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Drug-induced orthostatic hypotension: A systematic review and meta-analysis of randomised controlled trials

['Cini Bhanu', 'Research Department Of Primary Care', 'Population Health', 'University College London', 'United Kingdom', 'Danielle Nimmons', 'Irene Petersen', 'Mine Orlu', 'Ucl School Of Pharmacy', 'Daniel Davis']

Date: 2021-11

Main findings

We have conducted a systematic review and meta-analysis of 69 placebo-controlled RCTs to investigate the extent to which specific medications are associated with OH in adults. Compared with placebo, beta-blockers and TCAs were associated with a 6- to 7-fold increased odds of OH. Alpha-blockers, second-generation antipsychotics, centrally acting antihypertensives, and SGLT-2 inhibitors were associated with up to a 2-fold increased risk of OH, compared to placebo. There was no difference in odds of OH with CCBs, ACE inhibitors/ARBs, and SSRIs compared to placebo. These findings are based on varied certainty of evidence, which ranged from low to high. Our study has characterised a range of commonly prescribed drug classes according to OH risk to guide selective prescribing and monitoring of postural BP in practice.

Reports on antihypertensives and risk of OH in the literature are conflicted. There have been reports of OH with ACE inhibitors [12] and diuretics [14,9] that were not replicated in our study. It is possible that risk of OH was attenuated in our study due to the selective younger, fitter RCT population. Antihypertensives also induce OH through their therapeutic effect; such drugs often require much higher doses to observe adverse effects [23]. However, many studies suggest a protective postural effect associated with ACE inhibitors [9,24]. Juraschek and colleagues recently found that intensive BP-lowering treatment does not increase risk of OH [12]. It is known that hypertension itself increases risk of OH [13], so it is likely the complex interaction between baseline risk of OH in well-controlled hypertensive patients and antihypertensive drug effects complicates the true picture. Current consensus suggests that optimal control of BP (even among older adults) should be prioritised over potential risk of OH [12,25].

Beta-blockers induce OH through sympathetic inhibition decreasing heart rate and contractility, alongside combined independent vasodilatory effects [10,26]. Previous observational studies with strict measurement of postural BP have reported that beta-blockers are strongly associated with OH, independent of comorbidities, consistent with our results [13,27]. Current consensus states that beta-blockers should not be prescribed in preference for hypertension, due to both its potential to cause harm and lack of efficacy relative to other antihypertensives [27].

Among the drugs identified, alpha-blockers were associated with least risk. This is likely related to the majority of alpha-blockers in our study being uroselective (such as tamsulosin and alfuzosin), which have fewer cardiac effects [26]. Nevertheless, alpha-blockers almost doubled the odds of OH compared to placebo and are widely prescribed for prostatic hypertrophy to treat LUTS [28]. Dizziness and OH associated with alpha-blockers is a particular problem among older patients, and patients frequently discontinue alpha-blocker treatment in clinical practice [28]. The use of 5-alpha reductase inhibitors (5-ARIs) could reduce the need of alpha-blockers for LUTS [29]. Discontinuation of alpha-blocker treatment after 6 months in patients receiving combination therapy has been recommended and has been shown to have no significant effect on LUTS [28].

TCAs similarly exert their effects on postural BP through combined sympathetic inhibition and reduced vascular resistance [26]. Clinical guidelines support prescription of SSRIs in preference to TCAs for depression due to fewer adverse effects [10,30]. However, TCAs are still the second most prescribed antidepressant in older people (likely related to low-dose off-label use for pain and insomnia) [31]. While our study focused on TCAs at higher doses for depression and identified a 6-fold increase in odds of OH compared to placebo, it is likely that TCAs at lower doses also cause harm, especially in older adults at higher risk of OH due to a decrease in baroreflex sensitivity [32].

Interestingly, SGLT-2 inhibitors were the only drugs among vasodilators associated with significantly higher odds of OH. Their cardiac effects are exerted through diuresis and independent cardio-inhibitory effects (that are less well understood), alongside vasodilation [33]. SGLT-2 inhibitors are now considered preferential as second-line treatment for T2DM [34]. T2DM itself can increase the risk of OH, as a manifestation of autonomic neuropathy. However, improved glucose control and other positive effects on body weight related to SGLT-2 therapy can reduce the risk of neuropathic complications [34]. Therefore, the relationship between SGLT-2 use and OH in patients with T2DM is complex, similar to antihypertensives.

The drugs associated with highest odds of OH in our study (alpha-blockers, alpha-agonists, antipsychotics, beta-blockers, and TCAs) all share a common key mechanism of sympathetic inhibition causing cardioinhibitory effects [10,26]. Among these, beta-blockers and TCAs demonstrate the strongest association, with 6 to 7 times increased odds of OH compared to placebo. Both these groups induce OH through combined mechanisms of sympathetic inhibition and vasodilatory effects suggesting that OH risk rises with cumulative drug targets. This suggests that coprescription of drugs with the potential to cause OH may also result in cumulative harm, in keeping with a growing body of evidence [3,35].

[END]

[1] Url: https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003821

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