pemberian aspirin dengan ckd

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Hypertension and Aspirin

Aspirin Is Beneficial in Hypertensive Patients

With Chronic Kidney Disease A Post-Hoc Subgroup Analysis of a Randomized Controlled Trial

Meg J. Jardine, MBBS, PHD,*† Toshiharu Ninomiya, MD, PHD,* Vlado Perkovic, MBBS, PHD,*

Alan Cass, MBBS, PHD,* Fiona Turnbull, MBBS, PHD,* Martin P. Gallagher, MBBS, MPH,*†

Sophia Zoungas, MBBS, PHD,*‡ Hiddo J. Lambers Heerspink, PHARMD, PHD,*

John Chalmers, MD, PHD,* Alberto Zanchetti, MD§

Sydney and Melbourne, Australia; and Milan, Italy

Objectives The purpose of this study was to determine the benefit and risk associated with antiplatelet therapy in the

chronic kidney disease (CKD) population.

Background Cardiovascular and possibly bleeding risks are elevated in patients with CKD. The balance of benefit and harm

associated with antiplatelet therapy remains uncertain.

Methods The HOT (Hypertension Optimal Treatment) study randomly assigned participants with diastolic hypertension to

aspirin (75 mg) or placebo. Study treatment effects were calculated using univariate proportional hazards re-

gression models stratified by baseline estimated glomerular filtration rate (eGFR) with trends tested by adding

interaction terms. End points included major cardiovascular events, total mortality, and major bleeding.

Results The study included 18,597 participants treated for 3.8 years. Baseline eGFR was 60 ml/min/1.73 m2 in 3,619

participants. Major cardiovascular events were reduced by 9% (95% confidence interval [CI]: 9% to 24%), 15%

(95% CI: 17% to 39%), and 66% (95% CI: 33% to 83%) for patients with baseline eGFR of 60, 45 to 59, and

45 ml/min/1.73 m2, respectively (p trend 0.03). Total mortality was reduced by 0% (95% CI: 20% to

17%), 11% (95% CI: 31% to 40%), and 49% (95% CI: 6% to 73%), respectively (p trend 0.04). Major bleed-

ing events were nonsignificantly greater with lower eGFR (hazard ratio [HR]: 1.52 [95% CI: 1.11 to 2.08], HR:

1.70 [95% CI: 0.74 to 3.88], and HR: 2.81 [95% CI: 0.92 to 8.84], respectively; p trend 0.30). Among every

1,000 persons with eGFR 45 ml/min/1.73 m2 treated for 3.8 years, 76 major cardiovascular events and 54

all-cause deaths will be prevented while 27 excess major bleeds will occur.

Conclusions Aspirin therapy produces greater absolute reduction in major cardiovascular events and mortality in hypertensive

patients with CKD than with normal kidney function. An increased risk of major bleeding appears to be out-

weighed by the substantial benefits. (J Am Coll Cardiol 2010;56:956–65) © 2010 by the American College of

Cardiology Foundation

Chronic kidney disease (CKD) is common in the general

community. Population-based studies have shown that 10%to 15% of the adult population has CKD (1–3), and thisproportion is increasing (4). Most people with CKD haverelatively mild disease and are unlikely to ever requiredialysis or a kidney transplant; however, even early CKDconfers an increased risk of cardiovascular events and death

(5–11). Recent work has demonstrated that lipid lowering

(12) and blood pressure lowering (13,14) are both effective

See page 966

in reducing the risk of cardiovascular events in people withearly CKD; however, less is known about the balance of risks

*From The George Institute for Global Health and †Concord Repatriation GeneralHospital, Sydney, Australia; ‡School of Public Health, Monash University, Melbourne, Australia; and the §University of Milan and Istituto Auxologico Italiano, Milan, Italy. AlanCass is supported by a National Health and Medical Research Council Senior ResearchFellowship, and has received lecture fees from Servier. Sophia Zoungas is supported by aNationalHealth and Medical Research Council Health Professional Research Fellowship; has

served as anadvisory board member forMerck Sharpeand Dohmeand NovoNordisk; andhasreceived lecture fees from Servier and GlaxoSmithKline. Fiona Turnbull is supported by aNational Heart Foundation post-doctoral Fellowship. Alberto Zanchetti is supported by the

