Primecuts – This Week In The Journals

By Ian Henderson, MD

Peer Reviewed

An apple a day keeps the doctor away, right? Viewed by the public to be so healthy as to prevent doctor’s visits, the apple may be losing its health luster in the eyes of some Americans. This past Friday, the US government approved the planting of genetically modified apples [1]. Called Arctic apples, they have been genetically engineered to be resistant to turning brown when cut or bruised. The fruit, while deemed safe to eat and not harmful to other plants, has been making noise in the agricultural community as many feel it has no place and could hurt exports of apples to other countries.

Genetically modified foods have been a controversial subject among Americans, as they are viewed by some as potentially unhealthy and dangerous. Consumer and environmental groups were highly critical of the Arctic apple approval. Wenonah Hauter, the executive director of Food & Water Watch, said of the Arctic apple, “This GMO apple is simply unnecessary. Apple browning is a small cosmetic issue that consumers and the industry have dealt with successfully for generations.” Many groups are placing pressure on food companies to reject Arctic apples. One of the biggest criticisms is the apple’s labeling. The company will not label the fruit as GMO, but instead it will be labeled as Arctic with links to the company’s website where it is disclosed that the fruit is engineered.

The apple is not expected to be available for a few years. Four growers will plant a total of 20,000 Arctic apple trees this spring with the hopes of producing five to ten thousand pounds of apples by the fall of 2016. This amount should be enough to provide samples to potential buyers such as food service companies. The product could hit stores as early as 2017, though in very small quantities.

In medical news this week…

The Length of Dual Antiplatelet Therapy After Drug Eluting Stent Placement

Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with placement of a drug eluting stent (DES) has become standard of care. A period of DAPT is required to prevent thrombotic complications such as in- stent thrombosis (ST) and recurrent MI [2]. The exact duration of DAPT therapy remains unclear. Several randomized controlled trials have attempted to address the question of what the safest duration of DAPT (ranging from 3 to 6 months) would be following DES implantation [3]. Each of these trials has had limited statistical power due to the rarity of in-stent restenosis.

In an attempt to elucidate the appropriate duration of DAPT, Giustino et al. conducted a meta-analysis of ten randomized controlled trials comparing the efficacy and safety of short vs long term DAPT (S-DAPT vs. L-DAPT) [4]. A total of 32,135 patients were included with a mean follow up time of 19.6 months. The mean weighted exposure time to DAPT was 8.5 months in S-DAPT and 23.2 months in L-DAPT. The primary efficacy endpoint was defined as incidence of definite/probable ST, and the primary safety endpoint was clinically significant bleeding (definition determined by each individual study).  Treatment with S-DAPT had an almost two times greater risk of ST than L-DAPT with an odds ratio (OR) of 1.7. When further stratified for generation of DES, the risk of ST with S-DAPT became more evident as ST was four times as likely to occur with S-DAPT than L-DAPT (OR 3.94, 95% CI: 2.20 – 7.05). S-DAPT was associated with a reduced risk of clinically significant bleeding when compared to L-DAPT (OR 0.63, 95% CI: 0.52 – 0.75). To extrapolate further, for every ST prevented with L-DAPT, approximately 2.4 more clinically significant bleeding events were estimated to occur.

This meta-analysis demonstrates that longer-term DAPT reduces the rate of ST but at an increased risk of bleeding, without one effect clearly outweighing another. An exception to this is with first generation DES, where there appears to be a clear benefit for L-DAPT in these patients. In general though, the risks and benefits of DAPT must be evaluated on an individual basis, and the decision made by physician in concert with their patient.

What Should be the Target Blood Pressure Goal in Type 2 Diabetics?

The association between elevated blood pressure (BP) and increased risks of both macrovascular and microvascular disease in diabetic patients is well appreciated. Despite this, the concept of lowering BP in diabetic patients remains controversial. Indeed, there are conflicting opinions on this in literature, with current JNC-8 guidelines recommending a goal of 140/90, while others would suggest treating diabetics to a goal BP of 130/80 [5].

