Primecuts – This Week in the Journals

January 31, 2020

PrimeCuts 8 min read

By Pamela Boodram, MD

Peer Reviewed

With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature. This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.

Morphine and cardiovascular outcomes among patients with non-ST-segment elevation acute coronary syndromes undergoing coronary angiography [1]

The 2014 ACC/AHA Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes (NSTE-ACS) recommends the use of IV morphine for persistent ischemic pain in spite of maximal anti-ischemic therapy, barring any contraindications to opioids [2]. It lists the level of evidence for this recommendation as class B, recognizing that no randomized controlled trials have been conducted to assess morphine’s safety and efficacy [2]. Morphine and other opioids, however, have been shown to reduce the antiplatelet effects and delay the absorption of oral antiplatelet agents, including clopidogrel [3].

This observational study sought to determine whether the use of morphine with clopidogrel in patients presenting with NSTE-ACS is associated with a higher risk of cardiac ischemic events. The authors performed a post-hoc subanalysis of the EARLY ACS trial [4]. Clopidogrel use within 24 hours before randomization and IV morphine use within seven days before randomization were recorded, allowing the authors to identify the 5,438 patients who were given clopidogrel, 88.7% of whom were not given IV morphine.

In patients treated with clopidogrel, morphine use was associated with higher rates of a composite outcome of death, non-fatal MI, and recurrent ischemia requiring intervention within 96 hours of presentation, with an adjusted odds ratio of 1.4 (95% CI, 1.04–1.87; p=0.026). The difference in rates of death or MI at 30 days was not statistically significant, but there was a trend for higher rates in the morphine group (adjusted odds ratio 1.29; 95% CI, 0.98–1.70; p=0.072). They also looked at patients treated with IV morphine, but not clopidogrel, and found that morphine was not associated with either outcome in this group.

While this study has the potential to impact clinical practice, it’s riddled with limitations. First, as this is a post-hoc analysis, there may be a number of unmeasured confounders that prevent a definitive causal relationship from being established. Second, this study only looked at patients with NSTE-ACS, for which the need for antiplatelet agents is debated, rather than patients with STEMIs. Lastly, there are many points of imprecision, including the timing of administration of either drug and how vastly different the two groups were in size. Therefore, it would be difficult to base any clinical decisions off of this one study, but it is a foundation for further research.

Hospital level care at home for acute ill adults: a randomized control trial [5]

In the US, hospitals remain the standard setting of care for acute illnesses, but there are many disadvantages to inpatient care. For one, hospital care accounts for nearly 33% of national health expenditures [6]. Costs aside, studies have shown that our patients themselves are negatively impacted by their hospital stays in myriad ways: lengthy emergency room waits, elderly patients developing hospital-acquired infections, patients suffering from “post-hospital syndrome,” and many patients requiring readmission within 30 days of discharge [7, 8, 9, 10]. Given these findings, some developed countries are offering home hospital care, in which acute care services are provided in patients’ homes [11]. While these “home hospitals” are proposed to reduce cost, healthcare use, and readmissions – as well as improve patient experience – no US randomized controlled trials evaluated this until now [12].

This RCT of 91 patients admitted via the ED assigned them to receive either home hospital care (intervention) or traditional hospital care (control). Exclusion criteria included being considered as high risk for clinical deterioration based on validated algorithms. Patients included in the study tended to be elderly and frail, with the median ages of the intervention and control groups being 80 and 72, respectively. They also generally had strong emotional support and fair health literacy. Patients within the two groups had similar primary diagnoses.

The at-home group received daily visits from an attending internist, as well as an RN, and had access to respiratory therapy, PT/OT, certain specialists via telehealth, IV medications, and point-of-care testing. All patients were interviewed upon admission, discharge, and 30 days post-discharge. Researchers found that the adjusted mean cost of each episode was 38% lower in the home hospital group (95% CI, 0.24%–0.49%; p<0.001). Additionally, members of the at-home group had fewer tests done, spent less time sedentary, and were readmitted less frequently. Patients in both groups endorsed high satisfaction with their care and there were similar lengths of stay.

While this study does demonstrate the potential benefits of “home hospitals,” it does have some limitations. Its small size and selection for patients at low risk of clinical deterioration inhibit its generalizability. Also, given that it included a broad category of diagnoses, it was unable to evaluate disease-specific outcomes. Overall, it seems that it would be incredibly difficult to widely adopt this practice, as whether a patient can do well with home hospital care is likely dependent on a host of factors not analyzed by this study, including health literacy, at-home support, diagnosis, and disease severity. Home hospitals can be great, but likely only for certain patients. Specifically identifying those patients could be the next step.