European Commission Project InGenious HyperCare (Integrated Genomics, Clinical Re-search and Care in Hypertension, project no. LSHM-CT-2006-037093). Hiddo LambersHeerspink is financially supported by a grant from the Dutch Kidney Foundation and by anInternational Society of Hypertension Visiting Postdoctoral Fellowship awarded by theFoundation for High Blood Pressure Research Council of Australia. Dr. Zanchetti hasreceived lecture fees from Menarini International, Recordati, and Merck. The original HOT

(Hypertension Optimal Treatment) study was supported by AstraZeneca.Manuscript received September 18, 2009; revised manuscript received January 28,2010, accepted February 1, 2010.

Journal of the American College of Cardiology Vol. 56, No. 12, 2010© 2010 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. doi:10.1016/j.jacc.2010.02.068

Downloaded from ClinicalKey.com at ClinicalKey Global Guest Users May 16, 2016.For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.



and benefits associated with other potential preventativetherapies.

In trials of secondary prevention of cardiovascular disease,treatment with aspirin clearly delivers a net benefit of harmreduction over harm caused. The Antithrombotic Trialists’Collaborative Group meta-analysis of individual participant

data confirmed that aspirin reduces the yearly risk of majorcardiovascular outcomes (strokes and coronary events) by about15 events per 1,000 patient-years (15). However, the sameanalysis demonstrated that, overall, among participants with nohistory of previous cardiovascular events (primary prevention),the absolute benefit of aspirin in preventing 0.6 events per1,000 patient-years is comparable to the number of majorgastrointestinal and extracranial bleeds caused (0.3 events per1,000 patient-years). Analyses of the effect of aspirin in anumber of defined subgroups failed to identify a primary prevention patient group that benefited from aspirin.

Patients with CKD have high cardiovascular risk; there-

fore, the absolute benefits of aspirin might be greater forthem than for people with normal kidney function. How-ever, patients with CKD have abnormal platelet function,leaving them at potentially increased hemorrhagic risk whentreated with anticoagulants, including antiplatelet agents(16). Substantial uncertainty persists regarding the balancebetween the risks and benefits associated with antiplateletagents for patients with CKD. Consistent with this uncer-tainty, patients with CKD (17) and end-stage kidney disease (18) have been shown to be less likely to beprescribed aspirin after an acute myocardial infarction.

The HOT (Hypertension Optimal Treatment) trial, one

of the largest individual primary prevention trials, randomly allocated 18,790 participants 50 to 80 years of age withelevated diastolic blood pressure to aspirin or matchingplacebo for an average of 3.8 years (19). It was a primary prevention study with 2% of participants having a priorhistory of myocardial infarction. In the HOT study overall,a significant 15% reduction in major cardiovascular events(1.6 events per 1,000 patient-years) was observed, but thisneeds to be weighed against a significant 80% increase in therisk of major nonfatal bleeding (1.4 events per 1,000patient-years). Analyses demonstrated there was no inter-action between the blood pressure–lowering effect and

aspirin effects (19,20). Subsequent analyses of the HOTstudy population used serum creatinine thresholds to ex-plore how impairment of renal function influences the effectof aspirin (5,6). A trend to increased benefit from aspirin was demonstrated for patients with an elevated serumcreatinine. However, the balance of benefits and harmsassociated with aspirin usage in CKD have not beenpreviously reported, nor has the level of renal function below which benefits may overcome harms been established.

Since these subgroup analyses, estimated glomerular fil-tration rate (eGFR) using the Modification of Diet in RenalDisease equation (21) has become standard in the staging of

CKD (22). This analysis, therefore, investigates whether thebalance of benefits and harms of aspirin therapy in HOT

study participants is influenced by kidney function evaluated contin-uously and categorically by CKDstage based on eGFR levels.

