Week 44 – Early TIPS in Cirrhosis with Variceal Bleeding

“Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding”

N Engl J Med. 2010 Jun 24;362(25):2370-9. [free full text]

Variceal bleeding is a major cause of morbidity and mortality in decompensated cirrhosis. The standard of care for an acute variceal bleed includes a combination of vasoactive drugs, prophylactic antibiotics, and endoscopic techniques (e.g. banding). Transjugular intrahepatic portosystemic shunt (TIPS) can be used to treat refractory bleeding. This 2010 trial sought to determine the utility of early TIPS during the initial bleed in high-risk patients, when compared to standard therapy.

Population: cirrhotic patients with acute esophageal variceal bleeding, either Child-Pugh class C with score 10-13 or class B (score 7-9) with active bleeding at diagnostic endoscopy

Notable exclusion criteria: Child-Pugh score > 13, age > 75, HCC that did not meet transplantation criteria, bleeding gastric varices, total portal vein thrombosis, prior TIPS

All patients received endoscopic band ligation (EBL) or endoscopic injection sclerotherapy (EIS) at the time of diagnostic endoscopy. All patients also received vasoactive drugs (terlipressin, somatostatin, or octreotide).

Intervention: TIPS performed within 72 hours after diagnostic endoscopy

Comparison: 1) treatment with vasoactive drugs with transition to nonselective beta blocker when patients free of bleeding followed by 2) addition of isosorbide mononitrate to maximum tolerated dose, and 3) a second session of EBL at 7-14 days after the initial session (repeated q10-14 days until variceal eradication was achieved)

Outcome:
Primary – composite of failure to control acute bleeding or failure to prevent “clinically significant” variceal bleeding (requiring hospital admission or transfusion) at 1 year after enrollment

Secondary, selected

  • mortality at 1 year
  • failure to control acute bleeding
  • early rebleeding (at 5 days and 6 weeks)
  • rate of development of hepatic encephalopathy (HE)
  • ICU days, time in hospital

 

Results:
359 patients were screened for inclusion, but ultimately only 63 were randomized. Baseline characteristics were similar among the two groups except that the early TIPS group had a higher rate of patients with previous hepatic encephalopathy. Among early TIPS patients, the mean portal pressure dropped from 20.2±7 mmHg to 6.2±3 mmHg.

The primary composite endpoint of failure to control acute bleeding or rebleeding within 1 year occurred in 14 of 31 (45%) patients in the pharmacotherapy-EBL group and in only 1 of 32 (3%) of the early TIPS group (p = 0.001). The 1-year actuarial probability of remaining free of the primary outcome was 97% in the early TIPS group vs. 50% in the pharmacotherapy-EBL group (ARR 47 percentage points, 95% CI 25-69 percentage points, NNT 2.1).

Regarding mortality, at one year, 12 of 31 (39%) patients in the pharmacotherapy-EBL group had died, while only 4 of 32 (13%) in the early TIPS group had died (p = 0.001, NNT = 4.0).

Regarding HE: the 1-year actuarial probability of HE was 28% in the early TIPS group vs. 40% in the pharmacotherapy-EBL group (p = 0.13). Most of the episodes of HE occurred during the index bleed. Following discharge from index hospitalization, the 1-year risk of additional HE episodes was 10% in the pharmacotherapy-EBL group and 19% in the early TIPS group (p = 0.80).

There were no group differences in 1-year actuarial probability of new or worsening ascites.

There were no group differences in length of ICU stay or hospitalization duration.

Implication/Discussion:
Early TIPS in acute esophageal variceal bleeding, when compared to standard pharmacotherapy and endoscopic band ligation, improved control of index bleeding, reduced recurrent variceal bleeding at 1 year, and reduced all-cause mortality.

Prior studies had demonstrated that TIPS reduced the rebleeding rate but increased the rate of hepatic encephalopathy without improving survival. As such, TIPS had only been recommended as a rescue therapy. Obviously, this study presents compelling data that challenges these paradigms.

The authors note that in “patients with Child-Pugh class C or in class B with active variceal bleeding, failure to initially control the bleeding or early rebleeding contributes to further deterioration in liver function, which in turn worsens the prognosis and may preclude the use of rescue TIPS.”

Authors at UpToDate note that, given the totality of evidence to date, the benefit of early TIPS in preventing rebleeding “is offset by its failure to consistently improve survival and increasing morbidity due to the development of liver failure and encephalopathy.” Today, TIPS remains primarily a salvage therapy for use in cases of recurrent bleeding despite standard pharmacotherapy and EBL. There may be a subset of patients in whom early TIPS is the ideal strategy, but further trials will be required to identify this subset.


Further Reading/References
:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Prevention of recurrent variceal hemorrhage in patients with cirrhosis”

Summary by Duncan F. Moore, MD

Week 43 – Vancomycin vs. Metronidazole for C. Diff

“A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile-Associated Diarrhea, Stratified by Disease Severity”

Clin Infect Dis. 2007 Aug 1;45(3):302-7. [free full text]

Clostridium difficile-associated diarrhea (CDAD) is a common nosocomial illness that is increasing in incidence, severity, and recurrence. This trial, initiated in 1994, sought to investigate whether metronidazole PO or vancomycin PO was the superior initial treatment strategy in both mild and more severe disease.

Population: patients with diarrhea (3+ non-formed stools within 24hrs) and either stool C. difficile toxin A positivity within 48hrs after study entry or pseudomembranous colitis per endoscopy

(Patients were dropped from the study if the toxin A assay resulted negative.)

Notable exclusion criteria: prior failure of CDAD to respond to either study drug or treatment with either study drug during the previous 14 days.

Stratification: Prior to treatment randomization, patients were stratified to groups of either mild (0-1 points) or severe (≥2 points) CDAD.

  • One point: age > 60, T > 38.3º C, albumin < 2.5 mg/dL, WBC >15k within 48hrs of enrollment
  • Two points: endoscopic evidence of pseudomembranous colitis or treatment in the ICU

Intervention: vancomycin liquid 125mg QID and placebo tablet QID x 10 days

Comparison: metronidazole 250mg PO QID and “an unpleasantly-flavored” placebo liquid QID x 10 days

Outcome:
Primary

  1. Cure = resolution of diarrhea by day 6 of tx and negative toxin A assay at 6 and 10 days
  2. Treatment failure = persistence of diarrhea and/or positive toxin A assay after 6 days, the need for colectomy, or death after 5 days of therapy
  3. Relapse = recurrence of CDAD by day 21 after initial cure

 

Results:
172 patients were randomized. 90 had mild disease, and 82 had severe disease. 22 patients withdrew from the study prior to completion of 10 days of therapy. This study analyzed only the 150 patients who completed the trial (81 with mild disease, 69 with severe disease). Within severity groups, there were no differences in baseline characteristics among the two treatment groups.

