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. 2017 Aug 23;2017(8):CD012769. doi: 10.1002/14651858.CD012769

Pharmacotherapy for resistant hypertension in adults

Jaykaran Charan 1,✉, Mayur Chaudhari 2, Summaiya Mulla 3, Tea Reljic 4, Rahul Mhaskar 4, Ambuj Kumar 4
PMCID: PMC6483763

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the benefits and harms of adding a new drug to the current triple‐drug regimen for management of resistant hypertension in adults versus continuation of treatment with triple‐drug therapy alone.

Background

Description of the condition

Hypertension is a common non‐communicable disease defined as an abnormal elevation in arterial blood pressure. It is associated with many cardiovascular and non‐cardiovascular events such as stroke, myocardial infarction, heart failure, and kidney failure (Gu 2008; Juarez‐Rojas 2008; Klungel 2000). Global prevalence of hypertension among adults is estimated to be 26% and is expected to increase to 29% by 2025 (Kearney 2005). Ability to reduce blood pressure using drug therapy in patients with hypertension is associated with a lower incidence of cardiovascular events compared to uncontrolled hypertension (Musini 2009; Okin 2012; Wright 2009).

Resistant hypertension is a hypertensive condition in which blood pressure control with medication is difficult. That is, blood pressure remains above target values despite treatment with drugs from three different classes, including one diuretic at optimum dose (Calhoun 2008). Daugherty 2012 reported that one out of every 50 patients who started antihypertensive treatment developed resistant hypertension, despite treatment with a three‐drug regimen. These patients needed at least four drugs to achieve adequate blood pressure control (Daugherty 2012). Prevalence of resistant hypertension is estimated to be 12% to 15% (Egan 2011; Persell 2011; Roger 2011), though clinical trial data suggest that the actual prevalence of resistant hypertension may be even higher (Cushman 2002; de la Sierra 2011). The likelihood of adverse cardiovascular outcomes is higher among people with resistant hypertension than those with controlled hypertension. According to one estimate, people with resistant hypertension exhibit a 50% increase in cardiovascular events compared to those whose blood pressure is controlled by triple‐drug therapy (Daugherty 2012). This finding is important because, although duration of hypertension was the same for people with resistant hypertension and controlled hypertension, an increase in the number of adverse cardiovascular events in people with resistant hypertension was evident.

Several risk factors are associated with resistant hypertension. These include obesity, diabetes, chronic kidney disease, race, sex, left ventricular hypertrophy and age (Epstein 2007; Pickering 2007). Inappropriate or inadequate use of antihypertensive drug combinations is another important factor in the development of resistant hypertension. The Hanselin 2011 study reported that only 3% of people with resistant hypertension were taking chlorthalidone, a first‐line drug, and very few were taking aldosterone antagonists. However, around 16% were taking an angiotensin‐converting enzyme (ACE) inhibitor plus an angiotensin receptor blocker (ARB), which is not recommended (Chobanian 2003; Hanselin 2011). Another study found only 55% achieved blood pressure control within one year of diagnosis of resistant hypertension (Daugherty 2012a). Intensification of treatment for management of resistant elevated blood pressure was significantly associated with a reduction in blood pressure, however, on average, people with resistant hypertension received less intensified treatment than expected (Daugherty 2012a). Determining the comparative benefits and harms of add‐on therapies used in the management of resistant hypertension is necessary for informed decision making by patients and physicians.

Description of the intervention

A number of drugs have been considered as potential add‐ons to triple‐drug therapy for people with resistant hypertension. Hyperaldosteronism, that is, elevated aldosterone production, is one important factor in resistant hypertension. Spironolactone is a drug that competes for the receptor on which aldosterone acts, and so blocks it. Additionally, spironolactone acts as a diuretic, as it blocks the receptors in the distal kidney, which is where aldosterone‐dependent absorption of sodium occurs. A few clinical trials have explored the effect of spironolactone in resistant hypertension (Abolghasmi 2011; Pisoni 2012; Vaclavik 2011). In the ASPIRANT (addition of spironolactone in patients with resistant arterial hypertension) randomized controlled trial (RCT), adult participants with resistant hypertension were allocated to spironolactone (25 mg) versus placebo. This produced a significant reduction in systolic blood pressure in the spironolactone group compared to the placebo group, however there was no reduction in diastolic blood pressure (Vaclavik 2011). The reduction in blood pressure was observed only among elderly participants (age > 62 years) and was independent of baseline blood pressure or secondary causes of elevated blood pressure (Vaclavik 2012; Vaclavik 2013). Additionally, low dose spironolactone can be useful in treating resistant hypertension among people with chronic kidney disease (Abolghasmi 2011; Pisoni 2012).