Methods

Participants and HOT trialdesign. The HOT study designhas been described in detail else- where (19,23). In brief, 18,790participants age 50 to 80 years(mean 61.3 years) from 26 coun-tries in Europe, North and South America, and Asia, and with a diastolic blood pressure between 100 and 115 mmHg, were randomly assigned to 2 interventions in a factorialdesign: aspirin 75 mg daily (n 9,399) or matching placebo(n 9,391), and 1 of 3 diastolic blood pressure targets

(

90,

85, or

80 mm Hg). The blood pressure targets were randomly assigned in an open-label fashion. There wasno exclusion on the basis of renal function. The conduct of the study was overseen by a steering committee and ap-proved by national and local ethics committees and regula-tory bodies at all participating centers. An independentsafety committee regularly reviewed safety data. All patientsprovided written informed consent.

The current analysis included 18,597 participants as-signed to aspirin or placebo for whom baseline serumcreatinine values were available. Analyses of the change inrenal function were performed on participants for whom

serum creatinine values were also available at study end.Glomerular filtration rate was estimated using the 4-variableModification of Diet in Renal Disease equation (21) andcategorized using Kidney Disease Outcomes Quality Initia-tive (KDOQI) stages (24).End points. The primary end point of this study was acomposite of major cardiovascular events consisting of myocardial infarction, stroke, and death due to cardiovas-cular disease. Secondary end points included myocardialinfarction (nonfatal myocardial infarction and death due tocoronary heart disease [including sudden death]), stroke(fatal and nonfatal stroke), cardiovascular mortality, total

mortality, death due to kidney failure, and change in eGFR.Cardiovascular and mortality events were reviewed and validated by an independent clinical event committee. Sec-ondary end points also included investigator-reported majorhemorrhage (fatal, life-threatening, disabling, or requiringhospital admission) and minor hemorrhage (all other re-ported bleeding events). The first event of each relevantoutcome type was included for analysis.

Participants were recruited from October 1992 until April 1994, with follow-up concluding in August 1997,resulting in an average follow-up period of 3.8 years (range3.3 to 4.9 years) (19).

Statistical methods. The risk estimates for each outcomeassociated with eGFR at baseline were estimated using a

Abbreviations

and Acronyms

CI confidence interval

CKD chronic kidney

disease

eGFR estimated

glomerular filtration rate

HR hazard ratio

KDOQI Kidney Disease

Outcomes Quality Initiative

957JACC Vol. 56, No. 12, 2010 Jardine et al.

September 14, 2010:956–65 Aspirin in Chronic Kidney Disease




Cox proportional hazards regression model after adjustingfor potentially confounding baseline covariates includingage, sex, systolic blood pressure, history of diabetes mellitus,history of cardiovascular disease, total cholesterol, body mass index, and smoking. The variances of each risk estimate were calculated using the floating absolute risk

method (25,26). The regression lines for the risk estimatesaccording to eGFR at baseline were fitted using linearregression analysis with inverse variance weighting (27).

The effect of randomization to aspirin was assessedaccording to baseline eGFR categories of 60, 45 to 59(KDOQI CKD stage 3a), and 45 ml/min/1.73 m2

(KDOQI stage 3b, 4, and 5). The hazard ratio (HR) and95% confidence interval (CI) associated with active treat-ment for each end point was estimated using a univariateCox proportional hazards regression model stratified by eGFR levels at baseline. The presence of heterogeneity inthe treatment effect across eGFR categories was assessed by

adding an interaction term to the relevant Cox model. To assess whether there was any threshold level of eGFR,

below which the effect of treatment changed, the risk estimate was investigated by fitting univariate Cox propor-tional hazards model below an eGFR threshold, which wasprogressively changed using 3 ml/min/1.73 m2 increments.

The absolute effect of randomization to aspirin wascalculated as the number of people in whom events wereprevented or caused per 1,000 patients treated for 3.8 yearsfor the overall study population and for categories of kidney function.

