysis by treatment and overall meta-analysis for outcomes of total stroke, nonfatal stroke, fatal stroke and transient ischemic attack (see facing page). ARB: Angiotensin receptor blocker; BB: b-blocker; : Dihydropyridine calcium channel blocker; TIA: Transient ischemic attack. with Blinding of End point (PROBE) design. The majority of studies that made treatment versus treatment comparisons had small losses to follow-up that were comparable across the active treatment and placebo groups. The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial did not state the loss to follow-up. The SHELL trial had a 12.3 and 11% loss to follow-up in the lacidipine and chlorthalidone groups; however, the risk may be low as the attrition was similar across groups and the analysis was by the intention-to-treat principle. Effect of antihypertensive treatment compared with placebo on neurologic & cognitive outcomes Meta-analysis demonstrated that compared with placebo, antihypertensive treatment reduced the risk of overall stroke (RR: 0.67 [95% CI: ]), fatal stroke (RR: 0.69 [95% CI: ]) and nonfatal stroke (RR: 0.74 [95% CI: ]) (Figure 2). In terms of the individual trials, a significant reduction in total stroke was found in six clinical trials [89,1112,16,18]., b-blocker (BB) and regimens, including regimens that involved addition of an angiotensin converting enzyme inhibitor (ACEI), were among those treatments that resulted in significant reductions in stroke as compared with placebo. There were several other trials comparing similar treatment regimens to placebo that did not demonstrate a significant effect on stroke reduction [1416,19]. There was a significant reduction in nonfatal stroke for angiotensin receptor blocker (ARB) compared with placebo, however, this reduction was not significant for fatal and total stroke [13]. The RR was lower for regimens compared placebo than that of other drug classes, which were all fairly similar in magnitude. There were sufficient studies to conduct a meta-analysis on total stroke outcome for diuretic, and and diuretic regimens compared with placebo. A significant reduction in total stroke was found for these treatments versus placebo (Figure 2). The regimens had similar risk ratios that were lower than those of the diuretic regimens in meta-analysis. There were sufficient studies to conduct a metaanalysis on fatal and nonfatal strokes for the drug class compared with placebo, and a significant reduction was found for both outcomes (Figure 2). A significant reduction in fatal stroke was also found in meta-analysis of the diuretic drug class compared with placebo. The relative lack of evidence for ACEIs and ARBs compared with placebo is likely explained by the risk reduction found in earlier studies for diuretics and CCBs versus placebo, making antihypertensive compared with placebo unethical in later studies. The overall meta-analysis of antihyper tensive treatment versus placebo found a significant reduction in nonfatal, fatal and total stroke. The Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) found that a BB regimen resulted in fewer TIAs as compared with placebo [9]. Another study evaluating a diuretic regimen compared with placebo found a nonsignificant reduction in TIA [8]. The overall meta-analysis of antihypertensive treatment versus placebo found a significant reduction in TIA (Figure 2). Studies that compared antihypertensive treatment to placebo on the development of cognitive decline or dementia did not show significant reductions [78,10,13,17]. Meta-analysis of individual drug classes and overall metaanalysis of antihypertensive treatment versus placebo found small, nonsignificant reductions in cognitive decline and dementia (Figure 3). The Systolic Hypertension in Europe trial 2 (Syst-Eur 2) showed that early as opposed to delayed antihypertensive treatment resulted in a significant decrease in dementia (OR: 0.46; CI: ) [10]. It is important to note that conclusions should not be drawn about the relationship between cognitive decline and blood pressure control based on the data as the followup periods may be insufficient to infer a causal effect. There were few comparisons of sufficient studies with the same intervention to apply the I 2 statistic of inconsistency. The I 2 statistic for versus placebo in nonfatal and fatal stroke was 0% indicating that substantial heterogeneity between studies (defined as an I 2 statistic >50%) was not present

