Week 21 – HACA

“Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest”

by the Hypothermia After Cardiac Arrest Study Group

N Engl J Med. 2002 Feb 21;346(8):549-56. [free full text]

Neurologic injury after cardiac arrest is a significant source of morbidity and mortality. It is hypothesized that brain reperfusion injury (via the generation of free radicals and other inflammatory mediators) following ischemic time is the primary pathophysiologic basis. Animal models and limited human studies have demonstrated that patients treated with mild hypothermia following cardiac arrest have improved neurologic outcome. The 2002 HACA study sought to prospectively evaluate the utility of therapeutic hypothermia in reducing neurologic sequelae and mortality post-arrest.

Population: European patients who achieve return of spontaneous circulation after presenting to the ED in cardiac arrest

inclusion criteria: witnessed arrest, ventricular fibrillation or non-perfusing ventricular tachycardia as initial rhythm, estimated interval 5 to 15 min from collapse to first resuscitation attempt, no more than 60 min from collapse to ROSC, age 18-75

pertinent exclusion: pt already < 30ºC on admission, comatose state prior to arrest d/t CNS drugs, response to commands following ROSC

Intervention: Cooling to target temperature 32-34ºC with maintenance for 24 hrs followed by passive rewarming. Pts received pancuronium for neuromuscular blockade to prevent shivering.

Comparison: Standard intensive care

Outcomes:

Primary: a “favorable neurologic outcome” at 6 months defined as Pittsburgh cerebral-performance scale category 1 (good recovery) or 2 (moderate disability). (Of note, the examiner was blinded to treatment group allocation.)

Secondary:
– all-cause mortality at 6 months
– specific complications within the first 7 days: bleeding “of any severity,” pneumonia, sepsis, pancreatitis, renal failure, pulmonary edema, seizures, arrhythmias, and pressure sores

Results:
3551 consecutive patients were assessed for enrollment and ultimately 275 met inclusion criteria and were randomized. The normothermia group had more baseline DM and CAD and were more likely to have received BLS from a bystander prior to the ED.

Regarding neurologic outcome at 6 months, 75 of 136 (55%) of the hypothermia group had a favorable neurologic outcome, versus 54/137 (39%) in the normothermia group (RR 1.40, 95% CI 1.08-1.81, p = 0.009; NNT = 6). After adjusting for all baseline characteristics, the RR increased slightly to 1.47 (95% CI 1.09-1.82).

Regarding death at 6 months, 41% of the hypothermia group had died, versus 55% of the normothermia group (RR 0.74, 95% CI 0.58-0.95, p = 0.02; NNT = 7). After adjusting for all baseline characteristics, RR = 0.62 (95% CI 0.36-0.95). There was no difference among the two groups in the rate of any complication or in the total number of complications during the first 7 days.

Implication/Discussion:
In ED patients with Vfib or pulseless VT arrest who did not have meaningful response to commands after ROSC, immediate therapeutic hypothermia reduced the rate of neurologic sequelae and mortality at 6 months.

Corresponding practice point from Dr. Sonti and Dr. Vinayak and their Georgetown Critical Care Top 40: “If after ROSC your patient remains unresponsive and does not have refractory hypoxemia/hypotension/coagulopathy, you should initiate therapeutic hypothermia even if the arrest was PEA. The benefit seen was substantial and any proposed biologic mechanism would seemingly apply to all causes of cardiac arrest. The investigators used pancuronium to prevent shivering; [at MGUH] there is a ‘shivering’ protocol in place and if refractory, paralytics can be used.”

This trial, as well as a concurrent publication by Benard et al., ushered in a new paradigm of therapeutic hypothermia or “targeted temperature management” (TTM) following cardiac arrest. Numerous trials in related populations and with modified interventions (e.g. target temperature 36º C) were performed over the following decade, and ultimately led to the current standard of practice.

Per UpToDate, the collective trial data suggest that “active control of the post-cardiac arrest patient’s core temperature, with a target between 32 and 36ºC, followed by active avoidance of fever, is the optimal strategy to promote patient survival.” TTM should be undertaken in all patients who do not follow commands or have purposeful movements following ROSC. Expert opinion at UpToDate recommends maintaining temperature control for at least 48 hours. There is no strict contraindication to TTM.

