Primecuts – This Week In The Journals

July 11, 2016

dallasBy Amar Parikh, MD

Peer Reviewed

Just days after the United States celebrated its 240th birthday, the nation was devastated by the tragic deaths of two young black men and five Dallas police officers amidst the country’s ongoing struggle over race relations. Alton Sterling was shot to death in Baton Rouge, Louisiana during an encounter with two police officers, while Philando Castile was killed in Falcon Heights, Minnesota during a routine stop for a broken taillight. The grisly footage of both their deaths was widely shared on social media, spreading rapidly across the nation and sparking outrage over police brutality. During subsequent protests in Dallas, snipers killed five police officers, making it the deadliest assault on US law enforcement since the 9/11 terrorist attacks. These horrific events continue to expose deep-seated issues with racism, gun control, and justice in our country, and have ignited a heated debate on the state of race relations in America.

As we mourn those who lost their lives and contemplate the future of our embattled nation, we turn now to the medical journals to draw optimism from the most recent advances in the literature this week.

Is Ticagrelor More Effective Than Aspirin in the Prevention of Recurrent Stroke or Transient Ischemic Attack?

In patients who suffer from ischemic stroke or transient ischemic attack, the risk of recurrent ischemic events in the first 90 days afterwards is notably high at approximately 10-15%. Patients are frequently placed on antiplatelet therapy such as aspirin for secondary stroke prevention, however its efficacy is limited and is associated with an increased risk of hemorrhage. Ticagrelor (trade name Brilinta) is a potent P2Y12 receptor inhibitor similar in mechanism of action to clopidogrel, however it has the advantage of not being limited by variable metabolic activation, a key drawback to clopidogrel. In the SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes), investigators compared ticagrelor with aspirin for the prevention of recurrent cerebrovascular events in patients over a period of 90 days after presenting with acute cerebral ischemia [1].

SOCRATES was a multicenter, randomized, double-blinded trial that randomized 13,199 patients to receive ticagrelor versus aspirin therapy. Patients were randomly assigned within 24 hours of symptom onset to ticagrelor or aspirin with appropriate loading and maintenance doses of each for 90 days. The primary end point was time from randomization to first occurrence of stroke (ischemic or hemorrhagic), myocardial infarction, or death. Primary end-point events occurred in 442 of the 6589 patients (6.7%) in the ticagrelor group and in 497 of the 6610 patients (7.5%) in the aspirin group (hazard ratio 0.89; 9% CI 0.78 to 1.01; P = 0.07). The authors concluded that ticagrelor did not reduce the recurrence of major cardiovascular events in the first 90 days compared to aspirin therapy. In regards to safety, similar rates of major bleeding occurred in both the ticagrelor group (31 patients, 0.5%) and in the aspirin group (38 patients, 0.6%), demonstrating that the more potent P2Y12 inhibitor did not lead to an increased risk of bleeding. Interestingly, however, about a third of the enrolled patients were already taking aspirin at the time of initial presentation and subsequent randomization to the ticagrelor group, and were therefore briefly on short-term dual antiplatelet therapy. Subgroup analysis showed that the rates of ischemic stroke were lower in these patients, though this was not statistically significant. This does, however, suggest a possible benefit of combination therapy with aspirin and ticagrelor that may warrant further study. Regardless, it is evident that determining the optimal antiplatelet agent for secondary stroke prevention remains an unsettled question.

How Do Palliative Care Interventions in the Patient with Chronic Critical Illness Impact the Psychological Health of Family Surrogates?

Patients with chronic critical illness are a uniquely challenging population, and are defined as those suffering from acute illness requiring prolonged mechanical ventilation but neither recover or die within days to weeks [2]. Surrogate decision makers for these patients grapple with highly challenging choices about whether to continue life-prolonging treatments given their uncertain outcomes. Faced with the burden of having to make such difficult decisions, surrogate decision makers and family members often experience symptoms of anxiety, depression, and post-traumatic stress disorder in the months following a family member’s stay to the intensive care unit. Given the importance of communication regarding prognosis and goals of care between health care providers and family members for these tenuous patients, investigators sought to determine whether family meetings led by palliative care specialists had any impact on reducing symptoms of anxiety and depression in family members compared to routine support by primary ICU teams.

