In adults with diabetes, aspirindoes not prevent CV eventscompared with placebo

Reference: Kunutsor SK, Seidu S, Khunti K. Aspirin for primary prevention of cardiovascularand all-cause mortality events in diabetes: updated meta-analysis of randomizedcontrolled trials. Diabet Med. 2016. [Epub ahead of print].

Date of presentation: 95.12.7Presented By: dr sadr nia

Question

In patients with diabetes, whatare the efficacy and safety ofaspirin for primary prevention ofcardiovascular (CV) events andmortality?

Review scope

Included studies compared aspirin with placebo orno treatment for ≥ 12 months in adults ≥ 18 years ofage who had diabetes mellitus and no history orclinical evidence of CV diseases(CVD)

MethodsPatients: (n = 16 690, age range 18 to 90 y,treatment duration 3.6 to 10y, aspirin dose75 mg to 650 mg daily)

Exclusion criteria: included comparisons ofaspirin with other antiplatelet agents orstudies involving patients with known CVD

Design:randomized controlled trials (RCTOutcomes:included major adverse CV events (MACE) (composite ofnonfatal myocardial infarction [MI], nonfatal stroke, orCV mortality), MI, stroke, coronary heart disease, CVmortality, all-cause mortality, and bleeding.

Main results

Main results are in the Table. Whenanalyses were restricted to trials ofpatients without prevalent CVD, aspirindid not reduce MACE or any individualoutcomes compared with placebo or notreatment

Table & figure

Conclusion

In patients with diabetes and nocardiovascular disease, aspirin did notprevent cardiovascular events orincrease bleeding compared withplacebo or no treatment

Commentary

Aspirin has been recommended for primary prevention of CVDbased on RCTs that showed reduced risk for nonfatal MI .Theeffect of aspirin on CVD is modest, and the decision to initiateaspirin therapy should be individualized to optimize overallbenefit Diabetes is a risk factor for CVD, so aspirin might beeffective in preventing CVD in patients with diabetes. However,the updated meta-analysis by Kunutsor and colleagues confirmsearlier reviews indicating that the effects of aspirin are, at best,limited in reducing the risk for overall CVD in diabetes patientswithout known CVD.

Aspirin for primary prevention of CVD in patients withoutdiabetes has the most favorable benefit-to-risk ratio inpatients with increased risk for CVD and lower risk forgastrointestinal complications.Subgroup analyses by Kunutsor and colleagues suggestedthat patients with lower risk for CVD might derive greaterbenefit from aspirin than patients with higher risk for CVD,but the difference was not statistically significant. Thisconclusion is counter to most recommendations and, as asecondary analysis, should be cautiously interpreted.Currently, the largest clinical trial with targeted enrollment ofpatients with diabetes (n > 15 000) is ongoing and mightclarify the benefits and risks of aspirin therapy for primaryCVD prevention and which subgroups benefit most

Commentary

Given the current lack of conclusive evidencesupporting the use of aspirin for primary prevention ofCVD in patients with diabetes, how can clinicians bestminimize CVD risks?With the notable exception of lipid-lowering therapy,most clinical trials have not shown a benefit of lifestyleinterventions, weight loss, or blood pressure control onprimary CVD prevention in patients with diabetes (4).Nevertheless, these interventions can be justified due totheir beneficial effects on glycemic control andmicrovascular disease along with an exceptional safetyprofile.

Commentary

major bleeding and hemorrhagic stroke with direct oralanticoagulants in patients with renal failure: systematicreview and meta-analysis of randomized trials .Raccah BH, Perlman A, Danenberg HD, Et Al.

Reference: Chest. 2016;149:1516-24

Date of presentation: ١٣٩۵/٨/٢Presented By:Dr. Tamizifar

Question?

In patients with renal failure, do direct oralanticoagulants (DOACs) reduce risks for hemorrhagicstroke and major bleeding compared with vitamin Kantagonists (VKAs)?

