Primecuts – This Week in the Journals

November 13, 2017

By Dixon Yang, MD

Peer Reviewed

“It’s MAGA Day. And we’ll celebrate it like Bastille Day,” states Steve Bannon, former advisor to President Trump in an interview with the New York Times last week. Bannon called for the ousting of Senate Majority Leader Mitch McConnell for lack of support to the President [1]. This interview comes in the wake of sweeping Republican losses on Election Day, with the first openly transgender woman, Danica Roem, elected to a state legislature, providing early indication in a public rejection of Trumpism [2,3].

Meanwhile, both Kevin Spacey and Louis C.K. are faced with accusations of sexual misconduct and harassment, as more individuals in show business are stepping forward after extensive sexual harassment allegations surfaced against Harvey Weinstein, former film executive [4]. In health news, Boston University neuropathologist Dr. Ann McKee and her team share their report of former football star, Aaron Hernandez’s brain autopsy. They find the most severe case of chronic traumatic encephalopathy seen for his age, with lesions in areas noted for memory, judgment, and emotion, though of course, no connection can be claimed between his conviction for first-degree murder and pathology [5].

On that note, this week’s PrimeCuts will explore recent investigations related to cerebrovascular disease with applications in cardiovascular disease, chronic kidney disease, and anticoagulant selection and safety.

Patent foramen ovale (PFO) closure plus antiplatelets reduces risk of recurrent stroke in patients with cryptogenic stroke when compared to antiplatelets alone.

Cryptogenic stroke is an ischemic stroke without a single identified probable cause despite full diagnostic evaluation. They account for about a quarter of ischemic strokes and are often attributed to occult arrhythmias or paradoxical emboli [6]. Several randomized control trials studying secondary stroke prevention with interatrial shunt closure after cryptogenic stroke have been inconclusive [7,8]. Recently, the European multicenter “Patent Foramen Ovale Closure or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence” or CLOSE trial compared transcatheter closure of PFO plus long-term antiplatelet therapy against antiplatelet therapy alone for prevention of stroke recurrence after recent cryptogenic stroke attributed to PFO [9].

The CLOSE trial enrolled patients aged 16 to 60 years with ischemic stroke within the last 6 months with no identifiable possible cause other than a PFO with ultrasound features of atrial septal aneurysm or large interatrial shunt. A total of 663 patients were randomized equally into treatment arms of PFO closure plus antiplatelets, antiplatelets alone, or anticoagulants alone. All patients who had PFO closure received 75mg aspirin and 75mg of clopidogrel daily for 3 months, followed by single antiplatelet therapy (aspirin, clopidogrel, or aspirin with extended-release dipyridimole) for the duration of the trial. Patients assigned to the antiplatelet alone group received only single antiplatelet therapy. There were no differences in the selection of single antiplatelet therapy between the PFO closure and antiplatelet only groups. Patients in the anticoagulation arm received either vitamin K antagonists or direct oral anticoagulants, but ultimately were not statistically analyzed due to underpowering. Participants were followed for a total of five years, with assessments at 2 months, 6 months, and every 6 months thereafter.

No patients in the PFO closure group suffered recurrent stroke, while 4.9% of the antiplatelet only group had recurrent stroke with no identifiable cause other than PFO on repeat investigations (hazard ratio, 0.03; 95% confidence interval [CI], 0 to 0.26; P<0.001). Further, patients who received PFO closure had significantly less transient ischemic attacks than those with antiplatelet therapy alone (3.4% vs. 8.9%; hazard ratio, 0.39; 95% CI, 0.16 to 0.82; P = 0.01). Patients receiving PFO closure developed significantly more new atrial fibrillation or flutter than antiplatelet therapy alone, however the majority were not persistent by completion of the trial. There were no differences in serious adverse events between groups.

In summary, this randomized multicenter study concludes PFO closure with antiplatelet therapy is superior to antiplatelet therapy alone in patients with recent cryptogenic stroke and PFO. Pooled analysis of prior inconclusive trials suggests similar findings. One stroke may be avoided at 5 years for every 20 patients treated with PFO closure, with no difference in serious adverse events. While patients were not evaluated with prolonged arrhythmia monitoring and anticoagulant therapy could not be analyzed, this is the first study to conclude a benefit to PFO closure in patients with cryptogenic stroke.

Addition of low-dose rivaroxaban to aspirin in well-controlled stable coronary artery disease reduces major vascular events, including stroke.