Among patients with mild disease, 37 of 41 (90%) metronidazole patients were cured and 39 of 40 (98%) vancomycin patients were cured (p = 0.36). Among patients with severe disease, 29 of 38 (76%) metronidazole patients were cured and 69 of 71 (97%) vancomycin patients were cured (p = 0.02).

Among patients with mild disease, 3 of 37 (8%) metronidazole patients relapsed and 2 of 39 (5%) of vancomycin patients relapsed (p = 0.67). Among patients with severe disease, 6 of 29 (21%) of metronidazole patients relapsed and 3 of 30 (10%) of vancomycin patients relapsed (p = 0.30).


Implication/Discussion
:
Patients with mild CDAD had similar cure rates (> 90%) with oral metronidazole and oral vancomycin, however, patients with severe disease had higher cure rates with vancomycin than with oral metronidazole.

This randomized, placebo-controlled trial was the first trial comparing oral metronidazole and vancomycin in CDAD that was blinded and that stratified patients by disease severity.

The authors hypothesize that “a potential mechanism for our observation that metronidazole performs less well in patients with severe disease is that the drug is delivered from the bloodstream through the inflamed colonic mucosa, and stool concentrations decrease as disease resolves.”

Study limitations include single-center design, low N, high dropout rates, lack of intention-to-treat analysis, and slow recruitment (1994-2002). The slow recruitment and long duration of the trial is particularly notable, given that the organism itself, disease prevalence in community settings, host factors, and disease-inciting antibiotic regimens shifted significantly over this extended period.

At the time of publication of this study (2007), the CDC was not recommending vancomycin as first-line therapy for CDAD (for fear of spread of VRE).

Following this study, the 2010 update to the IDSA/SHEA guidelines for the treatment of CDAD recommended metronidazole PO for the initial treatment of mild-to-moderate CDAD, vancomycin 125mg PO QID for the initial treatment of severe CDAD, and vancomycin + metronidazole IV for severe, complicated CDAD.

However, both the disease and the evidence base for its treatment have evolved over the past 8 years. In March 2018, an update to the IDSA/SHEA guidelines was published. As a departure from prior recommendations, vancomycin 125mg PO QID (or fidaxomicin 200mg PO BID) x10 days is now the first-line treatment for non-severe C. diff. See Table 1 of these updated guidelines for a summary of pertinent definitions and treatment regimens.


Further Reading/References
:
1. Wiki Journal Club
2. 2 Minute Medicine
3. “Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA).”
4. “Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).” Clin Infect Dis. 2018 Mar 19;66(7).

Summary by Duncan F. Moore, MD

Week 42 – IDNT

“Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes”

aka the Irbesartan Diabetic Nephropathy Trial (IDNT)

N Engl J Med. 2001 Sep 20;345(12):851-60. [free full text]

Diabetes mellitus is the most common cause of ESRD in the US. In 1993, a landmark study in NEJM demonstrated that captopril (vs. placebo) slowed the deterioration in renal function in patients with T1DM. However, prior to this 2002 study, no study had definitively addressed whether a similar improvement in renal outcomes could be achieved with RAAS blockade in patients with T2DM. Irbesartan (Avapro) is an angiotensin II receptor blocker that was first approved in 1997 for the treatment of hypertension. Its marketer, Bristol-Meyers Squibb, sponsored this trial in hopes of broadening the market for its relatively new drug.

Population: patients age 30-70 with T2DM, HTN, proteinuria (≥ 900mg/24hrs), and Cr 1.0-3.0 in women and 1.2-3.0 in men

Intervention: irbesartan, titrated from 75mg to 300mg per day

Comparison #1: amlodipine, titrated from 2.5mg to 10mg per day
Comparison #2: placebo

(All patients had a target SBP goal ≤ 135, and all patients were allowed non-ACEi/non-ARB/non-CCB drugs as needed.)

Outcomes:
Primary – time to doubling of serum Cr, onset of ESRD, or all-cause mortality

Secondary

  • individual components of the primary outcome
  • composite cardiovascular outcome – death from CV causes, nonfatal MI, hospitalization for CHF, CVA with permanent neurologic deficit, or lower limb amputation above ankle

Results:
1715 patients were randomized. Baseline characteristics were similar among the groups, except for a slightly lower proportion of women in the placebo group. The mean blood pressure after the baseline visit was 144/77 in the irbesartan group, 141/77 in the amlodipine group, and 144/80 in the placebo group (p = 0.001 for pairwise comparisons between irbesartan or amlodipine and placebo).

Regarding the primary composite renal endpoint, the unadjusted relative risk was 0.80 (95% CI 0.66-0.97, p = 0.02) for irbesartan vs. placebo, 1.04 (95% CI 0.86-1.25, p = 0.69) for amlodipine vs. placebo, and 0.77 (0.63-0.93, p = 0.006) for irbesartan vs. amlodipine.

The groups also differed with respect to individual components of the primary outcome. The unadjusted relative risk of creatinine doubling was 33% lower among irbesartan patients than among placebo patients (p = 0.003) and was 37% lower than among amlodipine patients (p < 0.001). The relative risks of ESRD and all-cause mortality did not differ significantly among the groups.

There were no significant group differences with respect to the secondary, cardiovascular outcome (see Table 3).

Sensitivity analyses were performed. Inclusion of baseline covariates in a Cox regression of the primary outcome did not alter the conclusions. Similarly, the conclusions of the primary analysis were not impacted significantly by adjustment for mean arterial pressure achieved during follow-up.

Hyperkalemia occurred in 1.9% of the irbesartan patients, but only 0.5% of the amlodipine patients and 0.4% of the placebo patients (p = 0.01 for both pairwise comparisons with irbesartan).


Implication/Discussion
:
Irbesartan treatment in T2DM resulted in superior renal outcomes when compared to both placebo and amlodipine. This beneficial effect was independent of blood pressure lowering.

This was a well-designed, double-blind, randomized, controlled trial. However, it was industry-sponsored, and in retrospect, its choice of study drug seems quaint.

The direct conclusion of this trial is that irbesartan is renoprotective in T2DM. In the discussion of IDNT, the authors hypothesize that “the mechanism of renoprotection by agents that block the action of angiotensin II may be complex, involving hemodynamic factors that lower the intraglomerular pressure, the beneficial effects of diminished proteinuria, and decreased collagen formation that may be related to decreased stimulation of transforming growth factor beta by angiotensin II.”

In September 2002, on the basis of this trial, the FDA broadened the official indication of irbesartan to include the treatment of type 2 diabetic nephropathy.

This trial was published concurrently in NEJM with the RENAAL trial. RENAAL was a similar trial of losartan vs. placebo in T2DM, and demonstrated a similar reduction in the doubling of serum creatinine, as well as a 28% reduction in progression to ESRD.

In conjunction with the original 1993 ACEi in T1DM study, these two 2002 ARB in T2DM studies led to the overall notion of a renoprotective class effect of ACEis/ARBs in diabetes.

