NEJM journal discussion

Dr. J.A. CoetserDr. J-M Nel

24 February 2011

What we already know

Activation of mineralocorticoid receptors by aldosterone and corticosteroids have negative effects on the failing heart.

Mineralocorticoid antagonism reduces the rate of all-cause mortality and hospitalization in NYHA class III-IV systolic heart failure◦ RALES trial (NYHA class III-IV)◦ EPHESUS trial (systolic dysfunction following MI)

Current guidelines recommend adding spironolactone or eplerenone if patient has moderate to severe symptomatic systolic failure

EMPHASIS-HF

Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure

Aim◦ To assess the effect on clinical outcomes of adding eplerenone to

evidence-based treatment for mildly symptomatic (NYHA class II) heart failure

Method◦ 2737 patients◦ NYHA class II systolic heart failure, with LVEF <35%◦ Randomized to receive along with recommended therapies

Placebo or Eplerenone up to max 50mg dly po

Primary outcome◦ Composite of death from cardiovascular cause and hospitalization for

heart failure

EMPHASIS-HF

EMPHASIS-HF

Eplerenone group Placebo

Primary outcome 18,3% 25,9%(p <0,001)

Death (CV cause) 10,8% 13,5%(P=0,01)

s-K+ >5,5mmol/L 11,8% 7,2%(P<0,001)

Conclusion

Eplerenone reduces risk of death and hospitalization in patients with systolic heart failure and mild symptoms

Original articles relating toproton pump inhibitors

November 25, 2010

What we already know

Omeprazole

Other PPI’s

Method

◦Cohort study◦840 968 babies born alive in Denmark between

1996 and 2008◦5082 exposures to PPI’s during pregnancy,

between 4/52 preconception to end of 1st trimester

◦Major birth defects documented Defined by EUROCAT (European surveillance of

congenital anomalies) However, genetic syndromes and chromosomal

abnormalities were excluded

Results

Results

Adjusted odds ratio for prevalence of birth defects with any PPI use = 1,1 (95% CI 0,95 – 1,34)

None of the PPI’s were found to be significantly associated with major birth defects when given during 1st trimester

Lanzoprazole only PPI with significantly increased risk if started within 4/52 preconception

November 11, 2010

What we already know

Therapies reducing gastric pH reduces bleeding complications related to antiplatelet drugs

Concerns have recently been raised by observational studies regarding the potential for PPI’s to blunt the efficacy of clopidogrel◦In vitro studies showed inhibition of clopidogrel

effect on platelets◦Genetic polymorphisms have been identified that

could be associated with decreased response to clopidogrel

COGENT trial

Clopidogrel and the Optimization of Gastrointestinal Events Trial◦International◦Randomized◦Double-blinded◦Double-dummy◦Placebo-controlled

Clopidogrel 75mg + omeprazole 20mg dly vs. clopidogrel 75mg alone

COGENT trial

Primary GIT endpoint◦ composite of overt or occult bleeding◦ symptomatic gastroduodenal ulcers or erosion◦ obstruction◦ perforation

Primary cardiovascular endpoint composite of death cardiovascular causes nonfatal myocardial infarction Revascularization stroke

COGENT trial

Results◦3761 pts included in analysis◦GIT events

Clopidogrel + omeprazole = 1,1% Clopidogrel alone = 2,9%

◦Cardiovascular events Clopidogrel + omeprazole = 4,9% (hazard ratio

0,99) Clopidogrel alone = 5,7%

COGENT trial

No apparent cardiovascular interaction between clopidogrel and omeprazole, but a clinically meaningful difference in cardiovascular events due to use of a PPI is not ruled out

What we already know

ITP is a disorder characterised by immune destruction and decreased production of platelets

Standard 1st line treatment◦Glucocorticoids◦IVIG◦Anti-D immunoglobulin

Second line treatment◦Azathioprine◦Rituximab◦Splenectomy

Treatments are short-acting, have severe side-effects and toxicity

Romiplostim

A thrombopoietin mimetic which stimulates the thrombopoietin receptor

Study design

MulticenterRandomizedControlled52-weekOpen-label234 patients with ITP who had not yet

undergone splenectomy◦77 patients receive standard treatment◦157 patients receive weekly s/c romiplostim

Study design

Primary end point◦incidences of treatment failure and

splenectomySecondary end points

◦rate of a platelet response (a platelet count >50×109 per liter at any scheduled visit)

◦safety outcomes◦quality of life

Results

Standard Rx Romiplostim

Treatment failure 30% 18%

Need for splenectomy 36% 9%

Serious adverse events 37% 23%

Compared to standard Rx, romiplostim group had◦ Fewer bleeding episodes◦ Less need for transfusion◦ Improved quality of life◦ Slight increased thrombotic rate compared to standard

treatment

Worthwhile review articles

Bibliography

Bhatt et al. Clopidogrel with or without Omeprazolein Coronary Artery Disease. N Engl J Med 2010;363:1909-17.

Kuter et al. Romiplostim or Standard of Care in Patients with Immune Thrombocytopenia. N Engl J Med 2010;363:1889-99.

Pasternak et al. Use of Proton-Pump Inhibitors in EarlyPregnancy and the Risk of Birth Defects. N Engl J Med 2010;363:2114-23.

Zannad et al. Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. N Engl J Med 2011;364:11-21.