9 Systematic Review Parsons, Murad, Andersen, Mookadam & Labonte Head-to-head studies of antihypertensive treatment effect on neurologic & cognitive outcomes The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) demonstrated that an ACEI regimen resulted in a significant increase in total stroke as compared with conventional antihypertensives, such as, BB and diuretic regimens [22,23], while other studies with similar comparisons did not demonstrate significant outcomes [24,25]. The Second Australian National Blood Pressure Study (ANBP2) found that ACEI treatment compared with diuretic treatment had significantly higher fatal stroke outcomes, however, this relationship was not significant for total stroke [25]. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial demonstrated that an ARB regimen resulted in a significant decrease in total stroke and fatal stroke as compared with conventional antihypertensives [26], while other studies with similar comparisons did not demonstrate significant outcomes [2729]. The Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) trial showed that an ARB regimen resulted in a significant reduction in stroke and TIA as compared with a regimen [30]. The ALLHAT demonstrated that an a-blocker regimen was significantly less effective in preventing total and fatal stroke as compared with a diuretic regimen [31]. The Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA) demonstrated that a regimen compared with a BB regimen resulted in significantly fewer strokes [32]. The SHELL trial found that diuretic and DHP- CCB regimens showed no significant difference in the incidence of stroke [33]. Strict treatment (SBP <140 mmhg) versus mild treatment (SBP <160 mmhg) with regimens did not result in a significant difference in stroke incidence in the JATOS trial [34]. Studies meeting inclusion criteria that described nonfatal stroke outcomes among different therapies did not show significant outcomes. Studies comparing the effect of different treatment regimens on TIA incidence did not have significant results [3336]. No studies met inclusion criteria that compared different antihypertensive treatments on the incidence of cognitive decline or dementia. There were insufficient studies comparing one drug class or regimen versus another for meta-analysis for all outcomes of interest. Discussion We conducted a systematic review and metaanalysis of randomized trials to evaluate the effects of antihypertensive treatment on neurological and cognitive outcomes in elderly patients. Meta-analysis demonstrates that antihypertensive treatment significantly reduced fatal, nonfatal and total stroke. The confidence in the presented estimates is moderate to high. There were insufficient trials in this systematic review to compare any effect between drug classes. Individual headto-head comparisons varied in their findings and significance. Antihypertensive treatment did not result in significant reductions in the incidence of cognitive decline or dementia. The effect of antihypertensive treatment on cognitive decline or dementia may not be reliably assessed based on the included trials as the duration of follow-up may be insufficient for the development of these conditions. Studies with longer follow-up are needed to evaluate this association. The results of this analysis are grossly consistent with earlier reviews. A Cochrane review assessing the long-term effects of antihypertensive drug therapy as compared with control in the elderly indicated a significant reduction in cerebro vascular morbidity and mortality (OR: 0.63 [95% CI: ]; number of events prevented by treating 1000 patients for approximately 5 years = 20 [95% CI: 1425]) [37]. Most of the ten included trials evaluated diuretic and BB therapies. Another meta-analysis concluded that placebocontrolled trials provided strong evidence of the benefits of ACEIs and calcium antagonists in preventing stroke in the elderly, but that there was weak evidence of the differences between treatment regimens of differing intensities or different drug classes [38]. Observational epidemiological studies have shown a positive association between hyper tension and incident dementia; however, controlled trials have shown conflicting results on the effect of antihypertensive treatment on cognition. Metaanalyses of the trials have not elucidated this effect. These findings were reflected in our review. The incidence of dementia after 8 years in the longterm follow-up of the Syst-Eur study was 55% lower in the nitrendipine group compared with control [39]. However, chlorthalidone had no effect on cognitive function in the SHEP trial [8], and no difference was noted between the candesartan group and controls in the Study on Cognition and Prognosis in the Elderly (SCOPE) [13]. The Hypertension in the Very Elderly Trial (HYVET) 244 Future Cardiol. (2016) 12(2)

