SMJR

Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes

2010-09-02T05:33:16Z

Review by Kevin Blaine

Ieda M. Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors. Cell 2010; 142: 375-86.

Background: Fibroblasts constitute nearly 50% of the cell mass of the normal heart, though these cells do not contribute to contractility. Fibroblasts are generally considered terminally differentiated cells incapable of further differentiation into another cell type.

Methods/Results: Microarray analysis was used to identify genes present in rat neonatal cardiac cells, and high-throughput screens identified 3 genes (Gata4, Mef2c, and Tbx5; GMT) capable of inducing expression of cardiomyocyte-specific target genes. When isolated transgenic rat fibroblasts expressing a GFP expression vector were then exposed to GMT, they were able to express GFP and target genes (including the troponin cTnT, ryanodine receptor Ryr2, and connexin Gja1) present in normal adult cardiomyocytes but not adult fibroblasts. Importantly, genes present in embryonic myocytes were not induced in fibroblasts, suggesting that it was not necessary for these cells to revert back to pluripotent stems for differentiation. Mechanistic expression analysis showed that the GMT combination induced transcription by a demethylation. To confirm that the mechanism was conversion of existing fibroblasts and not activation of rare cardiac stem cells, the authors induced identical changes in dermal fibroblasts. Finally, fibroblasts induced by GMT were also shown to be spontaneously contractile. When GMT was infused in vivo into rat hearts, fibroblasts in heart tissue were shown to develop the induced cardiomyocyte phenotype.

Implications:Evidence exists that damaged myocardium may be replaced when infusion of stem cells. These data suggest that endogenous cells may instead by activated to replace tissue by infusion of GMT. Additional advantages is avoidance of tumor formation seen with direct stem cell infusions. Large amounts of fibroblasts can be easily cultured from endocardial biopsy by routine cell culture techniques, and reprogrammed cells can infused back into the heart without concern for donor mismatch. The presence of abundant fibroblasts in cardiac tissue ensures a large reservoir of potential progenitor cells.

Further Reading

Yoshida Y. Recent stem cell advances: induced pluripotent stem cells for disease modeling and stem cell-based regeneration. Circulation 2010 Jul 6; 122(1): 80-7.

Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors

2010-09-02T05:16:19Z

Review by Kevin Blaine

Ieda M. Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors. Cell 2010; 142: 375-86.

Implications: Evidence exists that damaged myocardium may be replaced when infusion of stem cells. These data suggest that endogenous cells may instead by activated to replace tissue by infusion of GMT. Additional advantages is avoidance of tumor formation seen with direct stem cell infusions. Large amounts of fibroblasts can be easily cultured from endocardial biopsy by routine cell culture techniques, and reprogrammed cells can infused back into the heart without concern for donor mismatch. The presence of abundant fibroblasts in cardiac tissue ensures a large reservoir of potential progenitor cells.

Further Reading:

Yoshida Y. Recent stem cell advances: induced pluripotent stem cells for disease modeling and stem cell-based regeneration. Circulation 2010 Jul 6; 122(1): 80-7.

TREAT - Darbepoetin in DM2 & CKD

2010-01-15T04:16:26Z

TREAT. A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease. NEJM 2009; 361: 2019.

Background: Study of the outcome effect of increasing hemoglobin levels in patients with type 2 diabetes and CKD.

Methods: Multi-national, randomized, double-blind, placebo-controlled trial. Included patients with DM2, CKD (GFR 20-60 [MDRD]), anemia (Hb < 11.0), and transferrin saturation of 15%. Excluded uncontrolled HTN, kidney transplant, current use of IV ABx, chemo, XRT, cancer (x BCCA or SCCA of the skin), HIV, active bleeding, heme disorder, or pregnancy. n = 4038.

Treatment: darbepoetin alfa to achieve Hb of 13 g/dL v rescue darbepoetin when Hb < 9.0.

Results: darbepoetin v placebo

Death (any cause): 20.5 v 19.5%, p = 0.48

MI: 6.2 v 6.4%, p = 0.73

Stroke: 5.0 v 2.6, p = <0.001, NNH = 42

Heart failure: 10.2 v 11.3, p = 0.24

Myocardial ischemia: 2.0 v 2.4, p = 0.40

ESRD: 16.8 v 16.3, p = 0.83

Additional reading:

Normal Hematocrit Study. Besarab A. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. NEJM 1996; 339: 584.