Direct renin inhibitors, such as aliskiren, are another class of potential add‐on drugs. Renin converts angiotensinogen to angiotensin 1. Direct renin inhibitors block renin, which prevents formation of angiotension 1 and angiotensin 2, and of peptides associated with blood pressure elevation, through a variety of physiological pathways. Since renin inhibitors have a different mechanism of action from ACE inhibitors and ARB, they are suitable candidates for the treatment of resistant hypertension. In one study, aliskiren was found to reduce both systolic and diastolic blood pressure at three‐month follow‐up (Yoshitomi 2013).

Endothelin antagonists are also used as add‐on drugs to reduce blood pressure in resistant hypertension. Endothelin is a vasoconstrictor released normally in blood vessels. However, if over‐expressed, endothelin may lead to an increase in blood pressure. Consequently, endothelin antagonists are a viable option as add‐on drugs. One RCT that investigated the effect of the endothelin antagonist darusentan found that it reduced both systolic and diastolic blood pressure after 14 weeks of treatment (Black 2007).

Finally, drug combinations such as amlodipine (a calcium channel blocker) and olmesartan (an angiotensin 2 receptor antagonist), and the combination of phosphodiesterase inhibitors and nitrates have also been suggested for use as add‐on drugs for resistant hypertension because of their varied and synergistic mechanisms of action (Ding 2013; Oliver 2010). Additionally, newer molecules, like aldosterone synthase inhibitors, have been explored in the treatment of resistant hypertension, but with inconclusive results (Karns 2013).

How the intervention might work

People with resistant hypertension have an increased risk of adverse cardiovascular events compared to people whose blood pressure is controlled by triple‐drug therapy (Daugherty 2012; Pierdomenico 2005). RCTs that have explored the addition of any new drug to the current triple‐drug regimen for resistant hypertension have shown that certain drugs can decrease the blood pressure (Black 2007; Vaclavik 2011). Since blood pressure is a surrogate marker for many cardiovascular events, including stroke and myocardial infarction, there are chances that this decrease in blood pressure may actually decrease the incidence of these clinical endpoints, and hence mortality and morbidity. The use of darusentan, an endothelin receptor antagonist, as an add‐on drug to be taken in addition to triple‐drug therapy has been explored in a clinical trial for people with resistant hypertension; it was found to decrease both systolic and diastolic blood pressure in a dose‐dependent manner. Furthermore, target levels of systolic blood pressure were achieved in more participants in the darusentan group than in the placebo group. Oedema and fluid retention were major side effects observed in the treatment group (Black 2007). Similarly in the ASPIRANT trial it was observed that low‐dose spironolactone decreased systolic blood pressure significantly after eight weeks of therapy with comparable side effects to those seen in the placebo group (Vaclavik 2011).

Why it is important to do this review

Resistant hypertension is known to be associated with increased cardiovascular morbidity and mortality, and the current reported prevalence of resistant hypertension is between 12% to 15% (Egan 2011; Persell 2011; Roger 2011). At present, no clear understanding exists regarding the use of any pharmacological agent as an add‐on to the routine triple‐drug therapy that is already taken for resistant hypertension (Black 2007; Vaclavik 2011). Other clinical trials have investigated the use of aldosterone antagonists such as spironolactone, a renin inhibitor (aliskiren), and combinations of nitrates and phosphodiesterase inhibitors for resistant hypertension (Abolghasmi 2011; Ding 2013; Oliver 2010; Pisoni 2012; Yoshitomi 2013). However, no systematic review has evaluated the effectiveness of this practice. A systematic compilation of published and unpublished evidence is needed to understand the use of any pharmacological agents as add‐on drugs in people with resistant hypertension. The objective of this review is to compare the addition of an add‐on drug to triple‐drug therapy versus triple‐drug therapy alone in people with resistant hypertension, in order to aid clinical decision making and help shape future research and policy on the topic.

Objectives

To assess the benefits and harms of adding a new drug to the current triple‐drug regimen for management of resistant hypertension in adults versus continuation of treatment with triple‐drug therapy alone.

