VA NEPHRON-D Trial: Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy
The VA NEPHRON-D trial tackled an important question about the combination therapy of ACEi and ARBs. We know from the RENAAL trial that losartan has significant benefits in diabetic nephropathy. The authors of the VA NEPHRON-D tiral aimed to assess if the addition of an ACE inhibitor to ARB therapy prevent eGFR reduction, ESRD, or death in patients with T2DM, CKD stage 2-3, and elevated urine albumin: creatinine. The trial included a reasonable number of 1448 patients who were randomized to losartan + placebo group and combination group of losartan and lisinopril. The trial was ended earlier due to inconclusive results. The authors of VA NEPHRON-D trial concluded that combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. Source: NEJM
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REWIND Trial: Dulaglutide and cardiovascular outcomes in type 2 diabetes
The REWIND trial aimed to assess the cardiovascular (CV) safety of dulaglutide, a glucagon-like peptide-1 (GLP-1) agonist, in patients with type 2 diabetes mellitus at higher risk for CV events. The trial involved 9,901 patients and randomized them to dulaglutide and compared outcomes with placebo. The results of the REWIND trial indicated that once-weekly dulaglutide administered via subcutaneous injection is superior to placebo in improving glycemic control and reducing CV events in patients with type 2 diabetes and higher CV risk. There was also a significant reduction in nonfatal strokes and improvement in the composite renal outcomes. Source: Lancet
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ATLAS Trial: 10 years vs. 5 years of tamoxifen in patients with breast cancer
In ATLAS trial, Davies C et al. randomized 12,894 females with early breast cancer diagnosed and receiving adjuvant tamoxifen to either 10 years continued tamoxifen or 5 years of tamoxifen therapy. The primary goal of the trial was to study breast cancer recurrence and mortality in these patients. The results of the ATLAS trial were significantly in favor of pursuing the 10 years prolong therapy as compared with 5 years. The authors concluded that for women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. The ATLAS trial proved to be a big breakthrough in terms of practice-changing implications. Source
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FIDELITY Trial: Arthroscopic Partial Meniscectomy versus Sham Surgery for a Degenerative Meniscal Tear
2013, Arthroscopic Partial Meniscectomy versus Sham Surgery for a Degenerative Meniscal Tear, Source: NEJM
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MSH Trial: Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia
| MSH Trial: 1995, Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell Anemia. Source: NEJM |
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MET-REMODEL Trial: Metformin on LVH in patients with CAD without diabetes
2019, MET-REMODEL Trial: Metformin on left ventricular hypertrophy in patients with coronary artery disease without diabetes, Source: EHJ
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ASCENT COPD Trial: Effect of Aclidinium Bromide on Major Cardiovascular Events and Exacerbations in High-Risk Patients With COPD
2019, ASCENT-COPD Trial: Effect of Aclidinium Bromide on Major Cardiovascular Events and Exacerbations in High-Risk Patients With Chronic Obstructive Pulmonary Disease; The ASCENT-COPD Randomized Clinical Trial. Source: JAMA
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VADT Trial: Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes
2009, VADT Trial: Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes, Source
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CENSER Trial: Early Use of Norepinephrine in Septic Shock Resuscitation
CENSER Trial 2019. Early Use of Norepinephrine in Septic Shock Resuscitation. Source: AJRCC
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ALIVE Trial: Amiodarone as Compared with Lidocaine for Shock-Resistant Ventricular Fibrillation
2002, ALIVE Trial Visual Summary: Amiodarone as Compared with Lidocaine for Shock-Resistant Ventricular Fibrillation. NEJM
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ARREST Trial: Amiodarone for Resuscitation after Out-of-Hospital Cardiac Arrest Due to Ventricular Fibrillation
ARREST Trial: 1999, Amiodarone for Resuscitation after Out-of-Hospital Cardiac Arrest Due to Ventricular Fibrillation. NEJM
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RE-SPECT ESUS Trial: Dabigatran for Prevention of Recurrent Stroke after Cryptogenic Stroke
2019, RE-SPECT ESUS Trial Summary: Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source | Source: NEJM
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CREDENCE Trial: Canagliflozin and renal outcomes in type II diabetes and nephropathy
CREDENCE Trial Visual Abstract
In CREDENCE trial, the authors objective was to assess the effect of canagliflozin on renal outcomes in patients with type 2 DM and CKD. 4,401 patients with CKD and DM2 were enrolled to be treated with either 100 mg canagliflozin daily or matched placebo. The primary outcome of ESRD, worsening CKD or CV death was significantly lower in patients on canagliflozin (P=0.0001). The authors concluded that canagliflozin can significantly protect kidney in patients with diabetes. Take a look and share the visual abstract for quick learning.
Source: NEJM
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ALCOHOL-AF Trial: Impact of Alcohol Abstinence in Moderate Drinkers With Atrial Fibrillation
The goal of ALCOHOL-AF trial was to assess effect of alcohol abstinence on recurrence of AF and AF burden in patients with paroxysmal or persistent AF. The trial showed results significantly in favor of alcohol abstinence. Take a look at the visual abstract.
Source: ACC
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TABLET Trial (2019): Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception
TABLET Trial Summary: Dhillon-Smith R et al. randomized 952 women with positive testing for thyroid peroxidase antibodies and normal thyroid function
Source: NEJM
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LEAP trial (2019): Early vs Delayed Levodopa in Parkinson’s Disease
LEAP Trial Summary: The LEAP trial was a Multicenter, randomized, double-blind, placebo-controlled, delayed-start trial that randomized 445 patients with Parkinson’s disease (mean age 65) and similar baseline clinical characteristics to
for 80 weeks) (n=222) or delayed-start group (Placebo for 40 wks then
levodopa +
Summarized by Ricardo Vivanco
Source: NEJM
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PARTNER 3 Trial (2019): Transcatheter Aortic-Valve Replacement With a Balloon-Expandable Valve in Low-Risk Patients
PARTNER 3 Trial Summary: Mack MJ et al. randomized 1000 patients (mean age, 73 years), male population (69.3%), with lower STS-PROM scores (mean 1.9%) and fewer comorbidities (low-risk surgical candidates) to either TAVR with balloon-expanded valve or surgery. The primary objective was to compare outcomes with TAVR vs. surgical AV replacement in patients with severe AS and low surgical risk. Based on the results the composite of death from any cause, stroke, or rehospitalization was significantly lower in patients undergoing TAVR as compared with surgery. (P<0.001 for noninferiority, P=0.001 for superiority). The authors of PARTNER 3 trial concluded that among patients with severe AS who were at low surgical risk, the rate of the composite of death, stroke, or rehospitalization at 1 year was significantly lower with TAVR than with surgery.
Source: NEJM
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PIVOTAL Trial (2019): Intravenous Iron in Patients Undergoing Maintenance Hemodialysis
PIVOTAL Trial Summary: Macdougall et al. randomized 2141 adults undergoing maintenance HD to receive either high-dose IV iron sucrose in a proactive fashion (400 mg monthly, unless ferritin >700 μg/l or transferrin saturation ≥40%), or low-dose IV iron, in a reactive fashion (0 to 400mg monthly, with a ferritin<200 μg/l or a transferrin saturation <20% being a trigger for iron administration). The primary objective was to assess if high-dose intravenous iron regimen administered proactively was superior to a low-dose regimen given reactively to patients on maintenance hemodialysis. The primary outcome (composite of nonfatal MI, stroke, hospitalization for HF, or death) was significantly lower in patients receiving high-dose proactive iron therapy. The authors of the PIVOTAL trial concluded that Among patients undergoing hemodialysis, a high-dose intravenous iron regimen administered proactively was superior to a low dose regimen administered reactively and resulted in lower doses of
Source: NEJM
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CARRESS-HF Trial (2012): Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome
CARRESS HF Trial Summary: Bart et al. randomized 188 patients with decompensated acute heart failure and worsening renal function (Increase in serum creatinine ≥0.3 mg/dL) – [cardiorenal syndrome] to ultrafiltration (fluid removal of 200 mL/hr, n=94) or medical therapy (Protocol driven IV diuresis, n=94). The primary objective was to assess if ultrafiltration improves volume removal, renal function, and reduce HF complications when compared to medical therapy in acutely decompensated heart failure and cardiorenal syndrome. The results showed worsening of change in serum creatinine level and change in weight at day 4 in the ultrafiltration group (P=0.003). The authors of CARRESS HF trial concluded that in patients with acute decompensated HF and cardiorenal syndrome, ultrafiltration is associated with more adverse events, worsening renal function, and no change in weight when compared to medical therapy.
Source: NEJM
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Effectiveness and safety of 0·5% colchicine cream vs. photodynamic therapy in the treatment of actinic keratosis
Trial Summary:
Effectiveness and safety of 0•5% colchicine cream vs. photodynamic therapy with methyl aminolaevulinate in the treatment of actinic keratosis and skin field cancerization of the forearms: a randomized controlled trial
The objective of the study was to evaluate the effectiveness and safety of 0•5% colchicine (COL) cream vs. methyl
36 patients were included in the study. The sample size was calculated to detect a reduction difference of more than 10% between groups and SDs of equivalent differences. Inclusion criteria: outpatients attending a public dermatology clinic at UNESP Medical School (Botucatu‐SP, Brazil), over the age of 18 years, from both sexes, with a clinical diagnosis of AK on the forearms (3–10 lesions) and had not received treatment for AK (except for sunscreen) for at least 6 months.
In the COL group, whole forearms were treated with 0•5% COL cream twice daily for 10 days. In the MAL-PDT group,
The primary outcome was a reduction in AK count on the forearms 60 days after treatment. AK count was reduced in 45% of patients treated with COL and 40% of those treated with MAL‐PDT. P<0.01 for both groups, for a reduction in AK count. P = 0•56 between groups. AK count was compared according to time and to groups (over time) by a linear mixed effects model with robust covariance matrix and probability adjustment for each distribution. Post hoc analysis was performed using the sequential Sidak procedure.
The study concluded that a 10-day course of COL 0•5% cream and a single session of MAL‐PDT are safe and effective for treating skin field cancerization of the forearms. Side effects were minimal and similar between the groups.
Summarized by: Jonas A. Adalsteinsson, UConn Department of Dermatology
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PreVent Trial (2019): Bag-Mask Ventilation during Tracheal Intubation of Critically Ill Adults
PreVent Trial Summary: Casey et al. randomized 401 adults (age, ≥18 years) undergoing induction and tracheal intubation to either bag-mask ventilation during the bridging process or no ventilation. The primary objective was to assess whether positive-pressure ventilation with a bag-mask device during tracheal intubation of critically ill adults prevents hypoxemia without increasing the risk of aspiration. The results showed that patients who did not undergo ventilation have significant lowest oxygen saturation events between induction and 2 minutes after tracheal intubation. No additional risk of aspiration was noted. The authors of PreVent trial concluded that among critically ill adults undergoing tracheal intubation, patients receiving bag-mask ventilation had higher O2 saturation and a lower incidence of severe hypoxemia than those receiving no ventilation.
Source: NEJM
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CHANCE Trial (2013): Clopidogrel with aspirin in acute minor stroke or transient ischemic attack
CHANCE Trial Summary: Wang et al. randomized 5,170 patients (≥40 years) with either minor ischemic stroke (NIHSS score ≤3) or high-risk TIA (ABCD2 score ≥4) to either aspirin/clopidogrel combination or aspirin alone. The primary objective was to assess if early administration of aspirin/clopidogrel reduces rates of subsequent strokes when compared to aspirin monotherapy in patients with acute TIA or minor ischemic stroke.
The results showed a significant decrease in recurrence of stroke (P<0.001; NNT=29). Bleeding risk did not show a significant difference between both groups (P=0.09). The results were based on Chinese population. In 2018, the POINT trial studied similar outcomes and showed an increased risk of bleeding with dual antiplatelet therapy.
The authors of the CHANCE trial concluded that in patients with minor ischemic stroke or high-risk TIA, starting aspirin/clopidogrel within 24h of symptom onset reduces the 90-day stroke incidence without increasing bleeding rates, when compared to aspirin monotherapy.
Source: NEJM
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HYPRESS Trial (2016): Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis
HYPRESS Trial Summary: Keh D, et al. randomized 380 patients with sepsis defined by ≥2 SIRS criteria, proven infection, and ≥1 organ with new dysfunction to either IV hydrocortisone or placebo. The objective was to assess if early hydrocortisone therapy reduces progression to septic shock compared to placebo in patients with severe sepsis. The results showed no difference in the development of septic shock in both groups P=0.70. The authors of HYPRESS trial concluded that among adults with severe sepsis not in septic shock, use of hydrocortisone compared with placebo did not reduce the risk of septic shock within 14 days.
Source: JAMA
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SEPSISPAM Trial (2014): High versus low blood-pressure target in patients with septic shock
SEPSISPAM Trial Summary:
Source: NEJM
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BRIDGE Trial (2015): Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation
BRIDGE Trial Summary: Douketis JD et al. randomized 1,884 patients on warfarin (INR 2-3 for ≥3m) with AF or A-flutter and CHADS2 Score ≥1 to LMWH: dalteparin (100 IU/kg BID) or placebo. The objective was to assess if bridging anticoagulation reduce rates of arterial thromboembolism compared to no bridging in patients with atrial fibrillation undergoing an invasive procedure. The results showed noninferiority (P=0.01) of the primary outcome (TIA or stroke or arterial embolism) in patients with no bridging as compared with bridging. The authors of the BRIDGE trial concluded that among patients with low- and intermediate-risk atrial fibrillation receiving anticoagulation and undergoing an invasive procedure, periprocedural bridging anticoagulation with LMWH did not reduce the incidence of arterial thromboembolism when compared to no bridging, but did increase the risk of major bleeding.
