Hypertension is a major modifiable risk factor, which significantly and independently increases the risk of developing major cardiovascular and cerebrovascular complications. Furthermore, effective hypertension treatment substantially reduces the risk of developing such complications; however, the control of blood pressure (BP) remains largely unsatisfactory worldwide. Recent analysis of data collected from Europe on BP control rate have demonstrated that only 20–30% of treated hypertensive patients achieve the recommended BP goals Citation[1–5]. For example, a recent analysis, which took into account studies performed in Italy from 2005 to 2011 and included approximately 160,000 patients with hypertension mainly followed in the context of general practitioners, reported that only 57% of hypertension patients were adequately treated, among which only 37% achieve effective BP control Citation[6]. In addition, in almost all studies reported in this analysis, the systolic BP was greater than 140 mmHg Citation[6], thus confirming the clinical challenge to achieve effective and sustained BP control, particularly for systolic BP.
Inadequate BP control increases the risk of developing major cardiovascular complications, including myocardial infarction, stroke and congestive heart failure.
In all hypertensive patients, it is important to reduce BP until systolic and diastolic BP values below 140/90 mmHg are achieved Citation[7]. These BP goals are recommended for all adult patients with hypertension, regardless of gender, age, ethnicity or other concomitant clinical conditions Citation[7]. While observational data from clinical studies indicated that the percentage of patients with hypertension under treatment that achieved the recommended BP goals (140/90 mmHg) did not exceed 30–40% Citation[1–6], interventional clinical trials, based on the use of rational and integrated therapeutic strategies, have demonstrated that it is possible to reach an effective BP control in 70–80% of treated patients with different grades of hypertensive and cardiovascular risk profiles Citation[8–10]. In particular, in the ALLHAT trial, in which the investigators were general practitioners, initial BP control was 22% on monotherapy and was progressively improved to ~70% by enrolling approximately two out of three patients on combination therapy Citation[11].
In order to bridge the gap between the attained and expected BP control rate and to achieve more effective cardiovascular complicaiton prevention, the Italian Society of Arterial Hypertension developed a national-based strategy, aimed at reaching the ambitious target of approximately 70% controlled hypertensive patients by 2015 Citation[12]. This goal can be realistically achieved by the rational use of modern tools and support and also by implementing combination therapy, especially if this approach can be simplified into a single pill (fixed combination therapy).
Other national hypertension societies, such as the France League Against Hypertension and the France Society of Hypertension Citation[13], have developed a very similar program in order to improve BP control and reduce the burden of hypertension-related cardiovascular and renal diseases. The strategy to move forward in treating hypertension to effectively fight cardiovascular disease is supported by similar initiatives at political levels started in the USA, where the threat is represented by approximately 45 million patients with hypertension Citation[14]. In the UK, the National Health Service has now considered BP control as a pivotal public health goal and has effectively introduced BP control as one of the major prevention tasks among the general population Citation[15].
How to move towards 70% of treated patients having controlled hypertension
The choice of the best antihypertensive therapeutic strategy should be based on the individual’s cardiovascular risk profile, as well as on BP levels and treatment tolerability. Other factors should be taken into consideration when choosing a given antihypertensive therapy and subsequent therapeutic algorithms. First of all, a thorough and reliable measurement of BP profile according to clinical, home and 24-h ambulatory BP monitoring should be taken. This may help for adequately distinguishing between different forms of hypertension (e.g., isolated clinic hypertension, masked hypertension, sustained hypertension, resistant or pseudoresistant hypertension) Citation[16], as well as to better identify the most appropriate therapeutic options among currently available antihypertensive drug classes Citation[17]. It is important that guideline recommendations based on results of the main randomized controlled clinical trials, which have tested the clinical efficacy, safety and tolerability of different drugs in monotherapy or in combination therapy, according to the principles of modern evidence-based medicine, should always be taken into account when starting any antihypertensive strategy.
Interventions of lifestyle, education & communication
In any case, an optimal therapeutic strategy for hypertension management should always be preceded and/or accompanied by the adoption of a healthy lifestyle at all stages of the disease.
Lifestyle changes are a necessary and essential component of any strategy aimed at improving BP control. They represent the first step that a patient suffering from hypertension must be motivated to take, in order to obtain BP normalization and a reduction of cardiovascular risk, and to facilitate the counselling of doctors and the feasibility of a ‘healthy lifestyle’. In the modern era, several options have been tested and proposed to improve beneficial lifestyle habits. For example, the media have circulated information for the general population to avoid a sedentary lifestyle, junk food, alcohol and carbonated drinks, as well as to reduce smoking at the individual and the community level. These initiatives, promoted by national health care systems at the general population level, have documented evidence of a reduced incidence of hospitalization for cardiovascular diseases and noncardiovascular morbidity and mortality Citation[18]. In the future, a more thorough and ‘real time’ link between healthcare systems and citizens via the internet may further improve strategies for more effective management of cardiovascular diseases worldwide. For example, the Italian Society of Hypertension is now moving toward a modern approach of communication throughout social networks and interactive websites, to reach larger proportions of patients with hypertension.