Enalapril and lisinopril’s patents expired in 2000 and 2002, respectively. Shortly afterward, generic, once-daily ACE inhibitors entered the US market. Ultimately, such drugs ended up commandeering much of the diabetic-nephropathy-in-T2DM market share for which irbesartan’s owners had hoped.


Further Reading/References
:
1. “The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group.” NEJM 1993.
2. CSG Captopril Trial @ Wiki Journal Club
3. IDNT @ Wiki Journal Club
4. IDNT @ 2 Minute Medicine
5. US Food and Drug Administration, New Drug Application #020757
6. RENAAL @ Wiki Journal Club
7. RENAAL @ 2 Minute Medicine

Summary by Duncan F. Moore, MD

Week 41 – PROVE IT-TIMI 22

“Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes”

by the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators

N Engl J Med. 2004 Apr 8;350(15):1495-504. [free full text]

Statins are a cornerstone of therapy for the primary and secondary prevention of atherosclerotic cardiovascular disease. In the early 2000s, atorvastatin (Lipitor) was an immensely popular and profitable drug for its maker Pfizer. Notably, the 2001 MIRACL trial demonstrated that early use of high-intensity atorvastatin after UA/NSTEMI significantly reduced the risk of adverse cardiovascular outcomes at 16 weeks. In this context, Bristol-Meyers Squibb designed a non-inferiority trial to compare a relatively low dose of its new drug pravastatin (Pravachol) to high-intensity atorvastatin 80mg for the prevention of adverse cardiovascular outcomes following ACS.

Population: adults with ACS in the preceding 10 days, post-PCI (if planned/applicable), with total cholesterol < 240 (< 200 if already on lipid-lowering therapy)

Intervention: pravastatin 40mg PO daily

Note – the dose of pravastatin could be increased to 80mg daily in a blinded fashion if LDL remained > 125 mg/dL on two consecutive follow-up visits.

Comparison: atorvastatin 80mg PO daily (“intensive therapy”)

Outcome:
Primary – composite of all-cause mortality, MI, UA requiring rehospitalization, revascularization > 30 days after randomization, and stroke

The authors pre-specified an upper limit of non-inferiority as a 17% increase in the hazard ratio for the primary outcome within the pravastatin group at 2 years.

Secondary:

  • composite of death from CAD, non-fatal MI, or revascularization
  • composite of death from CAD or non-fatal MI
  • the individual components of the composite primary outcome

Subgroup analyses of primary outcome: sex, baseline LDL > 125, UA, MI, DM

Results:
4162 patients were randomized. Baseline characteristics were similar among the two groups, aside from a higher rate of peripheral arterial disease among the pravastatin group. Regarding the type of ACS, approximately 1/3 of cases were UA, 1/3 were NSTEMIs, and 1/3 were STEMIs. 69% of patients received PCI prior to randomization. Approximately 25% of patients were taking statins at the time of inclusion. At inclusion, the median LDL level was 106 mg/dL.

During follow-up, the median LDL level among pravastatin patients was 95 mg/dL and 62 mg/dL in the intensive therapy (atorvastatin) patients. Ultimately, 8% of pravastatin patients had their dose uptitrated to 80mg daily due to LDL levels remaining above 125 mg/dL.

At two-year follow-up, the primary composite outcome was noted in 26.3% of patients in the standard-dose pravastatin group but only 22.4% of the intensive-therapy atorvastatin group (ARR = 3.9%, p = 0.005, NNT = 25.6). Pravastatin therapy failed to meet its prespecified non-inferiority criteria; in fact, atorvastatin was decidedly superior.

The composite of death due to CAD, non-fatal MI, or revascularization was reduced by 25% in the atorvastatin group (p < 0.001). The composite of death due to CAD or non-fatal MI was not different among the two groups. Regarding individual components of the primary outcome: there was a 14% reduction in the need for revascularization and a 29% reduction in recurrent UA in the atorvastatin group (p = 0.04 and 0.02, respectively). There were no group differences in all-cause mortality, MI, or stroke. Discontinuation rates were 21.4% in the pravastatin group and 22.8% in the atorvastatin group (p = 0.11).

Implication/Discussion:
Among patients with recent ACS, high-intensity atorvastatin was superior to standard-dose pravastatin in preventing a composite of cardiovascular outcomes.

Bristol-Meyers Squibb had counted on this trial to show the non-inferiority of its new drug pravastatin to high-intensity atorvastatin in the secondary prevention of ASCVD. Instead, this trial established the dominance of high-intensity statin therapy for secondary prevention.

The treatment groups in this trial differed both by drug and by relative dosage intensity of the assigned drug. Whether the improvements in outcomes were from one or both of these factors is unknown. The marked group difference in LDL reduction correlates with these interventions and outcomes, but this paper does not establish a causal relationship between LDL reduction and improved cardiovascular outcomes.

The current standard of care is to initiate high-intensity statin therapy as early as possible after the diagnosis of ACS. Per UpToDate, atorvastatin 80mg is the best-studied high-intensity statin regimen and an excellent default. However, rosuvastatin 20mg or 40mg is an acceptable alternative. Their expert opinion also recommends adding ezetimibe 10mg daily in patients with LDL > 70 mg/dL despite high-intensity statin therapy.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate “Low density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome”

Summary by Duncan F. Moore, MD

Week 40 – TORCH

“Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary Disease”

by the Towards a Revolution in COPD Health (TORCH) investigators

N Engl J Med. 2007 Feb 22;356(8):775-89. [free full text]

When the TORCH study was published in 2007, no prospective study to date had demonstrated a mortality benefit of inhaled corticosteroids (ICS) in COPD. Pulmonary inflammation occurs in COPD, and it had been hypothesized that ICS would improve COPD in multiple measures. Previously, ICS had been shown to reduce the frequency of COPD exacerbations, and retrospective data suggested that ICS reduced mortality, particularly when used in combination with a long-acting beta-agonist (LABA). TORCH was designed to evaluate prospectively the potential mortality benefit of combined ICS/LABA vs. ICS vs. LABA vs. placebo.

Population: COPD patients age 40-80, current or former smokers with ≥ 10-pack-year smoking hx, FEV1 < 60% predicted value and increase in FEV1 < 10% with albuterol administration, and prebronchodilator FEV1/FVC ratio of ≤ 70%

Intervention: combination salmeterol 50 µg and fluticasone propionate 500 µg BID

Comparisons:

  1. placebo BID
  2. salmeterol 50 µg BID
  3. fluticasone 500 µg BID

Note: all patients underwent a two-week run-in period during which the use of all corticosteroids and long-acting bronchodilators was stopped. Other classes COPD medications were allowed throughout the study.