Results

The study population, consisting of 18,597 of 18,790(99.0%) randomized patients with serum creatinine dataavailable, had a median eGFR of 73 ml/min/1.73 m2

(interquartile range 63 to 84 ml/min/1.73 m2). Of these,14,978 (80.5%) had an eGFR 60 ml/min/1.73 m2, 3,083(16.6%) had an eGFR of 45 to 59 ml/min/1.73 m2, and 536(2.9%) an eGFR of 45 ml/min/1.73 m2 ( Table 1). Only 9patients (0.05%) had an eGFR of 15 ml/min/1.73 m2.

A total of 671 people experienced at least 1 majorcardiovascular event. Strokes were experienced by 289 par-ticipants, and myocardial infarctions were experienced by 349. There were 582 deaths from any cause, including 268deaths from cardiovascular causes and 8 from renal failure(3 in the aspirin group and 5 in the placebo group). There were 15 fatal bleeding events (7 in the aspirin group and 8

Baseline Characteristics of Participants According to eGFR Categories and Aspirin RandomizationTable 1 Baseline Characteristics of Participants According to eGFR Categories and Aspirin Randomization

Overall

eGFR (ml/min/1.73 m2

)

>60 45–59 <45

Aspirin

(n 7,517)

Placebo

(n 7,461)

Aspirin

(n 1,527)

Placebo

(n 1,556)

Aspirin

(n 264)

Placebo

(n 272)

eGFR, ml/min/1.73 m2 77 (69–88) 77 (69–89) 55 (52–58) 55 (52–58) 40 (34–43) 39 (32–43)

Serum creatinine, mol/l 81 (71–93) 81 (71–93) 99 (92–115) 100 (93–115) 142 (121–174) 150 (121–177)

Characteristics at baseline

Age, yrs 60.6 7.2 60.6 7.2 65.0 7.5 64.9 7.5 66.1 8.2 66.1 7.9

Female 3,185 (42) 3,197 (43) 1,036 (68) 1,026 (66) 169 (64) 175 (64)

Systolic BP, mm Hg 169 14 169 14 171 15 171 14 173 16 173 16

Diastolic BP, mm Hg 105 3 105 3 105 3 105 3 105 3 105 3

Total cholesterol, mmol/l 6.0 1.1 6.0 1.1 6.2 1.2 6.2 1.2 6.2 1.3 6.1 1.1

Body mass index, kg/m2 28.4 4.6 28.4 4.6 28.4 4.7 28.6 4.9 28.5 5.3 28.6 4.9

Diabetes mellitus 578 (8) 600 (8) 138 (9) 110 (7) 31 (12) 31 (11)

Previous myocardial infarction 109 (1) 103 (1) 28 (2) 27 (2) 6 (2) 9 (3)

Previous other coronary heart disease 425 (6) 424 (6) 109 (7) 113 (7) 18 (7) 18 (7)

Previous stroke 78 (1) 72 (1) 24 (2) 31 (2) 9 (3) 6 (2)

Current smokers 1,274 (17) 1,282 (17) 160 (10) 168 (11) 39 (15) 30 (11)

History of ACE inhibitor use 1,442 (19) 1,546 (21) 318 (21) 364 (23) 80 (30) 56 (21)

History of beta-blocker use 1,122 (15) 1,114 (15) 247 (16) 222 (14) 40 (15) 41 (15)

History of calcium-channel blocker use 1,637 (22) 1,587 (21) 394 (26) 373 (24) 81 (31) 81 (30)

History of diuretic use 1,225 (16) 1,262 (17) 311 (20) 350 (23) 63 (24) 63 (23)

History of other BP-lowering agent use 410 (5) 407 (5) 97 (6) 90 (6) 22 (8) 27 (10)

History of use of 2 BP-lowering agents 1,540 (20) 1,583 (21) 377 (25) 412 (26) 83 (31) 81 (30)

Trial assignment

More intensive BP treatment 2,509 (33) 2,465 (33) 515 (34) 543 (35) 76 (29) 86 (32)

Blood pressure during follow-up, mm Hg

Systolic BP achieved 142 12 141 12 143 12 142 12 145 14 143 12

Diastolic BP achieved 84 5 83 5 83 5 83 5 83 6 82 6

Values are median (interquartile range), mean SD, or n (%).

