By Ian Henderson, MD
Peer Reviewed
This past Tuesday The 2015 NCAA College Basketball tournament began. The yearly event, always filled with bracket busting upsets and edge-of-your-seat buzzer beaters, normally stars players and coaches. During the first round matchup between number 14 seed Georgia State and 3 seed Baylor, it was a seat that stole the show(1). This wasn’t a seat bolted to the floor in the stands but rather a stool with four wheels on it. Georgia State coach Ron Hunter, after an Achilles tendon injury he sustained while celebrating a previous victory, patrolled the sideline in his cast from the stool. Hunter and the seat became the center of attention when they went tumbling over on the court after Hunter’s son RJ Hunter hit a three to upset Baylor. The moment was more than another comical celebration and viral sensation. The moment beautiful summed up what is so special this time of the year, the excitement of watching and coaching your son hit an upset winning three point shot, is the staple of March Madness.
Revascularization Method in Multivessel CAD
The generally preferred revascularization method for patients with multivessel coronary artery disease (CAD) is coronary artery by-pass graft surgery (CABG) due it’s proven long term mortality benefit (2-5). This recommendation, however, is based on trials done before the advent of second generation drug eluting stents (DES). These newer stents not only contain different drugs but are also by nature of their design less thrombogenic and pro-inflammatory, leading to a lower rate of stent thrombosis, MI, and death compared to first generation DES.
In a observational registry-based study, Bangalore, et al.(6) compared revascularization with an everolimus-eluting second generation DES (esDES) to CABG in patients with multivessel CAD, defined as > 70% in at least 2 epicardial coronary arteries. The study included a total of 18,446 patients with multivessel CAD who underwent revascularization and the primary outcome was all cause mortality. Secondary outcomes included MI, stroke, and repeat revascularization. After a mean follow-up of 2.9 years?, PCI with esDES was associated with a similar risk of death as CABG (HR 1.04, CI 0.93-1.17, P=0.5). In a subgroup analysis of diabetics, a group in which CABG is traditionally favored, the risk remained the same. Patient’s undergoing PCI had a higher risk of initial MI than CABG (HR 1.51, P<0.001), but had a lower risk of stroke (HR 0.62, P<0.001). When looked further, it was found that the increased risk of MI was only statically significant for patient who did not have complete revascularization with PCI.
This study, though observational in nature, suggests that PCI with esDES may be equivalent to CABG in terms of long term mortality. The increased risk of MI with PCI appears to only occur when complete revascularization is not achieved. When complete revascularization is possible with PCI, it may be an equivalent option to CABG and offers patients with multivessel CAD a less invasive, yet equally effective treatment. Given the observational nature of this study, further randomized data is needed to change guideline recommendations.
Treatment of Severe Sepsis: to follow protocol or not?
Mortality from severe sepsis and septic shock has significantly decreased over the past decade, from 46.5% in the control arm of the Rivers, et al. trial of 2001(7), to 28.3% in the 2012 Surviving Sepsis Campaign (SSC) study(8). The decrease in mortality may be from institution of the SSC guidelines, based on Rivers, et al.’s early goal directed therapy (EGDT) strategy. In the decade since River’s landmark study, there have been many changes to the management of sepsis. To address the question of whether a full EGDT protocol is still necessary, a group of investigators designed three studies comparing usual care in that region to an EGDT protocol based strategy.
In the third of these studies, which was completed in England, Mouncey et al.(9) enrolled 1260 patients with severe sepsis or septic shock, which defined as known or proven infection, two or more SIRS criteria, and refractory hypotension. The primary outcome of the study was all cause mortality at 90 days. The patients were randomized to the usual group received treatment at the discretion of the treating physician for the initial 6 hours whereas patient’s in the EGDT group received treatment per SSC guidelines for the initial 6 hours. Treatment after the initial 6 hours was at the discretion of the treating physician. Mortality at 90 days did not significantly differ amount the two treatment groups (RR 1.01, CI 0.85-1.2, P=0.90). In the EGDT group, patients received more central venous lines, more RBC transfusions, a larger median volume of intravenous fluids, as well as more frequent treatment with vasopressors or inotropic agents. The outcome of this study is in line with the outcomes of its two sister studies, done previously in America(10) and Australia(11).
In combination, these studies show that current usual care for the treatment of severe sepsis and septic shock is as effective as protocol based EGDT therapy. This is likely due to advancements in care adopted and learned over the last decade, including some from the Rivers, et al. trial. A strict EGDT based treatment protocol for sepsis may not be necessary and may lead to greater resource utilization, as well as potentially increased morbidity from invasive procedures and transfusions . A closer look at this data, however, reveals the patients in these three studies had an overall lower severity of illness as compared to those in the Rivers, et al. study. Patients in this current study and the Australian study had lower mean APACHE-II scores, 18 and 15 respectively, compared to 20 in the Rivers study. In patients with a greater severity of illness, there may still be benefit to following EGDT.
Folic Acid Supplementation for Stroke Prevention
Stroke is a major cause of morbidity and mortality both in American and worldwide. This is even more pronounced in countries without folate-enriched food, such as China, where stroke is the leading cause of death (12). Primary prevention of stroke is exceedingly important given that 77% of strokes are first events and are always potentially devastating(13). Many trials have previously studied the use of folate supplementation for the secondary prevention of cardiovascular disease, with inconsistent results.