Outcome:
Primary – time to all-cause mortality by 3 years, per log-rank test

Secondary

  • time to all-cause mortality, per Cox proportional hazards model
  • time to all-cause mortality, per log-rank test stratified by smoking status and country of residency
  • frequency of COPD exacerbations
  • quality of life per the St. George’s Respiratory Questionnaire
  • lung function, per postbronchodilator spirometry
  • incidence of pneumonia

 

Results:
6184 patients were randomized, but only 6112 were included in the final analyses (several sites excluded for not adhering to quality standards). The four groups were similar in all baseline characteristics (see Table 1).

All-cause mortality at 3 years was 12.6% in the combination-therapy group, 15.2% in the placebo group, 13.5% in the salmeterol group, and 16.0% in the fluticasone group. The hazard ratio for the comparison between combination-therapy and placebo was 0.825 (95% CI 0.681–1.002, p = 0.052, per log-rank test). See Figure 2B. This comparison was repeated in a pre-specified secondary analysis, using the Cox proportional hazards model, which yielded a HR of 0.811 (95% CI 0.670-0.982, p = 0.03), and in another pre-specified secondary analysis, using the log-rank test stratified according to smoking status and country of residency, which yielded a HR of 0.815 (95% CI 0.673-0.987, p = 0.04). In the primary analysis, the mortality risk did not differ among the salmeterol or fluticasone groups relative to the placebo group (see Table 2). Mortality risk in the combination-therapy group was less than that of the fluticasone group (HR 0.774, 95% CI 0.641-0.934, p = 0.007).

COPD exacerbations occurred at an annual rate of 0.85 in the combination therapy group and 1.13 in the placebo group, thus the rate ratio for exacerbations was 0.75 (95% CI 0.69-0.81, p < 0.001, NNT = 4). Exacerbation rates were also lower in the salmeterol and fluticasone groups (see Table 2).

The adjusted mean quality of life score per the St. George’s Respiratory Questionnaire improved in the combination-therapy, salmeterol, and fluticasone groups, and worsened slightly in the placebo group (see Table 3). All groups initially demonstrated an improvement in quality of life. In pairwise comparisons, combination therapy was superior to placebo, salmeterol, and fluticasone (p ranging from < 0.001 to 0.02).

Mean postbronchodilator FEV1 averaged over 3 years improved in the combination therapy group and decreased in the other groups. In all groups, the overall trend was a decrease in FEV1 following an initial improvement (see Figure 2E). In pairwise comparisons, combination therapy was superior to the other groups with respect to change in FEV1 (see Table 3).

The incidence of pneumonia was increased in groups receiving an ICS. The probability of developing pneumonia within the 3 year period was 19.6% in the combination-therapy group, 12.3% in the placebo group, 13.3% in the salmeterol group, and 18.3% in the fluticasone group (p < 0.001 for comparison between both combination-therapy versus placebo and fluticasone versus placebo).

44% of patients in the placebo group withdrew from the study. Only 34% of the combination-therapy group withdrew.


Implication/Discussion
:
In this large, international, double-blind, placebo-controlled, randomized, parallel-group trial of patients with COPD, combination therapy with ICS/LABA did not improve mortality when compared to a placebo. However, combination therapy improved the frequency of COPD exacerbations, improved quality of life, and slowed the decline in FEV1 relative to placebo.

It is notable that, according to this study’s pre-specified secondary analyses of mortality per Cox proportional hazards and log-rank test stratified by smoking status and location, there was a mortality benefit of combination therapy.

The authors suspect that there is indeed a mortality benefit, but that the trial was underpowered to detect it. Furthermore, the higher rate of treatment-group withdrawal among placebo patients may have biased the study toward a null result, given the intention-to-treat analysis.

In the years since TORCH, meta-analyses that included TORCH have concluded that ICS therapy in COPD slows the rate of decline in FEV1 and decreases the rate of COPD exacerbations when compared with placebo, but it does not reduce mortality.

Today, inhaled corticosteroids remain an integral component of our management of moderate to very severe COPD. See the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Pocket Guide to COPD Diagnosis, Management, and Prevention (2017) pages 14-16.


Further Reading/References
:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate “Role of inhaled glucocorticoid therapy in stable COPD”
4. “Inhaled corticosteroids for stable chronic obstructive pulmonary disease.” Cochrane Database Syst Rev (2012).
5. Global Initiative for Chronic Obstructive Lung Disease (GOLD) Pocket Guide to COPD Diagnosis, Management, and Prevention (2017)

Summary by Duncan F. Moore, MD

Week 39 – ACCORD

“Effects of Intensive Glucose Lowering in Type 2 Diabetes”

by the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group

N Engl J Med. 2008 Jun 12;358(24):2545-59. [free full text]

We all treat type 2 diabetes mellitus (T2DM) on a daily basis, and we understand that untreated T2DM places patients at increased risk for adverse micro- and macrovascular outcomes. Prior to the 2008 ACCORD study, prospective epidemiological studies had noted a direct correlation between increased hemoglobin A1c values and increased risk of cardiovascular events. This correlation implied that treating T2DM to lower A1c levels would result in the reduction of cardiovascular risk. The ACCORD trial was the first large RCT to evaluate this specific hypothesis through comparison of events in two treatment groups – aggressive and less-aggressive glucose management.

Population: patients with T2DM and A1c ≥ 7.5% and if age 40-79 with prior cardiovascular disease or if age 55-79 had “anatomical evidence of significant atherosclerosis,” albuminuria, LVH, or ≥ 2 additional risk factors for cardiovascular disease (dyslipidemia, HTN, current smoker, or obesity)

Notable exclusion criteria: “frequent or recent serious hypoglycemic events,” unwillingness to inject insulin, BMI > 45, Cr > 1.5, or “other serious illness”

Intervention: intensive therapy targeted to A1c < 6.0%

Comparison: standard therapy targeted to A1c 7.0-7.9%

Outcome:
Primary – composite of first nonfatal MI or nonfatal stroke and death from cardiovascular causes

Reported secondary outcomes included:

  • all-cause mortality
  • severe hypoglycemia
  • heart failure
  • motor vehicle accidents in which the patient was the driver
  • fluid retention
  • weight gain

Results:
10,251 patients were randomized. The average age was 62, the average duration of T2DM was 10 years, and the average A1c was 8.1%. There were no group differences in baseline characteristics (see Table 1). Both groups lowered their median A1c quickly, and median A1c values of the two groups separated rapidly within the first four months (see Figure 1). The intensive-therapy group had more exposure to antihyperglycemics of all classes (see Table 2), and drugs were more frequently added, removed, or titrated in the intensive-therapy group (4.4 times per year, versus 2.0 times per year in the standard-therapy group). At one year, the intensive-therapy group had a median A1c of 6.4% versus 7.5% in the standard-therapy group.

The primary outcome of MI/stroke/cardiovascular death occurred in 352 (6.9%) intensive-therapy patients versus 371 (7.2%) standard-therapy patients (HR 0.90, 95% CI 0.78-1.04, p = 0.16).

