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Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial

Author/s: 
Hermida, R.C., Crespo, J.J., Domínguez-Sardiña, M, Otero, A., Moyá, A., Ríos, M.T., Sineiro, E., Castiñeira, M.C., Callejas, P.A., Pousa, L., Salgado, J.L., Durán, C., Sánchez, J.J., Fernández, J.R., Mojón, A., Ayala, D.E., Hygia Project Investigators

AIMS:

The Hygia Chronotherapy Trial, conducted within the clinical primary care setting, was designed to test whether bedtime in comparison to usual upon awakening hypertension therapy exerts better cardiovascular disease (CVD) risk reduction.

METHODS AND RESULTS:

In this multicentre, controlled, prospective endpoint trial, 19 084 hypertensive patients (10 614 men/8470 women, 60.5 ± 13.7 years of age) were assigned (1:1) to ingest the entire daily dose of ≥1 hypertension medications at bedtime (n = 9552) or all of them upon awakening (n = 9532). At inclusion and at every scheduled clinic visit (at least annually) throughout follow-up, ambulatory blood pressure (ABP) monitoring was performed for 48 h. During the 6.3-year median patient follow-up, 1752 participants experienced the primary CVD outcome (CVD death, myocardial infarction, coronary revascularization, heart failure, or stroke). Patients of the bedtime, compared with the upon-waking, treatment-time regimen showed significantly lower hazard ratio-adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL cholesterol, asleep systolic blood pressure (BP) mean, sleep-time relative systolic BP decline, and previous CVD event-of the primary CVD outcome [0.55 (95% CI 0.50-0.61), P < 0.001] and each of its single components (P < 0.001 in all cases), i.e. CVD death [0.44 (0.34-0.56)], myocardial infarction [0.66 (0.52-0.84)], coronary revascularization [0.60 (0.47-0.75)], heart failure [0.58 (0.49-0.70)], and stroke [0.51 (0.41-0.63)].

CONCLUSION:

Routine ingestion by hypertensive patients of ≥1 prescribed BP-lowering medications at bedtime, as opposed to upon waking, results in improved ABP control (significantly enhanced decrease in asleep BP and increased sleep-time relative BP decline, i.e. BP dipping) and, most importantly, markedly diminished occurrence of major CVD events.

TRIAL REGISTRATION:

ClinicalTrials.gov, number NCT00741585.

Keywords 
antihypertensives blood pressure hypertension medication

Rivaroxaban Versus Vitamin K Antagonist in Antiphospholipid Syndrome: A Randomized Noninferiority Trial

Author/s: 
Ordi-Ros, J, Sáez-Comet, L., Pérez-Conesa, M., Vidal, X., Riera-Mestre, A., Castro-Salomó, A., Cuquet-Pedragosa, J., Ortiz-Santamaria, V., Mauri-Plana, M., Solé, C., Cortés-Hernández, J.

BACKGROUND:

The potential role of new oral anticoagulants in antiphospholipid antibody syndrome (APS) remains uncertain.

OBJECTIVE:

To determine whether rivaroxaban is noninferior to dose-adjusted vitamin K antagonists (VKAs) for thrombotic APS.

DESIGN:

3-year, open-label, randomized noninferiority trial. (EU Clinical Trials Register: EUDRA [European Union Drug Regulatory Authorities] code 2010-019764-36).

SETTING:

6 university hospitals in Spain.

PARTICIPANTS:

190 adults (aged 18 to 75 years) with thrombotic APS.

INTERVENTION:

Rivaroxaban (20 mg/d or 15 mg/d, according to renal function) versus dose-adjusted VKAs (target international normalized ratio, 2.0 to 3.0, or 3.1 to 4.0 in patients with a history of recurrent thrombosis).

MEASUREMENTS:

The primary efficacy outcome was the proportion of patients with new thrombotic events; the primary safety outcome was major bleeding. The prespecified noninferiority margin for risk ratio (RR) was 1.40. Secondary outcomes included time to thrombosis, type of thrombosis, changes in biomarker levels, cardiovascular death, and nonmajor bleeding.

