Primecuts – This Week in the Journals

October 30, 2020

PrimeCuts 9 min read

By Joshua Novack, 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.

Efficacy of Toclizumab in Patients Hospitalized with Covid-19 [1]

This randomized, double-blind, placebo-controlled trial sought to evaluate if treatment with tocilizumab, a monoclonal antibody blocking the IL-6 receptor, would lower rates of intubation or death in moderately ill patients hospitalized with Covid-19. There is some evidence that patients with Covid-19 become severely ill due to a cytokine storm from the immune response to the infection, as opposed to progression of the viral disease. Higher levels of IL-6 correlate with worse outcomes.2,3 The investigators attempted to determine whether IL-6 receptor blockade with tocilizumab would prevent patient deterioration.

The study enrolled 243 patients from seven Boston-area hospitals and randomized them in a 2:1 fashion to receive intravenous tocilizumab 8 mg/kg versus placebo. The inclusion criteria were patients between age 19-85, confirmed SARS-CoV-2 infection, with at least two of the following: fever, pulmonary infiltrates, or requiring supplemental oxygen. In addition, patients had to have evidence of inflammation in the form of elevation in at least one of CRP, ferritin, D-dimer, or LDH. The primary outcome was a composite of intubation or death over 28 days post-enrollment.

The study found that 10.6% of patients in the tocilizumab group and 12.5% of patients in the placebo group were intubated or died within 28 days, yielding a hazard ratio of 0.83 (95% CI 0.38 – 1.81; P = 0.64). The two groups had similar rates of time to clinical worsening and time to discontinuation of supplemental oxygen.

This study was a rigorous randomized, double-blind, placebo controlled trial. While it failed to find a benefit to tocilizumab therapy, there are limitations to the study. First, the trial was likely underpowered to detect the possible effect size, as the investigators expected to have a 30% rate of death or intubation in the placebo group, compared to the observed 12.5% rate. Second, IL-6 level was not an inclusion criteria in this study; it is possible that by selecting for and recruiting patients with markedly elevated IL-6, the drug may be effective in preventing intubation or death. However, if there is a benefit to tocilizumab therapy, the benefit is unlikely to be large based on the results of this trial.

In summary, this study did not find a benefit for tocilizumab therapy in moderately ill hospitalized patients with Covid-19.

 Sodium/Glucose Cotransporter 2 (SGLT2) Inhibitors

Dapagliflozin in Patients with Chronic Kidney Disease [4]

This trial, DAPA-CKD, is a randomized, double-blind, placebo controlled trial that sought to determine if treatment with dapagliflozin, an SGLT2 inhibitor, led to sustained decline in estimated GFR, end-stage kidney disease, or death from renal or cardiovascular causes in patients with chronic kidney disease with and without type 2 diabetes. Currently, despite CKD’s high prevalence worldwide, ACE inhibitors and ARBs are the only medications shown to slow progression.5,6 There remains a need for more medications that can slow progression of disease.

DAPA-CKD enrolled 4304 patients internationally with an estimated GFR of 25-75 mL/min/1.73 m2 BSA and a urine albumin-creatinine ratio of 200-5000 mg/g. The patients were also on a stable dose of either ACE inhibitor or ARB, or had a documented intolerance to those medications. Patients were excluded if they had type 1 diabetes, polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis. Patients were randomized to receive oral dapagliflozin 10 mg daily or placebo. The primary endpoint for the trial was a composite of sustained decline in estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.

The trial was stopped early due to observed benefit after a median follow up of 2.4 years. The primary outcome occurred in 9.2% in the intervention group, and 14.5% in the placebo group, for a hazard ratio of 0.61 (95% CI 0.5 – 0.72; P < 0.001), with a number needed to treat of 19 (95% CI 15 – 27) over the trial period. Benefits were seen in all elements of the primary composite outcome, and among participants with and without type 2 diabetes. Of note, the risk of all-cause mortality, a secondary outcome, had a hazard ratio of 0.69 (95% CI 0.53 – 0.88, P = 0.004).

Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure [7]

EMPEROR-Reduced is a randomized, double-blind, placebo controlled trial that evaluated the efficacy of empagliflozin, a SGLT2 inhibitor, to reduce rates of renal and cardiovascular outcomes in patients with heart failure with reduced ejection fraction. In 2019, DAPA-HF showed that dapagliflozin reduces risk of cardiovascular death or hospitalization for heart failure.8 EMPEROR-Reduced sought to investigate whether the same benefits existed for empagliflozin in a population containing a larger percentage of patients with more severe left ventricular dysfunction.

3730 patients with NYHA class II-IV, with left ventricular ejection fraction less than or equal to 40%, were randomized to receive either empagliflozin 10 mg daily or placebo. Patients with an EF > 30% had to have a hospitalization for heart failure within the past year or markedly NT-pro-BNP levels depending on their particular EF in order to qualify for the study. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure.

The primary outcome occurred in 19.4% of patients receiving empagliflozin, and 24.7% of patients receiving placebo, for a hazard ratio of 0.75 (95% CI 0.65 – 0.86; P < 0.001), driven predominantly by a decrease in hospitalizations (HR 0.69; 95% CI 0.59 – 0.81) as compared to cardiovascular death (HR 0.92; 95% CI 0.75 – 1.12). These findings were consistent across patients with and without type 2 diabetes.

Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes [9]

VERTIS CV is an international, randomized, double-blind, placebo controlled trial primarily investigating the cardiovascular safety of ertugliflozin in patients with type 2 diabetes and atherosclerotic cardiovascular disease. However, the trial protocol was amended after the publication of EMPA-REG OUTCOME. In 2015, that trial found that empagliflozin lowered the rates of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (also known collectively as major adverse cardiovascular events, or MACE), hospitalizations for heart failure, and all cause mortality.10 VERTIS CV was amended to investigate, besides its primary outcome of noninferiority in rates of MACE, new secondary outcomes including a composite of death from cardiovascular causes and heart failure hospitalizations, and a composite of various renal outcomes. The trial population was doubled to provide adequate power to detect such findings.

8246 patients with type 2 diabetes and atherosclerotic cardiovascular disease were randomized in a 1:1:1 fashion to ertugliflozin 5 mg daily, ertugliflozin 15 mg daily, and placebo. Both ertugliflozin doses were pooled for analysis. The trial found equivalent rates of MACE in both the intervention and control arm of 11.9%, with a hazard ratio of 0.97 (95.6% CI 0.85 – 1.11; P <0.001 for noninferiority). Death from cardiovascular causes or heart failure hospitalizations occurred in 8.1% of the ertugliflozin group and in 9.1% of the control group for a hazard ratio of 0.88 (95% CI 0.75 – 1.03; P = 0.11). Hazard ratios for death from cardiovascular causes alone and the composite renal outcomes both numerically favored the intervention arm, but were not statistically significant.

Summary:

It is unclear why VERTIS-CV with ertugliflozin had negative findings, whereas other trials with SGLT2 inhibitors, including empagliflozin and canagliflozin, have found reduction in rates of MACE in patients with type 2 diabetes.10,11 However, a trial looking at dapagliflozin failed to find a reduction in rates of MACE, but did find reduction in heart failure hospitalization rates, and a composite renal outcome.12

SGLT2 inhibitors can be sorted based on the degree of selectivity for SGLT2 over SGLT1. It may be thought that degree of selectivity for SGLT2 could explain differing results. However, ertugliflozin has a 2500-fold selectivity for SGLT2 over SGLT1, to a similar degree as empagliflozin.13 As shown in EMPA-REG OUTCOME, empagliflozin has been shown to have benefits in this population.10 As it remains unclear how SGLT2 inhibitors provide their cardiovascular benefits, there may be specific elements of each drug that result in cardiovascular benefits, explaining the absence of an effect across the entire class of SGLT2 inhibitors.

Meanwhile, DAPA-CKD and EMPEROR-Reduced show that SGLT2 inhibitors have use outside of patients with type 2 diabetes. DAPA-CKD shows an impressive reduction in slowing CKD progression, while EMPEROR-Reduced showed a reduction in a composite of heart failure hospitalizations and cardiovascular death, powered mostly through reduced rates of heart failure hospitalizations.4,7 Like ertugliflozin above, it will be interesting to see whether the benefits in heart failure and chronic kidney disease extend to the entire class of SGLT2 inhibitors, or specific drugs within that class.