The trial was stopped early at a mean follow-up of 3.5 years due to increased all-cause mortality in the intensive-therapy group. 257 (5.0%) of the intensive-therapy patients died, but only 203 (4.0%) of the standard-therapy patients died (HR 1.22, 95% CI 1.01-1.46, p = 0.04). For every 95 patients treated with intensive therapy for 3.5 years, one extra patient died. Death from cardiovascular causes was also increased in the intensive-therapy group (HR 1.35, 95% CI 1.04-1.76, p = 0.02).

Additional secondary outcomes: the intensive-therapy group had higher rates of hypoglycemia, weight gain, and fluid retention than the standard-therapy group (see Table 3). There were no group differences in rates of heart failure or motor vehicle accidents in which the patient was the driver.

Implication/Discussion:
Intensive glucose control of T2DM increased all-cause mortality and did not alter the risk of cardiovascular events. This harm was previously unrecognized.

The authors performed sensitivities analyses, including non-prespecified analyses, such as group differences in use of drugs like rosiglitazone, and they were unable to find an explanation for this increased mortality.

The target A1c level in T2DM remains a nuanced, patient-specific goal. Aggressive management may lead to improved microvascular outcomes, but it must be weighed against the risk of hypoglycemia. As summarized by UpToDate [https://www.uptodate.com/contents/glycemic-control-and-vascular-complications-in-type-2-diabetes-mellitus], while long-term data from the UKPDS suggests there may be a macrovascular benefit to aggressive glucose management early in the course of T2DM, the data from ACCORD suggest strongly that, in patients with longstanding T2DM and additional risk factors for cardiovascular disease, such management increases mortality.

The 2017 American Diabetes Association guidelines suggest that “a reasonable A1c goal for many nonpregnant adults is < 7%.” More stringent goals (< 6.5%) may be appropriate if they can be achieved without significant hypoglycemia or polypharmacy, and less stringent goals (< 8%) may be appropriate for patients “with a severe history of hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications…”

Of note, ACCORD also simultaneously cross-enrolled its patients in studies of intensive blood pressure management and adjunctive lipid management with fenofibrate. See this 2010 NIH press release and the links below for more information.

ACCORD Blood Pressure – NEJM, Wiki Journal Club

ACCORD Lipids – NEJM, Wiki Journal Club


Further Reading/References
:
1. Wiki Journal Club
2. 2 Minute Medicine
3. American Diabetes Association – “Glycemic Targets.” Diabetes Care (2017).
4. “Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial.” Lancet (2010).

Summary by Duncan F. Moore, MD

Week 38 – POISE

“Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery: a randomised controlled trial”

aka the PeriOperative Ischemic Evaluation (POISE) trial

Lancet. 2008 May 31;371(9627):1839-47. [free full text]

Non-cardiac surgery is commonly associated with major cardiovascular complications. It has been hypothesized that perioperative beta blockade would reduce such events by attenuating the effects of the intraoperative increases in catecholamine levels. Prior to the 2008 POISE trial, small- and moderate-sized trials had revealed inconsistent results, alternately demonstrating benefit and non-benefit with perioperative beta blockade. The POISE trial was a large RCT designed to assess the benefit of extended-release metoprolol succinate (vs. placebo) in reducing major cardiovascular events in patients of elevated cardiovascular risk.

Population: patients age 45+ undergoing non-cardiac surgery with estimated LOS 24+ hrs and elevated risk of cardiac disease à either 1) hx of CAD, 2) peripheral vascular disease, 3) hospitalization for CHF within past 3 years, 4) undergoing major vascular surgery, 5) or any three of the following seven risk criteria: undergoing intrathoracic or intraperitoneal surgery, hx CHF, hx TIA, hx DM, Cr > 2.0, age 70+, or undergoing urgent/emergent surgery.

Notable exclusion criteria: HR < 50, 2nd or 3rd degree heart block, asthma, already on beta blocker, prior intolerance of beta blocker, hx CABG within 5 years and no cardiac ischemia since

Intervention: metoprolol succinate (extended-release) 100mg PO starting 2-4 hrs before surgery, additional 100mg at 6-12 hrs postoperatively, followed by 200mg daily for 30 days.

Patients unable to take PO meds postoperatively were given metoprolol infusion.

Comparison: placebo PO / IV at same frequency as metoprolol arm

Outcome:
Primary – composite of cardiovascular death, non-fatal MI, and non-fatal cardiac arrest at 30 days

Secondary (at 30 days)

  • cardiovascular death
  • non-fatal MI
  • non-fatal cardiac arrest
  • all-cause mortality
  • non-cardiovascular death
  • MI
  • cardiac revascularization
  • stroke
  • non-fatal stroke
  • CHF
  • new, clinically significant atrial fibrillation
  • clinically significant hypotension
  • clinically significant bradycardia

Pre-specified subgroup analyses of primary outcome:

Results:
9298 patients were randomized. However, fraudulent activity was detected at participating sites in Iran and Colombia, and thus 947 patients from these sites were excluded from the final analyses. Ultimately, 4174 were randomized to the metoprolol group, and 4177 were randomized to the placebo group. There were no significant differences in baseline characteristics, pre-operative cardiac medications, surgery type, or anesthesia type between the two groups (see Table 1).

Regarding the primary outcome, metoprolol patients were less likely than placebo patients to experience the primary composite endpoint of cardiovascular death, non-fatal MI, and non-fatal cardiac arrest (HR 0.84, 95% CI 0.70-0.99, p = 0.0399). See Figure 2A for the relevant Kaplan-Meier curve. Note that the curves separate distinctly within the first several days.

Regarding selected secondary outcomes (see Table 3 for full list), metoprolol patients were more likely to die from any cause (HR 1.33, 95% CI 1.03-1.74, p = 0.0317). See Figure 2D for the Kaplan-Meier curve for all-cause mortality. Note that the curves start to separate around day 10. Cause of death was analyzed, and the only group difference in attributable cause was an increased number of deaths due to sepsis or infection in the metoprolol group (data not shown). Metoprolol patients were more likely to sustain a stroke (HR 2.17, 95% CI 1.26-3.74, p = 0.0053) or a non-fatal stroke (HR 1.94, 95% CI 1.01-3.69, p = 0.0450). Of all patients who sustained a non-fatal stroke, only 15-20% made a full recovery. Metoprolol patients were less likely to sustain new-onset atrial fibrillation (HR 0.76, 95% CI 0.58-0.99, p = 0.0435) and less likely to sustain a non-fatal MI (HR 0.70, 95% CI 0.57-0.86, p = 0.0008). There were no group differences in risk of cardiovascular death or non-fatal cardiac arrest. Metoprolol patients were more likely to sustain clinically significant hypotension (HR 1.55, 95% CI 1.38-1.74, P < 0.0001) and clinically significant bradycardia (HR 2.74, 95% CI 2.19-3.43, p < 0.0001).