In a fascinating and innovative study published in JAMA, a multicenter randomized clinical trial was conducted where 256 patients with 365 surrogate decision makers were enrolled and randomized to intervention and control groups. The intervention group included two structured conversations delivered by palliative care-trained consultants that focused on providing information regarding prognosis, emotional support, and discussing the patient’s values and preferences. The surrogates in the control group received “usual care” which included an informational brochure and family meetings conducted by primary ICU teams. The primary outcome was a measure of surrogates’ symptoms of depression and anxiety 3 months after the patient’s hospitalization based on the Hospital Anxiety and Depression Scale (HADS). The results of the study were surprising – the investigators observed no difference between groups for surrogates’ symptoms of depression and anxiety at 3-month follow-up, as the mean score measured by HADS in the intervention group was 12.2 compared to 11.4 in the control group (95% CI, [-0.9 to 2.6]; P = 0.34). Perhaps most unexpectedly, the intervention was found to have actually increased surrogates’ posttraumatic stress symptoms at 3-month follow-up.

The authors offer several explanations for these results. They theorize that the direct and honest focus on poor prognosis may have been emotionally traumatic for surrogates and possibly increased their risk of developing PTSD symptoms. They also point out that the intervention sessions may have been limited as palliative care teams led them exclusively without direct participation by ICU clinicians, potentially creating discordance in communication as compared to a more integrated intervention. Another consideration is that the ‘dose’ of the intervention, on average 1.4 intervention sessions per participant, was too small to affect the surrogates’ mental health or their decision-making regarding life-prolonging therapies. This is a landmark study, as it is the first multicenter randomized trial examining palliative care-led support interventions for surrogate decision makers of patients with chronic critical illness, and while it does not support routine palliative-care led discussions of goals of care for all families of these patients, it does show with striking clarity that developing support interventions for surrogates of ICU patients is a vital area of further research.

Is dexmedetomidine the best therapy for agitation after haloperidol?

The use of dexmedetomidine (precedex) as a sedative for intubated patients with hyperactive delirium is very common in the ICU setting – it has impressive sedative, analgesic, and anxiolytic effects with a reduced risk of respiratory depression, and is easily titratable with minimal drug interaction. However, in nonintubated ICU patients suffering from agitation, its use is less established. Haloperidol is the most commonly used agent to manage agitation, however guidelines are less clear about the drug of choice when haloperidol is contraindicated or fails at high doses.

In the past issue of Critical Care Medicine, investigators published the first known study examining the efficacy and safety of dexmedetomidine to treat agitated delirium refractory to haloperidol in nonintubated patients [3]. The investigators intended to design the study as a controlled, randomized, double-blinded trial comparing haloperidol, dexmedetomidine, and placebo, however the Hospital Committee on Bioethics and Human Research did not authorize this approach on ethical grounds, as dexmedetomidine is only approved for cases where haloperidol has already failed. As a result, the investigators were forced to switch to a nonrandomized, controlled design where dexmedetomidine was used only after failure of haloperidol. 132 patients met inclusion criteria (nonintubated patients with a RASS score between +1 to +4 points and prominent scores on several ICU delirium scoring systems including CAM-ICU and Intensive Care Delirium Screening Checklist [ICDSC]), and all patients initially received IV haloperidol boluses. 86 patients responded to haloperidol with a subsequent RASS of 0 to -3, while 46 patients were classified as non-responders that then received infusions of dexmedetomidine. The primary endpoint was time to satisfactory sedation – dexmedetomidine achieved 33.4% more time in adequate sedation than haloperidol. Importantly, due to the added analgesic benefit of dexmedetomidine, patients received six times less morphine than those treated with haloperidol, reducing the potential exacerbation of delirium by additional opioids. The primary safety endpoint was oversedation, however no patients treated with dexmedetomidine suffered from this, in contrast to the haloperidol group where sedation had to be suspended in 10 patients and managed with noninvasive ventilation. The incidence of other side effects, such as bradycardia associated with dexmedetomidine and QTc prolongation with haloperidol, was low and did not reach statistically significant differences between the two groups.