10 Antihypertensive treatment on the incidence of stroke & cognitive decline in the elderly Systematic Review Statistics for each study Group by intervention Study (year) Outcome Risk ratio Lower limit Upper limit p-value Risk ratio and 95% CI ARB ARB Overall SCOPE (2003) HYVET-COG (2008) SHEP (2001) Cognitive decline Cognitive decline Cognitive decline Favors antihypertensive Favors placebo Statistics for each study Group by intervention Study (year) Outcome Risk ratio Lower limit Upper limit p-value Risk ratio and 95% CI ARB ARB Overall SCOPE (2003) Syst-Eur (1998) SHEP (1991) HYVET-COG (2008) Dementia Dementia Dementia Dementia Favors antihypertensive Favors placebo Figure 3. Meta-analysis by treatment and overall meta-analysis for outcomes of cognitive decline and dementia. ARB: Angiotensin receptor blocker; : Dihydropyridine calcium channel blocker. also found that antihypertensive treatment with diuretic and add-on ACEI in elderly patients does not statistically reduce the incidence of dementia [17]. There may be varied efficacy among antihypertensives in diminishing the risk for dementia; however, there were insufficient trials to conduct a meta-analysis of different antihypertensive drug classes versus placebo and no trials met inclusion criteria that compared different treatments. The difference may also reflect the longer follow-up of the Syst-Eur study. A Cochrane review assessing the effects of antihypertensive treatment on the prevention of dementia and cognitive decline in those without a history of cerebrovascular disease found that the combined result of four trials including 15,936 hypertensive subjects (mean age: 75.4 years) indicated no significant difference between treatment and placebo [40]. A meta-analysis assessing this effect in patients with cardiovascular and cerebrovascular disease also found no significant risk reduction and stated there was noticeable heterogeneity between the included trials [41]. More well-designed clinical trials of sufficient power and follow-up duration are needed to investigate if antihypertensive treatment in the elderly improves cognitive outcomes and if this effect varies significantly across drug classes. Furthermore, the HYVET was the only trial meeting inclusion criteria with a mean age or subjects greater than 80 years. Data are particularly lacking in this age group. Limitations Antihypertensive regimens and dosages were heterogeneous across trials. Control subjects may have received antihypertensive treatment, usually with an older class of antihypertensive than that of the active treatment arm, if their blood pressures exceeded preset values. Additionally, numerous trials had add-on therapy to both the treatment and control arms if certain blood pressure goals were not met, that could cloud the effect of the main antihypertensive regimen. The definitions of high blood pressure and cognitive decline varied across the studies and may limit comparability. The methods used to screen and diagnose cognitive decline were hetero geneous, although the diagnosis of 245

11 Systematic Review Parsons, Murad, Andersen, Mookadam & Labonte dementia followed established, standardized criteria. Conclusion & future perspective The elderly population is widely affected by hypertension and its associated neurocognitive effects, representing a major target for preventative health improvements. Meta-analysis of existing randomized trials shows that antihypertensive treatment is associated with a significant reduction in stroke in the elderly. Reductions in dementia and cognitive decline were not significant, but fewer high-quality trials were available for this analysis and follow-up duration may have been insufficient. Longer trial periods may reveal that antihypertensive treatment improves cognitive outcomes, recommending treatment of hyper tension in the elderly despite adverse effects and possible polypharmacy in order to improve this significant quality of life factor. Further trials are needed to better direct management of hyper tension in the elderly, especially to guide choice of agent and goal blood pressures to achieve significant improvement in clinical end points and minimize adverse effects. Data are particularly sparser on the newer agents. Antihypertensive drugs with reninangiotensin blockade may prove more efficacious in improving neurocognitive outcomes owing to vascular effects beyond blood pressure control. We suspect that strict blood pressure targets will not be advisable based on existing evidence. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. EXECUTIVE SUMMARY Meta-analysis of antihypertensive treatment versus placebo found a significant reduction in transient ischemic attack, total stroke, nonfatal stroke and fatal stroke in the elderly. Meta-analysis of antihypertensive treatment versus placebo found no significant reduction in cognitive decline or dementia in the elderly; however, this may reflect an inadequate duration of follow-up in included studies. Insufficient studies met inclusion criteria that utilized the same antihypertensive class compared with placebo to facilitate meta-analysis of all antihypertensive drug classes. A significant reduction in total stroke was found for meta-analysis of diuretic, dihydropyridine calcium channel blocker () and and diuretic regimens compared with placebo. The -pooled risk ratio for total stroke was lower than that of the diuretic. Few head-to-head trials of antihypertensive therapies were available with insufficient data for meta-analysis. More high-quality randomized controlled trials comparing antihypertensive treatments on neurocognitive outcomes in the elderly are needed in order to guide clinical decision-making in this population. References Papers of special note have been highlighted as: of interest; of considerable interest 1 WHO. The top ten causes of death. (2012). 