JACC in a Flash
Featured topics in the current and recent issues of the JACC family of journals

ROCKET AF Reinforces ‘Right Drug for Right Patient’

Gastrointestinal (GI) bleeding is more common when taking rivaroxaban compared with warfarin, but the absolute fatality from bleeding was low with both drugs, according to a new study published in JACC.

Gastrointestinal bleeding is a common complication of oral anticoagulants, occurring in 1%-3% of patients on chromic oral anticoagulant therapy. The management of oral anticoagulants and gastrointestinal bleeding is controversial and there is no established optimal therapy.

The ROCKET AF trial examined rivaroxaban vs. warfarin and found rivaroxaban to be noninferior to warfarin for the prevention of stroke and systemic embolism, while rates of major and non-major clinically relevant bleeding were similar between the two drugs. Patients taking rivaroxaban experienced more gastrointestinal bleeding. The current analysis aimed to investigate the incidence and severity of gastrointestinal bleeding, the factors associated with gastrointestinal bleeding, and antithrombotic management of gastrointestinal bleeding through the ROCKET AF trial.

A total of 14,236 patients were enrolled in the ROCKET AF trial and 684 patients had major and non-major clinically relevant gastrointestinal bleeds during follow-up. Of the patients experiencing gastrointestinal bleeds, 290 (42%) were on warfarin and 394 (58%) were on rivaroxaban. Patients with gastrointestinal bleeding were more often male and slightly older (median age = 75 vs. 73 years). Patients with gastrointestinal bleeding were more likely to have a history of it.

Of the gastrointestinal bleeds, 48% were in the upper gastrointestinal tract, 23% in the lower tract, and 29% in rectal locations. These frequencies were similar between patients taking warfarin and rivaroxaban.

There were significantly more gastrointestinal bleeds in patients treated with rivaroxaban compared with those treated with warfarin (3.61 vs. 2.60 events/100 patient-years; hazard ratio 1.42; 95% confidence interval 1.22-1.66). When separated by clinical severity, patients treated with rivaroxaban experienced more major and non-major clinically relevant gastrointestinal bleeding events. For the most severe bleeds, no statistically significant difference was detected between the groups. There was a very low absolute rate of fatal gastrointestinal bleeding, occurring in one patient treated with rivaroxaban and five patients treated with warfarin. The proportion of patients experiencing fatal or severe bleeding was low and similar between the two patient groups.

Aside from rivaroxaban use vs. warfarin use, the factors most strongly associated with gastrointestinal bleeding were anemia at baseline, a history of gastrointestinal bleeding, and chronic aspirin use.

The authors, led by Matthew W. Sherwood, MD, MHS, FACC, concluded that their findings “further highlight the importance of the risk-and-benefit consideration of oral anticoagulants in patients at risk for gastrointestinal bleeding and illustrate the need for minimizing modifiable risk factors for gastrointestinal bleeds.”

In an editorial comment accompanying the paper, Gregory Y.H. Lip, MD, FACC, and Deirdre A. Lane, PhD, wrote: “Notwithstanding the issues with [gastrointestinal] bleeding, we should not forget that overall the non-vitamin K antagonist (VKA) oral anticoagulants have changed the landscape for stroke prevention in atrial fibrillation (Afib). These drugs offer relative efficacy, safety, and convenience compared to the VKAs, and given the availability of various drugs as well as VKAs (assuming good therapeutic time in range), we are nowadays spoilt for choice, and have the opportunity to fit the drug to various patient characteristics. Even a single additional stroke risk factor confers a real increased risk of stroke and mortality that is significantly reduced by oral anticoagulants. [...] Thus, rather than a categorical approach to stroke risk stratification and treatment decisions, the initial step should be to identify those at ‘low risk’ (i.e. CHAD2DS2-VASc 0 in males, 1 in females) who do not need any antithrombotic therapy. The second step should then be to offer effective stroke prevention, which is oral anticoagulants, to those AFib patients with ≥ 1 additional stroke risk factors. Only such a proactive approach will help reduce the burden of stroke associated with this common arrhythmia.”

Sherwood MW, Nessel CC, Hellkamp AS, et al. J Am Coll Cardiol. 2015;doi:10.1016/ j.jacc.2015.09.024.

Transfusion Confusion: Hemoglobin Level and Hospital Mortality

In some critically ill patients, red blood cell transfusions can lead to reduced hospital mortality, according to a recent study published in JACC. Specifically, this benefit was found in patients with hemoglobin (Hgb) levels below 8 to 9 g/dl and 9 to 10 g/dl in patients with acute myocardial infarction (AMI).