ACE angiotensin-converting enzyme; BP blood pressure; eGFR estimated glomerular filtration rate.

958 Jardine et al. JACC Vol. 56, No. 12, 2010

Aspirin in Chronic Kidn ey Disease September 14, 2010:956– 65




in the placebo group), 187 nonfatal major bleeding events,and 208 minor bleeding events.Cardiovascular events and bleeding in subjects withkidney disease. Patients with lower eGFR levels experiencedgreater rates of cardiovascular events, bleeding events, anddeath: major cardiovascular event rates were 32.2, 46.4, and

80.2 per 1,000 patients with eGFR 60, 45 to 59, and 45ml/min/1.73 m2, respectively; myocardial infarction rates were17.2, 22.7, and 39.2 per 1,000 patients; stroke rates were 13.3,23.4, and 31.7 per 1,000 patients; cardiovascular mortality rates were 12.6, 18.5, and 42.9 per 1,000 patients; major bleedingevent rates were 10.8, 7.8, and 28.0 per 1,000 patients; andtotal mortality rates were 29.1, 32.8, and 84.0 per 1,000patients. Event rates were increased by 70% to 100% for every

halving of eGFR: major cardiovascular events (HR: 1.84, 95%CI: 1.37 to 2.46), myocardial infarctions (HR: 1.84, 95% CI:1.09 to 3.11), stroke (HR: 1.87, 95% CI: 1.28 to 2.73),cardiovascular mortality (HR: 1.99, 95% CI: 1.32 to 2.99),bleeding events (HR: 1.77, 95% CI: 1.09 to 2.86), and totalmortality (HR: 1.69, 95% CI: 0.82 to 3.49) (Fig. 1).

Effect of aspirin according to categories of reducedkidney function. MAJOR CARDIOVASCULAR EVENTS. Aspreviously reported (19), aspirin significantly reduced therisk of major cardiovascular events for the overall study population for whom creatinine measurements were avail-able (event rates for active and placebo groups were 3.32%and 3.90%, respectively; HR: 0.85, 95% CI: 0.73 to 0.98). The benefit provided by aspirin was significantly greater for

Figure 1 Increase in HR With Decline in eGFR

Hazard ratio (HR) for any cardiovascular event, myocardial infarctions, strokes, cardiovascular mortality, total mortality, and bleeding incidence increases as estimated

glomerular filtration rate (eGFR) declines, according to Kidney Disease Outcomes Quality Initiative categories of eGFR (median eGFR for Stage 0/1, 2, 3a, 3b, and 4 depicted).

CI confidence interval.






subjects with low eGFR: risk reductions of 9% (HR: 0.91,95% CI: 0.76 to 1.09), 15% (HR: 0.85, 95% CI: 0.61 to1.17), and 66% (HR: 0.34, 95% CI: 0.17 to 0.67) wereobserved for patients with eGFR 60, 45 to 60, and 45ml/min/1.73 m2, respectively (p for interaction 0.03)(Fig. 1). Event rates for subjects treated with aspirin fell from

3.38% to 3.10% for those with eGFR 60 ml/min/1.73 m2,from 5.01% to 4.26% for those with eGFR 45 to 60 ml/min/1.73 m2, and from 11.76% to 4.17% for those with eGFR 45ml/min/1.73 m2 over the mean 3.8 follow-up years in thestudy. There was no interaction between assignment to differ-ent diastolic blood pressure targets and assignment to aspirin(all p values for interaction 0.2; data not shown).

SECONDARY END POINTS. The protection afforded by aspi-rin for myocardial infarction increased as kidney functiondeclined (Fig. 2), although the interaction was of borderlinestatistical significance (p 0.08). Subjects with the highest

eGFR (60 ml/min/1.73 m2) had a borderline significantrisk reduction of 22% (HR: 0.78, 95% CI: 0.61 to 1.00),subjects with an eGFR of 45 to 59 ml/min/1.73 m2 had arisk reduction of 36% (HR: 0.64, 95% CI: 0.39 to 1.03), andsubjects with eGFR 45 ml/min/1.73 m2 had a risk reduction of 69% (HR: 0.31, 95% CI: 0.11 to 0.85). Event

rates for subjects treated with aspirin fell from 1.93% to1.52% for those with eGFR 60 ml/min/1.73 m2, from2.76% to 1.77% for those with eGFR 45 to 60 ml/min/1.73m2, and from 5.88% to 1.89% for those with eGFR 45ml/min/1.73 m2 over the mean 3.8 follow-up years in thestudy.

