Improving adherence with treatment-resistant hypertension

KEYWORDS:

• Hypertension
• adherence
• resistance
• adherence
• clinical practice

1. Introduction

Arterial hypertension is the most important risk factor for cardiovascular disease responsible for a large proportion of death and disability-adjusted life-year across the world [1]. Blood pressure control through the administration of first-line classes of antihypertensive drugs has been proven to significantly improve the clinical outcome of hypertension in the overall population and in the subgroups of patients with different degrees of severity of the disease. Suboptimal adherence to antihypertensive medication is one of the major contributors to poor blood pressure control, thus influencing cardiovascular outcomes and health-care costs. Adherence to treatment is a complex phenomenon involving socioeconomic factors, health-care system, the nature of medical conditions as well as therapy- and/or patient-related conditions [2]. Several methods, direct or indirect, have been suggested for adherence measurement, including biochemical screening, but no gold standard procedures have been identified for the assessment of adherence to antihypertensive treatment in daily clinical practice. Among the possible barriers to adherence, the insufficient patient–physician relationship as well as the number of daily pills and the individual drug tolerability seem to play the most relevant role from both the patient and the physician perspective [3]. They are key elements in diagnosing adherence and in attempting to choose interventions tailored to the patient’s profile. An improvement in individual adherence to blood pressure–lowering drugs can be achieved through a simplification of treatment regimen (e.g. the use of single-pill combinations) and/or by the implementation of a collaborative team-based approach supporting the importance of a correct drug treatment for the prevention of hypertension-related cardiovascular diseases [2]. A poor adherence to antihypertensive treatment can also be involved in the so-called treatment-resistant hypertension that is affecting a significant proportion of the hypertensive population. Actually, an estimated 10% to 30% of hypertensive patients can be considered resistant’to the expected effects of treatment with uncontrolled blood pressure despite the use of ≥3 drugs, one of which should be a diuretic [4]. A large number of cross-sectional and longitudinal studies have demonstrated that treatment-resistant hypertension is associated with an increased cardiovascular disease risk when compared to treatment sensitive. Many different mechanisms have been considered as responsible for treatment-resistant hypertension including poor diagnosis of secondary hypertension, incorrect drug treatment, and medical inertia, but in particular insufficient medical adherence to prescribed treatment (Table 1). This supports the pivotal role of an improved adherence to antihypertensive treatment as a solution for the problem of resistant hypertension [4].

Table 1. Causes of treatment-resistant hypertension in clinical practice

Clinical causes

Unknown (essential)

Lifestyle changes and metabolic diseases (metabolic syndrome and diabetes, serum uric acid)

Sleep apnea

Drug related causes (SNRI’s, NSAID’s, COX2-I, …)

Secondary causes of hypertension (adrenal, renal)

Functional mechanisms

Errors in blood pressure measurements

White coat effect

Physician inertia

Poor adherence to medication

Inadequate doses of antihypertensive drugs

Poor tolerability profile

Complexity of drug schedule

The first step for the promotion of a good adherence in treatment-resistant hypertension is certainly the widespread use of effective and well-tolerated antihypertensive drugs. Insufficient doses of the different medications are responsible for a poor blood pressure control despite the apparent use of multiple drugs in the same patient. In particular, the prescription of low doses of most common drugs does only marginally improve the blood pressure control with a limited perception of the therapeutic effect that encourages the withdrawal of antihypertensive drugs. Furthermore, the administration of low doses of drugs does not completely prevent the onset of significant drug-specific adverse events (e.g. cough, ankle edema, etc.) that further reduce the propensity of the patients to comply with a correct drug schedule [5]. Any decision about the doses of antihypertensive drugs to be prescribed to prevent treatment-resistant hypertension should be based on the results of the clinical trials/observational studies in terms of overall results and analysis of clinically relevant subgroups considering the characteristics of the patients, the drug history, and the presence of reliable reasons for dose adjustments.

