Primecuts – This Week In The Journals

December 8, 2014

By Amar Parikh, MD

Peer Reviewed

This week, the nation was rocked by the decision of a Staten Island grand jury to not indict Officer Daniel Pantaleo in the death of Eric Garner, who was killed after resisting arrest for suspicion of selling “loosies”, or single cigarettes from packs. This comes on the heels of the recent decision by the grand jury in Ferguson, Missouri to not indict Officer Darren Wilson in the shooting death of unarmed black teenager Michael Brown. In cities across the nation, citizens have surged through the streets chanting Mr. Garner’s final words – “I can’t breathe” – in protest of the grand jury’s decision. The events have sparked a heated nationwide debate about the current state of race relations, police brutality, and the fairness of the criminal justice system. Here in New York, protestors have staged “die-ins” at heavily trafficked city landmarks, including the bare floor of Grand Central Station and beneath the Christmas lights of Macy’s in Herald Square [1].

Amidst the national unrest, the medical journals produced several high-impact articles this week.

Dual Antiplatelet Therapy after Drug Eluting Stents – How Long To Treat?

Each year, millions of patients worldwide receive coronary artery drug eluting stents (DES) for the treatment of ischemic heart disease. Patients with DES are commonly treated with dual antiplatelet therapy (DAPT) consisting of a thienopyridine (a P2Y12-receptor inhibitor) such as clopidogrel or prasugrel, plus aspirin for 6 months to 1 year after DES placement. Little is known, however about the risks and benefits of DAPT treatment beyond 1 year. The DAPT study published in the NEJM by Mauri et al. this week is the first adequately powered, randomized trial to address this important clinical question [2].

In their trial, 9961 patients who had received a DES and had already completed 1 year of DAPT without ischemic events, major bleeding, or repeat revascularizations were randomized to two groups. One group received an additional 18 months of DAPT with aspirin plus clopidogrel or prasugrel, while the other group received an additional 18 months of aspirin alone. The coprimary endpoints were incidence of stent thrombosis and a composite of death, MI, or stroke.

Compared to aspirin alone, DAPT resulted in a 1% absolute risk reduction of in-stent thrombosis (0.4% vs 1.4%, 95% CI 0.17-0.48, P <0.001), and a 1.6% absolute reduction in major adverse cardiac and cerebrovascular events (4.3% vs 5.9%, 95% CI, 0.59 to 0.85, P < 0.001). The rate of moderate bleeding was 0.9% higher in the DAPT group (2.5% vs 1.6%, 95% CI 1.21-2.16, P = 0.001), however severe or fatal bleeding was uncommon and the rate did not differ significantly between the study groups. At 33 month follow-up, all-cause mortality was noted to be 2.3% in the DAPT group compared to 1.8% in the aspirin-only group, although this increase may have been due, at least in part, to an imbalance in preexisting cancer (and subsequently in cancer-related mortality) in that group.

There were several limitations to the study. The first is that by selecting patients who did not have a major adverse cardiac or cebrovascular event, moderate-severe bleeding, or stent thrombosis during the first 12 months of DAPT, the study design may have selected for patients who were already at lower risk for late adverse events and therefore excluded the very patients that would have benefitted the most from DAPT. In addition, while the study accounted for four different types of DES and two different platelet P2Y12 inhibitors, it is unclear if these results can be generalized to other types of drug-eluting stents or non-thienopyridine P2Y12 inhibitors. The conclusions were that in patients with DES, adding a thienopyridine to aspirin for an additional 18 months beyond the initial 1 year of recommended treatment reduced ischemic events, yet had an increased risk of moderate bleeding and non-cardiovascular mortality. While this trial does offer additional evidence supporting the clinical benefit of DAPT, the appropriate duration of therapy remains uncertain and must still be decided for each patient based on their individual risk of bleeding and thrombosis.

HARMONIZE – Proposing A Novel Treatment For Hyperkalemia?

Hyperkalemia is a common electrolyte abnormality that remains a challenge to manage in the outpatient setting. It is particularly common in patients with CKD and heart failure, who would often stand to benefit from renin-angiontensin-aldosterone-system (RAAS) blockade. Unfortunately, use of these agents can also put the patient at even higher risk for developing hyperkalemia. Currently, the main treatment option for hyperkalemia is sodium polystrene sulfonate, commonly known as kayexalate, yet its effectiveness is uncertain and has been associated with intestinal necrosis. However, help could soon be on the horizon. In JAMA this week, Kosiborod et al. have published the results of their HARMONIZE trial, evaluating the efficacy of a novel therapeutic agent called zirconium cyclosilicate in the management of hyperkalemia [3]. Sodium zirconium cyclosilicate (also known as ZS-9) is a highly selective inorganic cation exchanger that traps potassium in the intestine.