2 WHO. World Health Report 2013: Research for Universal Health Coverage. WHO Press, Geneva, Switzerland (2013). 3 Messerli FH, Williams B, Ritz E. Essential hypertension. Lancet 370(9587), (2007). 4 Rapsomaniki E, Timmis A, George J et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1.25 million people. Lancet 383(9932), (2014). 5 Lipsitz LA. A 91-year-old woman with difficult-to-control hypertension: a clinical review. JAMA 310(12), (2013). 6 Cherubini A, Lowenthal DT, Paran E, Mecocci P, Williams LS, Senin U. Hypertension and cognitive function in the elderly. Dis. Mon. 56(3), (2010). 7 Di Bari M, Pahor M, Franse LV et al. Dementia and disability outcomes in large hypertension trials: lessons learned from the systolic hypertension in the elderly program (SHEP) trial. Am. J. Epidemiol. 153(1), 7278 (2001). 8 Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 265(24), (1991). 9 Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP- Hypertension). Lancet 338(8778), (1991). 10 Forette F, Seux ML, Staessen JA et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic 246 Future Cardiol. (2016) 12(2)

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14 EDITORIAL For reprint orders, please contact: Central post-stroke pain: theories, diagnosis and treatment Jonathan Singer*,1 & Steven R Levine 1 Central post-stroke pain treatment is typically based on trial and error until pain relief is found and the result is usually a combination of several pharmaceutical and non-pharmaceutical treatments. First draft submitted: 14 December 2015; Accepted for publication: 17 December 2015; Published online: 11 January 2016 Theories, diagnosis & treatment of central post-stroke pain in thalamic strokes Stroke is the fourth leading cause of death and is the number one cause of disability worldwide [1]. Post-stroke pain (PSP) is an uncomfortable and disabling condition that has been reported to occur between 14 and 49% in ischemic stroke patients [2]. Numerous articles have reported that a third of PSP occurrences affect patients who have suffered a thalamic ischemic stroke [35]. In general, patients with pain experience greater cognitive and functional decline, lower quality of life (QoL), fatigue and depression compared with patients without pain [46]. Furthermore, patients tend to under-report their pain. As central PSP (CPSP) is not well recognized among many care providers, we provide a brief overview of this topic. PSP has been classified into two different types: CPSP, believed to be due to primarily CNS mechanisms [7] and pain following stroke triggered by peripheral/mechanical mechanisms (e.g., shoulder, arm and neck pain). We focus on the suspected causes of CPSP in thalamic strokes, diagnostic criteria and treatments. Strokes affecting the thalamic region have a tendency to yield a higher rate of CPSP [3,8] than nonthalamic strokes. In the late 1800s, CPSP was originally described by two French neurologist, Dejerine and Roussy, who labeled it as an unusual pain syndrome [9]. There are many hypotheses as to why CPSP is more common in thalamic strokes. Four general theories have come to the forefront: disinhibition, central imbalance, alterations in spinothalamic tract function and central sensitization [7]. Disinhibition theory was one of the earliest proposed mechanisms. In 1911, Holmes and Head hypothesized that injury to the lateral thalamus disinhibits medial thalamus activity and causes pain by disrupting inhibitory pathways between lateral and medial routes [10,11]. However, this theory is outdated. More recently, it was proposed that burning pain and cold allodynia are due to loss of normal inhibition of the thermal system KEYWORDS central post-stroke pain thalamic stroke 1 SUNY Downstate Medical Center & Stroke Center, 450 Clarkson Avenue, MSC 1213, Brooklyn, NY , USA *Author for correspondence: Tel.: ; jonathan.singer@downstate.edu part of /fnl Future Medicine Ltd Future Neurol. (2016) 11(1), 58 ISSN