Methods Review scope

Included studies compared DOACs (apixaban, dabigatran,edoxaban, or rivaroxaban) with VKAs in adults withnonvalvular atrial fibrillation (AF) or venousthromboembolism (VTE) and reported safety outcomesseparately for those with different levels of renalimpairment (estimated creatinine clearance [eCrCl] < 50mL/min or 50 to 80 mL/min). Exclusion criteria included useof placebo control.Outcomes were intracranial hemorrhage, and majorbleeding or a composite of major bleeding or clinicallyrelevant nonmajor bleeding.PROSPERO registry CRD42014013730

Review methods

MEDLINE, EMBASE/Excerpta Medica, and Cochrane Library (all to Nov 2015);ClinicalTrials.gov; Web sites; conference abstracts; and other systematic reviewswere searched for randomized controlled trials (RCTs).• 9 RCTs (eCrCl < 50 mL/min, n = 13 996; eCrCl 50 to 80 mL/min, n = 40 681) met

the inclusion criteria.• 5 RCTs were done in patients with AF (follow-up 1.6 to 2.8 y) and 4 in those with

acute VTE (follow-up 0.25 to 1 y).• 4 RCTs evaluated rivaroxaban, 2 each evaluated apixaban or edoxaban, and 1

evaluated dabigatran.• DOACs were compared with warfarin in 6 RCTs and enoxaparin followed by

warfarin in 3 RCTs. All 9 RCTs had adequate allocation concealment andadequate outcome data, and 6 blinded patients, study staff, and outcomeassessors. All RCTs were funded by pharmaceutical companies

Main results

DOACs reduced hemorrhagic stroke compared withVKAs in patients with eCrCl < 50 mL/min or 50 to 80mL/min (Table).DOACs reduced major bleeding compared with VKAs inpatients with eCrCl 50 to 80 mL/min; groups did notdiffer for major bleeding in patients with eCrCl < 50mL/min (Table).

Table 1: Direct Oral Anticoagulants (Doacs) Vs Vitamin KAntagonists (Vkas) In Patients With Atrial Fibrillation Or VenousThromboembolism And Renal Failure*

Conclusion

• In patients with atrial fibrillation or venousthromboembolism and renal failure, direct oralanticoagulants reduce risk for hemorrhagic strokecompared with vitamin K antagonists.

• Direct oral anticoagulants reduce risk for majorbleeding in those with estimated creatinineclearance 50 to 80 mL/min.

• The decision to use anticoagulation therapy, whether inpatients with AF or VTE, weighs the potential benefitsfor preventing or treating thrombosis against the risksfor hemorrhage, especially intracranial hemorrhage.

• Patients with renal disease have an increased risk forhemorrhage when receiving anticoagulation therapy (1)but are also at higher risk for arterial or venousthromboembolic disease.

Commentary 1

• In the past, VKAs, including warfarin, were the only available oral anticoagulants.However, they require frequent blood draws and dose adjustments to maintaintherapeutic activity and have multiple food and drug interactions.

• Newer DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) allow fixed dosingwith few modifications for age or organ failure and have fewer drug interactions.Large, multicenter RCTs have found the newer DOACs to be noninferior or superior towarfarin for preventing stroke in AF and noninferior to warfarin for preventingrecurrent VTE, with lower risks for major hemorrhage, especially intracranial bleeding(2).

• DOACs are also more cost-effective than warfarin (3). However, clinicians may bereluctant to use DOACs in patients with renal insufficiency because these drugs havesubstantial renal excretion and dosing may need to be reduced.

Commentary 2

• In the most comprehensive and rigorous meta-analysis of DOACsafety in patients with AF or VTE and renal failure, Raccah andcolleagues found that DOACs were associated with less majorhemorrhage (especially hemorrhagic stroke) than warfarin, includingin patients with eCrCl < 50 mL/min.

• In indirect network comparisons, apixaban, which has the least renalexcretion among DOACs, had the lowest risk for major bleeding inpatients with eCrCl < 50 mL/min.

• The absence of patients with severe renal insufficiency (eCrCl < 15mL/min) or on hemodialysis in trials included in the review precludedconclusions about the relative safety of DOACs in end-stage renaldisease.

Commentary 3

• DOACs, especially apixaban, are safer than warfarin inpatients with mild to moderate renal insufficiency (eCrCl 30to 80 mL/min), provide comparable efficacy with importantlogistic advantages, and have a favorable cost–benefit ratio.Safety is enhanced by dose modification, while efficacy ispreserved.