Source: NEJM
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VALIANT Trial (2003): Valsartan, Captopril, or Both in Myocardial Infarction
VALIANT Trial Summary: Pfeffer et al. randomized 14,703 patients with acute MI within prior 10 days complicated by HF and/or LVEF ≤35% to either valsartan or captopril or combination of both. The objective was to assess the efficacy of ARBs compared with ACE-I in patients in the post-MI period complicated by HF and/or LV systolic dysfunction. The results of the trial showed similar mortality rates among both ACE and ARB groups along with similar rates in combination of both. The authors of the VALIANT trial concluded that Valsartan was as effective as captopril in improving survival among patients with HF and/or LV dysfunction in the post-MI period.
Source: NEJM
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Project CLEAR Trial (2019): Decolonization to Reduce Postdischarge Infection Risk among MRSA Carriers
Project CLEAR trial summary: Huang et al. randomized 2,141 patients colonized with MRSA to hygiene education or hygiene education + decontamination. Decolonization involved chlorhexidine mouthwash, baths or showers with chlorhexidine, and nasal mupirocin for 5 days twice per month for 6 months. The primary objective was to assess the efficacy of postdischarge hygiene education, as compared with education plus decolonization, in patients colonized with MRSA (carriers). The results showed a significant decrease in MRSA infections in the decontamination group (P=0.03, NNT=30). The authors of the Project CLEAR trial concluded that postdischarge MRSA decolonization with chlorhexidine and mupirocin led to a 30% lower risk of MRSA infection than education alone.
Source: NEJM
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POINT Trial (2018): Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA
POINT Trial Summary: Johnston et al. randomized 4,881 patients who presented with low risk stroke or high risk TIA to either a combination of aspirin and clopidogrel or aspirin alone. Their objective was to assess the efficacy of dual antiplatelet therapy on recurrence of stroke, MI or mortality associated with ischemia. The results of POINT trial were significantly in favor of dual antiplatelet therapy when it comes to primary end point (P=0.02). However, the effect was masked by the increase in major hemorrhage risk that these patients were exposed to (P=0.01)
Full POINT trial results available at NEJM
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PLACIDE Trial (2013): Lactobacilli and bifidobacteria in preventing antibiotic-associated and C.diff diarrhea
PLACIDE trial summary: Allen SJ et al. conducted a multicenter, randomized, double blind, placebo-controlled trial to assess the efficacy of probiotics in preventing antiobiotics associated (AAD) or C.diff associated diarrhea (CDAD) in elderly hospitalized patients. Over 2,941 elderly patients with age >65 and exposure to antibiotics were enrolled and randomized to either a probiotic therapy or placebo therapy. The primary outcome of the PLACIDE trial was diarrhea onset within 8 weeks (if antibiotics assocaited) or 12 weeks if C.diff associated. The results showed no difference in outcomes and thus the study concluded that adding probiotics does not prevent AAD or CDAD.
Source: Lancet
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PANSAID Trial (2019): Paracetamol and Ibuprofen on Morphine Consumption in the Total Hip Arthroplasty
PANSAID Trial Summary: Hojgaard et al. randomized 556 patients who were scheduled to undergo total hip arthroplasty to pain control with a combination of paracetamol + ibuprofen or any one of them with placebo. The primary objective was to assess if post-op morphine requirement decreases with the use of adjunctive pain medications. The results showed significant decrease in morphine requirement when paracetamol and ibuprofen were used in combination full dose. Ibuprofen alone was also found to have signficant benefit in terms of decreasing the morphine requirement therefore, the authors concluded that isolated ibuprofen can be used as an adjunct pain medication to lessen the requirement of patient-controlled morphine in patients who undergo total hip arthroplasty.
Source: JAMA
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COMMANDER HF Trial (2018): Rivaroxaban in Patients with Heart Failure, Sinus Rhythm, and Coronary Disease
COMMANDER HF Trial Summary:
Source: NEJM
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TRED-HF Trial (2019): Withdrawal of treatment for HF in patients with recovered DCM
TRED-HF Trial Summary: Halliday et al. randomized 51 patients with dilated cardiomyopathy (LVEF<40%) who recovered with the improvement of symptoms to either continual treatment with HF medications or withdrawal of HF therapy. The objective was to assess the safety of withdrawing treatment in patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered. The results showed significant
Source: Lancet
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DECLARE TIMI 58 Trial (2019): Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes
DECLARE TIMI 58 Trial Summary: Wiviott et al. randomized 17,160 patients with DMII (HbA1c 6.5-12%) who had multiple risk factors for or had established atherosclerotic CV disease to either dapagliflozin or a placebo. Their objective was to assess the cardiovascular safety profile of dapagliflozin, a selective inhibitor of SGLT2 in patients with type 2 diabetes. The results were promising and showed a significant decrease in CV death and HF hospitalizations (P=0.005). No difference was noted in the major adverse CV events. The authors of DECLARE TIMI 58 trial concluded that in patients with type 2 DM who had or were at risk for atherosclerotic CV disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE but did result in a lower rate of CV death or hospitalization for heart failure.
Source: NEJM
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OPTIC Trial (2019): Omadacycline for Community-Acquired Bacterial Pneumonia
OPTIC Trial Summary: Stets et al. randomized 774 patients with community-acquired bacterial pneumonia (PSI risk class II, III, or IV) diagnosed clinically and with imaging to either
Source: NEJM
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MOMENTUM 3 Trial (2018): Magnetically Levitated Cardiac Pump in Heart Failure
MOMENTUM 3 Trial Summary: Mehra et al. randomized 366 patients with advanced HF (NYHA class III-IV, LVEF ≤ 25%), inotrope dependant, cardiac index < 2.2 without inotropes to either HeartMate III (centrifugal-flow LVAD) or HeartMate II (axial-flow LVAD). Their objective was to assess if is a magnetically levitated centrifugal-flow LVAD is superior to an axial-flow LVAD with regards to reoperation for device malfunction or disabling stroke in patients with advanced HF. The results showed the superiority of HeartMate III in terms of freedom from device failure. No differences in stroke were noticed. The authors of MOMENTUM 3 trial concluded that implantation of a fully magnetically levitated centrifugal-flow pump was associated with better outcomes at 6 months than was implantation of an axial-flow pump, primarily because of the lower rate of reoperation for pump malfunction.
Source: NEJM
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TRICC Trial (1999): Transfusion requirements in critical care
TRICC trial Summary: Hebert PC et al. randomized 838 critically ill patients with anemia Hb < 9.0 g/dL within 72 hours after the ICU admission to either restrictive transfusion strategy (Hb 7-9) or liberal strategy (Hb 10-12). The objective was to compare the effect of restrictive transfusion goal with a liberal transfusion goal on mortality in critically ill patients. The results showed no difference in
Source: NEJM
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TNT Trial (2005): Intensive lipid lowering with atorvastatin in patients with Stable CAD
TNT Trial Summary: LaRosa et al. randomized 10,001 patients with CAD defined by prior MI, prior or current anginal symptoms with evidence of CAD, prior revascularization to either high dose 80 mg atorvastatin or low dose 10 mg atorvastatin. Their objective was to assess if atorvastatin 80 mg PO daily have a greater reduction in CV events when compared to 10 mg atorvastatin in patients with stable CAD and hyperlipidemia. The results showed a significant decrease in major CV events. (P<0.001; NNT 45) These events were composite of CAD mortality, MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke. The authors of the
Source: NEJM
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Transfusion Strategies for Acute Upper Gastrointestinal Bleeding Trial (2013)
In 2013, Dr. Villanueva et al. randomly assigned over 921 patients with upper gastrointestinal bleed who presented with either hematemesis or melena to either low transfusion goal of >7 threshold or greater transfusion goal of >9 threshold.
Their goal was to assess all-cause mortality in these patients. Patients who received restrictive transfusion showed an almost double reduction in terms of primary outcome (P=0.02) as compared with the liberal group. It’s worthwhile to look at TRISS trial results here that studied the transfusion thresholds in patients with septic shock and found no difference in terms of mortality.
The authors concluded a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding.
Source: NEJM
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RE-DUAL PCI Trial (2017): Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation
RE-DUAL PCI Trial Summary
RE-DUAL PCI trial was a multi-center, randomized trial that compared the outcomes of triple and dual therapy as well as warfarin and dabigatran. Patients with AF who have undergone PCI (N=2,725) were randomly assigned to either triple therapy (aspirin, warfarin and a P2Y12 inhibitor) or dual therapy (dabigatran 150mg BD or 110mg BD and a P2Y12 inhibitor). In the triple therapy group, aspirin was discontinued 1 month in those who received a bare metal stent and after 3 months in those who received a
The primary end-point of the study was the first ISTH major bleed or clinically relevant non-major bleed. The trial also tested for noninferiority in the efficacy of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin and the occurrence of a composite of MI, stroke, systemic embolization, death, or unplanned revascularization. The mean duration of treatment with the anticoagulants was 12.3 months, and the mean
Compared with the warfarin group, the primary safety endpoint occurred in a smaller proportion of the dual therapy group with 110mg BD of dabigatran (15.4%, HR 0.52, 95% CI 0.42-0.63, P<0.001), followed by the 150mg BD group (20.2%, HR 0.72, 95% CI 0.58-0.88, P<0.001). The incidence of the primary endpoint in the warfarin group was 26.9% in all patients and 25.7% when excluding elderly patients outside the US. The incidence of the composite efficacy endpoint in the combined dabigatran group and triple therapy groups were 13.7% and 13.4% respectively (HR 1.04, 95% CI 0.84-1.29, P=0.005 for noninferiority).
Summarized by Dr. Tarek Nafee
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WOEST Trial (2013): Clopidogrel with or without aspirin in patients taking OAC and undergoing PCI
WOEST Trial Summary
WOEST trial was an open-label randomized controlled trial in patients who were on oral anticoagulants and underwent PCI with coronary stenting. Patients who were on oral anticoagulants and underwent PCI with coronary artery stenting (N=573) were randomly assigned to 2 groups: Dual therapy (Clopidogrel and OAC) or triple therapy (Aspirin, clopidogrel, and OAC).
The primary outcome observed was any bleeding episode that occurred within 1 year of PCI. The secondary
TIMI major and minor bleeding events occurred in 14% and 31.3% of the double and triple therapy groups respectively with
Summary by:
BIDMC, Mass
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AF-CHF Trial (2008): Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure
AF-CHF Trial Summary: Roy D et al. randomized 1,376 patients with nonvalvular atrial fibrillation and HFrEF (LVEF ≤35% and NYHA II-IV symptoms) were randomized to rhythm control (pharmacologic or electrical approach) or rate control (target <80 bpm at rest). The objective was to assess if rhythm-control reduce CV mortality in patients with AF and HFrEF as compared to rate control. The results showed no difference in terms of CV mortality in both groups. (P=0.59) The authors of the AF CHF trial concluded that among patients with AF and HFrEF, rhythm-control did not reduce cardiovascular mortality but did reduce AF related hospitalizations, as compared to rate control.
Source: NEJM
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SPRINT MIND Trial (2019): Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia
SPRINT-MIND Trial Summary: Authors of this trial randomized 9,361 adults aged 50 years or older with hypertension but without diabetes or history of stroke to either intensive control (SBP < 120 mmHg) or standard control (SBP < 140 mmHg). The objective was to assess if intensive blood pressure control reduces the occurrence of dementia as compared moderate control. The results showed no difference in terms of adjudicated probable dementia (P=0.10). However, it did show a significant decrease in mild cognitive impairment in patients whose BP was intensively controlled. (P=0.007) The authors of SPRINT-MIND trial concluded that in ambulatory adults with hypertension, intensive BP control (SBP < 120 mmHg) did not reduce the risk of probable dementia but significantly reduced mild cognitive impairment.
Source: JAMA
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PROVE IT Trial (2004): Intensive vs Moderate Lipid Lowering with Statins after ACS
PROVE IT Trial Summary
In 2004, Dr. Cannon et al. randomly assigned over 4,162 patients with acute coronary syndrome within past 10 days to either high dose atorvastatin 80 mg or moderate dose 40 mg pravastatin. Their goal was to assess
The authors concluded that among patients with
The current ESC, as well as ACC/AHA
guidelines recommend starting all patients with ACS on high dose statin therapy.Grade IA. Source
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FREGAT Trial (2019): Minimally Invasive Esophagectomy for Esophageal Cancer
Source: NEJM
FREGAT Trial Key Points
- Minimally invasive esophagectomy (MIE) was found to have significantly lower complications and side effects compared to open esophagectomy.
- The 3 years survival rate was also higher among patients undergoing minimal invasive esophagectomy.
- Open esophagectomy is known to have significant morbidity ranging from 17.9% to 58%, with up to 6% mortality. Therefore, the minimally invasive hybrid procedure is now being utilized to limit the adverse events.
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Algorithm: Diagnostic Workup of Primary Aldosteronism
Primary Aldosteronism Diagnosis Algorithm
Primary aldosteronism is characterized by elevated plasma aldosterone levels that
In order to discuss the diagnostic approach for primary aldosteronism in terms of both blood tests and imaging tests, I have designed this algorithm after reading the society of endocrine guidelines and indications of each test.
Feel free to contact me in case there’s any discrepancy between this algorithmic approach versus standard approach of diagnosing primary aldosteronism.
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SMART-DATE Trial (2018): 6 vs 12 months of DAPT after PCI with DES in ACS
The SMART-DATE trial tested the hypothesis as to whether 6 months of dual antiplatelet therapy (DAPT) is non-inferior to 12 months of DAPT in patients who underwent percutaneous coronary intervention (PCI) with drug-eluting stents (DES) and require DAPT. Source
SMART-DATE Trial Key Points:
6 months DAPT was found to be
The SMART-DATE trial tested the shorter duration and is comparable to DAPT trial which tested 18 months duration of DAPT versus 12 months standard management.