15 Editorial Singer & Levine It appears that the development of new, high-resolution imaging technology, longitudinal-based observation and clinical trial research may lead us to a more consolidated understanding of central post-stroke pain while also providing a standard of care. of nociceptive neurons [8]. This theory appears to be more fitting because thalamic stroke has been shown to lead to burning pain and cold allodynia. The central imbalance theory and the alterations in spinothalamic tract function are based on the same premise: spinothalamic pathway alterations and damage are the reasons for CPSP. Patients with CPSP exhibit difficulty with pain and temperature sensitivity, including sensitivity to touch, vibration and other phenomena, which are believed to course mainly through lemniscus pathways [12] of the spinothalamic tract. Moreover, impaired spinothalamic function is associated with pathogenesis of CPSP and that medial lemniscus involvement is neither necessary nor sufficient [1114]. The central imbalance theory goes further and suggests that when a stroke affects the thalamic region, an imbalance between the lateral and medial pain systems occur [11]. This theory is supported by research, which has found that insular activity and decreased anterior cingulate cortex activity in CPSP patients can occur [5]. Also, imbalance occurs between the spinothalamic and medial lemniscus pathways. It has been shown that spinothalamic tract damage results in the transmission of pain signals through alternative pathways and proposed that the medial lemniscus pathway probably undertakes these functions [1214]. Therefore, these pain pathways could produce tactile allodynia and result in CPSP. Central sensitization theory is characterized by the hyperexcitability of central nociceptive neurons, which may be responsible for spontaneous pain and allodynia. In a study that examined microelectrode recordings in patients, there was abnormal spontaneous evoked bursting activity within deafferented regions of lateral and medial thalamic nuclei in some patients with CPSP [11]. The abnormal firing of thalamic neurons leads to a lack of generalized increase in thalamic excitation, and therefore, causes a decrease in thalamic activity and may be the root of CPSP. This theory is built on the basis that NMDA antagonists, GABA agonist and channel blockers are effective in reducing pain associated with CPSP [5]. There is neither a consolidated definition nor clinical characteristics that have been generally agreed upon when investigating CPSP. There are a number of studies that have attempted to formulate diagnostic criteria for CPSP. However, a consensus remains elusive. In a recent study, it was stated that suffering from pain could be related to the meaning of the pain as much as it is due to the intensity [15]. A systematic review combined main points from the literature and established reoccurring trends, which were organized into mandatory and supportive criteria [7]. Yet, they stated that a definite diagnosis is difficult due to the heterogeneous clinical picture, the many types of pain and the lack of diagnostic criteria for CPSP. The mandatory criterion they identified was that pain must be in an area of the body that corresponds to the lesion in the CNS, and other causes of the pain, such as a nociceptive or peripheral neuropathic pain, should be ruled out. They defined supportive criteria as having no primary relation to movement, inflammation or other local tissue damage. They also stated that descriptors such as burning, painful cold, electric shocks, stinging and allodynia or dysesthesia to touch should be considered. More recently, it was stated that the diagnosis of CPSP should be based on a combination of history, sensory examination, findings obtained by applying multiple somatosensory stimuli and neuroimaging findings of the brain lesion [5]. They concluded that if available, measurements of somatosensory-evoked potentials, laser evoked potentials and contact heat-evoked potentials should all be utilized. Notwithstanding the studies outlined above, the diagnostic criteria for CPSP needs to be consolidated and new studies need to be developed to formulate a more precise definition. Also, creating a more accurate diagnostic schema could yield better treatment and management practices. A number of different treatments and management practices for CPSP have been reported. However, CPSP treatment is typically based on trial and error until pain relief is found and the result is usually a combination of several pharmaceutical and nonpharmaceutical treatments [7]. Antidepressants, specifically adrenergically active antidepressants, are usually the first pharmaceutical treatment prescribed for CPSP [5,6,13]. However, to our knowledge, there are no published clinical trials on polypharmacy for CPSP and the only study on prevention of CPSP was a small study of 39 patients. This prospective, double-blinded, placebo-controlled study of amitriptyline (75 mg per day) found no significant prophylactic 6 Future Neurol. (2016) 11(1)