Anti-hypertensive drugs deprescribing: an updated systematic review of clinical trials

Polypharmacy is defined by the National Institute for Health as the administration of at least 5 different drugs for reducing the risk of morbidity and mortality [1]. It is a common issue among older persons, who are frequently affected by multi-morbidity that requires often complex pharmacological treatments [2]. In Italy, people aged ≥65 years received on average 7.7 different drugs in 2019, which increases to an average of 8.8 among persons aged ≥85 years [3]. One of the most serious issues associated with polypharmacy is the increased risk of drug-drug interactions (DDIs) that are clinically significant modifications in the pharmacokinetics and/or pharmacodynamics of one drug by the administration of another drug [4, 5]. DDIs can increase the risk of adverse drug reactions (ADRs), both in the primary or secondary care setting [6]. The chances of a DDI increase as the number of prescribed drugs increases [7‐9]. As such, it is essential to implement preventive strategies to eliminate inappropriate drug prescribing, minimizing the overall amount of medicines taken on daily basis by the patients. Deprescribing is one potential approach to reduce inappropriate prescribing. Specifically, deprescribing is defined as the withdrawal or dose reduction of medications which are either inappropriate [10] or unnecessary [11], particularly among patients with polypharmacy. A systematic review and meta-analysis of studies evaluating the impact of deprescribing on mortality among the elderly found that among non-randomized studies, deprescribing significantly reduced mortality risk [odds ratio (OR) 0.32, 95% confidence interval (95% CI): 0.17–0.60)], while among randomized clinical trials (RCTs) this decreasing trend did not reach statistical significance (OR 0.82, 95% CI 0.61–1.11) [10, 12]. A more recent systematic review of RCTs suggested that the number of relevant trials was very low, with a high risk of bias and generally of low quality [13].

Of note, anti-hypertensive medications are of particular interest because they are very commonly used in Italy and can lead to ADRs especially among the elderly [3]. Age-related physiological changes, multimorbidity and polypharmacy may indeed alter pharmacokinetics and pharmacodynamics in elderly, thus altering significantly the effect of pharmacological treatment with advancing age [14]. Therefore, scaling down the number of medications taken, including anti-hypertensive drugs, by deprescribing, may lead to reduced adverse effects and improved quality of life in older people.

To date there is one guideline on clinical- and cost-effectiveness of stopping anti-hypertensive drugs [1]. This guideline identified very low quality evidence from 3 RCTs dated back to the ‘80s. Although such evidence suggested that for some people stopping anti-hypertensive drugs was significantly associated to the return to hypertension, the National Institute for Health and Care Excellence (NICE) Guideline Development Group concluded that deprescribing anti-hypertensive drugs may be beneficial for reducing polypharmacy and side effects, and for increasing quality of life, especially in “low risk” patients (e.g. people who have maintained blood pressure at normal levels for a long period of time or people with no history of cardiovascular events) [1]. Similarly, a Cochrane systematic review of six RCTs investigating the effect of anti-hypertensive medications in older people (i.e. aged ≥50 years) published in 2020 by Reeve et al. showed no evidence of an effect of discontinuing compared with continuing anti-hypertensives used for hypertension or primary prevention of cardiovascular disease on all-cause mortality and myocardial infarction. Furthermore, since the certainty of the evidence was low to very low, mainly because of the small size of the studies and low event rates, it was not possible to draw firm conclusions about the effect of anti-hypertensives deprescribing on these outcomes [12].

The aim of this systematic review was to synthesize current evidence on the assessment of the benefit-risk profile of anti-hypertensive drug deprescribing, including more recently published studies.

This systematic review has summarized data from two RCTs including 1636 adults treated with anti-hypertensive drugs. We did not find observational studies meeting the inclusion criteria for this systematic review. One of the main findings of this systematic review was the dearth of robust information on the risks and benefits of deprescribing of anti-hypertensive drugs. Indeed, the review carried out only identified two new studies. Furthermore, the quality of the included studies was generally not high. Robust studies on deprescribing are needed to update and inform clinical guidelines.

Evidence from the included studies indicates that, in terms of blood pressure control, a strategy of medication reduction is non-inferior compared to standard care [21, 22]. However, these trials focused on two different specific populations and evaluated different outcomes, thus making it difficult to draw conclusions generalizable to individuals not included in such populations. Specifically, the OPTIMISE trial enrolled patient aged at least 80 years who were prescribed with two or more anti-hypertensive drugs for at least 12 months, selected based on the general practitioner opinion that they might benefit from deprescribing. Although the patient population in this study was generalizable to primary care, this trial did not establish whether or not anti-hypertensive drug deprescribing should be attempted or which patients should be targeted with such an intervention [21]. On the other hand, the ECSTATIC study enrolled younger patients, aged between 40 and 70 years, without history of cardiovascular diseases and with low risk of future cardiovascular diseases. In this pragmatic trial, the increase in predicted 10-year cardiovascular risk in the 2 years after the first visit was assessed, with the main objective to answer the question of whether a structured deprescribing strategy in low-cardiovascular-risk patients is effective when implemented in general practice. Moreover, in this study medication reduction was part of a medication review but not specifically mandated; the choice to leave the decision to deprescribe to the patient and their general practitioners and the choice to use an active control group may have resulted in an underestimation of the effect of the intervention on cardiovascular risk [22].

