19 March 2010
This case control study of lower CV risk patients found that, compared to the combination of diuretic plus beta-blocker, patients taking diuretic plus calcium channel blocker had approximately double the odds of MI, but a similar risk of stroke. The study did not detect a statistically significant difference in the risk of stroke and MI among patients taking diuretic plus ACE-inhibitor or A2RA.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Health professionals should continue to follow NICE guidance on management of hypertension. NICE considers thiazide diuretics and calcium channel blockers as equal first-line choices in black people of any age and others aged 55 years or older. As we said in MeReC Bulletin volume 17 no.1 from Sept 2006, given that a choice has to be made, prescribers may decide to use diuretics preferentially in view of their lower acquisition costs, unless there are good reasons to do otherwise. There is very limited evidence on the optimal combinations of hypertensive agents, and most currently available guidance is based on pharmacological principles and expert consensus. In people whose blood pressure is not controlled, NICE recommends adding an ACE-inhibitor rather than combining a diuretic and calcium channel blocker, and this recommendation is supported by this study. (An A2RA could be used as an alternative to an ACE inhibitor if a patient cannot tolerate the ACE inhibitor due to cough). NICE suggests usually reserving beta-blockers for fourth line use, on the basis of data from randomised controlled trials (RCTs). It seems probable that this one observational study would be judged as not providing evidence of sufficient strength to significantly amend that guidance.
What is the background to this?
Choice of first line anti-hypertensive agent, at least in people older than about 55 years, is well supported by data from RCTs. For example, a review of the ALLHAT study concluded that diuretics were unsurpassed in reducing the risk of patient oriented outcomes. However, many patients require more than one drug to attain target blood pressure, and the best combination of drugs is unclear. The best drug to add to a diuretic has not been identified in an RCT.
This case-control study included patients aged 30 to 79 years enrolled in a health maintenance organisation in Washington State. Subjects chosen had no evidence of cardiovascular disease (see study details). The study compared the risk of fatal or non fatal myocardial infarction (MI) or fatal or non fatal stroke among people taking certain antihypertensive drugs.
What does this study claim?
Users of diuretics plus calcium channel blockers had a statistically significantly increasedrisk of MI (adjusted odds ratio [OR] 1.98, 95%CI 1.37 to 2.87) but not of stroke (OR1.02, 95%CI 0.63 to 1.64) compared with users of diuretics plus beta blockers,. The observed odds of MI and stroke in users of diuretics plus ACE inhibitors or A2RAs were not statistically significantly different from those in users of diuretics plus beta blockers (for MI: OR 0.76, 95%CI 0.52 to 1.11; for stroke: OR 0.71, 95%CI 0.46 to 1.10). It may be that the size of the study meant it lacked sufficient power to detect a true effect. The combination of diuretic and ACE inhibitor or A2RA did significantly reduce the risk of ischaemic stroke (OR 0.56, 95%CI 0.33 to 0.96)
This observational study supports NICE guidance with regard to the choice of additional drug in patients who do not respond adequately to diuretic monotherapy. That is, it suggests avoiding the combination of diuretic and calcium channel blocker dual therapy and would support the combination of diuretic plus ACE inhibitor (or A2RA in those few patients who cannot tolerate an ACE inhibitor due to cough). It does not provide sufficient evidence to support the combination of diuretic plus beta blocker as being routinely preferable to this. It also did not consider the other possible combination in NICE guidance, of calcium channel blocker plus ACE inhibitor, as US guidance (on which the study design was based) does not suggest initiation with a calcium channel blocker.
Unless there are compelling reasons to do otherwise, beta-blockers are recommended as best avoided in combination with thiazide diuretics because of the increased risk of developing diabetes (although the clinical significance of the development of certain biochemical changes similar to diabetes is not clear). The NICE full hypertension guideline estimated the risk of development of diabetes as one extra case per 250 patients per year. However, beta-blockers are indicated in other circumstances, such as after an MI.
The NICE full guideline also noted that in head-to-head RCTs, beta-blockers were less effective than the comparator drug at reducing major cardiovascular events, in particular stroke. This was not seen in the study discussed here, but RCTs provide a higher standard of evidence than observational studies; observational data are more prone to bias and confounding. Unlike in an RCT, in ‘real life’ treatment plans are chosen, changed, or actively not chosen in the light of individual patients’ risk factors, preferences and tolerability or response to other drugs. Thus observed differences in outcomes may well be due to differences among the patients, not only the different treatments. Observational studies attempt to adjust for these differences by statistical modelling, but this requires certain assumptions and of course can take into account only those factors that have been recognised.
Design: Case control study
Cases and controls: Cases (n=353) were patients aged 30 to 79 years enrolled in a health maintenance organisation in Washington State, currently treated with one of the following combinations: diuretics plus beta blockers; diuretics plus calcium channel blockers; or diuretics plus ACE inhibitors or A2RA, and who had had a fatal or non fatal myocardial infarction (MI) or fatal or non fatal stroke between July 1989 and December 2005. Controls (n=952) came from the same cohort but had not had an MI or stroke, and were frequency matched to myocardial infarction cases — the largest case group — by age (within a decade), sex, and calendar year of the cases’ diagnoses, at a ratio of between 2:1 and 3:1. All subjects had no previous coronary heart disease, heart failure, stroke, diabetes or chronic kidney disease. Results were adjusted for age, sex, year of event and other possible confounders including smoking status and total cholesterol levels.
Outcomes and results Compared with users of diuretics plus beta blockers, users of diuretics plus calcium channel blockers had an increased risk of MI (adjusted OR 1.98, 95%CI 1.37 to 2.87) but not of stroke (OR 1.02, 95%CI 0.63 to 1.64). The differences in observed odds of MI and stroke in users of diuretics plus ACE inhibitors or A2RAs did not reach conventional levels of statistically significance (for MI: OR 0.76, 95% CI 0.52 to 1.11; for stroke: OR 0.71, 95% CI 0.46 to 1.10). The combination of diuretic and ACE inhibitor or A2RA did significantly reduce the risk of ischaemic stroke (OR 0.56, 95% CI 0.33 to 0.96).
Sponsorship Supported in part by grants from the National Heart, Lung, and Blood Institute. No competing interests declared
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