Methods

Criteria for considering studies for this review

Types of studies

We plan to include only randomized controlled trials in which participants who are currently taking standard triple‐drug therapy for resistant hypertension are allocated to triple‐drug therapy plus an additional drug or triple‐drug therapy alone. We will not include any observational studies in this systematic review.

Types of participants

We will include studies that enrolled adults with resistant hypertension. Resistant hypertension is defined as being present in men and non‐pregnant women over 18 years of age when systolic blood pressure exceeds 140 mmHg or diastolic blood pressure exceeds 90 mmHg, despite treatment with three antihypertensive drugs including a diuretic at optimum dose. We will include studies that enrolled individuals with resistant hypertension only, or had mixed populations but reported outcomes for individuals with resistant hypertension separately.

Types of interventions

Intervention: the addition of any antihypertensive drug to a triple‐drug regimen that is already being taken for the management of hypertension. Comparison: addition of placebo or nothing to a triple‐drug regimen that is already being taken for the management of hypertension.

Types of outcome measures

Primary outcomes

All‐cause mortality captured as a dichotomous outcome.

Secondary outcomes

Our secondary outcomes are:

  • fatal and non‐fatal stroke (dichotomous);

  • fatal and non‐fatal myocardial infarction (dichotomous);

  • total cardiovascular events (fatal and non‐fatal stroke, fatal and non‐fatal myocardial infarction and congestive heart failure (fatal or requiring hospitalization) (dichotomous);

  • withdrawals due to adverse effects (dichotomous);

  • change from baseline in mean systolic blood pressure (continuous);

  • change from baseline in mean diastolic blood pressure (continuous);

  • serious adverse events (dichotomous);

  • quality of life (continuous).

Search methods for identification of studies

Electronic searches

The Cochrane Hypertension Information Specialist will search the following databases from date of inception for published, unpublished, and ongoing studies:

  • the Cochrane Hypertension Specialised Register via the Cochrane Register of Studies (CRS‐Web);

  • the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies (CRS‐Web);

  • MEDLINE Ovid (from 1946 onwards), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations;

  • Embase Ovid (from 1974 onwards);

  • ClinicalTrials.gov (www.clinicaltrials.gov)

  • World Health Organization International Clinical Trials Registry Platform (www.who.it.trialsearch).

The subject strategies for databases will be modelled on the search strategy designed for MEDLINE in Appendix 1. Where appropriate, these will be combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0, Box 6.4.b. (Higgins 2011a)).

Searching other resources

  • The Hypertension Information Specialist will search the Hypertension Specialised Register segment (which includes searches of MEDLINE and Epistemonikos for systematic reviews) to retrieve published systematic reviews related to this review title, so that we can scan their reference lists to identify additional relevant trials. The Specialised Register also includes searches of CAB Abstracts & Global Health, CINAHL, ProQuest Dissertations & Theses and Web of Knowledge.

  • We will check the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials.

  • We will contact experts/organisations in the field to obtain additional information on relevant trials.

  • We may contact original authors for clarification and further data if trial reports are unclear.

  • We will search conference abstracts from the last two scientific meetings of the International Society of Hypertension (ISH), the American Society of Hypertension (ASH) and the European Society of Hypertension (ESH).

  • We will search the Database of Abstracts of Review of Effects (DARE) and the metaRegister of Controlled Trials.

Data collection and analysis

Selection of studies

Two authors will independently review all titles, abstracts, and full‐text manuscripts retrieved. We will include randomized controlled trials that randomized participants with resistant hypertension to either the current triple‐drug regimen plus an additional drug versus continuing on the current triple‐drug regimen alone.

We will match references for author names, location and setting, specific intervention details, and number of participants to avoid including duplicate publications. Any disagreements between authors during the study selection will be resolved by consensus with a third author.

Data extraction and management

Two authors will extract data independently using a standardized data extraction form according to Chapter 7 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). They will extract data on the following items:

  • general information: study title, authors, source;

  • study characteristics: study design, setting, duration of follow‐up;

  • participant characteristics: number of participants enrolled, number of participants included in the analysis, participant age, sex;

  • interventions: name, dose, route, administration schedule, and any associated therapies (that is, the current triple‐drug regimen);

  • outcomes: incidence of all‐cause mortality, cardiovascular mortality, mortality due to stroke, mortality due to myocardial infraction, incidence of stroke and myocardial infarction, change from baseline in mean systolic and diastolic blood pressure, incidence of any reported grade three or four adverse events, quality of life;

  • items relevant for risk of bias judgements.