Subgroup analysis did not reveal any significant interaction with the primary outcome by RCRI, sex, type of surgery, or anesthesia type.

Implication/Discussion:
In patients with cardiovascular risk factors undergoing non-cardiac surgery, the perioperative initiation of beta blockade decreased the composite risk of cardiovascular death, non-fatal MI, and non-fatal cardiac arrest and increased the overall mortality risk and risk of stroke.

This study affirms its central hypothesis – that blunting the catecholamine surge of surgery is beneficial from a cardiac standpoint. (Most patients in this study had an RCRI of 1 or 2.) However, the attendant increase in all-cause mortality is dramatic. The increased mortality is thought to result from delayed recognition of sepsis due to masking of tachycardia. Beta blockade may also limit the physiologic hemodynamic response necessary to successfully fight a serious infection. In retrospective analyses mentioned in the discussion, the investigators state that they cannot fully explain the increased risk of stroke in the metoprolol group. However, hypotension attributable to beta blockade explains about half of the increased number of strokes.

Overall, the authors conclude that “patients are unlikely to accept the risks associated with perioperative extended-release metoprolol.”

A major limitation of this study is the fact that 10% of enrolled patients were discarded in analysis due to fraudulent activity at selected investigation sites. In terms of generalizability, it is important to remember that POISE excluded patients who were already on beta blockers.

Currently, per expert opinion at UpToDate, it is not recommended to initiate beta blockers preoperatively in order improve perioperative outcomes. POISE is an important piece of evidence underpinning the 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery, which includes the following recommendations regarding beta blockers:

  • Beta blocker therapy should not be started on the day of surgery (Class III – Harm, Level B)
  • Continue beta blockers in patients who are on beta blockers chronically (Class I, Level B)
  • In patients with intermediate- or high-risk preoperative tests, it may be reasonable to begin beta blockers
  • In patients with ≥ 3 RCRI risk factors, it may be reasonable to begin beta blockers before surgery
  • Initiating beta blockers in the perioperative setting as an approach to reduce perioperative risk is of uncertain benefit in those with a long-term indication but no other RCRI risk factors
  • It may be reasonable to begin perioperative beta blockers long enough in advance to assess safety and tolerability, preferably > 1 day before surgery

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Management of cardiac risk for noncardiac surgery”
4. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines.

Summary by Duncan F. Moore, MD

Week 37 – PARADIGM-HF

“Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure”

by the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) investigators

N Engl J Med. 2014 Sep 11;371(11):993-1004. [free full text]

Thanks to the CONSENSUS and SOLVD trials, angiotensin-converting enzyme (ACE) inhibitors have been a cornerstone of the treatment of heart failure with reduced ejection fraction (HFrEF) for years.

Neprilysin is a neutral endopeptidase that degrades several peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Inhibiting neprilysin increases levels of these substances and thus counteracts the neurohormonal overactivation of heart failure (which would otherwise lead to vasoconstriction, sodium retention, and maladaptive remodeling). Prior experimental data has demonstrated that, in terms of cardiovascular outcomes, neprilysin inhibition with an ARB is superior to ARB monotherapy. However, a clinical trial of concurrent neprilysin-inhibitor and ACE inhibitor therapy resulted in unacceptably high rates of serious angioedema. This study sought to show improved cardiac and mortality outcomes with neprilysin inhibition plus an ARB when compared to enalapril alone.

Population:
Inclusion Criteria: ≥18 y/o; NYHA class II, III, or IV; LVEF ≤ 35%; BNP ≥ 150 or NT-proBNP ≥600

Exclusion Criteria: Symptomatic hypotension, SBP < 100mmHg at screening or 95mmHg at randomization, eGFR < 30, or decrease in eGFR by 25% between screening and randomization, K+ > 5.2, or history of angioedema/side effects to ACE inhibition or ARBs

Intervention: sacubitril/valsartan 200mg BID

Comparison: enalapril 10mg BID

Trial design notes: Screened patients were initially given sacubitril/valsartan, followed by enalapril in single blinded run-in phases, in order to ensure similar tolerance of the drugs prior to randomization. Subsequently, patients who tolerated both drugs were randomized in a double-blind manner to treatment with one of the drugs. 

Outcome:
Primary – composite of death from cardiovascular causes or first hospitalization for heart failure

Secondary


Results:
4187 patients were randomized to the sacubitril/valsartan group, and 4212 were randomized to the enalapril group.

The primary endpoint (composite death due to cardiovascular causes or first hospitalization for HF) occurred in 914 patients (21.8%) in the sacubitril/valsartan group and 1117 patients (26.5%) in the enalapril group (p < 0.001; NNT = 21). Death due to cardiovascular causes occurred 558 times in the sacubitril/valsartan group and 693 times in the enalapril group (13.3% vs. 16.5%, p < 0.001; NNT = 31). Hospitalization for heart failure occurred (at least once) 537 times in the sacubitril/valsartan group and 658 times in the enalapril group (12.8% vs. 15.6%, p <0.001; NNT = 36).

Regarding secondary outcomes, the mean change in KCCQ score was a reduction of 2.99 points (i.e. a worsening of symptoms) in the sacubitril/valsartan group, versus a reduction of 4.63 points in the enalapril group (p = 0.001). There was no significant group difference in time to new-onset atrial fibrillation or time to diminished renal function.

Regarding safety outcomes, patients in the sacubitril/valsartan group were more likely to have symptomatic hypotension compared to patients in the enalapril group (14.0% vs. 9.2%; p <0.001; NNH = 21). However, patients in the enalapril group were more likely to have cough, serum creatinine ≥2.5, or potassium ≥6.0 compared to sacubitril/valsartan (p value varies, all significant). There was no group difference in rates of angioedema (p = 0.13).


Implication/Discussion:
In patients with HFrEF, inhibition of both angiotensin II and neprilysin with sacubitril/valsartan significantly reduced the risk of cardiovascular death or hospitalization for heart failure when compared to treatment with enalapril alone.

This study had several strengths. The treatment with sacubitril/valsartan was compared to treatment with a dose of enalapril that had previously been shown to reduce mortality when compared with placebo. Furthermore, the study used a run-in phase to ensure that patients could tolerate an enalapril dose that had previously been shown to reduce mortality. Finally, more patients in the enalapril group than in the sacubitril/valsartan group stopped the study drug due to adverse effects (12.3% vs. 10.7%, p=0.03).

This study ushered in a new era in heart failure management and added a new medication class – Angiotensin Receptor-Neprilysin Inhibitors or ARNIs – to the arsenal of available heart failure drugs. Entresto (sacubitril/valsartan), the ARNI posterchild, has been advertised widely over the past several years. However, clinical use so far has been lower than expected. Novartis, Entresto’s drug maker, is currently sponsoring PARAGON-HF, a trial of Entresto in patients with heart failure with preserved ejection fraction (HFpEF).

