October 2009 Archives

Rerks-Ngarm S. MOPH-TAVEG Investigators. NEJM 2009; 361: 1.

Background: After disappointing results with a glycoprotein 120 (gp120) B/B (AIDSVAX B/B) vaccine and a canary pox vector ALVAC-HIV vCP1452 vaccine, there was some promise after the initial failure of the AIDSVAX B/E vaccine alone in IVDU but proof of some efficacy with the ALVAC-HIV plus AIDSVAX B/E (prime-boost) has led to this large test-of-concept study.

Methods: Community-based, randomized, multicenter, double-blind, placebo-controlled efficacy trial. Recruited Thai men and women, 18-30, not infected with HIV, without controlling for HIV risk. 26,676 assessed, 17,350 screened, and 16,402 randomized. Follow-up is 3 years.

Treatment: Vaccines administered at baseline (day 0), and then 4, 12, and 24 weeks later. ALVAC-HIV administered at all four visits, the AIDSVAX boost at the 2nd & 4th visit.

Results:

Primary Endpoint: HIV Infection
All subjects: RRR 31.2%, ARR (per person-years) 0.00087, NNT 1149/person-years, ARR 0.0029 (study), NNT 350
*Note: There was no difference in the high risk population (22/1896 v 23/1929)

Postinfection Viral Load & CD4+ T-Cell Count: no difference

Secondary Endpoint: Immunogenicity, relevance unknown
T-cell-line adapted neutralizing antibody: 71% response
Antibody-directed, cell-mediated cytotoxicity, CD4+ lymphoproliferation:

61% response to gp20 MN, 63% response to gp120 CM244

CD8+ T-cells: 24% response to (51)Cr-release cytotoxic T-cell assay, 17% +ELISPOT

 

EVEREST Outcome Trial. JAMA 2007; 297: 1319.

Background: Vasopressin mediates fluid retention in heart failure. Tolvaptan, a vasopressin V2 receptor blocker may be an effective adjunct in the management of heart failure.

Methods: Multicenter, randomized, double-blind, placebo controlled study. N = 4133.

Treatment: Oral tolvaptan 30 mg daily vs placebo for 60 days.

Results:

Primary Outcome: mortality 25.9% v 26.3%, p = 0.68, no difference

Secondary Outcomes:

cardiovascular mortality: no difference
cardiovascular death or hospitalization: no difference
worsening heart failure: no difference

 

Breathing Not Properly Study. NEJM 2002; 347: 3.

Background: In an attempt by the Centers for Medicare and Medicaid Services to provide cost-effective treatment for patients with CHF, rapid and accurate differentiation of CHF from other causes of dyspnea must be accomplished.

Methods: Prospective, multi-center, International study. N = 1586. Exclusions include < 18y, clearly not CHF related dyspnea (trauma), AMI, ARI, and UA.  BNP levels were blinded to the physician.

Gold Standard: Two cardiologists who independently classified the diagnosis as 1) dyspnea due to CHF, 2) acute dyspnea due to noncardiac causes in a patient with h/o LV dysfunction, or 3) dyspnea not due to CHF. They were allowed to use the Framingham CHF score (2 major or 1 major and 2 minor) and/or the NHANES CHF score (3+).

Baseline: Mean age 64 years, 56% men, 49% white, 45% black, 7% had an S3 canter, 43% had rales, 22% had JVD, and 42% had edema.

Results:

BNP: Area under the ROC = 0.91 (p < 0.001). Using 100 pg/mL had a sensitivity of 90%, a specificity of 76%, a PPV 79%, a NPV 89%, a positive likelihood ratio of 3.75, and a negative likelihood ratio of 0.13. Using a cutoff of 50 pg/mL, the NPV was 96%. The mean BNP differed per NYHA classes. The levels were approximately 244, 389, 640, and 817, for class I, II, III, & IV, respectively.

Application:

Using the Boston Heart Failure Criteria (Marantz. Circulation 1988; 77: 607), patients who have "possible" HF by the criteria will have an underlying incidence (pretest probability) of LVEF < 40%, 20-35% of the time. Using the +LR (3.75) of a BNP > 100 we see that the posttest probability in that patient is 40-60%. The presence of a JVD increases the posttest probability to about 80%, an S3 to 92%.

  

ECASS III. NEJM 2008; 359: 1317.

Background: to study the efficacy and safety of IV alteplase when given between 3 and 4.5 hours after the onset of stroke.

Methods: Prospective, multi-center, randomized, double-blind trial. Exclusions similar to NINDS plus patients > 80y, NIHSS > 25, both previous stroke and diabetes, and on anticoagulation regardless of INR. n = 821.

Primary Outcome: disability at 90d (favorable = Rankin score 0 or 1, unfavorable = Rankin score 2-6)

Favorable outcome with alteplase: 52.4% vs 45.2%, ARR 7.2%, NNT = 13.8, p = 0.04 

Adverse Events

Any intracranial hemorrhage: 27.0% vs 17.6%, ARI 9.4%, NNT 10.6, p = 0.001
Symptomatic ICH: 2.4% vs 0.2%, ARI 2.2%, NNT = 45, p = 0.008
Mortality: 7.7% vs 8.4%, p = 0.68 

Additional Reading

NINDS. NEJM 1995; 333: 1581.
ATLANTIS. JAMA 1999; 282: 2019.
ECASS II. Lancet 1998; 352: 1245.
Marler JR. Lancet 2004; 363:768.