Patients with stable coronary artery disease are at risk for myocardial infarction, ischemic stroke, and cardiovascular death through atherosclerotic plaque rupture, which activates platelet aggregation and coagulation cascade [10]. It is generally not recommended to add or substitute an oral anticoagulant with antiplatelet therapy for stable coronary artery disease due to higher risk of serious bleeding and limited evidence in improved cardiovascular event prevention [11]. In 2012, the ATLAS 2 trial reported adjunctive low-dose rivaroxaban in patients with recent acute coronary syndrome benefited from reduced vascular event related mortality. While they had higher rates of major bleeding, none were fatal, and the group proposed the addition of low-dose rivaroxaban may be a new treatment strategy [12]. This prompted further studies with rivaroxaban.

The “Cardiovascular Outcomes for People Using Anticoagulation Strategies” (COMPASS) trial examines low-dose rivaroxaban in patients with stable coronary artery disease [13]. The randomized, double-blinded, multicenter study included about 24,000 patients meeting criteria for coronary artery disease, peripheral arterial disease, or both. Patients with atrial fibrillation were excluded. Participants were randomized equally into groups of low-dose rivaroxaban plus aspirin, rivaroxaban alone (with aspirin placebo), or aspirin alone (with rivaroxaban alone) and were seen at 1 month, 6 months, and every 6 months after first treatment for average follow up of about 2 years.

Participants receiving low-dose rivaroxaban (2.5mg twice daily) with aspirin had significantly less composite vascular events including first occurrence of stroke, myocardial infarction, and cardiovascular death when compared with those receiving aspirin alone (HR 0.74, 95% CI 0.65–0.86, p<0.0001). Rivaroxaban alone did not demonstrate any difference with aspirin alone. Major bleeding, defined as fatal, symptomatic, or leading to hospital visit or admission, was significantly higher in both rivaroxaban groups (rivaroxaban and aspirin: HR 1.66, 95% CI 1.37–2.03, p<0.0001; rivaroxaban alone: HR 1.51, 95% CI 1.23–1.84, p<0.0001), with increased intracranial bleeding in rivaroxaban alone but not with low-dose rivaroxaban plus aspirin. The most common site of bleeding was gastrointestinal. A post hoc analysis suggests the risk of bleeding from addition of rivaroxaban to aspirin decreases after the first year, while the composite reduction in vascular events remains constant. Moreover, the study reports a number needed to treat to prevent one vascular event after two years was 72, with number needed to harm for fatal or symptomatic bleeding was 471.

Similar to the ATLAS 2 trial, the COMPASS group concludes the addition of low-dose rivaroxaban to aspirin reduces risk of vascular events including myocardial infarction, stroke, and cardiovascular death, but with unsurprising increased major bleeding risks. However, no bleeding was fatal or intracranial. Given the reported number needed to treat and harm, possible risk reduction in bleeding after one year, and consistent vascular benefits, the authors conclude the benefits of adding low-dose rivaroxaban outweigh the risks.

Markers for CKD are associated with worsened global cognitive function.

CKD is a well-established risk factor for cardiovascular disease that extends to all vascular beds, therefore unsurprisingly increases risk of cognitive impairment as well, likely through cerebrovascular disease [14]. Biomarkers of CKD and cognitive decline are not as well studied and have not been examined with neuroimaging. The “Systolic Blood Pressure Intervention Trial” (SPRINT) assessed markers of CKD and cognitive function in a subset of participants with high cardiovascular disease risk though free of DM or stroke [15].

SPRINT enrolled participants 50 years or older with an average baseline SBP ≥130 mmHg and evidence of cardiovascular disease, CKD, 10-year Framingham cardiovascular disease risk score ≥15%, or age 75 years or older to compare standard with intensive SBP treatment goals. Patients with CKD at least stage 3 were heavily recruited. A subset of about 2700 older SPRINT participants also underwent neurocognitive testing, with about 640 receiving brain MRIs. Urine albumin to creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were quantified as markers of CKD.

Both ACR and eGFR are independently associated with worse global cognitive functioning, with additional deficits in executive function and attention negatively associated with ACR and poorer memory with lower eGFR. Even low levels of ACR were associated with worse cognitive testing, while eGFR had a threshold for significance. Notably, with each doubling of ACR, a patient was estimated to have aged by 6 to 14 months cognitively. Those who underwent brain MRI were found to have a greater burden of abnormal white matter volume with higher ACR, but not with a decline in eGFR. These neuroimaging changes are thought to be reflective of cognitive decline associated with cerebrovascular disease [16].