If we identify any studies that have multiple publications, we will extract data on outcomes from the publication with longest, most complete follow‐up. We will use prior publications to extract data on methodology and baseline characteristics if necessary. In cases where the method of analysis was not specified by the investigators and only the number of events was reported, we will use the number randomized as the denominator (i.e. according to intention‐to‐treat analysis (ITT)).

Assessment of risk of bias in included studies

Two review authors will assess the risk of bias in the included studies independently using the Cochrane tool for assessing risk of bias, as outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions; decisions will be based on extracted information (Higgins 2011c). Any disagreement between the two authors will be resolved by a third author. Additionally, we will evaluate the risk of random error by extracting data on the investigator's predetermined effect difference, alpha, power, and sample size.

Specifically, for assessment of risk of bias, we will grade each component of methodological quality as being at low, high, or unclear risk of bias according to the following scale:

  • low risk of bias: plausible bias unlikely to seriously alter the results, if all criteria were met;

  • high risk of bias: plausible bias that seriously weakens confidence in the results, if one or more criteria were not met;

  • unclear risk of bias: plausible bias that raises some doubt about the results, if one or more criteria were assessed as unclear.

We will include the following items the risk of bias assessment for included trials:

  • sequence generation (whether randomization sequence was adequately generated);

  • allocation concealment (whether allocation was adequately concealed);

  • masking or blinding (whether the knowledge of the allocated intervention was adequately prevented during the study, that is, we will extract data regarding who was blinded (participants, personnel, outcome assessors, data analysts, etc.);

  • incomplete outcome data (whether incomplete outcome data were adequately addressed, whether incomplete outcome data were addressed for every outcome separately); also whether ITT analysis was undertaken in the study;

  • selective outcome reporting (whether reports of the study were free of selective outcome reporting)

In addition, we will evaluate the risk of random error by the following.

  • Expected difference in the primary outcome (whether the effect size (Δ) was prespecified):

    • low risk: if trial authors specified the expected effect size a priori (for example Δ = 60%);

    • high risk: if trial authors did not specify the expected effect size a priori;

    • unclear: if there was insufficient information to permit judgment of ‘Yes’ or ‘No'.

  • Alpha error (whether type I error, the probability of incorrectly rejecting the null hypothesis if it is true, was prespecified):

    • low risk: if trial authors specified the level of significance a priori (for example α = 0.05);

    • high risk: if trial authors did not specify the level of significance a priori;

    • unclear: if there was insufficient information to permit judgment of ‘Yes’ or ‘No'.

  • Beta error (whether the probability of failing to reject the null hypothesis when it is false, was prespecified):

    • low risk: if trial authors specified either the beta error (for example ß = 0.20) or power a priori;

    • high risk: if trial authors did not specify either the beta error or power a priori;

    • unclear: if there was insufficient information to permit judgment of ‘Yes’ or ‘No'.

  • Sample size (whether sample size was prespecified):

    • low risk: if trial authors specified the sample size to be accrued a priori (for example, n = 200 per arm);

    • high risk: if trial authors did not specify the sample size a priori;

    • unclear: if there was insufficient information to permit judgment of ‘Yes’ or ‘No'.

Measures of treatment effect

Dichotomous data

We will summarize dichotomous data (i.e. overall mortality, fatal and non‐fatal stroke and fatal and non‐fatal myocardial infarction, total cardiovascular adverse events) from each study using risk ratios (RR). We will pool data from similar studies with similar interventions using the random‐effects model and report RR with 95% confidence intervals (CI).

Continuous data

For continuous measures (i.e. change from baseline in systolic and diastolic blood pressures, quality of life), we will extract the mean and standard deviation. If original investigators report a median only, we will use the methods by Hozo and colleagues to approximate the mean (Hozo 2005). We will summarize data using mean difference (MD) for the change in systolic and diastolic blood pressure outcomes. If different scales are used to measure the same outcome, we will use standardized mean difference (SMD) for the quality of life outcome, which we will pool using the random‐effects model and report with 95% CI.

Unit of analysis issues

Since we only plan to include prospective randomized trials with parallel or cross‐over study designs, we do not anticipate unit of analysis issues associated with cluster‐randomized trials. Where there is repeated follow‐up (e.g. reporting of mortality at one year and three years), we will use the longest follow‐up from each study. We will treat any recurring events (e.g. adverse events) as a single event occurring in one participant (e.g. four occurrences of grade‐three headache in one participant will be considered as one participant with grade‐three headache). We do not expect unit of analysis issues associated with multiple treatment attempts or use of multiple body parts. In the case of multiple intervention arms, we will combine arms together to create a single pair‐wise comparison if the arms contain similar regimens (except for dose or route). If one or more arms contain a different regimen, it/they will be included separately.