Hbg level thresholds are used to determine red blood cell transfusion practices. In this study, Yew Y. Ding, MBBS, MPH, and colleagues hoped to determine the Hbg level below which transfusion is associated with reduced hospital mortality across key cardiac conditions.

The authors performed a secondary analysis of 258,826 Veterans Affairs (VA) intensive care unit (ICU) episodes over a 5-year period. A total of 30,086 (11.6%) hospital deaths occurred and transfusion was documented in 32,097 (12.4%) of episodes during the first 30 days of ICU admission. Those who died in the hospital were older, had lower Hgb, were more likely to have heart disease and most other comorbidities, and stayed longer in the ICU. They were also almost twice as likely to have received transfusion during the first 30 days of ICU admission.

In the total cohort, the odds ratio (OR) for the interaction between blood transfusion and Hgb was 1.22 (95% confidence interval [CI]: 1.20 to 1.25), which indicated that for each 1 g/dl increase in Hgb, transfusion was associated with a 22% increase in the odds of hospital mortality. Lower hospital mortality was associated with transfusion at lower Hgb levels. The ORs for comorbid heart disease and AMI diagnosis at ICU admission were 0.82 (95% CIL 0.76 to 0.88) and 0.78 (95% CI: 0.69 to 0.88) respectively, showing that transfusion was associated with lower hospital mortality when these two conditions were present. “In other words,” the authors wrote, “for any given Hgb, benefit associated with transfusion was greater when there was comorbid heart disease or when admitted to ICU for AMI.” These differences in benefits were not seen when unstable angina or congestive heart failure were present. Mortality decreased with higher Hgb for both patients who received transfusion and those who did not.

Through these findings, the authors determined that 7 to 8 g/dl is the Hbg level below which transfusion is associated with reduced hospital mortality.

The authors noted that certain conditions could lead to different transfusion decisions. “Suggested transfusion thresholds, at best, serve as a general guide and physicians should look beyond them for more complex patients with advanced age, multimorbidity, or frailty in addition to their cardiac illnesses,” they wrote. “For them, transfusion decisions are best guided by considered clinical judgement at the bedside.”

In an accompanying editorial comment, Sunil V. Rao, MD, FACC, and Amit N. Vora, MD, MPH, discussed the study, noting that “Ding and colleagues provide additional insight into differential transfusion thresholds in the presences of cardiac disease.” They added that the “analysis adds to a remarkably consistent body of knowledge. [...] Describing the hazard of blood transfusion in critically ill patients and a higher transfusion threshold among patients presenting with AMI.”

Rao and Vora also discussed the use of the principle component analysis technique by the researchers. In the end, they concluded that “the way forward may be a combination of approaches: utilizing novel statistical techniques in observational databases to glean additional insights while incorporating recent advances in clinical trial methodology to design a simple, pragmatic trial to determine the optimal transfusion strategy among AMI patients.”

Ding YY, Kader B, Christiansen CL, et al. J Am Coll Cardiol. 2015;doi:10.1016/ j.jacc.2015.09.056.

Medical Therapy or Revascularization for Ischemia? For Now, No Resolution to the Debate

A new review paper published in JACC examined the debate over the treatment of patients with stable ischemic heart disease (SIHD) and whether it is better to treat these patients with guideline-directed medical therapy or medical therapy revascularization.

Clinical practice guidelines and appropriate use criteria (AUC) endorse guideline-directed medical therapy for all SIHD patients, but also recommend the consideration of revascularization in patients with significant ischemia or symptoms that continue even with medical therapy. There are strong opinions on all sides of the revascularization debate. Gregg W. Stone, MD, FACC, and colleagues look at the evidence for routine revascularization with medical therapy vs. medical therapy alone and encourage readers to be open to the opinions that are the opposite of their own.