RESULTS:

After 3 years of follow-up, recurrent thrombosis occurred in 11 patients (11.6%) in the rivaroxaban group and 6 (6.3%) in the VKA group (RR in the rivaroxaban group, 1.83 [95% CI, 0.71 to 4.76]). Stroke occurred more commonly in patients receiving rivaroxaban (9 events) than in those receiving VKAs (0 events) (corrected RR, 19.00 [CI, 1.12 to 321.9]). Major bleeding occurred in 6 patients (6.3%) in the rivaroxaban group and 7 (7.4%) in the VKA group (RR, 0.86 [CI, 0.30 to 2.46]). Post hoc analysis suggested an increased risk for recurrent thrombosis in rivaroxaban-treated patients with previous arterial thrombosis, livedo racemosa, or APS-related cardiac valvular disease.

LIMITATION:

Anticoagulation intensity was not measured in the rivaroxaban group.

CONCLUSION:

Rivaroxaban did not show noninferiority to dose-adjusted VKAs for thrombotic APS and, in fact, showed a non-statistically significant near doubling of the risk for recurrent thrombosis.

PRIMARY FUNDING SOURCE:

Bayer Hispania.

Keywords 
rivaroxaban thrombosis wafarin

Meta-Analysis of Oral Anticoagulant Monotherapy as an Antithrombotic Strategy in Patients With Stable Coronary Artery Disease and Nonvalvular Atrial Fibrillation

Author/s: 
Lee, SR, Rhee, TM, Kang, DY, Choi, EK, Oh, S, Lip, GYH

Guidelines recommend oral anticoagulant (OAC) monotherapy without antiplatelet therapy (APT) in patients with nonvalvular atrial fibrillation (AF) with stable coronary artery disease (CAD) of >1 year after myocardial infarction or percutaneous coronary intervention. More evidences are required for the safety and efficacy of OAC monotherapy compared with OAC plus APT. PubMed, EMBASE, and Cochrane Database of Systematic Reviews were systematically searched up to February 2019. Nonrandomized studies and randomized clinical trials comparing OAC monotherapy with OAC plus single APT (SAPT) for patients with stable CAD and nonvalvular AF. The primary end point was major adverse cardiovascular events (composite of ischemic or thrombotic events) and secondary outcomes included major bleeding, stroke, all-cause death, and net adverse events (composite of ischemic, thrombotic, or bleeding events). From 6 trials, 8,855 patients were included. There was no significant difference in major adverse cardiovascular event in patients with AF treated using OAC plus SAPT compared with those treated with OAC monotherapy (hazard ratio [HR] 1.09; 95% confidence interval [CI] 0.92 to 1.29). OAC plus SAPT was associated with a significantly higher risk of major bleeding compared with OAC monotherapy (HR 1.61; 95% CI 1.38 to 1.87), as well as in terms of net adverse event (HR 1.21; 95% CI 1.02 to 1.43). There were no significant differences in rates of stroke and all-cause death. In conclusion, in this meta-analysis, OAC monotherapy and OAC plus SAPT treatment showed similar effectiveness, but OAC monotherapy was significantly associated with a lower risk of bleeding compared with OAC plus SAPT in patients with nonvalvular AF and stable CAD.

Keywords 
atrial fibrillation coronary artery disease CAD myocardial infarction stroke

Left Atrial Appendages Occlusion: Current Status and Prospective

Author/s: 
Sharma, S.P., Park, P., Lakkireddy, D.

Stroke continues to be a major cause of morbidity and mortality in atrial fibrillation (AF) patients. Oral anticoagulation (OAC) provides protection against stroke and peripheral embolization in AF but significant proportion of patients could not be started on anticoagulation because of bleeding complications. Left atrial appendage harbors clot in about 90% of nonvalvular AF. The advent of left atrial appendage occlusion (LAAO) techniques has provided these patients with alternative to OAC for stroke prophylaxis. Multiple LAAO devices are currently available with Watchman and Amulet being the most commonly used in clinical practice. Randomized studies are available for Watchman device only. Data on Amplatzer Cardiac Plug, Amulet and Lariat devices are limited by the paucity of randomized data. Long-term data on different LAAO techniques are showing promising results. Device related thrombosis continues to be a serious complication associated with LAAO. Future studies should look into comparative effectiveness between different LAAO techniques, optimal patient selection, risk of complications, and anticoagulant treatment after LAAO. This article aims to provide current available evidence on efficacy and safety of different LAAO devices and future prospective.