In attempt to better understand the role of folate in primary prevention of stroke in a Chinese population, Huo et al.(14) designed a randomized control trial comparing treatment with folate supplementation plus enalapril to enalapril alone. A total of 20,702 hypertensive patients with average of 60 were enrolled. Patients with a history stroke, MI, heart failure, or coronary revascularization were excluded. The rates of hyperlipidemia, diabetes, antiplatelet drug use were low (<4%) in these patients. Patients in both groups were treated with 10mg of enalapril daily, and patients in the intervention arm were given 0.8 mg of folic acid daily. Baseline folate levels and MTHFR (the main enzyme in folate metabolism) polymorphisms were checked in all patients. The primary outcome was first stroke; hemorrhagic or ischemic, fatal or non-fatal. After a median treatment period of 4.5 years, treatment with folate and enalapril was associated with a statically significant reduced risk of first stroke when compared to treatment with enalapril alone(HR 0.79, 95% CI 0.68-0.93). The folic acid supplementation group also had reduced rates of first ischemic stroke and a composite cardiovascular events outcome consisting of MI, stroke, and cardiovascular death. When stratifying patients by baseline folate level, there was a statistically non-significant trend toward a greater beneficial effect of folate supplementation in the lowest quartile serum folate levels.
This study, though not applicable to the United States, is of importance to the management of non-communicable disease from a global health perspective. Many countries outside of North America do not have folate-enriched foods, and as such have lower serum folic acid levels. Huo, et al. clearly demonstrate a beneficial effect of folate supplementation in preventing a first stroke. Given the global disease burden of stroke, an argument can be made for enriching food with folate or providing supplemental folate to members of these countries. It is unknown what benefit folate supplementation would have in patients with multiple risk factors for stroke, including diabetics and those with hyperlipidemia, as there were so few included in the study.
Second line treatment options for Rheumatoid Arthitis:
The mainstay of treatment of Rheumatoid Arthritis (RA) is the first line disease-modifying antirheumatic drug (DMARD) methotrexate. Despite treatment with methotrexate, many patients will continue to have symptoms and disease progression. With the advent of the biologic class of tumor necrosis factor(TNF) inhibitors, rheumatologists gained a powerful new class of second line add-on treatments. These drugs do not come without risks and are a large financial burden on the health care system, with international spending on these drugs exceeding $23 billion(15).
In this week’s edition of the British Medical Journal, Scott, et al. (15) conducted an open label randomized non-inferiority study comparing treatment of RA patients who have failed methotrexate with the addition a TNF inhibitor or additional DMARDs. A total of 214 patients were randomized and were given treatment per study guideline. For those treated with TNF inhibitors, treatment was consistent with National Institute for Health and Care Excellence (NICE) guidance. For those treated in the DMARD group, medication choices were made at the discretion of the treating rheumatologist and were permitted to be on up to 5 DMARDs. The primary outcome of the study was the score on the health assessment questionnaire at 12 months. In previous studies of RA, this score has been shown to be sensitive to change and equal in performance to disease activity measures, such as joint count (16,17). Patients in both groups experienced statistically significant decreases in their scores on the health assessment questionnaire at 12 months, -0.30 (95% CI -0.42 to -0.19) for the TNF group compared to ?0.45 (95% CI ?0.55 to ?0.34) for the DMARD group. Both of these reductions represent a reduction in patient disability and symptoms. The mean difference between the scores, -0.14(95% CI ?0.29 to 0.01) was below the pre-specified non-inferiority margin of 0.22. When looked at over shorter time intervals, patients treated with TNF had great reduction in disease activity scores at 3 and 6 months, though the scores at 12 months became similar.
This study demonstrates that treatment with 2nd line disease modifying agents in addition to methotrexate is at least equally efficacious as current standard of care treatment with a TNF inhibitor and methotrexate. This provides patients and health care providers with a more economical option to biologic therapy and provides patients intolerant to TNF inhibitors with a non-inferior treatment option. A disadvantage of DMARD treatment is patients are likely to have to take many medications as 55.8% in the DMARD group took 3 or more medications. TNF inhibitors appear to have a faster onset of symptom reduction and should be considered in patients whom need rapid treatment. Weaknesses of this study include its unblinded design and the variability in treatment regimens given among the DMARD group. It is possible that one of these DMARD regimens drove the non-inferior findings of the group, and other regimens are not as efficacious, as the authors did not do a stratified analysis.
Now for some fresh takes:
An article in this week’s issue of Gastroenterology, quantified and detailed, the growing problem that Nonalcoholic Steatohepatits(NASH) has become in America. NASH is now the 2nd leading cause of cirrohosis among adults awaiting transplant with the number of adults awaiting transplants tripling since 2004(18).
Statins are one of the most frequently prescribed drugs by internist and are felt to be generally safe. Despite the teratogenic risk of statins in humans is not known. This week’s BMJ has a cohort study looking the safety of statins in pregnancy(19).
An article in these week’s edition of JAMA shows the benefits of aspirin prevention in colon cancer vary by genotype. In fact, there may be some in whom aspirin use increases colon cancer risk(20).
Dr. Ian Henderson is a 1st year resident at NYU Langone Medical Center
Peer reviewed by Gregory Schrank, associate editor, Clinical Correlations
References:
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20. Bateman Brian T, Hernandez-Diaz Sonia, Fischer Michael A, Seely Ellen W, Ecker Jeffrey L, Franklin Jessica M et al. Statins and congenital malformations: cohort study BMJ 2015; 350: h1035 http://www.bmj.com/content/350/bmj.h1035