Beta blockers for peripheral arterial disease
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of the use of β blockers in peripheral arterial disease.
Background
Intermittent claudication is most commonly caused by atherosclerotic peripheral arterial disease and reflects decreased blood flow to the extremities during exercise (Lassila 1986). The incidence of intermittent claudication increases with advancing age, cigarette smoking, impaired glucose tolerance, and hypertension (Hughson 1978). Men are twice as likely to be affected by intermittent claudication (Kannel 1985).
People with peripheral arterial disease (PAD) have increased rates of mortality due to concurrent coronary artery disease and hypertension (Criqui 1985).
Beta (ß) blockers have a proven track record in improving mortality in people with hypertension and coronary artery disease. Besides being used primarily for their cardiovascular effects to treat arrhythmias (variations in the normal rhythm of the heart beat), they are also used to treat migraine headaches, essential tremors, thyrotoxicosis (excessive production of thyroid hormones), glaucoma, anxiety, and various other disorders.
Beta blockers are a large group of drugs and although all are competitive inhibitors of β receptors, they may have additional pharmacodynamic properties. Beta 1 receptors increase the force and rate of myocardial contraction and atrio‐ventricular (AV) node conduction velocity. Beta 1 blockade, therefore, reduces heart rate, blood pressure, myocardial contractility, and myocardial oxygen consumption. Beta 2 receptor blockade inhibits relaxation of smooth muscle in blood vessels, bronchi, and the gastro‐intestinal and genito‐urinary tract. In addition, β2 blockade inhibits the breakdown of glycogen (main carbohydrate storage compound) to glucose (glycogenolysis) and the formation of sugar from protein and fat in the absence of glucose or carbohydrate (gluconeogenesis). Non‐specific β blockers such as propranolol, timolol, nadolol, and pindolol demonstrate equal affinity for both β1 and β2 receptors. Commonly used cardioselective (β1) blockers are atenolol and metoprolol.
In general, blockade of β receptors results in decreased production of intracellular cyclic adenosine monophosphate (cAMP), with a resultant blunting of multiple metabolic and cardiovascular effects of circulating catecholamines.
Beta blockers are a Class I indication for use post myocardial infarction (MI), continuing or recurrent ischaemic pain, tachyarrhythmias (rapid increased heart rates associated with an irregularity in the normal heart rhythm), and also Non ST‐elevation MI (ACC/AHA 2003).
Optimal therapy for either coronary artery disease or hypertension accompanied by intermittent claudication has been controversial due to presumed peripheral haemodynamic consequences of β blockers leading to worsening of the symptoms in patients with PAD (George 1974). This has been attributed to decreased cardiac output and unopposed alpha (α) adrenergic drive.
The British National Formulary (BNF) discourages the use of this drug in moderate to severe PAD (BNF 2003). But is there any real evidence to support this?
Objectives
To assess the effects of the use of β blockers in peripheral arterial disease.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) of ß blockers used for PAD.
Types of participants
Patients with moderate to severe peripheral arterial disease, with or without additional co‐morbidity (additional disease or condition), for example, diabetes mellitus. Peripheral arterial disease will be defined as a typical history of intermittent claudication and reduced ankle brachial pressure (ABPI) index (less than 0.9).
Types of interventions
Selective β blockers (β1) and non‐selective β blockers (β1 and β2) will be considered. Some β blockers with additional alpha (α) blocking properties will not be considered. The placebo analysed will be a neutral drug and if sufficient quality data become available we will analyse other antihypertensive medications, used as a comparator, separately.
Types of outcome measures
Primary outcome measures will include initial claudication distance in metres and maximal walking distance in metres (as assessed by treadmill).
Secondary outcome measures will include calf blood flow (ml/100 ml/min), calf vascular resistance, skin temperature (degrees Celsius). Mortality data and complications of β blockers in patients with stable peripheral arterial disease such as development of critical ischaemia, cardiovascular morbidity and mortality, and all‐cause mortality, and drug withdrawal will be sought. Any additional information on other drugs that may influence walking distance (such as statins or cilostazol) will be studied. Finally, if available, quality of life data will be searched for in the studies.
Search methods for identification of studies
All publications describing (or which might describe) RCTs of ß blockers in PAD will be sought through electronic searches of the Specialised Trials Register of the Peripheral Vascular Diseases Group, and the Cochrane Central Register of Controlled Trials (CENTRAL) database. The Peripheral Vascular Diseases Group Register contains citations of RCTs and controlled clinical trials (CCTs) identified through electronic searches of MEDLINE (1966 to date) and EMBASE (1980 to date), and through handsearching journals and conference proceedings. The full list of journals that have been handsearched, as well as the search strategies for the electronic databases, are described in the 'Search strategies for the identification of studies' section within the editorial information about the Cochrane PVD Group in The Cochrane Library.
The authors will conduct additional searches of MEDLINE and EMBASE using a randomised controlled trial filter and the following search terms:
Beta Blockers #1
Peripheral arterial disease #2
Non‐electronic searches will be made of bibliographies of all identified articles, review articles and major vascular textbooks. In addition, pharmaceutical companies will be contacted for details of unpublished and ongoing trials.
Data collection and analysis
Selection of trials
DM, VG, and ADS will review abstracts of potential trials involving ß blockers in PAD. We will obtain full papers for those fulfilling the relevant criteria, or where clarification is required. To minimise bias, all three authors will independently measure relevant outcomes.
Quality of trials
ADS, DM, and VG, will independently assess the methodological quality of selected trials using the methods described by Jadad (Jadad 1996) and Schulz (Schulz 1995). The Schulz method is based on concealment of allocation only, whereas the Jadad scale measures three items: method of randomisation, blinding, withdrawal, and dropouts from the study.
We will not use these scales to exclude potential trials but to explore potential heterogeneity of method and quality.
Data extraction
VG and DM will independently extract data using the proforma designed by the Peripheral Vascular Diseases Group. ADS will resolve any outstanding issues. Additional information will be sought from the authors of the trials, if required.
Statistical analysis
Statistical analysis will be performed according to the statistical guidelines for reviewers by the Cochrane Peripheral Vascular Diseases Group. Where there are sufficient data, we will calculate a summary statistic for each outcome using both a fixed‐effect model and a random‐effects model. Heterogeneity in the data will be noted and cautiously explored using previously identified characteristics of the studies, particularly assessments of quality. We will undertake sensitivity analyses to examine the stability of the results in relation to a number of factors including study quality, the source of the data (published and unpublished) and patient type. Where continuous scales of measurement have been used to assess the effects of treatment, these data will be analysed in continuous form (i.e. weighted mean difference). If different scales have been used in different studies, where possible the results will be standardised and then combined (i.e. standardised mean difference).