Guidelines based on SMART-DATE trial
The last ACC/AHA guidelines were before this trial and recommends:
Complete 12 months of DAPT in patients who underwent PCI with either DES or BMS. (recommendation: 1a, LOE: A)
For patients who have complications such as bleeding, guidelines recommend that DAPT can be discontinued after 6 months.
(recommendation: IIa)For patients at low risk of bleeding, DAPT can be continued beyond 12 months. (recommendation: IIa)
http://www.onlinejacc.org/content/68/10/1082
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MIRACL Trial (2001): Atorvastatin use for early recurrent ischemic events in ACS
2001, Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA
MIRACL Trial Key Points:
- In addition to lowering the cholesterol and LDL levels, statins have been coined to lower the platelet aggregability, thrombus deposition and vascular inflammation as well.
- This observation led to the hypothesis that statins might be useful in lowering the recurrence of ischemic events after UA or NSTEMI.
- The MIRACL trial tested this hypothesis and showed 2.6% absolute reduction in recurrent ischemic events after early initiation of atorvastatin in patients who presented with UA or NSTEMI.
Guidelines changes
The 2014 ACC/AHA guidelines on NSTEMI recommends:
Initiate or continue high-intensity statin therapy in patients with no contraindications (Grade I, LOE: A)
Obtain a fasting lipid profile, preferably within 24 h (Grade IIa, LOE: C)
http://www.ncbi.nlm.nih.gov/pubmed/25260718
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VANISH Trial (2016): VT Ablation vs Escalation of Antiarrhytmic drugs
2016, VANISH Trial – Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs, NEJM
VANISH Trial Key Points:
- Patients with ischemic cardiomyopathy and LVEF < 35% are candidated for ICD implantation but high VT burden in these patients is associated with higher mortality despite ICD placement.
- Previously, antiarrhythmic therapy (AAT) specifically amiodarone has been used to suppress VT in these patients. However, newer data suggested VT ablation in addition to AAT lowers mortality further.
- The VANISH trial answered this particular question of using VT ablation rather than escalating AAT for patients with recurrence of VT despite being on AAT.
- The trial showed 10% absolute decrease in composite outcome of death, VT storm (3 more episodes of VT within 24 hours), and appropriate ICD shock after 2 years of follow up.
Guideline Changes based on VANISH trial:
The 2017 AHA/ACC/HRS guidelines recommend:
In patients with prior myocardial infarction and recurrent episodes of symptomatic sustained ventricular tachycardia (VT), or who present with VT or ventricular fibrillation storm and have failed or are intolerant of amiodarone (Level of Evidence B-R) or other antiarrhythmic medications (Level of Evidence B-NR), catheter ablation is recommended.
https://www.acc.org/latest-in-cardiology/ten-points-to-remember/2017/10/29/08/56/2017-guideline-for-management-of-patients-with-ventricular-arrhythmias
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CANTOS Trial (2017): Canakinumab for Atherosclerotic Disease
2017, CANTOS Trial: Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease, NEJM
The CANTOS trial evaluated the inflammatory nature of coronary artery disease where hypothesis was that decreasing the inflammation marker such as interleukin 1B will result in lower incidence of cardiovascular events. For this purpose, canakinumab which is a monoclonal antibody against IL-1B was tested against a placebo. The only dose that achieved significance after multiplicity-adjusted threshold for statistical significance was the 150 mg group.
The patients that responded best were those who achieved on-treatment hsCRP concentrations less than 2 mg/L. The authors observed a 25% decrease in major cardiovascular events in these patients. This was in contrast to those who continued to elevated hsCRP levels despite treatment. Based on this observation, the CANTOS trial authors concluded, “the magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment.”
With CANTOS trial results, Dr. Paul Ridker et al. decided to take a step forward and tried to inhibit the chain of inflammatory markers including IL-1, IL6 and CRP. They utilized methotrexate for this purpose and described their results in the CIRT trial.
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FOURIER Trial (2017): Evolocumab and Clinical Outcomes in Patients with CVD
FOURIER Trial Key Points:
- FOURIER trial established the role of PCSK9 inihibitor therapy in reducing future cardiovascular events and mortality.
- Evolocumab showed benefit in terms of cardiovascular disease but didn’t show any mortality benefit.
- These agents were utilized in patients who were already on moderate to high intensity statin therapy.
- PCSK9 inhibition was well-tolerated without excess new-onset diabetes or neurocognitive effects despite dramatic LDL reduction.
Guidelines on PCSK9 inhibition – ACC 2017 Update for Non-Statin Therapy
- If patients with clinical ASCVD and comorbidities require >25% additional lowering of LDL-C, a PCSK9 inhibitor may be preferred as the initial non-statin agent.
- If patients with clinical ASCVD and baseline LDL-C ≥190 mg/dL require >25% additional lowering of LDL-C or have additional comorbidities as defined in the previous text, a PCSK9 inhibitor may be preferred as the initial non-statin agent.
- If high-risk patients with baseline LDL-C ≥190 mg/dL require additional LDL-C lowering (<50% reduction in LDL-C, may consider LDL-C ≥100 mg/dL or
non –HDL-C ≥130 mg/dL) after the addition of a single non-statin agent (i.e., ezetimibe) to maximally tolerated statin therapy, it is reasonable to consider the addition of a second non-statin agent (i.e., ezetimibe plus PCSK9 inhibitor). - Read full guidelines at ACC
Source: NEJM
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STOP-IT Trial (2015): Short Course of Antibiotics for Intraabdominal Infections
2015, Short-Course Antimicrobial Therapy for Intraabdominal Infection, NEJM
STOP-IT Trial Key Points:
- A shorter course (3-5 days) of antibiotics was found to be non-inferior when compared to
traditional course of 4 to 7 or 7 to 14 days. Important point was to adequately control the source which means draining the abscess in case there is one or any other nidus of infection.
Guidelines Related to STOP-IT trial
The 2009 IDSA guidelines suggested 4-7 days course of antibiotics once the source is adequately controlled. The STOP-IT trial tested more restrictive therapy of 3 to 5 days of antibiotics and found no difference in outcomes. The study addressed an important issue
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FRISC II Trial (2006): Invasive vs non-invasive treatment in unstable CAD
1999, Invasive compared with non-invasive treatment in unstable coronary-artery disease, The Lancet
The FRISC II trial established the role of early intervention in patients with UA/NSTEMI. The study compared maximal medical therapy or
The combine MI and/or mortality was found to be significantly lower after 5 years in patients who underwent invasive approach compared with
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RENAL Trial (2009): Intensity of CRRT in Critically Ill Patients
2009, Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients (RENAL), NEJM
The RENAL trial was one of the largest trials that addressed an important question of doing continuous renal replacement therapy (CRRT) in critically ill patients with renal impairment. Based on this trial, high intensity CRRT at flow rate of 40 ml/kg/hr was found to have no benefits when compared to conventional CRRT at 25 ml/kg/hr.
Prior to this trial, the ATN trial was done in 2008 and compared high intensity renal replacement therapy with conventional approach in similar critically ill population. Both trials showed no benefits in the high intensity approach. In ATN trial, the stable patients were randomized to intermittent hemodialysis (HD) and the CRRT was reserved for unstable patients only. In contrast, RENAL trial addressed the intensity of CRRT and didn’t involve HD.
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TIMACS Trial (2009): Early versus Delayed Invasive Intervention in ACS
2009, TIMACS trial: Early vs delayed invasive intervention in acute coronary syndrome, NEJM
TIMACS trial addressed the question of when to intervene in patients who come to
The ABOARD and OPTIMA trial were done during the same year but these were smaller trials with limited study population compared to TIMACS trial. The FRISC II trial (1999) also showed benefits of early intervention within 7 days in terms of
The 2014 ACC/AHA guidelines on NSTE-ACS recommends early invasive strategy (within 24 hours of admission) over a delayed invasive strategy (within 25 to 72 hours) for initially stabilized high-risk patients with NSTE-ACS.
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IABP-SHOCK II Trial (2012): Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock
2012, Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock, NEJM
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RESPECT Trial (2013): Closure of PFO versus Medical Therapy after Cryptogenic Stroke
2013, Closure of Patent Foramen Ovale versus Medical Therapy after Cryptogenic Stroke, NEJM
RESPECT Trial Key Points:
- Patients with cryptogenic stroke have higher incidence of PFO compared to general population. This led to the concept that closing PFO might be beneficial in terms of preventing recurrence of stroke in this population.
- The initial CLOSURE I trial showed no benefits of closing PFO percutaneously. In contrast, RESPECT trail showed benefits of PFO closure with the Amplatzer device.
- Patients deriving the maximum benefit from PFO closure were those with high grade shunt with presence of left atrial aneurysm.
- CLOSE and REDUCE are two more recent trials that show similar benefits of PFO closure over medical management.
Guideline changes based on the RESPECT Trial:
The last AHA/ASA guidelines were from 2014 which were published based on results of CLOSURE I and RESPECT trial. They recommended:
For patients with an ischemic stroke or TIA and a PFO who are not on anticoagulation therapy, antiplatelet therapy is recommended. (Class I, LOE B)
For patients with an ischemic stroke or TIA and both a PFO and a venous source of embolism, anticoagulation is indicated, depending on stroke characteristics. (Class I, LOE A). When anticoagulation is contraindicated, an inferior vena cava filter is reasonable. (Class IIa, LOE C).
For patients with a cryptogenic ischemic stroke or TIA and a PFO without evidence for DVT, available data does not support a benefit for PFO closure. (Class III, LOE A)
In the setting of PFO and DVT, PFO closure by a transcatheter device might be considered, depending on the risk of recurrent DVT. (Class IIb, LOE C)
http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@smd/documents/downloadable/ucm_462196.pdf
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ACCORD Trial (2008): Effects of Intensive Glucose Lowering in Type 2 Diabetes
| ACCORD Trial Summary: Gerstein et al randomized 10,251 patients with type 2 diabetes mellitus, hemoglobin A1c ≥7.5% with CAD or ≥2 cardiovascular risk factors (dyslipidemia, HTN, current smoking, obesity) to either standard glycemic control HbA1c 7-7.9% (n=5,123) or intensive glycemic control HbA1c <6% (n=5,128). The primary objective was to assess if intensive glycemic control targeting a HbA1c <6% versus standard glycemic control targeting a HbA1c 7-7.9% reduce the risk of CV events in patients with type II diabetes. The primary outcome of nonfatal MI or nonfatal stroke or CV death was non-significant among both groups. However, Source: 2008, Effects of Intensive Glucose Lowering in Type 2 Diabetes, NEJM |
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PACIFIC Trial (2017): Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC
PACIFIC Trial Summary (NEJM 2018): Scott J et al. randomized 713 patients with stage III unresectable nonsmall cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy were randomized to either Durvalumab 10mg/kg body weight twice weekly for 12 months (n=473) or matching placebo (n=236). The primary objective was to assess if Durvalumab prolongs survival and increases the time to death or prevent distant metastasis in patients with stage 3 unresectable nonsmall cell lung cancer. The primary outcome of 24-month overall survival rate was significantly higher in the
Source: 2018, Durvalumab in non small cell lung cancer, NEJM
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DEFUSE-3 Trial (2018): Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging
DEFUSE-3 Trial Summary: Gregory W et al. randomized 182 patients with proximal middle-cerebral-artery or internal carotid artery occlusion, an initial infarct size of <70 ml, and a ratio of the volume of ischemic tissue to infarct volume ≥ 1.8 to either thrombectomy endovascular therapy group (n=92) or medical therapy group (n=90). The primary objective was to assess the utility of thrombectomy in patients 6 to 16 hours after they were last known to be well and who were likely to have salvageable ischemic brain tissue. The primary outcome of the modified Rankin scale score at 90 days was 3 in the thrombectomy group compared to 4 in medicine group (OR 2.77, 95% CI 1.63 – 4.70; P<0.001). The authors of the DEFUSE-3 trial concluded that endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone.
Source: 2018, Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging, NEJM
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SURVIVE Trial (2007): Levosimendan vs dobutamine for patients with acute decompensated heart failure
ATHOS-3: Angiotensin II for the Treatment of Vasodilatory Shock
ATHOS-3 Trial Summary:
A total of 321 patients with vasodilatory shock on high dose catecholamines were randomized to angiotensin II or placebo. Within 3 hours, ~70% of in the angiotensin II group showed significant improvement in their mean arterial pressure as compared with 23.4% patients in
ATHOS-3 Trial 2017, Angiotensin II for the Treatment of Vasodilatory Shock, NEJM
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ULTIMATE Trial: IVUS vs Angiography-Guided Implantation of DES
ULTIMATE Trial Key Points:
- At 12 months, patients undergoing IVUS guided PCI had lower rate of target vessel failure when compared to traditional andiography guided PCI.
- Enrolled patients had complex coronary disease including multi vessel disease as well as bifurcation blockages.
- The study re-emphasized the rationale for the more routine use of IVUS to guide PCI.
Current Guidelines on Use of IVUS for PCI
ESC guidelines:
- IVUS in selected patients for optimizing stent implantation. (Class IIa, LOE: B)
- IVUS to assess severity and guide management of unprotected left main stem disease. (Class IIa, LOE: C)
AHA/ACC Guidelines
- IVUS reasonable for assessment of angiographically indeterminate left main CAD. (Class IIa, LOE: B)
2018, IVUS vs angiography guided implantation of DES, JACC
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AVERT Trial: Apixaban to Prevent VTE in Patients with Cancer
2018, Apixaban to Prevent Venous Thromboembolism in Patients with Cancer, NEJM
The AVERT trial evaluated the use of apixaban for preventing venous thromboemboli such as deep venous thrombosis and pulmonary embolism in patients with cancer who were scheduled to start chemotherapy. These patients were at high risk of VTE based on the Khorana score.