There was no significant benefit in the total study population from aspirin therapy for total mortality, cardiovascular mortality, or stroke (Fig. 2). However, aspirin didconfer significant protection for subjects with an eGFR 45 ml/min/1.73 m2 for whom total mortality was reduced

Figure 2 Effect of Aspirin According to eGFR Category

Effect of randomized aspirin on outcomes according to estimated glomerular filtration rate (eGFR) category. CI confidence interval.






by roughly one-half (event rates for active and placebogroups 11.03% and 5.68%, respectively; HR: 0.51, 95% CI:0.27 to 0.94), cardiovascular mortality by nearly two-thirds(event rates for active and placebo groups 6.25% and 2.27%,respectively; HR: 0.36, 95% CI: 0.14 to 0.90), and stroke by nearly four-fifths (event rates for active and placebo groups

5.15% and 1.14%, respectively; HR: 0.21, 95% CI: 0.06 to0.75). The benefit for cardiovascular mortality and totalmortality was significantly greater for patients with reducedkidney function than for subjects with normal kidney function (p for both interactions 0.04) and was nearly significantly greater for stroke (p for interaction 0.06).

KIDNEY FUNCTION DEFINES THRESHOLD OF ASPIRIN BENEFIT.

We performed sensitivity analyses to identify any eGFR threshold level below which the benefit associated withaspirin therapy changed and to confirm that our analyses didnot appear vulnerable to adjustments in the cut-off between

the eGFR categories. The benefit from aspirin therapy progressively, but not linearly, increased (declining risk ratioamong subjects randomly assigned to aspirin therapy) aseGFR declined for all end points (Fig. 3). However, therisk reduction of aspirin therapy for cardiovascular mortality,total mortality, and stroke became large and significant whenbaseline eGFR was 45 ml/min/1.73 m2.

HARMS OF ASPIRIN ACCORDING TO eGFR CATEGORY. In

the overall study population, aspirin increased the risk of major bleeding by 61% (HR: 1.61, 95% CI: 1.21 to 2.14)(Fig. 4). The risk of major bleeding associated with aspirin

was nonsignificantly greater with categories of lower eGFR (HR: 2.81, 95% CI: 0.90 to 8.84 for eGFR 45 ml/min/1.73 m2; HR: 1.70, 95% CI: 0.74 to 3.88 for eGFR 45 to 59ml/min/1.73 m2; and HR: 1.52, 95% CI: 1.11 to 2.08 foreGFR 60 ml/min/1.73 m2; p trend 0.30). There were15 fatal bleeds in the study, 7 among subjects assignedaspirin therapy and 8 among subjects assigned placebo. Allfatal bleeds were in subjects with an eGFR 60 ml/min/1.73 m2. There was a trend toward an increased risk of any bleeding as categories of eGFR declined, althoughthe absolute numbers of events in subjects with reduced

kidney function were few (p for interaction

0.08). There was no interaction between assignment to differentdiastolic blood pressure targets and assignment to aspirin (allp values for interaction 0.2; data not shown).Net absolute effect. Overall, 6 major cardiovascular events will be prevented for every 1,000 participants treated for 3.8 years, while there will be 6 major bleeds and 6 minor bleeds( Table 2). Both the benefits and risks increase as kidney function declines, with the net benefit appearing to increase.For every 1,000 people with eGFR 45 ml/min/1.73 m2

treated with aspirin for 3.8 years, 76 people will avoid amajor cardiovascular event, and 40 myocardial infarctions,

40 strokes, 40 cardiovascular deaths, and 54 all-cause deaths will be prevented. Conversely, 27 major bleeding episodes

and 12 minor bleeding episodes would be caused by aspirintherapy for persons with an eGFR 45 ml/min/1.73 m2.Effect of aspirin on kidney function. Aspirin therapy didnot affect renal function in the overall study population nor within any eGFR category ( Table 3).