Finally, although dexmedetomidine is 17 times more expensive than haloperidol, a cost-benefit analysis showed that patients treated with dexmedetomidine had a markedly reduced length of stay in the ICU as compared to haloperidol, resulting in mean savings of $4,370 per patient. While the data supporting more widespread use of dexmedetomidine is very encouraging from an efficacy, safety, and monetary perspective, the authors were unable to perform a randomized, controlled, double-blinded trial due to ethical constraints, which would have been the gold standard. A larger, appropriately designed, and ethically acceptable trial evaluating the use of dexmedetomidine in agitated, nonintubated patients is merited to further explore these very promising initial results.


Supporting pioneering claims made by our very own Dr. Martin Blaser in his recent book Missing Microbes, a study published in Gastroenterology found that the administration of antibiotics to children before the age of 2 increased their risk of childhood obesity [4, 5]. This adds to the growing body of evidence demonstrating that early, frequent administration of antibiotics during childhood development increases the risk of obesity and autoimmune disease through their impact on the human microbiome.

A recent study in JAMA Internal Medicine compared patterns of end-of-life-care and family-rated quality of care for patients dying with different critical illnesses. Perhaps not unexpectedly, family-reported quality of end-of-life care was significantly better for patients with cancer and those with dementia than for patients with end-stage-renal-disease, cardiopulmonary failure, or frailty [6]. This emphasizes the need for clinicians to better recognize the importance of appropriate end-life-of-care for patients with all serious illnesses.

In a study published in the Journal of the American College of Cardiology called EARLY-BAMI, investigators examined the impact of intravenous beta-blockers before primary percutaneous intervention (PPCI) on infarct size and clinical outcomes in patients presenting with STEMI [7]. Early IV metoprolol before PPCI was not associated with a reduction in infarct size, though it did decrease the incidence of malignant arrhythmias.

Dr. Amar Parikh is a 3rd year internal medicine resident at NYU Langone Medical Center. 

Peer reviewed by Dr. Kerrilynn Carney, chief resident of internal medicine at NYU Langone Medical Center 

Image courtesy of 


  1. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack. N Engl J Med. 2016; 375: 35-43. DOI: 10.1056/NEJMoa1603060
  2. Carson SS, Cox CE, Wallenstein S, et al. Effect of Palliative Care–Led Meetings for Families of Patients With Chronic Critical Illness: A Randomized Clinical Trial. JAMA. 2016;316(1):51-62. doi:10.1001/jama.2016.8474.
  3. Carrasco G, Baeza N, Cabre, L, et al. Dexmedetomidine for the Treatment of Hyperactive Delirium Refractory to Haloperidol in Nonintubated ICU Patients: A Nonrandomized Controlled Trial. Critical Care Medicine. 2016:44 (7): 1295-1306
  4. Blaser, Martin J., MD. “Modern Plagues”. Missing Microbes. New York: Picador, 2014
  5. Scott FI, Horton DB, Mamtani R, et al. Administration of Antibiotics Before Age 2 Years Increases Risk for Childhood Obesity. Gastroenterology. 2016:151(1): 120-129
  6. Wachterman MW, Pilver C, Smith D, Ersek M, Lipsitz SR, Keating NL. Quality of End-of-Life Care Provided to Patients With Different Serious Illnesses. JAMA Intern Med. Published online June 26, 2016. doi:10.1001/jamainternmed.2016.1200.
  7. Roolvink V, Ibáñez B, Ottervanger JP, et al. Early intravenous beta-blockers in patients with ST-segment elevation myocardial infarction before primary percutaneous coronary Intervention. J Am Coll Cardiol, 67 (2016), pp. 2705–2715