The developing use of better documented drug classes & combination therapies
A relatively low proportion of hypertensive patients (20–30%) can be initially treated and maintained long-term on a single class of antihypertensive medication (monotherapy) Citation[7,19]. In view of the documented antihypertensive efficacy equivalence and in terms of reducing the risk of major cardiovascular events, five antihypertensive drug classes are available, including angiotensin-converting enzymes (ACEs) inhibitors, angiotensin receptor blockers (ARBs), β blockers, calcium-channel blockers (CCBs) and diuretics, for starting and maintaining antihypertensive treatment as a monotherapy.
In the selection of the first-line antihypertensive drug class, it should be considered that, in the presence of a substantial equivalence in terms of antihypertensive efficacy, there are significant differences in terms of tolerability and compelling indications. Clinical studies have shown, with a better tolerability profile drugs that antagonize the renin–angiotensin system, especially ARBs, but also ACE inhibitors, compared with CCBs, β blockers and diuretics Citation[20,21].
A larger proportion of hypertensive patients (70–80%) require combination therapy based on at least two classes of drugs in order to achieve the recommended BP goals Citation[19]. Clinical trials have demonstrated that this type of strategy allows significant improvement in both systolic and diastolic BP control Citation[8–10]. Large meta-analyses have also demonstrated that the use of combination therapy is characterized by an antihypertensive efficacy approximately fivefold greater than doubling the dose of monotherapy Citation[22,23]. At this time, combination therapy based on renin–angiotensin system blockers with either diuretics or CCBs is viewed as the most effective and tolerated antihypertensive strategy in several clinical settings Citation[24].
In 20–30% of patients who do not achieve satisfactory BP control with a combination therapy using two classes of antihypertensive drugs (dual combination therapy), it should be beneficial to use a combination strategy of three classes of antihypertensive drugs (triple combination therapy) Citation[24], including either ARBs or ACE inhibitors, CCBs and thiazide diuretics Citation[24–26].
If the recommended BP targets are not achieved under triple combination therapy, a fourth antihypertensive drug class should be added. The addition of any antihypertensive class, different from the previous three classes (β blockers, α blockers, antialdosteronic agents, direct renin inhibitors, centrally acting agents) has demonstrated the ability to provide additional BP reductions and achieve effective BP control in a number of patients with moderate-to-severe hypertension, or patients who are difficult to treat. Current medical literature suggests the additional use of an antialdosteronic agent or an α blocker.
If the recommended BP targets are not achieved under triple or fourth-combination therapy, it is appropriate to refer the patient to a clinical center specific for hypertension management and control, in order to assess if resistant (or refractory) hypertension is present and to evaluate the possibility of nonpharmacological treatment options. Among these, renal artery denervation has proven to be an effective, safe and well-tolerated therapeutic option for reducing BP levels in patients with true resistant hypertension Citation[27] even in the long-term Citation[28] and is now recommended for these patients Citation[29].
It should also be noted that some combination therapies are not recommended, due to the high risk of developing side effects or adverse reactions. Among these strategies are the following: combination therapy based on ARBs plus ACE inhibitors should not be used in the treatment of essential hypertension because of additive antihypertensive effect and the potential risk of adverse effects (worsening renal function) Citation[30]; combination therapy based on ACE inhibitors or ARBs plus direct renin inhibitors (aliskiren), since preliminary analysis of a recent clinical trial seems to suggest a potential increased risk of adverse events (worsening renal function and nonfatal cerebrovascular events) in normotensive patients with diabetes mellitus and moderate renal failure (eGFR 30–60 mg/ml/min) who were treated with direct renin inhibitors in combination with ACE inhibitors or ARBs compared with placebo Citation[31]; combination therapy based on β blockers plus diuretics should not be used in the treatment of essential hypertension, unless there are specific indications, because of the potential risk of new onset diabetes in predisposed patients Citation[32], except for those β blockers with vasodilating action Citation[33,34] and β1-selective blockers Citation[35].
Finally, there are few randomized, controlled clinical trials of adequate size and study design, that compared fixed- versus free-combination therapy. A recent meta-analysis Citation[36], based on a limited number of randomized controlled clinical trials, has shown that fixed-combination therapy in a single pill provides a slightly better BP control compared with free combination therapy, in terms of reducing both systolic and diastolic BP values. In addition, fixed combination therapy seems to have the advantage of an easier therapeutic regimen to be taken as a single pill that has relevant consequences on pill burden and improves patient compliance and adherence to their prescribed antihypertensive therapy.
Conclusions
In conclusion, a more extensive use of combination therapy based on two or three classes of antihypertensive drugs, acting together synergistically, could help to significantly improve BP control. The association between pre-established drugs that block the renin–angiotensin system with either diuretics or CCBs, when used in adequate doses, can facilitate the achievement and maintenance of optimal BP level. They also display limited side effects, thus contributing to the reduction of major cardiovascular events and the reduction of associated healthcare costs.
Financial & competing interests disclosure
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.
No writing assistance was utilized in the production of this manuscript.
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