The HARMONIZE trial was a phase 3, randomized controlled trial that enrolled ambulatory patients with a potassium of 5.1 mEq/L or greater. Exclusion criteria were dialysis requirement, diabetic ketoacidosis, and active treatment with kayexalate or lactulose, among others. 258 patients were assigned to 10 g of ZS-9 three times daily in the initial 48-hour, open-label phase. 98% of patients achieved normokalemia (3.5-5.0 mEq/L), and were then randomized to one of three daily doses of ZS-9 (5, 10, or 15g) or to placebo for 28 days. Any patient who developed hypokalemia < 3.0, hyperkalemia > 6.2, or significant arrhythmia was excluded from the study.

The primary end point was comparison of mean serum potassium levels between placebo and each of the 3 treatment groups during days 8-29 of the randomized phase. All 3 doses of the drug resulted in statistically significant lower potassium levels for up to 28 days (4.8 mEq/L, 4.5 mEq/L, and 4.4 mEq/L with 5, 10, and 15 g of ZS-9 respectively) compared with a mean of 5.1 mEq/L with placebo. Adverse events were comparable between the drug and placebo groups, though edema was noted to be more common in patients taking the highest dose (15 g) of ZS-9.

While this offers an exciting new treatment option for patients with hyperkalemia, this study only evaluated the use of this agent for 28 days, therefore the long-term effects of ZS-9 are unknown. The edema noted with higher doses of ZS-9 would also be undesirable in the patient population that would benefit most from these therapies, specifically those with proteinuric kidney disease and systolic heart failure, where edema is likely already of concern. Regardless, this study shows that zirconium cyclosilicate is a promising agent, especially given the sparse options clinicians currently have for managing this frequently encountered condition.

Screening for CAD with CT Angiography in Diabetic Patients – Is There Any Benefit?

The results of another large, clinically relevant trial were published in JAMA this week by Muhlestein et al., called the FACTOR-64 study [4]. Diabetes mellitus is the most important risk factor for coronary artery disease (CAD). Diabetic patients frequently develop aggressive but asymptomatic coronary disease, with myocardial infarction oftentimes serving as the first symptom of underlying CAD. This strongly suggests the need for an effective method of screening high-risk, asymptomatic patients for CAD. The FACTOR-64 study was a randomized clinical trial in which 900 patients with type 1 or type 2 diabetes of at least 3 to 5 years’ duration and without symptoms of CAD were randomized to CAD screening with coronary computed tomography angiography (CCTA) (n = 452) or to standard national-guidelines based optimal diabetes care (A1c < 7.0%, LDL < 100 mg/dL, SBP < 130mmHg) (n = 448). The primary outcome was a composite of all-cause mortality, nonfatal MI, or unstable angina requiring hospitalization. The secondary outcome was major ischemic cardiac events, which was a composite of CAD death, nonfatal MI, or unstable angina. Patients in the CCTA screening group who were found to have normal coronaries or only mild stenosis continued standard diabetes care. Patients with moderate stenosis underwent pharmacologic stress testing or cardiac MRI, and those with severe stenosis underwent diagnostic coronary angiography.

At a mean follow-up time of 4.0 years, the primary outcome event rates were not statistically significant between the CCTA screening and control groups (6.2% [28 events] vs. 7.6% [34 events], 95% CI 0.49-1.32; P=0.38). The incidence of the composite secondary end point of major ischemic cardiovascular events also did not differ between the groups (4.4% [20 events] vs. 3.8% [17 events], [95% CI 0.60-2.19]; P=0.68). The study concluded then that among asymptomatic patients with type 1 or 2 diabetes, screening for CAD with CCTA did not reduce the rate of all-cause mortality, nonfatal MI, or unstable angina at 4 years, and therefore, screening for CAD with CCTA in this particular patient population is not recommended.

While this can be considered a disappointing result, the authors believe that the most likely explanation was that patients in the control group had better than expected baseline medical therapy. The average LDL and blood pressure in the control group was well below targets, and the rate of major cardiac events in the control group was less than the usual 2% annual threshold used to define a patient population as high risk. Therefore, the trial may be underpowered because patients in the control group were medically managed much better than expected, and perhaps should not be classified as “high-risk” patients at all. An important take-away point is that medical management of diabetes through appropriate control of lipids and blood pressure is clearly very effective at lowering the risk of cardiovascular events in high-risk diabetic patients. Therefore, guideline-directed medical therapy in asymptomatic patients with diabetes is more important than cardiac imaging at this time.

How Does the Use of Epinephrine Impact Recovery in Patients Post-Cardiac Arrest?

Finally, we arrive at a fascinating study published in the Journal of the American College of Cardiology this week by Dumas et al. that may make us reconsider the use of a mainstay in our crash carts and ACLS algorithms – epinephrine [5]. While epinephrine is associated with a greater likelihood of return of spontaneous circulation (ROSC), the early benefit has been reported elsewhere not to translate to an increased rate of overall survival [6]. In this study that appeared in JACC, 1,556 patients with out of hospital cardiac arrest (OHCA) who achieved ROSC were subdivided into those who received epinephrine (n = 1,134) vs. no epinephrine (n = 442), and the epinephrine group was further subdivided by dose (1mg, 2 to 5mg, > 5mg). A favorable discharge outcome was coded using a Cerebral Performance Category 1 or 2, which assesses neurologic function. Only 194 of the 1134 patients (17%) who were treated with epinephrine had a favorable neurologic outcome as per the Cerebral Performance Category score versus 255 of 422 patients (63%) in the nontreated group (p < 0.001). This adverse association of epinephrine was observed regardless of length of resuscitation or subsequent in-hospital interventions performed. This poses an intriguing question of whether the use of a vasopressor agent during cardiac arrest will actually result in improved survival, not just ROSC.