Lipoprotein (a) reduction in persons with cardiovascular disease [13]

Based on growing evidence, elevated lipoprotein (a) is considered an independent genetic risk factor for cardiovascular disease [14]. Often, these patients cannot achieve lower LDL levels with established therapy, including PCSK9i, as lipoprotein (a) is co-measured with LDL cholesterol [15, 16]. There are currently no approved therapies to specifically lower lipoprotein (a). However, prior studies have shown that an agent directed against non-hepatocyte production of apolipoprotein (a) reduced levels in both healthy adults with elevated lipoprotein (a), as well as those with established cardiovascular disease [17]. Given that hepatocytes are the source of roughly 99% of plasma lipoprotein (a), a new agent, APO(a)-LRx, targeted against hepatocyte production, was shown to cause a dose-dependent reduction in lipoprotein (a) levels [18, 19]. This subcutaneous drug demonstrated a half-life of one month, leading the authors to conduct this randomized, double-blind, placebo-controlled, dose-ranging trial with longer dosing intervals.

This trial involved 286 patients with established cardiovascular disease and elevated screening lipoprotein (a) levels. Patients were divided into groups; each group received different doses of APO(a)-LRx at varying intervals, or placebo. Entry lipoprotein (a) levels were compared to those at six months. There was a dose-dependent decrease in lipoprotein (a) levels compared to placebo (p values ranged from 0.003 to <0.001). The most common adverse event was an injection site reaction.

This trial could signify a new, effective, and safe therapy for patients with cardiovascular disease unresponsive to traditional therapies. However, it is impossible to generalize the results of this trial, as 97% of patients were white. Therefore, more studies involving a diverse population would be needed, as well as studies on the longitudinal impact of lowering lipoprotein (a) levels on cardiovascular outcomes.

Minicuts

Effect of vitamin C, hydrocortisone and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock [20]

This multi-center, open-label, randomized clinical trial recruited 216 patients with septic shock from ICUs in Australia, New Zealand, and Brazil. Patients were randomized to the intervention group, receiving IV vitamin C, hydrocortisone, and thiamine, or to the control group, receiving solely IV hydrocortisone. Both groups received treatment until resolution of shock or up to 10 days. This study found no difference between the two groups in the duration of time spent alive and vasopressor-free up to day 7.

Pre-operative N-terminal pro-B type natriuretic peptide and cardiovascular events after noncardiac surgery: a cohort study [21]

This prospective cohort study sought to determine whether obtaining pre-op NT-proBNP levels can improve the risk prediction of vascular death and myocardial injury within 30 days after non-cardiac surgery. Researchers enrolled 10,402 patients from 16 hospitals across nine countries undergoing inpatient non-cardiac surgery. Four groups were created based on pre-op NT-proBNP levels. The adjusted hazard ratios and incidence of vascular death and cardiac events increased directly with NT-proBNP levels. Levels were also significantly associated with 30-day all-cause mortality. Adding NT-proBNP levels to already established risk stratification tools may help physicians better classify, and thereby optimize, patients prior to non-cardiac surgery.

Early high dose vitamin D3 for critically ill, vitamin D-deficient patients [22]

This double-blind, placebo-controlled phase 3 trial randomized 1,360 vitamin D-deficient patients to receive either a single PO dose of 540,000 IU of vitamin D3 or placebo within 12 hours of admission to an ICU. There was no significant difference in 90-day mortality between the two groups, nor was there an effect of baseline severity of vitamin D deficiency on the results.

Dr. Pamela Boodram is a third-year resident in internal medicine at NYU Langone Health

Peer reviewed by Christian Torres, MD, chief resident, internal medicine, NYU School of Medicine