First, the authors present the case for routine revascularization in patients with SIHD and ischemia. Revascularization may prevent death, MI, unstable angina, and may improve quality of life. Observational studies have shown a strong relationship between the extent of ischemia and subsequent death and/or MI, with a possible benefit from revascularization. One analysis found that 2-year rates of cardiac death were lower with revascularization within 60 days in patients with moderate to severe ischemia and other studies have found revascularization to be associated with improved survival, and one even found this benefit in patients aged 75 and older. Additional studies have also found revascularization to be safe. The authors noted that most trials comparing medical therapy with percutaneous coronary intervention (PCI) used bare-metal stents (BMS), but first-generation drug-eluting stents (DES) have been shown to reduce recurrent ischemia compared with BMS. These outcomes may improve in second-generation DES. There is also evidence of poorer outcomes in patients treated only with medical therapy. Notably, the FAME 2 trial was halted due to an excess of events in the medical therapy arm of the study. Finally, the authors noted that the cost and inconvenience of taking medications may lead to a preference for revascularization. Many patients also prefer the immediate reduction in symptoms that comes with revascularization. Finally, surgery may serve as a “wake-up call” to patients, leading to greater medication compliance.

Next, the authors discussed the evidence supporting guideline-directed medical therapy for patients with SIHD and ischemia, which they wrote should be initiated in all patients regardless of whether or not revascularization is performed. Risk-factor control through lifestyle and pharmacological interventions is associated with a 50% reduction in mortality over 5 years in SIHD patients with diabetes. Adherence has been shown to be suboptimal after revascularization, which must be improved. Studies have shown that the extent of ischemia is not related to death and MI in the era of contemporary guideline-directed medical therapy. There have also been trials suggesting revascularization does not reduce death or MI, even with ischemia, and does not improve quality of life. In COURAGE, there was no difference between the two groups for rates of death or MI and in BAR 2D, 5-year survival rates for patients with type 2 diabetes did not differ between revascularization and medical therapy. It is also important to consider the cost-effectiveness of routine revascularization in SIHD. If it does not reduce death or MI when added to medical therapy, it is hard to justify the cost for patients with mild or no symptoms. Finally, patients should be educated regarding the potential risk of undergoing versus not undergoing revascularization so that they can make an informed choice.

The authors wrote that “the optimal approach to patients with SIHD remains unsettled because all prior randomized trials, either by design or execution, have limitations.” For example, different COURAGE nuclear substudy results can be used to support either routine revascularization or a more conservative approach. When there is conflicting data, meta-analysis can often be used to provide a consensus. However, there may be varying results of meta-analyses depending on the variables of the included studies.

The authors also noted that current U.S. and European guidelines differ regarding the strength of evidence for revascularization, although they both emphasize the importance of medical therapy. Strong arguments can be made for either approach, which stresses the importance of shared decision making between the physicians and patient. Currently, there is a state of “community equipoise,” with only 35% to 65% of SIHD patients with moderate or severe ischemia undergoing cardiac catheterization within 90 days.

Stone and colleagues concluded the paper by examining the ongoing ISCHEMIA trial, which aims to determine whether an initial invasive strategy of cardiac catheterization and optimal revascularization plus guideline-directed medical therapy will reduce cardiovascular death or nonfatal MI in SIHD patients with moderate or severe ischemia compared with medical therapy alone. Angina-related quality of life is the major secondary endpoint of the trial. Patients with advance chronic kidney disease are randomized in a parallel substudy. Enrollment began in 2012 and is expected to end in 2017 with an average follow-up of 3 years. There are currently about 300 participating sites in 30 countries. ISCHEMIA aims to address limitation of previous trials by: 1) enrolling patients before catheterization so as not to exclude high-risk patients; 2) reenrolling a higher-risk group with moderate ischemia; 3) minimizing crossovers; 4) using contemporary DES and physiological-guided decision making to achieve ischemic (rather than anatomic) revascularization; and 5) being adequately powered in order to show whether routine revascularization reduces cardiovascular death or nonfatal MI in SIHD patients with at least moderate ischemia. These results will be important regarding guidelines for revascularization for SIHD.

Looking ahead, Stone and colleagues recommended that primary care providers, cardiologists, and cardiac surgeons around the world “enthusiastically support enrollment of their patients” into ISCHEMIA in order to “provide much needed prospective evidence to inform the optimal management of patients with SIHD, substantial myocardial ischemia, and angina symptoms that are controlled or absent.”

Stone GW, Hochman JS, Williams DO, et al. J Am Coll Cardiol. 2015;doi:10.1016/j.jacc.2015.09.057

Clinical Topics: Anticoagulation Management

Keywords: Anticoagulants, Embolism, Erythrocyte Transfusion, Hemoglobins, Hemorrhage, Hospital Mortality, Myocardial Infarction, Stroke, Warfarin, CardioSource WorldNews

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