CHOIR. Singh AK. Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease. NEJM 2006; 355: 2085.

PROWESS - Activated Protein C

2009-11-02T10:11:48Z

PROWESS. Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis. NEJM 2001; 344: 699.

Background: Drotrecogin alfa (activated) has antithrombotic, antiinflammatory, and profibrinolytic properties. This phase 3 trial was designed to assess if DAA would reduce the rate of death in patients with severe sepsis.

Methods: Randomized, double-blind, placebo-controlled, multicenter trial. Three out of four SIRS criteria and organ failure were used as entry criteria. n = 1690.

Treatment: DAA was started within 24 hours of diagnosis, dosed at 24 micrograms per kilogram per hour for a total of 96 hours.

Results: Mortality was 24.7 v 30.8%. ARR 6.1%, p = 0.005. NNT = 16

Adverse Events: Serious bleeding event was 3.5 v 2.0%. ARI 1.5%, p = 0.06. NNH = 7

AIDSVAX & ALVAC to prevent HIV-1

2009-10-27T02:29:51Z

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

Effects of Oral Tolvaptan for Worsening Heart Failure

2009-10-21T05:05:07Z

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

Rapid Measurement of BNP in the Diagnosis of HF

2009-10-20T05:46:56Z

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%.

Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke

2009-10-19T04:18:45Z

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.

A Comparison of Rate Control and Rhythm Control in Patients with Atrial Fibrillation

2009-07-21T07:08:48Z

AFFIRM. NEJM 2002; 347(23): 1825.

Randomization: 7401 eligible, 4060 enrolled. 2027 in rate-control group, 2033 in rhythm-control group.

Baseline: Mean age 69.7y, 40% women, 11% ethnic minorities, 71% HTN, 38% CAD, 5% valvular disease, 23% CHF, 35% had first episode of afib, 90% had afib in last 6wks, 69% had afib > 2d.

Therapy:

Rate-control: Initial treatment was 49% digoxin, 47% beta-blockers, 30% diltiazem, 10% verapamil. 70% had used digoxin at least once. At five years 35% in sinus rhythm, 80% in afib had rate control, and 15% had crossover to rhythm-control. Continuous anticoagulation with goal INR 2-3.

Rhythm-control: Initial treatment was 33% digoxin, 22% beta-blockers, 38% amiodarone, & 31% sotalol. 63% had used amiodarone at least once. At five years, 63% were in sinus rhythm and 37.5% had crossover to rate-control. Anticoagulation could be stopped if NSR > 4 wks, preferably > 12 wks. Goal INR 2-3.

Primary Outcome: rate vs rhythm

Overall mortality: 25.9% vs 26.7%, ARR 0.8%, NNT 125, p = 0.08

Secondary Outcomes: rate vs rhythm

Composite death, disabling stroke, encephalopathy, bleed, arrest: 32.7 vs 32.0%, p = 0.33

Cardiac arrest: no difference

Encephalopathy: no difference

Ischemic stroke: 5.5 vs 7.1%, p = 0.79

Myocardial infarction: 4.9 vs 6.1%, p = 0.60

Pulmonary embolism: no difference

Adverse Events:

Hemorrhage not involving CNS: 7.7 vs 6.9%, p = 0.44

Effect of IV Albumin on Renal Impairment and Mortality in Patients with Cirrhosis and SBP

2009-07-03T11:34:03Z

Sort P. NEJM 1999; 341(6): 403-9.

RESULTS

Randomization: 199 consecutive patients with cirrhosis who had spontaneous bacterial peritonitis, 73 excluded, 126 randomized.

Baseline: Average age 62y, 30% had alcoholic cirrhosis, 11% had hepatocellular carcinoma, average Child-Pugh score was 10.2, 44% had renal failure, 65% on diuretic therapy, 57% had isolated organism, most being E. coli.

Outcomes:

Resolution of infection: 98 vs 94%, p = 0.36
Renal impairment: 10 vs 33%, ARR 23%, NNT 4.3, p = 0.002
Death, in hospital: 10 vs 29%, ARR 19%, NNT 5.3, p = 0.01
Death, at three months: 22 vs 41%, ARR 19%, NNT 5.3, p = 0.03

Adverse Events: no reported adverse events

Discussion: Cost of albumin is between $5 and $25 per gram in the US. For the average 70kg man, this would cost between $875 to $4,375 per patient, and $4,375 to $23,200 to save one life. Mortality rates from SBP have been steadily decreasing over the last 15 years, this serves as another tool for prevention of hepatorenal syndrome and death.