Image courtesy of piqsels.com

References

  1. Furtado, RHM, Nicolau, JC, Guo J, et al. Morphine and Cardiovascular Outcomes Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Undergoing Coronary Angiography. J Am Coll Cardiol. 2020 Jan, 75 (3) 289-300. https://www.sciencedirect.com/science/article/pii/S0735109719385171
  2. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol, 2014 Dec, 64 (24) e139-e228. http://www.onlinejacc.org/content/64/24/e139?_ga=2.109267648.454172651.1580487193-1456473339.1580487193
  3. Hobl EL, Stimpfl T, Ebner J, et al. Morphine Decreases Clopidogrel Concentrations and Effects: A Randomized, Double-Blind, Placebo-Controlled Trial. J Am Coll Cardiol, 2014 Feb, 63 (7) 630-635. https://www.sciencedirect.com/science/article/pii/S0735109713062049
  4. Giugliano RP, White JA, Bode C, et al. Early vs delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med, 2009, 360: 2176-2190. https://www.nejm.org/doi/full/10.1056/NEJMoa0901316
  5. Levine DM, Ouchi K, Blanchfield B, et al. Hospital level care at home for acute ill adults: a randomized control trial. Ann Intern Med, 2020, 172 (2) 7-85. https://annals.org/aim/fullarticle/2757637/hospital-level-care-home-acutely-ill-adults-randomized-controlled-trial
  6. Centers for Disease Control and Prevention.FastStats: health expenditures. 2017. www.cdc.gov/nchs/fastats/health-expenditures.htm [accessed on 22 Jan 2020]
  7. Horwitz LI, Green J, Bradley BH. US emergency department performance on wait time and length of visit. Ann Emerg Med. 2010; 55: 133-141. https://www.annemergmed.com/article/S0196-0644(09)01283-9/fulltext
  8. Hung WW, Ross JS,  Farber J, et al. Evaluation of the Mobile Acute Care of the Elderly (MACE) service. JAMA Intern Med. 2013; 173: 990-996. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1680133
  9. Krumholz HM. Post-hospital syndrome—an acquired, transient condition of generalized risk. N Engl J Med. 2013; 368: 100-102. https://www.nejm.org/doi/full/10.1056/NEJMsa0803563
  10. Jencks SF, Williams MV, Coleman EA.  Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med. 2009; 360: 1418-1428. https://www.nejm.org/doi/full/10.1056/NEJMsa0803563
  11. Leff B. Defining and disseminating the hospital-at-home model. CMAJ. 2009; 180: 156-157. https://www.cmaj.ca/content/180/2/156
  12. Cryer L, Shannon SB, VanAmsterdam M, et al. Costs for ‘hospital at home’ patients were 19 percent lower, with equal or better outcomes compared to similar inpatients. Health Aff (Millwood). 2012; 311237-1243. https://www.healthaffairs.org/doi/10.1377/hlthaff.2011.1132
  13. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein (a) reduction in persons with cardiovascular disease. N Engl J Med. 2020; 382:244-255. https://www.nejm.org/doi/10.1056/NEJMoa1905239
  14. Nordestgaard BG, Langsted A. Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J Lipid Res 2016;57:1953-1975. https://www.jlr.org/content/57/11/1953.full
  15. Yeang C, Witztum JL, Tsimikas S. ‘LDL-C’= LDL-C+Lp(a)-C: implications of achieved ultra-low LDL-C levels in the proprotein convertase subtilisin/kexin type 9 era of potent LDL-C lowering. Curr Opin Lipidol 2015;26:169-178. https://journals.lww.com/co-lipidology/Abstract/2015/06000/_LDL_C____LDL_C___Lp_a__C__implications_of.4.aspx
  16. Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017;390:1962-1971. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32290-0/fulltext
  17. Tsimikas S, Viney NJ, Hughes SG, et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 2015;386:1472-1483. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61252-1/fulltext
  18. Crooke ST, Witztum JL, Bennett CF, Baker BF. RNA-targeted therapeutics. Cell Metab 2018;27:714-739. https://www.cell.com/cell-metabolism/fulltext/S1550-4131(18)30182-7
  19. Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016;388:2239-2253. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31009-1/fulltext
  20. Fujii T, Luethi N, Young PJ, et al. Effect of vitamin C, hydrocortisone and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock. JAMA. 2020. https://jamanetwork.com/journals/jama/fullarticle/2759414
  21. Duceppe E, Patel A, Chan MTV, et al. Pre-operative N-terminal pro-B type natriuretic peptide and cardiovascular events after noncardiac surgery: a cohort study. Ann Intern Med. 2020; 172(2): 96-104. https://annals.org/aim/article-abstract/2758032/preoperative-n-terminal-pro-b-type-natriuretic-peptide-cardiovascular-events
  22. Ginde, AA, Brower RG, Caterino JM, et al. Early High-Dose Vitamin D3 for Critically Ill, Vitamin D–Deficient Patients. N Engl J Med 2019; 381:2529 -2540. https://www.nejm.org/doi/10.1056/NEJMoa1911124