Dealing with missing data

Where data are missing, we will follow the recommendations from Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011d). That is, we will attempt to contact the principal investigator, corresponding author (or both) of the study to request the missing information. If the corresponding author is unable to provide the missing data, we will include the study in the systematic review, but exclude it from the meta‐analysis for the outcome with missing data.

Assessment of heterogeneity

We will assess heterogeneity between pooled studies using the I2 statistic (Deeks 2011). An I2 greater than 50% will indicate high heterogeneity, an I2 between 30% and 50% will indicate moderate heterogeneity and an I2 below 30% will indicate low heterogeneity. We will assess potential sources of heterogeneity by conducting a sensitivity analysis on the collected aspects of study quality.

Assessment of reporting biases

We plan to use a funnel plot to assess potential publication bias if at least ten studies contribute data to a particular meta‐analysis (Egger 1997; Sterne 2011). In addition, we will attempt to evaluate selective reporting of outcomes within studies by comparing the outcomes reported with those prespecified in the study protocol, if one is available.

Data synthesis

Provided that the trials are clinically sufficiently similar, we will pool data on similar outcomes and analyse the data using Review Manager 5.3 (RevMan 2014). We will employ a random‐effects model using the DerSimonian‐Laird approach to pool studies for all analyses (DerSimonian 1986).

'Summary of findings' table

We will summarize the review findings in a 'Summary of findings' table created using GRADEpro software (GRADEpro GDT 2014), presenting the effect estimates and the quality of the body of evidence associated with the primary outcomes of the Cochrane Review (Schünemann 2013). We will use the GRADE approach to prioritise the importance of the variables we will include in the 'Summary of findings' table (Guyatt 2011). We have preselected the following outcomes to be included in the 'Summary of findings' table: all‐cause mortality, cardiovascular mortality, change from baseline in systolic blood pressure, change from baseline in diastolic blood pressure, and any reported serious adverse events.

Additionally, we will evaluate and report the quality of evidence for each outcome according to GRADE guidelines (Balshem 2011; Guyatt 2011a; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e).

Subgroup analysis and investigation of heterogeneity

If sufficient data are available, we will perform subgroup analysis on the basis of:

  • different drug classes;

  • number of drugs added to control resistant hypertension.

Sensitivity analysis

In order to evaluate the robustness of our findings, we will perform a sensitivity analysis according to all aspects of methodological quality (i.e. low risk versus high or unclear risk).

Acknowledgements

We would like to thank the Cochrane reviewers and editors for critical appraisal of our protocol and helpful feedback.

Appendices

Appendix 1. MEDLINE search strategy

Database: Ovid MEDLINE(R) 1946 to Present with Daily Update ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ 1 (resistant adj5 hypertens$).mp. 2 exp antihypertensive agents/ 3 (pharmacotherap$ or therap? or treated or treatment?).tw,kf. 4 (ad or ae or dt or tu).fs.

5 or/2‐4 6 randomized controlled trial.pt. 7 controlled clinical trial.pt. 8 randomized.ab. ) 9 placebo.ab. 10 drug therapy.fs. 11 randomly.ab. 12 trial.ab. 13 groups.ab. 14 or/6‐13 15 animals/ not (humans/ and animals/) 16 14 not 15 17 1 and 5 and 16 18 remove duplicates from 17

What's new

Last assessed as up‐to‐date: 27 July 2017.

Date Event Description
23 August 2017 Amended corrected minor error in search strategy
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Contributions of authors

JC, MC, SM, TR, RM and AK contributed to the initiation and design of this protocol.

Sources of support

Internal sources

  • All India Institute of Medical Sciences, Jodhpur, India, India.

    salary for authors JC

  • University of South Florida, USA.

    salary for authors TR, RM and AK

  • Govt. Medical College, Surat, India, India.

    Salary of MC and SM

External sources

  • No sources of support supplied

Declarations of interest

AK: no conflicts of interest to report

JC: no conflicts of interest to report

MC: no conflicts of interest to report

RM: no conflicts of interest to report

SM: no conflicts of interest to report

TR: no conflicts of interest to report

Edited (no change to conclusions)

References

Additional references

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