]]> METHODS

Sponsors: Grants from the Fondo de Investigacion Sanitaria (FIS) and the Hospital Clinic

Study Type: open-label, randomized control trial, seven university hospitals.

Time Frame: November 1995 to September 1997

Inclusion: PMN > 250 cells/mm3, age 18 to 80y

Exclusion: (1) Antibiotic treatment within 1 week of dx, (2) shock, (3) GI bleeding, (4) ileus, (5) grade 3 or 4 hepatic encephalopathy, (6) cardiac failure, (7) findings suggestive of organic nephropathy, (8) HIV, (9) any disease that could affect short-term prognosis, and (10) serum creatinine < 3.0 mgdL

Treatment: Creatinine clearance adjusted dose cefotaxime and (1) albumin 1.5g/kg IV in the first 6 hours, and then 1.0 g/kg on day 3 vs (2) antibiotic alone.

Outcomes: (1) Resolution of infection, (2) duration of antibiotic therapy, (3) hospital stay, (4) renal impairment, (5) death, in hospital, (6) and death at three months.

ADDITIONAL READING

Gines P. Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 1988; 94: 1493-1502.

Luca A. Beneficial effects of intravenous albumin infusion on hemodynamic and humoral changes after total paracentesis. Hepatology 1995; 22: 753-58.

Gines A. Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by parecentesis. Gastroenterology 1996; 111: 1002 - 10.

Castellote J. Rapid diagnosis of spontaneous bacterial peritonitis by use of reagent strips. Hepatology 2003 Apr; 37(4): 893-6.

Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes

2009-07-02T10:37:19Z

Duckworth W. NEJM 8 Jan 2009; 360(2): 129-39. Supplement

Randomization: 20,027 patients screened, 17,788 (88.8%) excluded by chart review, 2239 (11.2%) provided consent, 448 (20.0%) excluded, 1791 (80%) underwent randomization. 899 received standard treatment, 892 received intensive treatment.

Baseline: Mean age 60.4y, diabbetes diagnosed for a mean of 11.5y, mean BMI 31.3, mean HBA1c was 9.4%, HTN in 72%, at least one cardiovascular event in 40%, 52% receiving insulin, 62% had microvascular complications.

Follow-up: SBP 125 vs 127, DBP 69 vs 68, LDL 80 vs 80, HDL 41 vs 40, quit smoking 77% vs 86%.

Primary Outcome:

HBA1c: 6.9% vs 8.4%
Time to first occurence of a cardiovascular event: no significant difference
MI: ARR 1.5%, NNT 66, p = 0.24
Stroke: ARR 0.8%, NNT 115, p = 0.32
Amputation: ARR 0.6%, NNT 152, p = 0.26
CV Death: ARR -1.0%, NNH 97, p = 0.26

Secondary Outcomes:

All Cause Mortality: ARR (-)0.8%, NNH 115, p = 0.62
Sudden Death: ARR (-)0.8%, NNH 115, p = 0.07
Otherwise, there were no significant differences between the groups

Microvascular Events: no significant differences

Adverse Events:

Hypoglycemia: Absolute Risk Increase 5.4%, NNH 18.5%, p = 0.000

]]> METHODS

Sponsors: Sanofi-Aventis, GSK, Novo Nordisk, Roche, Kos Pharmaceuticals, Amylin

Study Type: open-label, randomized control trial

Time Frame: December 1, 2000 to May 30, 2003

Inclusion: Inadequate response to maximal doses of an oral agent or insulin therapy.

Exclusion: (a) Glycated hemoglobin < 7.5%, (b) CV event in last 6m, (c) advanced CHF, (d) severe angina, (e) life expectancy < 7y, (f) BMI > 40, (g) Cr > 1.6 mg/dL, ALT 3x nL

Treatment: Those with BMI > 27 started on metformin and rosiglitazone, if less than 27, started on glimepiride and rosiglitazone. Intensive group started on maximal doses and insulin added to keep HBA1c < 6%. Standard group received half maximal doses and insulin added to keep HBA1c < 9%.