The point that differentiated AVERT trial from other similar trials of using drugs for prevention of VTE in cancer patients was that it enrolled patients who did not have a history of VTE and the primary target was to lower the first incidence of VTE. In comparison, the CLOT and Hokusai VTE trials studied the use of LMWH for secondary prevention of VTE.
The study did show benefits of apixaban in preventing the first episode of VTE but this was countered by significant increase in bleeding risk. Currently based on guidelines, LMWH are preferred agents of choice for secondary prevention of VTE in patients with cancer. The 2012 CHEST guidelines on antithrombotic therapy recommend:
In patients with DVT of the leg and cancer, we suggest LMWH over VKA therapy (Grade 2B). In patients with DVT and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2B).
Source
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BLOCK HF: Biventricular versus Right Ventricular Pacing in Heart Failure Patients with AV Block
2013, Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block, NEJM
BLOCK HF Trial Summary
The Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) trial is a prospective, multicentric, double-blinded, industry (Medtronic) sponsored, randomized controlled trial conducted to evaluate role of biventricular (BiV) pacing in patients with high-degree atrioventricular (AV) block (as a surrogate for obligatory RV pacing) and LV systolic dysfunction in comparison to standard right ventricular (RV) pacing.
691 patients were randomized 1:1 to BiV pacing (n=349) or RV pacing (n=342) in 58 centers in the United States and 2 centers in Canada between 2003 and 2011. Initially, patients enrolled in the study received pacemakers only. However, with evidence supporting the use of implantable cardioverter–defibrillator (ICD) therapy in patients with heart failure and left ventricular dysfunction for the primary prevention of sudden cardiac death, the protocol was revised in December 2005 to allow ICD implantation in such patients.
The study included patients with Class I or IIa indication for pacemaker implantation owing to high-degree AV block who also had NYHA class I-III heart failure with LVEF <= 50%. High-degree AV block was defined as documented complete AV block (including patients who had AV node ablation) or demonstration of second-degree AV block or PR interval >= 300 ms when paced at 100 beats/min. It excluded previous recipient of a cardiac implantable electrical device, patients with unstable angina or acute myocardial infarction, percutaneous or surgical coronary intervention within 30 days before enrollment, valvular disease with an indication for valvular repair or replacement and patients with an indication for a CRT device.
Baseline characteristics were similar in both groups. Mean LVEF was 40 +/- 8.3%. Most were NYHA II or III patients. Baseline mean heart rate was 68.8 bpm, QRS duration was 123 ms. 48.8% had third-degree AV block, 31.6% had second-degree and 19.3% had first-degree AV block. 29.8% had left bundle branch block and 21.6% had right bundle branch block. The mean ventricular pacing in both groups was more than 97%.
After mean follow-up of 37 months, there was a statistically significant difference in favor of BiV pacing (45.8%) over RV pacing (55.6%) in the primary outcome of time to death from any cause, an urgent care visit for heart failure (HF) that required IV therapy, or >= 15% increase in left ventricular end-systolic volume index (surrogate marker for LV remodeling) (HR 0.74; 95% credible interval, 0.60 to 0.90). When patients were stratified according to the type of device implanted- pacemaker or ICD, the results were similar (for BiV pacing: HR in pacemaker only cohort was 0.73; 95% credible interval, 0.58 to 0.9; and HR in ICD cohort was 0.75; 95% credible interval, 0.57 to 1.02).
Secondary outcome of – death or urgent care visit for HF, death or hospitalization for HF, and HF hospitalization alone were all in favor for BiV pacing. But death alone was similar for the two groups.
The study concluded that BiV pacing provided significant clinical benefit over RV pacing in patients with LV dysfunction and AV block who required ventricular pacing.
In patients with high-degree AV block and HF with LV systolic dysfunction, the BiV pacing is associated with a approximately 10% absolute risk reduction in death, urgent HF care and adverse LV remodeling compared with RV pacing, and this is primarily driven by reduced HF hospitalizations and reduced LV remodeling.
Reviewed by Saurabh Joshi, MD
Affiliation: Department of Cardiovascular disease, University of Connecticut Health Center
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EXCEL: Everolimus-Eluting Stents or Bypass Surgery for Left Main CAD
2016, Everolimus-Eluting Stents or Bypass Surgery for Left Main Coronary Artery Disease, NEJM
EXCEL Trial Summary
Summarized by Lina Ya’qoub, MD – Cardiovascular disease fellow at Louisiana State University
Methods
The Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization (EXCEL) trial is an international, open-label, non-inferiority, multicenter randomized trial that compared everolimus-eluting stents with CABG in patients with left main coronary artery disease. Inclusion criteria were stenosis of the left main coronary artery of 70% or more, as estimated visually, or stenosis of 50-69% if determined by means of noninvasive or invasive testing to be hemodynamically significant, and a consensus among the members of the heart team regarding eligibility for revascularization with either PCI or CABG. In addition, participants were required to have low-to-intermediate anatomical complexity of coronary artery disease, as defined by a site-determined SYNTAX score, with low score being <=22 and intermediate score being 23-32.
Randomization
Among the 1905 patients who underwent randomization, 948 were assigned to the PCI group and 957 to the CABG group. Baseline clinical and angiographic characteristics were well balanced between the groups. Among the 948 patients assigned to the PCI group, 942 underwent revascularization; PCI was the first procedure in 935 patients. A mean of 2.4 stents with a mean total stent length of 49.1 mm were implanted per patient; 99.2% of the stents implanted were everolimus-eluting stents. Among the 957 patients assigned to the CABG group, 940 underwent revascularization; CABG was the first procedure in 923 patients. A mean of 2.6 grafts per patient were placed; an internal thoracic artery graft was used in 98.8% of the patients.
Follow-up/end-point events
The median duration of follow-up was 3.0 years (interquartile range, 2.4 to 3.0) in both groups. The primary composite end-point event of death, stroke, or myocardial infarction at 3 years occurred in 15.4% of the patients in the PCI group and in 14.7% of the patients in the CABG group (difference, 0.7 percentage points; upper 97.5% confidence limit, 4.0 percentage points; P=0.02 for noninferiority; hazard ratio, 1.00; 95% confidence interval [CI], 0.79 to 1.26; P=0.98 for superiority).
At 30 days, the composite end-point event of death, stroke, or myocardial infarction had occurred in 4.9% of the patients in the PCI group and in 7.9% of the patients in the CABG group (difference, −3.1 percentage points; upper 95.0% confidence limit, −1.2 percentage points; P<0.001 for noninferiority).At 3 years, the composite end-point event of death, stroke, myocardial infarction, or ischemia-driven revascularization had occurred in 23.1% of the patients in the PCI group and in 19.1% of the patients in the CABG group (difference, 4.0 percentage points; upper 95% confidence limit, 7.2 percentage points; P=0.01 for noninferiority).
Author Comments
Several studies have shown that outcome and safety of left main disease percutaneous coronary intervention (PCI) is similar to caronary artery bypass graft (CABG) in selected patients. The EXCEL trial aim was to assess major adverse cardiac events (death, stroke, MI) for PCI versus CABG over 3 years in patients with low-intermediate syntax scores. This randomized controlled trial proved that PCI was non-inferior to CABG in this population.
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FREEDOM: PCI vs CABG in Patients with Diabetes and multivessel CAD
2012, Percutaneous Coronary Intervention (PCI) vs CABG in Patients with Diabetes and multivessel CAD
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BICAR-ICU: Sodium Bicarbonate in Severe Metabolic Acidaemia
2018, Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit, The Lancet
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AGE: Mammographic screening from age 40 years
2006, Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years, The Lancet
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EPHESUS: Eplerenone in patients with LV dysfunction after MI
2003, Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction, NEJM
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CURE: Effects of Clopidogrel plus Aspirin in Patients with NSTEMI
2001, Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes without ST-Segment Elevation, NEJM
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CAST I: Use of Antiarrhythmics post-MI for Cardiac Arrhythmia Suppression
1991, Mortality and morbidity in patients receiving encainide, flecainide, or placebo, NEJM
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CHARISMA: Aspirin/clopidogrel vs. aspirin for CV prevention
2006, Clopidogrel and aspirin versus aspirin alone for prevention of atherothrombosis, NEJM
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LESS: Epidural Glucocorticoid Injections for Spinal Stenosis
2014, epidural glucocorticoid + lidocaine vs lidocaine only injections for spinal stenosis, NEJM
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POISE: Metoprolol succinate in patients undergoing non-cardiac surgery
2008, Extended-release metoprolol succinate in patients undergoing non-cardiac surgery, The Lancet
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SALT-ED: Balanced crystalloids versus saline in non-critically ill adults
2018, Lactated Ringer’s or Plasma-Lyte vs normal saline in non-critically ill patients, NEJM
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COMET: Comparison of Carvedilol and Metoprolol in Chronic Heart Failure
2003, Carvedilol vs Metoprolol in Heart Failure, The Lancet
The COMET trial randomized 3029 patients with NYHA Class II, III or IV heart failure and a reduced ejection fraction of 35% or less to receive either 25mg of carvedilol twice daily or 50mg of metoprolol twice daily on top of optimal therapy with diuretics and ACE inhibitors unless not tolerated. The co-primary endpoints were all-cause mortality and a composite of all-cause death or all-cause hospitalization.
Patients were followed for 5 years. Overall, 35% of patients assigned to the carvedilol group and 40% in the metoprolol group died (HR:0.83; 95%CI: 0.74 to 0.93; p=0.0017). This reduction in mortality was consistent across all pre-specified subgroups, including: sex, age, NYHA class, LVEF, heart rate, systolic blood pressure, or diabetic status. The co-primary composite endpoint occurred in 75% of patients in the carvedilol group and 74% of those in the metoprolol group (HR: 0.94; 95%CI: 0.86 to 1.02; p=0.122).
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POP-UP: Pantoprazole or Placebo for Stress Ulcer Prophylaxis
2016, Pantoprazole for reducing GI bleeding in intubated patients, Critical Care Medicine
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RACE II: Strict vs Lenient Control of Heart Rate in Atrial Fibrillation
2010, Heart Rate Control in patients with Atrial Fibrillation in Preventing CV events, NEJM
RACE II Visual Summary
RACE II was a randomized, prospective, open label, multicenter (33 centers in Netherlands), parallel-group,non-industry sponsored, controlled noninferiority trial investigatingthe role of lenient ratecontrol (HR<110 bpm) versus strict rate control (HR<80 bpm) in preventing cardiovascular events in patients with permanent atrial fibrillation (AF).
614 patients randomized [lenient rate control (n=311) vs. strict rate control (n=303)]. Enrollment was between 2005 & 2007 with follow up for 2-3 years.Patient <= 80 years, with permanent AF for up to 12 months, having mean resting HR > 80 bpm, and on oral anticoagulation therapy or aspirin (if no risk factors for thromboembolic complication present) were included. Those with paroxysmal AF, known contraindications to either strict or lenient rate control, NYHA class IV or HF admission <3 months, cardiac surgery <3 months, stroke, current or planned PPM, ICD or CRT, SSS or AV conduction disturbance, untreated hyperthyroidism, or inability to walk/bike were excluded.
AV nodal blocking agents (beta-blockers, non-dihydropyridine CCBs, or digoxin; alone or in combination) were administered and dose adjusted to achieve target heart rate. More patients in the lenient control arm achieved the target heart rate than in the strict control arm (97.7% vs 75.2%; P<0.001). The mean heart rate in the lenient and strict control arms were 93 & 76 bpm respectively at the end of dose adjustment phase and 85 & 76 bpm respectively at the end of the study follow up period. INR was similar in the two arms.
Primary outcome was the composite of cardiovascular death, HF hospitalization, stroke, systemic embolism, major bleeding and arrhythmic events (syncope, sustained VT, cardiac arrest, life-threatening adverse effect of rate control agents, and implantation of PPM or ICD). Primary outcome was met in 12.9% in the lenient control arm vs 14.9% in the strict control arm [absolute difference of 2% (90% CI -7.6 to 3.5%; P < 0.001); HR 0.84 (90% CI 0.58 to 1.21)].
Individual components of the primary outcome were similar in the two arms. All-cause death, symptoms from AF, number of patients in each NYHA class I to III, frequency of hospitalization and adverse events were similar in the two arms as well. Authors (Van Gelder IC et al) concluded that “in patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve”.
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HOPE: ACE inhibitors, ramipril in high risk CV patients
2000, Effect of ACE inhibitors, ramipril on cardiovascular morbidity and mortality, NEJM
HOPE Trial Summary
HOPE – “Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Cardiovascular Events in High-Risk Patients’ was a randomized, double-blinded, multi-national (267 centers), placebo-controlled, clinical trial (recruited patients between 1993 and 1995), which investigated the role of ACE inhibitor (ramipril 10mg oral daily) in patients >= 55 years of age with vascular disease (CAD, stroke, or PAD) or diabetes and one additional CV risk factor (HTN, elevated total cholesterol, low HDL, smoking, or microalbuminuria), but who did not have MI or stroke in the preceding 4 weeks, history of HF, LVEF <40%, uncontrolled HTN, overt nephropathy, and who were not already on ACE inhibitor.
After a run-in phase, 9541 patients were randomized. The study was terminated early because of the beneficial effect of ramipril. At 4 years, the primary outcome, which was the composite of MI, stroke and cardiovascular death, was significantly less with ramipril (14% vs 17.8%; RR: 0.78; 95% CI: 0.70-0.86; P<0.001). Of note, these beneficial effects became statistically significant at 2 years and continued to improve. Rates of individual components primary outcome were also statistically lower with ramipril.