Further Reading/References:
1. 2 Minute Medicine
2. Wiki Journal Club
3. Georgetown Critical Care Top 40, page 23 (Jan. 2016)
4. PulmCCM.org, “Hypothermia did not help after out-of-hospital cardiac arrest, in largest study yet
5. Cochrane Review, “Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation”
6. The NNT, “Mild Therapeutic Hypothermia for Neuroprotection Following CPR”
7. UpToDate, “Post-cardiac arrest management in adults”

Summary by Duncan F. Moore, MD

Week 20 – CHADS2

“Validation of Clinical Classification Schemes for Predicting Stroke”

JAMA. 2001 June 13;285(22):2864-70. [free full text]

Atrial fibrillation is the most common cardiac arrhythmia and affects 1-2% of the overall population, with increasing prevalence as people age. Atrial fibrillation also carries substantial morbidity and mortality due to the risk of stroke and thromboembolism, although the risk of embolic phenomenon varies widely across various subpopulations. In 2001, the only oral anticoagulation options available were warfarin and aspirin, which had relative risk reductions of 62% and 22%, respectively, consistent across these subpopulations. Clinicians felt that high risk patients should be anticoagulated, but the two common classification schemes, AFI and SPAF, were flawed. Patients were often classified as low risk in one scheme and high risk in the other. The schemes were derived retrospectively and were clinically ambiguous. Therefore, in 2001 a group of investigators combined the two existing schemes to create the CHADS2 scheme and applied it to a new data set.

Population (NRAF cohort): Hospitalized Medicare patients ages 65-95 with non-valvular AF not prescribed warfarin at hospital discharge. Patient records were manually abstracted by five quality improvement organizations in seven US states (California, Connecticut, Louisiana, Maine, Missouri, New Hampshire, and Vermont).

Intervention: Determination of CHADS2 score (1 point for recent CHF, hypertension, age ≥ 75, and DM; 2 points for a history of stroke or TIA)

Comparison: AFI and SPAF risk schemes

Measured Outcome: Hospitalization rates for ischemic stroke (per ICD-9 codes from Medicare claims), stratified by CHADS2 / AFI / SPAF scores.

Calculated Outcome: performance of the various schemes, based on c statistic (a measure of predictive accuracy in a binary logistic regression model)

Results:
1733 patients were identified in the NRAF cohort. When compared to the AFI and SPAF trials, these patients tended be older (81 in NRAF vs. 69 in AFI vs. 69 in SPAF), have a higher burden of CHF (56% vs. 22% vs. 21%), more likely to be female (58% vs. 34% vs. 28%), had a history of DM (23% vs. 15% vs. 15%) and prior stroke or TIA (25% vs. 17% vs. 8%). The stroke rate was lowest in the group with a CHADS2 = 0 (1.9 per 100 patient years, adjusting for the assumption that aspirin was not taken). The stroke rate increased by a factor of approximately 1.5 for each 1-point increase in the CHADS2 score.

CHADS2 score            NRAF Adjusted Stroke Rate per 100 Patient-Years
0                                      1.9
1                                      2.8
2                                      4.0
3                                      5.9
4                                      8.5
5                                      12.5
6                                      18.2

The CHADS2 scheme had a c statistic of 0.82 compared to 0.68 for the AFI scheme and 0.74 for the SPAF scheme.

Implication/Discussion
The CHADS2 scheme provides clinicians with a scoring system to help guide decision making for anticoagulation in patients with non-valvular AF.

The authors note that the application of the CHADS2 score could be useful in several clinical scenarios. First, it easily identifies patients at low risk of stroke (CHADS2 = 0) for whom anticoagulation with warfarin would probably not provide significant benefit. The authors argue that these patients should merely be offered aspirin. Second, the CHADS2 score could facilitate medication selection based on a patient-specific risk of stroke. Third, the CHADS2 score could help clinicians make decisions regarding anticoagulation in the perioperative setting by evaluating the risk of stroke against the hemorrhagic risk of the procedure. Although the CHADS2 is no longer the preferred risk-stratification scheme, the same concepts are still applicable to the more commonly used CHA2DS2-VASc.

This study had several strengths. First, the cohort was from seven states that represented all geographic regions of the United States. Second, CHADS2 was pre-specified based on previous studies and validated using the NRAF data set. Third, the NRAF data set was obtained from actual patient chart review as opposed to purely from an administrative database. Finally, the NRAF patients were older and sicker than those of the AFI and SPAF cohorts, thus the CHADS2 appears to be generalizable to the very large demographic of frail, elderly Medicare patients.