Keywords 
Watchman device left atrial appendage stroke atrial fibrillation amulet

Management of Patients With Acute Ischemic Stroke

Author/s: 
Cifu, A.S., Brorson, J.R.

Guideline title 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke

Release date January 24, 2018

Prior version 2013

Developer American Heart Association (AHA)/American Stroke Association (ASA)

Funding source AHA/ASA

Target population Adult patients with acute arterial ischemic stroke

Major recommendations

  • Regional systems of stroke care should be developed that include health care facilities providing initial emergency care and those capable of endovascular stroke treatment, to which rapid transport can be arranged when appropriate (high-quality evidence; strong recommendation).

  • Intravenous alteplase is recommended for patients meeting detailed eligibility requirements within 3 hours of ischemic stroke onset (high-quality evidence; strong recommendation) and between 3 and 4.5 hours of ischemic stroke onset (moderate-quality evidence; strong recommendation).

  • Mechanical thrombectomy with a stent retriever is recommended for patients with a causative occlusion of the internal carotid artery or proximal middle cerebral artery with at least moderately severe presenting stroke deficits (National Institutes of Health Stroke Scale [NIHSS] score ≥6) and absence of evidence of widespread established infarction on brain imaging, when endovascular treatment can be initiated within 6 hours of symptom onset (high-quality evidence; strong recommendation).

  • Mechanical thrombectomy with a stent retriever is also recommended for certain acute ischemic stroke (AIS) patients presenting at later times (moderate- to high-quality evidence; strong recommendation).

Keywords 
stroke ischemia stents

Cardiovascular Events and Mortality in White Coat Hypertension: A Systematic Review and Meta-analysis

Author/s: 
M.G., Cohen, J.B., Lotito, M.J., Denker, M.G., Cohen, D.L., Townsend, R.R.

BACKGROUND:

The long-term cardiovascular risk of isolated elevated office blood pressure (BP) is unclear.

PURPOSE:

To summarize the risk for cardiovascular events and all-cause mortality associated with untreated white coat hypertension (WCH) and treated white coat effect (WCE).

DATA SOURCES:

PubMed and EMBASE, without language restriction, from inception to December 2018.

STUDY SELECTION:

Observational studies with at least 3 years of follow-up evaluating the cardiovascular risk of WCH or WCE compared with normotension.

DATA EXTRACTION:

2 investigators independently extracted study data and assessed study quality.

DATA SYNTHESIS:

27 studies were included, comprising 25 786 participants with untreated WCH or treated WCE and 38 487 with normal BP followed for a mean of 3 to 19 years. Compared with normotension, untreated WCH was associated with an increased risk for cardiovascular events (hazard ratio [HR], 1.36 [95% CI, 1.03 to 2.00]), all-cause mortality (HR, 1.33 [CI, 1.07 to 1.67]), and cardiovascularmortality (HR, 2.09 [CI, 1.23 to 4.48]); the risk of WCH was attenuated in studies that included stroke in the definition of cardiovascular events(HR, 1.26 [CI, 1.00 to 1.54]). No significant association was found between treated WCE and cardiovascular events (HR, 1.12 [CI, 0.91 to 1.39]), all-cause mortality (HR, 1.11 [CI, 0.89 to 1.46]), or cardiovascular mortality (HR, 1.04 [CI, 0.65 to 1.66]). The findings persisted across several sensitivity analyses.

LIMITATION:

Paucity of studies evaluating isolated cardiac outcomes or reporting participant race/ethnicity.

CONCLUSION:

Untreated WCH, but not treated WCE, is associated with an increased risk for cardiovascular events and all-cause mortality. Out-of-office BP monitoring is critical in the diagnosis and management of hypertension.