Primary Outcome: time to first occurrence of composite of cardiovascular events (MI, stroke, death from CV causes, new or worsening CHF, surgical intervention for cardiac, cerebrovascular, or peripheral vascular disease, inoperable coronary artery disease, and amputation for ischemic gangrene)

Secondary Outcome: (1) New or worsening angina, (2) new TIA, (3) new intermittent claudication, (4) new critical limb ischemia, (5) and death from any cause. Also to include microvascular complications (retinopathy, nephropathy, neuropathy)

ADDITIONAL READING

ADVANCE. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. NEJM 2008; 358: 2560-72.

ACCORD. Effects of intensive glucose lowering in type 2 diabetes. NEJM 2008; 358: 2545-59.

Holman RR. 10-Year follow-up of intensive glucose control in type 2 diabetes. NEJM 2008; 359: 1577-89.

Holman RR. Long-Term Follow-Up after Tight Control of Blood Pressure in Type 2 Diabetes. NEJM 2008; 359: 1565-76.

Multidetector Computed Tomography for Acute Pulmonary Embolism

2009-07-01T11:41:22Z

Stein PD. NEJM 1 June 2006; 354(22): 2317-27.

RESULTS

Randomization: 7284 screened, 3262 eligible, 1090 enrolled. 238 did not receive reference diagnosis, 824 underwent subsequent analysis (11% of those screened, 25% of those eligible).

Baseline: mean age 51.7y, majority had low or moderate probability of pulmonary embolism (Wells score).

Reference Diagnosis: 192/824 diagnosed with PE (23%), of the 632 ruled out, 592 had interpretable CTA, 590 did not receive anticoagulatants, 2/590 had initially unrecognized PE.

Wells Score | Table 4 | Table 5

Results of CTA:

Sensitivity 83% (76-92%)
Specificity 96% (93-97%)
Likelihood ratio for a positive test was 19.6 (13.3 - 29.0)
Likelihood ratio for a negative test was 0.18 (0.13 - 0.24)
PPV 86% (79-90%)
NPV 95% (92-96%)

PPV for PE in main or lobar artery 97%
PPV for PE in segmental vessel 68%
PPV for PE in subsegmental vessel 25%

Results of CTA-CTV:

Sensitivity 90% (84-93%)
Specificity 95% (92-96%)
Likelihood ratio for a positive test was 16.5 (11.6 - 23.5)
Likelihood ratio for a negative test was 0.11 (0.07 - 0.16)
PPV 85% (78-94%)
NPV 97% (94-97%)

Results using the Wells score:

High Clinical Probabiltiy: PPV 96%, NPV 60%
with CTV, PPV 96%, NPV 82%

Discussion: In high clinical probability patients, a positive CTA provides sufficient evidence to start treatment. Venous phase imaging increased the sensitivity by 7%. In high clinical probability patients who have a negative CT, the false negative rate was 40% which poses a dilemna regarding treatment.

]]> METHODS

Study: Prospective, multicenter (8) study sponsered by NHLB Institute

Inclusion: (a) 18y +, (b) clinically suspected of acute PE.

These patients were seen in either outpatient or inpatient centers, and mostly recruited during the daytime and weekdays.

Exclusion: (a) inability to complete testing in 36h (19%), (b) abnormal creatinine levels or on long-term HD (19%), (c) long-term anticoagulant use (13%), (d) critically ill, (e) on mechanical ventilation, (f) allergic to contrast, (g) had an MI in last 30d, (h) possible pregnancy, (i) s/p IVC filter, (j) no suspected PE, (k) had UE DVT, (l) previously enrolled in the study.

Time Frame: September 2001 to July 2003

Composite Reference Standard: (1) V/Q scan showing high probability of PE, (2) Abnormal findings on DSA (digital subtraction angiography), (3) Abnormal findings on venous ultrasonography and nondiagnostic V/Q scanning.

Exclusion of PE Required: (1) Normal findings on DSA or (2) Normal V/Q scan or (3) V/Q scan with low or very low probability, Wells score < 2, and normal venous LE U/S

Follow-up: 3 months & 6 months

Machines: 4-slice, 8-slice, and 16-slice MDCT, mostly 4-slice

ADDITIONAL READING

van Belle A. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 11 Jan 2006; 295(2): 172-9.