Other outcomes- death from any cause, worsening angina and heart failure were less with ramipril as well. The benefit with ramipril, in terms of the primary outcome, was also observed in the predefined subgroups- above or below 65 years of age, male or female, with or without diabetes, with or without evidence of vascular disease, with or without history of HTN, with or with or without microalbuminuria.
Worth mentioning, the BP at baseline was similar in the two groups (139/79 mmHg) and very small reduction in systolic and diastolic BP (3 and 2 mmHg respectively) was noticed in the ramipril arm.
Authors of this trial (Yusuf S., et al) concluded: “treating 1000 patients with ramipril for four years prevents about 150 events in approximately 70 patients”.
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CRYSTAL-AF: Cryptogenic Stroke and Underlying Atrial Fibrillation
2014, 30 Days AF monitoring in patients with Cryptogenic Stroke, NEJM
CRYSTAL AF Trial Summary
The Cryptogenic Stroke and Underlying Atrial Fibrillation (CRYSTAL AF) trial randomized 441 patients ,who were 40 years or older and with a diagnosis of cryptogenic stroke or transient ischemic attack within 90 days, in a 1:1 ratio to Insertable Cardiac Monitor (ICM) implantation or routine monitoring at the investigator’s discretion. Prior to randomization, all patients underwent at least 24 hours of ECG monitoring and had no evidence of atrial fibrillation at baseline. Patients were enrolled in 55 centers in Canada, Europe, and the United States. The primary endpoint was the time to first detection of atrial fibrillation, lasting >30 seconds, within 6 months. Approximately, 8.9% of patients in the ICM group were diagnosed with AF, compared with 1.4% in the control group (HR: 6.4; 95%CI: 1.9 to 21.7; p<0.001). Results were consistent through 12 months and 36 months. Atrial fibrillation diagnosed in the ICM group was more frequently asymptomatic than in the control group. Prescription of oral anticoagulants was more than doubled in the ICM group, as compared with the control group, at both 6 and 12 months.
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SYNTAX: PCI vs CABG in Severe CAD
2009, Percutaneous Coronary Intervention versus CABG for Severe Coronary Artery Disease, NEJM
SYNTAX Trial Summary
SYNTAX trial was a noninferiority, randomized, prospective, multicenter (85 sites in 17 countries), open label, industry sponsored, parallel-group trial to investigate the outcomes (at 12 monthsof follow up) with two different revascularization strategies- PCI (with Taxus Express paclitaxel-eluting stents) vs. CABG, in patients with known LMCAD (with or without additional epicardial CAD)or 3 vessel CAD. The lesions had to be >=50%, previously untreated, and in patients with angina or atypical chest pain or asymptomatic with evidence of myocardial ischemia. Patients were screened between March 2005 and April 2007, and 1800 patients were randomly assigned (1:1) to either of the groups. They were also stratified according to the presence or absence of LM CAD. Coronary angiograms were scored according to the SYNTAX score algorithm. The primary end point of major cardiac or cerebrovascular events (cumulative of death from any cause, stroke, MI, and repeat revascularization) at 12 months were significantly higher in the PCI group than CABG group (17.8% vs. 12.4%; P =0.002). At 12 months, individual components of primary end point- death from any cause and MI were similar in the two groups, but stroke rates were higher in the CABG group whereas repeat revascularizations were higher in the PCI group. The rates of major cardiac or cerebrovascular events were similar in the two groups (PCI & CABG) and higher in the PCI group in the pre-stratified subgroups of LM CAD and 3 vessel CADrespectively. Of importance, the rates of major cardiac or cerebrovascular events were similar in the two groups for the low SYNTAX score (<=22), non-statistically numerically higher in the PCI group for the intermediate SYNTAX score (23-32), and statistically higher in the PCI group for the high SYNTAX score (>=33).
Serruys, P.W. et al. NEJM. March 2009.
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HACA: Hypothermia in Cardiac Arrest
2002, Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest, NEJM
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COURAGE: PCI vs Medical Therapy in Stable CAD
2007, PCI + medical therapy vs medical therapy only in stable coronary artery disease, NEJM
Courage Trial Summary
COURAGE was a randomized, open label, multicenter (50 centers in US & Canada), co-industry sponsored, clinical trial which tested the hypothesis that PCI with optimal medical therapy (OMT) is superior to OMT alone in reducing primary outcome of all cause death and nonfatal MI in patients with stable CAD.
Patients with >=70% stenosis in at least one proximal epicardial coronary artery with objective evidence of ischemia (ST segment depression or TWI on resting ECG, or inducible ischemia with exercise or pharmacologic vasodilator stress) or at least one coronary stenosis of >= 80% with classic angina without provocative test were included. Those with >=50% LM CAD, class IV angina, markedly positive stress test (ST depression or hypotension in Bruce stage I), coronary anatomy not suitable for PCI, in-stent restenosis, LVEF <30%, refractory HF, or revascularization in last 6 months were excluded.
Enrolled between 1999 and 2004, 2287 patient were randomized and followed for median of 4.6 years, with 9% lost to follow up. 85% were male, 86 % were white, 58% had class II or III angina, 69% had multivessel CAD and 34% had proximal LAD CAD. In those who received stents, only 31 had DES.
OMT included antiplatelet therapy with aspirin, anti-ischemic therapy with long acting metoprolol, amlodipine, or isosorbide mononitrate (alone or in combination), along with lisinopril or losartan and aggressive lipid therapy. In PCI group, in addition to OMT, patients received second antiplatelet agent (clopidogrel), and the target vessel revascularization was always attempted with complete revascularization as clinically appropriate.
Primary outcome (composite of all-cause death and nonfatal MI) was similar in PCI group (PCI + OMT) and medical therapy group (OMT alone) (19% vs 18.5% respectively; HR 1.05, 95% CI 0.87-1.27; P=0.62), and so were its individual components and secondary outcome (composite of death, MI and stroke). No difference was seen in terms of hospitalization for ACS and even with ethe xclusion of periprocedural MI, the primary outcome did differ in the 2 groups. Primary outcome was similar even in the prespecified subgroups of multivessel CAD, prior MI and diabetes. Substantial reduction in angina was seen in both groups, more so in the PCI group.
Authors (Boden WE et al) concluded :“as an initial management strategy in patients with stable CAD, PCI did not reduce the risk of death, myocardial infarction, or other major cardiovascular events when added to OMT”.
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NELSON: CT Screening For Lung Cancer in High Risk Population
Full trial results to follow the publication. This abstract format was presented at the WCLC 2018.
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COAPT Trial: Mitral Valve Repair in Heart Failure Patients with Functional Mitral Regurgitation
2018, Transcatheter mitral valve repair in patients with Heart failure, NEJM, ACC
COAPT Trial Summary
COAPT trial was an open label, multicentered, parallel-group and industry-sponsored randomized controlled trial investigating the outcomes with ‘transcatheter mitral valve repair with MitraClip device’ vs. ‘guideline directed medical & device therapy only’ in heart failure patients with dilated cardiomyopathy (CM) (both ischemic and non-ischemic) who had moderate to severe and severe secondary (functional) mitral regurgtation. In addition, these patients were NYHA class II, III or IVa, had LVEF >=20% &<=50%, had LVEDD <=7mm, were on maximally tolerated GDMT and CRT (if indicated), were determined not to be apprpriate for mitral valve surgery, and did not have HCM, RCM, infiltrative CM or constritive pericarditis. Primary end point of all heart failure hospitalization within 24 months was significantly lower in the MitraClip device group (hazard ratio of 0.53; NNT 3.1). Primary safety end point of freedom from MitraClip device-related complications at 12 months was better (at 96.6%) than the set performance goal (of 88%). All 10 prespecified secondary end point were in favor of MitraClip device, including statistically significant lower all-cause mortality within 24 months (NNT of 5.9) and better quality of life.
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MERINO Trial: Piperacillin-Tazobactam vs Meropenem in ESBL infections
MERINO Trial: 2018, Pip-Tazo vs Meropenem in patients with E-coli or Klebsiella infections, JAMA
Earlier cohort studies yielded conflicting results when it comes to treating ceftriaxone-resistant E-coli and Klebsiella infections. Some studies reported noninferiority of piperacillin-tazobactam when compared to meropenem while others reported almost doubling of mortality.
In the MERINO trial, the patients were randomized to assess for non-inferiority of pip-tazo IV therapy versus IV meropenem. The results showed 12.3% 30-day mortality in the pip-tazo group compared to 3.7% with meropenem. Therefore, the study concluded that for E-coli and Klebsiella bloodstream infections, pip-tazo antibiotic is inferior to meropenem in terms of 30 days mortality.
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POET Trial: IV vs PO Antibiotics in Left Heart Endocarditis
2018, POET Trial: Partial Oral vs Intravenous Antibiotic Treatment of Endocarditis | NEJM
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Rifaximin and Lactulose for HE trial
2013, Rifaximin plus Lactulose in Treatment of Hepatic Encephalopathy, The American Journal of Gastroenterology
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BeSt trial: DMARD ± prednisone or infliximab in RA
2005, BeSt trial Visual Abstract: DMARD ± prednisone or infliximab in RA, Arthritis Rheum
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SPYRAL HTN-ON MED Trial: Renal Denervation in Uncontrolled Hypertension
The SPYRAL HTN-ON MED trial was a large multicenter global scale trial that compared the effect of renal denervation + antihypertensive medications with antihypertensive medications alone. The results were significantly in favor of renal denervation in patients who had uncontrolled hypertension noticed in the clinic settings. Check out the visual abstract and following text for the trial summary.
SPYRAL HTN-ON MED trial Summary
The role of the sympathetic nervous system in the pathogenesis of hypertension (HTN) is well known. Activation of afferent sympathetic fibers results in renin release, retention of sodium, and reduction in renal blood flow that lead to the increase in blood pressure (BP) values. Hypertension usually requires life-long medication regimen; however, many studies have highlighted the averseness of many patients to maintain the stable regimen.
Recently, surgical renal denervation (RDN) has emerged as an efficient way of diminishing the renal sympathetic stimulation, decreasing the release of renin, while maintaining the normal glomerular filtration rate and renal blood flow.
SPYRAL HTN-ON MED trial is a randomized, single-blind, sham-controlled proof-of-concept trial carried out by Kandazi DE, et al. to assess the safety and efficacy of renal denervation on BP in patients with uncontrolled HTN who were on antihypertensive medication. The RDN of the main renal artery and accessory branches was performed with a Spyral multi-electrode radiofrequency ablation device. The primary results of the first 80 patients in the SPYRAL HTN-ON MED trial were published in 2018, which demonstrated a significant decrease in office and 24-hour ambulatory BP from baseline to 6 months in RDN group compared to sham-control, with a mean drug adherence of 60%.
The previous SPYRAL HTN-OFF MED trial of the SPYRAL series by Townsend RR, et al. was published in 2017. This trial used the similar ablation device as in HTN-ON MED trial but was conducted in the absence of antihypertensive medications. This trial also demonstrated a significant reduction in 24-hour ambulatory BP from baseline at 3 months follow-up.
Furthermore, the reduction in systolic BP of approximately 5.5 to 9 mmHg in these SPYRAL trials corresponds to the effect of one antihypertensive drug. It is also important to note that the short-term safety profile of this new intervention is favorable with no major adverse effects recorded. These results have shown a promising future of RDN in the treatment of HTN, especially in patients with medication noncompliance or those with adverse effects of medication.
However, before RDN becomes a mainstream management option for the treatment of HTN, further research needs to show the improvements in cardiovascular morbidity and mortality with the use of RDN. Additionally, further research is also needed to establish a long-term safety beyond the initial 6 months post-procedure.
Summary Reviewer: Mustafa Rahim, MD, FACP, FASPC (1)
1. Department of Medicine, West Virginia University Robert C. Byrd Health Sciences Center, WV
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ATLAS ACS-2: Rivaroxaban after ACS
The ATLAS ACS-2 trial tested the use of rivaroxaban in addition to standard dual antiplatelet therapy in patients with acute coronary syndrome. The results showed a reduction in the composite of CV mortality, recurrent MI, and stroke, but increased the risk of nonfatal bleeding.
2012, ATLAS ACS-2 Trial Visual Abstract: Rivaroxaban after ACS, NEJM
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TRISS Trial: Restrictive vs Liberal Transfusion in Septic Shock
The TRISS trial studied the role of transfusion thresholds in septic shock. 998 patients were divided into two transfusion groups. One group received Hb transfusion with goal Hb of > 7 while the other group received with the goal of Hb > 9. No difference in mortality or ischemic events were noted after a mean follow up period of 90 days. However, Patients with goal Hb > 7 received 50% less amount of transfusion compared to those with goal > 9.
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PARAMEDIC2 Trial: Epinephrine in Out-of-Hospital Cardiac Arrest
The PARAMEDIC2 trial that was recently published in NEJM studied the use of epinephrine in the out-of-hospital cardiac arrest and compared the final outcome of survival with placebo. Patients who had a cardiac arrest out of hospital were treated with the standard resuscitation protocol. The patient population which was given epinephrine compared to placed were noted to have slightly better survival rates. Take a look at the visual abstract that is now published in ACC.
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COMPASS Trial: Rivaroxaban plus aspirin in stable cardiovascular disease
Does adding rivaroxaban to aspirin therapy in patients with stable cardiovascular disease affect outcomes? This was the question answered by the large-sized multi-center COMPASS trial that evaluated the combination of rivaroxaban and aspirin and compared it with aspirin alone. The results showed moderate improvement in outcomes at the expense of increased bleeding risk.