PRIMARY FUNDING SOURCE:

National Institutes of Health.

Keywords 
blood pressure stroke cardiovascular

Intensive Glucose Control in Patients with Type 2 Diabetes — 15-Year Follow-up

Author/s: 
Emanuele, N.V., Reaven, P.D., Wiitala, W.L., Bahn, G.D., Reda D.J., McCarren, M., Duckworth, W.C., Hayward, R.A., VADT Investigators

BACKGROUND

We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up.

METHODS

We observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome.

RESULTS

There were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P=0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75).

CONCLUSIONS

Participants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.)

Keywords 
diabetes glucose gangrene veterans military personnel heart failure stroke amputation diabetes, type 2

Dual antiplatelet therapy with aspirin and clopidogrel for acute high risk transient ischaemic attack and minor ischaemic stroke: a clinical practice guideline

Author/s: 
Reed A.C., Hao, Qiukui, Guyatt, Gordon H., O’Donnell, Martin, Lytvyn, Lyubov, Heen, Anja Fog, Agoritsas, Thomas, Vandvik, Per O., Gorthi, Sankar P., Fisch, Loraine, Jusufovic, Mirza, Muller, Jennifer, Booth, Brenda, Horton, Eleanor, Fraiz, Auxiliadora, Siemieniuk, Jillian, Fobuzi, Awah C., Katragunta, Neelima, Rochwerg, Bram, Prasad, Kameshwar

What is the role of dual antiplatelet therapy after high risk transient ischaemic attack or minor stroke? Specifically, does dual antiplatelet therapy with a combination of aspirin and clopidogrel lead to a greater reduction in recurrent stroke and death over the use of aspirin alone when given in the first 24 hours after a high risk transient ischaemic attack or minor ischaemic stroke? An expert panel produced a strong recommendation for initiating dual antiplatelet therapy within 24 hours of the onset of symptoms, and for continuing it for 10-21 days. Current practice is typically to use a single drug.

Keywords 
aspirin stroke long-term care clopidogrel transient ischemic attack

Stroke Prevention in Patients With Atrial Fibrillation: A Systematic Review Update

Author/s: 
Sanders, D. Gillian, Lowenstern, Angela, Borre, Ethan, Chatterjee, Ranee, Goode, Adam, Sharan, Lauren, Allen LaPointe, Nancy M., Raitz, Giselle, Shah, Bimal, Yapa, Roshini, Davis, J. Kelly, Lallinger, Kathryn, Schmidt, Robyn, Kosinski, Andrzej, Al-Khatib, Sana

Purpose of Review

To update a previous review in patients with atrial fibrillation/atrial flutter (AF) to determine the best assessment tools for predicting risk of stroke and bleeding, as well as the best treatment options to prevent stroke. Current treatments include new antithrombotic strategies, devices, and oral anticoagulants (oral direct thrombin inhibitors, factor Xa inhibitors).

Key Messages

  • CHADS2, CHA2DS2-VASc, and ABC risk scores have the best evidence to support prediction of stroke events.
  • HAS-BLED has the best evidence to support prediction of bleeding risk.
  • Imaging tools for stroke prediction require further evidence.
  • Dabigatran (150 mg dose) is superior to warfarin in preventing stroke or systemic embolism, with no evidence for a difference in major bleeding. There may also be no evidence for a difference in myocardial infarction or all-cause mortality.
  • Apixaban is superior to warfarin in preventing stroke or systemic embolism. Apixaban also has less risk for major bleeding and may also decrease all-cause mortality compared to warfarin.
  • Rivaroxaban may be similar to warfarin in preventing stroke or systemic embolism and in risk of major bleeding. Rivaroxaban is most likely similar to warfarin in the rate of all-cause mortality. However, inconsistent with the randomized controlled trial (RCT) findings, observational studies showed rivaroxaban may better prevent stroke or systemic embolism and may have a higher risk of major bleeding.
  • Edoxaban is most likely similar to warfarin in preventing stroke or systemic embolism and also most likely has less risk for major bleeding and hemorrhagic stroke than warfarin.
  • Further RCTs directly comparing oral anticoagulants, including thrombin inhibitors and individual Xa inhibitors, are needed.