Kline JA. Prospective multi-center evaluation of the pulmonary embolism rule-out criteria. J Thromb Haemost 2008; 6(5): 772.

Goodman LR. CT venography: continuous helical images versus reformatted discontinuous images using PIOPED II data. Am J Roentgenol 2007; 189: 409-12.

Goodman LR. CT venography and compression ultrasound are diagnostically equivalent: data from PIOPED II. Am J Roentgenol 2007; 189: 1071-76.

Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction

2009-06-30T12:19:54Z

Massie BM. I-PRESERVE. NEJM 4 Dec 2008; 359: 2456-67.

BACKGROUND: 50% of patients with heart failure have an ejection fraction > 45%. The renin-aldosterone-angiotensin system is involved in many processes associated with this syndrome - HTN, LVH, myocardial fibrosis, and vascular dysfunction. Inhibition of this system could possibly serve as a therapeutic intervention.

RESULTS

Randomization: 4564 patients screened, 4128 underwent randomization. 2067 assigned to receive Irbersartan, 2061 received placebo.

Baseline: Mean age 72y, 60% women, hypertensive heart disease 64%, HTN 88%, atrial fibrillation 29%, DM 27%, obese 41%, baseline NT-proBNP 339 pg/mL, diuretic use 83%, beta-blocker use 59%, CCB use 70%, spironolactone use 45%, ACEi use 25%

Primary Outcome: Composite end-point

All patients: 36% vs 37%, no significant differences between the two groups
All subgroups: no significant differences between the two groups

Figure 1

Secondary Outcomes: no significant differences between the two groups

Predetermined subgroup analysis: no significant differences between the two groups

Adverse Events: no significant differences between the two groups

Discussion: At the end of the study, 73% taking beta-blockers, 40% using ACEi which possibly leaves little room for more improvement. 34% discontinued drug use in both groups, consistent with other trials of this duration.

]]> METHODS

Sponsors: Bristol-Myers Squibb & Sanofi-Aventis

Study Type: 2 week run-in phase with placebo before randomization, then randomized and stratified to ACEi use. 293 sites, 25 countries (Europe, North America, South America, South Africa, and Australia).

Inclusion: (a) 60y +, (b) heart failure symptoms and LVEF > 45%, (c) required hospitalization for heart failure symptoms in last 6 months with NYHA class II, III, or IV, (d) if not hospitalized, had to have NYHA class III or IV with corroborative evidence (pulmonary congestion on CXR, LVH or LAE on echocardiogram, LVH or LBBB on ECG), (e) ACEi permitted when essential for indication other than uncomplicated hypertension.

Exclusion: (a) prior intolerance to ARB, (b) alternative problem causing symptoms, e.g. pulmonary disease, (c) any previous LVEF < 40%, (d) h/o ACS, coronary revascularization, or stroke in the last 3 months, (e) substantial valvular disease, (f) hypertrophic or restrictive cardiomyopathy, (g) pericardial disease, (h) cor pulmonale or other RHF, (i) SBP < 100 mm Hg or > 160 mm Hg, (j) DBP > 95 mm Hg, (k) life expectancy < 3y, (l) Hb < 11 g/dL, (m) Cr > 2.5 mg/dL, (n) increased LFTs.

Time Frame: June 2002 to April 2005

Treatment: (1) Irbesartan 75 mg PO daily, doubled to 150 mg after 1-2wks, then doubled to 300mg after 1-2 wks, versus (2) placebo.

Primary Outcome: Composite of death from any cause or hospitalization for cardiovascular cause (worsening heart failure, MI, stroke, unstable angina, ventricular or atrial dysrhythmia, or MI or stroke during any hospitalization).

Secondary Outcome: (1) death from any cause, (2) hospitalization for cardiovascular cause, (3) composite heart failure (death from heart failure, sudden death, or hospitalization for worsening heart failure), (4) change in Minnesota Living with Heart Failure scale at 6m, (5) change in plasma level of NT-proBNP at 6m, (6) composite cardiovascular event (death from cardiovascular cause, nonfatal MI, or nonfatal stroke, (7) death from cardiovascular cause

Predefined Subgroup Analysis: (1) Age <65y, 65y to 75y, >75y, (2) sex, (3) EF < 59% and > 59%, (4) ACEi use, (5) beta blocer use, (6) diabetes, (7) hospitalization for heart failure in the last 6 months, (8) geographic region

ADDITIONAL READING

NHLBI. Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function (TOPCAT). ClinicalTrials.gov NCTOOO94302 Aug 2006 - Jul 2011.