Source: NEJM
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PAMPer Trial: Prehospital Plasma in Trauma Patients
PAMPer trial is a multicenter randomized trial that evaluated the use of thawed plasma in addition to standard resuscitation measures in patients at risk of subsequent hemorrhagic shock. The results showed a significant 30-day mortality benefit in patients who received plasma transfusion in addition to standard resuscitation while en route to a trauma center.
Source: NEJM
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ACT Trial: Acetylcysteine in patients undergoing Angiography
ACT trial was the initial large sized randomized controlled trial that was initiated to test the role of acetylcysteine in protecting kidneys from contrast. More than 2000 patients were enrolled in this placebo-controlled trial. The results failed to establish any renal protective role of acetylcysteine in patients undergoing coronary or peripheral angiography.
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EXTRA Trial: Omalizumab in Severe Allergic Asthma Visual Abstract
Omalizumab is an anti-IgE monoclonal antibody that was coined to prevent asthma exacerbations in patients with severe allergic asthma. The hypothesis was tested in the EXTRA trial in which Omalizumab was added to patients with severe allergic asthma who were already on ICS and LABA therapy. The results showed 25% relative reduction in asthma exacerbations in patients using Omalizumab compared to placebo. The above visual abstract summarizes the primary findings of the trail.
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Bezafibrate in Primary Biliary Cholangitis
A Placebo-controlled Trial of Bezafibrate in Primary Biliary Cholangitis
Trial Summarized by:
Hajra Munawar, MBBS
Hasan Shafiq, MD
Contribution to literature
This trial revealed that the use of the Bezafibrate (PPAR-a agonist )add-on therapy with ursodeoxycholic acid (UDCA) in patients with primary biliary cholangitis, normalizes the serum levels of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, albumin, and prothrombin index at 24 months.
Description of the trail
The goal of this trial was to compare the Bezafibrate add-on therapy with placebo in patients with primary biliary cholangitis, who had an inadequate response to UDCA, at 24 months and assess the overall difference among complete biochemical markers (AST, ALT, ALP, PT, Total bilirubin and albumin).
Study Design
It was a two-group, randomized, double-blinded, placebo-controlled trial from September 2012 to December 2014, that recruited patients from 21 centers throughout France. Patients were randomly assigned, in a 1:1 ratio, to receive either Bezafibrate 400mg (50 patients) or placebo (50 patients) once daily, patients in both groups received UDCA therapy for 6 months or more and had an inadequate response. Follow up performed every 3 months for 24 months and USG of liver and liver stiffness measurement were performed at baseline, at 12 months and at 24
months.
- Total number of patients: 100
- Duration of follow up: 2 years
- Percentage white female: 95%
- Mean patient age: 53 years +/- 10
- Clinically significant pruritus: 40%
- Fatigue: 58%
- Advanced stages of disease: 54%
Inclusion criteria:
- 18 years and older
- Diagnosed cases of primary biliary cholangitis
- All patients were treated with UDCA for 6 months or more
- Inadequate biochemical response (ALP or AST >1.5 times of normal range and abnormal total bilirubin levels) to UDCA.
Exclusion criteria
- Patients with total bilirubin >3 mg/dl.
- Patients with autoimmune hepatitis.
Primary outcomes
30 % of the patients with PBC, who had an inadequate response to UDCA, in the bezafibrate group had complete biochemical response ( normal serum levels of ALP, AST, total bilirubin, Albumin, and PT) and 1 % in the placebo group, for a difference of 29% (95% CI,16 to 43; P<0.001) at 24 months.
Secondary Outcomes
- ALP Levels: At 24 months, 67% in the treatment group and 2 % in the placebo group had normal ALP levels with (95%CI ,47 to 79).
- Total bilirubin levels: Total bilirubin decreased 14% in the treatment group and increased by 18% in the placebo group.
- ALP and GGT: 60% median reduction in ALP and GGT in the treatment group at 3 moths.
- Pruritus and fatigue: Changes in pruritus and fatigue were consistent with the primary outcome
- Quality of life: No significant change in the quality of life scores.
- Liver fibrosis: Liver stiffness/fibrosis decreased 15 % in the treatment group and increased by 22% in the placebo group (95% CI, -64 to -8)
- Histologic data: Histologic data was limited to only 28 patients and no significant difference between the 2 groups.
- Portal HTN and liver complications: No significant difference in developing Portal HTN and liver complications in 2 groups.
Post hoc outcomes:
- Total and endogenous bile acids, UDCA and C4 (a marker of bile acid synthesis): no significant difference between the groups
- IgM, IgG levels, CRP, TNF a, IL12: no significant difference between the groups.
Interpretation (discussion):
The Trial demonstrated that among the patients with primary biliary cholangitis who had an inadequate response to UDCA, approximately one-third of the patients in the bezafibrate group, as compared with no patients in the placebo group, reached the normal levels of biochemical markers at 24 months. Parallel changes with respect to pruritus, fatigue and noninvasive liver fibrosis were
consistent with this result.
Though this trial has some limitations as well. The trial was not large enough or long enough to assess the effect of bezafibrate on hard outcomes, such as liver transplantation and death. Advanced cirrhosis and severe cholestasis should be considered as potential limiting factors for add-on therapy with bezafibrate. Bezafibrate was associated with a 5% increase in the serum creatinine. Stage 3 CKD developed during treatment with bezafibrate in one patient in this trial, who had diabetes and HTN. As a precaution, bezafibrate should be used carefully in patients with diabetes, HTN, or any known kidney disease.
In conclusion, in patients with primary biliary cholangitis, who had an inadequate response to UDCA, add-on therapy with bezafibrate for 24 months resulted in a higher rate of complete biochemical response than UDCA therapy plus placebo. Parallel changes in fatigue, pruritus and liver fibrosis were consistent with this effect. Bezafibrate was associated with an increase in creatinine levels. Longer and larger studies are needed to assess the effects of Bezafibrate on clinical outcome.
Source
Christophe Corpechot, M.D., Olivier Chazouillères, M.D., Alexandra Rousseau, Ph.D., Antonia Le Gruyer, M.D., François Habersetzer, M.D., Ph.D., Philippe Mathurin, M.D., Ph.D., Odile Goria, M.D., Pascal Potier, M.D., Anne Minello, M.D., Ph.D., Christine Silvain, M.D., Armand Abergel, M.D., Ph.D., Maryline Debette-Gratien, M.D., Ph.D., NEJM june 7,2018. Vol. 378 .no.23
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Basic Modes of Mechanical Ventilation Infographic
Mechanical ventilation is a complex topic to understand. With this infographic, I have tried to explain 4 most commonly used ventilator modes in intensive care units. The two broad categories are the volume limited and pressure limited ventilation while each of them have further sub-branches. In future posts, I’m going to create a basic flowchart of all ventilator modes with their benefits and disadvantages. Till then, use this infographic to understand the basic of mechanical ventilation and how pressure, flow and volumes are linked to each other.
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ANGIE02 Trial: Closed-Loop Insulin Delivery for Type II Diabetes Mellitus Trial Visual Absract
Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care
Summarized by: Tabinda Saleem, MBBS
Reviewed by: Usama bin Nasir, MD
Contribution to literature
This trial revealed that the use of the fully automated closed-loop insulin system can help physicians achieve a better glycemic control among hospitalized patients with type 2 diabetes without rendering them at risk of hypoglycemia.
Description of the trail
The goal of this trial was to compare the fully automated closed-loop insulin delivery system (artificial pancreas) with the conventional subcutaneous insulin therapy among thehospitalized type 2 diabetic patients receiving non-critical care, and assess the overall difference among the targeted glycemic control, variability of glucose levels and rate of hypoglycemia.
Study Design
It was a randomized, open-label trial that recruited patients From August 2, 2016 to December 11, 2017 from the general wards at the University Hospital in Bern, Switzerland, and at Addenbrooke’s Hospital in Cambridge, United Kingdom.
Patients were randomly assigned to either closed-loopinsulin delivery (70 patients) or to the control group with standard insulin therapy (66 patients). The treatment group received the rapid-acting insulin analogue (Humalog, Eli Lilly, or NovoRapid, NovoNordisk) by means of a trial pump (Dana Diabecare R, Sooil) through a cannula inserted into the abdomen. And the control group received the conventional subcutaneous insulin and other anti-hyperglycemic therapies according to the local clinical practice.
- Total number of patients: 136
- Duration of follow up: 15 days or until hospital discharge.
- Mean patient age: 67 years
- Percentage male: 50%
- Mean BMI: 32
- Mean HbA1c: 8%
Inclusion criteria
- 18 years and older
- Type 2 diabetics only
- In-patient hyperglycemia requiring subcutaneous insulin therapy.
Exclusion criteria
- Type 1 diabetes
- Pregnancy
- Breast-feeding
- Any physical or psychological disease
- Use of any such medication that can interfere with the conduct of the trial or the interpretation of the results
Other salient features
- Randomization was ensured on the basis of age, sex, glycated hemoglobin level, body-mass index (kg/m2), duration of diabetes and pretrial total daily insulin dose to balance the two groups.
- Throughout the trial patients were allowed to have standard hospital meals at usual mealtimes, according to local practice.
- Sepsis was the predominant reason for admission in approximately 43% of the patients.
- Safety end points included clinically significant hyperglycemia (>360 mg per deciliter) with ketonemia and severe hypoglycemia (<40 mg/dl) along with other adverse events.
Primary outcomes
- The mean (±SD) percentage of time that the sensor glucose measurement was in the target glucose range was 65.8±16.8% inthe closed-loop group and 41.5±16.9% in the control group, for a difference of 24.3±2.9 percentagepoints (95% confidence interval [CI], 18.6 to 30.0; P<0.001).
- The mean sensor glucose measurement was significantly lower in the closed-loop group than in the control group (154±29 mgper deciliter vs. 188±43 mg per deciliter; difference, 35±6 mg per deciliter; 95% CI, 23 to 47;P<0.001).
- Values above the target range (>180 mgper deciliter) were found in 23.6±16.6% of the patients in the closed-loop group and in 49.5±22.8%of those in the control group, a difference of25.9±3.4 percentage points (95% CI, 19.2 to 32.7;P<0.001).
Secondary Outcomes
- Hypoglycemic episodes with capillary glucose measurement of less than 63 mg per deciliter, occurred three times in the closed-loop group (3 patients) and nine times in the control group (8 patients).
- Overnight (midnight to 8 a.m.) and daytime (8 a.m. to midnight) glycemic control was also significantly better in the closed-loop system compared to the control, with difference of 19.8±3.8 percentage points (95% CI, 12.2 to 27.4; P<0.001) and 26.9±3.2 percentage points (95% CI, 20.6 to 33.3; P<0.001) respectively.
Interpretation (discussion)
This trial demonstrated that the hospitalized patients with type 2 diabetes who received insulin with a fully automated, closed-loop system had significantly better glucose control with lower rates of hyperglycemia and glucose variability than those who received standard subcutaneous insulin therapywithout changing the total daily insulin dose or increasing the risk of hypoglycemia.
The benefit of a closed-loop system is that the automated system instantaneously respond to the higher glucose level with insulin delivery and it continuously adapt to the changing insulin needs during the day and between days. In contrast conventional therapy are less responsive to glucose changes and insulin needs and are mainly dependent on the vigilance of the hospital staff, with tighter glycemic control increasing the risk of hypoglycemia with latterbeing a primary concern for many health care professionals and a reason to be reluctant to encourage tight glucose control.
The strength of this trial was that it had a longer follow up period (15 days) as compared to the previous randomized feasibility trial that evaluated the closed-loop system over a period of 72 hours. Also the sample size of this study was larger and included a diverse and complex inpatient population (including 19 patients on hemodialysis) from two different hospital settings from two different countries compared to the single hospital setting in the previous trail, increasing the utility of the current trial across different health care systems.
Though this trial has some limitations as well. The Sensor glucose measurements were more readily available for the closed-loop group than in the control group and the trial duration was also longer for the closed-loop group. The observed imbalance may be attributed to thedifferences in the burden of coexisting illnesses among the two groups (which was higher in the closed-loop group than in the control group) resulting in the collection of fewer sensor glucose data in the control group compared to the closed-loop group. That is why more work is required to determine the practical consideration of this system in the clinical practice and to facilitate its use by the health care professionals and to assess the costs.
In conclusion, in patients with type 2 diabetes who are receiving noncritical care, fully automated closed loop system can become an effective way of controlling glycemic levels compared to the standard insulin therapy withoutincreasing the risk of hypoglycemia in these patients.
Source
Bally L, Thabit H, Hartnell S, Andereggen E, Ruan Y, Wilinska ME, et al. Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care. New England Journal of Medicine. 2018 Jun 25; Source
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Algorithm for Management of Adult Patients with DKA
Diabetic ketoacidosis requires emergent intervention and treatment. The treatment of DKA requires careful monitoring of both acidosis as well as blood glucose levels. In order to streamline the treatment process, I have designed the following algorithm keeping in mind the complexity of the disease. This management algorithm is based on the American Diabetes association updated guidelines of 2009. Feel free to print this and share it without colleagues and students.
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TOPCAT trial: Spironolactone in HFpEF
Spironolactone is a well known survival improvement agent for heart failure with reduced ejection fraction. Its use in heart failure with preserved EF was however controversial. The TOPCAT trial established the failure of spironolactone to improve mortality in patients with HFpEF. The visual abstract illustrates the trial salient features.
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Abdominal Aortic Aneurysm Screening USPSTF 2014 Guidelines
The current USPSTF guidelines for screening of abdominal aortic aneurysm were published in 2014. The guidelines recommend one time ultrasound guided screening for men smokers between age of 65-75 years. On the other hand recommendations are against screening in non smokers women. Check out the MASS trial to understand the source and literature background of guidelines.