Discussion

Safe treatments to reduce the high risk of cardiovasculardisease for patients with CKD are urgently required. In thisanalysis, we confirm that aspirin therapy prevented signifi-cantly more cardiovascular events, cardiovascular deaths,and all-cause deaths in patients with CKD than in subjects with normal kidney function. Aspirin therapy had nodetrimental effect on renal function. Although the absoluterisk of bleeding was greater for subjects with CKD, theoverall cardiovascular benefits appear to outweigh bleedingrisks. These results suggest that primary prevention with

aspirin reduces the burden of cardiovascular disease and hasan overall net benefit among high-risk patients with CKD.

Our analysis confirms previous findings in the HOTstudy population and in other studies that cardiovascularrisk increases with declining CKD stage (5–7,28,29). Over-all, the HOT study participants were at low risk, with a5-year rate of myocardial infarction of 2.9% and of majorcardiovascular events of 5.1%, observed in the control arm.However, the HOT study participants with stage 3b CKDrandomly assigned to placebo had a 5-year myocardialinfarction rate of 7.7%, with a 5-year major cardiovascularevent rate of 15.5%. These high event rates underscore the

need for a clear understanding of the risks and benefits of potentially effective preventative therapies.

Aspirin appears to produce greater absolute benefits forpatients with CKD. The explanation for this greater benefitlies partly in the high baseline risk of these patients,translating a similar proportional benefit into a greaterabsolute benefit. In addition, the current analysis demon-strates greater proportional benefits with progressively lowereGFR. The explanation for this difference in proportionalbenefit is unclear. Patients with advanced CKD are knownto have abnormal platelet function and evidence of apredisposition to both thrombotic and bleeding events.

Patients with all stages of CKD (30–33) have higher ratesof thromboembolism than the general population. Con- versely, patients with kidney disease appear to have anincreased bleeding risk, with evidence in advanced kidney disease of decreased platelet aggregation and of a range of platelet abnormalities (34–37). Observational and random-ized clinical studies in dialysis patients sometimes (38), butnot always, report increased bleeding rates with antiplatelettherapy (39–41), although some of these studies excludedthose at high bleeding risk.

There are few other randomized trials describing theeffects of antiplatelet therapy involving substantial numbers

of subjects with CKD. The Antithrombotic Trialists’ Col-laborative Group reported the results of an individual






Figure 3 Effect of Aspirin on End Points

The effects of aspirin treatment on end points in the subgroup below each cut-off value of estimated glomerular filtration rate (eGFR). CI confidence interval.






patient data meta-analysis of antiplatelet therapy that in-cluded 99 cardiovascular events in 2,632 hemodialysis pa-tients. They found a 41% odds reduction (SE 16%) in the

risk of cardiovascular events among hemodialysis patients(40), compared with a 22% odds reduction (SE 2%) seen inthe overall study population, although the difference was notstatistically significant. The efficacy and harm of aspirin andother antiplatelet agents may not be homogeneous. Post-hoc analyses of the effect of additional clopidogrel overstandard therapy according to GFR categories has shown abenefit consistent with that in the population with normalrenal function in some (42) but not all (29) studies. For

patients with diabetes and albuminuria, the addition of clopidogrel to aspirin was associated with increased mortal-

ity not seen in nonalbuminuric diabetic patients or nondi-abetic patients in a post-hoc analysis (43).

This analysis has some important limitations. Only 2.9%of the study population had an eGFR 45 ml/min/1.73 m2,limiting our power to estimate bleeding risk in this group. The small number of participants with CKD stage 4 andabove (98 had an eGFR 30 ml/min/1.73 m2) mean thefindings cannot be extrapolated to patients with severeCKD or end-stage kidney disease. In addition, the HOTstudy, as in many randomized trials of aspirin administra-tion, did not report bleeding episodes with the sameprecision as cardiovascular outcomes, and bleeding episodes

were not validated by an expert committee. Furthermore,this is a post-hoc analysis of a trial that was not designed (orpowered) to examine the effects of aspirin according tocategories of kidney function. Finally, the participants inthis trial were at increased cardiovascular risk due to theblood pressure–based entry criteria, meaning extrapolationto persons with normal blood pressure levels is not possible.