Dumas et al. found the effects of epinephrine during resuscitation efforts of OHCA to be time-sensitive. When epinephrine was given within the first 9 minutes after cardiac arrest, patients had a better outcome (adjusted odds ratio [aOR]) 0.54; 95% CI 0.32 to 0.91) compared with those who received treatment between 10 and 15 minutes (aOR: 0.33; 95% CI), between 16 and 22 minutes (aOR: 0.23; 95% CI), and > 22 minutes after cardiac arrest (aOR: 0.17). There was also a dose-dependent risk of poor neurologic outcome compared to no epinephrine – 1 mg of epinephrine (aOR: 0.48), 2 to 5mg epinephrine (aOR: 0.30), and > 5 mg of epinephrine (aOR: 0.23).

The explanation proferred by the authors is that the alpha-effects of epinephrine can increase coronary and cerebral perfusion during the resuscitation period; however it may exert adverse effects during the post-recovery phase via its beta-adrenergic effects by contributing to myocardial dysfunction and increasing oxygen requirements.

However, there are several key limitations to the study. The first is that it is unknown why almost 25% of the patients who initially suffered from OHCA were not given epinephrine in the field. Second, the cohort of patients who needed epinephrine to achieve ROSC was generally older and less likely to present with a witnessed event or shockable rhythm. If the cohort of patients who received epinephrine was sicker to begin with, then that would explain why outcomes were poorer, rather than attributing it to the use of epinephrine. As a follow-on from this study, a randomized controlled trial comparing epinephrine to placebo or other vasopressors, and documenting the time to administration would provide further evidence for or against the use of epinephrine.

In other news…

A study published in the NEJM this week by Solomon et al. examined the use of crizotinib, an oral ALK inhibitor, versus intravenous chemotherapy in ALK-positive non-small-cell lung cancer [7]. Responses to crizotinib were observed in 74% of patients with an 11-month median duration of response compared to a 45% response rate and a 7-month median duration of response with chemotherapy. These promising results are being compared to the impact that imatinib had on the treatment of CML, and by targeting the specific genetic markers of particular tumor subgroups, this may signal a sea change in the way we choose to fight cancer.

With all the recent attention on Ebola, another dangerous virus that has wreaked havoc in Africa, India, and now the Caribbean has slipped under the radar – Chikungunya. A recent study published this week in The Lancet assessed the safety of a new candidate vaccine called the chikungunya virus-like particle (VPL) vaccine, and found it to be immunogenic, safe, and well tolerated [8]. This study represents a critical step in fighting this rapidly spreading global pathogen.

Finally, statins continue to be the subject of studies evaluating their novel use outside of lipid management, with a recent study in JAMA Internal Medicine looking at its potential role in reducing the risk of fractures [9]. Unfortunately, the study showed that among patients enrolled in the large-scale JUPITER trial that received rosuvastatin therapy for cardiovascular disease, statin therapy did not reduce the risk of fracture.

Dr. Amar Parikh is a 1st year resident at NYU Langone Medical Center.

Peer Reviewed by Cilian J. White, M.D., Internal Medicine Resident, NYU Langone Medical Center.

Image courtesy of NBC News.


1. Jaffre, A. Obama: ‘Too many Americans feel deep unfairness’. CNN Online. 4 Dec 2014.

2. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents. N Engl J Med. 2014;371:2155-2166. December 4, 2014.

3. Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients With Hyperkalemia: The HARMONIZE Randomized Clinical Trial. JAMA. 2014;312(21):2223-2233.

4. Muhlestein JB, Lappé DL, Lima JC, et al. Effect of Screening for Coronary Artery Disease Using CT Angiography on Mortality and Cardiac Events in High-Risk Patients With Diabetes: The FACTOR-64 Randomized Clinical Trial. JAMA. 2014;312(21):2234-2243.

5. Dumas F, Bougouin W, Geri G, et al. Is Epinephrine During Cardiac Arrest Associated With Worse Outcomes in Resuscitated Patients? JACC. 2014;64:2360-2367.

6. Hagihara AM. Hasegawa T, Abe T et al. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA. 2012;307:1161–1168.

7. Solomon BJ, Mok T, Kim D-W, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167-2177.

8. Chang LJ, Dowd KA, Mendoza FH, et al. Safety and tolerability of chikungunya virus-like particle vaccine in healthy adults: a phase 1 dose-escalation trial. The Lancet. 2014;384:2046-2052.

9. Peña JM, Aspberg S, MacFadyen J, et al. Statin Therapy and Risk of Fracture: Results From the JUPITER Randomized Clinical Trial. JAMA Intern Med. Published online December 01, 2014.