The 2017 ACC/AHA update to the guidelines for management of symptomatic HFrEF states that primary inhibition of the renin-angiotensin system with an ARNI in conjunction with evidence-based beta blockade and aldosterone antagonism is a Class I recommendation (Level B evidence). However, it does not favor this regimen over the Level-A-evidence regimens of an ARB or ACE inhibitor substituted for the ARNI. Yet the new guidelines also state that patients who have chronic symptomatic HFrEF of NYHA class II or III and tolerate an ACE inhibitor or ARB should substitute an ARNI for the ACE inhibitor or ARB in order to further reduce morbidity and mortality (Class I recommendation, level B evidence). See pages 15 and 17 here to read the details.

Bottom line: Among patients with symptomatic HFrEF, treatment with an ARNI reduces cardiovascular mortality and HF hospitalizations when compared to treatment with enalapril. Due to this study’s impact, the use of ARNIs is now a Class I recommendation by the 2017 ACC/AHA guidelines for the treatment of HFrEF. Despite its higher cost, the use of sacubitril/valsartan appears to be cost-effective in terms of QALYs gained.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. ACC/AHA 2017 Focused Update for Guideline Management of Heart Failure
4. CardioBrief, “After Slow Start Entresto Is Poised For Takeoff.”
5. PARAGON-HF @ ClinicalTrials.gov
6. McMurray et al., “Cost-effectiveness of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction.” Heart, 2017.

Summary by Patrick Miller, MD

Week 36 – Rivers Trial

“Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock”

N Engl J Med. 2001 Nov 8;345(19):1368-77. [free full text]

Sepsis is common, and severe sepsis and septic shock confer high mortality risks. Fundamentally, sepsis is a global mismatch between oxygen demand and delivery. Around the time of this seminal study by Rivers et al., there was increasing recognition of the concept of the “golden hour” in sepsis management – “where definitive recognition and treatment provide maximal benefit in terms of outcome” (1368). Rivers and his team created a “bundle” of early sepsis interventions that targeted preload, afterload, and contractility, dubbed early goal-directed therapy (EGDT), and evaluated this bundle’s effect on mortality and end-organ dysfunction.

Population: adults presenting to a single US academic center ED with ≥ 2 SIRS criteria and SBP ≤ 90 after a crystalloid challenge of 20-30ml/kg over 30min or lactate > 4mmol/L.

Notable exclusion criteria: acute CVA, MI, ACS, pulmonary edema, cardiac dysrhythmias, contraindication to central line, active GIB, trauma, “uncured cancer,” immunosuppression, or DNR status

Intervention: early goal-directed therapy

  • received a central venous catheter with continuous central venous O2 saturation (ScvO2) measurement
  • treated according to EGDT protocol (see Figure 2, or below) in ED for at least six hours
    • 500ml bolus of crystalloid q30min to achieve CVP 8-12mm
    • vasopressors to achieve MAP ≥ 65
    • vasodilators to achieve MAP ≤ 90
    • if ScvO2 < 70%, transfuse RBCs to achieve Hct ≥ 30
    • if, after CVP, MAP, and Hct were thusly optimized and ScvO2 remained < 70%, dobutamine was added and uptitrated to achieve ScvO2 ≥ 70 or until max dose 20 μg/kg/min
      • dobutamine was de-escalated if MAP < 65 or HR > 120
    • patients in whom hemodynamics could not be optimized were intubated and sedated, in order to decrease oxygen consumption
  • then transferred to inpatient ICU bed as soon as able, at which time ScvO2 measurement was discontinued
  • inpatient team was blinded to treatment group assignment

Comparison: standard of care

Outcome:
Primary – in-hospital mortality

Secondary

  • resuscitation end points
  • organ-dysfunction scores
  • coagulation-related variables
  • administered treatments
  • consumption of healthcare resources


Results
:
130 patients were randomized to EGDT, and 133 to standard therapy. There were no differences in baseline characteristics (see Table 1). There was no group difference in the prevalence of antibiotics given within the first 6 hours. Standard-therapy patients spent 6.3 ± 3.2 hours in the ED, whereas EGDT patients spent 8.0 ± 2.1 (p < 0.001).

In-hospital mortality was 46.5% in the standard-therapy group, and 30.5% in the EGDT group (p = 0.009, NNT 6.25); 28-day and 60-day mortalities were also improved in the EGDT group. See Table 3.

During the initial six hours of resuscitation, there was no significant group difference in mean heart rate or CVP. MAP was higher in the EGDT group (p < 0.001), but all patients in both groups reached a MAP ≥ 65. ScvO2 ≥ 70% was met by 60.2% of standard-therapy patients and 94.9% of EGDT patients (p < 0.001). A combination endpoint of achievement of CVP, MAP, and UOP (≥ 0.5cc/kg/hr) goals was met by 86.1% of standard-therapy patients and 99.2% of EGDT patients (p < 0.001). Standard-therapy patients had lower ScvO2 and greater base deficit, while lactate and pH values were similar in both groups.

During the period of 7 to 72 hours, the organ-dysfunction scores of APACHE II, SAPS II, and MODS were higher in the standard-therapy group (see Table 2). The prothrombin time, fibrin-split products concentration, and d-dimer concentrations were higher in the standard-therapy group, while PTT, fibrinogen concentration, and platelet counts were similar.

During the initial six hours, EGDT patients received significantly more fluids, pRBCs, and inotropic support than standard-therapy patients. Rates of vasopressor use and mechanical ventilation were similar.

During the period of 7 to 72 hours, standard-therapy patients received more fluids, pRBCs, and vasopressors than the EGDT group, and were more likely to be intubated and to have pulmonary-artery catheterization. Rates of inotrope use were similar.

Overall, during the first 72 hrs, standard-therapy patients were more likely to receive vasopressors, be intubated, and undergo pulmonary-artery catheterization. EGDT patients were more likely to receive pRBC transfusion. There was no group difference in total volume of fluid administration or inotrope use.

Regarding utilization, there were no group differences in mean duration of vasopressor therapy, mechanical ventilation, or length of stay. Among patients who survived to discharge, standard-therapy patients spent longer in the hospital than EGDT patients (18.4 ± 15.0 vs. 14.6 ± 14.5 days, respectively, p = 0.04).

Implication/Discussion:
Early goal-directed therapy reduced in-hospital mortality in patients presenting to the ED with severe sepsis or septic shock, when compared with usual care.

In their discussion, the authors note that “when early therapy is not comprehensive, the progression to severe disease may be well under way at the time of admission to the intensive care unit” (1376).

The Rivers trial has been cited over 10,100 times. It has been widely discussed and dissected for decades. Most importantly, it helped catalyze a then-ongoing paradigm shift of what “usual care” in sepsis is.