SOLVD. Effect of enalaprl on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. NEJM 1991; 325: 293-302.

Cohn JN. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. NEJM 2001; 345: 1667-75.

Pitt B. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. NEJM 1999; 341: 709-17.

Pfeffer MA. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003; 362: 759-66.

Yusuf S. Effects of candesartan in patients with chronic heart failure and preserved left ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003; 362: 777-81.

Cleland JG. The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) study. Eur Heart J 2006; 27: 2338-45.

Dexamethasone In Adults With Bacterial Meningitis

2009-06-29T15:17:22Z

De Gans J, Van De Beek D. NEJM NOV 14 2002; 347(20): 1549-56.

RESULTS

Randomization: 301 enrolled, 157 to the dexamethasone group, 144 to the placebo group. Intention to treat analysis. In the dexamethasone group, 11 withdrawn, 3 lost to follow-up. In the placebo group, 11 withdrawn, 4 lost to follow-up.

Baseline: headache (94%), fever (81%), neck stiffness (94%). Positive gram stain in 215 patients (74%), positive cultures in 234 patients (78%).

Primary Outcome: Unfavorable Outcome

All patients: ARR 10%, NNT 10, p = 0.03
S. pneumo: ARR 26%, NNT 3.8, p = 0.006
N. meningitidis: ARR 3%, NNT 33, p = 0.74
Other bacteria: ARR -11%, NNH 9, p = 0.55

Secondary Outcome: Death

All patients: 7% vs 15%, ARR 8%, NNT 12.5, p = 0.04
S. pneumo: 14% vs 34%, ARR 20%, NNT 5, p = 0.02
N. men: 4% vs 2%, ARR -2%, NNH 50, p = 1.00

table 2

Adverse Events: no significant difference in GI bleeding, hyperglycemia, herpes zoster, or fungal infections.

]]> METHODS

Study Type: prospective, randomized, double-blind, multicenter trial vs placebo

Inclusion: (a) 17y + & (b) suspected meningitis with cloudy CSF, bacteria in CSF on gram stain, or CSF leukocyte count > 1000/mm3.

Exclusion: (a) h/o hypersensitivity to beta-lactam ABx or corticosteroids, (b) pregnant, (c) CSF shunt, (d) treated with oral or IV ABx in last 48h, (e) h/o active TB or fungal infection, (f) recent h/o head trauma, neurosurgery, or PUD, or (g) enrolled in another trial

Time Frame: June 1993 to December 2001

Treatment: (1) Dexamethasone 10 mg IV q6h for four days versus (2) placebo. Treatment given 15-20 minutes before IV ABx, but after interim analysis, amended to allow treatment to be given concurrently with antibiotics. Antibiotic given was amoxicillin 2 g IV q4h for 7-10 days (Netherlands).

Primary Outcome: score on Glasgow Outcome Scale 8 weeks after randomization. Unfavorable outcome is a score of 1-4/5. A score of 1 = death, 2 = vegetative state, 3 = severe disability, 4 = moderated disability, 5 = mild or no disability.

Secondary Outcome: (1) death, (2) focal neurologic abnormalities (aphasia, cranial-nerve palsy, monoparesis, hemiparesis, and severe ataxia), (3) hearing loss, (4) GI bleeding, (5) fungal infection, (6) herpes zoster, (7) hyperglycemia (blood glucose > 144 mg/dL [8.0 mmol/L]).

Predefined Subgroup Analysis: Neisseria meningitidis, Streptococcus pneumoniae, other bacteria, and an unidentified cause.

ADDITIONAL READING

Nguyen TH. Dexamethasone in Vietnamese Adolescents and Adults with Bacterial Meningitis. NEJM Dec 13 2007; 357(24): 2431-40.

Scarborough M. Corticosteroids for Bacterial Meningitis in Adults in Sub-Saharan Africa. NEJM Dec 13 2007; 357(24); 2441-50.

Thomas R. Trial of dexamethasone treatment for severe bacterial meningitis in adults. Intensive Care Med 1999; 25: 475-80.

Girgis NI. Dexamethasone treatment for bacterial meningitis in children and adults. Pediat Infect Dis J 1989; 8: 848-51.