Overall, findings from the present systematic review are in line with the NICE guideline on anti-hypertensive drugs deprescribing, suggesting benefits, in terms of blood pressure management, especially low-risk patients (i.e. patients without history of cardiovascular events and whose blood pressure was maintained at normal levels for a long period of time). NICE guidelines on managing multi-morbidity in terms of anti-hypertensive prescribing state that there was a reduced risk of cardiovascular outcomes on discontinuing anti-hypertensive treatment, compared to continuing it [1]. On discontinuation, there was a risk of reverting to high blood pressure, but this was found to be uncommon. However, these guidelines focus on simply discontinuing a drug rather than the broader range of deprescribing options, such as dose reduction and other changes to the dosing regimen. In addition, these guidelines do not clearly state which clinical characteristics would make a person eligible for discontinuation. The studies upon which the guidelines were based were considered to be of low to moderate quality and date back to ‘80s.

In this regard, it is noteworthy that only two RCTs meeting our inclusion criteria have been published on this topic since 1986 [23], i.e. the year of publication of the last study included in the NICE guideline, highlighting the lack of evidence on such an important topic for such a long period of time.

Findings from this systematic review are also in line with those of the Cochrane systematic review published by Reeve et al. in June 2020 [12]. In this paper, the authors used different inclusion criteria, including also studies in which patients were treated with anti-hypertensive drugs for less than 1 year, excluding RCTs in which anti-hypertensive drugs were used for secondary prevention and setting age limits (i.e. only studies concerning people aged ≥50 years were included). They searched six bibliographic databases until April 2019 and included six RCTs in their systematic review: five of them were published between 1977 and 1997 and one in 2015. Only one [20] of these RCTs met the criteria established by our PICO and was already included in the NICE guidelines. Overall, evidence from this systematic review demonstrated that anti-hypertensive drug discontinuation had no effects on all-cause mortality, myocardial infarction or stroke, although there was low or very low certainty in these results [12]. As the authors stated, one of the main limitations of their systematic review was that five out of the six included RCTs were published more than 20 years ago. Indeed, over the past 20 years, several changes in standards of treatment and population risk factors have occurred and the number of the oldest old as well as the prevalence of polypharmacy among older adults has increased, thus affecting the applicability of the evidence to the current population of older adults.

Further information is needed on which patients can benefit most from deprescribing anti-hypertensive drugs because these drugs are widely used long-terms and over-used, especially among older persons [24]. Although these drugs are generally considered to be well-tolerated, they are still associated with ADRs, the risk of which may be increased also due to DDIs. For example, anti-hypertensives are associated with a higher risk of falls among elderly persons that are treated with several anti-hypertensives [25] as well as with other drugs with hypotensive effects such as trazodone [26] and tricyclic antidepressants [27].

An observational study conducted among elderly hospitalized patients found that 15% of moderately severe interactions occurred due to the use of angiotensin converting enzyme inhibitors and loop diuretics; the number of DDIs was proportionally associated with the risk of death [28]. A more recent observational study found that cardiovascular drugs are by far the most frequently involved drug class in DDI occurrence also in primary care [29]. If successfully implemented, deprescribing as a strategy to reduce polypharmacy may also lead to risk reduction of ADRs and DDIs and ultimately to optimization of healthcare costs [].

The present study has several strengths. The findings of this study are based on a systematic and independent review of available literature. This study has also built on previous systematic reviews to update them and avoid duplicating work. However, some study limitations warrant cautions. Although only high quality RCTs can provide robust evidence on the safety and efficacy of deprescribing, only two RCTs of medium quality were found. The evidence on deprescribing from observational studies is generally weak as drug discontinuation/switch to a lower dose may occur for several reasons which may be difficult to identify (e.g. short life expectancy with focus on palliative care, unwillingness to continue therapy, onset of ADRs, etc.) and may act as confounders that cannot be fully adjusted in naturalistic setting. Furthermore, due to the high risk of bias and the heterogeneity of the study designs and outcomes of the included studies, it was not possible to conduct a meta-analysis [31].

Future studies should address the impact of deprescribing of commonly used drugs, such as anti-hypertensive medications, in specific subpopulations (e.g. elderly patients) using clear definitions of deprescribing and clearly reporting which patients were eligible for deprescribing. Such studies should consider clinically meaningful outcomes when evaluating the risks and benefits of discontinuations, such as the risk of outcomes linked to mortality (e.g. hypotension, falls, pneumonia etc.) as well as focusing on populations at highest risk of ADRs, such as persons with well-defined polypharmacy and multi-morbidity, as well as elderly persons. Such studies should ideally be RCTs, as these studies are best-suited to measure the effectiveness of interventions, including deprescribing interventions. While observational studies may be useful to describe the real-world use of anti-hypertensives, the discontinuation of these drugs in a routine clinical setting may be driven by unmeasured confounders, such as disease severity and prescriber willingness to attempt deprescribing that cannot be totally addressed. The ideal study design to evaluate the impact of deprescribing may be a pragmatic study.

This updated systematic review of the risks and benefits of anti-hypertensive drugs deprescribing found that there are only two RCTs beyond those included in the guideline published in 2016 by NICE. Although included studies are of moderate quality, the overall evidence seems to suggest a positive effect of anti-hypertensive drugs deprescribing, in line with the NICE guideline. Given how widely used and potentially over-used anti-hypertensives are, especially among the elderly, high quality experimental studies are urgently needed to measure the effect of deprescribing interventions, as they can reduce the risk of DDIs, thereby improving the safety of drug use.