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WARFASA Trial: Aspirin for preventing VTE Recurrence
Summarized by / Author: Usama bin Nasir, MD
Contribution To Literature:
WARFASA trial established role of aspirin for prevention of recurrent VTE in patients who have completed 6-18 months course of anticoagulation and were no longer on it.
Guidelines Adaptation
According to ACCP (CHEST) Antithrombotic Therapy for VTE Disease 2016 guidelines, in patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, aspirin over no aspirin to prevent recurrent VTE (Grade 2B) is recommended.
Study Design
It was a multicenter, randomized, double-blind, placebo-controlled that took place and involved enrollment from 2004 to 2010. 403 patients were enrolled and distributed among the study groups. Median follow up period was 2 years.
Inclusion criteria:
- Age ≥18 years
- Completed therapy with 6-18 months of vitamin K antagonist for first, symptomatic, unprovoked, objectively confirmed proximal DVT, PE, or both
Exclusion criteria:
Important exclusion criteria included
- Cancer or major thrombophilia
- Indication for long-term anticoagulation
- Atherosclerotic disease requiring antiplatelet therapy
- Active bleeding
Primary outcomes:
- Recurrent VTE was significantly decreased in patients on aspirin compared to patients on placebo. (HR 0.58; 95% CI 0.36-0.93; P=0.02)
Secondary outcomes:
- Bleeding (4 events in each group) and death rates (HR 1.04; 95% CI 0.32-3.42; P=0.95) were similar in both groups.
Interpretation:
The WARFASA trial successfully established role of aspirin in prevention of VTE recurrence. Another trial that was done during same time period was the ASPIRE trial. The ASPIRE trial results were non-significant but the important difference between the trials was that in WARFASA all patients completed minimum of 6 months oral anticoagulation. Recurrent rates of VTE after 3-6 months of OAC for unprovoked VTE can reach up to 11% (2) once the anticoagulation is stopped therefore starting aspirin is important and carries grade 2B recommendation per CHEST 2016 guidelines.
References:
- Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21):1959-67. Source
- Prandoni P, et al. “The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients.”Haematologica 2007. 92(2):199-205.
- Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315-352.
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DAWN Trial: Mechanical Thrombectomy 6 to 24 Hours after Stroke
The DAWN trial was a major success when it comes to mechanical thromebectomy eligibility time.Both the DAWN and DEFUSE 3 trial led to modification of AHA/ACC 2018 guidelines for stroke which recommended that in selected acute stroke patients within 6-24 hours of last known normal who have large vessel occlusion in the anterior circulation and meet other DAWN eligibility criteria, mechanical thrombectomy with a stent retriever is reasonable.
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AMPLIFY Trial: Oral apixaban for VTE
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PROTECT AF Trial: Closure of the LAA versus warfarin therapy in patients with Atrial Fibrillation
We currently lack significant data or clear cut guidelines for closing left atrial appendage in patients with LAA for prevention of stroke. The current ACC/AHA/HRS guidelines recommends anticoagulation in patients with atrial fibrillation and CHA2DS2-VASc >2 (Grade Ia) irrespective of presence or absence of LAA.
The PROTECT AF trial was a randomized non-inferior trial that studied the usefulness of WATCHMAN device in closing LAA and prevention of stroke. The trial did show non-inferiority of the device closure vs warfarin anticoagulation but it was associated with higher side effects which were mostly periprocedural.
Based on this trial, the 2012 Focus European Society of Cardiology Guidelines called for “LAA closure/occlusion/excision” using percutaneous device in patients who are at high stroke risk and have contraindications for long-term oral anticoagulation (Class IIb; Level of Evidence B). The current AHA/ACC/HRS, however, does not include recommendations of LAA closure devices due to lack of enough robust evidence. However, both ESC and AHA/ACC guidelines suggest that surgical excision of the LAA may be considered in patients undergoing cardiac surgery or thoracoscopic atrial fibrillation surgery (Grade IIB)
Sources: Lancet, 2015 ACC/HRS/SCAI LAA Occlusion Device Societal Overview
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USPSTF/ACC/AHA guidelines for Statin Use for the Primary Prevention of Cardiovascular Disease in Adults
The USPSTF and ACC/AHA guidelines for statin use in adults aged 40-75 years are consistent over level of recommendation. Adults who have no history of cardiovascular disease but have 1 or more risk factors for developing CVD along with >10% ASCVD risk are recommended to be started on low- to moderate dose statin. (USPSTF = B). The ACC/AHA however recommends moderate to high dose statin for ASCVD risk of >7.5% for primary prevention (ACC/AHA Level I). The above visual abstract summarizes both the societies’ recommendations in to one easy to use graphic.
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Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function
Visual Abstract: Metformin use based on kidney function. Over ~1 million patients are not on guideline-directed therapy of metformin due to abnormal kidney function. Thee present study studies the relationship of metformin with lactic acidosis over a wide range of eGFR in patients. Patients were followed up for years and were assesed for decline in kidney function via eGFR calculation and risk of development of lactic acidosis due to metformin use. The results were consistent with previously stated guidelines as to which metformin is safe to use in eGFR > 30 over all ranges while risk of lactic acidosis doubles once eGFR drops below 30 mL/min/1.73 m2
Source: JAMA Intern Med
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Risks of concomitant aspirin therapy with oral anticoagulation in patients with atrial fibrillation
Summarized by: Usama bin Nasir, MD
Contribution To Literature:
Atrial fibrillation (AF) was noted to be a risk marker for stroke in the Framingham cohort in 1978. Since then anticoagulation is an important part of managing AF. Use of aspirin in patients with AF is a common practice based on this notion that it might add to prevention of MI or stroke in such patients. The ORBIT-AF study tackled this question by determining the risk factors associated with concomitant use of aspirin and oral anticoagulation (OAC) in patients with AF.
Study Design
The present study was a retrospective review of ORBIT-AF prospective registry that enrolled 7.347 patients with AF on OAC. The ORBIT-AF registry enrolled patients from 174 US sites. Follow up period of this review was of 6 months and the primary outcomes that were studied were: bleeding, hospitalization, CV events, and mortality.
Inclusion Criteria
- Age ≥ 18 years
- Atrial fibrillation on EKG
Exclusion Criteria
- Anticipated life expectancy <6 months
- Atrial flutter only
- Patients not taking oral anticoagulant
- Patients taking antiplatelet therapies other than ASA
- Transient AF secondary to a reversible condition
- Current enrollment in a randomized clinical trial of antithrombotic therapy for AF
AF Characterisitcs:
Among 7347 patients, 4804 were on OAC alone and 2543 patients were on both OAC plus aspirin.
| Overall (n=7347) | OAC Alone (n=4804) | OAC+ASA (n=2543) | ||
|---|---|---|---|---|
| AF type, % | ||||
| New onset | 4.0 | 3.8 | 4.6 | |
| Paroxysmal | 46 | 45 | 47 | |
| Persistent | 18 | 18 | 18 | |
| Long-standing persistent | 32 | 33 | 30 |
Primary Outcomes
- After adjustment for baseline characteristics the primary outcomes for OAC vs OAC + ASA were as follows:
Risk of major bleeding: HR 1.53 (1.20–1.96), p = 0.0006
(note, the risk for bleed is almost 1.5 times for OAC + ASA compared to OAC alone)
All-Cause Hospitalization: HR 1.08 (1.00–1.17), p = 0.06
Mortality: HR 1.26 (0.98–1.63), p = 0.08
Interpretation:
The present study indicates worse outcomes in terms of major bleeding and also indicates towards higher mortality and hospitalizations but the latter results are not significant. Based on the real-world National Cardiovascular Data Registry (NCDR) Practice Innovation and Clinical Excellence (PINNACLE) registry more than one-third of 210,380 patients who had CHA2DS2-VASc scores ≥2 were treated with aspirin alone, and not with oral anticoagulants as per ACC/AHA/HRS guidelines. (2) Using OAC is important for prevention of stroke in patients with AF and this has been presented in a number of studies. However, the use of aspirin in addition to OAC in AF has always been questioned. The current study tackled this very question. The results suggest that we should avoid combination therapy in patients who do not have history of CAD. While in patients with history of CAD, using combination therapy outweighs the risks. Note The 2011 ACC/AHA/HRS guidelines recommend using ASA + OAC in patients with history of MI. However, 2014 guidelines have not commented on combination therapy.
References
- Wolf PA, et al. “Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: The Framingham study.” Neurology.1978;28(10):973-977.
- Hsu J.C., Maddox T.M., Kennedy K., et al. (2016) Aspirin instead of oral anticoagulant prescription in atrial fibrillation patients at risk for stroke. J Am Coll Cardiol 67:2913–2923.
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Radial-Artery or Saphenous-Vein Grafts in CABG
Current ACC/AHA guidelines recommend (IIb) radial artery grafting for >70% LAD stenosis. Most surgeons, however, still prefer saphenous vein grafts in addition to LIMA for LAD stenosis. The following combines the population of 6 RCTs to perform a individual based analysis and showed that radial artery grafting has significant benefits over saphenous vein grafts in CABG.
Source: NEJM
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Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B
Summarized by / Author: Rooma Nankani MD (1), Rohini Manaktala MD (1)
Summary Reviewer: Paul Robert Anthony Jr. MD (2)
Contribution To Literature:
This trial showed that the maternal use of tenofovir in hepatitis B positive mothers did not result in significantly lower rate of perinatal hepatitis B transmission. However, it is known that the rate of mother to child HBV transmission is low with the use of hepatitis B immune globulin and hepatitis B vaccine in infants from hepatitis B positive mothers.
Description:
The goal of the trial was to determine the effect of tenofovir in preventing hepatitis B transmission from mother to infant. The trial was an effort to explore other alternatives besides hepatitis B immunoglobulin administration and hepatitis B vaccine in infants as the risk of transmission of hepatitis B remains elevated despite these measures.
Study Design
It was a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial performed at 17 public hospitals in Thailand from January 2013 to August 2015.
Patients enrolled in the study were hepatitis B e antigen (HBeAg) positive pregnant women with an ALT level of 60 IU/L or less who were randomly assigned in 1:1 ratio to receive 300 mg of tenofovir disoproxil fumarate (TDF) daily (n=168) or matching placebo (n=163) which involved taking similar tablets but without the active pharmaceutical ingredient. Both group were received their respective medication from 28 weeks of gestation to 2 months post partum. Infants of both groups received hepatitis B immune globulin at birth and hepatitis B vaccine at birth as well as at 1, 2, 4, and 6 months.
- Total number of patients: 331
- Duration of follow-up (maternal visits): 28, 32 and 36 weeks of gestation, at delivery and at 1, 2, 3, 4, 6 and 12 months post partum
- Duration of follow-up (infant visits): birth and 1, 2, 4, 6, 9 and 12 months of age for physical examination and blood work for determination of HBV infection status; and for recording of vaccinations until 6 months of age; and for signs/conditions suggestive of possible mitochondrial dysfunction at 6 and 12 months of age
- Median gestational age: 28.3 weeks
- Median HBV DNA level: 8log (10) IU/mL
- Median time from birth to administration of hepatitis B immune globulin: 1.3 hours
- Median time from birth to administration of hepatitis B vaccine: 1.2 hours
- Mode of infant delivery: 26% were Cesarean sections
Inclusion criteria:
- Pregnant women (from age 18 years or older) at 28 weeks of gestational age (within a window of +/- 10 days)
- Positive HbsAg and HBeAg tests
- ALT level of 30 IU/L or less at screening and 60 IU/L or less at trial entry
Exclusion criteria:
- Positive serologic test for HIV or hepatitis C virus
- Received TDF at any time
- Received any other anti-HBV treatment during the current pregnancy
- Estimated creatinine clearance of less than 50 mL per minute or had confirmed proteinuria or normoglycemic glycosuria
- Evidence of fetal anomaly that was incompatible with life
Other salient features/characteristics:
- Women with an elevated ALT level (>60 IU/L) at any trial visit had their level tested again within 2 weeks
- Pregnancies that resulted in multiple births were counted as one mother-infant pair and were counted as having HBV infection if at least one infant was infected
- Amniocentesis and Cesarean section delivery may be associated with increased risk of HBV transmission
Primary outcomes:
- The positive status of hepatitis B surface antigen (HBsAg) in the infant confirmed by the HBV DNA level at 6 months of age. Results found that none of the 147 infants in the TDF group were infected (0%, [CI] 0 to 2) as compared with three of 147 (2%, [CI] 0 to 6) in the placebo group (p=0.12).
- At 6 months follow up, 99% of the TDF and placebo groups had an HbsAg antibody level of at least 10 IU/L.
Secondary outcomes:
- Adverse events that were measured included: maternal hepatic flares (ALT level of >300 IU/L) after discontinuation of the trial regimen, and infant growth at 6 months.
- The incidence of maternal ALT level of more than 300 IU/L after discontinuation of the trial regimen was 6% in the TDF group and 3% in the placebo group (p=0.29).
- Overall, the rate of adverse events did not differ significantly between the two groups.
Interpretation:
Findings from this trial did not reach statistical significance with regards to detection of HBV infection in infants whose mothers received TDF. Although the observed rate of mother to child transmission in the TDF group was not statistically significant at short term follow up, the long-term risk of transmission among these infants was predicted to be less than 2.5%.
With regards to safety concerns of TDF, there was no significant maternal or infant safety incidence reported. Only notable events reported were maternal asymptomatic hepatic flares.
Moreover, prior to the completion of the trial it was expected in general that the rate of HBV transmission would be 7% or more among infants who received HBV vaccine, hepatitis B immune globulin and had been born to mothers with higher HBV DNA levels. Surprisingly, this trial found an overall lower rate of HBV transmission. This difference could be due to sampling variations (for example: sample size, differences in population baseline characteristics and duration of time between infant birth and first administration of the hepatitis B vaccine) compared to other similar studies.
