Summer Reading: Sizzling Data, Cool Discoveries

It's a cruel, cruel summer. You finally snag a few days off only to find yourself buried under papers upon return. CardioSource WorldNews is here to help. Assuming you didn't vacation at a medical meeting or take an armload of journals to the beach, you can peruse this collection of the best from recent conferences and publications.

PCCs Reverse Rivaroxaban

One drawback to the new generation of anticoagulants: the lack of agents to reverse their effects. In Europe, the main modes of emergency anticoagulation reversal rely on fresh frozen plasma (FFP) or prothrombin complex concentrates (PCC). The former contains normal levels of all the coagulation factors while PCCs contain Factors II, IX, and X with variable amounts of Factor VII in a concentrated form. Virally inactivated, PCCs can be given in a small volume without the need to thaw the product first, which is necessary for use of FFP.

Four-factor PCC rapidly corrects the effect of rivaroxaban on prothrombin time (PT) and thrombin generation in healthy adults. Recently, investigators examined the effects of a four-factor PCC and a three-factor PCC (dropping Factor VII) on PT and thrombin generation in adult volunteers receiving rivaroxaban.

In this open-label, single-center, parallel-group study, 34 healthy adults were treated with supra-therapeutic doses of rivaroxaban 20 mg twice daily for 4 days to attain steady-state concentrations. On day 5, 4 hours after rivaroxaban administration, subjects were randomized to receive either: three-factor PCC (Profilnine® SD; Grifols USA, LLC; Los Angeles, CA) single bolus dose of 50 IU/kg, four-factor PCC (Beriplex P/N; CSL Behring; King of Prussia, PA) single bolus dose of 50 IU/kg, or a control saline single bolus dose of 100 ml.

In the data presented, 34 subjects (mean age = 46 years; mean BMI = 25.8 kg/m2) completed the study. Within 30 minutes, four-factor PCC reduced the mean PT by 2.5–3.5 seconds versus a 0.6–1.0 second reduction with three-factor PCC. In contrast, however, three-factor PCC more effectively reversed rivaroxaban-induced changes in endogenous thrombin generation (area under the concentration–time curve, peak values, and time-to-peak values) than four-factor PCC. Changes in lag-time values did not differ greatly.

The explanation for the discrepant results on PT and thrombin generation remains unclear but may reflect the absence of Factor VII in three-factor PCC and the presence of heparin in four-factor PCC. Administration of PCCs in the presence of rivaroxaban was reported as safe and well-tolerated, with no signs of prothrombotic response.

"PCCs can be used to reverse the blood-thinning effects of anticoagulants such as warfarin and are important in emergency situations involving uncontrolled bleeding," said Marcel Levi, MD, professor of medicine and dean of medicine at the Academic Medical Center of the University of Amsterdam. "These data provide additional information on how to potentially reverse the anticoagulant effects of [rivaroxaban]."

Drive-by Patient Ed Doesn't Work

The saying goes that a little knowledge is a dangerous thing. But in a study from Poland, investigators wondered whether a little more knowledge about HF could benefit patients and their families.

It's certainly a debilitating condition that can negatively impact patients' everyday activities, yet members of the public still possess limited knowledge about HF. "This has undoubtedly influenced the attitudes of caregivers who don't fully appreciate the devastating impact that HF has on patients' lives," said Tomasz Rywik, MD, the first author of the study, from the National Institute of Cardiology, Warsaw, Poland.

With great optimism, 617 patients with HF from nine areas of Poland were randomized to an intervention group (n = 270) or a control group (n = 347). For the intervention group, patients and their caregivers were invited to attend a single educational session, lasting about 1 hour, plus handouts, nutritional information, and exercise guidelines personalized according to clinical status. The control group received usual care, with no educational sessions.

At 6 months, nearly half of both groups had low levels of social support (49% of patients in the experimental group vs. 47% in controls); high/very high levels of social support were seen in 22% of both groups. That half of all patients had low levels of support is concerning since this is likely to have an adverse influence on treatment compliance and ultimately prognosis. "Possibly a more successful approach would have been the development of personalized programs with patients and their families meeting health care workers on a regular basis," said Dr. Rywik. "Undoubtedly, we need to be doing more to educate the public about heart failure."

Precocious ACS Often Thromboembolic

Investigators at Northwestern University and Vanderbilt University evaluated 124 very-young patients (mean age 31±4 years for both sexes) who presented with ACS and underwent coronary angiography. Nearly half (49%) of the patients were obese, and 90% had at least one traditional risk factor—most commonly hyperlipidemia (63%) and smoking (60%). Of these patients, 52% underwent revascularization, mostly PCI, and 43% had intracoronary thrombus, including 30% with no detectable underlying coronary disease.