Together, this study suggests ACR and eGFR may have distinct pathophysiologic processes of cognitive dysfunction. While both are strong markers for cardiovascular disease, eGFR may also reflect muscle mass in serum creatinine concentration. A high eGFR may correspond to cachexia rather than kidney function alone, which can also lead to worse outcomes. Endothelial dysfunction in the glomerulus due to vascular disease leads to albuminuria [17,18]. Brain microvasculature may be affected in similar fashions. Clinical significance of these associations is unclear, but it highlights a possible need for cognitive screening in CKD patients, as these patients may be susceptible to delirium or have difficulty with independently following complex therapeutic regimen.

Risk of major gastrointestinal bleeding is similar between direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs), a recent systematic review finds.

DOACs, including direct thrombin and factor Xa inhibitors, have been shown to be noninferior or superior to traditional VKAs like warfarin for prophylaxis and treatment of venous thromboembolism (VTE) and stroke prevention in atrial fibrillation (AF) [19]. A major concern with anticoagulation is increased risk of major gastrointestinal (GI) bleeding, with several large trials suggesting DOACs confer greater risk of major GI bleeding than warfarin, with the exception of apixaban [20,21]. A recent systematic review and meta-analysis examined available evidence in major GI bleeding risk associated with DOACs when compared to VKAs [22].

Data for GI bleeding were available in 28 of 43 included randomized control trials representing about 130,000 patients that compared DOACs and VKAs for prevention and treatment of VTE and prevention of stroke in AF. Major GI bleeding was defined as a decrease in hemoglobin level of 2 g/dL or bleeding requiring transfusion of 2 or more units of packed red blood cells. Additionally, bleeding was characterized by clinically relevant nonmajor bleeding (CRNM) or overt bleeding not meeting criteria for major bleeding, minor GI bleeding, and bleeding by upper or lower GI tract.

The study finds no difference between DOACs collectively and VKAs in major GI bleeding risk (1.5% vs 1.3%, respectively; OR, 0.98; 95% CI, 0.80– 1.21). Moreover, no difference was seen in CRNM, minor, upper, and lower GI bleeding outcomes. Patients in Asian studies had relatively decreased GI bleeding risk with DOACs. Examiners then conducted a priori subgroup investigation to examine each DOAC individually. They find dabigatran and rivaroxaban are associated with increased odds of major GI bleed when compared with VKAs, but no difference for apixaban or edoxaban. Post hoc analysis attenuates these results when removing the RELY trial [23] and ROCKET AF trial [24], which are notably conducted for a longer duration of therapy.

Taken together, this recent systematic review finds no difference in GI bleeding risk between DOACs collectively and VKAs. While their subgroup analysis may suggest heterogeneity in GI bleeding risk among the DOACs, no difference was found when the AF trials RELY and ROCKET AF were removed, which had observed the highest GI bleeding event rates likely attributed to longer duration of therapy and larger sample sizes. It is unclear why a potential heterogeneity would exist, but may be related to medication coating or intraluminal anticoagulant activity observed in DOACs that is not seen in VKAs [25].

At present, selection of anticoagulants in patients continues as a case-by-case basis with considerations in history of bleeding or predisposition, renal and hepatic function, age, body weight, concomitant antiplatelet use, and access to routine follow up. Although for DOACs, this can be challenging as no validated scoring method for DOAC specific bleeding risk exists. The HAS-BLED score was studied with all oral anticoagulants for stroke prevention in AF [26]. Ultimately, studies with patient-based data would be needed to better elucidate GI bleeding risk with individual DOACs and VKAs.


In patients with minor ischemic stroke or transient ischemic attack, stress hyperglycemia measured by glucose/glycated albumin is associated with increased risk of recurrent stroke [27].

The Northern Manhattan Study (NOMAS) recently looked at Na:K dietary ratio in a large multiethnic urban population, finding an increased ratio is independently associated with higher risk of stroke. The study proposes implications in cardiovascular disease and the possible role of higher dietary potassium to offset detrimental effects of high dietary sodium [28].

A recent report in JAMA finds the $933.5 billion increase in annual United States healthcare spending from 1996 to 2013 is most strongly associated with increased service price and intensity across all health conditions and types of care. In other words, per visit costs, especially from retail pharmaceuticals for diabetes and low back/neck pain during inpatient care, contributed heavily to increased healthcare spending [29].

Dr. Dixon Yang is a resident at NYU Langone Health

Peer reviewed by David Kudlowitz, MD, NYU Internal Medicine Associates, NYU Langone Health

Image courtesy of Wikimedia Commons


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