Our results indicate that CKD predicts increased cardiovascular risk and greater net benefit with aspirin therapy.

Figure 4 Effect of Aspirin on Bleeding Rates

Effect of randomization to aspirin on bleeding rates according to

estimated glomerular filtration rate (eGFR) category. CI confidence interval.

Events Prevented and Caused by Aspirin Therapy for Every1,000 Patients Treated According to eGFR CategoryTable 2

Events Prevented and Caused by Aspirin Therapy for Every

1,000 Patients Treated According to eGFR Category

eGFR, ml/min/1.73 m2

Overall>60 45–59 <45

Events prevented by aspirin therapy

Major cardiovascular events 3 (3 to 8) 8 (7 to 22) 76 (31 to 121) 6 (0 to 11)

Myocardial infarctions 4 (0 to 8) 10 (1 to 20) 40 (7 to 72) 6 (2 to 10)

Stroke 1 (5 to 2) 0 (11 to 10) 40 (11 to 69) 0 (3 to 4)

Cardiovascular mortality 1 (5 to 3) 2 (8 to 11) 40 (6 to 74) 1 (3 to 4)

Total mortality 0 (5 to 5) 4 (9 to 17) 54 (7 to 100) 2 (3 to 7)

Events caused by aspirin therapy

Major bleeding 4 (1 to 8) 4 (2 to 10) 27 (1 to 55) 6 (3 to 8)

Minor bleeding 4 (1 to 8) 12 (3 to 21) 12 (8 to 31) 6 (2 to 9)

Any bleeding 8 (3 to 12) 16 (5 to 27) 39 (5 to 72) 10 (6 to 14)

Values are absolute risk change (95% confidence interval) per 1,000 patients treated for an average of 3.8 years.

eGFR estimated glomerular filtration rate.

Difference in Change in Renal Function DuringFollow-Up Between Group Randomized to Aspirinand Group Randomized to Placebo, According toeGFR Categories

Table 3

Difference in Change in Renal Function During

Follow-Up Between Group Randomized to Aspirin

and Group Randomized to Placebo, According to

eGFR Categories

eGFR Levels at Baseline

(ml/min/1.73 m2

)

Annual Change in eGFR During Follow-Up

for Aspirin Group Versus Placebo Group

(ml/min/1.73 m2

yr)

Mean (95% Confidence Interval)* p Value

eGFR 60 0.16 (0.33 to 0.01) 0.06

eGFR 45–59 0.08 (0.37 to 0.21) 0.57

eGFR45 0.30 (0.74 to 1.34) 0.57

Overall 0.15 (0.30 to 0.00) 0.06

*The difference in the annual changing rate of estimated glomerular filtration rate (eGFR) during

follow-up was estimated by subtracting the mean annual changing rate of eGFR in the placebo

group from that in the aspirin group. Negative value indicates greater reduction in eGFR during

follow-up in the aspirin group than the placebo group.






This finding reinforces calls to consider CKD when makingdecisions regarding treatment to mitigate cardiovascularrisk. These results suggest that aspirin might be used more widely as primary prevention for high-risk patients withCKD.

Acknowledgment

The authors gratefully acknowledge the kind assistance of Ingrid Warnold, PhD, AstraZeneca, Mölndal, Sweden.

Reprint requests and correspondence: Dr. Vlado Perkovic, TheGeorge Institute for Global Health, KGV Building, RPAH,Missenden Road, Camperdown, New South Wales 2050, Austra-lia. E-mail: [email protected].

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Key Words: aspirin y bleeding y cardiovascular risk y chronic kidney disease y mortality y primary prevention y risk-benefit analysis.



pemberian aspirin dengan ckd

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