The presence of thrombus in the absence of coronary disease suggests a thromboembolic event or de novo thrombotic occlusion, possibly pointing to primary hemostatic dysfunction in a considerable number of these patients.

Sex (Hormones) and the SCD-y

To the list of standard risk factors for heart disease, we may now be able to add sex hormones to sudden cardiac death (SCD). The findings could help improve clinical predictors in both men and women.

The data come from the Oregon Sudden Unexpected Death Study, a large prospective community-based study in Portland, which compared cases of SCD with age- and gender-matched patients with CAD (n = 149 in each group). Plasma was obtained to assess levels of testosterone and estrogen. Plasma testing showed that both groups had a similar proportion of common cardiac risk factors including diabetes, obesity, and mean cholesterol levels. However, levels of testosterone were significantly lower in male SCD patients, but slightly higher among female cases. Median estrogen levels were significantly higher and the testosterone/estrogen (T/E) ratio was lower in SCD cases for both genders.

After adjusting for age and diabetes status, among males, increase in testosterone lowered SCD odds (OR = 0.75; p = 0.02), while higher estradiol increased risk (OR = 2.0; p < 0.001); among females, estradiol increased SCD odds (OR = 3.5; p < 0.001), while testosterone was not significantly associated with SCD. A higher T/E ratio was associated with lower odds of SCD in males (OR = 0.5; p < 0.001), but not in females.

"Sudden cardiac arrest claims one life every 2 minutes and the only way we can help decrease these numbers is to identify clinical predictors of sudden cardiac death before it happens," said Sumeet S. Chugh, MD, FHRS, director of the Heart Rhythm Center at Cedars Sinai Heart Institute in Los Angeles. "Sex hormones are known to have significant effects on cardiovascular physiology, but this is the first study that shows a direct connection between hormone levels and SCD risk."


A Canadian team finds that operating without interrupting warfarin treatment at the time of cardiac device surgery is safe and markedly reduces the incidence of clinically significant hematomas compared to standard of care.

At least one-quarter of patients who require pacemaker or implantable cardioverter-defibrillator (ICD) surgery are taking warfarin to reduce the risk of a stroke. Current guidelines recommend bridging many of these patients to heparin treatment and stopping anticoagulation therapy in the days leading up to surgery, which can put a patient at risk of a stroke.

BRUISE CONTROL investigators randomly assigned patients with an annual risk of thromboembolic events of 5% or more to continued warfarin treatment or to bridging therapy with heparin. The data and safety monitoring board recommended termination of the trial after the second prespecified interim analysis. Clinically significant device-pocket hematoma occurred in 12 of 343 patients (3.5%) in the continued-warfarin group versus 54 of 338 (16.0%) in the heparin-bridging group (relative risk = 0.19; p < 0.001).

Major surgical and thromboembolic complications were rare and did not differ significantly between the study groups. They included one episode of cardiac tamponade and one MI in the heparin-bridging group and one stroke and one transient ischemic attack in the continued-warfarin group. The data were presented at HRS 2013 and published simultaneously in the New England Journal of Medicine.1

"We hope that BRUISE CONTROL will change how we are treating patients around the world," said lead author David Birnie, MD, director of the arrhythmia service at the University of Ottawa Heart Institute, Canada. "Our study conclusively shows that treating patients with a high risk of stroke with continued warfarin instead of heparin bridging will improve patient outcomes, decrease complications, and reduce hospitalization."

DEB Versus DES in Small Arteries

Drug-eluting balloon (DEB) technology is expanding options for in-stent restenosis and may challenge drug-eluting stents (DES) in small coronary arteries.

The data come from the BELLO (Balloon Elution and Late Loss Optimization) study, which enrolled 182 patients with small-vessel disease (<2.8 mm) to compare the safety and effectiveness of two medical devices: Medtronic's IN.PACT Falcon™ DEB and the Taxus™ DES from Boston Scientific.


MACE 10.0% 18.5%
MI 1.1% 5.5%
TLR 4.4% 9.8%

The previously presented 6-month angiographic outcomes of the BELLO study favored patients treated with the DEB (0.08 mm vs. 0.29 mm for DES; p = 0.001). The new data continue to demonstrate favorable outcomes for the IN.PACT Falcon DEB. At 1 year, the clinical outcomes of major adverse cardiac events (MACE), MI, and target lesion revascularization (TLR) were statistically similar for both devices (See Table).