Minicuts

Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes [14]

This randomized, double-blind, placebo controlled trial randomized patients with type 2 diabetes and CKD to finerenone, a non-steroidal mineralocorticoid receptor antagonist, and found that patients receiving finerenone had lower rates of progression of CKD and cardiovascular events (17.8% vs 21.1%). This adds a new drug, along with ACE inhibitors/ARBs, and SGLT2 inhibitors, to the list of medications shown to reduce progression of CKD in patients with type 2 diabetes.

Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrope (HOST-REDUCE-POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial [15]

This randomized, open-label multi-center trial in South Korea randomized patients to dual-antiplatelet therapy (DAPT) with aspirin 100 mg and prasugrel 10 mg versus DAPT with aspirin 100 mg and prasugrel dose-reduced from 10 mg to 5 mg after one month. The trial found that there was a decrease in bleeding risk in the reduced-dose group without an increase in ischemic events. This study provides a potentially useful strategy to reduce bleeding risks in selected patients without a concern for increased rates of thrombotic events.

Association of Lumbar Puncture With Spinal Hematoma in Patients with and without Coagulopathy [16]

This retrospective cohort study examined the rates of spinal hematoma after lumbar puncture in patients with and without coagulopathy, as defined by platelets less than 150 x109/L, INR > 1.4, or aPTT > 39 seconds. The 30-day risk of hematoma was 0.2% in patients without coagulopathy, and 0.23% in patients with coagulopathy. While the low rates may be due to bias in physicians selecting on which patients to perform lumbar punctures, they suggest lumbar punctures are well tolerated even for patients with coagulopathy.

Fluid Response Evaluation in Sepsis Hypotension and Shock [17]

This clinical trial randomized patients presenting in the emergency department with sepsis associated with hypotension undergoing ICU admission to either empiric fluid resuscitation versus fluid resuscitation guided by fluid responsiveness assessed by results of passive leg raise. The study found that patients whose fluid resuscitation was guided by results of passive leg-raise received lower volumes of intravenous fluid, experienced lower rates of renal replacement therapy, and lower rates of mechanical ventilation. However, when interpreting these results, it is important to remember that this trial used passive leg raise to guide resuscitation in the ICU only after initial empiric fluid resuscitation in the emergency department as opposed to patients who are intravenous fluid naive.

Dr. Joshua Novack is a 1st year resident at NYU Langone Health

Peer reviewed by David Kudlowitz, associate editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

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  2. Herold T, Jurinovic V, Arnreich C, et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020;146(1):128-136.e4. doi:10.1016/j.jaci.2020.05.008
  3. Del Valle DM, Kim-Schulze S, Huang H-H, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26(10):1636-1643. doi:10.1038/s41591-020-1051-9
  4. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. doi:10.1056/NEJMoa2024816
  5. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy. N Engl J Med. 2001;345(12):861-869. doi:10.1056/NEJMoa011161
  6. Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet Lond Engl. 1999;354(9176):359-364. doi:10.1016/S0140-6736(98)10363-X
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  8. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. doi:10.1056/NEJMoa1911303
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  10. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720
  11. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644-657. doi:10.1056/NEJMoa1611925
  12. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347-357. doi:10.1056/NEJMoa1812389
  13. Cinti F, Moffa S, Impronta F, et al. Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: evidence to date. Drug Des Devel Ther. 2017;11:2905-2919. doi:10.2147/DDDT.S114932
  14. Bakris GL, Agarwal R, Anker SD, et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020;0(0):null. doi:10.1056/NEJMoa2025845
  15. Kim H-S, Kang J, Hwang D, et al. Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial. The Lancet. 2020;396(10257):1079-1089. doi:10.1016/S0140-6736(20)31791-8
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  17. Douglas IS, Alapat PM, Corl KA, et al. Fluid Response Evaluation in Sepsis Hypotension and Shock: A Randomized Clinical Trial. CHEST. 2020;158(4):1431-1445. doi:10.1016/j.chest.2020.04.025