Corresponding practice point from Dr. Sonti and Dr. Vinayak and their Georgetown Critical Care Top 40: “Though we do not use the ‘Rivers protocol’ as written, concepts (timely resuscitation) have certainly infiltrated our ‘standard of care’ approach.”

The Rivers trial evaluated the effect of a bundle (multiple interventions). It was a relatively complex protocol, and the transfusion of blood to Hgb > 10 may have caused significant harm.

In aggregate, the most critical elements of the modern initial resuscitation in sepsis are early administration of antibiotics (notably not protocolized by Rivers) within the first hour and the aggressive administration of IV fluids (now usually 30cc/kg of crystalloid within the first 3 hours of presentation).

More recently, there have been three large RCTs of EGDT versus usual care and/or protocols that used some of the EGDT targets: ProCESS (2014, USA), ARISE (2014, Australia), and ProMISe (2015, UK). In general terms, EGDT provided no mortality benefit compared to usual care. Prospectively, the authors of these three trials planned a meta-analysis – the 2017 PRISM study – which concluded that “EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics.” Despite patients in the Rivers trial being sicker than those of ProCESS/ARISE/ProMISe, it was not found in the subgroup analysis of PRISM that EGDT was more beneficial in sicker patients. Overall, the PRISM authors noted that “it remains possible that general advances in the provision of care for sepsis and septic shock, to the benefit of all patients, explain part or all of the difference in findings between the trial by Rivers et al. and the more recent trials.”

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. Life in The Fast Lane
4. “A randomized trial of protocol-based care for early septic shock” (ProCESS). NEJM 2014.
5. “Goal-directed resuscitation for patients with early septic shock” (ARISE). NEJM 2014.
6. “Trial of early, goal-directed resuscitation for septic shock” (ProMISe). NEJM 2015.
7. “Early, Goal-Directed Therapy for Septic Shock – A Patient-level Meta-Analysis” PRISM. NEJM 2017.
8. Surviving Sepsis Campaign
9. UpToDate, “Evaluation and management of suspected sepsis and septic shock in adults

Summary by Duncan F. Moore, MD

Week 35 – PLCO

“Mortality Results from a Randomized Prostate-Cancer Screening Trial”

by the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial project team

N Engl J Med. 2009 Mar 26;360(13):1310-9. [free full text]

The use of prostate-specific-antigen (PSA) testing to screen for prostate cancer has been a contentious subject for decades. Prior to the 2009 PLCO trial, there were no high-quality prospective studies of the potential benefit of PSA testing.

Population: men ages 55-74 enrolled at 10 US academic centers

exclusion criteria – hx of prostate, lung, or colorectal cancer, current cancer tx, and > 1 PSA test in past 3 years

Intervention: annual PSA testing for 6 years with annual digital rectal exam (DRE) for 4 years

Comparison: usual care

Outcome:
Primary – prostate-cancer-attributable death rate
Secondary – incidence of prostate cancer

Subgroup analyses of primary outcome:

  • patients with no more than 1 PSA test prior to enrollment
  • patients with 2+ PSA tests prior to enrollment

Results:
38,343 patients were randomized to the screening group, and 38,350 were randomized to the usual-care group. Baseline characteristics were similar in both groups. Median follow-up duration was 11.5 years. Patients in the screening group were 85% compliant with PSA testing and 86% compliant with DRE. In the usual-care group, 40% of patients received a PSA test within the first year, and 52% received a PSA test by the sixth year. Cumulative DRE rates in the control group were between 40-50%.

By seven years, there was no significant difference in rates of death attributable to prostate cancer. There were 50 deaths in the screening group and only 44 in the usual-care group (rate ratio 1.13, 95% CI 0.75 – 1.70). At ten years, there were 92 and 82 deaths in the respective groups (rate ratio 1.11, 95% CI 0.83–1.50).

By seven years, there was a higher rate of prostate cancer detection in the screening group. 2820 patients were diagnosed in the screening group, but only 2322 were diagnosed in the usual-care group (rate ratio 1.22, 95% CI 1.16–1.29). By ten years, there were 3452 and 2974 diagnoses in the respective groups (rate ratio 1.17, 95% CI 1.11–1.22).

Treatment-related complications (e.g. infection, incontinence, impotence) were not reported in this study.

Implication/Discussion:
Yearly PSA screening increased the prostate cancer diagnosis rate but did not impact prostate-cancer mortality when compared to the standard of care.

However, there were relatively high rates of PSA testing in the usual-care group (40-50%). The authors cite this finding as a probable major contributor to the lack of mortality difference. Other factors that may have biased to a null result were prior PSA testing and advances in treatments for prostate cancer during the trial. Regarding the former, 44% of men in both groups had already had one or more PSA tests prior to study enrollment. Prior PSA testing likely contributed to selection bias.

PSA screening recommendations prior to this 2009 study:

  • American Urological Association and American Cancer Society – recommended annual PSA and DRE, starting at age 50 if normal risk and earlier in high-risk men
  • National Comprehensive Cancer Network: “a risk-based screening algorithm, including family history, race, and age”
  • 2008 USPSTF Guidelines: insufficient evidence to determine balance between risks/benefits of PSA testing in men younger than 75; recommended against screening in age 75+ (Grade I Recommendation)

The authors of this study conclude that their results “support the validity of the recent [2008] recommendations of the USPSTF, especially against screening all men over the age of 75.”

However, the conclusions of the European Randomized Study of Screening for Prostate Cancer (ERSPC), which was published concurrently with PLCO in NEJM, differed. In ERSPC, PSA was screened every 4 years. The authors found an increased rate of detection of prostate cancer, but, more importantly, they found that screening decreased prostate cancer mortality (adjusted rate ratio 0.80, 95% CI 0.65–0.98, p = 0.04; NNT 1410 men receiving 1.7 screening visits over 9 years). Like PLCO, this study did not report treatment harms that may have been associated with overly zealous diagnosis.

The USPSTF reexamined its PSA guidelines in 2012. Given the lack of mortality benefit in PLCO, the pitiful mortality benefit in ERSPC, and the assumed harm from over-diagnosis and excessive intervention in patients who would ultimately not succumb to prostate cancer, the USPSTF concluded that PSA-based screening for prostate cancer should not be offered (Grade D Recommendation).

However, this guideline is under active consideration as of March 2018. See https://screeningforprostatecancer.org/. The draft recommendations encourage men ages 55-69 to have an informed discussion with their physician about potential benefits and harms of PSA-based screening (Grade C Recommendation). The USPSTF continues to recommend against screening in patients over 70 years old.

Screening for prostate cancer remains a complex and controversial topic. While we await further guidelines, we should continue to provide our patients with the aforementioned informed discussion. UpToDate has a nice summary of talking points culled from several sources.

Further Reading/References:
1. 2 Minute Medicine
2. ERSPC @ Wiki Journal Club
3. UpToDate, Screening for Prostate Cancer

Summary by Duncan F. Moore, MD