Primecuts-This Week in the Journals

July 2, 2012

Alexander Volodarskiy, MD

With every new summer come hotter days, shorter nights, and the inevitable medical metamorphosis on July 1st: senior residents finally graduating and nervous, bright-eyed, bushy-tailed new interns, hearts in hand, arriving to save lives. With them in mind, we jump into this week’s section of Prime Cuts.

In this week’s New England Journal of Medicine, Kang et al. looked at whether patients with left-sided infective endocarditis could benefit from early surgery.[1,2] The study excluded patients with small vegetations (≤10 mm), right-sided vegetations, prosthetic valves, heart block, and moderate-to-severe congestive heart failure. Seventy-six patients in South Korea were randomized to either an early surgical group (37 patients scheduled to undergo surgery within 48 hours) or a conventional treatment group (39 patients). In the end, all of the patients in the early surgical group and 30 of 39 patients in the conventional group underwent surgery, but the results were markedly different. Only 3% of the early surgery group reached the primary end point of death or embolic event compared to 25% in the conventional group. This was largely driven by the large number of embolic events in the conventional group; the mortality difference was not statistically significant between the two groups. The findings of this study underscore the importance of early surgery for reducing morbidity of left-sided native valve endocarditis.

While endocarditis is a risk factor for cerebral embolic phenomena, it is far from the only factor. A JAMA study by Xian et al. looked at the risk of intracranial hemorrhage in patients receiving warfarin who are also given intravenous tissue plasminogen activator (TPA) for acute ischemic stroke.[3] They used data from the American Heart Association “Get with the Guidelines” Registry to identify 1,802 patients with pre-admission warfarin use and INR less than 1.7 who were treated with TPA and compared them to 21,635 controls that received TPA but were not on warfarin. Patients in the warfarin group were older (74.1 vs. 69.5 years old), had more comorbidities (atrial fibrillation, prosthetic valves, prior strokes or transient ischemic attacks, and peripheral vascular disease) and had more severe strokes. When evaluated for the primary outcome of symptomatic intracranial hemorrhage, the warfarin group had seemingly worse outcomes with a crude odds ratio of 1.22, although the 95% CI (0.99-1.51) included the null value of 1.0. However, when the groups were adjusted for the comorbidities, the two groups fared fairly equally with an adjusted odds ratio of only 1.01 (0.82-1.25). There results imply that TPA should be considered in all patients who meet criteria, regardless of their warfarin exposure, as long as their INR is less than 1.7.

A related article in The Lancet by Zinkstok and Roos looked at whether early administration of aspirin in patients treated with TPA may decrease the risk of re-occlusion after TPA-induced recanalization. [4,5] The study recruited 642 patients in the Netherlands who were randomized in an open label manner (but with blinded end point assessment) to an early aspirin group receiving 300 mg of IV aspirin within 90 minutes of TPA (322 patients) or a standard group receiving standard of care anti-platelet therapy 24 hours later. The primary end point was a favorable outcome at 3 months defined as a score of 0-2 on a modified Rankin scale, which is commonly used for measuring the degree of disability. A score of 0 means the patient has no symptoms, while a score of 2 indicates slight disability but the patient is still able to perform all ADLs and IADLs independently.

Unfortunately, the trial was terminated prematurely because of an excess of symptomatic intracranial hemorrhage and no evidence of benefit in the aspirin group. At 3 months there were 78 patients lost to follow up and 174 (54%) patients in the early aspirin group versus 183 (57%) patients in the standard treatment group had a favorable outcome, a result that wasn’t statistically significant. On the other hand, the early aspirin group had 14 (4.3%) episodes of symptomatic intracranial hemorrhage compared to 5 (1.6%) in the standard treatment group, a significant difference and the biggest reason for poor outcomes in the early aspirin group. These results suggest that we should continue to hold off for 24 hours before giving stroke patients aspirin after TPA administration.

While strokes are a significant source of morbidity and mortality in the elderly, Perissinotto et al. looked at another risk factor we don’t always consider – loneliness.[6] The investigators followed a cohort of 1,604 mostly Caucasian adults with a mean age of 71 years with a baseline and follow-up assessments every 2 years. At each visit, the investigators asked the study participants if they felt left out, isolated, or lacked companionship. Participants were then categorized as “not lonely” if they responded hardly ever to all 3 questions and “lonely” if they responded some of the time or often to any of the 3 questions. The investigators then looked at the primary outcome of time to death over 6 years and functional decline over 6 years on the following 4 measures:

• difficulty in an increased number of ADLs

• difficulty in an increased number of upper extremity tasks

• decline in mobility

• increased difficulty in stair climbing

The study found that while 18% of the participants lived alone, 43% reported feeling lonely. In fact, the majority of lonely persons lived with someone. And while lonely subjects were more likely to be depressed (37.5 v. 10.8%), most lonely subjects were not depressed (62.5%). The investigators found that over a 6-year follow-up period, loneliness was associated with an increased risk of death (22.8% v. 14.2%). Even when adjusted for confounders, including illness severity and depression, the adjusted hazard ratio was 1.45. Similarly, there was a decline in ability to perform ADLs (24.8% v. 12.5%; adjusted risk ratio of 1.59), difficulties with upper extremity tasks (41.5% v. 28.3%; adjusted risk ratio of 1.28), decline in mobility (38.1% v. 29.4%; adjusted risk ratio of 1.18) and difficulty in climbing stairs (40.8% v. 27.9%; adjusted risk ratio of 1.31). Although the mechanisms outlining the association between loneliness and health outcomes cannot be elucidated from an observation study such as this one, this study underscores the importance of recognizing it as a substantial risk in the elderly.

So, as we plunge into the next academic year, please remember, elderly or not, no patient or colleague should be left alone and if you see someone struggling, please lend a helping hand.

Alexander Volodarskiy, MD is a 3rd year resident at NYU Langone Medical Center

Peer Reviewed by Ishmeal Bradley, MD Section Editor, Clinical Correlations


1. Kang D-H, Kim Y-J, Kim S-H, et al. Early Surgery versus Conventional Treatment for Infective Endocarditis. New England Journal of Medicine 2012;366:2466-73.

2. Gordon SM, Pettersson GB. Native-Valve Infective Endocarditis — When Does It Require Surgery? New England Journal of Medicine 2012;366:2519-21.

3. Xian Y LLSEE, et al. Risks of intracranial hemorrhage among patients with acute ischemic stroke receiving warfarin and treated with intravenous tissue plasminogen activator. JAMA: The Journal of the American Medical Association 2012;307:2600-8.

4. Zinkstok SM, Roos YB. Early administration of aspirin in patients treated with alteplase for acute ischaemic stroke: a randomised controlled trial. The Lancet 2012.

5. Parsons MW, Levi CR. Reperfusion trials for acute ischaemic stroke. The Lancet 2012.

6. Perissinotto Cm SCICKE. Loneliness in older persons: A predictor of functional decline and death. Archives of internal medicine 2012:1-7.