Overall, this trial did not show a lower rate of HBV transmission from mother to infant with the administration of TDF in addition to hepatitis B immune globulin and vaccine to infant compared to placebo.
Jourdain G., Ngo-Giang-Huong, L., Harrison, L, et al. Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B. NEJM. 2018, 378 (10): 911-923. Source
Authors Affiliation:
1. Department of Internal Medicine, University of Connecticut Health Center
2. Department of Infectious Disease, Saint Francis Hospital, Hartford, Connecticut
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Helicobacter Pylori Treatment for the Prevention of Metachronous Gastric Cancer
Summarized by / Author: Rohini Manaktala MD (1), Rooma Nankani MD (1)
Summary Reviewer: Paul Robert Anthony Jr. MD (2)
Contribution To Literature:
This trial revealed the beneficial outcome of treating early gastric cancer with H.pylori eradication therapy and the reduction in future development of metachronous gastric cancer compared to placebo.
Description:
The goal of the trial was to determine the incidence of metachronous gastric cancer detected on endoscopy performed at 1-year follow up or later and improvement from baseline in the grade of glandular atrophy in the gastric corpus lesser curvature at the 3 year follow up for individuals with early gastric cancer status post resection and treatment with H.pylori eradication therapy.
Study Design
It was a prospective, single-center, double-blinded, placebo-controlled and randomized trial performed at the National Cancer Center in South Korea that enrolled patients from August 2003 through March 2013.
Patients were randomized in a 1:1 fashion before endoscopic resection to either H.pylori eradication therapy (n = 236) or placebo (n = 234). The treatment group received amoxicillin 1000 mg, clarithromycin 500 mg and proton-pump inhibitor rabeprazole 10 mg which were given twice daily for a week. The placebo group received rabeprazole 10 mg and placebo pills. Both groups received proton-pump inhibitor for additional 4 weeks to promote ulcer healing.
- Total number of patients: 470
- Duration of follow-up (endoscopy evaluation): at 3 months, 6 months, 1 year and then every 6 months or 12 months until the last enrolled patient reached the 3 year follow up point
- Mean patient age: 59 years
- Percentage male: 75%
Inclusion criteria:
- Between the ages of 18 and 75 years
- Histologically confirmed diagnosis of differentiated early gastric cancer or high grade adenoma
- Endoscopic localization of a mucosal tumor without ulceration and no lymph-node or distant organ metastasis on CT scan
- Confirmed scheduled endoscopic resection procedure
- Current H.pylori infection
Other salient features/characteristics:
- The stratification factor for group assignment was the severity of the baseline grade of histologic atrophy at the antrum
- Paients started the assigned trial medication within 1 week after endoscopic resection
- Quadruple antibiotic therapy (proton-pump inhibitor, bismuth, metronidazole, tetracycline) was provided for 10 days if H.pylori infection was detected at closeout endoscopic examination
Primary outcomes:
- The development of metachronous gastric cancer was found to have occurred in 7.2% of the treatment group and in 13.4% of the placebo group (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.26-0.94; P=0.03).
- The proportion of patients who had an improved grade of atrophy in the corpus lesser curvature was higher in the treatment group than in the placebo group (48.4% vs. 15.0%, P <0.001). The odds ratio for such improvement was 5.30 (95% CI, 3.08 to 9.13) in the treatment group as compared with the placebo group.
- The proportion of patients who had an improved grade of intestinal metaplasia at the same site was also higher in the treatment group than in the placebo group (36.6% vs. 18.3%, P <0.001). However, no significant difference in grade was found for either glandular atrophy or intestinal metaplasia at the antrum.
Secondary outcomes:
- Major adverse events included death from any cause which was reported in 11 patients in the treatment group and in 6 in the placebo group (HR, 1.95; 95% CI, 0.72-5.27; P=0.19).
- Minor adverse events included: taste alteration, nausea, vomiting, diarrhea, abdominal pain, hypersensitivity, dizziness, headache and insomnia. These events were more common in the treatment group than placebo (42.0% vs. 10.2%, P<0.001).
Interpretation:
The trial demonstrated a significant reduction in metachronous gastric cancer development among patients who had received treatment for H.pylori infection than those who had received placebo. This is because persistent inflammation of gastric mucosa from H.pylori infection promotes carcinogenesis and increases tumor growth/invasion. Findings from this trial are in agreement with results from previous systemic reviews and open label trials. Additionally, this trial found that the proportion of patients with improvement in the grade of gastric corpus atrophy from baseline was significantly higher in the treatment group than placebo at the 3 year follow up.
An advantage of this trial was a longer duration of follow up than previous trials (median follow up 5.9 years versus <3 years). However there are some limitations to the trial which include: (i) disappearance of preventive effect of H.pylori treatment on metachronous cancer after follow up duration of more than 5 years and (ii) exclusion of patients with synchronous gastric cancers that were initially missed but detected within 1 year after treatment. Moreover, in this trial hazard ratio for incidence of metachronous gastric cancer was found to be higher than previous trials which could be explained by the fact that H.pylori eradication was not confirmed and salvage treatment was not given to patients who failed eradication therapy due to the limitation of blinded process.
In conclusion, H.pylori therapy reduces but cannot completely eradicate the risk of metachronous gastric cancer. Also, it was found that H.pylori treatment did not affect the subsequent incidence of gastric adenoma or overall survival.
Choi I., Kook M., Kim Y., et al. Helicobacter Pylori Therapy for the Prevention of Metachronous Gastric Cancer. NEJM. 2018, 378 (12): 1085-1095. Source
Authors Affiliation:
1. Department of Internal Medicine, University of Connecticut Health Center
2. Department of Infectious Disease, Saint Francis Hospital, Hartford, Connecticut
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ProACT Trial: Procalcitonin-Guided Antibiotics for Lower Respiratory Tract Infection
Procalcitonin has proven to be a great marker for guiding antibiotics treatment in patients with concern for lower respiratory tract infections. However, it’s not yet established how much does clinicians adhere to using the antibiotic therapy based on procalcitonin results. The ProACT trial recently got published in NEJM. It showed that despite it’s usefulness, clinicians still base their antibiotic use on clinical suspicion. Take a look at our visual abstract for the findings.
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STOPAH Trial: Prednisolone or Pentoxifylline for Alcoholic Hepatitis
The use of steroids vs Pentoxifylline in severe alcoholic hepatitis has long been debated. The STOPAH trial published in NEJM in 2015 was a strong 2×2 factorial design, randomized trial that established that neither pentoxifylline nor prednisolone provided significant survival benefit in patients with severe alcoholic hepatitis. Take a look at my visual abstract for the trial. You can use it free for educational purposes.
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STRIVE Trial: Erenumab for Episodic Migraine
The STRIVE trial introduced Erenumab, a once monthly self injectable drug for prevention of episodic migraine. It’s calcitonin-gene-related peptide (CGRP) antagonist. It is recently approved by FDA for its use in migraine. Check out the STRIVE trial visual summary and visual abstract to understand how effective was Erenumab for episodic migraine.
Source: NEJM
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Tenecteplase versus Alteplase for Ischemic Stroke
Source: NEJM
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Undetectable High-Sensitivity Cardiac Troponin T Level in the Emergency Department and Risk of Myocardial Infarction
Source: JACC
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PRESERVE Trial: Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine
Study Question: Does the use of sodium bicarbonate or acetylcysteine affect outcomes after angiography
Trial Summarized by: Hajra Munawar, MD; Hasan Shafiq, MD
Contribution to literature
This trial revealed that the patients with impaired kidney function who were undergoing angiography showed no benefit of periprocedural IV isotonic sodium bicarbonate over IV isotonic sodium chloride or of oral acetylcysteine over placebo with respect to major adverse kidney events, death, or acute kidney injury.
Description of the trail
The goal of this trial was to compare renal complications in patients who were scheduled for angiography to receive IV 1.26% sodium bicarbonate or IV 0.9% sodium chloride and 5 days of oral acetylcysteine or oral placebo, and assess the overall difference among the composite of death, need for dialysis, or a persistent increase of at least 50% from baseline in the serum creatinine levels at 90 days.
Study Design
It was a double-blinded, placebo and comparator-drug controlled, randomized trial sponsored by U.S Department of Veterans Affairs Cooperative Studies Program and George Institute for Global Health from February 2013 through March 2017, patients were enrolled at 53 medical centers in the United states (35 veterans Affairs sites),Australia(13 sites),Malaysia(3 sites) and New Zealand(2 sites).
Patients were randomly assigned to receive intravenous 1.26% sodium bicarbonate or intravenous 0.9% sodium chloride and oral acetylcysteine capsule or matched placebo capsules. The administration of trial IV fluids was based on protocol-specified ranges: 1 to 3 ml/kg/hr during a period of 1 to 12 hours for a total of 3 to 12 ml/kg/hr before angiography, 1 to 1.5 ml/kg/hr during angiography, 1 to 3ml/kg/hr during the period of 2 to 12 hrs for total volume of 6 to 12 ml/kg after angiography.
From each patient, a blood sample collected before the initiation of trial intravenous fluids and at 3 to 5 days and 90 t0 104 days after angiography. Urine samples are collected for local measurement of albumin and creatinine at the time of angiography and for PH measurement 2 to 4 hours after angiography.
- Total number of patients: 5177(4441 at Veterans Affairs sites and 736 at George Institute sites) underwent randomization after randomization 184 patients were withdrawn, which resulted in 4993 patients for primary analysis.
- Duration of follow up: from February through March 2017
- Mean patient age: 69 year
- Percentage male: 93.6%
- Percentage diabetics:80.9%
- Median serum Cr:1.5mg/dl
- Median eGFR:50.2 ml per min per 1.73m2
- Median volume of contrast material administered was 85ml.
- Median volume of trial IV fluid administered was 344ml before,114ml during,570ml after angiography.
- After angiography mean urine PH was 6.7 +/- 0.8 in the sodium bicarbonate group and 6 +/_ 0.8 in sodium chloride group (p=<.001)
Statistical Analysis:
Modified intention to treat analysis was used that included all the patients who had undergone randomization and who had received the assigned trial interventions, regardless of whether they had undergone angiography. The comparison was done using the t-test for normally distributed continuous variables, the Wilcoxon rank-sum test for variables without a normal distribution and the chi-square test for categorical variables. To test the interaction between sodium bicarbonate and acetylcysteine, a multivariable logistic regression model was used.
Inclusion criteria
- Patients who were scheduled to undergo coronary or noncoronary angiography
- Patients who had an eGFR of 55 -44.9ml per min per 1.73 m2
- Patients with diabetes mellitus and e GFR 45 -59.9 ml per minute per 1.73 m2
Exclusion criteria
Patients who were undergoing emergency angiography
Patients with unstable baseline levels of blood creatinine( increase or decrease of >25% within 3 days before angiography)
Primary outcomes
- The primary composite endpoint occurred in 110 patients in the sodium bicarbonate group as compared with 116 patients in the sodium chloride groups(odds ratio: 0.93; 95% CI, 0.72 to 1.22 ;P =0.62) and in 114 patients in the acetylcysteine group as compared with 112 in the placebo group (odds ratio:1.02; 95% CI ,0.78 – 1.33 ;P = 0.88).There were no significant differences in the primary composite end point in the comparison of treatment combination groups.
- There was also no significant difference in the need for dialysis, or a persistent increase of at least 50% from baseline in serum creatinine level at 90 to 140 days after angiography in the comparison of sodium bicarbonate with sodium chloride or in the combinations of acetylcysteine with placebo.
- There was a significantly higher risk of the primary composite endpoint in sodium bicarbonate as compared to sodium chloride in patients who have undergone noncoronary angiography.(odds ratio,3.19;95%CI ,1.03 to 9.94)
Secondary Outcomes
- Contrast associated acute kidney injury occurred in 239 patients in the sodium bicarbonate group as compared with 206 in the sodium chloride group (odds ratio ,1.16;CI,0.96-1.41 ;P=0.13)and in 228 patients in the acetylcysteine group as compared with 217 in the placebo group (odds ratio ,1.06;95%CI, 0.87 -1.28; P =0.58)
- There were no significant differences in the incidence of, death within 90 days; dialysis of any kind within 90 days; confirmed persistent kidney impairment at 90 to 104 days; hospitalization with ACS, heart failure or stroke within 90 days; and hospitalization for any cause within 90 days.
Conclusion:
In patients with chronic kidney disease who underwent angiography, no benefit of IV sodium bicarbonate over IV sodium chloride or of oral acetylcysteine was seen compared to placebo. Unlike most previous trials in which primary endpoint was a small increase in the blood creatinine level occurring within days after the IV contrast, the primary endpoint in this trial was a composite of serious adverse outcomes such as mortality, need for dialysis and worsening of renal function.
SOURCE:
Steven D. Weisbord, M.DMartin Gallagher, M.D., Ph.D., Hani Jneid, M.D., Santiago Garcia, M.D., Alan Cass, M.D., Ph.D., Soe-Soe Thwin, Ph.D., Todd A. Conner, Pharm.D., Glenn M. Chertow, M.D., M.P.H., Deepak L. Bhatt, M.D., M.P.H., Kendrick Shunk, M.D., Ph.D., Chirag R. Parikh, M.D., Ph.D., Edward O. McFalls, M.D., PhD., et al., for the PRESERVE Trial Group*
Source: NEJM
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PRECISION Trial: Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis
This visual abstract represents the important findings of the PRECISION trial. The trial compares the COX-2 selective NSAID celecoxib with traditionally used NSAIDs such as naproxen and ibuprofen. It establishes non inferiority in terms of cardiovascular events and superiority in terms of GI and renal safety. As of March 2017, no guidelines have been published that reflect the results of this trial.
Source: NEJM
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MODIFY I / II Trials: Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection
Source: NEJM