In an attempt to present the evidence for optimal BP control on micro- and macrovascular events, Emdin et al. conducted a meta-analysis of 40 trials, with a total enrollment of 100,354 patients, looking at the effects of BP control in type 2 diabetics [5]. The primary endpoints were mortality, four surrogates of marcovascular disease (cardiovascular disease events, major coronary heart disease events, stroke, and heart failure), and three surrogates of microvascular disease (renal failure, retinopathy, and albuminuria). A reduction of 10mm Hg systolic BP (SBP) was shown to decrease the risk of mortality, and all macrovascular/microvascular disease surrogates. The authors performed further sub-analysis of the data, stratifying patients by pre-treatment mean SBP and mean achieved SBP. In patients with pre-treatment SBP greater than or equal to 140, the risk of mortality and all macrovascular and microvascular disease surrogates were decreased with SBP reduction of 10mm Hg. In contrast to this, patients with starting mean SBPs less than 140 only saw a decrease in the risk of stroke and albuminuria. In patients whose mean achieved SBP was 130 or greater had a statistically significant reduction in mortality and all surrogates for macrovascular and microvascular disease.  Those patients whose mean achieved SBP was less than 130 had a statistically significant reduction in stroke and albuminuria but no other end points.

This meta-analysis reaffirms the beneficial effects of BP lowering in diabetics. These results further support the current JNC guidelines of a blood pressure goal of 140/90 for diabetic patients with two possible exceptions. Diabetic patients at high risk for stroke and albuminuria may benefit from tighter BP control than current guidelines, with a goal of 130/80.

The Role of Endovascular Therapy in Acute Ischemic Stroke:

Endovascular intervention with thrombectomy for ischemic stroke has yet to have a well-defined therapeutic role. Previous studies of endovascular therapy have yielded neutral findings. In the largest of these trials, the Interventional Management of Stroke 3 (IMS-3) study was halted for futility, as there was no additional benefit with endovascular therapy plus TPA when compared to TPA alone [6]. In an attempt to better define the role of endovascular therapy in patients with acute ischemic stroke, Campbell et al. designed a randomized controlled trial comparing endovascular thrombectomy plus TPA to TPA alone [7].

A total of 75 patients with acute anterior circulation infarct were enrolled, who presented within 4.5 hours of symptom onset. Eligible patients were deemed as those who were candidates to receive TPA, had acute occlusion of the internal carotid artery or the first or second branch of the middle cerebral artery on CTA, and who had salvageable brain tissue on CT perfusion imaging. Co-primary outcomes were reperfusion (measured by the percentage reduction in perfusion lesion volume on repeat imaging at 24 hrs) and early neurologic recovery defined as a reduction of eight points or more on the NIHSS, or a score of 0 or 1 at 3 days. All patients received alteplase at a dose of 0.9 mg per kilogram as standard care. Patients were randomly assigned in a 1:1 ratio to receive either alteplase plus endovascular therapy (endovascular-therapy group) or no further therapy (alteplase-only group). For those patients in the endovascular-therapy group, results showed an increased percentage of reperfusion at 24 hours when compared to the alteplase-only group, with 100% median reperfusion vs 37% median reperfusion (P<0.001). Endovascular therapy also led to a six times greater chance of early neurologic recovery (OR 6.0, 95% CI: 2.0 to 18.0). The authors also looked at long term functional outcomes using the modified Rankin scale at 90 days. Patients treated with endovascular therapy were four times as likely to have independent functional outcome at 90 days as compared to controls (OR 4.2, 95% CI: 1.4 to 12).

This study highlights that for a specific population of patients with acute ischemic stroke, endovascular therapy provides enhanced anatomic and functional neurologic benefit when compared to alteplase-only therapy. This benefit appears to be durable over time as measures of both short- and long-term functional outcomes were improved. A weakness of the study is its small sample size. Given that only 35 patients underwent randomization to the endovascular treatment arm, it is not well powered to conclude that this treatment does not indeed pose potential risks, such as intracranial bleeding, that could potentially out weight its benefits.

Dietary Supplement for the Treatment of Pressure Ulcers

Malnutrition is considered a contributing factor to pressure ulcer formation and impaired healing. Indeed, nutritional assessment and oral supplementation are part of the recommended treatment of poorly healing pressure ulcers. In literature to date, the composition of oral supplements to best optimize pressure ulcer healing has not been extensively presented.

In the Annals of Internal Medicine this week, Cereda, et al. present a randomized controlled trial to compare the effects of a nutritional supplement rich in arginine, zinc, and antioxidants to a standard high calorie, high protein nutritional supplement on pressure ulcer healing [8]. The authors enrolled 200 malnourished patients with stage II, III, or IV pressure ulcers. Patients were randomized 1:1 to experimental formula rich in arginine, zinc, and antioxidants or a standard formula. The primary endpoint was percentage change of pressure ulcer area at eight weeks. Their research found that patients given the experimental supplement had a mean reduction of pressure ulcer size of 60.9% at eight weeks, compared to a mean reduction of 45.2% in patients receiving the control supplement. Furthermore, pressure ulcers in the experimental group reduced in size by 18.7% more than compared to controls.