Structured Abstract

Objectives. This review updates previous reviews regarding the optimal risk stratification tools for stroke and bleeding prediction, and treatment options for stroke prevention in patients with atrial fibrillation.

Data sources. We searched PubMed®, Embase®, and the Cochrane Database of Systematic Reviews for relevant English-language comparative studies published from January 1, 2000, to February 14, 2018.

Review methods. Two investigators screened each abstract and full-text article for inclusion, abstracted data, rated quality and applicability, and graded evidence. When possible, random-effects models were used to compute summary estimates of effects.

Results. Our review included 320 articles (185 unique studies). This included 61 studies relevant to predicting thromboembolic risk, 38 relevant to predicting bleeding risk, and 117 relevant to interventions for preventing thromboembolic (TE) events. Data suggest that the CHADS2, CHA2DS2-VASc, and ABC risk scores have the best evidence predicting TE risk (moderate strength of evidence [SOE] for limited prediction ability of each score) and that the HAS-BLED score has the best evidence to predict bleeding risk (moderate SOE).

We found that a thrombin inhibitor (dabigatran 150 mg) was superior to warfarin in preventing stroke (including hemorrhagic) or systemic embolism (relative risk [RR] 0.66; 95% confidence interval [CI] 0.53 to 0.82), with no statistically significant difference in the occurrence of major bleeding (RR 0.93; 95% CI 0.81 to 1.07) (high SOE for both outcomes). The Xa inhibitor apixaban was superior to warfarin in preventing stroke or systemic embolism (hazard ratio [HR] 0.79; 95% CI 0.66 to 0.95; high SOE), major bleeding (HR 0.69; 95% CI 0.60 to 0.80; high SOE), and all-cause mortality (HR 0.89; 95% CI 0.80 to 0.998; low SOE). Apixaban was also superior to aspirin in preventing stroke or systemic embolism (HR 0.45; 95% CI 0.32 to 0.62), with similar risk for major bleeding (HR 1.13; 95% CI 0.74 to 1.75) in patients who are not suitable for warfarin (moderate SOE for both outcomes). The Xa inhibitor edoxaban reduced hemorrhagic stroke and major bleeding compared to warfarin (moderate SOE for both outcomes) but had no evidence of a difference in stroke or systemic embolism (moderate SOE) or myocardial infarction (moderate SOE). The Xa inhibitor rivaroxaban was similar to warfarin in preventing stroke or systemic embolism (HR 0.88, 95% CI 0.74 to 1.03; moderate SOE), with similar rates of major bleeding (low SOE) and death (moderate SOE). Low SOE for major bleeding was due to a trend toward an increase in risk of major bleeding with rivaroxaban seen in observational studies. Comparative effectiveness findings for stroke prevention were limited by the direct comparisons between individual direct oral anticoagulants. Evidence regarding nonpharmacologic interventions was sparse, but left atrial appendage (LAA) closure devices showed a trend toward benefit over warfarin for strokes, major bleeding, and all-cause mortality that did not reach statistical significance. Higher adverse events (excessive bleeding or procedure-related complications) were observed with LAA (low SOE).

Conclusions. Overall, we found that CHADS2, CHA2DS2-VASc, and ABC scores have similar evidence regarding their ability to predict stroke risk in patients with atrial fibrillation, whereas HAS-BLED has the best evidence to predict bleeding risk. Direct oral anticoagulants (specifically apixaban and dabigatran) demonstrate reductions in stroke events and reductions (apixaban) or similar (dabigatran) rates in bleeding events when compared with warfarin, while rivaroxaban was similar in both benefits and harms to warfarin. Edoxaban reduced hemorrhagic stroke and major bleeding compared to warfarin but had no evidence of a difference in other outcomes. More studies are needed directly comparing oral anticoagulants, including thrombin inhibitors and individual Xa inhibitors.

Keywords 
stroke atrial fibrillation atrial flutter
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