As CHADS2 became widely used clinically in the early 2000s, its application to other cohorts generated a large intermediate-risk group (CHADS2 = 1), which was sometimes > 60% of the cohort (though in the NRAF cohort, CHADS2 = 1 accounted for 27% of the cohort). In clinical practice, this intermediate-risk group was to be offered either warfarin or aspirin. Clearly, a clinical-risk predictor that does not provide clear guidance in over 50% of patients needs to be improved. As a result, the CHA2DS2-VASc scoring system was developed from the Birmingham 2009 scheme. When compared head-to-head in registry data, CHA2DS2-VASc more effectively discriminated stroke risk among patients with a baseline CHADS2 score of 0 to 1. Because of this, CHA2DS2-VASc is the recommended risk stratification scheme in the AHA/ACC/HRS 2014 Practice Guideline for Atrial Fibrillation. In modern practice, anticoagulation is unnecessary when CHA2DS2-VASc score = 0, should be considered (vs. antiplatelet or no treatment) when score = 1, and is recommended when score ≥ 2.

Further Reading:
1. AHA/ACC/HRS 2014 Practice Guideline for Atrial Fibrillation
2. CHA2DS2-VASc (2010)
3. 2 Minute Medicine

Summary by Ryan Commins, MD

Week 19 – RAVE

“Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis”

by the Rituximab in ANCA-Associated Vasculitis-Immune Tolerance Network (RAVE-ITN) Research Group

N Engl J Med. 2010 Jul 15;363(3):221-32. [free full text]

ANCA-associated vasculitides, such as granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) and microscopic polyangiitis (MPA) are often rapidly progressive and highly morbid. Mortality in untreated generalized GPA can be as high as 90% at 2 years (PMID 1739240). Since the early 1980s, cyclophosphamide (CYC) with corticosteroids has been the best treatment option for induction of disease remission in GPA and MPA. Unfortunately, the immediate and delayed adverse effect profile of CYC can be burdensome. The role of B lymphocytes in the pathogenesis of these diseases has been increasingly appreciated over the past 20 years, and this association inspired uncontrolled treatment studies with the anti-CD20 agent rituximab that demonstrated promising preliminary results. Thus the RAVE trial was performed to compare rituximab to cyclophosphamide, the standard of care.

Population:
ANCA-positive patients with “severe” GPA or MPA and a Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG) of 3+.

notable exclusion: patients intubated due to alveolar hemorrhage, patients with Cr > 4.0

Intervention:
rituximab 375mg/m2 IV weekly x4 + daily placebo-CYC + pulse-dose corticosteroids with oral maintenance and then taper

Comparison:
placebo-rituximab infusion weekly x4 + daily CYC + pulse-dose corticosteroids with oral maintenance and then taper

Outcome:
primary end point = clinical remission, defined as a BVAS/WG of 0 and successful completion of prednisone taper

primary outcome = noninferiority of rituximab relative to CYC in reaching 1º end point

authors specified non-inferiority margin as a -20 percentage point difference in remission rate

subgroup analyses (pre-specified) = type of ANCA-associated vasculitis, type of ANCA, “newly-diagnosed disease,” relapsing disease, alveolar hemorrhage, and severe renal disease

secondary outcomes: rate of disease flares, BVAS/WG of 0 during treatment with prednisone at a dose of less than 10mg/day, cumulative glucocorticoid dose, rates of adverse events, SF-36 scores


Results
:
197 patients were randomized, and baseline characteristics were similar among the two groups (e.g. GPA vs. MPA, relapsed disease, etc.). 75% of patients had GPA. 64% of the patients in the rituximab group reached remission, while 53% of the control patients did. This 11 percentage point difference among the treatment groups was consistent with non-inferiority (p < 0.001). However, although more rituximab patients reached the primary endpoint, the difference between the two groups was statistically insignificant, and thus superiority of rituximab could not be established (95% CI -3.2 – 24.3 percentage points difference, p = 0.09). Subgroup analysis was notable only for superiority of rituximab in relapsed patients (67% remission rate vs. 42% in controls, p=0.01). Rates of adverse events and treatment discontinuation were similar among the two groups.

Implication/Discussion:
Rituximab + steroids is as effective as cyclophosphamide + steroids in inducing remission in severe GPA and MPA.

This study initiated a major paradigm shift in the standard of care of ANCA-associated vasculitis. The following year, the FDA approved rituximab + steroids as the first-ever treatment regimen approved for GPA and MPA.  It spurred numerous follow up trials, and to this day expert opinion is split over whether CYC or rituximab should be the initial immunosuppressive therapy in GPA/MPA with “organ-threatening or life-threatening disease” (UpToDate).