This study highlights that nutritional supplementation with a supplement rich in arginine, zinc, and anti-oxidants improves pressure ulcer healing in malnourished patients when compared to standard nutrient supplementation, without any major adverse side effects. While these findings are very promising and suggest malnourished patients with pressure ulcers should be placed on an arginine, zinc, and antioxidant rich supplement, they should be taken in context. The patients in this study (despite being malnourished) did not have severe chronic illness (CHF, COPD, cirrhosis, ESRD, or malignancy), which could pose a predilection for ulcer formation and poor wound healing. It is unclear whether or not these supplements would also show similar benefit profiles in such patients with pressure ulcers.

And now for some quick hits…

GERD is a diagnosis commonly seen by many physicians. Despites its frequency, the diagnostic tests for GERD only have moderate sensitivity and specificity, and are expensive and invasive. This week in Gut, a study [9] was published looking at salivary pepsin levels for the diagnosis of GERD, proposing it as an alternative diagnostic tool in concert with patient questionnaire evaluation.

Screening for lung cancer, unlike other solid tumors, is not clearly defined. Patients with COPD are at high risk for lung cancer and represent a group of patients likely to benefit from screening. De-Torres, et al. [10] present a new lung cancer screening score for COPD patients, which they pitch as a “good predictor of lung cancer risk in patients with COPD”.

Peripheral arterial disease and metabolic bone disease are both common in ESRD, but are typically thought to be two unrelated disease processes. Several studies, however have shown an association between atherosclerosis and osteoporosis. In this week’s issue of the Journal of the American society of nephrology [11], a study of ESRD patients demonstrated a correlation between peripheral arterial disease and systemic bone disorders suggesting these may not be two unrelated processes.

Dr. Ian Henderson 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 Wikimedia Commons.

References

1. POLLACK, A. Gene-Altered Apples Get U.S. Approval. New York Times. http://www.nytimes.com/2015/02/14/business/gmo-apples-are-approved-for-growing-in-us.html?ref=health&_r=0 FEB. 13, 2015

2. Levine GN, Bates ER, Blankenship JC et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58:e44-122.

3. 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;371:2155-66.

4. Giustino G, Baber U, Sartori S, et al. Duration of Dual Antiplatelet Therapy Following Drug-Eluting Stent Implantation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Am Coll Cardiol. 2015. http://content.onlinejacc.org/article.aspx?articleID=2118965

5. Emdin CA, Rahimi K, Neal B, Callender T, et al. Patel A. Blood Pressure Lowering in Type 2 Diabetes: A Systematic Review and Meta-analysis. JAMA.2015;313(6):603-615. http://jama.jamanetwork.com/article.aspx?articleid=2108887

6. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368:893-903[Erratum, N Engl J Med 2013;368:1265.] http://www.nejm.org/doi/full/10.1056/NEJMoa1214300

7. Campbell, et al. Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection. N Engl J Med. 2015. http://www.nejm.org/doi/full/10.1056/NEJMoa1414792#t=article

8. Cereda E, Klersy C, Serioli M, et al. for the OligoElement Sore Trial Study Group. A Nutritional Formula Enriched With Arginine, Zinc, and Antioxidants for the Healing of Pressure Ulcers: A Randomized Trial. Ann Intern Med. 2015;162:167-174. http://annals.org/article.aspx?articleid=2107745

9. Hayat, et al. Pepsin in saliva for the diagnosis of gastro-oesophageal reflux disease Gut. 2015;64:373-380. http://gut.bmj.com/content/64/3/373.abstract

10. Juan P. de-Torres, David O. Wilson, Pablo Sanchez-Salcedo, et al. Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease. Development and Validation of the COPD Lung Cancer Screening Score. American Journal of Respiratory and Critical Care Medicine. 2015:191(3);285-291. http://www.atsjournals.org/doi/abs/10.1164/rccm.201407-1210OC#.VN0z9fnF-So

11. London, et al. Ankle-Brachial Index and Bone Turnover in Patients on Dialysis. JASN. 2015: 26(2); 476-483. http://jasn.asnjournals.org/content/26/2/476.abstract

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