Tolerability of antihypertensive drugs is the second step for the improvement of therapeutic adherence. Some years ago, Ambrosioni et al. [6] have clearly demonstrated that the rate of adverse events was the most important reason for the withdrawal of treatment in a large population of patients treated with blood pressure–lowering drugs. The same mechanism can be involved in patients with treatment-resistant hypertension whose attitude to fulfill the prescriptions can be largely endangered by the development of adverse events whether or not directly related to antihypertensive drugs or any other prescription indirectly related to hypertension (e.g. statins, ASA, etc.). Well-tolerated blood pressure–lowering drugs are associated with a significant improvement in persistence on treatment [7] and for this reason they should be preferred across the many classes of antihypertensive drugs. In particular, drugs inhibiting the renin–angiotensin system have been consistently described as the best tolerated antihypertensive medications in many different studies [7,8] and they should be always included among the recommended drugs for the treatment of hypertension, particularly in patients with a high risk of poor adherence (young active males, multi-treated patients, etc.). This suggestion is in agreement with the position of European Society of Hypertension (ESH) and International Society of Hypertension (ISH) Guidelines [2,9] that support the inclusion of RAAS inhibitors as first-line step in the treatment of most patients with hypertension, including those apparently resistant to blood pressure–lowering drugs. In particular, there could be a slight preference for angiotensin receptor blockers over angiotensin-converting enzyme inhibitors due to their even lower side effects that could further improve patient adherence to the treatment.

The third step for the improvement of medical adherence in patients with treatment-resistant hypertension is the widespread use of fixed-dose single-pill combinations of antihypertensive drugs. Among the reasons for poor adherence to treatment, a primary role is played by the number of pills prescribed with a close correlation between the level of persistence and the cumulative number of tablets taken by the patient [2,10,11]. The rate of adherence is largely independent on the type of drugs prescribed and directly proportional to the total amount of pills prescribed to reach the recommended blood pressure control. This therapeutic weakness can significantly contribute to the poor adherence particularly in patients with treatment-resistant hypertension where multiple drug treatment is crucial for the achievement of a reasonable blood pressure control and for the prevention of the excess in cardiovascular disease risk described in the literature [2,4,9]. The problem of low adherence to multiple drug treatment can be successfully prevented by the prescription of single-pill combinations of antihypertensive drugs that can promote blood pressure control with a single administration of multiple drugs with synergistic mechanism of action. The use of single-pill combinations of blood pressure–lowering drugs is highly recommended by the most important guidelines in the field of hypertension including ESH, ISH [2,9] that suggest this therapeutic strategy as a first step of treatment while AHA/ACC guidelines support the use of SPC in patients not responders to monotherapy or whose untreated blood pressure levels are above the target blood pressure by 20/10 mmHg for systolic and diastolic blood pressure [12].

2. Expert opinion

The favorable impact of single-pill combinations over free combinations of the same drugs in terms of adherence to treatment has been demonstrated by recent studies [13,14], and this results in a concomitant improvement in blood pressure control and rate of major cardiovascular events that can largely involve the patients with treatment-resistant hypertension. The same trend has been observed by the ‘polypill’ studies that have tested the clinical impact of free combination of different classes of drugs including blood pressure–lowering medications, statins and acetyl-salicylic acid in hypertensive patients with high cardiovascular risk profile [15]. In particular, in the Use of a Multidrug Pill In Reducing cardiovascular Events study [15] the single-pill multi-drug approach has clearly demonstrated a consistent reduction of blood pressure and LDL-cholesterol suggesting a double benefit in terms of adherence that involves multiple risk factors. This clearly suggests the importance of single-pill combinations as a pivotal strategy for the management of patients with treatment-resistant hypertension whose unsatisfactory response to blood pressure–lowering treatment cannot reasonably be attributed to a removable cause of hypertension.

Of course, a global promotion of a healthy lifestyle (e.g. exercise, diet) could also help reduce the prevalence of resistant hypertension and lead to a more relevant BP reduction and hopefully a reduction in medications (which would favor a greater patient adherence.

In conclusion, treatment-resistant hypertension is a clinical entity characterized by an unexpectedly poor response to antihypertensive treatment. Poor blood pressure decrease can have several different causes and is often attributable to a poor adherence to prescribed antihypertensive treatment. The improvement in individual adherence is the treatment of choice in these patients and can be promoted by a simple formula: give a single pill of the right doses of well-tolerated antihypertensive drugs.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.