"The BELLO study shows that treating de novo coronary lesions with the IN.PACT Falcon drug-eluting balloon is a viable option, with strong clinical outcomes to 1 year," according to Azeem Latib, MD, of San Raffaele Hospital and EMO-GVM Centro Cuore Columbus, Milan, Italy. "The 1-year results suggest that this novel angioplasty device should not necessarily be limited to only treating in-stent restenosis in coronary arteries." IN.PACT Falcon DEB is not commercially available in the United States.

Also at EuroPCR, investigators reported the results of the PEPCAD China ISR trial, comparing the SeQuent® Please paclitaxel-eluting balloon (B. Braun Melsungen AG; Berlin, Germany) to repeat stenting with the Taxus® Liberté™ (Boston Scientific; Natick, MA) paclitaxel-eluting stents in terms of safety.

The primary endpoint of in-segment late loss at 9 months was 0.46 ± 0.51 mm with SeQuent Please and 0.55 ± 0.61 mm with Taxus for a difference of -0.06 mm (p = 0.0005 for noninferiority). Run-Lin Gao, MD, who presented the data, said treatment with the DEB "should be a better alternative for DES restenosis than repeat implantation" by avoiding additional stent layers.

Intensive Lifestyle Intervention No Silver Bullet

A great deal of good can come from a long-term intensive lifestyle intervention program for obese patients with type 2 diabetes—just not in terms of a reduction in MI or stroke.

Data presented at the ADA annual meeting found that intensive lifestyle intervention focused on weight loss can:

  • improve physical quality of life
  • reduce microvascular complications
  • lower the risk of depression
  • lower medical costs by reducing hospitalizations, outpatient care, and medications

There was just no difference in morbidity and mortality during a follow-up of almost 10 years.

Conducted in 16 centers across the United States, Look AHEAD (Action for Health in Diabetes) involved more than 5,000 overweight or obese adults with type 2 diabetes aged 45–76 years. Participants were randomized to one of two interventions: lifestyle (involving physical activity and weight loss) or diabetes support and education (involving three counseling sessions per year on nutrition, physical activity, and social support).

The intensive lifestyle intervention was aimed at achieving and maintaining weight loss of at least 7% by focusing on reduced caloric intake and increased physical activity. Participants in the intensive lifestyle intervention group lost 8.6% of body weight and maintained a 6% loss at the end of intervention.2 The support and education group lost 0.7% of body weight initially and this had increased to 3.5% at the end of intervention.

The intervention strategy also reduced waist circumference, systolic BP, and glycated hemoglobin levels compared with the control group. Nevertheless, the intervention produced a neutral effect on CV outcomes, a finding that was consistent across all reported subgroups. Indeed, the trial was stopped early after a median follow-up of 9.6 years, when interim analyses suggested that it was very unlikely that further follow-up would yield a different result.

Rena Wing, PhD, trial chair and professor of psychiatry and human behavior at Alpert Medical School of Brown University, Providence, Rhode Island, said there were numerous possible explanations for the unexpected results, including the greater use of medications to lower LDL cholesterol in the comparison condition, which may have minimized any difference between the groups. The study cannot rule out the possibility that greater weight losses might impact CV risk.

In an editorial that accompanied the publication of the results in the New England Journal of Medicine, Hertzel C. Gerstein, MD, McMaster University, Hamilton, Ontario, said clinicians can use the results of the Look AHEAD study, as well as the group's previously published findings, to inform their care of patients with diabetes: "They can clearly assert that changes in activity and diet safely reduce weight, reduce the need for and cost of medications, reduce the rate of sleep apnea, improve well-being, and (in some cases) achieve a diabetes remission."3

With respect to CV outcomes, Dr. Gerstein wrote, clinicians can reassure their patients that intensive lifestyle interventions are unlikely to cause harm and may provide a modest benefit.


1. Birnie DH, Healey JS, Wells GA, et al. N Engl J Med. 2013;368:2084-93.
2. The Look AHEAD Research Group. N Engl J Med. 2013 July 11. [Epub ahead of print]
3. Gerstein HC. N Engl J Med. 2013 July 11. [Epub ahead of print]

Keywords: Life Style, Estradiol, Drug-Eluting Stents, Standard of Care, Risk Factors, Cholesterol, Quality of Life, Estrogens, Schools, Medical, Obesity, Diet, Death, Sudden, Cardiac, Diabetes Mellitus, Testosterone

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