The study’s double-blind, double-dummy RCT design is strong. However, a large shortcoming of this trial was that 101 patients (51%) already had relapsing disease at the time of inclusion in the study, which implies that they had likely already failed treatment with standard-of-care CYC. Thus both the superiority of rituximab in this subgroup and its noninferiority overall is much less impressive. Overall, the follow up duration of 6 months is relatively short compared to the extended timeframe of these relapsing diseases and the potentially late-appearing adverse effects of their treatments (e.g. therapy-induced malignancy). Finally, the authors do not justify why they chose the relatively-generous margin of -20 percentage points as their inferiority margin (in this case rituximab-induced remission could be 34% while CYC-induced could be 53% and rituximab would still be considered non-inferior). Non-inferiority trials are increasingly common, and careful attention needs to be paid to their methodologies. (See this 2017 NEJM review and http://www.rds-sc.nihr.ac.uk/study-design/quantitative-studies/clinical-trials/non-inferiority-trials/ for more details.)

Further Reading/References:
1. “Wegener granulomatosis: an analysis of 158 patients” (1992)
2. RAVE at ClinicalTrials.gov
3. “Challenges in the Design and Interpretation of Noninferiority Trials,” NEJM (2017)
4. “Clinical Trials – Non-inferiority Trials”
5. UpToDate,“Initial Immunosuppressive Therapy in Granulomatosis with Polyangiitis and Microscopic Polyangiitis
6. Wiki Journal Club
7. 2 Minute Medicine

Summary by Duncan F. Moore, MD

Week 18 – VERT

“Effects of Risedronate Treatment on Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis”

by the Vertebral Efficacy with Risedronate Therapy (VERT) Study Group

JAMA. 1999 Oct 13;282(14):1344-52. [free full text]

Bisphosphonates are a highly effective and relatively safe class of medications for the prevention of fractures in patients with osteoporosis. The VERT trial published in 1999 was a landmark trial that demonstrated this protective effect with the daily oral bisphosphonate risedronate.

Population: post-menopausal women with either 2 or more vertebral fractures per radiography or 1 vertebral fracture with decreased lumbar spine bone mineral density

Intervention: risedronate 2.5mg mg PO daily or risedronate 5mg PO daily

Comparison: placebo PO daily

Outcomes:
1. prevalence of new vertebral fracture at 3 years follow-up, per annual imaging
2. prevalence of new non-vertebral fracture at 3 years follow-up, per annual imaging
3. change in bone mineral density, per DEXA q6 months

Results:
2458 patients were randomized. During the course of the study, “data from other trials indicated that the 2.5mg risedronate dose was less effective than the 5mg dose,” and thus the authors discontinued further data collection on the 2.5mg treatment arm at 1 year into the study. All treatment groups had similar baseline characteristics. 55% of the placebo group and 60% of the 5mg risedronate group completed 3 years of treatment. The prevalence of new vertebral fracture within 3 years was 11.3% in the risedronate group and 16.3% in the placebo group (RR 0.59, 95% CI 0.43-0.82, p = 0.003; NNT = 20). The prevalence of new non-vertebral fractures at 3 years was 5.2% in the treatment arm and 8.4% in the placebo arm (RR 0.6, 95% CI 0.39-0.94, p = 0.02; NNT = 31). Regarding bone mineral density (BMD), see Figure 4 for a visual depiction of the changes in BMD by treatment group at the various 6-month timepoints. Notably, change from baseline BMD of the lumbar spine and femoral neck was significantly higher (and positive) in the risedronate 5mg group at all follow-up timepoints relative to the placebo group and at all timepoints except 6 months for the femoral trochanter measurements. Regarding adverse events, there was no difference in the incidence of upper GI adverse events among the two groups. GI complaints “were the most common adverse events associated with study discontinuance,” and GI events lead to 42% of placebo withdrawals but only 36% of the 5mg risedronate withdrawals.

Implication/Discussion:
Oral risedronate reduces the risk of vertebral and non-vertebral fractures in patients with osteoporosis while increasing bone mineral density.

Overall, this was a large, well-designed RCT that demonstrated a concrete treatment benefit. As a result, oral bisphosphonate therapy has become the standard of care both for treatment and prevention of osteoporosis. This study, as well as others, demonstrated that such therapies are well-tolerated with relatively few side effects.

A notable strength of this study is that it did not exclude patients with GI comorbidities.  One weakness is the modification of the trial protocol to eliminate the risedronate 2.5mg treatment arm after 1 year of study. Although this arm demonstrated a reduction in vertebral fracture at 1 year relative to placebo (p = 0.02), its elimination raises suspicion that the pre-specified analyses were not yielding the anticipated results during the interim analysis and thus the less-impressive treatment arm was discarded.

Further Reading/References:
1. Weekly alendronate vs. weekly risedronate
2. Comparative effectiveness of pharmacologic treatments to prevent fractures: an updated systematic review (2014)

Summary by Duncan F. Moore, MD