JC on 19th October 2012

Cochrane Database Syst Rev. 2012 Apr 18;4:CD003040.

Angiotensin receptor blockers for heart failure.

Heran BS, Musini VM, Bassett K, Taylor RS, Wright JM.

Source

Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada. bsheran@ti.ubc.ca

Abstract

BACKGROUND:

Chronic heart failure (HF) is a prevalent world-wide. Angiotensin receptor blockers (ARBs) are widely prescribed for chronic HF although their role is controversial.

OBJECTIVES:

To assess the benefit and harm of ARBs compared with ACE inhibitors (ACEIs) or placebo on mortality, morbidity and withdrawals due to adverse effects in patients with symptomatic HF and left ventricular systolic dysfunction or preserved systolic function.

SEARCH METHODS:

Clinical trials were identified by searching CENTRAL, HTA, and DARE , (The Cochrane Library 2010 Issue 3), as well as MEDLINE (2002 to July 2010), and EMBASE (2002 to July 2010). Reference lists of retrieved articles and systematic reviews were checked for additional studies not identified by the electronic searches.

SELECTION CRITERIA:

Double blind randomised controlled trials in men and women of all ages who have symptomatic (NYHA Class II to IV) HF and: 1) left ventricular systolic dysfunction, defined as left ventricular ejection fraction (LVEF) ≤40%; or 2) preserved ejection fraction, defined as LVEF >40%.

DATA COLLECTION AND ANALYSIS:

Two authors independently assessed risk of bias and extracted data from included studies.

MAIN RESULTS:

Twenty two studies evaluated the effects of ARBs in 17,900 patients with a LVEF ≤40% (mean 2.2 years). ARBs did not reduce total mortality (RR 0.87 [95% CI 0.76, 1.00]) or total morbidity as measured by total hospitalisations (RR 0.94 [95% CI 0.88, 1.01]) compared with placebo.Total mortality (RR 1.05 [95% CI 0.91, 1.22]), total hospitalisations (RR 1.00 [95% CI 0.92, 1.08]), MI (RR 1.00 [95% CI 0.62, 1.63]), and stroke (RR 1.63 [0.77, 3.44]) did not differ between ARBs and ACEIs but withdrawals due to adverse effects were lower with ARBs (RR 0.63 [95% CI 0.52, 0.76]). Combinations of ARBs plus ACEIs increased the risk of withdrawals due to adverse effects (RR 1.34 [95% CI 1.19, 1.51]) but did not reduce total mortality or total hospital admissions versus ACEI alone.Two placebo-controlled studies evaluated ARBs in 7151 patients with a LVEF >40% (mean 3.7 years). ARBs did not reduce total mortality (RR 1.02 [95% CI 0.93, 1.12]) or total morbidity as measured by total hospitalisations (RR 1.00 [95% CI 0.97, 1.05]) compared with placebo. Withdrawals due to adverse effects were higher with ARBs versus placebo when all patients were pooled irrespective of LVEF (RR 1.06 [95% CI 1.01, 1.12]).

AUTHORS' CONCLUSIONS:

In patients with symptomatic HF and systolic dysfunction or with preserved ejection fraction, ARBs compared to placebo or ACEIs do not reduce total mortality or morbidity. ARBs are better tolerated than ACEIs but do not appear to be as safe and well tolerated as placebo in terms of withdrawals due to adverse effects. Adding an ARB in combination with an ACEI does not reduce total mortality or total hospital admission but increases withdrawals due to adverse effects compared with ACEI alone.

Pubmed

Benzodiazepine use and risk of dementia

Journal club on 5th October 2012.

BMJ. 2012 Sep 27;345:e6231. doi: 10.1136/bmj.e6231.

Benzodiazepine use and risk of dementia: prospective population based study.

Billioti de Gage S, Bégaud B, Bazin F, Verdoux H, Dartigues JF, Pérès K, Kurth T, Pariente A.

Source

Université Bordeaux Segalen, F-33000 Bordeaux, France.

Abstract

OBJECTIVE:

To evaluate the association between use of benzodiazepines and incident dementia.

DESIGN:

Prospective, population based study.

SETTING:

PAQUID study, France.

PARTICIPANTS:

1063 men and women (mean age 78.2 years) who were free of dementia and did not start taking benzodiazepines until at least the third year of follow-up.

MAIN OUTCOME MEASURES:

Incident dementia, confirmed by a neurologist.

RESULTS:

During a 15 year follow-up, 253 incident cases of dementia were confirmed. New use of benzodiazepines was associated with an increased risk of dementia (multivariable adjusted hazard ratio 1.60, 95% confidence interval 1.08 to 2.38). Sensitivity analysis considering the existence of depressive symptoms showed a similar association (hazard ratio 1.62, 1.08 to 2.43). A secondary analysis pooled cohorts of participants who started benzodiazepines during follow-up and evaluated the association with incident dementia. The pooled hazard ratio across the five cohorts of new benzodiazepine users was 1.46 (1.10 to 1.94). Results of a complementary nested case-control study showed that ever use of benzodiazepines was associated with an approximately 50% increase in the risk of dementia (adjusted odds ratio 1.55, 1.24 to 1.95) compared with never users. The results were similar in past users (odds ratio 1.56, 1.23 to 1.98) and recent users (1.48, 0.83 to 2.63) but reached significance only for past users.

CONCLUSIONS:

In this prospective population based study, new use of benzodiazepines was associated with increased risk of dementia. The result was robust in pooled analyses across cohorts of new users of benzodiazepines throughout the study and in a complementary case-control study. Considering the extent to which benzodiazepines are prescribed and the number of potential adverse effects of this drug class in the general population, indiscriminate widespread use should be cautioned against.

Pub

Benzodiazepine use and risk of dementia: prospective population based study

This study demonstrates a clear association between the use of benzodiazepines and a subsequent diagnosis of dementia but it does not demonstrate causality.
Sleep disturbance is a common feature across many forms of neurodegenerative disease (1) and may precede a diagnosis of dementia by some years. A clear example of this is the strong association between a developing a REM sleep behavioural disorder (RBD) and alpha-synucleinopathies, including Dementia with Lewy bodies. The ten year risk of a significant neurodegenerative disease following ‘idiopathic’ RBD has been estimated at around 40% (2). Benzodiazepines remain a commonly used treatment for sleep disturbance and the introduction of benzodiazepines between years three and five of the study may indicate the onset of dementia pathology without the diagnosis being made until later.
Furthermore psychiatric symptoms and disorders other than depression (the only one considered in the analysis), including anxiety are common and may lead to the introduction of a benzodiazepine. These may therefore also herald the emergence of a neurodegenerative disorder or other dementia long before a formal diagnosis of dementia is made.
The authors admit that the indications for the introduction of a benzodiazepine may be prodromal symptoms of dementia but argue against this reverse causality confounding their results. They use a three year run-in time and exclude participants who have been exposed to benzodiazepines prior to or during this. This allows for adjustment for pre-existing factors already treated with benzodiazepines but not the emergence of new ones. The increase in association strength of new use of benzodiazepines and dementia diagnosis after about seven years of follow up does not differentiate between benzodiazepine use or any underlying symptomatic risk factors for dementia being treated. Similarly the lack of increase of association strength amongst cohorts of new benzodiazepines users at later stages of the study cannot be used to make inferences about the underlying causality. The small sample sizes and wide confidence intervals for hazard ratio for each subsequent cohort precludes significant comparisons of risk between them.
This paper raises an important issue but does not provide evidence of a causal link between benzodiazepines and dementia. It must be treated with caution, especially in view of the potential harm or anxiety induced by such reports or sudden changes in prescription practice.

BMJ