• Reluctance to prescribe DOACs in general, including inhigher-risk patients with renal insufficiency, is no longerjustified.

Commentary 4

TITLE OF ARTICLE

New oral anticoagulants increaseGI bleeding in venous thrombosis and ACS

18 February 2014 | ACP Journal Club | Volume © 2014 American College ofPhysician

Question

Do new oral anticoagulants (NOACs) increase risk forgastrointestinal (GI) or clinically relevant bleeding?

METHODS:

43 RCTs (n = 151 578, mean or median age range 56 to 73 y, 17% to 82%men, follow-up range 3 wk to 31 mo) met the inclusion criteria:21 used NOACs in orthopedic surgery, 8 in atrial fibrillation (AF),7 in acute deep venous thrombosis or pulmonary embolism, 5 in theacute coronary syndrome (ACS), and 2 in medically ill patients. 16RCTs evaluated rivaroxaban, 12 apixaban, 10 dabigatran, 4 edoxaban,and 1 betrixaban. All RCTs excluded patients with increasedrisk for GI bleeding. 31 RCTs had adequate allocation concealment,30 were reported as double-blind and all 43 blinded outcome assessors,and 23 reported loss to follow-up (0% to 2.5%).

Included studies compared NOACs (rivaroxaban, apixaban, dabigatran,edoxaban, or betrixaban) with standard care (low-molecularweightheparin, vitamin K antagonist, antiplatelet therapy, noadditional therapy, or placebo) in the target population for thedrug and reported bleeding as a safety outcome.Outcomes were GI bleeding or clinically relevant major or nonmajorbleeding.

Main results

Results of meta-analysis of NOACs vs standard care in differentsettings are reported in the Table. In subgroup analyses by drug,rivaroxaban increased risk for GI bleeding (5 RCTs, 2.1% vs 1.4%,relative risk increase [RRI] 47%, 95% CI 21 to 80) and clinicallyrelevant bleeding (16 RCTs, 12% vs 9.7%, RRI 27%, CI 4 to 54)compared with standard care, and dabigatran increased risk forGI bleeding (3 RCTs, 3.3% vs 2.1%, RRI 56%, CI 28 to 89); otherNOACs were not associated with increased risk for bleeding.

Conclusion

In patients with deep venous thrombosis or pulmonary embolism,or the acute coronary syndrome, new oral anticoagulants increaserisk for gastrointestinal bleeding compared with standard care.

Commentary

NOACs have been reported to be at least as effective and safeas standard therapies and are more convenient (1). Holster andcolleagues now report that these agents are associated with anincreased risk for GI bleeding compared with standard therapies,and an accompanying editorial questions whether the greaterconvenience of NOACs is worth the risk (2).

Commentary

The meta-analysis by Holster and colleagues shows that NOACs increase GIbleeding compared with standard therapies in patients with ACS andvenous thromboembolism, but not in those with AF. We urge cautiousinterpretation of these data. First, in the individual trials, the effects ofNOACs differed by indication and the NOAC and control used, as reflectedby substantial heterogeneity in the pooled estimates. The largest increasein GI bleeding was in ACS trials, where NOACs were compared withplacebo on a background of dual-antiplatelet therapy. We question whether the results of placebo-controlled trials should be pooled with thosefrom active-controlled trials.

Individual trials, each involving > 10 000 patients with AF, have shownthat dabigatran, 150 mg twice daily, and rivaroxaban, 20 mg daily (15mg daily in patients with creatinine clearance 30 to 49 mL/min), butnot apixaban, increase GI bleeding compared with warfarin (3-5), whichraises questions about the results of the meta-analysis in patients withAF. Second, despite increases in GI bleeding, NOACS are not associatedwith excess clinically relevant bleeding in the active controlled trialsbecause increases in GI bleeding were offset by decreases in bleedingat other sites.

What are the implications of these results for clinical practice?The data by Holster and colleagues are a timely reminder thatNOACs can increase the risk for bleeding but also highlightdifferences between drugs. Clinicians should consider risk forGI bleeding when making treatment recommendations, but inthe context of NOAC effects on all patient-important outcomes.

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